Tegaserod

Molecular formula CieH aNsO Molecular weight 301.39 CAS Registry No 145158-71 -0, 189188-57-6 (maleate) 

Sample preparation Add an equal volume of cold MeOH, 70% perchloric acid, or 10% trichloroacetic acid, cool on dry ice, centrifuge at 100 000 g for 10 min, inject an aliquot of the supernatant. 

Detector Radioactivity ( C) (scintillator flow 3 mL/min) MS, Finnigan MAT TSQ 700 triple-stage quadrupole, electrospray, 0.25 mL/min of column effluent mixed with 0.1 mL/min MeCN and entered the detector, sheath liquid methanol at 0.1 mL/min, sheath gas nitrogen 45 psi, auxiliary gas nitrogen 5 units, spray 4.5 kV, transfer capillary 240°, collision o et 30 V 

Vickers, A.E.M. Zollinger, M. Dannecker, R. Tynes, R. Heitz, F. Fischer, V. In vitro metabolism of tegaserod in human liver and intestine assessment of drug interactions. Drug Metab.Dispos., 2001, 29, 1269-1276. 

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Tegaserod maleate (Zelnorm) is a partial serotonin (5-HT4) receptor agonist that causes an increase in peristaltic activity and intestinal secretion and moderation of visceral sensitivity. It increases the frequency of bowel movements and reduces abdominal discomfort, bloating, and straining. It is indicated for the treatment of patients younger than 65 years of age who experience chronic idiopathic constipation. The most common adverse effects include headache, abdominal pain, diarrhea, and nausea. 

Slow-transit constipation can be treated with chronic administration of osmotic laxatives. Tegaserod maleate 6 mg orally twice daily is an acceptable treatment. Senna, bisacodyl, and other stimulants should be used only when the others fail to deliver the desired effect. 

Tegaserod maleate (Zelnorm) stimulates 5-HT4 receptors in the GI tract, thereby increasing intestinal secretion, peristalsis, and small bowel transit. It also reduces sensitivity related to abdominal distention. It has been shown to be more effective than placebo in improving global IBS symptoms and altered bowel habits in constipation-predominant IBS.21 Diarrhea is a possible adverse effect. 

Ischemic colitis has been observed in some patients taking tegaserod. The drug should be discontinued promptly if rectal bleeding, bloody diarrhea, or worsening abdominal pain occurs. 

In March of 2007, the FDA announced that tegaserod maleate would be voluntarily withdrawn from the market because of information indicating an increased risk of serious cardiovascular events (myocardial infarction, unstable angina, and stroke). 

Assess 5-HT4 receptor agonists (tegaserod) for relief of crampy abdominal pain and bloating. 

In the periphery, 5-HT4 receptor mRNA is found in vascular smooth muscle. Newly developed drugs that activate 5-HT4 receptors are of interest for their potential in treating cardiac arrhythmia. The 5-HT4 receptor is also located on neurons of the alimentary tract, for example the myenteric plexus of the ileum, and on smooth muscle cells and secretory cells of the gastrointestinal tract, where they evoke secretions and the peristaltic reflex. 5-HT4 receptor agonists (e.g. cisapride, prucalopride, tegaserod) are used therapeutically in the treatment of constipation-predominant irritable bowel syndrome and in functional motility disorders of the upper gastrointestinal tract. 

The current case history will focus on the discovery of tegaserod and will summarize the pharmacodynamic effects in the GI tract and its therapeutic efficacy in IBS-C and CC. 

From the indole carbazimidamides investigated, tegaserod (R5 = OMe, R9 = n-pentyl), a potent partial 5-HT4 agonist, was selected for clinical development for the treatment of functional motility disorders based on its overall in vitro and in vivo profile. 

Tautomerism. Owing to the presence of the guanidine moiety in the structure of tegaserod, the three tautomers shown below are possible. Tautomer 6a is assigned to the solid state of tegaserod, as confirmed by X-ray structure analysis of the 5-0-benzyl derivative. In solution, 6b and 6c also exist in equilibrium depending on the experimental conditions. For instance in DMSO, the solvent used to measure NMR spectra, 6b is preferred. Tautomer 6c is formed in methanol after exposure to xenon light, and from this solution the tautomer can even be separated by HPLC. 

Additionally, tegaserod at low nanomolar concentrations increases intracellular cAMP concentrations in crypt cells isolated from rat distal colon and stimulates chloride and water secretion by activation of 5-HT4 receptors [34,35], These findings suggest a modulatory effect on intestinal electrolyte and water secretion in vivo. 

Figure 1 Effects of tegaserod in a constipation model in conscious dogs. Tegaserod normalizes stool frequency, stool quantity and softens stool consistency. Mean SEM (n — 8) p < 0.05 versus Vehicle ftp < 0.05 versus Morphine. From Weber et al., Gastroenterology (2003), 124 A1806 (Please see Color Plate Section in the back of this book).

Figure 1 Inhibition by tegaserod of neuronal activity (firing rate) of rectal spinal afferents (n = 9) upon distention (50 mmHg) of feline colon and the antagonism by SB 203186, a competitive inhibitor at 5-HT4 receptors. From Schikowski et al. Neurogastroenterol. Mot. (2002), 14 221-227.

The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild-to-moderate hepatic or renal impairment [46,47]. 

Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid-catalyzed hydrolysis in the stomach followed by oxidation and conjugation, which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic... 

Interestingly, slices of human small intestine also metabolized tegaserod to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism of the drug. 

The clinical efficacy of tegaserod in female patients with constipation-predominant IBS was established in two prospective well-controlled studies,... 

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