Effects of exercise and weight loss on mental stress-induced cardiovascular responses in individuals with high blood pressure.

The purpose of this study was to determine the effects of exercise and weight loss on cardiovascular responses during mental stress in mildly to moderately overweight patients with elevated blood pressure. Ninety-nine men and women with high normal or unmedicated stage 1 to stage 2 hypertension (systolic blood pressure 130 to 179 mm Hg, diastolic blood pressure 85 to 109 mm Hg) underwent a battery of mental stress tests, including simulated public speaking, anger recall interview, mirror trace, and cold pressor, before and after a 6-month treatment program. Subjects were randomly assigned to 1 of 3 treatments: (1) aerobic exercise, (2) weight management combining aerobic exercise with a behavioral weight loss program, or (3) waiting list control group. After 6 months, compared with control subjects, participants in both active treatment groups had lower levels of systolic blood pressure, diastolic blood pressure, total peripheral resistance, and heart rate at rest and during mental stress. Compared with subjects in the control group, subjects in the exercise and weight management groups also had greater resting stroke volume and cardiac output. Diastolic blood pressure was lower for the weight management group than for the exercise-only group during all mental stress tasks. These results demonstrate that exercise, particularly when combined with a weight loss program, can lower both resting and stress-induced blood pressure levels and produce a favorable hemodynamic pattern resembling that targeted for antihypertensive therapy.

Exercise and weight loss reduce blood pressure in men and women with mild hypertension: effects on cardiovascular, metabolic, and hemodynamic functioning.

BACKGROUND: Lifestyle modifications have been recommended as the initial treatment strategy for lowering high blood pressure (BP). However, evidence for the efficacy of exercise and weight loss in the management of high BP remains controversial. METHODS: One hundred thirty-three sedentary, overweight men and women with unmedicated high normal BP or stage 1 to 2 hypertension were randomly assigned to aerobic exercise only; a behavioral weight management program, including exercise; or a waiting list control group. Before and following treatment, systolic and diastolic BPs were measured in the clinic, during daily life, and during exercise and mental stress testing. Hemodynamic measures and metabolic functioning also were assessed. RESULTS: Although participants in both active treatment groups exhibited significant reductions in BP relative to controls, those in the weight management group generally had larger reductions. Weight management was associated with a 7-mm Hg systolic and a 5-mm Hg diastolic clinic BP reduction, compared with a 4-mm Hg systolic and diastolic BP reduction associated with aerobic exercise; the BP for controls did not change. Participants in both treatment groups also displayed reduced peripheral resistance and increased cardiac output compared with controls, with the greatest reductions in peripheral resistance in those in the weight management group. Weight management participants also exhibited significantly lower fasting and postprandial glucose and insulin levels than participants in the other groups. CONCLUSIONS: Although exercise alone was effective in reducing BP, the addition of a behavioral weight loss program enhanced this effect. Aerobic exercise combined with weight loss is recommended for the management of elevated BP in sedentary, overweight individuals.

Phase I evaluation of crisnatol (BWA770U mesylate) on a monthly extended infusion schedule.

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.

Phase I and clinical pharmacology trial of crisnatol (BWA770U mesylate) using a monthly single-dose schedule.

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.