Heart rate and the rate-pressure product in patients with hypertension: the usefulness of chronotherapy

A chronotherapeutic approach to the management of hypertension and cardiovascular disease considers the circadian (day-night and/or awake-sleep cycles of the 24 h) rhythm of the body's internal clock. Therapies that focus on triggers of early morning cardiovascular events, such as increased heart rate and rate-pressure product and activation of the sympathetic nervous system? are preferable. Therefore, the rational choice in developing a chronotherapeutic antihypertensive, anti-anginal agent was to design a unique delivery system for the phenylalkylamine calcium antagonist verapamil. This agent has been demonstrated to reduce blood pressure, heart rate, and the rate-pressure product. To match drug delivery to the circadian blood pressure. heart rate and myocardial ischaemia rhythms, a controlled-onset extended-release delivery system (commercially available as GOER-24(TM)) was developed. This delivery system delays release of verapamil by approximately 4-5 h after administration. When taken at bedtime, GOER-24 verapamil hydrochloride (HCl) provides optimal drug concentrations approximately 11 h post-dosing, a time period that typically coincides with the early morning surge in blood pressure and heart rate. Pooled data from three randomized, double-blind and placebo-controlled clinical trials with GOER-24 verapamil HCl demonstrate that the previously repelled ability of this agent to reduce the rate-pressure product at peak times for myocardial ischaemia and other events is maintained in several subgroups of patients and may even be enhanced in women and older patients. The ongoing Controlled ONset Verapamil INvestigation of Cardiovascular End-points will provide data on the effectiveness of GOER-24 verapamil HCl in reducing cardiovascular endpoints.