356/L-GLUTAMINE PDR FOR NUTRITIONAL SUPPLEMENTS

Cao Y, Feng Z, Hoos A, Klimberg VS. Glutamine enhancesgut glutathione production. J Parenter Enteral Nutr.

1998;22:224-247.

Furukawa S, Saito H, Inoue T, et al. Supplemental glutamineaugments phagocytosis and reactive oxygen intermediateproduction by neutrophils and monocytes from postoperativepatients in vitro. Nutrition. 2000; 16:323-329.

Furukawa S, Saito H, Ming-Tsan L, et al. Enteraladministration of glutamine in purulent peritonitis. Nutrition.1999;15:29-31.

Haub MO, Potteiger JA, Nau KL, et al. Acute L-glutamineingestion does not improve maximal effort exercise. J SportsMed Phys Fitness. 1998;38:240-244.

Hond ED, Peeters M, Hiele M, et al. Effect of glutamine onthe intestinal permeability changes induced by indomethacin inhumans. Aliment Pharmacal Ther. 1999; 13:679-685.

Houdijk, APJ, Rijnsburger ER, Jansen J, et al. Randomized trialof glutamine-enriched enteral nutrition on infectious morbidityin patients with multiple trauma. wncet. 1998;352:772-776.

Huang EY, Leung SW, Wang CJ, et al. Oral glutamine toalleviate radiation-induced oral mucositis: a pilot randomizedtrial. Int J Rad Oncol Bioi Phys. 2000;46:535-539.

Ito A, Higashiguchi T. Effects of glutamine administration onliver regeneration following hepatectomy. Nutrition. 1999; 15:23-28.

Lacey JM, Wilmore OW. Is glutamine a conditionally essentialamino acid? Nutr Rev. 1990;48:297-309.

Mebane AH. L-Glutamineand mania. Am J Psychiatry.1984;141:1302-1303.

Neu J, Roig JC, Meetze WH, et al. Enteral glutaminesupplementation for very low birth weight infants decreasesmortality. J Pediatr. 1997;131:691-699.

Noyer CM, Simon 0, Borczuk A, et al. A double-blindplacebo-controlled pilot study of glutamine therapy for abnormalintestinal permeability in patients with AIDS. Am JGastroenterol. 1998;93:972-975.

Rogers LL, Pelton RB, Williams RJ. Voluntary alcoholconsumptionof rats following administrationof glutamine.JBioi Chem. 1955;214:503-506.

Rohde T, MacLean OA, Klarlund Pedersen B. Glutamine,lymphocyteproliferation and cytokine production.Scan JIrnrnunol. 1996;44:648-650.

Rohde T, MacLean OA, Pedersen BK. Effect of glutaminesupplementation on changes in the immune system induced byrepeated exercise. Med Sci Sports Exerc. 1998;30:856-862.

Sacks GS. Glutamine supplementation in catabolic patients. AnnPharmacother. 1999;33:348-354.

Wilmore OW, Schloerb PR, Ziegler TR. Glutamine in thesupport of patients following bone marrow transplantation. CurrOpin Clin Nutr Metab Care. 1999;2:323-327.

Windmueller HG, Spaeth AF. Identification of ketone bodies

and glutamine as the major respiratory fuels in vivo forpostabsorptive rat small intestine. J Bioi Chern. 1978;253:69-76.

Ziegler TR, Benfell K, Smith RJ, et al. Safety and metabolic

effects of L-glutamine administration in humans. J Parenter

Enteral Nutr. 1990;14:137S-146S.

L- HistidineDESCRIPTION

L-histidine is a protein amino acid that is found in theproteins of all life forms. Although most L-histidine is foundin proteins, a small amount of free L-histidine does exist inplants and fermented foods. The naturally occurring dipep-tides found in muscle, carnosine and anserine are bothcomprised of L-histidine and beta-alanine.

L-histidine is one of the 10 essential amino acids for infants.It has never been clear if L-histidine is an essential aminoacid for adults. At the very least, it is a conditional essentialamino acid for adults. That is, even though L-histidine issynthesized in adult human tissues, sufficient quantities maynot be made to meet the physiological requirements imposedby certain stress or disease situations.

L-histidine is a solid water-soluble substance. Chemically, itis called (S)-alpha-amino-IH-imidazole-4-propanoic acid;alpha-amino-4 (or 5)-imidazolepropionic acid; L-2-amino-3-(lH-imidazol-4yl) propionic acid, and glyoxaline-5-alanine.Its IUPAC abbreviation is His, and its one-letter abbreviationis H. L-histidine is classified as a basic amino acid. L-histidine has the following structural formula:

a

OH

L-Histidine

ACTIONS AND PHARMACOLOGY

ACTIONS

The actions of supplemental L-histidine are entirely unclear.It may have some immunomodulatory as well as antioxidantactivity.

MECHANISM OF ACTION

Since the actions of supplemental L-histidine are unclear,any postulated mechanism is entirely speculative. However,some facts are known about L-histidine and some of itsmetabolites, such as histamine and trans-urocanic acid,which suggest that supplemental L-histidine may one day be

SUPPLEMENT MONOGRAPHS L-HISTIDINE /357

shown to have immunomodulatory and/or anti~xidant activi-ties. Low free histidine has been found in the serum of somerheumatoid arthritis patients. Serum concentrations of otheramino acids have been found to be normal in these patients.L-histidine is an excellent chelating agent for such metals ascopper, iron and zinc. Copper and iron participate in areaction (Fenton reaction) that generates potent reactiveoxygen species that could be destructive to tissues, includingjoints.

L-histidine is the obligate precursor of histamine, which isproduced via the decarboxylation of the amino acid. Inexperimental animals, tissue histamine levels increase as theamount of dietary L-histidine increases. It is likely that thiswould be the case in humans as well. Histamine is known topossess immunomodulatory and antioxidant activity. Sup-pressor T cells have Hz receptors, and histamine activatesthem. Promotion of suppressor T cell activity could bebeneficial in rheumatoid arthritis. Further, histamine hasbeen shown to down-regulate the production of reactiveoxygen species in phagocytic cells, such as monocytes, bybinding to the Hz receptors on these cells. Decreased reactiveoxygen species production by phagocytes could play antioxi-dant, anti-inflammatory and immunomodulatory roles insuch diseases as rheumatoid arthritis.

This latter mechanism is the rationale for the use ofhistamine itself in several clinical trials studying histaminefor the treatment of certain types of cancer and viral diseases.In these trials, down-regulation by histamine of reactiveoxygen species formation appears to inhibit the suppressionof natural killer (NK) cells and cytotoxic T lymphocytes,allowing these cells to be more effective in attacking cancercells and virally infected cells.

PHARMACOKINETICS

L-histidine is absorbed from the small intestine via 'an activetransport mechanism requiring the presence of sodium. Fromthe small intestine, L-histidine is transported to the liver bymeans of the portal circulation, where some is metabolizedand from whence some enters the systemic circulation to bedistributed to various tissues in the body.

L-histidine is metabolized in several different ways. It is asubstrate for protein synthesis; decarboxylation produceshistamine; it is converted to trans-urocanate in the skin; itforms the dipeptides carnosine and anserine in muscle; it is aprecursor of the thiol antioxidant, L-ergothioneine; and itforms alpha-ketoglutarate.

INDICATIONS AND USAGE

L-histidine may be indicated for use in some with rheuma-toid arthritis. It is not indicated for treatment of anemia oruremia or for lowering serum cholesterol.

RESEARCH SUMMARY

It has been reported that rheumatoid arthritis (RA) sufferershave abnormally low blood levels of this amino acid. In apilot study, RA patients received up to 6 grams ofsupplemental histidine daily and were said to benefit with aslittle as I gram daily. A subsequent study with 4.5 gramsdaily in some with more active and prolonged disease foundmuch less benefit-but still enough to warrant furtherresearch.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRAINDICA TIONS

L-histidine supplementation is contraindicated in anyonehypersensitive to any component of the preparation.

PRECAUTIONS

L-histidine supplements should .be avoided by children,pregnant women and nursing mothers. Those with allergiesor peptic ulcer disease should only use L-histidine supple-ments under strict medical supervision. Although there areno reports of adverse events in these groups, increasedhistamine production from L-h!stidine might negativelyaffect those with these conditions.

ADVERSE REACTIONS

Mild gastrointestinal side effects have been reported. L-histidine is generally well tolerated.

INTERACTIONS

Medroxyprogesterone Acetate: L-histidine was observed toenhance (in tissue culture) the effect of medroxyprogesteroneacetate in reducing the number of human breast cancer cellsthat were in the S phase.

HJ and Hz Blockers: Although not reported, L-histidine, viaits metabolism to histamine, might decrease the efficacy ofHI and Hz blockers.

No other drug, nutritional supplement, food or herb interac-tion are known.

OVERDOSAGE

None reported.

DOSAGE AND ADMINISTRATION

Tablets and capsules typically are available in 500 milligramto 1000 milligram dosages. Dosages have ranged from 500milligrams to 4.5 grams daily.

LITERATURE

Blumenkrantz MJ, Shapiro OJ, Swendseid ME, Kopple JD.Histidine supplementation for treatment of anaemia of uraemia.Br Med J. 1975; 2(5970):530-533.

Gerber DA. Decreased concentration of free histidine in serumin rheumatoid arthritis, an isolated amino acid abnormality notassociated with generalized hypoaminoacidemia. J Rheumatol.1975; 2:384-392.

358/ L-HISTIDINE PDR FOR NUTRITIONAL SUPPLEMENTS

Gerber DA. Low free serum histidine concentration inrheumatoid arthritis. A measure of disease activity. J ClinInvest. 1975; 55:1124-1173.

Gerber DA, Sklar JE, Niedwiadowiez J. Lack of effect of oralL-histidine on the serum cholesterol in human subjects.Am JClin Nutr. 1971; 24:1382-1383.

Gerber DA, Tanenbaum L, Ahrens M. Free serum histidinelevels in patients with rheumatoid arthritis and control subjectsfoIlowing an oral load of free L-histidine. Metabolism. 1976;

25:655-657.

Ghezzo F, Racca S, Conti G, et al. L-histidinemedroxyprogesterone acetate interaction modulates human breastcancer ceIl growth and progestin receptor expression in vitro.Pharmacy Res. 1997; 35:119-122.

Griswold DE, Alessi S, Badger AM, et al. Inhibitions of Tsuppressor cell expression by histamine type 2 (Hz) receptorantagonists.J Immunol. 1984; 132:3054-3057.

HeIlstrand K, Dalgren C, Hermodsson S. Histaminergicregulation of NK ceIls. Role of monocyte-derived reactiveoxygen metabolites.J Immunol. 1994; 153:4940-4947.

Lee NS, Fitzpatrick D, Meier E, Fisher H. Influence of dietaryhistidine on tissue histamine concentr~tion, histidinedecorboxylase and histamine methyl transferase activity in therat. Agents Actions. 1981; 11:307-31l.

Pinals RS, Harris ED, Burnett 18, Gerber DA. Treatment ofrheumatoid arthritis with L-histidine: a randomized, placebo-controIled,double-blind trial. J Rheumatol. 1977;4:414-419.

L-LysineDESCRIPTION

L-lysine is protein amino acid. It is classified as an essentialamino acid for humans and therefore must be supplied in thediet. Certain proteins, such as those found in meat, poultryand milk are rich in L-lysine. Proteins found in grains,cereals and their products are typically low in L-lysine. Forexample, wheat is low in L-lysine; wheat germ, however, isrich in L-lysine. Small amounts of free L-lysine are found invegetables, vegetable juices and in such fermented foods asmiso and yogurt.

L-lysine's popularity as a nutritional supplement arose as aresult of some studies suggesting that the amino acid maydecrease the recurrence rate of some infected with herpessimplex virus.

L-lysine is a basic amino acid and carries a positive charge atphysiological pH. It is a solid substance that is very solublein water. L-lysine has three pKa's: pKaI=2.20, pKaz=8.90and pKa3=1O.28. L-lysine is marketed as a nutritionalsubstance, either as L-lysine monohydrochloride or as thefree base, L-lysine. The molecular weight of L-lysine is

146.19 daltons, its molecular formula is C6H14NzOz,and itsstructural formula is:

L-lysine

L-lysine is also known as (S)- 2, 6, -diaminohexanoicacidand alpha, epsilon-diaminocaproic acid It is abbreviated asLys or by its one letter abbreviation, K. L-lysine and lysineare frequently used interchangeably. The D-stereoisomer (D-lysine) is not biologically active.

ACTIONS AND PHARMACOLOGY

ACTIONS

Supplemental L-lysine has putative anti-herpes simplex virusactivity. There is preliminary research suggesting that it mayhave some anti-osteoporotic activity.

MECHANISM OF ACTION

Proteins of the herpes simplex virus are rich in L-arginine,and tissue culture studies indicate an enhancing effect onviral replication when the amino acid ratio of L-arginine toL-lysine is high in the tissue culture media. When the ratio ofL-lysine to L-arginine is high, viral replication and thecytopathogenic:ity of herpes simplex virus have been foundto be inhibited.

L-lysine may facilitate the absorption of calcium from thesmall intestine.

PHARMACOKINETICS ,

Following ingestion, L-lysine is absorbed from the lumen ofthe small intestine into the enterocytes by an active transportprocess. Some metabolism of L-lysine takes place within theenterocytes. That which is not metabolized is transported tothe liver via the portal circulation. In the liver, L-lysine,along with other amino acids, participates in protein biosyn-thesis. Some is metabolized to L-alpha-aminoadipic acidsemialdehyde, which is further metabolized to acetoacetyl-CoA. The intermediate in this pathway is saccharopine. L-lysine does not participate in transamination. It is theexception to the general rule that the first step in catabolismof an amino acid is the removal of its alpha-amino group bytransamination to form the respective alpha-keto acid. L-lysine is both a glycogenic and a ketogenic amino acid. Itcan participate in the formation of D-glucose and glycogen,as well as lipids. It can also participate in the production ofenergy.

L-lysine that is not metabolized in the liver is transported tothe various tissues of the body, where it is involved in