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Orthostatic intolerance induced by the 5‐HT2C antagonist SB‐247853 in healthy volunteers during head‐up tilting
Author(s) -
Theis J. G.,
McEniery C. M.,
Maltby K.,
Overend P.,
Price J. A.,
Smith T.,
Ostenfeld T.,
Wilkinson I.,
Brown J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.143
Subject(s) - medicine , orthostatic intolerance , placebo , orthostatic vital signs , supine position , heart rate , antagonist , blood pressure , clinical pharmacology , anesthesia , pharmacology , receptor , pathology , alternative medicine
Background SB‐247853 is a highly specific 5‐HT2c receptor antagonist. During the first dose‐escalation study, 6 mg SB‐247853 induced orthostatic intolerance in healthy volunteers. Therefore, we performed a study using head‐up tilting (HUT) to investigate the propensity of SB‐247853 to induce orthostatic intolerance. Methodology Single‐blind, placebo controlled, non‐randomised, cross‐over study in 8 healthy male volunteers. Head‐up tilt‐table challenges lasting for 10 minutes were performed 2.5 and 3.5 hours after administration of placebo (day 1) and 6 mg SB‐247853 (day 2). Results While the volunteers were in supine position, SB‐247853 had no effects on blood pressure (BP), heart rate (HR) or cardiac output (CO). During HUT, five SB‐247853‐treated volunteers became presyncopal 3 to 9 minutes after onset of HUT. In contrast, only one placebo‐treated subject became presyncopal 9 minutes after the onset of HUT. The main characteristics of the presyncopal events were large reductions in systolic and diastolic BP with a slight or no decrease in HR and no significant reduction in CO. Conclusions 5‐HT2c receptor antagonism interferes with the ability to maintain cardiovascular homeostasis over time during HUT. The observed orthostatic intolerance appears to be of the vasodepressor type. This indicates that the 5‐HT2c receptor is involved in the regulation of cardiovascular tone during orthostatic stress. Clinical Pharmacology & Therapeutics (2005) 77 , P66–P66; doi: 10.1016/j.clpt.2004.12.143