Critical assessment of combination therapy development.
Although antihypertensive treatment has been found to reduce cardiovascular morbidity and mortality, hypertensive patients are still at a significantly increased risk compared with normotensive controls. One of the reasons is that blood pressure control is often suboptimal. In fact, less than 40% of patients reach the target set by the treating physician. The development of wisely chosen fixed combinations could be one means, among others, to improve blood pressure control without compromising tolerability. The prescription, in a single pill, of two antihypertensive agents has the potential advantage of improving compliance by reducing the number of pills that need to be taken per day. There should be a pharmacological rationale, with the two agents having different and complementary modes of actions to reduce blood pressure: for example, a vascular selective calcium antagonist lowers total peripheral resistance and a beta-blocker lowers heart rate and, thus, cardiac output. These drugs can also mutually neutralise some of each others' side-effects, such as the initial heart rate increases which may occur with dihydropyridine calcium antagonists, and the rise in peripheral resistance elicited by some beta-blockers. The creation of a fixed-dose combination for effective and safe treatment of hypertension requires a complex programme of development. An example is the formulation of a combination tablet of felodipine and metoprolol in which extended-release techniques were applied to ensure that blood pressure control was maintained throughout the 24-h dosing interval. Evaluation included pharmacokinetic studies of the formulation, interaction studies and clinical trials of crossover and parallel-group designs to establish the 24-h efficacy and safety of the product.(ABSTRACT TRUNCATED AT 250 WORDS)
Ménard
J
J
Service de Médecine Préventive Cardio-Vasculaire, Hôpital Broussais, Paris, France.
D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004338:Drug Combinations; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic
D000959:Antihypertensive Agents; D004338:Drug Combinations