Alosetron
Encyclopedia
Alosetron 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.
In 2001, the editor
of the renowned medical journal The Lancet
, Richard Horton
, critizised the FDA's handling of alosetron in an unusually sharp language. 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 California
n corporation Prometheus in late 2007.
(obstruction, perforation, impaction
, toxic megacolon
, secondary colonic ischaemia, death
) was 1 in 1000.
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.
5-HT3 antagonist
The 5-HT3 antagonists are a class of medications that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain....
used for the management of severe diarrhea-predominant irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
(IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego
San Diego, California
San Diego is the eighth-largest city in the United States and second-largest city in California. The city is located on the coast of the Pacific Ocean in Southern California, immediately adjacent to the Mexican border. The birthplace of California, San Diego is known for its mild year-round...
), 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.In 2001, the editor
Editor in chief
An editor-in-chief is a publication's primary editor, having final responsibility for the operations and policies. Additionally, the editor-in-chief is held accountable for delegating tasks to staff members as well as keeping up with the time it takes them to complete their task...
of the renowned medical journal The Lancet
The Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...
, Richard Horton
Richard Horton
Richard Horton, FRCP FMedSci, is the present editor-in-chief of The Lancet, a United Kingdom-based medical journal.-Education and career:...
, critizised the FDA's handling of alosetron in an unusually sharp language. 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
Center for Drug Evaluation and Research
The Center for Drug Evaluation and Research is a division of the U.S. Food and Drug Administration that monitors most drugs as defined in the Food, Drug, and Cosmetic Act. Some biological products are also legally considered drugs, but they are covered by the Center for Biologics Evaluation and...
is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives of GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
.
It is not known whether alosetron has been filed for registration in the EU
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
.
GSK sold Lotronex to the California
California
California is a state located on the West Coast of the United States. It is by far the most populous U.S. state, and the third-largest by land area...
n corporation Prometheus in late 2007.
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 constipationConstipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
(obstruction, perforation, impaction
Impaction
Impaction, from the Latin impingere, is a medical term used to describe several different types of blockage.- In Reptiles : Impaction occurs in reptiles when they consume something that they cannot digest. Common causes of impaction are rocks and sand which might be accidentally consumed when the...
, toxic megacolon
Toxic megacolon
Toxic megacolon is an acute form of colonic distension. It is characterized by a very dilated colon , accompanied by abdominal distension , and sometimes fever, abdominal pain, or shock....
, secondary colonic ischaemia, death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
) was 1 in 1000.
Pharmacodynamics and mechanism of action
Alosetron has an antagonist action on the 5-HT3 receptors of the enteric nervous systemEnteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
of the gastrointestinal tract. While being a 5-HT3 antagonist like ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
, 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.