A dose-titration trial of guanadrel as step-two therapy in essential hypertension.

The efficacy and safety of low-dose guanadrel sulfate were evaluated in 20 patients with essential hypertension based on seated diastolic blood pressures (SDBP) ranging from 95 to 115 mm Hg despite a trial dosage of hydrochlorothiazide 50 mg/d for up to five weeks. These patients had been resistant to, or intolerant of, one or more step-two antihypertensive drugs in the past (i.e., methyldopa, beta-adrenergic blocking agents, clonidine, or prazosin). The majority of patients demonstrated a satisfactory response (SDBP 95 mm Hg or reduction in SDBP of 10 mm Hg) to guanadrel. Nine patients responded at a low dosage, 10 to 20 mg/d and remained free from adverse effects throughout the study (up to 12 weeks of treatment). Of the remaining 11 patients titrated to higher dosages of guanadrel (30 to 60 mg/d), three had no discernible response while six developed adverse effects. The results of the study suggest that guanadrel has an acceptable benefit-to-risk ratio only when used in low dosages (10 to 30 mg/d) and may be successfully employed as step-two antihypertensive therapy in patients resistant to, or intolerant of, other step-two agents.

Crossover comparison of captopril and propranolol as step 2 agents in hypertension.

The efficacy of captopril treatment was compared with that of propranolol in a single-blind crossover study in 14 patients with essential hypertension uncontrolled on diuretic alone. Both captopril (37.5 to 75 mg daily) and propranolol (60 to 120 mg daily), in combination with hydrochlorothiazide (50 mg daily), caused a significant fall in sitting systolic and diastolic blood pressure. Heart rate, plasma renin activity, and plasma aldosterone data were consistent with the effects of converting enzyme inhibition or beta blockade. Both drugs were well tolerated. Captopril appeared to be equivalent in efficacy and safety to propranolol when added to hydrochlorothiazide. It may be considered as an alternative step 2 antihypertensive agent, especially in patients experiencing unwanted effects on beta blockers.

Effect of captopril and hydrochlorothiazide on the response to pressor agents in hypertensives.

The effect on arterial pressure of incremental doses of norepinephrine (2 to 10 micrograms/min) and angiotensin II (50 to 800 ng/min) administered over 10 min periods was studied in sodium-replete hypertensive patients after crossover oral treatments with placebo, captopril 50 mg in a single dose, captopril 50 mg three times daily for one week and hydrochlorothiazide 50 mg daily for a week. Neither captopril nor hydrochlorothiazide affected the dose response to infusions of angiotensin II. In comparison to placebo responses, however, both single and multiple-dose captopril therapy, and hydrochlorothiazide attenuated the pressor responses to infusions of norepinephrine. Captopril significantly depressed angiotensin converting enzyme activity from pre-dose levels and angiotensin II infusions significantly elevated plasma aldosterone concentrations. These results confirm findings reported for single dose captopril in normotensive volunteers and indicate that attenuation of the vascular responsiveness to sympathetic stimulation may contribute to the antihypertensive effects of captopril and hydrochlorothiazide therapy.

Disposition of intravenous and intraperitoneal cefoxitin during chronic intermittent peritoneal dialysis.

The disposition of intravenous and intraperitoneal administered cefoxitin was evaluated in four males undergoing intermittent peritoneal dialysis. Each patient received 1 g of cefoxitin intravenously prior to an eight-hour dialysis; subsequently, one patient received another 1 g intravenous dose prior to an 18-hour dialysis while each of the other three patients had 100 mg of cefoxitin added to their eight hourly exchanges of dialysis fluid with 2 L per exchange. Serial blood, dialysate, and urine samples were collected and analyzed for cefoxitin by a microbiologic assay. Twenty-four hours after intravenous administration, serum cefoxitin concentrations were greater than 16 micrograms/mL (therapeutic breakpoint) in each patient. Mean cefoxitin dialysate concentrations averaged 7.8 +/- 3.8 micrograms/mL and were greater than 16 micrograms/mL in only 2 of 43 exchanges. After intraperitoneal administration, serum cefoxitin concentrations were highest after the eighth exchange (range 5.6 to 10.6 micrograms/mL). Thus, diffusion of cefoxitin across the placental membrane was not extensive. Dialysis removed only 10% to 20% of the intravenous dose.

Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination.

Enalapril maleate is an investigational oral prodrug whose hydrolyzed diacid metabolite is a potent angiotensin-converting enzyme inhibitor. Fourteen patients with mild to moderate hypertension were evaluated after receiving placebo, and two weeks of treatment with each of the following: enalapril maleate (20 mg b.i.d.), hydrochlorothiazide (25 mg b.i.d.), and the two in combination. In comparison to placebo, the magnitudes of the blood pressure reduction after enalapril and hydrochlorothiazide alone were comparable. The reduction in blood pressure following enalapril was evident throughout the 12-hour dosing interval. The combination of enalapril and hydrochlorothiazide resulted in a marked further reduction in blood pressure that was greater than that predicted from the responses to the individual drugs (P less than 0.05). Biochemical parameters confirmed inhibition of angiotensin-converting enzyme during enalapril treatment; serum angiotensin-converting enzyme activity proved an excellent monitor of compliance. Enalapril was generally well tolerated. Adverse effects included symptomatic hypotension in three patients when enalapril was first added to hydrochlorothiazide and hyperesthesia of the oral mucosa without a loss of taste in one patient on enalapril. Enalapril maleate alone and especially in combination with hydrochlorothiazide appears to be an effective, well-tolerated converting enzyme inhibitor with at least a 12-hour duration of action.

Effect of captopril and propranolol, alone and in combination, on the responses to isometric and dynamic exercise in normotensive and hypertensive men.

This study evaluated the effects of single doses of the angiotensin converting enzyme inhibitor captopril and the beta-adrenergic blocking agent propranolol, alone or in combination, on the blood pressure, heart rate and humoral responses to both isometric (handgrip) and dynamic (ergometric) exercise in normotensive and hypertensive men. Single oral doses of either placebo, captopril 50 mg, propranolol 80 mg, or the latter two in combination were administered to age-matched groups (n = 5) of normotensive and hypertensive men in a random, double-blind manner. Captopril alone was indistinguishable from placebo after both isometric and ergometric exercise. Propranolol suppressed heart rate after both types of exercise and tended to decrease systolic blood pressure only in the hypertensive group; combination with captopril did not alter these responses. These data suggest that in sodium-replete subjects undergoing short-term vigorous exercise, the renin-angiotensin system, as measured by captopril inhibition, is less important than the sympathoadrenal system, as measured by propranolol inhibition, in the reflex cardiovascular adjustments accompanying acute isometric and dynamic exercise in both normotensive and hypertensive men.

Relationships among timolol doses, plasma concentrations and beta-adrenoceptor blocking activity.

1 We investigated the relationships among dose, plasma concentration and beta-adrenoceptor blockade after single and repeated doses (0.5-20 mg) of timolol and placebo in six normal men. 2 Maximal suppression of exercise-induced tachycardia (bicycle ergometry) was dose-dependent and greater at 2 than at 6 h after dosing; activity up to 12 h was evident on the last dosing day. 3 Attenuation of exercise-induced tachycardia was strongly correlated with the timolol dosage over the 0.5 to 5-10 mg range. 4 A plasma timolol concentration of 27 ng/ml was associated with maximal suppression of exercise-induced tachycardia. 5 Suppression of exercise-induced tachycardia and areas under the plasma concentration-time curves did not differ significantly on the first and last dosing days.

Comparison of the effects of captopril, diuretic and their combination in low- and normal-renin essential hypertension.

The purpose of this study was to compare the effects of captopril (CAP) and hydrochlorothiazide (HTZ), alone and in combination, on mean (+/- S.D.) blood pressure (BP), plasma renin activity (PRA), and plasma aldosterone concentration (PAC) in equal groups of six patients with low-renin and normal-renin essential hypertension. Renin classification was determined after furosemide (80 mg) stimulation; control measurements were made after each patient had been off all medications for at least 1 week. After a single 25 mg dose of CAP, BP decreased, PRA increased, and PAC decreased more (p less than 0.05) in the normal- than in the low-renin group. Each patient was then given the following in sequence for at least 2 weeks: CAP 25 mg t.i.d., HTZ 50 mg/day, and the combination. The results at the end of each treatment period indicated a modest, but significant reduction in blood pressure in both groups following CAP and HTZ; the effect of the combination was additive. Within each renin group under similar conditions there was no significant difference in mean PRA or PAC after each treatment. Thus, while the short-term effect of CAP on BP differed in patients with low- and normal-renin essential hypertension, the effect after chronic CAP was similar, comparable to that of HTZ and additive in combination in both groups.

Adrenocortical function after chronic inhalation of fluocortinbutyl and beclomethasone dipropionate.

Fluocortinbutyl (FCB) is a C-21 ester, topically active corticosteroid; no adrenal suppression has been noted after large doses. We compared safety and effects on adrenocortical function of orally inhaled FCB (40 mg/day), beclomethasone dipropionate (BDP) (2 mg/day), and placebo administered in four monitored divided doses for 4 wk by three groups of five healthy men. Circadian plasma cortisol concentration and daily urinary free cortisol excretion were determined before and after 3- and 4-wk exposure. Although pretreatment mean area under the curve (micrograms . hr . dl-1) for plasma cortisol did not differ among groups, mean values after weeks 3 and 4 of treatment were lower (p less than 0.05) in the BDP group (95.1 and 83) than in the FCB (155.8 and 153.7) and placebo (141 and 135.8) groups. Mean urinary cortisol excretion after week 4 for the BDP group (29 micrograms) was less (p less than 0.05) than in the FCB (59 micrograms) and the placebo (69 micrograms) groups. Slopes of individual regression lines noting time trends in plasma and urinary cortisol in the BDP group were negative and less (p less than 0.05) than those of the other groups. A cosyntropin test given intravenously after 4 wk of exposure resulted in similar plasma cortisol responses among groups. No serious adverse effects were noted. Thus after long-term high-dose treatment BDP but not FCB suppressed basal adrenocortical function, but neither suppressed the adrenocortical response to cosyntropin.