Effect of doxazosin on the symptoms of benign prostatic hyperplasia: results from three double-blind placebo-controlled studies.

The urinary symptoms characteristic of benign prostatic hyperplasia (BPH) can have a considerable impact on patients' quality of life. Symptom score assessment is now used in BPH, although a number of different instruments are available. Controlled clinical trials with selective alpha 1 adrenoceptor antagonists such as doxazosin, prazosin and terazosin have shown these agents to be effective in the treatment of BPH. The effects of doxazosin on the severity and bothersomeness of BPH symptoms were determined in three multicentre, double-blind, placebo-controlled clinical studies, involving a total of 609 normotensive and hypertensive patients. Doxazosin was initiated at a dosage of 0.5 or 1 mg once daily, with a final dose range of up to 12 mg once daily. The duration of active treatment was 12 to 14 weeks. Significant improvements were seen in symptom severity and bothersomeness with doxazosin compared with placebo, in both patient populations. The onset of symptomatic improvement was rapid, occurring within two weeks of treatment initiation, and efficacy was sustained throughout the treatment period. A long-term, open label extension of these studies has demonstrated sustained efficacy during 48 months of follow-up. Since symptom relief is the primary goal of therapy in BPH, and since doxazosin's effects are rapid in onset and sustained in duration, it appears that doxazosin is an effective agent for the treatment of symptomatic BPH in both normotensive and hypertensive men.

Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. The Multicenter Study Group.

PURPOSE: We evaluated the sustained efficacy and safety of doxazosin for long-term treatment (up to 48 months) of normotensive and hypertensive patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 272 normotensive and 178 mildly to moderately hypertensive men entered a long-term extension study of doxazosin therapy (1 to 8 and 1 to 12 mg. 1 time daily, respectively) for BPH following participation in double-blind, placebo controlled studies. The starting dose of doxazosin was 1 mg. with upward titrations at 2-week intervals to a stable, efficacious and well tolerated dose. At the time of data analysis patients had received between 1 and 48 months of stable dose doxazosin therapy (mean 668 days for normotensive and 807 for hypertensive patients). Mean daily doses were 4 and 6.4 mg. for normotensive and hypertensive men, respectively. RESULTS: At the end point analysis doxazosin treatment resulted in significant increases above baseline in maximum and average urinary flow rates (1.9 and 1.0 ml. per second, respectively). As assessed by the patient, total, obstructive and irritative BPH symptoms also improved significantly with doxazosin treatment. In the 28 patients who completed 45 to 48 months of treatment improvement in symptom bothersomeness (13.2%) was similar to that of the overall group at the end point (14.8%). Sustained blood pressure decreases (approximately 8/11 mm. Hg systolic/diastolic blood pressure) with doxazosin were statistically and clinically significant in hypertensive patients. Blood pressure decreases in normotensive patients were not clinically significant (approximately 4/2 mm. Hg) and few withdrew from study for reasons related directly to decreased blood pressure or hypotension. Changes in heart rate were not significant. Doxazosin was well tolerated with almost 90% of adverse experiences considered mild or moderate in severity. The most common adverse events were dizziness, headache and fatigue in normotensive and hypertensive patients. CONCLUSIONS: In this study long-term doxazosin treatment was significantly effective and well tolerated for treating BPH in normotensive and hypertensive patients.

Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study.

A 16-week, double-blind, placebo controlled, dose titration study was done on 100 normotensive patients age 45 years or older to determine the efficacy and safety of doxazosin, a selective alpha 1-adrenoceptor antagonist, in the treatment of benign prostatic hyperplasia (BPH). Of the 41 efficacy evaluable patients 88% underwent dose titration to a maximum of 8 mg. doxazosin once daily. Maximum and average urinary flow rates increased significantly above baseline with doxazosin (2.9 ml. per second and 1.4 ml. per second, respectively) compared with placebo (0.7 ml. per second and 0.3 ml. per second, respectively). A significant effect on maximum flow rate was noted as early as week 2 of double-blind treatment at the initial efficacy evaluation. Doxazosin was superior to placebo in patient and investigator assessments of total, obstructive and irritative BPH symptoms. The onset of efficacy for total patient-assessed symptoms was significant for doxazosin compared to placebo 4 weeks after the start of the treatment regimen. Statistically significant decreases in mean blood pressure of 4 to 6 mm. Hg were noted with doxazosin compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 44% of patients given doxazosin and 30% of those given placebo. Our results strongly demonstrate that doxazosin is significantly superior to placebo in the treatment of BPH in normotensive patients, with the patient experiencing significant relief early after initiation of therapy.

Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension: a double-blind, placebo-controlled, dose-response multicenter study.

A total of 248 hypertensive patients 45 years old or older with benign prostatic hyperplasia (BPH) was included in this 16-week, multicenter, double-blind, placebo-controlled, parallel-group dose-response study. Doxazosin, a selective alpha 1-adrenoceptor antagonist, produced a significant increase in maximum urinary flow rate (2.3 to 3.6 ml. per second) at doses of 4 mg., 8 mg. and 12 mg., and in average flow rate (8 mg. and 12 mg.) compared with placebo. The increase in maximum flow rate was significant with doxazosin versus placebo within 1 week of initiating double-blind therapy. Doxazosin compared to placebo significantly decreased patient-assessed total, obstructive and irritative BPH symptoms. Blood pressure was significantly lower with all doxazosin doses compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 48% of patients on doxazosin and 35% on placebo. Our results strongly support the use of doxazosin as a nonoperative therapeutic alternative in the management of uncomplicated BPH. Doxazosin would also be particularly useful in the management of patients who have BPH and hypertension.

Cell and molecular studies of renin secretion.

Renin secretion has been studied in the past at the level of the whole kidney, but the control of the genetic basis of renin synthesis is poorly understood. We have studied the regulation of renin gene expression in the fetus and also in the adult rat in response to angiotensin converting enzyme (ACE) inhibition with enalapril in the presence and absence of angiotensin II (AII). In the fetus, vascular smooth muscle cells of the renal afferent arteriole and feeder vessels contain renin mRNA and immunostain for renin. With maturation, these vessels progressively lose the capacity to synthesize renin, and only the juxtaglomerular cells retain this capacity in the adult. However, in response to ACE inhibition, the adult renal feeder vessels acquire the capacity to synthesize and secrete renin within 7 days. This effect is partially reversed with co-administration of AII. In order to study renin biosynthesis and secretion at the cellular level, we have developed a new method of study of individual renin-secreting cells, the reverse hemolytic plaque assay (RHPA). Utilizing this method, we have demonstrated that ACE inhibition with enalapril increases the number of renin secreting cells by over 15-fold at physiologic calcium concentrations. Enalapril also induced a 3-fold increase in the amount of renin released as estimated by the area of the hemolytic plaques formed. Transmission electron microscopy (EM) of the renin-secreting cell at the center of a hemolytic plaque demonstrates modified vascular smooth muscle cells with cytoplasmic granules. In summary, ACE inhibition stimulates renin mRNA accumulation and redistributes renal renin content toward that observed in early fetal life. AII inhibits renal renin mRNA accumulation. ACE inhibition increases the number of renin secreting cells as well as the amount of renin secreted by each cell. The individual renin secreting cell is a modified vascular smooth muscle cell with cytoplasmic secretory granules. Further studies of the cellular pathways for renin secretion can be provided by EM immunocytochemistry of the individual renin secreting cell.

Comparison of molecular properties of the voltage-sensitive Ca2+ channel from longitudinal smooth muscle of rabbit ileum with the channel purified from transverse tubules of rabbit skeletal muscle.

Dihydropyridine-sensitive calcium channels in membrane preparations from the longitudinal smooth muscle of rabbit ileum bound [3H]PN 200-110 with KD = 0.42 nM and Bmax = 265 fmol/mg. Calcium channels were labelled with [3H]PN 200-110 and solubilized with digitonin. The detergent-solubilized calcium channel had a sedimentation coefficient of 20.9 S in close agreement with the value of 20 S determined for the skeletal muscle calcium channel. Antibodies against the alpha-subunits of the skeletal muscle calcium channel specifically precipitated the calcium channel from smooth muscle. Our results suggest that the calcium channel from smooth muscle has a similar size and homologous alpha-subunits to those of the purified skeletal muscle calcium channel.

Binding of 4(5)-[2-(4-azido-2-nitroanilino)ethyl]imidazole to histamine receptors in guinea pig cerebral cortical membranes.

The interaction of 4(5)-[2-(4-azido-2-nitroanilino)ethyl]imidazole (AAH), a photolabile histamine receptor antagonist, with the binding of histamine, mepyramine, and tiotidine to guinea pig cerebral cortical membranes was examined to evaluate the specificity of AAH for histamine H1 and H2 receptors. Saturable, specific binding of [3H]histamine, [3H]mepyramine, and [3H]tiotidine to the membranes was observed. Competition assays were used to assess the relative affinity of AAH for H1- and H2-receptors. The rank order of IC50 values obtained was (most to least potent) (i) for competing with [3H]histamine binding: histamine greater than AAH much greater than mepyramine approximately equal to tiotidine; (ii) for competing with [3H]mepyramine binding: mepyramine much greater than AAH greater than histamine greater than tiotidine; and (III) for competing with [3H]tiotidine binding: tiotidine much greater than mepyramine greater than histamine approximately equal to AAH. The affinity of AAH for H1 receptors was ca. 14-fold greater than for H2 receptors. These findings support previous evidence obtained in isolated smooth muscle preparations that AAH shows H1-receptor selectivity as an antagonist.

Sensitivity changes in the smooth muscle of the guinea-pig isolated vas deferens after treatment of animals with 6-hydroxydopamine.

Postjunctional supersensitivity of the smooth muscle of the guinea-pig vas deferens induced by denervation, decentralization and treatment of animals with reserpine has been attributed, in part, to a partial membrane depolarization (8-10 mV) resulting from reduced electrogenic Na+,K+-pumping activity. This study was undertaken to characterize sensitivity changes which occur after treatment of animals with 6-hydroxydopamine (100 mg/kg + 250 mg/kg i.v., 1 day apart). Seven days after the second injection, concentration-response curves for isometric contractile responses to norepinephrine, methoxamine, acetylcholine and histamine were shifted 40.6-, 1.7-, 3.6- and 2.7-fold, respectively, to the left of control; however, the sensitivity to KCl was not increased, which contrasts with the results after denervation, decentralization and reserpine treatment. Ouabain (10(-5) M) produced 1.8- and 1.3-fold leftward shifts of the KCl concentration-response curves in tissues from control and 6-hydroxydopamine-treated animals, respectively. The pronounced effect of ouabain in tissues from treated animals may be an indication that 6-hydroxydopamine treatment does not result in as much inhibition of electrogenic Na+,K+-pumping, and resultant membrane depolarization, as other methods which induce supersensitivity of the guinea-pig vas deferens.