Alosetron

Sample preparation Condition a 100 mg LRC Bond Elut ethyl (C2) SPE cartridge with 1 mL isopropanol and 1 mL buffer. Mix 1.1 mL plasma or serum with 1 mL buffer containing 10 ng/mL IS, vortex, add 2 mL to the SPE cartridge, wash with 2 mL buffer, dry with nitrogen for 30 s, wash with 2 mL MeCN, elute with two 2 mL aliquots of MeCN buffer 90 10. Evaporate the eluate to dr5mess under a stream of nitrogen at 40°, reconstitute the residue with 300 xL mobile phase, vortex, inject a 200 xL aliquot. (The buffer was 10 mM ammonium acetate adjusted to pH 4.0 with glacial acetic acid.) 

Mobile phase MeOH THF 10 mM pH 4.0 ammonium acetate buffer 24 6 70 

Noninterfering amitriptyline, carbamazepine, carmustine, chlorpromazine, cimeti-dine, cisplatin, cyclophosphamide, dexamethasone, diazepam, digoxin, etoposide, furo-semide, haloperidol, ibuprofen, imipramine, indomethacin, methotrexate, phenobarbi-tal, phen3doin, propranolol, ranitidine, theophylline, triazolam, warfarin 

Gooding, A.E. AUanti, J.R. Determination of alosetron in human plasma or serum by high-performance liquid chromatography with robotic sample preparation, J.Chromatogr.B, 

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Methyl-l,2,3,9-tetrahydro-4H-carbazol-4-one, the key building block of the neuroactive compound alosetron, was easily obtained from 3-[(2-halophenyl)(methyl)amino]cyclohex-2-en-l-one by pyrrole ring formation via Heck reaction under microwave irradiation [94], While the iodo substrate gave an excellent yield in only 30 min at 100 °C the corresponding bromo derivative converted only poorly under the same reaction conditions (Scheme 88). 

Stimulation of 5-HT3 receptors triggers hypersensitivity and hyperactivity of the large intestine. Alosetron (Lotronex) is a selective 5-HT3 antagonist that blocks these receptors and is used to treat women with severe diarrhea-predominant IBS. Eligible patients should have frequent and severe abdominal pain, frequent bowel urgency or incontinence, and restricted daily activities. Alosetron has been shown to improve overall symptoms and quality of life. Alosetron can cause constipation in some patients. 

Because alosetron has been associated with ischemic colitis, it may be prescribed only under strict guidelines, including signing of a consent form by both patient and physician. Patients selected for therapy should exhibit chronic IBS symptoms and have failed to respond to conventional therapy. 

Evaluate 5-HT3 receptor antagonists (alosetron) for relief of abdominal pain and fecal incontinence. 

If taking alosetron, determine compliance with special use requirements. 

Fluvoxamine Alosetron Increased alosetron AUC (sixfold) and half-life (threefold)... 

Alosetron (Lotronex) Irritable bowel syndrome Serious gastrointestinal events, especially ischemic colitis and constipation 2000 [53]... 

Mayer, E.A. and Bradesi, S., Alosetron and irritable bowel syndrome, Expert Opin. Pharmacother., 4,2089-2098,2003. 

Alosetron hydrochloride Lotronex Glaxo Wellcome Gastrointestinal 2/9/2000 11/28/2000 9 months Ischemic colitis 50.4 million... 

Alosetron, a 5-HTj receptor antagonist, retards colonic transit (58) and is used to treat diarrhea-predominant IBS. Although genetic variants in the 5-HT receptors have been discovered, their physiological relevance has yet to be determined. 

Fig. 13.4 Response of colonic transit to treatment with alosetron is greater in homozygous long vs heterozygous SERT-P genotype. 5-HT, serotonin. (Reproduced from ref. 63.)...

In addition, other drugs such as alosetron (2), cyproheptadine (12), diazepam (13) or tamoxifen (49) are AT-demethylated by various microorganisms as a major metabolic route. The carboxylic acid resulting from the oxidative cleavage of the piperidine ring of phencyclidine (36), probably proceeding through an... 

Serious Gl adverse events, some fatal, have been reported with the use of alosetron. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, blood transfusion, surgery, and death. 

Only physicians who have enrolled in GlaxoSmithKline s Prescribing Program for Lotronex, based on their attestation of qualifications and acceptance of responsibilities, should prescribe alosetron (see Administration and Dosage). Alosetron is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional... 

Alosetron should be discontinued immediately in patients who develop constipation or symptoms of ischemic colitis. Physicians should instruct patients to immediately report constipation or symptoms of ischemic colitis. Alosetron should not be resumed in patients who develop ischemic colitis. Physicians should instruct patients who report constipation to immediately contact them if the constipation does not resolve after discontinuation of alosetron. Patients with resolved constipation should resume alosetron only on the advice of their treating physician. 

IBS (alosetron) Because of serious Gl adverse events, some fatal, alosetron is indicated only for women with severe diarrhea-predominant IBS who have ... 

Prescribing Program - For safety reasons, only health care providers who enroll in the GlaxoSmithKline prescribing program foralosetron should prescribe alosetron. 

Adult dosage - To lower the risk of constipation, alosetron should be started at a dosage of 0.5 mg twice a day. Patients well controlled on 0.5 mg twice a day may be maintained on this regimen. If, after 4 weeks, the 0.5 mg twice daily dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day, the dosage used in controlled clinical trials. 

Alosetron should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron should not be restarted in patients who develop ischemic colitis. 

Special populations - Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease Gl motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if alosetron is prescribed for these patients. 

Pharmacists information - A oseiron may be dispensed only on presentation of a prescription for alosetron with a sticker for the prescribing program for alosetron attached. A MedGuide for alosetron must be given to the patient each time alosetron is dispensed as required by law. No telephone, facsimile, or computerized prescriptions are permitted with this program. Refills are permitted to be written on prescriptions. 

Pharmacokinetics The elimination half-lives of these drugs range from 4 to 8 hours. Elimination is primarily via hepatic metabolism. Plasma concentrations of alosetron are 30% to 50% lower and less variable in men compared with women given the same dose. Plasma protein binding is 82% for alosetron, 65% for granisetron and 70% to 76% for ondansetron. The terminal elimination half-life of alosetron is approximately 1.5 hours. 

Alosetron Do not initiate alosetron in patients with constipation. Alosetron is contraindicated in patients ... 

Constipation Serious complications of constipation, including obstruction, perforation, impaction, toxic megacolon, secondary colonic ischemia, and death have been reported with use of alosetron. Immediately discontinue alosetron treatment in patients who develop constipation. 

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