The Safety, Pharmacokinetics, and Nervous System Effects of Two Natural Sources of Caffeine in Healthy Adult Males.

This double-blind crossover clinical trial randomized 12 adult males to receive 200 mg of caffeine from a green coffee extract, a guayusa leaf extract, and a synthetic control to compare their safety, absorption, and effect on neurotransmitters. The results showed no statistically significant changes in blood pressure or heart rate from baseline to 120 min postdose of each natural source compared with changes from baseline in the control (0.094 < = P < = 0.910). The ratios of Cmax , AUC0-4 , and AUC0-∞ of each natural source to the control were bioequivalent by US Food and Drug Administration standards (90% CI within 80-125%). The guayusa leaf extract stimulated a significantly lower increase in epinephrine compared with the control (+0.5 vs. +2.78 µg/gCr, P = 0.04), while the green coffee extract provoked an increase in epinephrine similar to the control (+3.21 vs. +2.78 µg/gCr, P = 0.569). Implications for future clinical research are discussed.

Mechanisms in obesity-related hypertension: role of insulin and catecholamines.

Although the association of obesity and hypertension is well recognized, the mechanisms involved in the pathogenesis of increased blood pressure in the obese are poorly understood. Recent studies addressing the impact of 1) body fat distribution on blood pressure and 2) dietary intake on sympathetic nervous system (SNS) activity suggest a plausible hypothesis that relates the hypertension of the obese to hyperinsulinemia and SNS stimulation. Hypertension in the obese is associated with fat accumulation in the upper body segments; this type of obesity is also characterized by hyperinsulinemia and insulin resistance. Insulin, moreover, is an important signal in the relationship between dietary intake and SNS activity: increased insulin levels are associated with SNS stimulation. The hyperinsulinemia of obesity may, therefore, increase blood pressure by 1) direct effects of insulin to stimulate renal sodium reabsorption, and 2) sympathetic stimulation of the heart, blood vessels, and kidney. Conversely, SNS suppression and diminished insulin following caloric restriction may explain the hypotensive effects of caloric restriction in obese hypertensive subjects. The hypothesis presented here emphasizes the important role of diet in the treatment of obese hypertensive subjects. The efficacy of caloric restriction, weight loss, and exercise in reducing blood pressure in the obese is linked to diminished insulin and SNS activity and may be viewed as evidence in favor of this hypothesis.

Obesity, metabolism, and the sympathetic nervous system.

The association of hypertension and obesity is poorly understood. Studies conducted in our laboratory over the last decade, in conjunction with recent clinical and epidemiological observations, suggest that hypertension in the obese is derived from a fundamental relationship between dietary intake and sympathetic nervous system (SNS) activity. The application of kinetic techniques to the measurement of norepinephrine (NE) turnover rate in sympathetically innervated tissues of laboratory rodents has defined a relationship between the SNS and dietary intake. Fasting or caloric restriction suppresses sympathetic activity in a variety of organs of the rat, including heart and interscapular brown adipose tissue. Overfeeding a mixed, palatable, "cafeteria" diet stimulates sympathetic activity in these same tissues. The stimulatory effect of mixed diets is due to the carbohydrate and fat content, because these two latter nutrients stimulate sympathetic activity even when total caloric intake is not increased. Insulin-mediated glucose metabolism within central neurons associated with the ventromedial hypothalamus (VMH) plays an important role in the relationship between dietary intake and SNS activity as indicated by the following observations: (1) Hypoglycemia (noninsulin-mediated) is associated with suppression of the SNS (despite concomitant adrenal medullary stimulation); (2) 2-deoxyglucose, an intracellular inhibitor of glucose metabolism, decreases sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity.

The safety and efficacy of a mixture of ephedrine (75-150mg), caffeine (150mg) and aspirin (330mg), in divided premeal doses, were investigated in 24 obese humans (mean BMI 37.0) in a randomized double blind placebo-controlled trial. Energy intake was not restricted. Overall weight loss over 8 weeks was 2.2kg for ECA vs. 0.7 kg for placebo (p < 0.05). 8 of 13 placebo subjects returned 5 months later and received ECA in an unblinded crossover. After 8 weeks, mean weight loss with ECA was 3.2 kg vs 1.3 kg for placebo (p = 0.036). 6 subjects continued on ECA for 7 to 26 months. After 5 months on ECA, average weight loss in 5 of these was 5.2 kg compared to 0.03 kg gained during 5 months between studies with no intervention (p = 0.03). The sixth subject lost 66 kg over 13 months by self-imposed caloric restriction. In all studies, no significant changes in heart rate, blood pressure, blood glucose, insulin, and cholesterol levels, and no differences in the frequency of side effects were found. ECA in these doses is thus well tolerated in otherwise healthy obese subjects, and supports modest, sustained weight loss even without prescribed caloric restriction, and may be more effective in conjunction with restriction of energy intake.