PerspectiveDesperately Seeking Serotonin… A Commentary on the Withdrawal of Tegaserod and the State of Drug Development for Functional and Motility Disorders
Section snippets
Tegaserod and Ischemia: Real or Fluke?
The abrupt nature of events took many by surprise. A large study of electrocardiographic changes in patients on tegaserod had been previously reported to show no significant effects of the drug.1 A reanalysis of these data by Novartis, based on the presence or absence of cardiovascular risk factors, reveals a higher frequency of ST-segment depression in high-risk patients on tegaserod (3.7% vs 1.3% on placebo). However, the company also reports that postmarketing cardiac events remained close
Serotonin Modulators and IBS: Not a Smooth Ride So Far
The cardiovascular risks with tegaserod is therefore relatively small, lacks satisfactory mechanistic explanation, and may reflect a fluke occurrence. However, these warnings follow those about ischemic colitis with the use of this drug about 3 years ago. This is the same condition that led to the withdrawal of alosetron (a 5-HT3 antagonist for diarrhea-predominant IBS) and indeed has been associated with several other agents in this class including Solvay’s cilansetron (another 5-HT3
Challenges in Drug Development for Functional and Motility Disorders
IBS exacts a huge toll on health care resources, estimated to be $33 billion per year in direct and indirect medical costs.3 What is even more surprising is that pharmacotherapy accounts for only 6% of the direct costs associated with IBS as compared with gastroesophageal reflux disease (GERD), where the corresponding figure is 63%.4
Why has development of drugs for FMD lagged behind other areas? Much of this has to do with the dearth of valid molecular targets to pursue. Drug discovery is a
Emerging Candidates and Paths Toward the Future
Much of the pharmaceutical effort over the past 2 decades has been preoccupied with serotonin and 2 of its receptors, 5-HT3 and 5-HT4. These are logical and attractive targets for drugs in this field because of their well-established role in initiating peristaltic and secretory reflexes in the gastrointestinal tract, as well as conveying sensory information to the central nervous system.10 However, their participation in downstream enteric circuitry and in the genesis of more complex
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