Alosetron

drugbox
IUPAC_name = 5-methyl-2- [(4-methyl-1H-imidazol-5-yl)methyl] -
3,4-dihydro-2"H"-pyrido [4,3-"b"] indol-1(5"H")-one

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CAS_number = 122852-42-0
ATC_prefix = A03
ATC_suffix = AE01
PubChem = 2099
ChemSpiderID = 2015
DrugBank = APRD00580
C=17 | H=18 | N=4 | O=1
molecular_weight = 294.351 g/mol
bioavailability = 50–60%
protein_bound = 82%
metabolism = Hepatic (including CYP2C9, CYP3A4 and CYP1A2)
elimination_half-life = 1.5–1.7 hours
excretion = Renal 73%, faecal 24%
pregnancy_category = B (U.S.)
legal_status = ℞-only (U.S.)
routes_of_administration = Oral

Alosetron (initial brand name: Lotronex; originator: GSK) is a 5-HT₃ antagonist used for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name "Lotronex".

History

Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted; it was the first drug ever returned to the U.S. market after withdrawal for safety concerns.cite news | url = http://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin | title = F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk | last = Pollack | first = A | work = The New York Times | date = 2006-03-09 | accessdate = 2008-03-13 ]

In 2001, the editor of the renown medical journal "The Lancet", Richard Horton, critizised the FDA's handling of alosetron in an unusually sharp language. [Horton R. "Lotronex and the FDA: a fatal erosion of integrity." Lancet. 2001;357:1544-5. PMID 11377636] Horton accused the FDA of collusion with the pharmaceutical industry.

It is not known whether Alosetron has been filed for registration in the EU.

GSK sold "Lotronex" to the Californian corporation Prometheus in late 2007. [Prometheus Laboratories Inc. [http://phx.corporate-ir.net/phoenix.zhtml?c=130685&p=irol-newsArticle_print&ID=1074178&highlight= "Press Release of 7 November 2007."] Retrieved on 27 August 2008.]

Adverse effects

Alosetron was withdrawn in 2000 following the association of alosetron with serious life-threatening gastrointestinal adverse effects. The cumulative incidence of ischaemic colitis was 2 in 1000, while serious complications arising from constipation (obstruction, perforation, impaction, toxic megacolon, secondary colonic ischaemia, death) was 1 in 1000. [GlaxoSmithKline plc. Lotronex (U.S. Prescribing Information). Brentford: GlaxoSmithKline; 2002.]

Pharmacodynamics

Alosetron has an antagonist action on the 5-HT₃ receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT₃ antagonist like ondansetron, it is not an antiemetic.

References