5-hydroxytryptamine syndrome

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

FDA, Combined Use of 5-Hydroxytryptamine Receptor Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result in Life-Threatening Serotonin Syndrome , FDA Public Health Advisory (2006) http //www.fda.gov/Cder/Drug/advisory/ S SRI S S200607.htm... 

A life-threatening condition, when selective serotonin reuptake inhibitors (SSRIs) and 5-hydroxytryptamine receptor agonists (triptans) are used together. However, many other drugs have been implicated (see below). Signs and symptoms of serotonin syndrome include the following ... 

List of Abbreviations Ach, acetylcholine AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid CNS, central nervous system COMT, catechol-O-methyltransferase DA, dopamine DRP-2, dihy-dropyrimidinase-related protein 2 DSM, diagnostic and statistical manual of mental disorders GNAS1, guanine nucleotide-binding protein (G-protein) alpha stimulating activity polypeptide 1 5-HIAA, 5-hydroxyindole acetic acid 5-FIT, serotonin (5-hydroxytryptamine) MAO, monoamine oxidase MHPG, 3-methoxy-4-hydroxyphenylglycol NE, norepinephrine NMDA, N-methyl-D-aspartate PCP, phencyclidine SSRI, selective serotonin reuptake inhibitor SDS, schedule for the deficit syndrome... 

Carcinoid is a tumor of the enterochromaffin cells that normally synthesize 5-hydroxytrytophan and 5-hydroxytryptamine. The carcinoid syndrome is seen when there are significant metastases of the primary tumor in the liver. It is characterized by increased gastrointestinal motility and diarrhea, as well as by regular periodic flushing. These symptoms can be attributed to systemic release of large amounts of serotonin and can be controlled with inhibitors of tryptophan hydroxylase, such as p-chlorophenylalanine. The synthesis of 5-hydroxytryptamine in advanced carcinoid syndrome may be so great that as much as 60% of the body s tryptophan metabolism proceeds by this pathway, compared with about 1% under normal conditions. A significant number of... 

During a period of 60 min the behaviour of the rats was scored manually every 5 minutes. The behaviour scored was repeated sniffing, repeated licking and rearing as dopamine receptor stereotyped behaviour and flat body posture and lower lip retraction as indications of the 5-hydroxytryptamine (5-HT, serotonin) behavioural syndrome. The behaviour was scored when it lasted for more than half the observation period. The effects of the compounds were compared to a saline-treated control group. 

Certain vitamins can be synthesized by humans in limited quantities. Niacin can be formed from tryptophan (Chapter 17). This pathway is not active enough to satisfy all the body s needs however, in calculating the RDA for niacin, 60 mg of dietary tryptophan is considered equivalent to 1 mg of dietary niacin. In Hartnup s disease (see Table 38-1 and Chapter 17), a rare hereditary disorder in the transport of monoaminomonocarboxylic acids (e.g., tryptophan), a pellagra-like rash may appear, suggesting that over a long period of time dietary intake of niacin is insufficient for metabolic needs. This pattern also occurs in carcinoid syndrome in which much tryptophan is shunted into the synthesis of 5-hydroxytryptamine. 

Pellagra-like symptoms can occur in Hartnup s disease and carcinoid syndrome. Hartnup s disease is an inherited disorder of amino acid transport (Chapter 17) in which niacin deficiency presumably develops because niacin intake is inadequate to supply metabolic needs when combined with the decreased absorption of dietary tryptophan. In carcinoid syndrome, up to 60% of available dietary tryptophan is diverted to formation of 5-hydroxytryptamine (serotonin) by what is normally a minor pathway. 

Bearcroft CP, Perrett D, Farthin MJG. Postprandial plasma 5-hydroxytryptamine in diarrhea predominant irritable bowel syndrome A pilot study. Gut 1988 42 42-46. 

Not understood. The reactions appear to be related to the serotonin syndrome, which can occur with two or more serotonergic drugs (see The serotonin syndrome , (p.9)). MAOIs may inhibit the metabolism of 5-hydroxytryptamine (serotonin), formed from tryptophan, so resulting in its accumulation. ... 

Tryptophan is a precursor of serotonin (5-hydroxytryptamine) and the authors point out that the symptoms resemble the serotonin syndrome, which occurs when serotonin levels are increased. They warn against the concurrent use of tryptophan with fluoxetine or other serotonin reuptake inhibitors. This caution is echoed by most of the manufacturers of the SSRIs the UK manufacturer of paroxetine additionally mentions oxitriptan [L-5-hydroxytryptophan]... 

Cesium exhibits marked effects on the nervous system, both peripherally and centrally. This may be the consequence of the purported interchangeability of cesium with other group I metals. Certainly cesium ions will increase the frequency of miniature end-plate potentials, thought to be due to the slow entry of cesium ions into the nerve terminal [32]. In the central nervous system, it seems that cesium can share the same receptor as glycine and exerts its effects by activating the same chloride channel as the inhibitory neurotransmitter, glycine [33]. Indeed, in consequence of this action, cesium has been implicated as a causative agent of some epileptiform seizures [34]. More recently, pretreatment of rats with cesium chloride, followed by administration of the monoamine oxidase inhibitor tranylcypramine, has been shown to enhance 5-hydroxytryptamine (5-HT) behavioral syndrome. This may be due to either an increased amount of 5-HT synthesis and/or release, or a direct enhancement of the postsynaptic action of 5-HT [34b]. 

Kahler, H. J. and Heilmeyer, L., Klinik und Pathophysiologic des Karzinoids und Karzinoid-syndroms unter besonderer Berucksichtigung der Pharmakologie des 5-Hydroxytryptamins, Ergebn. inn. Med., NF, 16, 292 (1961). 

Another area of clinical interest which has benefited from the use of BCD is the study of tryptophan metabolism. Tryptophan is an essential amino acid which can be metabolized in a number of ways as illustrated in Figure 3. One of the minor pathways leads to the synthesis of the neurotransmitter 5-hydroxytryptamine (5HT), abnormal brain levels of which have been associated with a number of diseases including Down s syndrome[15] and depression [lb] As part of a study into the biochemistry of depressive illnesses, I investigated methods for the determination of tryptophan metabolites in blood and urine. HPLC proved to be a useful technique for separating these compounds, so the possibility of using BCD was examined [17]. 

This is a tumour of argentaffin cells (cells which stain with silver salts), usually sited in the ileum or appendix, or less commonly in the bronchus, pancreas or stomach. These cells normally synthesize the hormone serotonin (5-hydroxytryptamine) which is a powerful smooth-muscle stimulant and vasoconstrictor. In carcinoid syndrome this hormone is secreted in excess amounts. The clinical symptoms of this condition include flushing, diarrhoea and bronchospasm. Carcinoid syndrome can be diagnosed biochemically by detection of the serotonin metabolite, 5-hydroxyindoleacetic acid, in excess amounts in the urine. 

A metabolite of the hormone, serotonin (5-hydroxytryptamine). It is excreted in excess amounts in the urine of patients with carcinoid syndrome, a condition in which there is excessive synthesis of serotonin. 

An intermediate in the conversion of tryptophan to 5-hydroxy tryptamine (serotonin). In some cases of carcinoid syndrome it i excreted in large amounts in the urine, even though the 5 hydroxyindoleacetic acid excretion may be normal. This i thought to be because the cells lack the decarboxylase whicl converts 5-hydroxytryptophan to 5-hydroxytryptamine. 

Monoester 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-l-carboxylic acid 59 (Figure 4.17) is a building block of many potential therapeutic candidates for inhibitors of 11-p-hydroxysteroid dehydrogenase type 1 enzyme and their use in the treatment of non-insulin-dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and CNS disorders. It is also required for the synthesis of 5-hydroxytryptamine receptor agonists, useful for the treatment of anxiety disorders and schizophrenia [90,91]. 

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