If this is not your name, click here.
| | If this is not your name, click here. | | |
| | Contact Us | Order Now | Journals | Bookstore | Register a colleague | | |
| |  ACCP: Researchers Investigate Headaches Caused By New Drug, BMS-207940 By Mike Fillon TAMPA, FL -- October 6, 2003 -- Headaches associated with an experimental hypertension and heart failure drug are influenced by dose and exposure to the agent. Tolerance to this side effect appears to build up within a couple of weeks. Inhibition of endothelin (ET) receptors is a potential therapy for hypertension and heart failure. BMS-207940 is a unique selective endothelin A (ETA) receptor antagonist developed by Bristol-Myers Squibb. In several preclinical models, BMS-207940 lowered blood pressure. In phase 1 studies, headache was the most frequent adverse effect associated with oral administration. Recently, researchers undertook two studies to investigate why. In study CV154004, they assessed the temporal pattern of headache attributable to BMS-207940. In study CV154007, they assessed the biotransformation and mean balance of the drug. In a retrospective analysis of the two studies the researchers investigated the relationship between (ETA) inhibition, plasma concentration of BMS-207940 and its metabolites and headache. Results of the study were presented at the 32nd Annual Meeting of the American College of Clinical Pharmacology (ACCP) by Simon Zhou, PhD of Bristol-Myers Squibb. For the CV154004 trial, 15 healthy subjects were randomly assigned in a 1:1:1 ratio to one of three dosing groups. Group A received once-daily doses of 2.5 mg of BMS-207940 for one week and then 10 mg for a second week. Group B received 10 mg for two weeks. Group C received matching placebo for two weeks. Serial blood samples were taken for pharmacokinetic assessment, and all subjects reported headache intensity scores using a scale of 1 to 10. Transcranial Doppler ultrasound of middle cerebral artery blood flow velocity was obtained in a subset of subjects, who in the opinion of the investigator were experiencing significant headaches. For the CV154007 open label trial, nine healthy subjects received a single oral dose of 10 mg of BMS-207940 following an overnight fast. Blood samples were collected for 120 hours post-dose. Plasma radioactivity and concentration of BMS-207940 were measured. Urine and faecal samples were collected over seven days for assessment of total mass balance. The major metabolites in plasma, urine and faecal samples were isolated and identified. The researchers concluded that the headaches caused by BMS-207940 related to dose and exposure, which peaked on days three and four. Tolerance appeared to develop after repeated doses within two weeks. The peak headache effect caused by BMS-207940 was associated with increased cerebral blood flow. The time of peak headache effect correlated well with the achievement of steady state plasma levels of BMS-207940 plus its active metabolite. Bristol-Myers Squibb sponsored the study.
[Study title: CV154004: PK and tolerance in healthy volunteers & CV154007: Mass Balance studies.]
|
