Robert R. Luther

Overall safety of terazosin as an antihypertensive agent

The safety of terazosin, an effective agent for the treatment of hypertension, was assessed by analyzing data from 1,006 hypertensive patients who were enrolled in short-term and/or long-term studies. The total experience with terazosin in this article represents 422.5 patient-years. Changes in pulse rate measurements from pretreatment to posttreatment were not significantly different between the terazosin- and placebo-treated patients (-1.0 beat per minute for the terazosin group and -1.0 beat per minute for the placebo group, in the supine position). Dizziness, headache, and asthenia were the most commonly reported adverse experiences among all terazosin-treated patients, although the incidence of headache in placebo-controlled trials was not significantly different between the terazosin and placebo groups. As a whole, patients receiving terazosin had a tendency to gain small amounts of weight (2 pounds). In addition, there was a trend for slight decreases in hemoglobin, hematocrit, white blood cell count, total protein, and albumin levels in those patients who received terazosin, suggesting hemodilution. Overall, terazosin was shown to be safe in patients with mild to moderate essential hypertension.

The effects of terazosin and methyclothiazide on blood pressure and serum lipids.

This study compared the antihypertensive efficacy and the effects on serum lipids of terazosin, a new selective alpha 1-adrenergic antagonist, of methyclothiazide (MCTZ), and of the two drugs used as combination therapy. Adult patients with supine diastolic blood pressure ranging from 95 to 120 mm Hg were eligible to enter this double-blind, randomized, parallel-group study. Analyses of the blood pressure data from the 194 evaluable patients revealed that all three treatments produced significant (p less than 0.001) reductions in supine and standing systolic and diastolic blood pressures from baseline values. Moreover, combination therapy resulted in significantly greater mean blood pressure reductions than were observed with either drug used as monotherapy. In the group receiving terazosin monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level fell significantly (median changes of 3.7%, 5.0%, and 16.3%, respectively, p less than 0.05). However, in the group receiving MCTZ monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level increased significantly (4.7%, 7.1%, and 12.5%, respectively, p less than 0.001). In contrast, no significant changes from baseline values were observed for any lipid variable in the group receiving terazosin/MCTZ combination therapy. We conclude that terazosin is effective antihypertensive therapy that has a potentially beneficial effect on the serum lipid profile when used as monotherapy and that it counteracts the negative impact of MCTZ monotherapy on the serum lipid profile when used concurrently with this thiazide diuretic.

Efficacy of terazosin as an antihypertensive agent.

A total of 713 patients with hypertension were evaluated in eight randomized, double-blind, placebo-controlled trials of terazosin administered in single daily doses ranging from 1 to 40 mg. In three of these studies, terazosin or placebo was added to ongoing antihypertensive drug therapy. Patient response was categorized (from excellent to inadequate) according to the change in supine diastolic blood pressure from baseline and the value at the final visit. The distribution of patients in these response categories differed significantly between patients treated with terazosin and those treated with placebo. Overall, 52 percent of terazosin-treated patients in these eight studies, compared with 30 percent of placebo-treated patients, had good to excellent responses. Subgroup analysis revealed that blood pressure response was not dependent on sex or age, although white patients appeared to achieve better responses to terazosin in comparison with placebo than did black patients. These studies demonstrate that terazosin administered once daily, either as monotherapy or in combination with other antihypertensive agents, effectively controls blood pressure in patients with mild to moderate hypertension.

Sustained Hemodynamic Effects of the Selective Dopamine-1 Agonist, Fenoldopam, during 48-Hour Infusions in Hypertensive Patients: A Dose-Tolerability Study

Eight patients with stage I‐II hypertension received a continuous IV infusion of the selective dopamine‐1 agonist, fenoldopam, for up to 48 hours at rates from 0.4 to 1.9 μg/kg/min. Hemodynamics and clinical symptoms during infusion were compared to the same parameters in the 24‐hour periods before and after infusion. Fenoldopam lowered blood pressure and increased heart rate. Greatest changes occurred during the first 12 hours of infusion and gradually returned toward preinfusion values throughout the remaining 36 hours in the six patients who completed 48 hours of infusion. Fenoldopam was discontinued within 2 hours of starting the infusion in two patients who received drug rates of 0.9 μg/kg/min and 1.9 μg/kg/min because of precipitous bradycardia. Clinical symptoms noted at fenoldopam doses higher than 0.8 μg/kg/min were headache, dizziness, diaphoresis, nausea and vomiting, and restlessness. In this pilot study, fenoldopam effectively reduced blood pressure in patients with stage I‐II hypertension for up to 48 hours, but fixed‐dose infusion rates above 0.8 μg/kg/min were associated with a high frequency of clinically significant and often intolerable adverse effects.

Clinical trials with terazosin: General methods

Terazosin has been studied in a variety of clinical trials conducted in hypertensive patients with supine diastolic blood pressures of 95 mm Hg or greater before treatment. Blood pressure, pulse rate, body weight, clinical laboratory variables, and adverse experience data were evaluated periodically throughout each study. Patients generally were seen at weekly or biweekly intervals. Total daily doses of terazosin ranged from 1 to 40 mg. Terazosin was administered alone and in combination with other antihypertensive agents. Clinical trials consisted of double-blind, controlled studies and long-term, follow-up studies. The controlled clinical trials employed three principal designs: studies in which the dose was titrated according to blood pressure response; studies in which the dose was increased to a fixed level regardless of blood pressure response; and randomized withdrawal studies. Efficacy evaluations were based on mean blood pressure changes from baseline to the final visit and on the distribution of patient responses, which were categorized from excellent to inadequate. Safety evaluations were based principally on comparisons of specific safety parameters before and after the study.

Long-term treatment of angina pectoris with carteolol: a new beta-adrenergic receptor blocking agent

Seventy-two patients entered the treatment phase of an open, long-term, dose-ranging trial of carteolol in stable, exercise-induced angina pectoris. Patients were to be treated with progressive doses of carteolol (2.5, 5, 10, 20, 40, and 60 mg), given as a single daily oral dose. Thirty of the patients (42%) completed one year of treatment with carteolol as the sole antianginal therapy. The most frequent final carteolol doses were 20 mg and 40 mg once daily. Statistically significant improvements from baseline in exercise tolerance as reflected in time to onset of angina, time to the endpoint of exercise and time to the onset of 1 mm S-T segment change on ECG were observed in carteolol-treated patients. Exercise-induced increases in heart rate and double-product were significantly suppressed, compared to baseline, throughout the study. Resting heart rate and double-product were modestly decreased. Carteolol was shown to be effective and safe when administered on a long-term basis to patients with angina pectoris.

Carteolol Treatment of Essential Hypertension: A Long-Term Study of Safety and Efficacy

The long-term safety and antihypertensive efficacy of carteolol were evaluated in an open-label, multicenter trial of 245 hypertensive patients. For those patients maintained on carteolol monotherapy, three months of treatment with once-daily oral doses of carteolol ranging from 2.5 to 60 mg reduced the mean recumbent blood pressure by 12/14 mm Hg from baseline values of 151/100. Blood pressure reductions observed at three months were maintained throughout the study. The final daily dose of carteolol for most patients was 10 mg or less. Carteolol was shown to be safe and well tolerated by most patients.

Toxicity of uricosuric diuretics in rat hepatocyte culture

Several aryloxyacetic acid diuretics have shown hepatotoxicity in humans, yet there continues to be interest in developing these compounds because of the uricosuric properties of some of them. This study was designed to test the utility of the hepatocyte monolayer culture as a model for studying these compounds. In addition, an attempt was made to define the structural components that are common to hepatotoxicity. Ticrynafen, indacrinone, ethacrynic acid and A-49816, an investigational compound, were found to be toxic in hepatocyte cultures; thus, with the exception of indacrinone, paralleling the experience in humans. The toxic compounds share a ketodichlorophenoxyacetic acid chemical structure. A-56234, an investigational uricosuric, was also found to be toxic in cultures but has not been demonstrated to be hepatotoxic in humans in limited clinical experience. It does not possess the ketodichlorophenoxyacetic acid structure proper but may be metabolized to a closely related structure. Furosemide, which does not have the ketodichlorophenoxyacetic acid structure, was not toxic in hepatocyte cultures and has not been hepatotoxic in humans. Thus, the structure common to the toxic compounds is ketodichlorophenoxyacetic acid or a closely related compound. The hepatocyte monolayer system appears to be a good model for demonstrating toxicity and, perhaps, for predicting toxicity of new compounds under development.

A Comparison of Carteolol and Nadolol in the Treatment of Stable Angina Pectoris

In a multicenter, dose‐ranging, double‐blind study, 63 patients diagnosed as having stable angina pectoris were randomly assigned to treatment with carteolol (33 patients) or nadolol (30 patients). Following a 2 to 4‐week dose‐ranging period, an optimal dose was determined for each patient and treatment with that dose continued for 6 weeks. Data from all 63 patients were analyzed for drug safety; data for 52 patients (27 carteolol and 25 nadolol) were analyzed for drug efficacy. The most commonly chosen dosage levels were 20 mg of carteolol and 80 mg of nadolol. There were no statistically significant differences between the carteolol and nadolol groups in changes in exercise tolerance as reflected by time to onset of angina, end‐point of exercise, and onset of 1 mm ST segment change on ECG. Both drugs significantly suppressed tachycardia and double product during treadmill exercise. The nadolol‐treated group demonstrated a significantly greater reduction in resting heart rate (18.7 bpm) as compared with the carteolol‐treated group (3.1 bpm). Carteolol possesses intrinsic sympathomimetic activity (ISA), which may account for the fact that carteolol effectively reduces exercise‐induced tachycardia while producing relatively little effect on resting heart rate. The frequency of anginal attacks and the use of sublingual nitroglycerin were reduced to a similar extent in both treatment groups. The most commonly reported side effect in both treatment groups was asthenia. Bradycardia occurring for the first time during double‐blind treatment was observed in 70% of the nadolol‐treated patients versus only 3% of the carteolol‐treated patients.

Pharmacologic Effects of A‐56234, a New High‐Ceiling Diuretic

The pharmacologic effects of A‐49816, a high‐ceiling, loop diuretic, were evaluated in a single‐blind, placebo‐controlled, randomized trial. Eighteen (18) normal volunteers aged 19 to 40 years were divided into three groups. The subjects in each group received either placebo or three increasing doses of A‐49816 with at least a one‐week washout between doses. Nine doses of A‐49816 (0.5 to 20 mg) were administered during the entire study. Urine volume and excretion of electrolytes were measured at timed intervals following dosing. A‐49816 increased urine volume and excretion of sodium and chloride. Significant saluresis, chloruresis and diuresis were seen in most time periods following administration of the highest doses (12.5, 15 and 20 mg) of A‐49816. Kaluresis was not consistently seen at any dose. The mean rates of urine output and sodium and chloride excretion were increased relative to placebo within 2 hours of drug administration. The mean rates of urine formation and sodium and chloride excretion peaked at 2–4 hours and often remained elevated at the 6–12 hour interval.