Tetrahydrobiopterin: a novel antihypertensive therapy.

Tetrahydrobiopterin (BH(4)) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH(4) will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH(4) was given to subjects with poorly controlled hypertension (BP >135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg(-1) day(-1) of BH(4) (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH(4) (n=16) was given in divided doses for 4 weeks. Study 1: significant reductions in systolic (P=0.005) and mean BP (P=0.01) were observed with both doses of BH(4). Systolic BP was 15+/-15 mm Hg (P=0.04) lower after 5 weeks and persisted for the 8-week study period. Study 2: subjects given 400 mg BH(4) had decreased systolic (P=0.03) and mean BP (P=0.04), with a peak decline of 16+/-19 mm Hg (P=0.04) at 3 weeks. BP returned to baseline 4 weeks after discontinuation. Significant improvement in endothelial function was observed in Study 1 subjects and those receiving 400 mg BH(4). There was no significant change in subjects given the 200 mg dose. This pilot investigation indicates that oral BH(4) at a daily dose of 400 mg or higher has a significant and sustained antihypertensive effect in subjects with poorly controlled hypertension, an effect that is associated with improved endothelial NO bioavailability.

Tuberculous meningitis at a large inner-city medical center.

Tuberculosis in the United States has become primarily an inner-city disease. We examined the epidemiology of culture-confirmed tuberculous meningitis among patients cared for at an urban public hospital in Atlanta. During an 11.5-year period (January 1984-June 1995) cerebrospinal fluid cultures for Mycobacterium tuberculosis were positive in 34 patients, accounting for 1.5% of all culture-confirmed tuberculosis cases. All patients were born in the United States, 31 (91%) were black, 16 (47%) of 34 were human immunodeficiency virus (HIV) seropositive, 9 (26.5%) were HIV seronegative, and 9 (26.5%) had an unknown HIV serostatus. No significant differences were seen in clinical presentation, cerebrospinal fluid, or other laboratory data between HIV seropositive and HIV seronegative/ unknown groups, except for a lower serum white blood cell count among HIV seropositive patients. Mortality was striking; 14 (41.2%) died because of tuberculous meningitis despite appropriate therapy initiated a mean of 3 days after admission. Six survivors had permanent neurologic sequelae. Univariate analysis of outcome was not statistically associated with any measured demographic, laboratory value, stage at presentation, treatment regimen, or HIV serostatus. Multivariate analysis of outcome using 13 independent variables also demonstrated no significant association between these variables and outcome, although a trend was seen for increased mortality for white people (P = 0.09) and increasing age (P = 0.09). Tuberculous meningitis among inner-city residents remains a devastating disease associated with high morbidity and mortality that has changed little during the past 4 decades. HIV infection does not change markedly the clinical presentation or the response to therapy.