Tryptophan, eosinophilia-myalgia

L-tryptophan is a naturally-produced, natural amino acid used as a dietary supplement. Samples from one manufacturer were found to be contaminated by trace amounts of another naturally occurring compound — l,l -ethylidene bis-[i.-tryptophan]. The latter compound appears to have been responsible for causing a number of deaths and additional cases of chronic eosinophilia-myalgia,111 some of which might have been prevented had there... 

The amino acid precursor for 5-HT, L-tryptophan, increases the biosynthesis 5-HT and, therefore, has been investigated for potential antidepressant properties, but with mixed results (Green and Costain, 1979). It was withdrawn in 1990, following a number of fatal cases of eosinophilia myalgia (a disorder characterised by severe muscle pain and abnormally high levels of one type of white blood cell, the eosinophil) in individuals principally using it as a natural hypnotic. 

FDA recalls all OTC dietary supplements containing L-tryptophan because of a clear link to an outbreak of eosinophilia-myalgia syndrome (EMS). By 1990, more than 1,500 cases of EMS - 38 deaths are confirmed, with an estimated 3,000 to 10,000 unreported cases. 

L-Tryptophan. Open label studies suggest that tryptophan, the amino acid precursor to serotonin, administered at 500-2000mg/day, may be effective for OCD. This has not been tested in controlled studies. Furthermore, the clinical utility of tryptophan snpplementation has been limited by the association of one batch of tryptophan with the eosinophilia myalgia syndrome. Therefore, we cannot recommend the rontine nse of tryptophan supplementation for OCD. 

Add tryptophan to a standard antidepressant (usually an SSRI). There is a danger that the serotonin syndrome may occur however and occasionally the eosinophilia myalgia syndrome. The symptoms that occur with increasing severity are restlessness, diaphoresis, tremor, shivering, myoclonus, confusion, convulsions, death. 

Sullivan, E.A., Kamb, M.L., Jones, J.L., Meyer, P., Philen, R.M., Falk, H., and Sinks, T. (1996) The natural history of eosinophilia-myalgia syndrome in a tryptophan-exposed cohort in South Carolina. Arch Intern Med 156 973-975. 

Hermoni M, Lerer B, Ebstein RP, et al Chronic lithium prevents reserpine-induced supersensitivity of adenylate cyclase. J Pharm Pharmacol 32 510-511, 1980 Hertzman PA, Blevins WL, Mayer J, et al Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan [see comments]. N Engl J Med 322 869-873, 1990... 

Limited evidence indicates that the amino acid precursor of 5-HT, l -tryptophan, may be useful, alone or in combination with other antimanic agents to enhance overall efficacy. Contaminants in the production of this agent led to several cases of the eosinophilia myalgia syndrome (EMS) and its removal from the market for several years. 

The reliability and consistency of commercial melatonin has been questioned (3). One group analysed three commercial melatonin formulations and identified analogues of the contaminant of L-tryptophan compounds implicated in an epidemic of eosinophilia-myalgia syndrome in the 1980s (27). There have been no reports of this condition associated with melatonin consumption, but food supplements are not required to comply with the same manufacturing and monitoring quality control standards as drugs. 

Hill RH Jr, Caudill SP, Philen RM, Bailey SL, Flanders WD, Driskell WJ, Kamb ML, Needham LL, Sampson EJ. Contaminants in L-tryptophan asso-ciatedwith eosinophilia-myalgia syndrome. Arch Environ Contam Toxicol 1993 25 134-142. 

Williamson, B. L. Tomlinson, A. I Mishra, P. K. Gleich, G. J. Naylor, S. 1998. Structural characterization of contaminants found in commercial preparations of melatonin similarities to case-related compounds from L-tryptophan associated with eosinophilia-myalgia syndrome. Chem. Res. Toxicol., 11,234-240. 

Analysis of L-tryptophan for etiology of eosinophilia-myalgia syndrome, JAMA, 264 2620 (1990). 

Another case, much more serious and also more pertinent to the chemical process development area, occurred in 1989 when over 1600 people became ill with eosinophilia-myalgia syndrome (EMS) and 38 died, worldwide, after taking l-tryptophan (Trp) manufactured by one producer in Japan. Prior to the outbreak, this producer whose Trp met the >98.5% purity specification had decided to employ a new genetically modified strain of the established Bacillus amyloliquefaciens and also to halve the amount of activated charcoal used in the purification step. These changes cause the Trp product to become contaminated with several new impurities, principally I to III, all associated to some extent (using a crude animal model) with EMS.5... 

Tryptophan Amino acid Precursor of serotonin Eosinophilia-myalgia syndrome... 

The syndrome appears to be only part of a spectrum of adverse effects associated with tryptophan (15). There has been much discussion, but finally it appears that the links are causal, as consistent findings were found in multiple independently conducted studies and the incidence of eosinophilia-myalgia syndrome in the USA fell abruptly once tryptophan-containing products were recalled (16). 

Kilbourne EM, Philen RM, Kamb ML, Falk H. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl 1996 46 81-8. 

Hypersensitivity reactions can occur due to the presence of contaminants or excipients in pharmaceutical dosage forms (e.g., outbreaks of eosinophilia-myalgia syndrome associated with oral tryptophan contaminants in various drugs). Another example is the anaphylactoid reactions to the surfactant Cremaophor EL, which is used in paclitaxel (Taxol). 

Another issue with safety of dietary supplements is the purity of the ingredients. The supplements are not required to go through any control measures before they are put on the market unlike drugs. Cases such as the L-tryptophan one in 1989 are therefore subject to be repeated. The impurities of this product led to an epidemic of eosinophilia-myalgia syndrome, with 1500 reported cases and 37 deaths. 

Figure 1 Biosynthesis of i-tryptophan. (Reproduced from Mayeno AN and Gleich GJ (1994) Eosinophilia-myalgia syndrome and tryptophan production A cautionary taie. Trends in Biotechnology 12 346-352, with permission from Elsevier.)...

Occasional + +, common + + +, very common. Reproduced from Varga J (1993) L-Tryptophan-associated eosinophilia-myalgia syndrome Clinical and pathological features of an evolving new disease and current concepts of etiology. Journal of Intensive Care Medicine 8 229-242. 

Medsger TA Jr. (1990) Tryptophan-induced eosinophilia-myalgia syndrome. New England Journal of Medicine 322 926-928. 

Naylor S, Williamson BL, Johnson KL, and Gleich GJ (1999) Structural characterization of case-associated contaminants peak G and FF in L-tryptophan implicated in eosinophilia-myalgia syndrome. Advances in Experimental Medicine and Biology 467 453—460. 

Philen RM, Hill RH Jr., et al. (1993) Tryptophan contaminants associated with eosinophilia-myalgia syndrome. The eosinophilia-myalgia studies of Oregon, New York and New Mexico. American Journal of Epidemiology 138 154-159. 

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