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Alosetron
Systematic (IUPAC) name
5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indol-1-one
Identifiers
CAS number 122852-42-0
ATC code A03AE01
PubChem 2099
DrugBank APRD00580
ChemSpider 2015
Chemical data
Formula C17H18N4O 
Mol. mass 294.351 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 50–60%
Protein binding 82%
Metabolism Hepatic (including CYP2C9, CYP3A4 and CYP1A2)
Half life 1.5–1.7 hours
Excretion Renal 73%, faecal 24%
Therapeutic considerations
Pregnancy cat. B (U.S.)
Legal status ℞-only (U.S.)
Routes Oral
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Alosetron (initial brand name: Lotronex; originator: GSK) is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name Lotronex.

Contents

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Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability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.[1]

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.[2] Horton argued that the treatment of a non-fatal condition did not justify the use of a drug with potentially lethal side effects, and that the FDA should have revoked the approval for alosetron sooner when postmarketing surveillance revealed that many patients had suffered constipation necessitating surgical intervention and ischaemic colitis. He asserted that FDA officials were improperly motivated to maintain and reinstate the approval for alosetron because of the extent to which the FDA's Center for Drug Evaluation and Research is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives of GlaxoSmithKline.

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.[3]

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Alosetron was withdrawn in 2000 following the association of alosetron with serious life-threatening gastrointestinal adverse effects.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.[4]

Pharmacodynamics and mechanism of action

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 classified or approved as an antiemetic. Since stimulation of 5-HT3 receptors is positively correlated with gastrointestinal motility, alosetron's 5-HT3 antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.[4]

References

  1. ^ Pollack, A (2006-03-09). "F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk". The New York Times. http://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin. Retrieved 2008-03-13. 
  2. ^ Horton, R. (2001). "Lotronex and the FDA: a fatal erosion of integrity". The Lancet 357: 1544–1545. doi:10.1016/S0140-6736(00)04776-0.  edit
  3. ^ Prometheus Laboratories Inc. Press Release of 7 November 2007. Retrieved on 27 August 2008.
  4. ^ a b Prometheus Laboratories Inc. Lotronex (U.S. Prescribing Information) 2008 [1].
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