Alternative Medicine Review Monographs of Micronutrients ( Carnitine, Thiamine, Riboflavin, Taurine, Lysine, etc) 0972581502, 9780972581509

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Acetyl-L-Carnitine: Metabolism and Applications in Clinical Practice John H. Furlong N.D. Abstract Recent research has clarified many of the clinical applications of L-Carnitine and its related compounds, leading into new areas of potential use. Promising therapeutic applications of an ester form of carnitine, acetyl-L-Carnitine (ALC) are derived from observations that this compound readily crosses the blood- brain barrier and improves neuronal energetics and repair mechanisms while modifying acetylcholine production in the CNS. Studies show that HIV infection and CFIDS, Alzheimer’s dementia and depression of the elderly, and diabetic neuropathies may respond positively to ALC administration. Effects of ALC on ethyl alcohol (ETOH) metabolism have been observed and hold significant potential in preventing sequelae of habitual ETOH abuse. (Alt Med Rev 1996;1(2):85-93)

Synthesis and Function L-Carnitine is synthesized in mammalian liver, kidney and brain tissue with lysine, methionine and vitamin C among the required substrates and co-factors. The main body stores are in skeletal and cardiac muscle. Acetyl-L-Carnitine is one of the esters of carnitine and is found along with free plasma carnitine and other acyl esters of varying chain length.1 The formation of ALC originates with cytoplasmic thiokinase (See Figure 1) which forms acylcoenzyme A from free-fatty acids, ATP and Coenzyme A (CoA). This substance is combined with carnitine to form acylcarnitine via carnitine palmitoyltransferase I. Entry into the mitochondrial matrix occurs through an exchange system of acylcarnitine/carnitine via carnitine-acylcarnitine translocase. For each acylcarnitine molecule traversing the inner mitochondrial membrane, a molecule of carnitine is shuttled out. On the inner mitochondrial membrane, carnitine palmitoyltransferase II converts acylcarnitine to carnitine, liberating acylCoA. Finally, the production of ALC and CoA from carnitine and acetylCoA (obtained via ß oxidation of acyl CoA) occurs via carnitine acetyltransferase present in the mitochondrial matrix.2 Carnitine and its esters prevent toxic accumulations of fatty acids and acyl CoA (in the cytoplasm and mitochondria, respectively) while providing acetyl CoA for energy generation in the mitochondria. ALC’s enzymatic formation in the mitochondrial matrix is reversible, providing free Coenzyme A and acetyl CoA which can readily be exchanged across membranes, thus providing metabolic energy to intracellular organelles.3 Carnitine acetyltransferase is a reversible enzyme system which appears to be linked with choline acetyltransferase (ChAT), thereby supplying intracellular acetylcholine while the opposite reaction liberates acetylCoA. Alternative Medicine Review ◆ Volume 1, Number 2 ◆ 1996

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FIGURE 1.

ATP Free Fatty Acids

Acyl CoA

Thiokinase CoA

Carnitine

Carnitine Palmitoyl Transferase I

CoA Outer Mitochondrial Membrane

CarnitineAcylcarnitine Translocase

Inner Mitochondrial Membrane

Carnitine Acylcarnitine

Carnitine Palmitoyl Transferase II

Beta Oxidation Acetyl CoA

-

CoA

--

Carnitine Acetyltransferase

Inhibition

--

--

L-Acetyl-Carnitine

Acyl CoA

CoA

Carnitine

CoA

--

Mitochondrial Matrix

Cytoplasm

Acylcarnitine

---

Choline Acetyl Transferase

Kreb’s Cycle + Choline ATP

Acetylcholine

This mechanism can explain the improved cholinergic neurotransmission and enhanced intracellular energetics observed in ALC research.4, 5 Studies in humans and guinea pigs have shown that supplemental choline is able to decrease the urinary excretion of carnitine while resulting in increased muscle carnitine stores, giving further evidence of this enzymatic linkage.6

HIV, CFS and Immunomodulation HIV infection presents numerous problems related to the carnitines. Human and

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animal studies show an increased urinary excretion of carnitine when pivampicillin is administered. Animal studies indicate that pivampicillin interferes with myocardial carnitine metabolism subsequent to pivalocarnitine formation in the heart, leading to increased excretion. AZT can result in muscle carnitine depletion, contributing to the lipid accumulation and mitochondrial dysfunction characteristic of this myopathy. Malabsorption may decrease carnitine availability at the cellular level, while HIV-related renal dysfunction may increase excretion of the compound. Thus it is postulated that a subgroup

Alternative Medicine Review ◆ Volume 1, Number 2 ◆ 1996

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ALC and L-Carnitine’s effect on leukocyte proliferation and production of tumor necrosis factor-α (TNF-α) provide new potential applications of the compounds in HIV-infected individuals. Both mitogenic and antigenic proliferation of lymphocytes have been increased with LC and ALC in vitro.7 Peripheral blood monocytes in AIDS patients are low in intracellular carnitine. Serum levels may be high, low or normal and is therefore unreliable as an indicator of carnitine metabolism.10,11 Peripheral blood monocytes from HIV-infected individuals were cultured with the mitogen PHA and ALC for 48 hours. PHA-induced proliferation was significantly improved and a dimunition of TNF-α released by the cultured monocytes was also observed to be significant. As TNF-α has a key role in HIV-mediated apoptotic cell destruction, decreased levels of this cytokine may have protective effects on CD4+ cell populations.12 In a brief clinical trial with AIDS patients, L-Carnitine was administered (6 g/day for 14 days) and lymphocyte proliferation improved in response to mitogen stimulation. Importantly, the increased monocyte production did not lead to increased HIV proliferation. TNF-a levels were decreased and ß-2 microglobulin, an indicator of HIV progression to AIDS was also diminished.13,14 Thus, LC and ALC represent novel approaches in complementary treatment of HIV infections and may correct secondary carnitine deficiencies found in these patients. Another potential application of ALC involving immunomodulation is in the management of Chronic Fatigue Syndrome (CFS). Low serum levels of ALC have been observed

in many CFS patients. The clinical presentation of marked fatigue correlates with periods of low serum ALC while periods of recovery are characterized by higher levels of ALC. 15 Further implications for ALC treatment of CFS patients are findings that plasma levels of ßendorphin and cortisol are raised in humans given an I.V. bolus of ALC.16 As abnormal cortisol levels have been observed in some patients with CFS, and the myalgic symptoms in this condition are well known, ALC administration might be particularly helpful in normalizing HPA perturbations via feedback mechanisms and decreasing myalgic pain via peripheral neuron response to ß-endorphin.17

Alzheimer’s Dementia/CNS Effects Research has examined the effects of ALC in various dementias, cognitive defects and age-related disorders. These observations represent the clearest understanding and application of ALC in clinical practice. It has been established that ALC traverses the bloodbrain barrier efficiently, with CSF concentrations increasing significantly via both an I.V. and oral route in patients with severe dementia.18 There are multiple mechanisms of action responsible for ALC-induced CNS changes: enhanced cholinergic neurotransmission, neuronotrophic effects (via binding of cortisol and increased nerve growth factor production in the hippocampus),muscarinic receptor changes as well as decreased free radical generation and lipofuscin deposits in animal models.18,19 Calvani, et al summarized the neuroprotective benefits of ALC in the hippocampus, prefrontal cortex, substantia nigra and muscarinic receptor portions of the brain. These included antioxidant activity, improved mitochondrial energetics, stabilization of intracellular membranes and cholinergic neurotransmission. In the 500+ patients with

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Acetyl-L-Carnitine

of HIV-infected individuals are burdened with secondary carnitine deficiencies.7-9

Alzheimer’s or other age-related dementias presented in this review, it was concluded that oral ALC administration may slow the progression of degeneration. The dose of ALC varied from 1.5 grams/day to 3.0 grams/day. Patient tolerance was excellent with no clinically significant differences in side effects between the treatment and placebo groups. 20 Patients with Alzheimer’s dementia showed improvement in both clinical and CNS measurements in one double-blind placebo controlled trial over a 1-year period. Although this was a small study (7 patients in the treatment group), the findings were significant in elucidating the protective/reparative effects of ALC on the neuronal membranes.21 Another study showed significant improvements in all cognitive, behavioral and emotive measurements except anxiety in a 40-day double-blind, placebo-controlled study of 40 patients with Alzheimer’s. This work was particularly helpful in outlining clinical methods of patient assessment which may be applicable in the outpatient setting. 22 A study of 6 months duration on an out-patient basis showed mild improvements in tasks of attention and timing. Memory facilitation was improved only in the more impaired subset of the treatment group. This subset also showed a significant increase of ALC levels in the CSF. 23 Martignoni’s study showing increased ß-endorphin production in response to ALC administration presents yet another potential benefit of ALC in the patient with Alzheimer’s dementia because of their tendancy to have reduced ß-endorphin levels. Some positive results in the above studies may be due to enhanced memory trace formation, a key issue in cognitive research. Animal models indicate that protein kinase C translocation from the cytosol (soluble form) to the neuronal membrane (particulate form) Page 88

of the hippocampus and cortex may serve as a marker for memory formation. ALC is able to increase particulate protein kinase C in rat cortex at a dose (60mg/kg) that also elicits improvements in learning, providing evidence of ALC’s participation in memory formation via neuronal membrane modification. This effect was lost after long incubation times or higher concentrations of ALC, suggesting multiple control mechanisms for the protein kinase C.24

Depression/Cortisol Levels The effects of ALC on cortisol levels have been varied. In one 40-day study of depressed elderly adults, significant normalization of elevated cortisol levels and improved scores on mood assessments resulted from ALC administration (0.5g/qid p.o.). In 43% of the patients, the treatment was so successful that they were determined to be in clinical remission.25 This supports an earlier study of 24 depressed adults treated over a 2-month period where the depressive symptoms improved to a high degree of significance, especially in the group with the most severe clinical presentation.26 However, in the study by Martignoni, with non-depressed healthy male volunteers, the intravenous administration of ALC raised cortisol levels along with ß-endorphin. It appears that ALC may have an amphoteric effect on cortisol levels, raising or lowering levels according to HPA feedback mechanisms.

Diabetes/Neurological Symptoms Peripheral neuropathy associated with diabetes mellitus (DM) is extremely common, approaching over 28% of some populations.27 Various mechanisms of neuronal damage have been postulated, including polyol pathway generation of sorbitol and free radical damage. Reduced nerve conduction velocities occur in DM and have led to experimental models assessing this function in rats. Animals

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visual evoked potential amplitude among both healthy volunteers and patients with various dementias. The changes persisted over a 50-90 minute period, showing the rapid clearing of the substance by renal tubular mechanisms. 35

Human studies also show beneficial effects of ALC in neuropathies. Intramuscular administration of the compound given to 63 patients with painful neuropathy for 15 days showed significant improvement in motility and subjective measures.31 A small doubleblind study in humans again using the I.M. route of administration, showed highly significant improvement in painful neuropathies. Again the anti-oxidant function of ALC was believed to be a likely mechanism of action.32

Repair of tissue atrophy after neuronal damage is a function of the length of denervation time and rate of regeneration of neuronal tissue. In a comparison study of the nerve-regeneration effects of L-Carnitine and ALC, there were significant improvements in the ALC group of animals compared to the L-Carnitine group. This was postulated to be related to ALC’s unique ability to supply acetyl groups for mitochondrial energy production.36

Aging and Repair of Neuronal Tissue The changes which occur in CNS tissue of aged laboratory animals as well as tissue samples from humans have both structural and metabolic components. One of these changes is the reduced surface contact area found in dendritic networks. The capacity for recovery and expansion of the dendritic network does, however, remain present in older individuals.33 ALC was administered orally to rats over a 6-22 month period after which brain synaptic tissue was evaluated for size and number of junctions. The expected decline in synaptic contact area was partially reversed in the treatment groups.34 Human studies confirm the impact ALC can have on neurological function. Bonavita observed significant improvements in aged subjects participating in a 40-day, double-blind trial with oral ALC, 3 g/day. The first changes tended to relate to spatial recognition, judgment and depression; second-phase changes centered on short and long-term memory, self-care, and sociability. Intravenous administration of ALC elicited increased

Clinical applications of the neuro-regenerative effects of ALC were investigated in an experimental model of post-ischemic cerebral injury. In a simulation of the cerebral ischemia present after cardiac arrest, ALC was administered intravenously to canines. Their recovery was assessed via neurologic deficit scores and neurochemical markers. The ALC group fared significantly better than controls in post-ischemic recovery parameters. 37

Cardiovascular Effects Acetyl-L-Carnitine is a substance which retains the well-known effects of LCarnitine on muscle tissue; i.e., long-chain fatty acid transport for ATP production within the mitochondria. ALC’s further impact on both skeletal muscle and the myocardium include antioxidant effects leading to less lipid peroxidation, thus protecting exercising muscle tissue from free-radical damage.38 Additionally, it may improve cardiolipin levels in the aged heart, a substance which maintains crucial membrane factors in cardiac mitochondria and thus ensures efficient phosphate transport for energy. In a rat mitochondrial model, it was shown that ALC

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Acetyl-L-Carnitine

given ALC after experimental diabetes induction have improved nerve conduction velocities.28,29 Correction of abnormal enteric peptides associated with autonomic neuropathies was also observed in animal models. 30

administered to aged animals returned cardiolipin levels to that of young ones. 39 Cerebral and peripheral circulation are apparently affected differently by administration of ALC. Ten patients with recent cerebral vascular accidents were given ALC intravenously which resulted in acute enhancement of cerebral blood flow to areas of ischemia via sensitive SPEC tomography assessments.40 In evaluation of patients with peripheral arterial occlusive disease, two studies show that the effect of carnitine esters on improved walking distance was due to metabolic vs. hemodynamic changes and that L-Propionylcarnitine was clearly superior to L-Carnitine in this effect. These studies demonstrate the ability of carnitine esters to positively influence tissue energetics which may prove beneficial in a chronic administration model.41,42

Acetyl-L-Carnitine and Ethanol A number of interesting reports on the relationship between hepatic detoxification of ethanol and carnitines have been produced. It is observed that pretreatment of both rats and chickens with carnitines resulted in a prolonged half-life of ethanol in the blood.43,44 Additionally, a protective effect on prenatal ethanol damage to thalamic and cortical regions in rats was observed with administration of ALC.47 Two studies by Cha and Sachan with isolated rat hepatocytes harvested after pretreatment with ALC elucidate the mechanism of these interesting effects. An inhibition of alcohol dehydrogenase was present and significantly increased when the nicotinamide adenine dinucleotide:ALC ratio was low. It was also shown that L-Carnitine itself was much less effective at producing this inhibition.47,48 As a final addition to these findings of great therapeutic interest, oral administration of ALC was shown to improve the cognitive impairments of 55 chronic alcoholics.48

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We may infer from this work that patients with high ethanol intake may have prolonged ethanol half-life if they are concurrently taking ALC supplementation. This effect may be due in part to low niacin levels and could be modified by niacin administration. ALC’s cerebro-thalamic protection observed in rat pups exposed to ethanol prenatally and the apparent hepato-protective effects observed in models of chronic alcohol use provide exciting possibilities for preventing the intergenerational sequelae of high ethanol intake.

Adverse Effects/Interactions In 130 patients studied by Spagnoli, et al over a one-year duration, the administration of oral ALC (2 grams/day) slowed the progression of Alzheimer’s disease. Patients in the treatment group experienced significant positive effects, ascertained by neuropsychological tests, in a variety of areas. At the 3month mark, agitation was experienced by 11% of patients taking ALC and 6% of patients taking placebo, a difference which was not statistically significant. The incidence of agitation in both groups decreased to 7% by the 6-month follow-up.49 Adverse reactions occurred in a small study of 36 patients with Alzheimer’s dementia. Eight of the 11 withdrawals from the active group reported nausea/vomiting or agitation/aggression within the first 14 days of the trial. No laboratory abnormalities were noted in the study. It was suggested that administration of the ALC follow a meal to minimize symptoms.50 In addition to the minor adverse reactions to ALC from the above human trials, a cautionary note may be extrapolated from rat studies whereby an intracerebral injection of ALC induced epileptic phenomena.51 Another researcher found however, no changes in cell excitability and no epileptic discharges in

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• Administer ALC with food; • Inform patients that ALC may modify ETOH tolerance; • Inform patients/families of potential agitation, nausea or vomiting; and • Screen for epileptic history if ALC is to be used I.V.

clinical trials, future applications of ALC hold exciting promise in the practice of complementary medicine.

References 1.

Conclusions As ALC is easily transported across the blood-brain barrier, multiple benefits in CNS function have been observed in human studies. Models of aging, stroke, Alzheimer’s dementia, diabetic neuropathy and neuropeptide release have been positively influenced by ALC administration. Acetyl-L-Carnitine is able to exert profound effects on some depressed patients with high cortisol levels and participates in immunomodulatory mechanisms which hold promise in the treatment of HIV infection. ALC modifies ethanol metabolism in animal models; paradoxically increasing the half-life of ethanol while decreasing hepatic damage. Because of ALC’s excellent tolerability, with infrequent and often temporary side effects, it has great potential of being a safe and efficacious therapeutic compound. Oral doses from 1.5 grams to 3.0 grams per day are typically in the therapeutic range for most conditions, the I.M. route was used for treatment of neuropathy. Although many of ALC’s effects overlap those of L-Carnitine, the vast experience with the simpler compound in ischemic heart disease should not be abandoned. For conditions regarding CNS and neuronal damage, the L-Acetyl form of carnitine is clearly superior. With additional research and

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Goa KL, Brogden A. L-Carnitine, a preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic cardiac disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. Drugs 1987;34:1-24. Harper’s Review of Biochemistry, 23rd Ed. R.K. Murray,D.K. Granner, P.A. Mayes and V.W. Rodwell; Eds. Appleton-Lange Medical Publications pp 220-223. Calvani M, Carta A. Clues to the mechanism of action of acetyl-L-carnitine in the central nervous system. Dementia 1991;2:1-6. White HL, Scates PW. Acetyl l-carnitine as a precursor of acetylcholine. Neurochem Res 1990;15:597-601. Piovesan P, Quatrini G, Pacifici L, et al. Acetyl-l- carnitine restores choline acetyltransferase activity in the hippocampus of rats with partial unilateral fimbria-fornix transection. Int J Devl Neuroscience 1995;13:13-19. Daily JW, Sachan DS. Choline supplementation alters carnitine homeostasis in humans and guinea pigs. J Nutr 1995;125:1938-1944. Famularo G, Tzantzoglou S, Santini G, et al. L-carnitine - a partner between immune response and lipid metabolism. Mediators Inflamm 1993;2: s29-s32. Diep QN, Brors O, Bohmer T. Formation of pivaloylcarnitine in isolated rat heart cells. Biochem Biophys Acta 1995;1259:161-165. Mintz M. Carnitine in human immunodeficiency virus type I infection / acquired immune deficiency syndrome. J Child Neurol 1995;10:s40-s44. DeSimone C, Tzantzglou S, Jirillo E, et al. L-carnitine deficiency in AIDS patients. AIDS 1992;6:203-205.

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ALC- treated rats exposed to high-frequency stimulation.19 From the clinical and experimental research, it seems prudent to:

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DeSimone C, Famularo G, Tzantzoglou S, et al. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS 1994; 8:655660. Famularo G, DeSimone C. Apoptosis, antiapoptotic compounds and TNF-α release. Immunol Today 1994;5:495-496. Famularo G, DeSimone C. A new era for carnitine? Imunol Today 1995; 16:211-213. DeSimone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1-12. Kuratsune H, Yamaguti K, Takahashi M, et al. Acylcarnitine deficiency in chronic fatigue syndrome. Clin Infect Dis 1994:18; s62-s67. Martignoni E, Facchinetti F, Sances G, et al. Acetyl-L-carnitine acutely administered raises ß-endorphin and cortisol plasma levels in humans. Clin Neuropharmacol 1988;11:472477. Blalock JE. The syntax of immune-neuroendocrine communication. Immunol Today 1994;15:504-511. Parnetti L, Gaiti A, Mecocci P, et al. Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type. Eur J Clin Pharmacol 1992;42:89-93. Davis S, Markowska AL, Wenk GL, et al. Acetyl-L-carnitine: behavioral, electrophysiological, and neurochemical effects. Neurobiol Aging 1993;14:107-115. Calvani M, Carta A, Caruso G, et al. Action of acetyl-l-carnitine in neurodegeneration and Alzheimer’s disease. Ann NY Acad Sci 1992;663:483-486. Pettigrew JW, Klunk WE, et al. Clinical and neurochemical effects of acetyl-l-carnitine in Alzheimer’s disease. Neurobiol of Aging: 1995;16:1-4. Bonavita E. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. Int J Clin Pharmacol Ther Tox 1986;24:511-516.

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Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with alzheimer’s disease. Arch Neurol 1992; 49:1137-1141. Pascale A, Milano S, Corsico N, et al. Protein kinase C activation and anti-amnesic effect of acetyl-L-carnitine:in vitro and in vivo studies. Eur J Pharmacol 1994;265:1-7. Gecele M, Francesetti G, Meluzzi A. AcetylLcarnitine in aged subjects with major depression: clinical efficacy and effects on the circadian rhythm of cortisol. Dementia 1991;2:333-337. Tempesta E, Casella L, Pirrongelli C, et al. Lacetylcarnitine in depressed elderly subjects. A cross-over study vs. Placebo. Drugs Exp Clin Res 1987; 13:417-423. Young MJ, Boulton AJM, Macleod AF, et al. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetalogica 1993;36:150-154. Lowitt S, Malone JI, Salem AF, et al. AcetylL-carnitine corrects the altered peripheral nerve function of experimental diabetes. Metabolism 1995; 44:677-680. Merry AC, Kamijo M, Lattimer S, et al. Long-term prevention and intervention effects of acetyl-L-carnitine on diabetic neuropathy in BB/W-rats. Diabetes 1994;43:108A. Gorio A, DiGiulo AM, Tenconi B, et al. Peptide alterations in autonomic diabetic neuropathy prevented by acetylcarnitine. Int J Clin Pharm Res 1992;12:225-230. Onofrj M, Fulgente T, Melchionda D, et al. L-acetylcarnitine as a new therapeutic approach for peripheral neuropathies with pain. Int J Clin Pharm Res 1995;15:9-15. Quatraro A, Roca P, Donzella C, et al. Acetyll-carnitine for symptomatic diabetic neuropathy. Diabetalogica 1995;38:123. Bertoni-Freddari C, Fattoretti P, Casoli T, et al. Morphological adaptive response of the synaptic junctional zones in the human dentate gyrus during aging and alzheimer’s disease. Brain Res 1990;517:69-75.

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Bertoni-Freddari C, Fattoretti, P, Casoli T, et al. Dynamic morphology of the synaptic junctional areas during aging: the effect of chronic acetyl-L-carnitine administration. Brain Res 1994;656:359-366. Gambi D, Onofrj M, Calvani M, et al. Neurophysiological studies of Lacetylcarnitine administration in man. Drugs Exp Clin Res 1989;15:435-446. Fernandez E, Pallini R, Gangitano C, et al. Effects of L-carnitine, L-acetylcarnitine and gangliosides on the regeneration of the transected sciatic nerve in rats. Neurological Res 1989;11:57-62. Rosenthal RE, Williams R, Yolanda BA, et al. Prevention of postischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-L-carnitine. Stroke 1992;23:1312-1318. DiGiacomo C, Latteri F, Fichera C, et al. Effect of acetyl-L-carnitine on lipid peroxidation and xanthine oxidase activity in rat skeletal muscle. Neurochem Res 1993;18:1157-1162. Paradies G, Ruggiero FM, Gadaleta MN, et al. The effect of aging and acetyl-L-carnitine on the activity of the phosphate carrier and on the phospholipid compostion in rat heart mitochondria. Biochem Biophys Acta 1992;1103:324-326. Postiglione A, Soricelli A, Cicerano U, et al. Effect of acute administration of lac on cerebral blood flow in patients with chronic cerebral infarct. Pharmacol Res 1991;23:241-246. Sabba C, Berardi E, Antonica G, et al. Comparison between the effect of lpropionylcarnitine, l-carnitine and nitroglycerine in chronic peripheral arterial disease: a haemodynamic double blind echo-doppler study. Eur Heart J 1994;15:1348-1352. Brevetti G, Perna S, Sabba C, et al. Superiority of L-propionylcarnitine vs. L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J 1992; 13: 251-255

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Smith MO, Cha YS, Sachan DS. Carnitine prolongs the half-life of ethanol in broilers. Comp Biochem Physiol Physiol 1994;109:177-180. Sachan DS, Berger R. Attenuation of ethanol metabolism by supplementary carnitine in rats. Alcohol 1987;4:31-35. Santarelli M, Granato A, Sbriccoli A, et al. Alterations of the thalamo-cortical system in rats prenatally exposed to ethanol are prevented by concurrent administration of acetylL-carnitine. Brain Res 1995;698:241-247. Cha YS, Sachan DS. Acetylcarnitinemediated inhibition of ethanol oxidation in hepatocytes. Alcohol 1995;12:289-294. Sachan DS, Cha YS. Acetylcarnitine inhibits alcohol dehydrogenase. Biochem Biophys Res Comm 1994;203:1496-1501. Tempesta E, Troncon R, Janiri L, et al. Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin Pharm Res 1990 X(1-2):101-107. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology 1991;41:1726-1732. Rai G, Wright G, Scott L, et al. Doubleblind, placebo controlled study of acetyl-Lcarnitine in patients with Alzheimer’s dementia. Curr Med Res Opin 1990;11:638-647. Fariello RG, Zeeman E, Golden GT, et al. Transient seizure activity induced by acetylcarnitine. Neuropharmacol 1984;23:585-587.

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Acetyl-L-Carnitine

34.

L-Carnitine

Monograph

Chemical Structure of L-Carnitine

CH3 _

+

OOCCH2CHCH2 N OH

CH3

CH3

L-Carnitine Introduction

A trimethylated amino acid, roughly similar in structure to choline, L-carnitine is a cofactor required for transformation of free long-chain fatty acids into acylcarnitines, and for their subsequent transport into the mitochondrial matrix, where they undergo beta-oxidation for cellular energy production. Conditions that appear to benefit from exogenous supplementation of L-carnitine include anorexia, chronic fatigue, cardiovascular disease, diphtheria, hypoglycemia, male infertility, muscular myopathies, and Rett syndrome. Preterm infants, dialysis patients, and HIV-positive individuals seem to be prone to a deficiency of L-carnitine and benefit from supplementation. Although discovered in 1905, the crucial role of L-carnitine in metabolism was not elucidated until 1955, and its deficiency was not described until 1972. The most significant source of L-carnitine in human nutrition is meat, although humans can synthesize L-carnitine from dietary amino acids.

Biochemistry and Pharmacokinetics

Synthesis of carnitine begins with methylation of the amino acid L-lysine by S-adenosylmethionine (SAMe). Magnesium, vitamin C, iron, vitamins B3 and B6, and alpha-ketoglutarate – along with the cofactors responsible for creating SAMe (methionine, folic acid, vitamin B12, and betaine) – are all required for endogenous carnitine synthesis. Evidence indicates L-carnitine is absorbed in the intestine by a combination of active transport and passive diffusion.1 Reports of bioavailability following an oral dose have varied substantially, with estimates as low as 16-18 percent2,3 and as high as 54-87 percent.4,5 Oral supplementation of L-carnitine in individual dosages greater than 2 g appears to offer no advantage, since the mucosal absorption of carnitine appears to be saturated at about a 2-g dose.2 Maximum blood concentration is reached approximately 3.5 hours after an oral dose and slowly decreases, with a half-life of about 15 hours.4 Elimination of carnitine occurs primarily through the kidneys.4 The heart, skeletal muscle, liver, kidneys, and epididymis have specific transport systems for carnitine that concentrate carnitine within these tissues. Despite evidence indicating increased levels of free carnitine and carnitine metabolites in the blood and urine following an oral dose, no significant change in red blood cell carnitine levels was noted in healthy subjects, suggesting either a slow repletion of tissue stores of carnitine following an oral dose or a low capability to transport carnitine into tissues under normal conditions.6

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L-Carnitine

Monograph

Mechanisms of Action

Carnitineʼs primary mechanism of action is apparently attributable to its role as a cofactor in the transformation of free long-chain fatty acids into acylcarnitines for subsequent transport into the mitochondrial matrix.7 Carnitine is involved in the metabolism of ketones for energy8 and the conversion of branchedchain amino acids – valine, leucine, and isoleucine – into energy.9

Deficiency States and Symptoms

Although L-carnitine is supplied exogenously as a component of the diet and can also be synthesized endogenously, evidence suggests both primary and secondary deficiencies do occur. Carnitine deficiency can be acquired or a result of inborn errors of metabolism.10 Pre-term infants are at risk for developing a carnitine deficiency due to impaired synthesis and insufficient renal tubular resorption.11 Deficiency can result in cardiomyopathy, congestive heart failure, encephalopathy, hepatomegaly, impaired growth and development in infants, and neuromuscular disorders. Primary carnitine deficiency, although rare, is characterized by low plasma, red blood cell, and tissue levels of carnitine, and generally presents with symptoms such as muscle fatigue, cramps, and myoglobinemia following exercise. Additional symptoms of chronic carnitine deficiency can include hypoglycemia, progressive myasthenia, hypotonia, or lethargy. Secondary carnitine deficiency is not as rare and is most commonly associated with dialysis in chronic renal failure, although it can also be induced by intestinal resection, severe infection, and liver disease. Other conditions associated with a carnitine deficiency include cancer,12 diabetes, Alzheimerʼs disease, and heart failure.11 Pathological manifestations of chronic deficiency include accumulation of neutral lipid within skeletal muscle, cardiac muscle, and liver; a disruption of muscle fibers; and an accumulation of large aggregates of mitochondria within skeletal and smooth muscle.

Clinical Indications Anorexia

Combined use of L-carnitine and adenosylcobalamin in patients with anorexia nervosa has been shown to accelerate body weight gain, normalize gastrointestinal function, decrease fatigue, and improve physical performance.13,14 Children with infantile anorexia responded to a combination of carnitine and adenosylcobalamin with improved appetite.15

Athletic Performance

A clinical study reported improved running speed and decreased average oxygen consumption and heart rate following prolonged L-carnitine supplementation,16 while other researchers reported increased maximal oxygen uptake and decreased plasma lactate when L-carnitine was supplemented acutely one hour prior to beginning exercise.17 A small study on L-carnitineʼs effect on high-repetition squat exercise found significant benefit from 2 g carnitine daily compared to placebo on blood parameters of muscle recovery – myoglobin, creatine kinase, and malondialdehyde.18 In contrast, other research has shown no ergogenic effects of either chronic or acute L-carnitine supplementation.19-21

Cardiovascular Disease Angina and Ischemia

L-carnitine (oral doses ranging from 9003,000 mg daily) has been shown to moderately improve exercise tolerance and reduce ECG indices of ischemia in patients with stable angina. Estimates suggest upward of 22 percent of subjects might become angina-free during supplementation periods. Increasing benefits are often observed with longer supplementation.22-25 Angina patients receiving L-carnitine have experienced functional improvement, including a reduction in the number of premature ventricular contractions at rest, an increase in maximal systolic arterial blood pressure, and a reduction in ST-segment depression during maximal effort. In addition, a concomitant increase in the number of patients belonging to class I of the NYHA classification (as opposed to classes II and III) and a reduction in the consumption of cardioactive drugs has been reported.26

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In subjects with ischemia-induced NYHA II or III cardiac insufficiency, L-carnitine supplementation (1 g three times daily for 120 days), in addition to the usual medications (digitalis, beta-blockers, calcium antagonists, nitrates), resulted in improvements in exercise performance and hemodynamic parameters. Benefits were maintained beyond the L-carnitine supplementation period.27

Peripheral Vascular Disease

In a double-blind, crossover study of subjects with peripheral vascular disease, walking distance improved from an average of 174 minutes with placebo to 306 minutes with L-carnitine at a dose of 2 g twice daily for three weeks.28 In healthy subjects, Lcarnitine was found to inhibit fatty-acid induced endothelial dysfunction intended to simulate that seen in obesity or type 2 diabetes.29

Cardiogenic Shock

L-carnitine supplementation during cardiogenic shock improved metabolic acidosis and survival rate in hospitalized individuals.30,31

Cardiomyopathy

Long-term supplementation of L-carnitine (2 g daily) for the treatment of heart failure caused by dilated cardiomyopathy resulted in improvement in survival rate, ejection fraction, Weber classification, maximal time of cardiopulmonary exercise test, peak VO2 consumption, arterial and pulmonary blood pressure, and cardiac output.32,33

Myocardial Infarction

Following a recent myocardial infarction (MI), a marked reduction in mortality was observed with 12-month supplementation of 4 g daily L-carnitine (1.2%) when compared to controls (12.5%). Significant improvements were also noted in heart rate and anginal attacks.34 Additional research confirms a benefit in terms of reduced mortality in individuals given L-carnitine following MI.35-37

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Hyperlipidemia

L-carnitine (2-3 g daily) resulted in improved lipid profiles in individuals with hyperlipidemia, with reductions in total and LDL-cholesterol and increased plasma apolipoprotein A-1 and B levels. Normalization of lipid levels occurred in a substantial number of subjects with continued supplementation for one year.38,39 L-carnitine supplementation (2 g daily) also decreased triglycerides in individuals with essential hypertension.40 In a study of pediatric patients on dialysis, oral L-carnitine at 50 mg/kg/day for 30 days resulted in significant decrease in apolipoprotein B levels, with no changes in other lipid parameters.41 L-carnitine (2 g daily) significantly reduced lipoprotein(a) (Lp(a)) levels in 14 of 18 subjects. Reductions in Lp(a) were greater in individuals with more marked elevations prior to supplementation; in a significant number of subjects the reduction of Lp(a) resulted in a return to the normal range.42 Similar results were found in hypercholesterolemic patients newly diagnosed with type 2 diabetes, with significant decreases in Lp(a) levels noted after three and six months of 1 g L-carnitine twice daily. Other measurements taken but not significantly impacted by L-carnitine were body mass index, fasting glucose, postprandial glucose, glycosylated hemoglobin, LDL- and HDL-cholesterol, total cholesterol, triglycerides, and apolipoproteins A-1 and B.43

Diabetes/Insulin Resistance

Healthy volunteers and type 2 diabetics received an infusion of L-carnitine or saline, after which plasma glucose and insulin levels were analyzed. Insulin-mediated glucose uptake was significantly higher in both groups receiving L-carnitine compared to the saline groups, indicating improved insulin sensitivity from carnitine.44 A small study found 500-mg intramuscular injections of L-carnitine twice daily for 15 days resulted in improvement in painful diabetic neuropathy.45

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Fatigue

Cancer-Associated Fatigue

In a small study, 15/18 cancer patients presented with carnitine deficiency, which was postulated to be a significant cause of fatigue in this population.12 Dosage began at 250 mg/day, increasing in increments of 500 mg, to a maximum dose of 3 g daily. After one week of supplementation, patients experienced significant improvement in fatigue, depression, and sleep quality.

Chronic Fatigue Syndrome

Thirty-five patients with chronic fatigue syndrome (CFS) were found to have low free carnitine, total carnitine, and acylcarnitine compared to controls, with a statistically significant correlation between total and free carnitine levels and clinical symptomology.46 In a crossover study, 30 patients with CFS were treated with L-carnitine or amantadine (a drug that provides benefit for fatigue in patients with multiple sclerosis). Each substance was administered for two months with a two-week washout period. Half of the patients dropped out of the study, mainly due to intolerance of the amantadine. However, the carnitine supplementation resulted in only one dropout and improvement in 12 of 18 parameters studied.47

Hepatic Effects Fatty Liver

L-carnitine ameliorates ethanol-induced fatty liver in animals;48 however, it has not been investigated in humans for this condition.

Hepatitis

A study found plasma carnitine levels were significantly lower in children with chronic hepatitis B than in healthy controls. In addition, carnitine levels corresponded inversely to extent of liver fibrosis and inflammation.49 In a single case report, a patient with hyperammonemia associated with a combination of hepatitis C, dialysis, and low free carnitine levels responded to IV L-carnitine. Within three hours of a single 2-g dose, the patient progressed from comatose to normal mental status.50

Hepatic Encephalopathy from Cirrhosis

L-carnitine (2 g twice daily) or placebo was administered to 120 patients with hepatic encephalopathy for 60 days. Fasting serum ammonia levels were significantly lower at 30 and 60 days compared to baseline and placebo. Mental function was also significantly improved by L-carnitine, as measured by NCT-A, an accepted psychometric test for mental status in cirrhotic patients. The researchers speculate L-carnitine decreases brain and blood ammonia levels by stimulating ureagenesis.51

HIV and Immunity

Daily infusions of L-carnitine (6 g) for four months resulted in an increase in CD4 counts in HIVpositive subjects who were not taking anti-retroviral therapy.52 Administration of L-carnitine (6 g daily for two weeks) to AIDS patients treated with zidovudine (AZT) resulted in improved immunity and a reduction in serum levels of tumor necrosis factor-alpha.53 In another study on HIV patients on AZT and didanosine (DDI), a subgroup was assigned to also receive 6 g L-carnitine daily. Addition of carnitine greatly reduced the negative effects of the drugs, including apoptosis of CD4 and CD8 cells and oxidative stress. No toxicity or decrease in drug effectiveness was noted.54

Hyperthyroidism

L-carnitine is believed to be a peripheral antagonist of thyroid hormone activity in some tissues. A randomized, double-blind, placebo-controlled, sixmonth trial reported both 2- and 4-g daily doses of L-carnitine prevented and reversed hyperthyroidismrelated symptoms, including exerting a beneficial effect on bone mineralization.55

Male Infertility

Oral administration of L-carnitine (3 g daily for four months) resulted in significant improvements in sperm number, quality, and motility in patients with inadequate sperm.56,57 In another double-blind, crossover trial, 100 infertile males were supplemented with 2 g L-carnitine daily or placebo for two months, followed by a two-month washout period, and finally

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two months on the opposite treatment. Statistically significant improvements in sperm count and motility were observed in the L-carnitine group.58 The same researchers conducted a second study on 56 infertile males and found the combination of L-carnitine (2 g daily) and acetyl-L-carnitine (1 g daily) led to significant improvement in sperm motility.59

Renal Failure/Dialysis

L-carnitine has been extensively studied for patients in renal failure. Supplementation, either orally or intravenously, mitigates some of the disorders associated with dialysis, including renal anemia, cardiac dysfunction, insulin resistance, lipid abnormalities, and oxidative stress.60-63 Treatment for eight months with 1 g L-carnitine three times weekly, administered IV during dialysis sessions, resulted in improved left ventricular ejection fraction.64 The National Kidney Foundation – Kidney Disease Outcome Quality Initiative recommends the use of L-carnitine for the treatment of anemia associated with chronic renal failure.65

Respiratory Distress in Premature Infants

A combination of L-carnitine (4 g daily for five days) and betamethasone given to women in the prenatal period reduced both the incidence of respiratory distress syndrome and the mortality of premature newborns.66 L-carnitine supplementation to preterm infants at a dose of 30 mg/kg/day in one study67 and 15 mg/kg/day in a second study68 did not result in significant differences between supplementation and placebo groups in frequency of apnea, weight gain, or length of hospital stays. From the above studies, it appears prenatal supplementation may be of more benefit than newborn supplementation. A case of siblings presenting with apnea and periodic breathing, along with biochemical defects consistent with a non-specific abnormality of betaoxidation, suggests L-carnitine might prevent some cases of sudden infant death syndrome.69

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Weight Loss

In a double-blind study, investigators found no effect of L-carnitine supplementation on weight loss or any variable of body composition measured.70

Nutrient-Nutrient Interactions

A deficiency of ascorbic acid may decrease endogenous biosynthesis of carnitine.71,72 In guinea pigs, supplementing the diet with ascorbic acid increased carnitine biosynthesis.73 A case report describes normalization of carnitine levels following administration with riboflavin.74 In rats, administration of vitamin B12 increased carnitine biosynthesis.75 Choline supplementation appears to decrease carnitine synthesis.76

Drug-Nutrient Interactions

Anticonvulsant medications, including phenobarbital, valproic acid, phenytoin, and carbamazepine, have a significant lowering effect on carnitine levels.77 The antibiotic pivampicillin negatively impacts carnitine metabolism.78 L-carnitine should be used cautiously, if at all, with pentylenetetrazole, since evidence suggests the combination might exacerbate the side effects of the drug.79 Evidence suggests supplemental L-carnitine might prevent cardiac complications secondary to interleukin-2 immunotherapy in cancer patients80 and cardiac toxicity secondary to adriamycin.81 L-carnitine, when used concurrently with AZT, appears to prevent the drug-induced destruction of myotubes, preserve the structure and volume of mitochondria, and prevent the accumulation of lipids.82 L-carnitine supplementation helps prevent elevation in liver enzymes, as well as the myalgia, weakness, and hypotension induced by isotretinoin.83 Emetine (ipecac) appears to promote carnitine deficiency.84 A case report suggests carnitine deficiency was induced in a patient receiving sulfadiazine and pyrimethamine.85

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Evidence also suggests L-carnitine potentiates the anti-arrhythmic effect of propafenone and mexiletine in patients with ischemia.86

Side Effects and Toxicity

A variety of mild gastrointestinal symptoms have been reported, including transient nausea and vomiting, abdominal cramps, and diarrhea. The LD50 in mice is 19.2 g/kg. Mutagenicity data indicate no mutagenicity; however, experiments to determine long-term carcinogenicity have not been conducted.

Dosage

4.

5.

6.

7. 8.

The average therapeutic dose is 1-2 g two to three times daily for a total of 2-6 g daily. No advantage appears to exist in giving an oral dose greater than 2 g at one time, since absorption studies indicate saturation at this dose.

9.

Warnings and Contraindications

11.

L-carnitine is listed as pregnancy category B, indicating animal studies have revealed no harm to the fetus but that no adequate studies in pregnant women have been conducted. L-carnitine has been given to pregnant women late in pregnancy with resulting positive outcomes. The racemic mixture (D,L-carnitine) should be avoided. D-carnitine is not biologically active and might interfere with the proper utilization of the L isomer. In uremic patients, use of the racemic mixture has been correlated with myasthenia-like symptoms in some individuals.

10.

12.

13.

14.

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Bach AC, Schirardin H, Sihr MO, Storck D. Free and total carnitine in human serum after oral ingestion of L-carnitine. Diabete Metab 1983;9:121-124. Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr 1991;121:539-546. Baker H, Frank O, DeAngelis B, Baker ER. Absorption and excretion of L-carnitine during single or multiple dosings in humans. Int J Vitam Nutr Res 1993;63:22-26. Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci 2004;1033:17-29. Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids 2004;70:243-251. Platell C, Kong SE, McCauley R, Hall JC. Branched-chain amino acids. J Gastroenterol Hepatol 2000;15:706-717. Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004;1033:42-51. Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit – when supplementation is necessary? Curr Pharm Biotechnol 2003;4:211219. Cruciani RA, Dvorkin E, Homel P, et al. L-carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: a preliminary analysis. Ann N Y Acad Sci 2004;1033:168-176. Korkina MB, Korchak GM, Medvedev DI. Clinicoexperimental substantiation of the use of carnitine and cobalamin in the treatment of anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1989;89:82-87. [Article in Russian] Korkina MV, Korchak GM, Kareva MA. Effects of carnitine and cobamamide on the dynamics of mental work capacity in patients with anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1992;92:99-102. [Article in Russian] Giordano C, Perrotti G. Clinical studies of the effects of treatment with a combination of carnitine and cobamamide in infantile anorexia. Clin Ter 1979;88:51-60. [Article in Italian] Swart I, Rossouw J, Loots JM, Kruger MC. The effect of L-carnitine supplementation on plasma carnitine levels and various performance parameters of male marathon athletes. Nutr Res 1997;17:405-414. Vecchiet L, Di Lisa F, Pieralisi G, et al. Influence of L-carnitine administration on maximal physical exercise. Eur J Appl Physiol Occup Physiol 1990;61:486-490. Page 47

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Monograph

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Derosa G, Cicero AF, Gaddi A, et al. The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clin Ther 2003;25:1429-1439. Mingrone G, Greco AV, Capristo E, et al. Lcarnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr 1999;18:77-82. Cakir N, Yetkin I, Karakoc A, et al. L-carnitine in the treatment of painful diabetic neuropathy and its effect on plasma beta-endorphin levels. Curr Ther Res Clin Exp 2000;61:871-876. Plioplys AV, Plioplys S. Serum levels of carnitine in chronic fatigue syndrome: clinical correlates. Neuropsychobiology 1995;32:132-138. Plioplys AV, Plioplys S. Amantadine and Lcarnitine treatment of chronic fatigue syndrome. Neuropsychobiology 1997;35:16-23. Sachan DS, Rhew TH, Ruark RA. Ameliorating effects of carnitine and its precursors on alcoholinduced fatty liver. Am J Clin Nutr 1984;39:738744. Selimoglu MA, Yagci RV. Plasma and liver carnitine levels of children with chronic hepatitis B. J Clin Gastroenterol 2004;38:130-133. DaVanzo WJ, Ullian ME. L-carnitine administration reverses acute mental status changes in a chronic hemodialysis patient with hepatitis C infection. Clin Nephrol 2002;57:402-405. Malaguarnera M, Pistone G, Astuto M, et al. Lcarnitine in the treatment of mild or moderate hepatic encephalopathy. Dig Dis 2003;21:271-275. Moretti S, Alesse E, Di Marzio L, et al. Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: a pilot study. Blood 1998;91:3817-3824. De Simone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1-12. Moretti S, Famularo G, Marcellini S, et al. Lcarnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002;4:391-403. Benvenga S, Ruggeri RM, Russo A, et al. Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, doubleblind, placebo-controlled clinical trial. J Clin Endocrinol Metab 2001;86:3579-3594. Costa M, Canale D, Filicori M, et al. L-carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26:155-159.

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Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21:157-159. Lenzi A, Lombardo F, Sgro P, et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril 2003;79:292-300. Lenzi A, Sgro P, Salacone P, et al. A placebocontrolled double-blind randomized trial of the use of combined L-carnitine and L-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril 2004;81:1578-1584. Gunal AI, Celiker H, Donder E, Gunal SY. The effect of L-carnitine on insulin resistance in hemodialysed patients with chronic renal failure. J Nephrol 1999;12:38-40. Vesela E, Racek J, Trefil L, et al. Effect of Lcarnitine supplementation in hemodialysis patients. Nephron 2001;88:218-223. Matsumoto Y, Amano I, Hirose S, et al. Effects of L-carnitine supplementation on renal anemia in poor responders to erythropoietin. Blood Purif 2001;19:24-32. Elisaf M, Bairaktari E, Katopodis K, et al. Effect of L-carnitine supplementation on lipid parameters in hemodialysis patients. Am J Nephrol 1998;18:416421. Romagnoli GF, Naso A, Carraro G, Lidestri V. Beneficial effects of L-carnitine in dialysis patients with impaired left ventricular function: an observational study. Curr Med Res Opin 2002;18:172-175. Golper TA, Goral S, Becker BN, Langman CB. L-carnitine treatment of anemia. Am J Kidney Dis 2003;41:S27-S34. Kurz C, Arbeiter K, Obermair A, et al. L-carnitinebetamethasone combination therapy versus betamethasone therapy alone in prevention of respiratory distress syndrome. Z Geburtshilfe Perinatol 1993;197:215-219. [Article in German] OʼDonnell J, Finer NN, Rich W, et al. Role of Lcarnitine in apnea of prematurity: a randomized, controlled trial. Pediatrics 2002;109:622-626. Whitfield J, Smith T, Sollohub H, et al. Clinical effects of L-carnitine supplementation on apnea and growth in very low birth weight infants. Pediatrics 2003;111:477-482. Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatr Pulmonol 1995;20:167-171.

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L-Carnitine 70.

71.

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75.

76. 77.

78.

79. 80.

81.

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Villani RG, Gannon J, Self M, Rich PA. LCarnitine supplementation combined with aerobic training does not promote weight loss in moderately obese women. Int J Sport Nutr Exerc Metab 2000;10:199-207. Johnston CS, Solomon RE, Corte C. Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coll Nutr 1996;15:586-591. Ha TY, Otsuka M, Arakawa N. The effect of graded doses of ascorbic acid on the tissue carnitine and plasma lipid concentrations. J Nutr Sci Vitaminol (Tokyo) 1990;36:227-234. Otsuka M, Matsuzawa M, Ha TY, Arakawa N. Contribution of a high dose of L-ascorbic acid to carnitine synthesis in guinea pigs fed high-fat diets. J Nutr Sci Vitaminol (Tokyo) 1999;45:163-171. Triggs WJ, Roe CR, Rhead WJ, et al. Neuropsychiatric manifestations of defect in mitochondrial beta oxidation response to riboflavin. J Neurol Neurosurg Psychiatry 1992;55:209-211. Podlepa EM, Gessler NN, Bykhovskii VIa. The effect of methylation on the carnitine synthesis. Prikl Biokhim Mikrobiol 1990;26:179-183. [Article in Russian] Dodson WL, Sachan DS. Choline supplementation reduces urinary carnitine excretion in humans. Am J Clin Nutr 1996;63:904-910. Hug G, McGraw CA, Bates SR, Landrigan EA. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802. Melegh B, Pap M, Molnar D, et al. Carnitine administration ameliorates the changes in energy metabolism caused by short-term pivampicillin medication. Eur J Pediatr 1997;156:795-799. Herink J. Enhancing effect of L-carnitine on some abnormal signs induced by pentylenetetrazol. Acta Medica (Hradec Kralove) 1996;39:63-66. Lissoni P, Galli MA, Tancini G, Barni S. Prevention by L-carnitine of interleukin-2 related cardiac toxicity during cancer immunotherapy. Tumori 1993;79:202-204. Kawasaki N, Lee JD, Shimizu H, Ueda T. Longterm L-carnitine treatment prolongs the survival in rats with adriamycin-induced heart failure. J Card Fail 1996;2:293-299.

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82.

83.

84. 85. 86.

Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of L-carnitine on the zidovudineinduced destruction of human myotubes. Part I: Lcarnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994;71:102-112. Georgala S, Schulpis KH, Georgala C, Michas T. L-carnitine supplementation in patients with cystic acne on isotretinoin therapy. J Eur Acad Dermatol Venereol 1999;13:205-209. Kuntzer T, Reichmann H, Bogousslavsky J, Regli F. Emetine-induced myopathy and carnitine deficiency. J Neurol 1990;237:495-496. Sekas G, Paul HS. Hyperammonemia and carnitine deficiency in a patient receiving sulfadiazine and pyrimethamine. Am J Med 1993;95:112-113. Mondillo S, Faglia S, DʼAprile N, et al. Therapy of arrhythmia induced by myocardial ischemia. Association of L-carnitine, propafenone and mexiletine. Clin Ter 1995;146:769-774. [Article in Italian]

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Sambucus nigra

Sambucus nigra (Photo Biopix.dk)

Monograph

Sambucus nigra (Elderberry) Introduction

Sambucus nigra, or European elder, is a tall tree-like shrub, native to Europe, Asia, and North Africa, and naturalized in the United States. Various parts of the elder have long been used in traditional medicine as a diaphoretic, diuretic, astringent, laxative, and emetic. The berries were used traditionally as a food to make elderberry wine and pies, and as a flavoring or dye. Currently, extracts of the berries are used primarily as antiviral agents for colds, influenza, and Herpes virus infection. Research has also demonstrated Sambucus nigra has immune-modulating, antioxidant, and insulin-stimulating properties.

Description

The Sambucus nigra plant is a member of the Caprifoliaceae or honeysuckle family, and can be found growing in shady, moist areas in Europe, Asia, North Africa, and North America. It tolerates relatively poor soil conditions and is often found growing as part of the underbrush in forests. The naturalized plant in North America is known as Sambucus nigra ssp canadensis, Sambucus canadensis, or North American elderberry. The tree-like shrub has light brown or gray stippled bark and narrow, dark green, serrated leaves. In early summer, Sambucus nigra blooms with large clusters of small, fragrant, creamy-white flowers that develop into shiny, purplish-black berries by late summer and early fall.1,2 Historically, the leaves, bark, flowers, and berries have all been used medicinally, but most of the clinical studies have been conducted on the therapeutic uses and properties of the elderberry.

Active Constituents

The fruit of Sambucus nigra (elderberries) contains several constituents responsible for pharmacological activity. Among these are the flavonoids quercetin and rutin, anthocyanins identified as cyanidin-3-glucoside and cyanidin-3-sambubioside,3 the hemagglutinin protein Sambucus nigra agglutinin III (SNA-III),4 cyanogenic glycosides including sambunigrin,5,6 viburnic acid, and vitamins A and C.2

Pharmacokinetics

Due to limited research, the pharmacokinetics of many constituents of Sambucus nigra are not completely understood. Available research has focused on the absorption and urinary excretion of the anthocyanin constituents. Historically, researchers were uncertain whether anthocyanins were absorbed unless they were first hydrolyzed in the gastrointestinal tract. Recently, however, several small pharmacokinetic studies of elderberry extract in healthy volunteers demonstrated elderberry anthocyanins are indeed absorbed and excreted in an intact form. Alternative Medicine Review ◆ Volume 10, Number 1 ◆ 2005

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Sambucus nigra

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Within four hours of consuming 12 g elderberry extract containing 720 mg total anthocyanins, the two major anthocyanins in elderberry extract were identified in the urine of four elderly women.3 A second similar study involving 16 healthy volunteers confirmed the presence of the same two anthocyanins in the urine of study subjects after oral administration of elderberry extract.7 In another study involving six healthy volunteers, a single oral dose of 30 mL elderberry extract (147.3 mg total anthocyanins) resulted in a rapid urinary excretion rate of intact anthocyanins with only 0.37 percent of the original dose being present in the urine at seven hours post-ingestion.8 One study investigated the absorption of elderberry anthocyanins in a single male subject given 25 g elderberry extract (1.5 g total anthocyanins); highperformance liquid chromatography (HPLC) analysis detected two anthocyanin peaks in plasma collected 30 minutes post-dose.9 Another study detected anthocyanins from elderberry in glycoside form in both plasma and urine four hours after dosing.10

Mechanisms of Action Antiviral

While there are several mechanisms responsible for the beneficial effects of Sambucus nigra and extracts of its berries, perhaps the most important and best studied are the antiviral effects. Mumcuoglu, an Israeli virologist, was the first to discover elderberry constituents neutralize the activity of the hemagglutinin spikes found on the surface of several viruses. When these hemagglutinin spikes are deactivated the viruses can no longer pierce cell walls or enter the cell and replicate.11 Based on these findings, Sambucol®, a syrup containing 38-percent standardized extract of black elderberry, was developed. Numerous studies using the Sambucol preparation have shown it to neutralize and reduce the infectivity of influenza viruses A and B,12,13 HIV strains and clinical isolates,14 and Herpes simplex virus type 1 (HSV-1) strains and clinical isolates.15 It probably does so in the same manner as with influenza viruses, via neutralization of the virus resulting in reduced infectivity.

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S-sambunigrin

O O

H

OH

CH2OH HO HO

C N

Immune Modulation via Cytokine Production

Elderberry extracts also have immune-modulating activity in healthy individuals as well as in those with viral infections or other diseases characterized by immunosuppression. Production of certain cytokines leads to activation of phagocytes and facilitates their movement to inflamed tissues.16 Two studies using blood-derived monocytes from healthy donors demonstrated the ability of several Sambucol extracts to significantly increase cytokine production. Cytokines tested were tumor necrosis factor-alpha (TNFα), and interleukins (IL) -1β, -6, and -8.17 A second similar study also measured monocyte production of IL-10 when exposed to various Sambucol preparations and confirmed the results of the first study. A 1.3- to 6.2-fold increase in cytokine production was observed compared to control. A 2.3-fold increase in IL-10 was also observed.18

Antioxidant

Elderberries contain several anthocyanin flavonoids known to possess significant antioxidant properties. Research has demonstrated low-level concentrations (4 mcg/mL) of elderberry anthocyanins can efficiently regenerate alpha-tocopherol from alpha-tocopheroxyl radicals in models of copper-mediated LDL oxidation.19 Since it has been observed that anthocyanin glycosides are indeed absorbed in humans,3,7-10 it is likely that supplementing with elderberry extracts containing anthocyanins provides significant antioxidant benefit.

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It has been established that endothelial cell dysfunction results in changes in the redox status of cells.20 Based on this premise and previous research on elderberryʼs antioxidant potential, Youdin et al demonstrated elderberry anthocyanin incorporation into endothelial cells confers increased protection against oxidative stress. Human aortic endothelial cells incorporated elderberry anthocyanins into both the membrane and cytosol, affording significantly enhanced resistance to damage from reactive oxygen species. The most pronounced affect was seen with protection against H2O2-induced loss in cell viability.21

Clinical Indications Viral Infections Influenza

Two randomized, placebo-controlled, double-blind studies demonstrated the elderberry extract, Sambucol, effectively inhibited both influenza A and B strains when given orally to patients in the first 48 hours of influenza symptoms. In the earlier study, 27 individuals experiencing typical early flu symptoms were given Sambucol or placebo daily for three days – 2 tablespoons (children) or four tablespoons (adults). Patients were followed for six days and symptoms monitored. Serum from all subjects was analyzed for antibodies to influenza A and B at the initial dose and during the convalescent phase. In the treatment group, significant improvement in flu symptoms was observed in 93.3 percent of subjects within two days after initial dosing, while 91.7 percent of the control group demonstrated improvement after six days. A complete resolution was achieved in the treatment group in 90 percent of patients after 2-3 days, while the placebo group yielded similar results after six days. Of these 27 patients, 23 had laboratory confirmation of influenza B.12 In a second study, 60 patients (ages 18-54 years) experiencing early influenza symptoms were given 15 mL of Sambucol or placebo syrup four times daily for five days. Symptoms were monitored for eight days. In the treatment group, the majority of patients reported “pronounced improvement” after an average of 3-4 days, while the placebo group required 7-8 days to reach the same level.13

Herpes simplex

Mumcuoglu et al examined the effects of Sambucol against HSV-1 in human diploid fibroblasts. Four strains of HSV-1 were utilized – a reference strain, two acyclovir-resistant strains, and a strain isolated from a patient. Viral replication was completely inhibited in all four strains, whether the cells were pre-incubated with the extract, simultaneously incubated with extract, or the extract was added 30 minutes after viral adsorption to cells. The complete inhibition of four strains of HSV-1 in vitro by elderberry extract warrants further clinical trials in humans.15 A formula of Sambucus nigra (flower extract) in combination with Hypericum perforatum and Saponaria officinalis was also found to inhibit the replication of HSV-1 in vitro.22

HIV

Sambucol was studied for the potential to inhibit the infectivity of HIV isolates in CD4+ cell lines, peripheral blood lymphocytes, and laboratory HIV strains. The elderberry extract at two different dilutions was pre-incubated with HIV virus prior to addition of the cells. A significant reduction was observed in the infectivity of all HIV strains. In patient isolates treated with the extract, no HIV antigen was detected at either five or nine days post-incubation.14 Anecdotal evidence (six case studies) reports a combination of elderberry extract and a thymus extract resulted in a reduction in viral load in people with HIV.23

Conditions Associated with Oxidative Stress

Numerous disease states are characterized by oxidative stress, including cardiovascular disease, cancer, neurodegenerative disease, peripheral vascular disease, autoimmune diseases, and multiple sclerosis. The ability of elderberry extract to provide antioxidant protection via inhibition of LDLoxidation and scavenging of free radicals makes it a potentially valuable tool in the treatment of disease resulting from oxidative stress.19 Elderberryʼs ability to incorporate into endothelial cells and potentially improve endothelial function may also indicate a role in prevention of vascular disease of various kinds.21

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Sambucus nigra

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Effect on Blood Lipids

A randomized, placebo-controlled study of 34 healthy subjects examined the effectiveness of low-dose, powdered elderberry juice (10% anthocyanins) versus placebo on lipid parameters. Elderberry was dosed at 400 mg capsuled powder (equal to 5 mL elderberry juice) three times daily for two weeks; patients were instructed to follow a diet containing 35-percent fat. Serum was obtained at baseline and at the end of the two-week period. Analysis of results showed a slight, but statistically insignificant, decrease at two weeks in all lipid parameters of the low-dose elderberry extract group compared to baseline. Total cholesterol was 199 mg/dL at baseline versus 190 mg/dL at the end of the two-week period. Slight reductions were also reported in triglycerides, and HDL- and LDL-cholesterol.24 Although improvements in lipid values were statistically insignificant, the dosage of elderberry extract was low and it is possible higher dosages might produce a more significant benefit. In addition, using subjects with normal lipid levels may not be as likely to produce significant results since the lipids are already within the normal range. Further study on patients with elevated lipid levels is warranted.

Diabetes

In folk medicine, Sambucus nigra flower was traditionally suggested as a remedy for diabetes.25 Researchers in Northern Ireland conducted an in vitro study to evaluate the effect on blood sugar. In the two-armed study, aqueous extract of elder flower significantly increased glucose uptake, glucose oxidation, and glycogenesis in rat abdominal muscle. Elder flower extract incubated with rat pancreatic cells also had a dose-dependent stimulatory effect on insulin secretion. The researchers concluded elder flowers contain water-soluble constituents capable of direct stimulation of insulin secretion and glucose metabolism.26 Further clinical study is warranted before Sambucus can be recommended for use in diabetes.

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Drug-Botanical Interactions

There are no confirmed drug interactions with elderberry extract. However, due to the ability of Sambucus flower extracts to potentiate insulin release in vitro,26 patients with diabetes should be advised to monitor blood sugar closely when using flower extracts.

Side Effects and Toxicity

Elderberry extracts are generally without side effects when taken in the suggested dosages.12 Berries should be cooked, as the consumption of uncooked berries or juice can result in vomiting and diarrhea.1 Certain constituents of the leaves, stems, flowers, and roots contain poisonous alkaloids.27 It has also been reported that small percentages of the general population have a type-1 allergy to Sambucus nigra as evidenced by positive-skin prick or RAST test.28

Dosage

Elderberry fruit syrups are often standardized to 30-38 percent elderberry. Powdered extracts are dosed at 500 mg (capsule) 2-3 times daily for 3-4 days, or if in liquid form, dosed at one tablespoonful (15 mL) three times daily. In the case of acute viral infections, course of treatment is generally at least three days.29

Warnings and Contraindications

Currently there are no reported adverse effects in regard to fetal development, pregnancy, or lactation. However, as elderberry is not a well-researched botanical, health care practitioners should use caution in recommending it to women who are pregnant or nursing.

References 1. 2. 3.

Lust J. The Herb Book. Reading, PA: Cox and Wyman Ltd.; 1974:174. Duke JA. Handbook of Medicinal Herbs. Boca Raton, FL: CRC Press; 1985:423. Wu X, Cao G, Prior RL. Absorption and metabolism of anthocyanins in elderly women after consumption of elderberry or blueberry. J Nutr 2002;132:1865-1871.

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4.

5. 6.

7. 8.

9. 10. 11. 12.

13.

14.

15.

16.

17.

Mach L, Scherf W, Ammann M, et al. Purification and partial characterization of a novel lectin from elder (Sambucus nigra L.) fruit. Biochem J 1991;278:667-671. Jensen SR, Nielsen BJ. Cyanogenic glucosides in Sambucus nigra L. Acta Chem Scand 1973;27:2661-2662. Buhrmester RA, Ebingerla JE, Seigler DS. Sambunigrin and cyanogenic variability in populations of Sambucus canadensis L. (Caprifoliaceae). Biochem Syst Ecol 2000;28:689695. Mulleder U, Murkovic M, Pfannhauser W. Urinary excretion of cyanidin glycosides. J Biochem Biophys Methods 2002;53:61-66. Bitsch I, Janssen M, Netzel M, et al. Bioavailability of anthocyanidin-3-glycosides following consumption of elderberry extract and blackcurrant juice. Int J Clin Pharmacol Ther 2004;42:293-300. Cao G, Prior RL. Anthocyanins are detected in human plasma after oral administration of an elderberry extract. Clin Chem 1999;45:574-576. Milbury PE, Cao G, Prior RL, Blumberg J. Bioavailability of elderberry anthocyanins. Mech Aging Dev 2002;123:997-1006. Personal communication with Madeleine Mumcuoglu, MD; January 25, 2005. Zakay-Rones Z, Varsano N, Zlotnik M, et al. Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama. J Altern Complement Med 1995;1:361-369. Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections. J Int Med Res 2004;32:132140. Sahpira-Nahor O, Zakay-Rones Z, Mumcuoglu M. The effects of Sambucol® on HIV infection in vitro. Ann Israel Congress Microbiol February 6-7, 1995. Morag AM, Mumcuoglu M, Baybikov T, et al. Inhibition of sensitive and acyclovir-resistant HSV-1 strains by an elderberry extract in vitro. Z Phytother 1997;25:97-98. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immuno Biology 5. The Immune System in Health and Disease. New York, NY: Garland Publishing; 2001: 12-13. Barak V, Halperin T, Kalickman I. The effect of Sambucol®, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw 2001;12:290-296.

18.

19.

20. 21.

22.

23.

24.

25. 26.

27. 28.

29.

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Barak V, Birkenfeld S, Halperin T, Kalickman I. The effect of herbal remedies on the production of human inflammatory and anti-inflammatory cytokines. Isr Med Assoc J 2002;4:S919-S922. Abuja PM, Murkovic M, Pfannhauser W. Antioxidant and prooxidant activities of elderberry (Sambucus nigra) extract in low-density lipoprotein oxidation. J Agric Food Chem 1998;46:4091-4096. Kehrer JP. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 1993;23:21-48. Youdim KA, Martin A, Joseph JA. Incorporation of the elderberry anthocyanins by endothelial cells increases protection against oxidative stress. Free Radic Biol Med 2000;29:51-60. Serkedjieva J, Manolova N, Zgorniak-Wowosielska I, et al. Antiviral activity of the infusion (SHS-174) from flowers of Sambucus nigra L., aerial parts of Hypericum perforatum L., and roots of Saponaria officinalis L. against influenza and herpes simplex viruses. Phytother Res 1990;4:97-100. No authors listed. Anecdotal reports: elderberry extract plus chondroitin and glucosamine sulfate and Thy-mate reduces viral load to non-detectable levels in 10 days. Posit Health News 1998;17:7-11. Murkovic M, Abuja PM, Bergmann AR, et al. Effects of elderberry juice on fasting and postprandial serum lipids and low-density lipoprotein oxidation in healthy volunteers: a randomized, double-blind, placebo-controlled study. Eur J Clin Nutr 2004;58:244-249. Atkinson M. Herbs for Your Health. New York, NY: Dalesman Books; 1979. Gray AM, Abdel-Wahab YH, Flatt PR. The traditional plant treatment, Sambucus nigra (elder), exhibits insulin-like and insulin-releasing actions in vitro. J Nutr 2000;130:15-20. Hardin JW, Arena JM, eds. Human Poisoning from Native and Cultivated Plants. 2nd ed. Durham, NC: Duke University Press; 1974. Forster-Waldl E, Marchetti M, Scholl I, et al. Type 1 allergy to elderberry (Sambucus nigra) is elicited by a 33.2 kDa allergen with significant homology to ribosomal inactivating proteins. Clin Exp Allergy 2003;33:1703-1710. Dietary Supplement Information Bureau http:// content.nhiondemand.com/dse/consumer/monoAllstyle.asp?objID=100055&ctype=ds&mtyp=1

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Lutein and Zeaxanthin Zeaxanthin

Monograph

OH

HO Lutein

OH

HO

Lutein and Zeaxanthin Introduction

Lutein and zeaxanthin belong to the xanthophyll family of carotenoids and are the two major components of the macular pigment of the retina. The macula lutea or “yellow spot” in the retina is responsible for central vision and visual acuity. Lutein and zeaxanthin are the only carotenoids found in both the macula and lens of the human eye, and have dual functions in both tissues – to act as powerful antioxidants and to filter high-energy blue light.1 Lutein is found in high amounts in human serum.2 In the diet it is found in highest concentrations in dark green, leafy vegetables (spinach, kale, collard greens, and others), corn, and egg yolks.3 Zeaxanthin is the major carotenoid found in corn, orange peppers, oranges, and tangerines (Table 1).4 In addition to playing pivotal roles in ocular health, lutein and zeaxanthin are important nutrients for the prevention of cardiovascular disease, stroke, and lung cancer. They may also be protective in skin conditions attributed to excessive ultraviolet (UV) light exposure.

Biochemistry and Pharmacokinetics

Lutein and zeaxanthin differ from other carotenoids in that they each have two hydroxyl groups, one on each side of the molecule. Zeaxanthin is a stereoisomer of lutein, differing only in the location of a double bond in one of the hydroxyl groups. The hydroxyl groups appear to control the biological function of these two xanthophylls.5 Some dietary lutein appears to be converted to a non-dietary form, meso-zeaxanthin. Infants have more lutein and less meso-zeaxanthin, possibly due to less efficient lutein conversion. Lutein appears to have an affinity for the peripheral retina and rods, while zeaxanthin seems to be preferentially taken up by the cones of the macula.6 Because xanthophylls are fat-soluble nutrients, bioavailability to tissues is dependent on a number of factors, including nutrient source (whole food or supplement), state of the food (raw, cooked, or processed), extent of disruption of the cellular matrix via mastication and digestive enzymes, and absorption by the enterocytes of the intestinal mucosa (primarily the duodenum). Cooking of lutein/zeaxanthin-containing foods may increase bioavailability by disrupting the cellular matrix and the carotenoid-protein complexes.7 After lutein and zeaxanthin are absorbed by the enterocytes they are transported across the intestinal lumen and incorporated into the chylomicrons. They reach the circulating blood and are subsequently taken up by hepatocytes, entering the hepatic circulation where they are incorporated into lipoproteins. In humans, low- and high-density lipoproteins transport lutein and zeaxanthin via the systemic circulation to various tissues.8 Data on xanthophyll Page 128

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Lutein and Zeaxanthin

Monograph

absorption is limited, but studies involving single dietary doses indicate lutein reaches peak concentrations in the chylomicron fraction at approximately two hours post-ingestion,9 and peaks in serum at about 16 hours post-ingestion.10 Lutein absorption from a purified crystalline lutein supplement is almost twice that from spinach or other vegetable sources.7 Non-dietary factors affecting absorption and bioavailability of lutein and zeaxanthin include age, body composition, gender, malabsorption of fats, alcohol consumption, smoking, and liver or kidney disease.11-14

Mechanisms of Action

Table 1. Lutein and Zeaxanthin Content of Foods

Food

Lutein content

Zeaxanthin content

Kale, cooked

20-33 mg*/1 cup

11-20 mg*/1 cup

Turnip greens, cooked

18.1 mg/1 cup

5.1-12.2 mg*/1 cup

Collard greens, cooked

10.2-17.2 mg*/1 cup

0.37-5.1 mg*/1 cup

12-15 mg*/1 cup

5.9-12.7* mg/1 cup

Spinach, raw

6.6 mg/1 cup

3.6 mg/1 cup

Broccoli, cooked

3.4 mg/1 cup

3.5 mg/1 cup

Brussels sprouts, cooked

3.4 mg/1 cup

2.0 mg/1 cup

Green peas

2.3 mg/1 cup

2.3 mg/1 cup

Corn, cooked

0.6 mg/1 cup

2.8-3.0 mg/1 cup

Persimmons

0.6 mg/1 cup

0.8 mg/1 cup

Egg yolks

0.3 mg/1 yolk

0.25 mg/1 yolk

Tangerines

0.3 mg/1 cup

0.2 mg/1 cup

Orange juice

0.3 mg/1 cup

0.34 mg/1 cup

–

1.7 mg/1 cup

Spinach, cooked

Orange sweet peppers * Depending on variety

Lutein and zeaxanthin are powerful antioxidants, and lutein is widely known as the primary nutrient for protecting ocular function. It has long been thought that carotenoid intake also reduces the risk of certain forms of cardiovascular disease,15-17 stroke,1819 and cancer.20-21 Lutein and zeaxanthin may prevent cellular damage in these conditions by quenching singlet oxygen or neutralizing photosensitizers. Lutein and zeaxanthin inhibit lipid peroxidation, a likely factor in the etiology of both retinal and cardiovascular disease. The presence of adhesion molecules on endothelial cell surfaces is a marker of atherosclerosis pathogenesis. In vitro research has demonstrated lutein incubation with cultured endothelial cells effectively inhibits the expression of these adhesion molecules.22 Other research has found

lutein and zeaxanthin can inhibit thickening of the walls of carotid arteries and LDL-induced migration of monocytes to human artery cell walls.23 These are potential mechanisms for luteinʼs protective effect in cardiovascular disease. In the case of skin health, lutein, zeaxanthin, and other carotenoids appear to be depleted in the skin under conditions of prolonged UV light exposure.24-25 Skin exposure to UV rays generates reactive oxygen species, inflammation in skin cells, and erythema. Intake of dietary antioxidants, including lutein and zeaxanthin, reduces this inflammatory response, as carotenoids are poor absorbers of UV light.26

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Lutein and Zeaxanthin Clinical Indications Ocular Conditions

Age-related Macular Degeneration

In older Americans, age-related macular degeneration (AMD) is the leading cause of blindness. It is characterized by atrophy of the macular disk. The retinal pigmented epithelium and photoreceptors (particularly the rods and the blue-light sensitive cones) are the most affected. There are two types of AMD – early or dry and late or wet. Early AMD is characterized by soft drusen accumulation and pigmentary changes in the retinal epithelium and macula, while late-stage AMD involves neovascularization of the retina, an exudative mound, and intraretinal hemorrhage and scarring.27-28 Numerous observational studies have examined the correlation between lutein and zeaxanthin concentrations in the macula, dietary intake, and macular degeneration. In the multicenter Eye Disease Case-Control study, Seddon et al evaluated the relationship between dietary intake of carotenoids and the risk of neovascular AMD in 356 subjects. After adjusting for risk factors, they found a 57-percent decreased risk for AMD in individuals with the highest intake of lutein/zeaxanthin (6 mg daily), compared to those who consumed the lowest level (0.5 mg daily).29 Other studies have examined the relationship between lutein/zeaxanthin intake, serum lutein/ zeaxanthin, and macular pigment density (MPD). In 278 healthy volunteers higher levels of dietary lutein intake correlated with higher serum lutein and zeaxanthin and significantly higher MPD.30 Bernstein et al also demonstrated lutein supplementation of 4 mg daily resulted in significantly higher MPD levels in AMD patients compared to control subjects not supplementing.31 These observational studies seem to indicate maintenance of macular pigment density is crucial to maintaining visual acuity and decreasing the risk of developing AMD. Since 2001, three double-blind, intervention studies have examined the effects of lutein supplementation on vision improvement in AMD patients. In a 12-month trial of 14 AMD patients, Richer demonstrated improvements of up to 92 percent in visual acuity tests after subjects consumed a diet containing

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five ounces of spinach (approximately 14 mg lutein) 4-7 times weekly.32 In 2004, Richer published the results of a follow-up study – the Lutein Antioxidant Supplementation Trial (LAST), a double-blind, randomized, placebo-controlled study. Ninety males with atrophic AMD were supplemented with either 10 mg lutein, 10 mg lutein plus a broad spectrum formula containing antioxidants/vitamins/minerals, or placebo for one year. The subjects were examined for MPD, photostress recovery, contrast sensitivity, and visual acuity at baseline, and every four months until the end of the study. The most significant finding was a 36-percent increase in MPD in the lutein group and a 43-percent increase in MPD in the lutein plus antioxidant group, compared to a slight decrease in MPD in the placebo group. Lutein supplementation also resulted in significant improvements in visual acuity, objective visual function parameters, photo-stress recovery, and contrast sensitivity. The LAST confirms lutein plays an important role in ocular health and that AMD appears to respond favorably to lutein supplementation.33 In an Italian study, 50 patients with AMD were given daily cocktails containing antioxidants and 15 mg purified lutein or placebo for 18 months. The study was published in Italian so details are not readily available, but the researchers demonstrated a two-fold increase in visual acuity in AMD patients compared to the placebo group.34

Cataracts

Cataracts are the leading cause of impaired vision in the United States, with a large percentage of the geriatric population exhibiting some signs of the lesion. Cataracts are developmental or degenerative opacities of the lens that result in a gradual, painless loss of vision. Oxidative insult appears to be a precipitating factor in cataracts, resulting in the development of insoluble, oxidized lens proteins. Higher levels of hydrogen peroxide have been found in cataractous lenses compared to normal lenses, indicating oxidative stress.35-36 Studies examining lutein and zeaxanthin levels in extracted cataractous lenses have found up to three-fold higher levels in the newer epithelial tissue of the lens than in the older inner cortex portion. The

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Monograph

epithelial cortex layer comprises 50 percent of the tissue, yet it has been found to contain 74 percent of the total lens lutein and zeaxanthin, supporting the hypothesis that these nutrients are protective against the oxidative damage causing cataract formation.37 The Nurses Health Study examined the effect of 12 years of carotenoid consumption on the risk of cataract formation in 77,466 female nurses, ages 45 and over. After controlling for other risk factors, nurses in the highest quintile for lutein and zeaxanthin consumption had a 22-percent decreased risk for cataract extraction, compared with those in the lowest quintile.38 Numerous other observational studies have found that increased consumption of foods high in lutein/zeaxanthin is associated with a decreased risk for cataracts or cataract extraction in both men and women. These studies provide strong evidence for a protective role for lutein/zeaxanthin against development of cataracts.39,40 The only randomized, double-blind trial on carotenoid supplementation and age-related cataracts measured visual acuity, glare sensitivity, and serum carotenoid levels in 17 clinically diagnosed patients. Patients received 15 mg lutein three times weekly for two years and were compared to patients receiving 100 mg alpha-tocopherol or placebo for the same period. In patients receiving lutein, statistically significant improvements in visual acuity and glare sensitivity and increased serum concentrations of lutein were observed, compared to the alpha-tocopherol and control patients.41

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a rare, inherited, degenerative disease characterized by atrophy of the light-sensing rods in the retina. The rods are responsible for vision in low-light situations; therefore, early RP (often in childhood) is frequently characterized by poor night vision. A progressive loss of peripheral vision occurs over time, resulting in tunnel vision in late stages of the disease. Although treatment is limited, high-dose vitamin A supplementation has been shown to slow the degeneration.42 In one study, Dagnelie et al found 40 mg lutein daily for nine weeks significantly improved visual acuity among 16 RP patients. Testing of visual acuity was via computersimulated self-test by RP patients.43 Ongoing double-

Lutein and Zeaxanthin blind, placebo-controlled trials are examining the effects of lutein supplementation in patients with RP.

Skin Health and Ultraviolet Light Exposure

Stahl et al examined the effect of mixed carotenoid and straight beta-carotene supplementation on skin erythema after exposure to UV light. Subjects were divided into two groups: Group 1 received a carotenoid supplement containing 24 mg beta-carotene and Group 2 received 24 mg mixed carotenoids (8 mg each of beta-carotene, lutein, and lycopene) daily for 12 weeks. Group 2 patients demonstrated increased serum levels of all three nutrients and a significant decrease in erythema was observed in both groups after UV exposure compared to pre-supplementation. This study suggests carotenoids deposited in the skin may protect against erythema and inflammation resulting from UV rays.44 In support of this hypothesis, other researchers have demonstrated the presence of lutein and its oxidative metabolites in human skin.45,46 Although a direct association between skin levels of lutein and lutein consumption has not been established, higher skin lutein levels are observed in humans who take a regular lutein-containing, multivitamin supplement.47

Cardiovascular Disease and Stroke

Epidemiological studies have long suggested an association between carotenoid intake and decreased risk of cardiovascular disease.16,48 Research has shown oxidized low density lipoprotein (LDL) to be a key factor in the initiation of atherosclerosis, one of the pathological processes involved in cardiovascular and cerebrovascular disease. LDL expresses numerous adhesion molecules that appear to enhance the binding of monocytes to aortic endothelium, where they may become transformed into foam cells and initiate atherosclerosis.22,49 Consequently, antioxidants, including carotenoids, have been investigated for the ability to scavenge free radicals and inhibit lipid peroxidation in cardiovascular and cerebrovascular disease. Case-control studies utilizing carotid intima-media thickness (IMT) to measure atherosclerotic progression in asymptomatic men and women

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Lutein and Zeaxanthin have found a moderate inverse association between lutein and zeaxanthin serum levels and carotid IMT. In a three-year study, 231 asymptomatic age-, sex-, race-, and field center-matched case subjects from the Atherosclerosis Risk in Communities (ARIC) study cohort demonstrated significantly lower serum lutein/zeaxanthin levels and an average IMT two times larger (1.2 ± 0.3 mm) than matched control subjects (0.6 ± 0.1 mm).50 More recently, the Los Angeles Atherosclerosis Study examined the association between plasma lutein/zeaxanthin levels, atherosclerotic progression, and carotid IMT. A total of 573 asymptomatic men and women were assessed via plasma lipid levels and carotid artery ultrasound at baseline and after 18 months. After adjustment for age, sex, and smoking status, changes in carotid IMT were significantly inversely associated with lutein and zeaxanthin levels. The researchers concluded higher levels of these carotenoids may be protective against early atherosclerosis.51 Two studies have investigated the hypothesis that high lutein/zeaxanthin might exert a protective effect against stroke in men. A prospective observational study of 43,738 men without cardiovascular disease or diabetes found a slightly significant association between xanthophyll intake and ischemic stroke. The relative risk for ischemic stroke for the top quintile of lutein intake compared with the bottom quintile was 0.63. Further studies are warranted.18 A second cohort study of 26,593 male smokers in Finland investigated the association between carotenoid intake and risk of stroke subtypes. An inverse association between lutein intake and subarachnoid hemorrhage was observed, and subjects in the highest quartile of lutein intake had a risk ratio of 0.47 for subarachnoid hemorrhage compared to those in the lowest quartile (risk ratio of 1.0).19

Monograph

food-item questionnaire. Consumption of carotenoidcontaining fruits and vegetables was associated with decreased risk of lung cancer. A decreased risk was also observed in those in the highest quintiles of lutein/zeaxanthin intake versus the lowest quintiles.20 A population-based survey of 20 South Pacific Island populations examined the association between lutein consumption and lung cancer rates. Researchers found an inverse association between lutein and lung cancer and a markedly lower incidence rate for lung cancer among Fijians, compared to other South Pacific populations. Fijians consume an average of 200 g dark greens (25 mg lutein) daily; whereas, inhabitants of other South Pacific countries consume diets in which colorful fruits and vegetables are less plentiful.53

Nutrient-Nutrient Interactions

Although inconclusive, some studies have demonstrated a competitive inhibition for absorption among carotenoids. The two carotenoids most often examined have been beta-carotene and lutein. Competition for absorption seemed only to be a factor in short-term studies (less than two years), while longer studies have not demonstrated this effect. Simultaneous feeding of lutein as the predominant carotenoid with beta-carotene appears to inhibit absorption of beta-carotene.54 Conversely, beta-carotene also appears to slightly inhibit lutein absorption in singlefeeding studies.10,11

Drug-Nutrient Interactions

Cancer

Certain drugs, nutritional supplements, and foods have been reported to decrease the absorption of lutein/zeaxanthin. Cholesterol-lowering medications, including cholestyramine (Questran®) and colestipol (Colestid®), and Xenocal®, a drug used to treat obesity, may reduce the absorption of fat-soluble carotenoids.55,56 Proton-pump inhibitors such as Prilosec®, Losec®, Prevacid®, Aciphex®, Protonix®, and Pantoloc® increase gastric pH and have been shown to decrease the absorption of a single dose of betacarotene. Whether or not these drugs have the same effect on lutein/zeaxanthin absorption has not been determined. Mineral oil, corn oil, medium chain triglycerides, olestra, and pectin may also inhibit the absorption of lutein and zeaxanthin.56

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In a 10-year study following 120,000 U.S. men and women, a significant reduction in lung cancer was observed in those with the highest intake of total carotenoids, including lutein and zeaxanthin.52 A second 14-year study assessed the same relationship in 27,000 Finnish male smokers via a

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Monograph

Side Effects and Toxicity

No toxicities or adverse reactions have been reported in the scientific literature for lutein/zeaxanthin at doses of up to 40 mg daily for two months.43 Fijians consume an average of 25 mg lutein daily throughout a lifetime without any toxic effects.53 High doses of beta-carotene supplements (>30 mg daily) have been associated with carotenodermia,57 and the same may occur with high doses of lutein and zeaxanthin. Studies of lutein and zeaxanthin in pregnant and nursing women have not been conducted, so pregnant and nursing women should obtain lutein/ zeaxanthin from daily servings of fruits, vegetables, and egg yolks. Ames testing has demonstrated an absence of any mutagenic effect for purified lutein.58

Dosage

Average daily intake for lutein and zeaxanthin in the United States is 2.0-2.3 mg daily for men and 1.7-2.0 mg daily for women,59 although dietary intakes of approximately 6-20 mg lutein daily appear to be necessary to decrease risk of macular degeneration.32-34 If taken in supplement form, lutein and zeaxanthin are available in either the free or esterified forms, which appear to have comparable bioavailability.60 Although commercially available lutein/zeaxanthin supplements often contain significantly more lutein than zeaxanthin, new products are being developed with higher amounts of zeaxanthin. Typically, lutein supplements are available in either 6- or 20mg tablets or capsules. While the 6-mg dose is based on early studies, the 20-mg dose is more typical and is usually taken once daily. Carotenoids are best absorbed in the presence of fat, but as little as 3-5 g in a meal appear to ensure carotenoid absorption.61

References 1. 2.

Landrum JT. Bone RA. Lutein, zeaxanthin, and the macular pigment. Arch Biochem Biophys 2001;385:28-40. Khachik F, Spangler CJ, Smith JC, et al. Identification, quantification, and relative concentrations of carotenoids and their metabolites in human milk and serum. Anal Chem 1997;69:1873-1881.

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4. 5. 6.

7.

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12. 13.

14.

15. 16.

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Sommerburg O, Keunen JE, Bird AC, van Kuijk FJ. Fruits and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes. Br J Ophthalmol 1998;82:907-910. Age-Related Macular Degeneration Foundation website: www.macular.org/nutrition/zeaxan.html Johnson EJ. The role of carotenoids in human health. Nutr Clin Care 2002;5:56-65. Bone RA, Landrum JT, Fernandez L, Tarsis SL. Analysis of the macular pigment by HPLC: retinal distribution and age study. Invest Ophthalmol Vis Sci 1988;29:843-849. Castenmiller JJ, West CE, Linssen JP, et al. The food matrix of spinach is a limiting factor in determining the bioavailability of beta-carotene and to a lesser extent of lutein in humans. J Nutr 1999;129:349-355. Yeum KJ, Russell RM. Carotenoid bioavailability and bioconversion. Annu Rev Nutr 2002;22:483504. OʼNeill ME, Thurnham DI. Intestinal absorption of beta-carotene, lycopene and lutein in men and women following a standard meal: response curves in the triacylglycerol-rich lipoprotein fraction. Br J Nutr 1998;79:149-159. Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance, and interactions between lutein and beta-carotene when administered to human adults in separate or combined oral doses. Am J Clin Nutr 1995;62:604610. Albanes D, Virtamo J, Taylor PR, et al. Effects of supplemental beta-carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1997;66:336-372. Alberg A. The influence of cigarette smoking on circulating concentrations of antioxidant micronutrients. Toxicology 2002;180:121-137. Brady WE, Mares-Perlman JA, Bowen P, Stacewicz-Sapuntzakis M. Human serum carotenoid concentrations are related to physiologic and lifestyle factors. J Nutr 1996;126:129-137. Williams AW, Boileau TW, Erdman JW Jr. Factors influencing the uptake and absorption of carotenoids. Proc Soc Exp Biol Med 1998;218:106108. Kritchevsky SB. Beta-carotene, carotenoids and the prevention of coronary heart disease. J Nutr 1999;129:5-8. Street DA, Comstock GW, Salkeld R, et al. Serum antioxidants and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk factors for myocardial infarction? Circulation 1994;90:1154-1161.

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18.

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22.

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28. 29.

Connor SL, Ojeda LS, Sexton G, et al. Diets lower in folic acid and carotenoids are associated with the coronary disease epidemic in Central and Eastern Europe. J Am Diet Assoc 2004;104:1793-1799. Ascherio A, Rimm EB, Hernan MA, et al. Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann Intern Med 1999;130:963-970. Hirvonen T, Virtamo I, Korhonen P, et al. Intake of flavonoids, carotenoids, vitamin C and E, and risk of stroke in male smokers. Stroke 2000;31:23012306. Holick CN, Michaud DS, Stolzenberg-Solomon R, et al. Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the AlphaTocopherol, Beta-Carotene cohort study. Am J Epidemiol 2002;156:536-547. Voorrips LE, Goldbohm RA, Brants HA, et al. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev 2000;9:357-365. Martin KR, Wu D, Meydani M. The effect of carotenoids on the expression of cell surface adhesion molecules and binding of monocytes to human aortic endothelial cells. Atherosclerosis 2000;150:265-274. Dwyer JH, Navab M, Dwyer KM, et al. Oxygenated carotenoid lutein and progression of early atherosclerosis; the Los Angeles Artherosclerosis Study. Circulation 2001;103:29222927. Ribaya-Mercado JD, Garmyn M, Gilchrest BA, Russell RM. Skin lycopene is destroyed preferentially over beta-carotene during ultraviolet irradiation in humans. J Nutr 1995;125:1854-1859. Sorg O, Tran C, Carraux P, et al. Oxidative stressindependent depletion of epidermal vitamin A by UVA. J Invest Dermatol 2002;118:513-518. Stahl W, Sies H. Carotenoids and protection against solar UV radiation. Skin Pharmacol Appl Skin Physiol 2002;15:291-296. Beatty S, Koh H, Phil M, et al. The role of oxidative stress in the pathogenesis of agerelated macular degeneration. Surv Ophthalmol 2000;45:115-134. Berkow R, Fletcher AJ, eds. The Merck Manual of Diagnosis and Therapy. 15th ed. Rahway, NJ: Merck & Co., Inc; 1987. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA 1994;272:14131420.

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Curran-Celentano J, Hammond BR Jr, Ciulla TA, et al. Relation between dietary intake, serum concentrations, and retinal concentrations of lutein and zeaxanthin in adults in a midwest population. Am J Clin Nutr 2001;74:796-802. Bernstein PS, Zhao DY, Wintch SW, et al. Resonance Raman measurement of macular carotenoids in normal subjects and in age-related macular degeneration patients. Ophthalmology 2002;109:1780-1787. Richer S. ARMD-pilot (case series) environmental intervention data. J Am Optom Assoc 1999;70:2436. Richer S, Stiles W, Statkute L, et al. Doublemasked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study. (Lutein Antioxidant Supplementation Trial). Optometry 2004;75:216-230. Massacesi AL, Faletra R, Gerosa F, et al. The effect of oral supplementation of macular carotenoids (lutein and zeaxanthin) on the prevention of agerelated macular degeneration: 18 months of follow up study. Assoc Res Vision Ophthalmol 2001;42: S234. Horton J. Disorders of the eye. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrisonʼs Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:168. Spector A, Garner WH. Hydrogen peroxide and human cataract. Exp Eye Res 1981;33:673-681. Yeum KJ, Shang FM, Schalch WM, et al. Fatsoluble nutrient concentrations in different layers of human cataractous lens. Curr Eye Res 1999;19:502-505. Chasen-Taber L, Willett WC, Seddon JM, et al. A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in U.S. women. Am J Clin Nutr 1999;70:509-516. Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and risk of cataract extraction in U.S. men. Am J Clin Nutr 1999;70:517-524. Tavani A, Negri E, La Vecchia C. Food and nutrient intake and risk of cataract. Ann Epidemiol 1996;6:41-46. Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with agerelated cataracts: a 2-y double-blind, placebocontrolled pilot study. Nutrition 2003;19:21-24.

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42. 43.

44.

45. 46.

47.

48.

49. 50.

51.

52.

53. 54. 55.

Berson EL. Nutrition and retinal degenerations. Int Ophthalmol Clin 2000;40:93-111. Dagnelie G, Zorge IS, McDonald TM. Lutein improves visual function in some patients with retinal degeneration: a pilot study via the Internet. Optometry 2000;71:147-164. Heinrich U, Gartner C, Wiebusch M, et al. Supplementation with beta-carotene or a similar amount of mixed carotenoids protects humans from UV-induced erythema. J Nutr 2003;133:98-101. Wingerath T, Sies H, Stahl W. Xanthophyll esters in human skin. Arch Biochem Biophys 1998;355:271274. Khachik F, Beecher GR, Smith JC Jr. Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer. J Cell Biochem Suppl 1995;22:S236-S246. Peng YM, Peng YS, Lin Y, et al. Concentrations and plasma-tissue-diet relationships of carotenoids, retinoids, and tocopherols in humans. Nutr Cancer 1995;23:233-246. Gaziano JM, Manson JE, Branch LG, et al. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann Epidemiol 1995;5:255260. Krieglstein CF, Granger DN. Adhesion molecules and their role in vascular disease. Am J Hypertens 2001;14:44S-54S. Iribarren C, Folsom AR, Jacobs DR Jr, et al. Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis. A case-control study. The ARIC Study Investigators. Atherosclerosis Risk in Communities. Arterioscler Thromb Vasc Biol 1997;17:1171-1177. Dwyer JH, Paul-Labrador MJ, Fan J, et al. Progression of carotid intima-media thickness and plasma antioxidants: the Los Angeles Atherosclerosis Study. Arterioscler Thromb Vasc Biol 2004;24:313-319. Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of lung cancer in 2 prospective U.S. cohorts. Am J Clin Nutr 2000;72:990-997. Le Marchand L, Hankin JH, Bach F, et al. An ecological study of diet and lung cancer in the South Pacific. Int J Cancer 1995;63:18-23. van den Berg H. Effect of lutein on beta-carotene absorption and cleavage. Int J Vitam Nutr Res 1998;68:360-365. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale, NJ: Medical Economics Company, Inc.; 2001.

Lutein and Zeaxanthin 56.

57. 58.

59.

60. 61.

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Tang G, Serfaty-Lacrosniere C, Camilo ME, Russell RM. Gastric acidity influences the blood response to a beta-carotene dose in humans. Am J Clin Nutr 1996;64:622-626. Granado F, Olmedilla B, Gil-Martinez E, Blanco I. Lutein ester in serum after lutein supplementation in human subjects. Br J Nutr 1998;80:445-449. Gonzalez de Mejia E, Ramos-Gomez M, LoarcaPina G. Antimutagenic activity of natural xanthophylls against aflatoxin B1 in Salmonella typhimurium. Environ Mol Mutagen 1997;30:346353. Food and Nutrition Board, Institute of Medicine. Appendix C: Dietary intake data from the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Washington DC: National Academy Press; 2001:594-605. Bowen PE, Herbst-Espinosa SM, Hussain EA, et al. Esterification does not impair lutein bioavailability in humans. J Nutr 2002;132:3668-3673. van Het Hof KH, West CE, Weststrate JA, Hautvast JG. Dietary factors that affect the bioavailability of carotenoids. J Nutr 2000;130: 503-506.

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Theanine

H

Monograph

NH2 C

HOOC

C C

N C

CH3 C

O

L-Theanine Introduction

L-theanine (γ-glutamylethylamide) is a unique amino acid present almost exclusively in the tea plant (Camellia sinensis). It appears to only occur in three other species; one mushroom species and two other species of the Camellia genus. Since tea is the second most consumed beverage in the world, a considerable amount of theanine is consumed daily throughout the world and is said to greatly contribute to the taste of green tea. Tea contains a number of constituents, including polyphenols, proteins, amino acids, organic acids, vitamins, minerals, and pigments. Theanine comprises 1-2 percent of the dry weight of tea leaves, makes up approximately 50 percent of the amino acids in tea, and is present as the free amino acid only – it does not occur in proteins. Theanine is synthesized in the root of the plant and concentrates in the leaves, where sunlight converts theanine to polyphenols. Because of this, some tea cultivators grow their plants out of direct sunlight to preserve the theanine content and thus the flavor.1

Biochemistry and Pharmacokinetics

L-theanine was discovered as a constituent of green tea in 1949 by Sakato,2 and in 1964 was approved as a food additive in Japan. It is a water-soluble compound and when ingested orally is absorbed in the small intestine. In rats, peak plasma concentration was found 30 minutes after oral dosing.3 Theanine crosses the blood-brain barrier via the large neutral amino acid (leucine-preferring) transport system. Theanine, when reaching the brain, has been shown in rats to increase both serotonin and dopamine production.4 Theanine is hydrolyzed in the kidney to glutamic acid and ethylamine by the enzyme glutaminase.3

Mechanisms of Action

In the brain L-theanine increases dopamine and serotonin production,4 although one study showed a decrease in serotonin in rats administered theanine.5 Regardless of the mechanism, theanine increases alpha-brain wave activity, a sign of induced relaxation.6 L-theanine has been studied extensively for its effects on tumor cells and the sensitivity of those cells to chemotherapeutic agents. It appears theanine competitively inhibits glutamate transport into tumor cells, which causes decreased intracellular glutathione (GSH) levels. Theanine also inhibits the efflux of chemotherapeutic agents, such as doxorubicin, idarubicin, cisplatin, and irinotecan, causing them to accumulate in tumor cells. Theanine also protects normal cells from damage by these drugs via antioxidant activity, specifically by maintaining cellular GSH levels.7-10 The antioxidant activity of L-theanine has been studied in regard to its effect on the oxidation of LDL cholesterol. In vitro testing using malondialdehyde as a marker of lipid peroxidation demonstrated inhibition of LDL oxidation with theanine, although the effect was weaker than the potent antioxidant effect of green tea polyphenols.11 L-theanine may counteract the stimulatory effect of caffeine. In rats, theanine administered intravenously after caffeine dosing, and at approximately the same dose, blunted the stimulant effect of caffeine seen on electroencephalographic recordings. When given by itself in a smaller dose (20-40% of the original dose), theanine administration resulted in excitatory effects, suggesting a dual activity of theanine, depending on the dose.12 Page 136

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Theanine

Monograph

A dose-dependent hypotensive effect of theanine was seen in vivo in spontaneously hypertensive rats injected with L-theanine.13 Glutamine (which is structurally similar to theanine) administration did not alter the blood pressure.14

Clinical Indications Stress/Anxiety

Studies show L-theanine induces alpha-brain wave activity, which correlates with a perceived state of relaxation. A small Japanese study of university students showed oral L-theanine administration of 200 mg led to increased alpha-brain waves and a subjective sense of relaxation. Theanine administration caused a dose-dependent relaxed, yet alert, state of mind without sedation, beginning approximately 40 minutes after oral dosing. 6 Green tea is often used as a relaxing beverage, although it can contain more caffeine than coffee. Theanine appears to counteract the stimulant effect of caffeine to some degree.12

Hypertension

In studies of spontaneously hypertensive rats, L-theanine administration caused a significant reduction in blood pressure.15,16 Whether humans will experience similar results has yet to be determined; however, theanine might find a place in antihypertensive treatment regimens.

Cancer

Numerous in vitro and animal studies have investigated L-theanineʼs effect on cancer. Theanine decreased the size of ovarian tumors in M5076 ovarian sarcoma-bearing mice, when given in conjunction with chemotherapeutics, including doxorubicin, idarubicin, pirarubicin, cisplatin, and irinotecan.7-10,15 Ltheanine, given along with doxorubicin, reduced the size of ovarian tumors and decreased metastases to the liver as well.15 In another study, theanine almost doubled the effect of doxorubicin in Erlich ascites carcinoma, while increasing the drugʼs concentration in tumor cells threefold.16 It appears theanine exerts an additive effect along with chemotherapy by reducing transport of glutamic acid into the cell, decreasing GSH levels in the cell, and increasing the

concentration of the drug in tumor cells. Theanine also protects normal cells from damage by chemotherapeutic drugs.7-10

Drug-Nutrient Interactions

L-theanine increases the activity of doxorubicin, idarubicin, pirarubicin, cisplatin, and irinotecan in tumor cells.7-10,15

Side Effects and Toxicity

L-theanine is generally well tolerated, and has an LD50 of greater than 5,000 mg/kg in rats. It is not mutagenic or carcinogenic in animals or bacteria.

Dosage and Administration

For relaxation, 200 mg L-theanine can be taken 2-3 times daily. For cancer in conjunction with chemotherapy the dose is speculative, as no human studies have been performed. However, a dosage of 400-800 mg three times daily can be used safely.

References 1.

2. 3. 4.

5.

6.

7.

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Juneja LR, Chu D, Okubo T, et al. L-theanine – a unique amino acid of green tea and its relaxation effect in humans. Food Sci Tech 1999;10:199-204. Sakato Y. The chemical constituents of tea: III. A new amide theanine. Nippon Nogeikagaku Kaishi 1949;23:262-267. Unno T, Suzuki Y, Kakuda T, et al. Metabolism of theanine, a gamma-glutamylethylamide, in rats. J Agric Food Chem 1999;47:1593-1596. Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T. Effect of theanine, rglutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res 1998;23:667-673. Yokogoshi H, Mochizuki M, Saitoh K. Theanineinduced reduction of brain serotonin concentration in rats. Biosci Biotechnol Biochem 1998;62:816817. Ito K, Nagato Y, Aoi N, et al. Effects of Ltheanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikagaku Kaishi 1998;72:153-157. Sugiyama T, Sadzuka Y. Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents. Biochim Biophys Acta 2003;1653:47-59.

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Theanine 8.

9.

10.

11.

12.

Sadzuka Y, Sugiyama T, Suzuki T, Sonobe T. Enhancement of the activity of doxorubicin by inhibition of glutamate transporter. Toxicol Lett 2001;123:159-167. Sugiyama T, Sadzuka Y, Nagasawa R, et al. Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin. Jpn J Cancer Res 1999;90:775-780. Sugiyama T, Sadzuka Y. Theanine, a specific glutamate derivative in green tea, reduces the adverse reactions of doxorubicin by changing the glutathione level. Cancer Lett 2004;212:177-184. Yokozawa T, Dong E. Influence of green tea and its three major components upon lowdensity lipoprotein oxidation. Exp Toxicol Pathol 1997;49:329-335. Kakuda T, Nozawa A, Unno T, et al. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem 2000;64:287-293.

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13. 14.

15.

16.

Yokogoshi H, Kobayashi M. Hypotensive effect of gamma-glutamylmethylamide in spontaneously hypertensive rats. Life Sci 1998;62:1065-1068. Yokogoshi H, Kato Y, Sagesaka YM, et al. Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats. Biosci Biotechnol Biochem 1995;59:615-618. Sugiyama T, Sadzuka Y. Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma. Clin Cancer Res 1999;5:413-416. Sadzuka Y, Sugiyama T, Miyagishima A, et al. The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin. Cancer Lett 1996;105:203-209.

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L-Arginine

Monograph

HN H2N

CNH(CH2)3CH(NH2)COOH

L-Arginine Introduction

L-Arginine is a semi-essential amino acid involved in numerous areas of human physiology, including production of nitric oxide (NO) – a key messenger molecule involved in vascular regulation, immune activity, and endocrine function. Arginine is also involved in protein production, wound healing, erectile function, and fertility. Arginine is not considered essential because humans can synthesize it de novo from glutamine, glutamate, and proline. However, dietary intake remains the primary determinant of plasma arginine levels, since the rate of arginine biosynthesis does not compensate for depletion or inadequate supply.1,2 Arginine is the most abundant nitrogen carrier in humans, containing four nitrogen atoms per molecule. Arginine is not a major inter-organ nitrogen shuttle; instead, it plays an important role in nitrogen metabolism and ammonia detoxification as an intermediate in the urea cycle.3

Biochemistry

Arginine is synthesized in mammals from glutamine via pyrroline 5-carboxylate (P5C) synthase and proline oxidase in a multi-step metabolic conversion.4 In adults, most endogenous arginine is produced from citrulline, a by-product of glutamine metabolism in the gut and liver. Citrulline is released into the circulation and taken up primarily by the kidney for conversion into arginine.5 Supplemental arginine is readily absorbed.6 About 50-percent of ingested arginine is rapidly converted in the body to ornithine, primarily by the enzyme arginase.7 Because of this fast turnover, sustained-release preparations are being investigated as a way to maintain a steadier blood level over time. Ornithine, in turn, can be metabolized to glutamate and proline, or through the enzyme ornithine decarboxylase into the polyamine pathway for degradation into compounds such as putrescine and other polyamines. In addition, arginine is a precursor for the synthesis of nitric oxide, proteins, urea, creatine, vasopressin, and agmatine.8 Arginine that is not metabolized by arginase to ornithine is processed by one of four other enzymes: nitric oxide synthase (to become nitric oxide); arginine:glycine amidinotransferase (to become creatine); arginine decarboxylase (to become agmatine); or arginyl-tRNA synthetase (to become arginyl-tRNA, a precursor to protein synthesis). Arginine is also an allosteric activator of N-acetylglutamate synthase, which synthesizes N-acetylglutamate from glutamate and acetyl-CoA.9

Mechanisms of Action

Arginine is the biological precursor of nitric oxide (NO), an endogenous gaseous messenger molecule involved in a variety of endothelium-dependent physiological effects in the cardiovascular system.10 Much of arginineʼs influence on the cardiovascular system is due to endothelial NO synthesis, which results in vascular smooth muscle relaxation and subsequent vasodilation, as well as inhibition of monocyte adhesiveness, platelet aggregation, and smooth muscle proliferation. A great deal of research has explored the biological roles and properties of nitric oxide,11,12 which is also of critical importance in maintenance of normal blood pressure,13 myocardial function,14 inflammatory response,15 apoptosis,16 and protection against oxidative damage.17

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Arginine is a potent immunomodulator. Supplemental arginine appears to up-regulate immune function and reduce the incidence of postoperative infection. Significant decreases in cell adhesion molecules and pro-inflammatory cytokine levels have also been observed. Arginine supplementation (30 g/day for three days) has been shown to significantly enhance natural killer (NK) cell activity, lymphokineactivated killer cell cytotoxicity, and lymphocyte mitogenic reactivity in patients with locally advanced breast cancer.18,19 Arginine has significant effects on endocrine function – particularly adrenal and pituitary secretion – in humans and animals. Arginine administration can stimulate the release of catecholamines,20 insulin and glucagon,21 prolactin,22 and growth hormone (GH);23,24 however, little is known about the specific mechanism(s) by which arginine exerts these effects.

Clinical Indications Cardiovascular Conditions

Arginineʼs effects on cardiovascular function are due to arginine-induced endothelial NO production. Endothelial nitric oxide synthase (eNOS) catalyzes this reaction, which produces NO and ornithine. Nitric oxide diffuses into the underlying smooth muscle and stimulates guanylyl cyclase, producing guanosine-3ʼ,5ʼ-cyclic monophosphate (cGMP), which in turn causes muscle relaxation and vasodilation. Arginine supplementation has been shown to increase flow-mediated brachial artery dilation in normal individuals as well as those with hyperlipidemia and hypertension.25,26 Nitric oxide is also responsible for creating an environment in the endothelium that is anti-atherogenic. Adequate NO production inhibits processes at the core of the atherosclerotic lesion, including platelet aggregation, monocyte adhesion and migration, smooth muscle proliferation, and vasoconstriction. Asymmetrical dimethylarginine (ADMA) competes with arginine for binding with eNOS, subsequently down-regulating activity of this vital enzyme. Increased plasma ADMA has been shown to be an independent risk factor for cardiovascular disease because of its inhibitory activity on eNOS. Oral arginine supplementation overrides the inhibitory effect

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of ADMA on eNOS, and improves vascular function in those with high ADMA levels.27-29

Angina Pectoris

Arginine supplementation has been effective in angina treatment in some, but not all, clinical trials. In 36 patients with chronic, stable angina given 6 g arginine daily for two weeks, significant improvement was noted in flow-mediated vasodilation, exercise time, and quality of life, compared to placebo. No improvement was seen in ischemia markers on ECG or in time-to-onset of angina.30 In a small, uncontrolled trial, seven of 10 people with intractable angina improved dramatically after taking 9 g arginine daily for three months.31 A double-blind trial in 22 patients with stable angina and healed myocardial infarction showed oral supplementation with 6 g arginine daily for three days increased exercise capacity.32 However, in men with stable angina, oral supplementation with arginine (15 g/day) for two weeks was not associated with improvement in endothelium-dependent vasodilation, oxidative stress, or exercise performance.33 In patients with coronary artery disease, oral supplementation of arginine (6 g/day for three days) did not affect exercise-induced changes in QT interval duration, QT dispersion, or the magnitude of ST-segment depression;34 however, it did significantly increase exercise tolerance. The therapeutic effect of arginine in patients with microvascular angina is considered to be the result of improved endothelium-dependent coronary vasodilation.35

Congestive Heart Failure

Six weeks of oral arginine supplementation (5.6-12.6 g/d) significantly improved blood flow, arterial compliance, and functional status in patients with congestive heart failure (CHF), compared to placebo, in a randomized, double-blind trial.36 Another double-blind trial found arginine supplementation (5 g three times daily) improved renal function in people with CHF.37 After a one-week oral dosing with 6 g arginine daily in 30 males with stable CHF, significant improvements were seen in exercise duration, anaerobic threshold, and VO2.38 African Americans are at significantly greater risk for development of CHF than Caucasians. However, the improvement

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in endothelial function seen with arginine dosing may be more pronounced in African Americans compared to Caucasians, as was seen in a study of 52 CHF patients treated with an intra-coronary infusion of arginine.39

Hypertension

Administration of arginine prevented hypertension in salt-sensitive rats, but not in spontaneously hypertensive rats.40 If arginine was provided early, hypertension and renal failure could be prevented. In healthy human subjects, intravenous (IV) administration of arginine had vasodilatory and antihypertensive effects.41 In a small, controlled trial, hypertensive patients refractory to enalapril and hydrochlorothiazide responded favorably to the addition of oral arginine (2 g three times daily).42 Small, preliminary trials have found oral43 and IV44 arginine significantly lowers blood pressure in healthy volunteers. IV infusion of arginine (15 mg/kg body weight/min for 35 min) improved pulmonary vascular resistance index and cardiac output in infants with pulmonary hypertension.45

Intermittent Claudication

Intravenous arginine injections significantly improved symptoms of intermittent claudication in a double-blind trial. Eight grams of arginine, infused twice daily for three weeks, improved pain-free walking distance by 230 ± 63 percent and the absolute walking distance by 155 ± 48 percent (each p < 0.05) compared to no improvement with placebo.46

Preeclampsia

Endothelial dysfunction appears to be involved in the pathogenesis of preeclampsia.47 In an animal model of experimental preeclampsia, IV administration of arginine (0.16 g/kg body weight/day) from gestational day 10 until term reversed hypertension, intrauterine growth retardation, proteinuria, and renal injury.48 Intravenous infusion of arginine (30 g) in preeclamptic women has reportedly increased systemic NO production and reduced blood pressure.49

Human Immunodeficiency Virus (HIV) Infection and Acquired Immunodeficiency Syndrome (AIDS)

Arginine may be of benefit in individuals with HIV/AIDS. In a small pilot study of arginine supplementation in individuals with HIV, 11 patients were given 19.6 g/day arginine or placebo for 14 days. NKcell cytotoxicity increased 18.9 lytic units, compared to an increase of 0.3 lytic units with placebo. This was not statistically significant, most likely due to the small number of patients in the study.50 A combination of glutamine, arginine, and hydroxymethylbutyrate (HMB) may prevent loss of lean body mass in individuals with AIDS cachexia. In a double-blind trial, AIDS patients with documented weight loss of at least five percent in the previous three months received either placebo or a combination of 3 g HMB, 14 g L-glutamine, and 14 g arginine given in two divided doses daily for eight weeks. At eight weeks, subjects consuming the mixture gained 3.0 ± 0.5 kg, while those supplemented with placebo gained only 0.37 ± 0.84 kg (p = 0.009). The weight gain in the supplemented group was predominately lean muscle mass, while the placebo group lost lean mass.51 A six-month, randomized, double-blind trial of an arginine/essential fatty acid combination was undertaken in patients with HIV.52 Patients received a daily oral nutritional supplement (606 kcal supplemented with vitamins, minerals, and trace elements). In addition, half of the patients were randomized to receive 7.4 g arginine plus 1.7 g omega-3 fatty acids daily. Body weight increased similarly in both groups, and there was no change in immunological parameters. Clinical trials evaluating the effect of arginine as monotherapy for AIDS patients have yet to be conducted.

Growth Hormone Secretion and Athletic Performance

In rats, NO stimulates secretion of GH-releasing hormone (GHRH), thereby increasing secretion of GH. However, GHRH then increases production of NO in somatotroph cells, which subsequently inhibits GH secretion. In humans, arginine stimulates release of GH from the pituitary gland in some populations,

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but the mechanism is not well understood. Most studies suggest inhibition of somatostatin secretion is responsible for the effect.53 At high doses (approximately 250 mg/kg body weight), arginine aspartate increased GH secretion,53 an effect of interest to body builders wishing to take advantage of the anabolic properties of the hormone.54 In a controlled clinical trial, arginine and ornithine (500 mg of each, twice daily, five times per week) produced a significant decrease in body fat when combined with exercise.55 Acute dosing of arginine (5 g taken 30 minutes before exercise) did not increase GH secretion, and may have impaired release of GH in young adults.56 Longer-term, lowdose supplementation of arginine and ornithine (1 g each, five days per week for five weeks) resulted in higher gains in strength and enhancement of lean body mass, compared with controls receiving vitamin C and calcium.57 Growth hormone has been observed to be lower in older males than young men; however, data suggest oral arginine/lysine (3 g each daily) is not a practical means of enhancing long-term GH secretion in older men.58

Burns and Critical Trauma

Burn injuries significantly increase arginine oxidation and can result in depletion of arginine reserves. Total parenteral nutrition (TPN) increases conversion of arginine to ornithine and proportionally increases irreversible arginine oxidation, which, coupled with limited de novo synthesis from its immediate precursors, makes arginine conditionally essential in severely burned patients receiving TPN.59 Several trials have demonstrated reduced length of hospital stay, fewer acquired infections, and improved immune function among burn60 and trauma61 patients supplemented with various combinations of fish or canola oil, nucleotides, and arginine.

Cancer

Animal research has shown large doses of arginine may interfere with tumor induction.62 Short-term arginine supplementation may assist in maintenance of immune function during chemotherapy. Arginine supplementation (30 g/day for three Page 142

days) reduced chemotherapy-induced suppression of lymphokine-activated killer cell cytotoxicity and lymphocyte mitogenic reactivity in patients with locally advanced breast cancer.18,19 In another study, arginine supplementation (30 g/day for three days prior to surgery) significantly enhanced the activity of tumor-infiltrating lymphocytes in human colorectal cancers in vivo.63 Arginine, RNA, and fish oil have been combined to improve immune function in cancer patients.64-66 On the other hand, arginine has also promoted cancer growth in animal and human research.67 Polyamines act as growth factors for cancers. In several types of cancer, drugs are being investigated to inhibit ornithine decarboxylase (ODC), and hence inhibit polyamine formation. The possibility of arginine stimulating polyamine formation might be a concern in chronic administration, since both arginase and ODC appear to be up-regulated in some cancers.

Diabetes and Insulin Resistance Syndrome

Endothelium-dependent vascular relaxation is impaired in type 1 and type 2 diabetes mellitus (DM), and endothelial NO deficiency is a likely explanation.68 Diabetes is associated with reduced plasma levels of arginine,69 and evidence suggests arginine supplementation may be an effective way to improve endothelial function in individuals with diabetes. An IV bolus of 3-5 g arginine reduced blood pressure and platelet aggregation in patients with type 1 diabetes.70 Low-dose IV arginine improved insulin sensitivity in obese patients and type 2 DM patients as well as in healthy subjects.71 Arginine may also counteract lipid peroxidation and thereby reduce microangiopathic long-term complications of DM.72 After one week of oral arginine supplementation (9 g daily), 10 women with type 2 DM showed significant improvement in endothelial function, noted by a 50-percent increase in flow-mediated brachial dilation.73 A double-blind trial found oral arginine supplementation (3 g three times daily) significantly improved, but did not completely normalize, peripheral and hepatic insulin sensitivity in patients with type 2 diabetes.74 In young patients with type 1 DM,

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however, oral arginine (7 g twice daily for six weeks) failed to improve endothelial function.75

Gastrointestinal Conditions Gastritis and Ulcer

Preliminary evidence suggests arginine accelerates ulcer healing due to its hyperemic, angiogenic, and growth-promoting actions, possibly involving NO, gastrin, and polyamines.76,77 No clinical trials have yet explored the efficacy of arginine supplementation as a treatment for gastritis or peptic ulcer in humans.

Gastroesophageal Reflux (GERD) and Sphincter Motility Disorders

A small, double-blind trial found oral arginine supplementation significantly decreased the frequency and intensity of chest pain attacks, as well as the number of nitroglycerin tablets taken for analgesia, in patients with esophageal motility disorders.78 However, in another study, arginine infusions (500 mg/kg body weight/120 min) failed to affect lower esophageal sphincter motility.79 No studies have yet explored the efficacy of arginine supplements for GERD.

Genitourinary Conditions Erectile Dysfunction (ED)

In a small, uncontrolled trial, men with ED were given 2.8 g arginine daily for two weeks. Forty percent of men in the treatment group experienced improvement, compared to none in the placebo group.80 In a larger double-blind trial, men with ED were given 1,670 mg arginine daily or a matching placebo for six weeks.81 Arginine supplementation was effective at improving ED in men with abnormal nitric oxide metabolism. However, another double-blind trial of arginine for ED (500 mg three times daily for 17 days) found the amino acid no more effective than placebo.82

Infertility, Female

Supplementation with oral arginine (16 g/ day) in poor responders to in vitro fertilization improved ovarian response, endometrial receptivity, and pregnancy rate in one study.83

Infertility, Male

Arginine is required for normal spermatogenesis. Over 50 years ago, researchers found that feeding an arginine-deficient diet to adult men for nine days decreased sperm counts by approximately 90 percent and increased the percentage of non-motile sperm approximately 10-fold.84 Oral administration of 500 mg arginine-HCl per day to infertile men for 6-8 weeks markedly increased sperm count and motility in a majority of patients, and resulted in successful pregnancies.85 Similar effects on oligospermia and conception rates have been reported in other preliminary trials.86-89 However, when baseline sperm counts were less than 10 million/mL, arginine supplementation produced little or no improvement.90,91

Interstitial Cystitis (IC)

In an uncontrolled trial, 10 patients with IC took 1.5 g arginine daily for six months. Supplementation resulted in a significant decrease in urinary voiding discomfort, lower abdominal pain, and vaginal/urethral pain. Urinary frequency during the day and night also significantly decreased.92 In a fiveweek uncontrolled trial, however, arginine supplementation was not effective, even at higher doses of 3-10 g daily.93 In a randomized, double-blind trial of arginine for IC, patients took 1.5 g arginine daily for three months. Twenty-nine percent of patients in the arginine group and eight percent in the placebo group experienced clinical improvement (i.e., decreased pain and urgency) by the end of the trial (p = 0.07). The results fell short of statistical significance, most likely because of the small sample size (n = 53).

Perioperative Nutrition

Arginine is a potent immunomodulator. Evidence is mounting for a beneficial effect of arginine supplementation in catabolic conditions such as sepsis and postoperative stress. Supplemental arginine appears to up-regulate immune function and reduce the incidence of postoperative infection.94 Two controlled trials have demonstrated increased lymphocyte mitogenesis and improved wound healing in experimental surgical wounds in volunteers given 17-25 g oral arginine daily.95,96 Similar results have been obtained in healthy elderly volunteers.97

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Preterm Labor and Delivery

Evidence from human and animal studies indicates nitric oxide inhibits uterine contractility and may help maintain uterine quiescence during pregnancy.98 IV arginine infusion (30 g over 30 min) in women with premature uterine contractions transiently reduced uterine contractility.99 Further research is needed to confirm the efficacy and safety of arginine in prevention of preterm delivery.

Senile Dementia

Arginine (1.6 g/day) in 16 elderly patients with senile dementia reduced lipid peroxidation and increased cognitive function.100

Side Effects and Toxicity

Significant adverse effects have not been observed with arginine supplementation. People with renal failure or hepatic disease may be unable to appropriately metabolize and excrete supplemental arginine and should be closely monitored when taking arginine supplements.

asthma has been proposed.102 Airway obstruction in asthma might be associated with endogenous NO deficiency caused by limited availability of NO synthase substrate (i.e., arginine). However, oral arginine (50 mg/kg body weight) in asthmatic patients triggered by a histamine challenge produced only a marginal, statistically insignificant improvement of airway hyper-responsiveness to histamine.103 In fact, it is unclear whether NO acts as a protective or a stimulatory factor in airway hyper-responsiveness. Since polyamines act as growth factors for cancers, and arginine may stimulate polyamine synthesis, chronic administration of arginine in cancer patients should probably be avoided until information arises regarding the safety of this practice.

References 1.

2. 3.

Dosage

Doses of arginine used in clinical research have varied considerably, from as little as 500 mg/day for oligospermia to as much as 30 g/day for cancer, preeclampsia, and premature uterine contractions. Typical daily doses fall into either the 1-3 g or 7-15 g range, depending on the condition being treated. Because of the pharmacokinetics of L-arginine, use of a sustained-release preparation may be preferable, in order to keep blood levels more constant over time.

Warnings and Contraindications

5. 6.

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It has been postulated, on the basis of older in vitro data101 and anecdotal reporting, that arginine supplementation might be contraindicated in persons with herpes infections (i.e., cold sores, genital herpes). The assumption is that arginine might stimulate replication of the virus and/or provoke an outbreak; however, this caution has not been validated by controlled clinical trials. Bronchoconstriction is reportedly inhibited by the formation of NO in the airways of asthmatic patients, and a bronchoprotective effect of NO in Page 144

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Yu YM, Ryan CM, Castillo L, et al. Arginine and ornithine kinetics in severely burned patients: increased rate of arginine disposal. Am J Physiol Endocrinol Metab 2001;280:E509-E517. Bower RH, Cerra FB, Bershadsky B, et al. Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized clinical trial. Crit Care Med 1995;23:436-439. Weimann A, Bastian L, Bischoff WE, et al. Influence of arginine, omega-3 fatty acids and nucleotide-supplemented enteral support on systemic inflammatory response syndrome and multiple organ failure in patients after severe trauma. Nutrition 1998;14:165-172. Takeda Y, Tominga T, Tei N, et al. Inhibitory effect of L-arginine on growth of rat mammary tumors induced by 7, 12, dimethlybenz(a)anthracine. Cancer Res 1975;35:390-393. Heys SD, Segar A, Payne S, et al. Dietary supplementation with L-arginine: modulation of tumour-infiltrating lymphocytes in patients with colorectal cancer. Br J Surg 1997;84:238-241. Kemen M, Senkal M, Homann HH, et al. Early postoperative enteral nutrition with arginineomega-3 fatty acids and ribonucleic acidsupplemented diet versus placebo in cancer patients: an immunologic evaluation of Impact. Crit Care Med 1995;23:652-659. Gianotti L, Braga M, Fortis C, et al. A prospective, randomized clinical trial on perioperative feeding with an arginine-, omega-3 fatty acid-, and RNAenriched enteral diet: effect on host response and nutritional status. JPEN J Parenter Enteral Nutr 1999;23:314-320. van Bokhorst-De Van Der Schueren MA, Quak JJ, von Blomberg-van der Flier BM, et al. Effect of perioperative nutrition, with and without arginine supplementation, on nutritional status, immune function, postoperative morbidity, and survival in severely malnourished head and neck cancer patients. Am J Clin Nutr 2001;73:323-332. Park KGM. The Sir David Cuthbertson Medal Lecture 1992. The immunological and metabolic effects of L-arginine in human cancer. Proc Nutr Soc 1993;52:387-401. Pieper GM. Review of alterations in endothelial nitric oxide production in diabetes. Hypertension 1998;31:1047-1060. Pieper GM, Siebeneich W, Dondlinger LA. Shortterm oral administration of L-arginine reverses defective endothelium-dependent relaxation and cGMP generation in diabetes. Eur J Pharmacol 1996;317:317-320. Giugliano D, Marfella R, Verrazzo G, et al. L-arginine for testing endothelium-dependent vascular functions in health and disease. Am J Physiol 1997;273:E606-E612.

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71.

72. 73.

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75.

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77.

78.

79.

80. 81.

82.

83.

84. 85.

Wascher TC, Graier WF, Dittrich P, et al. Effects of low-dose L-arginine on insulin-mediated vasodilatation and insulin sensitivity. Eur J Clin Invest 1997;27:690-695. Lubec B, Hayn M, Kitzmuller E, et al. L-arginine reduces lipid peroxidation in patients with diabetes mellitus. Free Radic Biol Med 1997;22:355-357. Regensteiner JG, Popylisen S, Bauer TA, et al. Oral l-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes. Vasc Med 2003; 8:169-175. Piatti PM, Monti LD, Valsecchi G, et al. Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 2001;24:875-880. Mullen MJ, Wright D, Donald AE, et al. Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study. J Am Coll Cardiol 2000;36:410-416. Brzozowski T, Konturek SJ, Sliwowski Z, et al. Role of L-arginine, a substrate for nitric oxidesynthase, in gastroprotection and ulcer healing. J Gastroenterol 1997;32:442-452. Brzozowski T, Konturek SJ, Drozdowicz D, et al. Healing of chronic gastric ulcerations by Larginine. Role of nitric oxide, prostaglandins, gastrin and polyamines. Digestion 1995;56:463471. Bortolotti M, Brunelli F, Sarti P, Miglioli M. Clinical and manometric effects of L-arginine in patients with chest pain and oesophageal motor disorders. Ital J Gastroenterol Hepatol 1997;29:320-324. Straathof JW, Adamse M, Onkenhout W, et al. Effect of L-arginine on lower oesophageal sphincter motility in man. Eur J Gastroenterol Hepatol 2000;12:419-424. Zorgniotti AW, Lizza EF. Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dysfunction. Int J Impot Res 1994;6:33-36. Chen J, Wollman Y, Chernichovsky T, et al. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized study. BJU Int 1999;83:269-273. Klotz T, Mathers MJ, Braun M, et al. Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int 1999;63:220-223. Battaglia C, Salvatori M, Maxia N, et al. Adjuvant L-arginine treatment for in vitro fertilization in poor responder patients. Hum Reprod 1999;14:16901697. Holt LE Jr, Albanese AA. Observations on amino acid deficiencies in man. Trans Assoc Am Physicians 1944;58:143-156. Tanimura J. Studies on arginine in human semen. Part II. The effects of medication with L-arginineHCl on male infertility. Bull Osaka Med School 1967;13:84-89.

86. 87. 88. 89. 90. 91. 92.

93.

94. 95.

96. 97. 98.

99. 100. 101. 102.

103.

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De Aloysio D, Mantuano R, Mauloni M, Nicoletti G. The clinical use of arginine aspartate in male infertility. Acta Eur Fertil 1982;13:133-167. Scibona M, Meschini P, Capparelli S, et al. Larginine and male infertility. Minerva Urol Nefrol 1994;46:251-253. Schacter A, Goldman JA, Zukerman Z. Treatment of oligospermia with the amino acid arginine. J Urol 1973;110:311-313. Schacter A, Friedman S, Goldman JA, Eckerling B. Treatment of oligospermia with the amino acid arginine. Int J Gynaecol Obstet 1973;11:206-209. Pryor JP, Blandy JP, Evans P, et al. Controlled clinical trial of arginine for infertile men with oligozoospermia. Br J Urol 1978;50:47-50. Mroueh A. Effect of arginine on oligospermia. Fertil Steril 1970;21:217-219. Smith SD, Wheeler MA, Foster HE Jr, Weiss RM. Improvement in interstitial cystitis symptom scores during treatment with oral L-arginine. J Urol 1997;158:703-708. Ehren I, Lundberg JO, Adolfsson J. Effects of Larginine treatment on symptoms and bladder nitric oxide levels in patients with interstitial cystitis. Urology 1998;52:1026-1029. Evoy D, Lieberman MD, Fahey TJ 3rd, Daly JM. Immunonutrition: the role of arginine. Nutrition 1998;14:611-617. Barbul A, Rettura G, Levenson SM, et al. Wound healing and thymotropic effects of arginine: a pituitary mechanism of action. Am J Clin Nutr 1983;37:786-794. Barbul A, Lazarou SA, Efron DT, et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990;108:331-337. Kirk SJ, Hurson M, Regan MC, et al. Arginine stimulates wound healing and immune function in elderly human beings. Surgery 1993;114:155-160. Buhimschi IA, Saade GR, Chwalisz K, Garfield RE. The nitric oxide pathway in pre-eclampsia: pathophysiological implications. Human Reprod Update 1998;4:25-42. Facchinetti F, Neri I, Genazzani AR. L-arginine infusion reduces preterm uterine contractions. J Perinat Med 1996;24:283-285. Ohtsuka Y, Nakaya J. Effect of oral administration of L-arginine on senile dementia. Am J Med 2000;108:439. Tankersley RW. Amino acid requirements of herpes simplex virus in human cells. J Bacteriol 1964;87:609-613. Ricciardolo FL, Geppetti P, Mistretta A, et al. Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma. Lancet 1996;348:374-377. de Gouw HW, Verbruggen MB, Twiss IM, Sterk PJ. Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma. Thorax 1999;54:1033-1035.

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Folic Acid

N

H2N dihydropteridine

Monograph

N

N N O

CH2 N

paba

COO C O

N

C

H

CH2

H

CH2

glutamate

Folic Acid

COO

Introduction

Folic acid, also known generically as folate or folacin, is a member of the B-complex family of vitamins, and works in concert with vitamin B12. Folic acid functions primarily as a methyl-group donor involved in many important body processes, including DNA synthesis. Therapeutically, folic acid is instrumental in reducing homocysteine levels and the occurrence of neural tube defects. It may play a key role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis. Folic acid also shows promise as part of a nutritional protocol to treat vitiligo, and may reduce inflammation of the gingiva. Furthermore, certain neurological, cognitive, and psychiatric presentations may be secondary to folate deficiency. Such presentations include peripheral neuropathy, myelopathy, restless legs syndrome, insomnia, dementia, forgetfulness, irritability, endogenous depression, organic psychosis, and schizophrenia-like syndromes.

Biochemistry

Folic acid is a water-soluble member of the B-complex family of vitamins. Folic acid is composed of three primary structures, a hetero-bicyclic pteridine ring, para-aminobenzoic acid (PABA), and glutamic acid. Because humans cannot synthesize this compound, it is a dietary requirement. Although folic acid is the primary form of folate used in dietary supplements or fortified foods, it comprises only 10 percent or less of folates in the diet. Dietary folic acid, or the form naturally found in foods, is actually a complex and variable mixture of folate compounds, such as polyglutamate (multiple glutamate molecules attached) conjugate compounds, reduced folates, and tetrahydrofolates. Although folates are abundant in the diet, cooking or processing destroys these compounds. The best folate sources in foods are green, leafy vegetables; sprouts, fruits, brewer’s yeast, liver, and kidney also contain high amounts of folates.

Pharmacokinetics

Human pharmacokinetic studies indicate folic acid has very high bioavailability, with large oral doses of folic acid substantially raising plasma levels in healthy subjects in a time- and dose-dependent manner. Subsequent to high-dose oral administration of folic acid (ranging from 25-1,000 mg/day), red blood cell (RBC) folate levels remain elevated for periods in excess of 40 days following discontinuation of the supplement. Folic acid is poorly transported to the brain and rapidly cleared from the central nervous system. The primary methods of elimination of absorbed folic acid are fecal (through bile) and urinary.1-4 Page 222

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After ingestion, the process of conversion of folic acid to the metabolically active coenzyme forms is relatively complex. Synthesis of the active forms of folic acid requires several enzymes, adequate liver and intestinal function, and adequate supplies of riboflavin (B2), niacin (B3), pyridoxine (B6), zinc, vitamin C, and serine. After the formation of the coenzyme forms of the vitamin in the liver, these metabolically active compounds are secreted into the small intestine with bile (the folate enterohepatic cycle), where they are reabsorbed and distributed to tissues throughout the body. Despite the biochemical complexity of this process, evidence suggests oral supplementation with folic acid is able to increase the body’s pool of the active reduced folate metabolites (such as methyl­ tetrahydrofolate) in healthy individuals.5 Enzyme defects, malabsorption or digestive system pathology, and liver disease can result in impaired ability to activate folic acid to the required coenzyme forms in the body. Evidence indicates some individuals have a severe congenital deficiency of the enzyme methyltetrahydrofolate reductase, which is needed to convert folic acid to the 5-methyl­ tetrahydrofolate coenzyme form of the vitamin. The existence of milder forms of this enzyme defect is strongly suspected and likely interacts with dietary folate status to determine risk for some disease conditions.6-10 In individuals with a genetic defect of this enzyme (whether mild or severe), greater dietary exposure to foods rich in folates and supplemental folates in the form of folinic acid or 5-methyltetrahydrofolate might be preferable to folic acid supplementation.

Mechanisms of Action

Folic acid’s primary mechanisms of action are through its role as a methyl donor in a range of metabolic and nervous system biochemical processes, as well as being necessary for DNA synthesis. Serine reacts with tetrahydrofolate, forming 5,10methylenetetrahydrofolate, the folate derivative involved in DNA synthesis. A methyl group is donated to cobalamin (B12) by 5-methyltetrahydrofolate, forming methylcobalamin. With the help of the enzyme methionine synthase, methylcobalamin donates a methyl group to the amino acid metabolite homocysteine, converting it to the amino acid methionine.

Methionine subsequently is converted to S-adenosylmethionine (SAMe), a methyl donor involved in numerous biochemical processes.

Deficiency States and Symptoms

Folic acid deficiency is considered to be one of the most common nutritional deficiencies. The following may contribute to a deficiency of folic acid: deficient food supply; defects in utilization, as in alcoholics or individuals with liver disease; malabsorption; increased needs in pregnant women, nursing mothers, and cancer patients; metabolic interference by drugs; folate losses in hemodialysis; and deficiencies in enzymes or cofactors needed for the generation of active folic acid.11 Absorption of folic acid appears to be significantly impaired in HIV disease, irrespective of the stage of the disease.12 Signs and symptoms of folate deficiency include macrocytic anemia, fatigue, irritability, peripheral neuropathy, tendon hyper-reflexivity, restless legs syndrome, diarrhea, weight loss, insomnia, depression, dementia, cognitive disturbances, and psychiatric disorders.13-18 Elevated plasma homocysteine can also indicate a dietary or functional deficiency of folic acid.

Clinical Indications Anemia

Folic acid has a long history of use in conjunction with vitamin B12 for the treatment of macrocytic anemia. Depending on the clinical status of the patient, the dose of folic acid required to reverse macrocytic anemia varies, but the therapeutic dose is usually 1 mg daily. Duration of therapy to reverse macrocytic anemia can be as short as 15 days after initiation of supplementation, or it may require prolonged supplementation.

Cervical Dysplasia

Research points to an association between folate status in adults and cervical dysplasia;19-21 however, its role as an efficacious therapeutic intervention is unclear. One report suggests folic acid supplementation (10 mg folic acid for three months) reverses cervical dysplasia in women taking oral contraceptives.22 In another study, 154 individuals with grade 1

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or 2 cervical intraepithelial neoplasia were randomly assigned either 10 mg folic acid or placebo daily for six months. No significant differences were observed between supplemented and unsupplemented subjects regarding dysplasia status, biopsy results, or prevalence of human papilloma virus type-16 infection.23 It is possible certain subsets of women (perhaps those with an oral contraceptive-induced deficiency) might be more amenable to treatment; however, additional research is required to clarify the therapeutic role of folic acid in cervical dysplasia.

Gout

There is no evidence demonstrating efficacy of folic acid supplementation in gout. Although some in vitro evidence suggests folate compounds are potent inhibitors of xanthine oxidase activity,24 it appears pterin aldehyde, a photolytic breakdown product of folic acid, and not folic acid itself, is responsible for the observed inactivation of xanthine oxidase.25 Available evidence has shown no ability of supplemental folic acid in oral daily doses up to 1,000 mg to significantly lower serum urate concentration, or to decrease urinary urate or total oxypurine excretion in hyperuricemic subjects.26

Homocysteinemia

An abnormally high plasma level of homocysteine, the de-methylated derivative of the amino acid methionine, is an independent risk factor for cardiovascular disease. Elevated plasma homocysteine has been connected to increased risk of neural tube defects and other birth defects, as well as to schizophrenia, Alzheimer’s disease, cognitive decline, osteoporosis, rheumatoid arthritis, kidney failure, and cancer.27-31 The activated coenzyme form of folic acid (5-methyltetrahydrofolate) is needed for optimal homocysteine metabolism, since it acts as a methyl donor, providing a methyl group to vitamin B12. The methylated form of vitamin B12 (methylcobalamin) subsequently transfers this methyl group to homocysteine. The result is a recycling of homocysteine to methionine, resulting in reduction in elevated plasma homocysteine. In healthy subjects even low doses of folic acid can lower homocysteine levels. A dose of 250 Page 224

mcg daily for four weeks reduced homocysteine an average of 11.4 percent in healthy 18- to 40-year-old women. A dose of 500 mcg daily for the same duration reduced levels an average of 22 percent.32 In a separate study, 650 mcg daily for six weeks resulted in an average plasma homocysteine reduction of 41.7 percent.33 In subjects with cardiovascular disease, 800 mcg folic acid daily resulted in an average decrease in homocysteine levels of 23 percent,27 while 2.5 mg daily resulted in an average decrease of 27 percent.34 In subjects receiving the higher dose, 94 percent experienced some degree of reduction in homocysteine.28 Evidence suggests individuals with higher initial homocysteine levels are likely to experience a greater reduction following folic acid supplementation.34 In addition to helping reduce blood levels of homocysteine, folic acid may also aid peripheral blood flow by increasing nitric oxide (NO) in vascular endothelial cells. Impaired endothelial NO activity is an early marker for cardiovascular disease, particularly atherosclerosis. In fact, most of the risk factors for atherosclerosis are associated with poor vasodilation due to insufficient NO production. Chronic, unopposed exposure of the vascular endothelium to homocysteine compromises the production of adequate amounts of NO, which leads to injury of the endothelial lining and the initiation/exacerbation of atherosclerosis and/or thrombus formation. Folic acid appears to improve NO synthesis by reducing plasma homocysteine levels, enhancing the availability of key endothelial NO cofactors, and reducing the production of superoxide anions, the net effect of which is improvement of peripheral blood flow.35,36 In a recent doubled-blind, placebo-controlled, crossover study of individuals with coronary heart disease, researchers found supplementation with high-dose folic acid (30 mg per day) improved blood flow to the heart muscle via the coronary arteries. Using positron emission tomography (PET scanning), researchers at Massachusetts General Hospital noted significant improvement in coronary blood flow with folic acid supplementation compared to placebo. The improvement was especially enhanced in areas of the heart that had shown reduced blood flow prior to supplementation. Folic acid supplementation also significantly lowered the study participants’ blood

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pressure. The findings from this high-dose folate study demonstrate another significant way this nutrient benefits the cardiovascular system.37 Although excellent results have been achieved with folic acid monotherapy, available evidence suggests an additive effect exists between folic acid and vitamins B6, B12, and betaine with respect to lowering homocysteine levels. Combinations of these nutrients typically produce greater reductions in homocysteine than does folic acid alone.27-29,38 Furthermore, the addition of vitamin C, L-arginine, tetrahydrobiopterin (BH4), and polyunsaturated fatty acids (PUFAs) has been suggested as a means of enhancing the effect of folic acid on endothelial NO production.35

Inflammatory Bowel Disease

Patients with inflammatory bowel disease (IBD) often have folate deficiencies, caused in part by the drug sulfasalazine, prescribed for IBD but also known to inhibit folate absorption.39 Evidence suggests folic acid supplementation might lower the risk, in a dose-dependent fashion, of colonic neoplasia in patients with ulcerative colitis. A review of 99 ulcerative colitis (UC) patient records found folic acid supplementation was associated with a 62-percent decreased risk of neoplasia compared to patients not taking folate supplements.39 In another similar study, the files of 98 UC patients disclosed dose-dependent protection from neoplasia by folic acid. The relative risk of developing neoplasia was 0.76 for 400 mcg folate and 0.54 for those taking 1 mg folate for at least six months compared to those not supplemented.40

Neuropsychiatric Applications

Neuropsychiatric diseases encompass a number of neurological, cognitive, and psychiatric presentations that may be secondary to folate deficiency. Such presentations include dementia, schizophrenialike syndromes, insomnia, irritability, forgetfulness, endogenous depression, organic psychosis, peripheral neuropathy, myelopathy, and restless legs syndrome.14-18 Lower serum and RBC folate concentrations have an association with depression, and deficiency might predict a poorer response to some antidepressant medications.30,41-47 Several studies have documented improvement in depression in some patients

subsequent to oral supplementation with the coenzyme form of folic acid (methyltetrahydrofolate) at doses of 15-50 mg daily.48,49 Folic acid (500 mcg per day) significantly improved the antidepressant action of fluoxetine in subjects with major depression.50 Limited evidence implies supplemental folic acid might positively affect morbidity of some bipolar patients placed on lithium therapy.51 A syndrome characterized by mild depression, permanent muscular and intellectual fatigue, mild symptoms of restless legs, depressed ankle jerk reflexes, diminution of vibration sensation in the legs, stocking-type hypoesthesia, and long-lasting constipation appears to respond to folic acid supplementation (5-10 mg per day for 6-12 months).52

Periodontal Disease

Folic acid can increase the resistance of the gingiva to local irritants and lead to a reduction in inflammation. A mouthwash containing 5 mg folate per 5 mL of mouthwash used twice daily for four weeks, with a rinsing time of one minute, appears to be the most effective manner of application. The effect of folate on gingival health appears to be moderated largely, if not totally, through a local influence.53-54

Pregnancy

Low dietary intake of folic acid increases the risk for delivery of a child with a neural tube defect (NTD). Periconceptional folic acid supplementation significantly reduces the occurrence of NTD.56-62 Supplemental folic acid intake during pregnancy results in increased infant birth weight and improved Apgar scores, along with a concomitant decreased incidence of fetal growth retardation and maternal infections.63-65

Vitiligo

In some individuals, administration of folic acid appears to be a rational aspect of a nutritional protocol to treat vitiligo. Degrees of re-pigmentation ranging from complete re-pigmentation in six subjects and 80-percent re-pigmentation in two subjects were reported in eight individuals who followed a threeyear protocol with a dosage of 2 mg folic acid twice daily, 500 mg vitamin C twice daily, and intramuscular injections of vitamin B12 every two weeks.66

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A two-year study using a combination of folic acid, vitamin B12, and sun exposure for treatment of vitiligo reported positive results. One hundred patients with vitiligo were treated, with re-pigmentation occurring in 52 subjects. Total re-pigmentation was seen in six patients and the spread of vitiligo was halted in 64 percent of the patients. Re-pigmentation was most evident on sun-exposed areas.67

Drug-Nutrient Interactions

A number of drugs can interfere with the pharmacokinetics of folic acid. Cimetidine and antacids appear to reduce folate absorption.68 Sulfasalazine interferes with folic acid absorption and conversion to the active form.69 Supplementation with folic acid (15 mg/day for one month) prevents folate deficiency in patients with inflammatory bowel disease treated with sulfasalazine.70 Continuous long-term use of acetaminophen and aspirin, ibuprofen, and other non-steroidal antiinflammatory drugs appears to increase the body’s need for folic acid.69 Although the mechanism is unclear, anticonvulsants, antituberculosis drugs, alcohol, and oral contraceptives produce low serum and tissue concentrations of folate.69,71 Folic acid reduces elevated liver enzymes induced by methotrexate therapy in rheumatoid arthritis; however, it had no effect on the incidence, severity, and duration of other adverse events.72 Folic acid supplementation prevents nitric oxide synthase dysfunction induced by continuous nitroglycerin use.73 Anti-seizure medications, including carbamazepine and phenobarbital, appear to utilize folic acid during hepatic metabolism. Folic acid supplementation can increase metabolism of these drugs, thus lowering blood levels of the drugs and possibly resulting in breakthrough seizures. Initiating folic acid therapy after starting these drugs in individuals should be done with caution.74 The anticonvulsant drugs phenytoin and valproic acid appear to interfere with folate absorption.75 Folic acid supplementation, at a time of day other than when taking an anticonvulsant, may be helpful to prevent deficiency. Page 226

There is conflicting information regarding the effects of folate supplementation in individuals treated with antifolate medications such as methotrexate (MTX) and 5-fluorouracil (5-FU). There is evidence folic acid might inhibit the activity of these drugs, although in some cases it may increase activity. In fact, the folic acid metabolite, folinic acid (also known as 5-formyltetrahydrofolate and leucovorin), is often used to “rescue” normal tissue after MTX or 5-FU therapy. Folic acid supplementation does not appear to interfere with methotrexate’s anti-arthritic or anti-inflammatory activity. Since these medications are used to treat a wide range of malignant and nonmalignant disorders, indiscriminate use of folates should be avoided until further investigation is conducted.

Nutrient-Nutrient Interactions

Some concern exists that supplementation with high doses of folic acid could mask a vitamin B12 deficiency, resulting in neurological injury secondary to undiagnosed pernicious anemia. If there is any possibility of B12-induced anemia in an individual needing folate therapy, dual therapy with B12 and folate should be administered. Some authors have suggested folic acid supplements might interfere with intestinal zinc absorption; however, doses as high as 15 mg folic acid daily do not appear to have any significant effect on zinc status in healthy, non-pregnant subjects.74

Side Effects and Toxicity

In doses typically administered for therapeutic purposes, folic acid is considered non-toxic. At doses of 15 mg daily and above, gastrointestinal complaints, insomnia, irritability, and fatigue have been mentioned as occasional side effects. Folic acid is considered safe during pregnancy, with an established recommended intake of 800 mcg daily.

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Dosage

The dose of folic acid required varies depending on the clinical condition. For lowering homocysteine, a minimum dose of 800 mcg daily is generally used. The most common therapeutic dose is in the range of 1-3 mg daily. Doses greater than 10 mg daily have been used in conditions such as ­ cervical dysplasia. Dosages of over-the-counter folic acid supplements are restricted to no more than 800 mcg of folic acid per serving, although prescription forms of folic acid are available in higher doses.

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Ulvik A, Evensen ET, Lien EA, et al. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum. Am J Med Genet 2001;101:246-254. Halsted CH. The intestinal absorption of dietary folates in health and disease. J Am Coll Nutr 1989;8:650-658. Revell P, O’Doherty MJ, Tang A, Savidge GF. Folic acid absorption in patients infected with the human immunodeficiency virus. J Intern Med 1991;230:227-231. Botez MI. Folate deficiency and neurological disorders in adults. Med Hypotheses 1976;2:135140. Audebert M, Gendre JP, Le Quintrec Y. Folate and the nervous system (author’s transl). Sem Hop 1979;55:1383-1387. [Article in French] Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:841-863. Metz J, Bell AH, Flicker L, et al. The significance of subnormal serum vitamin B12 concentration in older people: a case control study. J Am Geriatr Soc 1996;44:1355-1361. Quinn K, Basu TK. Folate and vitamin B12 status of the elderly. Eur J Clin Nutr 1996;50:340-342. Fine EJ, Soria ED. Myths about vitamin B12 deficiency. South Med J 1991;84:1475-1481. Liu T, Soong SJ, Wilson NP, et al. A case control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev 1993;2:525530. Grio R, Piacentino R, Marchino GL, Navone R. Antineoblastic activity of antioxidant vitamins: the role of folic acid in the prevention of cervical dysplasia. Panminerva Med 1993;35:193-196. Kwasniewska A, Tukendorf A, Semczuk M. Folate deficiency and cervical intraepithelial neoplasia. Eur J Gynaecol Oncol 1997;18:526-530. Butterworth CE Jr, Hatch KD, Gore H, et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;35:73-82. Zarcone R, Bellini P, Carfora E, et al. Folic acid and cervix dysplasia. Minerva Ginecol 1996;48:397-400. [Article in Italian] Lewis AS, Murphy L, McCalla C, et al. Inhibition of mammalian xanthine oxidase by folate compounds and amethopterin. J Bio Chem 1984;259:12-15. Spector T, Ferone R. Folic acid does not inactivate xanthine oxidase. J Biol Chem 1984;259:1078410786.

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39.

Monograph

Boss GR, Ragsdale RA, Zettner A, Seegmiller JE. Failure of folic acid (pteroylglutamic acid) to affect hyperuricemia. J Lab Clin Med 1980;96:783-789. Landgren F, Israelsson B, Lindgren A, et al. Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med 1995;237:381-388. Wilcken DE, Dudman NP, Tyrrell PA. Homocystinuria due to cystathionine beta-synthase deficiency – the effects of betaine treatment in pyridoxine-responsive patients. Metabolism 1985;34:1115-1121. Dudman NP, Wilcken DE, Wang J, et al. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurence, cofactor therapy, and enzymology. Arterioscler Thromb 1993;13:1253-1260. Fava M, Borus JS, Alpert JE, et al. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997;154:426-428. Miller AL, Kelly GS. Homocysteine metabolism: nutritional modulation and impact on health and disease. Altern Med Rev 1997;2:234-254. Brouwer IA, van Dusseldorp M, Thomas CMG, et al. Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomised trial. Indian Heart J 2000;52:S53-S58. Ubbink JB, Vermaak WJ, van der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927-1933. Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 2001;161:695-700. Das UN. Folic acid says NO to vascular diseases. Nutrition 2003;19:686-692. Hyndman ME, Verma S, Rosenfeld RJ, et al. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 2002;282:H2167H2172. Tawakol A, Migrino RQ, Aziz KS, et al. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol 2005;45:1580-1584. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria – the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448-453. Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology 1989;97:255259.

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51. 52.

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Lashner BA, Provencher KS, Seidner DL, et al. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 1997;112:29-32. Abou-Saleh MT, Coppen A. Serum and red blood cell folate in depression. Acta Psychiatr Scand 1989;80:78-82. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev 1997;55:145-149. Wesson VA, Levitt AJ, Joffe RT. Change in folate status with antidepressant treatment. Psychiatry Res 1994;53:313-322. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry 2004;65:1090-1095. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry 2004;65:10961098. Alpert M, Silva RR, Pouget ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J Clin Psychopharmacol 2003;23:309-313. Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry 2002;14:33-38. Passeri M, Cucinotta D, Abate G, et al. Oral 5’methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano) 1993;5:63-71. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392-395. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord 2000;60:121-130. Coppen A, Chaudhry S, Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord 1986;10:9-13. Botez MI, Peyronnard JM, Berube L, Labrecque R. Relapsing neuropathy, cerebral atrophy and folate deficiency. A close association. Appl Neurophysiol 1979;42:171-183. Vogel RI, Fink RA, Schneider LC, et al. The effect of folic acid on gingival health. J Periodontol 1976;47:667-668.

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Monograph

54.

55. 56.

57.

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Thomson ME, Pack AR. Effects of extended systemic and topical folate supplementation on gingivitis of pregnancy. J Clin Periodontol 1982;9:275-280. Pack AR. Folate mouthwash: effects on established gingivitis in periodontal patients. J Clin Periodontol 1984;11:619-628. No authors listed. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991;338:131-137. Vergel RG, Sanchez LR, Heredero BL, et al. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience. Prenat Diagn 1990;10:149-152. Milunsky A, Jick H, Jick SS, et al. Multivitamin/ folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847-2852. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-1835. Bower C, Stanley FJ. Dietary folate as a risk factor for neural tube defects: evidence from a casecontrol study in Western Australia. Med J Aust 1989;150:613-619. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 1993;269:1257-1261. Shaw GM, Schaffer D, Velie EM, et al. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995;6:219-226. Tamura T, Goldenberg RL, Freeberg LE, et al. Maternal serum folate and zinc concentrations and their relationships to pregnancy outcome. Am J Clin Nutr 1992;56:365-370. Scholl TO, Hediger ML, Schall JI, et al. Dietary and serum folate: their influence on the outcome of pregnancy. Am J Clin Nutr 1996;63:520-525. Frelut ML, de Courcy GP, Christides JP, et al. Relationship between maternal folate status and foetal hypotrophy in a population with a good socio-economical level. Int J Vitam Nutr Res 1995;65:267-271. Montes LF, Diaz ML, Lajous J, Garcia NJ. Folic acid and vitamin B12 in vitiligo: a nutritional approach. Cutis 1992;50:39-42. Juhlin L, Olsson MJ. Improvement of vitiligo after oral treatment with vitamin B12 and folic acid and the importance of sun exposure. Acta Derm Venereol 1997;77:460-462.

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Russell RM, Golner BB, Krasinski SD, et al. Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med 1988;112:458-463. Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs 1985;30:145-155. Pironi L, Cornia GL, Ursitti MA, et al. Evaluation of oral administration of folic and folinic acid to prevent folate deficiency in patients with inflammatory bowel disease treated with salicylazosulfapyridine. Int J Clin Pharmacol Res 1988;8:143-148. Backman N, Holm AK, Hanstrom L, et al. Folate treatment of diphenylhydantoin-induced gingival hyperplasia. Scand J Dent Res 1989;97:222-232. van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001;44:1515-1524. Gori T, Burstein JM, Ahmed S, et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 2001;104:1119-1123. Butterworth CE Jr, Tamura T. Folic acid safety and toxicity: a brief review. Am J Clin Nutr 1989;50:353-358. Goggin T, Gough H, Bissessar A, et al. A comparative study of the relative effects of anticonvulsant drugs and dietary folate on the red cell folate status of patients with epilepsy. Q J Med 1987;65:911-919.

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Glycyrrhiza glabra

Monograph

COOH

Glycyrrhizin H O

H

COOH

HO

O

HO HO HO

HO

O

O

H

Glycyrrhiza glabra

O COOH

Introduction

Glycyrrhiza glabra, also known as licorice and sweetwood, is native to the Mediterranean and certain areas of Asia. Historically, the dried rhizome and root of this plant were employed medicinally by the Egyptian, Chinese, Greek, Indian, and Roman civilizations as an expectorant and carminative. In modern medicine, licorice extracts are often used as a flavoring agent to mask bitter taste in preparations, and as an expectorant in cough and cold preparations. Licorice extracts have been used for more than 60 years in Japan to treat chronic hepatitis, and also have therapeutic benefit against other viruses, including human immunodeficiency virus (HIV), cytomegalovirus (CMV), and Herpes simplex. Deglycyrrhizinated licorice (DGL) preparations are useful in treating various types of ulcers, while topical licorice preparations have been used to sooth and heal skin eruptions, such as psoriasis and herpetic lesions.

Description

The licorice shrub is a member of the pea family and grows in subtropical climates in rich soil to a height of four or five feet. It has oval leaflets, white to purplish flower clusters, and flat pods. Below ground, the licorice plant has an extensive root system with a main taproot and numerous runners. The main taproot, which is harvested for medicinal use, is soft, fibrous, and has a bright yellow interior.1 Glycyrrhiza is derived from the ancient Greek term glykos, meaning sweet, and rhiza, meaning root.

Active Constituents

A number of components have been isolated from licorice, including a water-soluble, biologically active complex that accounts for 40-50 percent of total dry material weight. This complex is composed of triterpene saponins, flavonoids, polysaccharides, pectins, simple sugars, amino acids, mineral salts, and various other substances.2 Glycyrrhizin, a triterpenoid compound, accounts for the sweet taste of licorice root. This compound represents a mixture of potassium-calcium-magnesium salts of glycyrrhizic acid that varies within a 2-25 percent range. Among the natural saponins, glycyrrhizic acid is a molecule composed of a hydrophilic part, two molecules of glucuronic acid, and a hydrophobic fragment, glycyrrhetic acid.2 The yellow color of licorice is due to the flavonoid content of the plant, which includes liquiritin, isoliquiritin (a chalcone), and other compounds.3 The isoflavones glabridin and hispaglabridins A and B have significant antioxidant activity,4 and both glabridin and glabrene possess estrogen-like activity.5 Page 230

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Pharmacokinetics

After oral administration of licorice in humans, the main constituent, glycyrrhizic acid, is hydrolyzed to glycyrrhetic acid by intestinal bacteria possessing a specialized ß-glucuronidase.6,7 Glycyrrhetic acid is 200-1,000 times more potent an inhibitor of 11-ß-hydroxysteroid dehydrogenase (involved in corticosteroid metabolism) than glycyrrhizic acid; therefore, its pharmacokinetics after oral intake are more relevant. After oral dosing, glycyrrhetic acid is rapidly absorbed and transported via carrier molecules to the liver. In the liver it is metabolized to glucuronide and sulfate conjugates, which are subsequently rehydrolyzed to glycyrrhetic acid. Glycyrrhetic acid is then reabsorbed, resulting in a significant delay in terminal clearance from plasma.8 After oral administration of 100 mg glycyrrhizin in healthy volunteers, no glycyrrhizin was found in the plasma but glycyrrhetic acid was found at < 200 ng/mL. In the 24-hour period after oral administration, glycyrrhizin was found in the urine, suggesting it is partly absorbed as an intact molecule.3

Mechanisms of Action

The beneficial effects of licorice can be attributed to a number of mechanisms. Glycyrrhizin and glycyrrhizic acid have been shown to inhibit growth and cytopathology of numerous RNA and DNA viruses, including hepatitis A9 and C,10,11 herpes zoster,12 HIV,13,14 Herpes simplex,15,16 and CMV.17 Glycyrrhizin and its metabolites inhibit hepatic metabolism of aldosterone and suppress 5-ßreductase, properties responsible for the well-documented pseudoaldosterone syndrome. The similarity in structure of glycyrrhetic acid to the structure of hormones secreted by the adrenal cortex accounts for the mineralocorticoid and glucocorticoid activity of glycyrrhizic acid.18 Licorice constituents also exhibit steroidlike anti-inflammatory activity, similar to the action of hydrocortisone. This is due, in part, to inhibition of phospholipase A2 activity, an enzyme critical to numerous inflammatory processes.19 In vitro research has also demonstrated glycyrrhizic acid inhibits cyclooxygenase activity and prostaglandin formation (specifically prostaglandin E2), as well as indirectly inhibiting platelet aggregation, all factors in the ­inflammatory ­process.19,20

Certain licorice constituents possess significant antioxidant and hepatoprotective properties. Glycyrrhizin and glabridin inhibit the generation of reactive oxygen species (ROS) by neutrophils at the site of inflammation.21,22 In vitro studies have demonstrated licorice isoflavones, hispaglabridin A and B, inhibit Fe3+-induced mitochondrial lipid peroxidation in rat liver cells.23 Other research indicates glycyrrhizin lowers lipid peroxide values in animal models of liver injury caused by ischemia reperfusion.24 Licorice constituents also exhibit hepatoprotective activity by lowering serum liver enzyme levels and improving tissue pathology in hepatitis patients.25 Glycyrrhizin and other licorice components appear to possess anticarcinogenic properties as well. Although the exact mechanisms are still under investigation, research has demonstrated they inhibit abnormal cell proliferation, as well as tumor formation and growth in breast,26 liver,27 and skin28,29 cancer. Deglycyrrhizinated licorice formulations used in the treatment of ulcers do not suppress gastric acid release like other anti-ulcer medications. Rather, they promote healing by increasing mucous production and blood supply to the damaged stomach mucosa, thereby enhancing mucosal healing.30,31

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Clinical Indications Chronic Hepatitis

Other Viral Illnesses

In Japan, glycyrrhizin has been used for more than 60 years as a treatment for chronic hepatitis C. Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, has been extensively used with considerable success. In two clinical trials, SNMC has been shown to significantly lower aspartate transaminase (AST), alanine transaminase (ALT), and gamma-glutamyltransferase (GGT) concentrations, while simultaneously ameliorating histologic evidence of necrosis and inflammatory lesions in the liver.25,32 In recent years, several studies have been performed supporting this action.10,11 Presently, interferon (IFN) therapy is a predominant treatment for chronic hepatitis. Because its efficacy is limited, an alternative treatment is desirable. SNMC has profound effects on the suppression of liver inflammation and is effective in improving chronic hepatitis and liver cirrhosis. It also appears to have considerably fewer side effects than IFN.33 In a double-blind, randomized, placebo-controlled trial investigating IV infusions of SNMC, short-term efficacy of licorice was confirmed with regard to ALT levels. The study showed the need for daily IV administration of SNMC, which may be impractical for patients. The study also demonstrated that after cessation of therapy the ALT-decreasing effect of licorice disappeared, suggesting the need for long-term administration.25

Oral Lichen Planus

Patients with chronic hepatitis C often experience oral lichen planus, an inflammatory disease characterized by lymphocytic hyperkeratosis of the oral mucosa. It is rarely cured and effective treatments are limited. In an open clinical trial, 17 hepatitis C-positive patients with oral lichen planus were given either routine dental care or 40 mL IV glycyrrhizin daily for one month. Among nine patients taking glycyrrhizin, six (66.7%) noted improved clinical symptoms, such as decreased redness, fewer white papules, and less erosion of the mucosa. In the non-glycyrrhizin group of eight patients, only one (14.3%) reported any improvement.34

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It has been reported that licorice inhibits growth and cytopathology of many unrelated DNA and RNA viruses, while not affecting cell activity or cellular replication.15 Hepatitis A virus (HAV) causes acute hepatitis, a major public health concern in numerous countries. In vitro research with glycyrrhizin and a human hepatoma cell line has demonstrated glycyrrhizin completely suppresses the expression of the HAV antigen. In comparison to ribavirin (an antiviral agent used to treat hepatitis), glycyrrhizin proved to be 10 times more potent at reducing infectivity of HAV, as measured by reduction in viral titres. Glycyrrhizin also exhibited a five-fold greater cell selectivity than ribavirin in that it was less cytotoxic to the hepatoma cells. These results indicate glycyrrhizin may be a potential therapeutic adjunct in fighting HAV infections.9 Studies show licorice and its constituents, specifically glycyrrhizin, have antiviral activity against Herpes simplex and are capable of ­irreversibly inactivating the virus.16,35,36 Glycyrrhizin has also been shown to inhibit viral replication and infectivity of HIV,14,36 herpes zoster,37 Varicella zoster,12 and CMV.17,38,39 A case report demonstrated a two-percent topical glycyrrhizic acid cream (carbenoxolone sodium) applied six times daily in 12 patients with acute oral herpetic (Herpes simplex) infections resolved pain and dysphagia within 24-48 hours of beginning use. Moreover, the accompanying ulceration and lymphadenopathy gradually healed within 24-72 hours.16 A clinical study of three HIV patients with hemophilia investigated the effect of glycyrrhizin on HIV replication. Glycyrrhizin was administered IV at 400-1600 mg on six separate occasions over a onemonth period. The HIV p24 antigen was detected in all patients at the beginning of treatment courses. At the end of one month, p24 antigen levels had either decreased significantly or become negative. Tapering of the glycyrrhizin dose resulted in an immediate elevation in p24 antigen levels, suggesting the higher doses of glycyrrhizin were responsible for decreased antigen levels, probably via suppressed viral replication.13

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Glycyrrhiza glabra

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In a clinical trial of 31 patients with severely painful herpes zoster lesions, 12 patients were given 20 mg IV glycyrrhizin on six separate occasions. The remaining 19 patients received either zoster immune gamma-globulin, recombinant interferon-ß, or acyclovir. Glycyrrhizin ranked next to acyclovir for pain resolution at the end of one month.37 CMV is the most common cause of congenital and perinatal viral infections throughout the world. It manifests with profound liver dysfunction and poor weight gain. In a series of studies, both oral and IV preparations of licorice (SNMC) were administered to infants with CMV. Liver dysfunction and weight gain improved in nearly all cases compared to groups without treatment.17,38,39

Hepatocellular Carcinoma

In a retrospective study, long-term licorice administration for hepatitis C infection was effective in preventing hepatocellular carcinoma (HCC). Four hundred fifty-three patients diagnosed with hepatitis C were divided into three groups and given either licorice, in the form of SNMC at a dose of 100 mL daily for two months, or other natural treatments, such as vitamin K. The remaining group of patients was treated with a wider number of agents, including SNMC, corticosteroids, and immunosuppressive agents; as a result of the mixed medication regimen, this group was excluded from the study. After 10 years, analysis of the results showed 30/84 patients (35.7%) employing SNMC had normalized AST levels, compared with seven patients (6.4%) not treated with IV SNMC. Moreover, the 10- and 15-year appearance rate of HCC was 7 and 12 percent in the treated group compared to 12 and 25 percent in the untreated group, respectively.40 A summary of the literature on HCC and the use of SNMC has confirmed that IV glycyrrhizin not only decreases ALT levels but also improves liver histology and decreases incidence of hepatic cirrhosis.41

Aphthous Ulcers

In a double-blind, placebo-controlled trial, 24 patients with recurrent aphthous ulcers were randomly allocated to consume 2 g glycyrrhizin (carbenoxolone sodium) in 30 mL of warm water or a

placebo three times daily following meals for four weeks. In contrast to the placebo group, the use of the oral licorice mouthwash significantly reduced the average number of ulcers per day, pain scores, and the development of new ulcers.42 In a study of 20 patients instructed to use a DGL mouthwash four times daily, 15 experienced 50-75 percent clinical improvement after only one day, with complete healing of canker sores after three days.43

Peptic Ulcer Disease

Licorice has been used as a demulcent and emollient for 2,000 years to promote the healing of ulcers by acting on the mucosal layer. Glycyrrhizin (as carbenoxolone sodium) speeds healing of gastric ulcers and protects against aspirin-induced damage to the gastric mucosa. In a double-blind, placebo-controlled study, 70 patients with endoscopically-confirmed gastric or duodenal ulcers were given carbenoxolone sodium 300 mg or placebo daily during the first seven days, followed by 150 mg daily over the next 3-5 weeks. The authors concluded the carbenoxolone group had an increase in pH at the stomach antrum from 1.1 to 6.0, and a reduction in basal and histamine-induced gastric acid secretion at pH 3 and 5. Overall, 70 percent of ulcers in the glycyrrhizin group healed within 3-5 weeks of beginning therapy, compared to 36 percent employing placebo.44 Unfortunately, the side effects of licorice limit its potential to be used on a long-term basis for treatment of peptic ulcer disease. A processed form of licorice, DGL (removal of the glycyrrhizin), was produced to eliminate potential adverse effects, including licorice-induced hypertension.45 In a double-blind trial, 100 patients were randomly chosen to chew Caved S (DGL plus antacid), 760 mg three times daily, or take cimetidine (Tagamet®) 200 mg three times daily and 400 mg at night for 12 weeks. Endoscopy showed the healing rate between the two regimens was comparable at six (63 percent) and 12 (91 percent) weeks. Although both therapies reduced pain symptom scores in a comparable fashion during the day, cimetidine was more effective during the first two weeks at reducing nighttime pain.46 A two-year follow-up trial comparing the two therapies in the prevention of gastric ulcer recurrence noted the out-

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Glycyrrhiza glabra

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comes were similar, with a reported relapse rate of 29 percent (9/31) in the Caved S group and 25 percent (8/32) in the cimetidine group.47 Other clinical trials have demonstrated the effectiveness of DGL for gastric ulcer.48,49 A fourweek clinical trial by Turpie et al demonstrated a statistically significant greater reduction in ulcer size in patients receiving 760 mg of a DGL preparation compared to placebo.48 Helicobacter pylori infection is prevalent in individuals with peptic ulcer and is also a known risk factor for gastric cancer.50,51 Consequently, an in vitro study was performed to investigate the effects of licorice flavonoids on the growth of H. pylori. These flavonoid components showed promising anti-H. pylori activity against clarithromycin- and amoxicillin-resistant strains. As the antimicrobial property seems to be attributed to the flavonoid constituents of licorice, DGL preparations may provide therapeutic benefit for H. pylori infection.52 Other studies have demonstrated DGL’s benefit in healing duodenal ulcers. In a trial of 40 patients receiving either 3.0 or 4.5 g DGL daily for eight weeks, all patients showed significant improvement after 5-7 days. Patients were assessed for relief from epigastric pain, nausea, vomiting, x-ray of ulcer craters to determine changes in size, and frequency of relapse (return of ulcer pain for two days per week). Patients receiving the higher DGL dose showed the most improvement.53 In a large study of 874 patients with chronic duodenal ulcers, patients received either DGL, cimetidine, or antacids. Ninety-one percent of all ulcers healed, regardless of treatment type. Differences among treatment groups were not statistically significant, but patients in the DGL group experienced the fewest relapses.54

Other Therapeutic Considerations

In a trial of 15 normal-weight subjects (seven males, eight females, ages 22-26), 3.5 mg of a commercial licorice preparation daily for two months resulted in a decrease in body fat mass. Plasma renin activity and aldosterone were also suppressed. No changes in body mass index were noted. These results indicate licorice and its constituents can reduce body fat by inhibiting 11-ß-hydroxysteroid dehydrogenase in fat cells.55 Page 234

Armanini et al investigated the effect of licorice on serum testosterone in nine healthy women, ages 22-26, using the same licorice preparation as above, and found total serum testosterone decreased from 27.8 (± 8.2) to 19.0 (± 9.4) ng/dL after one month, and further decreased to 17.5 (± 6.4) ng/dL after the second month of therapy. This is likely due to inhibition of 17-hydroxysteroid dehydrogenase, ­indicating licorice may be of benefit in treating women with hirsutism and polycystic ovary syndrome.56 Several animal and in vitro studies indicate glycyrrhizin and its constituents possess anticarcinogenic activity against a variety of cancers, warranting further investigation in clinical trials.26-29 Studies also show licorice constituents to be effective in the treatment of eczema,57 melasma,58 eosinophilic peritonitis,59 postural hypotension,60 erosive gastritis,61 and as anti-malarial62 and anti-Leishmanial agents.63 More recently, animal studies indicate aqueous extracts of G. glabra may have memory-enhancing activity via reversal of chemically-induced amnesia, as measured by maze and passive avoidance testing in mice.64

Drug-Botanical Interactions

There is an increased likelihood of cardiac arrhythmias, particularly in individuals with ischemic heart disease, when licorice is used in conjunction with digoxin.65 Estrogen-based oral contraceptives may enhance the mineralocorticoid side effects of licorice in susceptible individuals. This may be due in part to estrogens reacting with mineralocorticoid receptors or inhibition of 11β-hydroxysteroid dehydrogenase.66 Hypokalemia, commonly associated with metabolic acidosis, may co-present with essential benign hypertension in patients using diuretics and licorice simultaneously.67

Side Effects and Toxicity

One of the most commonly reported side effects with licorice supplementation is elevated blood pressure. This is thought to be due to the effect of licorice on the renin-angiotensin-aldosterone system. It is suggested licorice saponins are capable of potentiating aldosterone action while binding to mineralocorticoid receptors in the kidneys. The phenomenon

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Glycyrrhiza glabra

Monograph

is known as “pseudoaldosteronism.” In addition to hypertension, patients may experience hypokalemia (potassium loss) and sodium retention, resulting in edema. All symptoms usually disappear with discontinuation of therapy.25 Many studies report no side effects during the course of treatment.32,33 Generally, the onset and severity of symptoms depend on the dose and duration of licorice intake, as well as individual susceptibility. Patients with delayed gastrointestinal transit time may be more susceptible to these side effects, due to enterohepatic cycling and reabsorption of licorice metabolites. The amount of licorice ingested daily by patients with mineralocorticoid excess syndromes appears to vary over a wide range, from as little as 1.5 g daily to as much as 250 g daily.68

6.

7.

8.

9. 10.

Dosage

Because individual susceptibility to various licorice preparations is vast, it is difficult to predict a dose appropriate for all individuals. Nevertheless, a daily oral intake of 1-10 mg of glycyrrhizin, which corresponds to 1-5 g licorice (2% glycyrrhizin), has been estimated to be a safe dose for most healthy adults.69 Studies of DGL for peptic ulcers employed dosages ranging from 760-2,280 mg DGL daily.

11.

12. 13.

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3.

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Olukoga A, Donaldson D. Historical perspectives on health. The history of liquorice: the plant, its extract, cultivation, and commercialisation and etymology. J R Soc Health 1998;118:300-304. Obolentseva GV, Litvinenko VI, Ammosov AS, et al. Pharmacological and therapeutic properties of licorice preparations (a review). Pharm Chem J 1999;33:24-31. Yamamura Y, Kawakami J, Santa T, et al. Pharmacokinetic profile of glycerrhizin in healthy volunteers by a new high-performance liquid chromatographic method. J Pharm Sci 1992;81:1042-1046. Vaya J, Belinky PA, Aviram M. Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med 1997;23:302-313. Tamir S, Eizenberg M, Somjen D, et al. Estrogenlike activity of glabrene and other constituents isolated from licorice root. J Steroid Biochem Mol Biol 2001;78:291-298.

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18.

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Hattori M, Sakamoto T, Yamagishi T, et al. Metabolism of glycyrrhizin by human intestinal flora. II. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. Chem Pharm Bull (Tokyo) 1985;33:210-217. Akao T, Akao T, Hattori M, et al. Hydrolysis of glycyrrhizin to 18 beta-glycyrrhetyl monoglucuronide by lysosomal beta-Dglucuronidase of animal livers. Biochem Pharmacol 1991;41:1025-1029. Ploeger B, Mensinga T, Sips A, et al. The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling. Drug Metab Rev 2001;33:125-147. Crance JM, Biziagos E, Passagot J, et al. Inhibition of hepatitis A virus replication in vitro by antiviral compounds. J Med Virol 1990;31:155-160. Van Rossum TG, Vulto AG, Hop WC, et al. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial. J Gastroenterol Hepatol 1999;14:1093-1099. Su XS, Chen HM, Wang LH, et al. Clinical and laboratory observation on the effect of glycyrrhizin in acute and chronic viral hepatitis. J Tradit Chin Med 1984;4:127-132. Baba M, Shigeta S. Antiviral activity of glycyrrhizin against Varicella-zoster virus in vitro. Antiviral Res 1987;7:99-107. Hattori T, Ikematsu S, Koito A, et al. Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS. Antiviral Res 1989;11:255-261. Ito M, Sato A, Hirabayashi K, et al. Mechanism of inhibitory effect of glycyrrhizin on replication of human immunodeficiency virus (HIV). Antiviral Res 1988;10:289-298. Pompei R, Flore O, Marccialis MA, et al. Glycyrrhizic acid inhibits virus growth and inactivates virus particles. Nature 1979;281:689690. Partridge M, Poswillo DE. Topical carbenoxolone sodium in the management of herpes simplex infection. Br J Oral Maxillofac Surg 1984;22:138145. Numazaki K, Umetsu M, Chiba S. Effect of glycyrrhizin in children with liver dysfunction associated with cytomegalovirus infection. Tohoku J Exp Med 1994;172:147-153. Armanini D, Karbowiak I, Funder JW. Affinity of liquorice derivatives for mineralocorticoid and glucocorticoid receptors. Clin Endocrinol (Oxf) 1983;19:609-612.

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Glycyrrhiza glabra 19.

20. 21.

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Okimasu E, Moromizato Y, Watanabe S, et al. Inhibition of phospholipase A2 and platelet aggregation by glycyrrhizin, an antiinflammation drug. Acta Med Okayama 1983;37:385-391. Ohuchi K, Tsurufuji A. A study of the antiinflammatory mechanism of glycyrrhizin. Mino Med Rev 1982;27:188-193. Akamatsu H, Komura J, Asada Y, Niwa Y. Mechanism of anti-inflammatory action of glycyrrhizin: effect on neutrophil functions including reactive oxygen species generation. Planta Med 1991;57:119-121. Wang ZY, Nixon DW. Licorice and cancer. Nutr Cancer 2001;39:1-11. Haraguchi H, Yoshida N, Ishikawa H, et al. Protection of mitochondrial functions against oxidative stresses by isoflavans from Glycyrrhiza glabra. J Pharm Pharmacol 2000;52:219-223. Nagai T, Egashira T, Yamanaka Y, Kohno M. The protective effect of glycyrrhizin against injury of the liver caused by ischemia-reperfusion. Arch Environ Contam Toxicol 1991;20:432-436. Van Rossum TG, Vulto AG, Hop WC, Schalm SW. Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C. Am J Gastroenterol 2001;96:2432-2437. Tamir S, Eizenberg M, Somjen D, et al. Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res 2000;60:5704-5709. Shiota G, Harada K, Ishida M, et al. Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice. Carcinogenesis 1999;20:59-63. Nishino H, Kitagawa K, Iwashima A. Antitumorpromoting activity of glycyrrhetic acid in mouse skin tumor formation induced by 7,12 dimethyl­ benz[a]anthracene plus teleocidin. Carcinogenesis 1984;5:1529-1530. Liu W, Kato M, Akhand A, et al. The herbal medicine Sho-saiko-to inhibits the growth of malignant melanoma cells by up-regulating Fasmediated apoptosis and arresting cell cycle through down regulation of cyclin dependent kinases. Int J Oncol 1998;12:1321-1326. Van Marle J, Aarsen PN, Lind A, et al. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol 1981;72:219-225. Goso Y, Ogata Y, Ishihara K, Hotta K. Effects of traditional herbal medicine on gastric mucin against ethanol-induced gastric injury in rats. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1996;113:17-21.

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Tsubota A, Kumada H, Arase Y, et al. Combined ursodeoxycholic acid and glycyrrhizin therapy for chronic hepatitis C virus infection: a randomized controlled trial in 170 patients. Eur J Gastroenterol Hepatol 1999;11:1077-1083. Iino S, Tango T, Matsushima T, et al. Therapeutic effects of stronger neo-minophagen C at different doses on chronic hepatitis and liver cirrhosis. Hepatol Res 2001;19:31-40. Da Nagao Y, Sata M, Suzuki H, et al. Effectiveness of glycyrrhizin for oral lichen planus in patients with chronic HCV infection. J Gastroenterol 1996;31:691-695. Hirabayashi K, Iwata S, Matsumoto H, et al. Antiviral activities of glycyrrhizin and its modified compounds against human immunodeficiency virus type 1 (HIV-1) and Herpes simplex virus type 1 (HSV-1) in vitro. Chem Pharm Bull (Tokyo) 1991;39:112-115. Pompei R, Pani A, Flore O, et al. Antiviral activity of glycyrrhizic acid. Experientia 1980;36:304. Aikawa Y, Yoshiike T, Ogawa H. Effect of glycyrrhizin on pain and HLA-DR antigen expression on CD8-positive cells in peripheral blood of herpes zoster patients in comparison with other antiviral agents. Skin Pharmacol 1990;3:268271. Numazaki K, Chiba S. Natural course and trial of treatment for infantile liver dysfunction associated with cytomegalovirus infections. In Vivo 1993;7:477-480. Numazaki K. Glycyrrhizin therapy for liver dysfunction associated with cytomegalovirus infection in immunocompetent children. Antimicrobics Infect Dis Newsl 1998;17:70-71. Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer 1997;79:1494-1500. Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [Stronger NeoMinophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology 2002;62:94-100. Poswillo D, Partridge M. Management of recurrent aphthous ulcers. Br Dent J 1984;157:55-57. Das SK, Das V, Gulati AK, Singh VP. Deglycyrrhizinated liquorice in apthous ulcers. J Assoc Physicians India 1989;37:647. Loginov AS, Speransky MD, Speranskaya IE, et al. The effectiveness of carbenoxolone in the treatment of gastro-duodenal ulcer patients. Scand J Gastroenterol Suppl 1980;65:85-91. Shibata S. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi 2000;120:849-862.

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Morgan AG, McAdam WA, Pacsoo C, Darnborough A. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982;23:545-551. Morgan AG, Pacsoo C, McAdam WA. Maintenance therapy: a two year comparison between CavedS and cimetidine treatment in the prevention of symptomatic gastric ulcer recurrence. Gut 1985;26:599-602. Turpie AG, Runcie J, Thomson TJ. Clinical trial of deglycyrrhizinized liquorice in gastric ulcer. Gut 1969;10:299-302. Glick L. Deglycyrrhizinated liquorice for peptic ulcer. Lancet 1982;2:817. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl J Med 1991;324:1043-1048. Parsonnet J. Helicobacter pylori in the stomach – a paradox unmasked. N Engl J Med 1996;335:278280. Fukai T, Marumo A, Kaitou K, et al. AntiHelicobacter pylori flavonoids from licorice extract. Life Sci 2002;71:1449-1463. Tewari SN, Wilson AK. Deglycyrrhizinated liquorice in duodenal ulcer. Practitioner 1973;210:820-823. Kassir ZA. Endoscopic controlled trial of four drug regimens in the treatment of chronic duodenal ulceration. Ir Med J 1985;78:153-156. Armanini D, De Palo CB, Mattarello MJ, et al. Effect of licorice on the reduction of body fat mass in healthy subjects. J Endocrinol Invest 2003;26:646-650. Armanini D, Mattarello MJ, Fiore C, et al. Licorice reduces serum testosterone in healthy women. Steroids 2004;69:763-766. Evans FQ. The rational use of glycyrrhetinic acid in dermatology. Br J Clin Pract 1958;12:269-274. Amer M, Metwalli M. Topical liquiritin improves melasma. Int J Dermatol 2000;39:299-301. Takeda H, Ohta K, Niki H, et al. Eosinophilic peritonitis responding to treatment with glycyrrhizin. Tokai J Exp Clin Med 1991;16:183186. Basso A, Dalla Paola L, Erle G, et al. Licorice ameliorates postural hypotension caused by diabetic autonomic neuropathy. Diabetes Care 1994;17:1356. Kolarski V, Petrova-Shopova K, Vasileva E, et al. Erosive gastritis and gastroduodenitis – clinical, diagnostic and therapeutic studies. Vutr Boles 1987;26:56-59. [Article in Bulgarian]

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Chen M, Theander TG, Christensen SB, et al. Licochalcone A, a new anti-malarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection. Antimicrob Agents Chemother 1994;38:1470-1475. Christensen SB, Ming C, Anderson L, et al. An antileishmanial chalcone from Chinese licorice roots. Planta Med 1994;60:121-123. Parle M, Dhingra D, Kulkarni SK. Memorystrengthening activity of Glycyrrhiza glabra in exteroceptive and interoceptive behavioral models. J Med Food 2004;7:462-466. Hoes AW, Grobbee DE, Peet TM, Lubsen J. Do non-potassium-sparing diuretics increase the risk of sudden cardiac death in hypertensive patients? Recent evidence. Drugs 1994;47:711-733. Clyburn EB, DiPette DJ. Hypertension induced by drugs and other substances. Semin Nephrol 1995;15:72-86. Olukoga A, Donaldson D. Liquorice and its health implications. J R Soc Health 2000;120:83-89. Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquorice – evaluation of health hazard. Food Chem Toxicol 1993;31:303-312. Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am 1994;23:359-377.

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L-Tryptophan

Monograph

L-Tryptophan

Tryptophan hydroxylase

Tryptophan pyrrolase

Kynurenine 5-Hydroxytryptophan B6

3-Hydroxykynurenine

B6

Xanthurenic acid

SAMe Serotonin

Melatonin

B6 3-Hydroxyanthranilic acid

other metabolites

Carboxymuconic aldehyde intermediate

Tryptophan Metabolism

Picolinic acid

Quinolinic acid

Nicotinic acid (Niacin)

L-Tryptophan Introduction

L-tryptophan (tryptophan; Trp) is a large neutral amino acid essential to human metabolism because it is the metabolic precursor of serotonin (a neurotransmitter), melatonin (a neurohormone), and niacin (vitamin B3). As a component of dietary protein, tryptophan is particularly plentiful in chocolate, oats, bananas, dried dates, milk, cottage cheese, meat, fish, turkey, and peanuts. Approximately 300 mg Trp is available in three ounces of turkey, lamb, beef, tuna, or peanuts.1 Relative to other amino acids, small amounts are needed to have a therapeutic effect, which is fortunate because Trp is the least abundant amino acid in the diet.2 In 1989, the importation of L-tryptophan was banned in the United States after cases of a deadly autoimmune illness called eosinophilia-myalgia syndrome were traced to an improperly-prepared batch of tryptophan.3 Although the tryptophan was isolated to a single Japanese factory that allowed a toxic bacterial metabolite through the purification process, the ban was maintained and Trp availability was limited to the prescription drug (Tryptan), infant formulas, and enteral feeding products. Since 1994 tryptophan has been available and marketed as a dietary supplement in the United States, while imported product remains limited by special regulations.

Pharmacokinetics

The most investigated aspect of tryptophan metabolism is the serotonin pathway that includes the subsequent creation of melatonin. Tryptophan hydroxylase is the rate-limiting enzyme for serotonin production and involves the conversion of Trp to 5-hydroxytryptophan (5-HTP). This enzyme can be inhibited by stress, insulin resistance, magnesium or vitamin B6 deficiency, or increasing age.4 The decarboxylation of 5-HTP to serotonin is dependent on the presence of the active form of vitamin B6, pyridoxal 5’-phosphate, while the further conversion to melatonin necessitates S-adenosyl-L-methionine (SAMe). Page 52

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L-Tryptophan

Monograph

Tryptophan and 5-HTP penetrate the bloodbrain barrier, although tryptophan requires active transport and competes for the same receptors with other neutral amino acids – tyrosine, phenylalanine, valine, leucine, and isoleucine.5,6 In fact, the best predictor of a given meal’s effect on brain tryptophan and serotonin levels is the serum ratio of Trp to the pool of large neutral amino acids.7 More clinically relevant, however, serotonin levels are enhanced by carbohydrate ingestion as insulin release accelerates the serum removal of competing valine, leucine, and isoleucine. Similarly, a higher percentage of protein in the diet slows serotonin elevation.5,8 Although tryptophan can be found free in the serum, most is bound to albumin. Nonesterified fatty acids out-compete Trp for albumin’s common binding site,9 while displacement from albumin is also associated with the release of free fatty acids during exercise.10 The urinary metabolites of tryptophan include 3-hydroxykynurenine, xanthurenic acid, and kynurenine. Serum kynurenine, however, is metabolized into niacin (vitamin B3). This conversion is inefficient since 60 mg of tryptophan are required to synthesize 1 mg of niacin, which also depletes stores of the vitamin cofactors B1, B2, and B6.11,12

Mechanism of Action

Tryptophan’s primary mechanism of action is its role as the metabolic precursor of the neurotransmitter serotonin. Other neurotransmitters and central nervous system (CNS) chemicals, such as melatonin, dopamine, norepinephrine, and beta-endorphin, have also been shown to increase following oral administration of tryptophan.13-16 There is limited data linking tryptophan’s modulation of the endocrine system. Tryptophan’s effects on cortisol levels have been inconsistent.17,18 Although intravenous tryptophan stimulates secretion of prolactin and growth hormone,19,20 such an association has not been tested with oral dosing.

Clinical Indications Premenstrual Syndrome (PMS)

A dose of 6 g tryptophan has been found to significantly (p=0.004) decrease mood swings, tension, and irritability in women with premenstrual

dysphoria. Three consecutive cycles, from ovulation to the third day of menstruation, were assessed using the Visual Analog Mood Scales.21 Tryptophan’s role in PMS may be attributed to the increased activation of tryptophan catabolism to kynurenine during the luteal phase of the menstrual cycle.22

Seasonal Affective Disorder (SAD)

In the case of SAD, tryptophan has shown benefit in non-responders to light therapy. Four weeks of treatment with Trp (2 g twice daily, increased to 2 g three times daily if initially no response) was compared to light therapy (10,000 lux x 30 min daily in the morning). At the end of seven weeks, similar significant responses were noted in both groups (p=0.014 in Trp group). However, when light therapy was discontinued patients quickly relapsed; whereas, patients on tryptophan had a slower relapse rate.23 Similar results were demonstrated in 13 SAD patients treated with light therapy or tryptophan.24

Sleep Disorders

Tryptophan has been researched for sleep disorders for 30 years. Improvement of sleep latency has been noted,25,26 even at doses as low as 1 g;27 increased stage IV sleep has been noted at even lower doses – 250 mg tryptophan.27 Significant improvement in obstructive sleep apnea, but not central sleep apnea, has been noted at doses of 2.5 g at bedtime, with those experiencing the most severe apnea demonstrating the best response.28 While many sedative medications have opioid-like effects, L-tryptophan administration does not limit cognitive performance or inhibit arousal from sleep.25,29

Depression and Other Mental Disorders

The tryptophan metabolite, 5-HTP, has shown significant clinical response for depression in 2-4 weeks, at doses of 50-300 mg three times daily.30-36 Although reduced levels of serum Trp have been linked to some forms of depression, depression was not relieved with intravenous tryptophan.37 Numerous studies, ­however, have found tryptophan depletion produced depressive relapse and even initiation of depressive symptoms in healthy subjects.38-42

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L-Tryptophan

Monograph

Tryptophan depletion has also been shown to promote relapse of bulimia43 and schizophrenia,44 indicating the pivotal requirements for tryptophan in mental disorders other than depression. Tryptophan supplementation should be avoided in depression with reversed diurnal variation (worse in the evening), which commonly presents with an elevated ratio of tryptophan to large neutral amino acids and poor response to serotonergic antidepressants.45

Smoking

Tryptophan (50 mg/kg/day) has been used as an adjunct therapy for smoking cessation. During a two-week study, tryptophan-treated subjects experienced fewer nicotine withdrawal symptoms and were able to abstain or smoke fewer cigarettes than controls.46

Diagnosis of a Vitamin B6 Deficiency

The Tryptophan Load Test is a lab evaluation of vitamin B6 status. Elevated urinary xanthurenic acid (>50 mg/24 hr) after 2 g Trp is commonly viewed as a sign of a deficiency of vitamin B6,47 although it can be falsely elevated in pregnancy48 and in women using oral contraceptives.49 Xanthurenic acid elevation has also been associated with cataract formation.50 Case reports of serotonin syndrome have noted a connection between tryptophan used concomitantly with monoamine oxidase inhibitors.51,52 This syndrome is characterized by agitation, confusion, delirium, tachycardia, diaphoresis, and blood pressure fluctuations. Although no reports have been published, it is possible that tryptophan, when taken in combination with a selective serotonin reuptake inhibitor (SSRI) such as Prozac®, Paxil®, or Zoloft®, may also precipitate serotonin syndrome. Potential side effects at high doses (100 mg/ kg/day, i.e., 7 g/150 lbs) include gastric irritation, vomiting, and head twitching.1

Page 54

Patients with liver cirrhosis should avoid tryptophan supplementation. Cirrhotics present with reduced activity of tryptophan pyrrolase (22%), with subsequent increased free tryptophan and half-life, with decreased clearance.53 The effects of supplemental tryptophan during pregnancy are scarce. One study monitored fetal breathing activity via ultrasound over a 3.5-hour period and noted alteration in fetal breathing activity after maternal Trp loading (1 g) was less than observed after glucose load (100 g).54 This, however, was a low dose of tryptophan. Further safety studies are warranted before use during pregnancy can be recommended.

Dosage

Evening oral doses of tryptophan as low as 250 mg have been shown to improve sleep quality, although the typical dosage range for sleep disorders and depression is 1-3 g daily. Safe and effective dosages for other disorders range from 0.5-4 g daily, while potentially higher doses (50 mg/kg/day) have been used short term as a smoking cessation intervention.

References 1. 2.

Drug-Nutrient Interactions

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L-Tryptophan

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Rossle M, Herz R, Klein B, Gerok W. Tryptophan metabolism in liver diseases: a pharmacokinetic and enzymatic study. Klin Wochenschr 1986;64:590-594. [Article in German] Devoe LD, Castillo RA, Searle NS, Searle JR. Maternal dietary substrates and human fetal biophysical activity. I. The effects of tryptophan and glucose on fetal breathing movements. Am J Obstet Gynecol 1986;155:135-139.

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Monograph

Eleutherococcus senticosus

Eleutherococcus senticosus Description

Eleutherococcus senticosus (also known as Acanthopanax senticosus or Ciwujia, and previously known as Siberian ginseng) is an approximately two-meter high, hardy shrub native to the far eastern areas of the Russian taiga and the northern regions of Korea, Japan, and China.1

Active Constituents

The active ingredients of this plant are typically concentrated in the root and mainly consist of chemically distinct glycosides called eleutherosides A-M.2 Other phytochemicals found in the root structure include ciwujianosides (minor saponins), eleutherans (polysaccharides), beta sitosterol, isofraxidin (a coumarin derivative), syringin, chlorogenic acid,3 sesamin2 (lignans), and friedelin (triterpene).2 Eleutherosides I, K, L, and M have also been identified and isolated from the leaf of the plant.2

Mechanisms of Action

Eleutherococcus is primarily known as an adaptogen. This term, coined by researcher I.I. Brekhman, suggests such a plant has four general properties: (1) it is harmless to the host; (2) it has a general, rather nonspecific, effect; (3) it increases the resistance of the recipient to a variety of physical, chemical, or biological stressors; and (4) for the user, it acts as a general stabilizer/normalizer.4 Using animals to test this theory, researchers found Eleutherococcus decreases adrenal hypertrophy and the subsequent depletion of adrenal vitamin C levels in stressed rats.5 Moreover, animals treated with an aqueous extract from the stem bark of this herb were able to increase their swimming time to exhaustion, confirming original research that mice exposed to Eleutherococcus have more stamina.5,6 In addition to its anti-fatigue and anti-stress effects, the plant also exhibits immunomodulatory effects. One study found intraperitoneal (i.p.) administration of an extract (primarily eleutherosides B and D) increased the cytostatic activity of natural killer cells by 200 percent after one week.7 Another in vitro study confirmed a liquid extract of the root inhibits replication of RNA viruses (human rhinovirus, respiratory syncytial virus, and influenza A virus), but not cells infected with DNA viruses such as adenovirus or Herpes simplex, type 1.8 Eleutherococcus affects cytokine expression. A fluid extract, at doses of 0.1-1.0 mg/mL and 0.03-1.0 mg/ mL, induced and enhanced the actions of IL-1 and IL-6, respectively, but not IL-2 in vitro.9 Studies using an animal model of cerebral ischemia demonstrated an anti-inflammatory and neuroprotective effect. Eleutherococcus markedly inhibited cyclooxygenase-2 (COX-2) expression and decreased cerebral ischemia in rats with induced cerebral artery occlusion.10 Other pharmacological actions associated with Eleutherococcus root include prevention of bone resorption during experimental, steroid-induced osteoporosis,11 protection against experimentally-induced fulminant hepatic failure (possibly via apoptosis or antioxidant mechanisms),12 radioprotection of the hematopoietic system in mice Alternative Medicine Review u Volume 11, Number 2 u 2006

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Eleutherococcus senticosus exposed to lethal radiation,13 inhibition of histamine release from rat peritoneal cells, and inhibition of systemic anaphylaxis in rats.14 Other research has noted the stem bark not only increases the concentration of biogenic amines (noradrenalin and dopamine) in the rat brain,15 but also prevents stress-induced gastric ulcerations in rats16 and induces apoptosis in human stomach cancer KATO III cells.17

Clinical Indications Athletic Performance

Eleutherococcus has been touted as the herb that builds Russian athletes. In his review of the Russian scientific literature, Farnsworth notes a single 4 mL dose of a 33-percent ethanolic liquid extract given to five male skiers 1-1.5 hours before a 20-50 kilometer race increased skier resistance to hypoxemia and enhanced their ability to adapt to increased exercise demands.18 In another summary of the Russian studies, Halstead cites research on runners given either 2 mL (n=34) or 4 mL (n=33) of the extract 30 minutes before participating in a 10-kilometer race. The results were compared to 41 participants who did not take the herb (control). Those who took either 2 or 4 mL of the extract completed the race in an average time of 48.7 minutes and 45 minutes, respectively, compared to 52.6 minutes for the control group.19 After establishing baseline maximal work loads (control) using bicycle ergometry, six healthy male athletes (ages 21-22) were given 2 mL (150 mg of the dried material) of a 33-percent ethanol extract of Eleutherococcus or a comparable placebo in the morning and evening 30 minutes before meals for eight days. Compared to control, individuals who took the herb had significant increases in overall work performance, including maximal oxygen uptake (p