Dose-ranging study to delineate the additive antihypertensive effect of guanabenz and captopril.

This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses--the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead-in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P less than .05) in a dose-related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hypertension.

Antihypertensive therapy with indoramin in the elderly.

The antihypertensive efficacy and safety of indoramin, an alpha 1-adrenergic antagonist, were evaluated in 215 elderly patients. Data were collected from patients aged 60 years and older who were treated under similar protocols with indoramin administered alone (n = 58) or in combination with a thiazide diuretic (n = 157). After at least 6 months of treatment, the mean daily dosage of indoramin was higher among patients who received indoramin alone (122 mg/day) than among those who received indoramin plus a diuretic (92 mg/day). Mean supine blood pressure decreased (p less than 0.001) from 174/105 to 152/191 mm Hg in indoramin-treated patients and from 179/101 to 150/91 mm Hg in patients who were treated with indoramin plus a diuretic. Clinically satisfactory blood pressure decreases occurred in the majority of the patients who received indoramin, either alone (69%) or with a diuretic (75%). Both treatments were well tolerated by elderly patients; only 15 patients (7%) discontinued therapy because of adverse effects. Drowsiness, fatigue, and dizziness were the most frequently reported side effects. The results of this analysis indicate that indoramin, administered alone or in combination with a thiazide diuretic, is a safe and effective therapeutic regimen for elderly hypertensive patients.

Effects of guanabenz in adolescent hypertension.

Fourteen adolescent patients, aged 12 to 21 years, with essential hypertension were treated on an open basis with guanabenz, a centrally acting antihypertensive agent. Guanabenz doses of 3-24 mg/day (0.08-0.20 mg/kg/day) given twice daily for 2 months effectively lowered mean supine blood pressure (p less than 0.05), standing blood pressure (p less than 0.01), and supine pulse rate (p less than 0.01). Body weight and standing pulse rate were unaffected. Adverse effects were mild, usually short lived, and did not interfere with therapy. No adverse effects were noted in laboratory test results or physical examinations. Baseline funduscopic photography revealed numerous but minor changes, including altered arteriovenous ratios and crossing changes. Prestudy echocardiograms revealed changes consistent with early hypertensive changes. Poststudy echocardiograms obtained in nine of the 14 subjects after 4-6 weeks of guanabenz therapy suggested that cardiac hypertrophy had regressed, but these changes did not reach statistical significance. These preliminary results suggest that guanabenz can be a safe and effective treatment for hypertensive children, that early hypertensive changes can be seen in the fundi and echocardiograms of mildly hypertensive adolescents, and that some echocardiographic changes may be reversed even after relatively short-term guanabenz therapy.

Antihypertensive therapy with guanabenz in patients with chronic obstructive pulmonary diseases.

The management of hypertension in patients with chronic obstructive pulmonary disease (COPD) may be complicated by the adverse effects of several antihypertensive agents on pulmonary function. The safety and antihypertensive efficacy of guanabenz, a centrally acting alpha-adrenergic agonist, were evaluated in 42 patients with asthma and 24 patients with other forms of COPD. Among the 64 patients with data evaluated for efficacy, pretreatment supine diastolic blood pressures (SDBP) were between 90 and 121 mm Hg (mean, 100 mm Hg). The patients were treated for 6 months with guanabenz as sole antihypertensive therapy in doses ranging from 8 to 64 mg/day (mean final dosage, 28 mg/day). At the end of the treatment period, a mean decrease in SDBP of 10 mm Hg was observed (p less than 0.001). Excellent or satisfactory blood pressure responses were obtained for 65% of the asthmatic patients and 83% of the patients with other forms of COPD. Mean supine pulse rate decreased by 7 beats/min (p less than 0.001), and mean body weight decreased by 2 lb. (p less than 0.05). Only one patient discontinued guanabenz treatment because of an exacerbation of asthma thought to be due to airway dryness. Because beta-adrenergic blocking agents, including the cardioselective drugs, have been known to exacerbate COPD, guanabenz treatment may be preferable as antiadrenergic antihypertensive therapy in patients with asthma and other forms of COPD.

Hypertension in patients with diabetes mellitus: treatment with a centrally acting agent.

This retrospective study was undertaken to evaluate the effectiveness and clinical characteristics of guanabenz, a centrally acting agent, as monotherapy in hypertensive patients with coexisting diabetes mellitus. Of 113 patients with data available for analysis, 21 were receiving concurrent therapy with insulin, 31 were receiving oral hypoglycemic agents, and 61 were being treated by a diabetic diet alone. During treatment with guanabenz (4-64 mg daily) for up to 2 years (mean duration, 7 months), diastolic blood pressure (measured in the supine posture) decreased by an average of 10 mm Hg; the effects were similar among the three subgroups of patients receiving the different diabetic therapies. Clinically satisfactory treatment outcomes occurred in 52%, 77%, and 57% of patients, respectively. Body weight remained constant throughout the study. The antihypertensive efficacy of guanabenz in this study and the nature and frequency of side effects produced were similar to those reported previously in nondiabetic hypertensive patients. Neither plasma glucose concentrations nor the diabetic therapy requirements of the diabetic patients in this study were altered by guanabenz treatment. There also was a small decrease in serum total cholesterol concentration (mean decrease, 15 mg/dl, p less than 0.001) during the study. Thus, antihypertensive monotherapy with guanabenz is effective in the treatment of a majority of patients with coexisting diabetes mellitus. Since it does not appear to interfere with the concurrent treatment of diabetes or cause unwanted metabolic side effects, guanabenz may be a rational and safe agent for the management of hypertension in the diabetic patient.

Guanabenz for adolescent hypertension.

Guanabenz, a centrally acting antihypertensive agent that acts through stimulation of central alpha-adrenergic receptors, appears to produce neither sodium retention nor clinically significant renal, cardiac, hepatic, or metabolic abnormalities. This 2-month open, uncontrolled dose-finding and short-term safety and efficacy trial was conducted in 11 male outpatients (12 to 21 years old) to establish the potential use of guanabenz in treating children with hypertension. Doses of 3 to 12 mg/day (0.07 to 0.17 mg/kg/day) given twice daily effectively lowered blood pressure in all patients. Mean supine blood pressure was significantly (P less than 0.05) reduced from 135/91/81 mmHg (phase I/IV/V) at baseline to 124/80/66 mmHg after approximately 2 months of treatment. Mean supine pulse rate also was significantly (P less than 0.05) reduced (10 beats/minute), while standing pulse rate and body weight were unaffected by guanabenz therapy. Adverse effects, the most common being headache, dry mouth, and drowsiness, were generally mild and did not interfere with continued therapy. No abnormal findings were noted in laboratory test results or physical examinations. These preliminary results suggest that guanabenz is safe and effective for the treatment of childhood hypertension.

Double-blind multicenter comparison of cyclacillin and amoxicillin for the treatment of acute otitis media.

A multicenter double-blind study of 363 pediatric outpatients with acute otitis media demonstrated that cyclacillin, administered in three divided doses (three times a day) for ten days, is as effective as and better tolerated than a similar regimen of amoxicillin. The bacteriologic cure rate for patients with middle-ear cultures was 98% in both treatment groups. Remission of signs and symptoms was significantly faster in the cyclacillin group (3.1 days) than in the amoxicillin group (4.3 days) (P less than 0.05). Of the 179 children treated with cyclacillin, three (1.7%) had drug-related diarrhea in contrast to 18 of the 184 (9.8%) children treated with amoxicillin (P less than 0.01). Cyclacillin produces a rapid resolution of symptoms and a low incidence of diarrhea.

Evaluation of guanabenz added to hydrochlorothiazide therapy in hypertension.

Guanabenz, a centrally acting alpha-adrenergic antihypertensive agent, produces neither the sodium retention seen with other centrally acting agents nor the metabolic abnormalities characteristic of diuretics. In this study, which involved 204 hypertensive out-patients, the additive effects of guanabenz and hydrochlorothiazide were compared with the effects of hydrochlorothiazide therapy alone. Before randomization to the 6-month blinded addition of either guanabenz or placebo, hydrochlorothiazide (50 or 100 mg/day; mean, 70 mg/day) was administered as sole therapy for 6 weeks. During this time, mean supine diastolic blood pressure (SDBP) decreased from 102 to 94 mm Hg (p less than 0.01), with a satisfactory clinical response rate of 62% and a mean weight loss of 2 lbs (p less than 0.01). No further change in mean SDBP occurred during the next 6 months of diuretic therapy, whereas the addition of guanabenz (mean dose, 24 mg/day) caused a further decrease in mean SDBP to 88 mm Hg (p less than 0.01), an increase in the response rate to 86%, and no weight change. Pulse rates in both groups were unchanged. The principal side-effects in both groups were dry mouth, drowsiness, weakness, and dizziness, with a greater incidence of each during the combination therapy. The usual laboratory abnormalities were associated with hydrochlorothiazide. Guanabenz was found to enhance the antihypertensive efficacy of hydrochlorothiazide without compromising its natriuretic properties or producing additional metabolic abnormalities.

Comparative antihypertensive effects of guanabenz and clonidine.

The safety and efficacy of guanabenz and clonidine were compared in 188 hypertensive patients during a 6-month double-blind trial. Mean supine diastolic blood pressure (SDBP) decreased from 103 to 88 mm Hg (p less than 0.01) among guanabenz patients and from 101 to 88 mm Hg (p less than 0.01) among clonidine patients who completed 6 months of b.i.d. therapy. Clinically significant individual SDBP decreases occurred in 85% of the guanabenz patients and 83% of the clonidine patients after 6 months. Adverse effects, consisting primarily of drowsiness, dry mouth, dizziness, and weakness, were similar in the two therapy groups. The responses obtained with guanabenz (b.i.d.) were maintained, along with a decrease in adverse effects, by an equivalent single daily dose of guanabenz during a second 6 months of therapy. Seventy-six per cent (13/17) of the patients whose blood pressure was not adequately controlled by guanabenz alone after 8 weeks of therapy subsequently responded to a combination of guanabenz and hydrochlorothiazide. Similarly, 85% (17/20) of the patients who failed to respond to clonidine alone subsequently responded to guanabenz either alone or in combination with hydrochlorothiazide. These results suggest that guanabenz or the combination of guanabenz and hydrochlorothiazide is effective therapy for the majority of hypertensive patients.

Long-term therapy of hypertension with guanabenz.

Guanabenz, a centrally acting antihypertensive (alpha-agonist) that does not induce secondary sodium retention or other metabolic disturbances, was evaluated for up to two years at 19 investigational sites. In 329 patients completing six months of therapy, the mean supine diastolic blood pressure (SDBP) fell from 101 to 90 mmHg (P less than 0.01). Clinically significant individual SDBP decreases occurred in 74% of the patients by week 2, and these reductions were maintained in 72% at six months. Mean weight was reduced 1.4 lb (P less than 0.01), and mean supine pulse rate was decreased 5 beats/min (P less than 0.01). The most frequent effective doses were 8 and 16 mg BID (range, 2 to 32 mg BID). Principal side effects, usually mild, were sedation (31%), dry mouth (24%), dizziness (6%), and weakness (6%). Postural hypotension, impotence, and abrupt discontinuation symptoms were rare or absent. There were no clinically significant drug-related laboratory changes other than a 10 mg/100 ml mean serum cholesterol decrease. Two hundred twenty-two patients completed one year of therapy, and 80 completed two years, with little change in any parameters other than improvement in mean SDBP to 85 mmHg and in individual response rate to 84%. These results suggest that guanabenz is safe and effective for initial and sole therapy of hypertension.

Comparative antihypertensive effects of guanabenz and methyldopa.

The effects of guanabenz acetate, a centrally acting alpha-adrenergic, non-sodium-retaining antihypertensive agent, were compared with those of methyldopa in 248 hypertensive outpatients during a one-year, double-blind, multi-center study. Mean supine diastolic blood pressure (SDBP) decreased from 102 to 91 mmHg (P less than 0.01) among 78 guanabenz-treated patients and from 101 to 92 mmHg (P less than 0.01) among 89 methyldopa-treated patients who completed six months of treatment. Clinically significant individual SDBP decreases occurred in 76% of the guanabenz-treated patients and in 63% of the methyldopa-treated patients (P less thn 0.05). Blood pressure remained unchanged during the second six months, with response of 82% and 60%, respectively, for guanabenz and methyldopa (P less than 0.05). Although drowsiness and dry mouth occurred more frequently with guanabenz, evidence of fluid retention, such as weight gain, edema, and congestive heart failure, was significantly more frequent with methyldopa than with guanabenz. Because it does not induce volume expansion, guanabenz, unlike methyldopa, may be useful as sole initial antihypertensive therapy.

Clinical experience with a human diploid cell rabies vaccine.

Between January 1975 and December 1977 the Center for Disease Control treated 255 persons with the human diploid cell strain rabies vaccine who did not have development of an antibody titer to duck embryo vaccine (DEV) or who were at risk for having a serious reaction to DEV. Two hundred eighteen persons were treated postexposure, and 37 persons were treated preexposure. The antibody response to the vaccine was excellent, and the reaction rates were low. No person treated has had development of rabies. This study corroborates other studies that suggest that the human diploid cell strain rabies vaccines are safe and induce excellent antibody titers to rabies.

Postexposure trial of a human diploid cell strain rabies vaccine.

A human diploid cell strain vaccine (HDCV) was evaluated in 90 persons treated after exposure to rabies, 21 of whom were bitten by proven rabid animals. Intramuscular doses of HDCV were given on days 0, 3, 7, 14, and 28, and human rabies immune globulin (HRIG) was given on day 0. Antibody to rabies virus was tested for by the rapid fluorescent focus inhibition test; adverse reactions were assessed from physician's forms. All 87 persons tested developed titers of greater than or equal to 0.5 international units (IU)/ml, with a maximum geometric mean titer of 15.0 IU/ml on day 42. One year after vaccination, all 33 persons tested had antibody to rabies virus. After one or more doses of vaccine, mild local or systemic reactions were reported in 19.0% and 21.4% of persons, respectively. No serious reactions occurred. The results show that this HDCV (plus HRIG) was safe and effective in eliciting antibody in postexposure prophylaxis of rabies. When it becomes available, it is recommended over the present treatment regimen.

Double-blind clinical trials of oral cyclacillin and ampicillin.

A double-blind study was performed to compare the clinical response and the incidence of side effects in 2,581 patients administered ampicillin or cyclacillin for infections of the genitourinary or respiratory tract, infections of the skin and soft tissues, or for otitis media. There was no significant difference in clinical response and bacterial eradication. All side effects, including diarrhea and skin rash, were approximately twice as frequent in patients treated with ampicillin.