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Elevated levels of endothelin-1 (ET-1) and von Willebrand factor (vWF), both markers indicative of endothelial function, are associated with hypertension. In a randomized open study we investigated the effect of antihypertensive treatment with the alpha-blocker doxazosin (n = 23) or the beta-blocker atenolol (n = 22) for 22 weeks on circulating levels of ET-1 and vWF in middle-aged men with essential hypertension. Blood pressure reduction was satisfactorily achieved with both drugs, although the decrease in the atenolol group was larger than that in the doxazosin group. A reduction in the levels of vWF occurred in both groups, being more pronounced in the alpha-blocker group compared with the decrease on beta blockers, p = 0.004 and p = 0.056, respectively. In the alpha-blocker group, there was a significant correlation (r = 0.50, p = 0.022) between the reduction in diastolic blood pressure and the decline in vWF. A highly significant decrease in plasma ET-1 was obtained during beta blockade (p = 0.007), whereas no significant change occurred within the alpha-blocker group. There was, however, no correlation between the decrease in blood pressure and the reduction in ET-1. The different favorable effects of alpha and beta blockers on endothelial function expressed as vWF and ET-1, could indicate that the effects are probably related not only to the blood pressure per se, but also to the different pharmacologic mechanisms of the drugs.
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In these patients, drug therapy may resolve the pathology, or allow the use of minimally invasive surgery (i.e. lasertherapy, transuretheral incision, etc.).
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The newly established method can be used in research and development of the enantiomers of three new drugs.
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The proposed method is simple, rapid, reproducible, and reliable with high measurement accuracy, which can be useful to estimate lipid-water partition coefficients of pharmaceuticals.
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In the 15 batches of different phytotherapeutic agents tested no interference secondary to contamination with alpha-blockers or 5alpha-reductase inhibitors was observed.
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The efficacy and safety of doxazosin (mean dosage 6.9 mg, range 1 to 16) in the treatment of essential hypertension were compared in a double-blind study with those of hydrochlorothiazide (HCTZ) (mean dosage, 84.6 mg, range 25 to 100) in 104 hypertensive patients treated once daily for 6 months. Thirty-five patients were also assessed for comparative effects of the 2 agents on serum lipid parameters. Doxazosin produced potentially favorable changes from baseline in the concentrations of serum lipid fractions (total triglycerides, total cholesterol, high density lipoprotein [HDL] cholesterol and the derived HDL/total cholesterol ratio) compared with HCTZ. The decreases in total triglyceride and total cholesterol concentrations and an increase in the HDL/total cholesterol ratio were significantly different (p less than 0.006) from the opposite changes observed with HCTZ. Clinically relevant decreases from baseline in supine and standing blood pressures at 24 hours after administration did not significantly differ between the 2 agents. The incidence and severity of side effects were similar for both drugs. Three patients receiving doxazosin and 6 receiving HCTZ were withdrawn due to drug-related clinical side effects including 2 patients receiving HCTZ who were withdrawn because of laboratory test abnormalities. Eight HCTZ- and 1 doxazosin-treated patients developed hypokalemia and 6 HCTZ-treated patients developed hyperuricemia. These findings indicate that doxazosin and HCTZ provide comparable antihypertensive efficacy after 6 months of treatment using a once-daily regimen, but doxazosin produces a beneficial effect on the serum lipid profile as well as fewer biochemical aberrations.
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To test the hypothesis that the spinal control of micturition involves alpha 1-adrenoceptors, the urodynamic effects of intrathecal and intraarterial alpha 1-adrenoceptor blockade on apomorphine-induced bladder activity in rats were studied. Continuous cystometry was performed in conscious female Sprague-Dawley rats with and without bladder outflow obstruction. In normal rats, subcutaneous apomorphine, 30 micrograms/kg, induced bladder activity that was abolished or attenuated by the alpha 1-adrenoceptor antagonists indoramin and doxazosin given intrathecally or intra-arterially. In rats with outlet obstruction, apomorphine 30 micrograms/kg caused no change in cystometric parameters. However, at a dose of 100 micrograms/kg the drug induced bladder activity, which was attenuated by intrathecal indoramin or doxazosin. These results suggest that the bladder activity evoked by apomorphine-stimulation of bulbospinal pathways can be influenced by alpha 1-adrenoceptors at the spinal and peripheral levels, both in normal rats and in rats with bladder hypertrophy secondary to outlet obstruction.
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Patients prescribed an alpha-blocker were significantly more likely to experience AUR (hazard ratio 2.32, 95%CI 1.37, 3.94) or surgery (hazard ratio 1.78, 95%CI 1.30, 2.44) than patients prescribed a 5ARI. These differences were sustained with sensitivity analyses.
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The aims of this study were to examine the effects of doxazosin on contractile responses to 5-hydroxytryptamine (5-HT), carbachol, and histamine, and to compare them with those of prazosin, alfuzosin, and terazosin, and then characterize a pharmacological profile of the 5-HT-induced contractile response using preparations of isolated longitudinal muscle strips from the rabbit gastric body. The results from these preparations showed that the contraction response to 5-HT, but not to carbachol or histamine, was found to be dose-dependently potentiated by doxazosin and its enantiomers. The specific potentiation effect on 5-HT was not observed in the preparations that were treated with prazosin, terazosin, or alfuzosin. The contractile response to 5-HT and its potentiation by doxazosin were not affected by treatment with phenoxybenzamine. However, 5-HT-induced contraction was competitively antagonized by nefazodone (with pA₂ value of 8.64 ± 0.17), and was almost completely inhibited by treatment with indomethacin. In conclusion, doxazosin, but not prazosin, alfuzosin, or terazosin, selectively potentiates 5-HT-induced contraction in the rabbit gastric body strips via an α₁-adrenoceptor-independent mechanism, without chiral recognition of its enantiomers. Additionally, the contraction to 5-HT was found to be mediated via 5-HT(₂) receptors, and was similar to PGs synthesis in the preparations.
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This report deals with perioperative treatment for a very rare disease called ectopic ACTH-producing pheochromocytoma in a 55-year-old woman. She showed high norepinephrine, cortisol, and ACTH levels, and diagnosed as ectopic ACTH-producing pheochromocytoma, by MIBG scintigraphy. An alpha-blocker and fluid loading for pheochromocytoma, and an adrenal cortex hormone synthesis inhibitor for Cushing's syndrome, were given simultaneously as a preoperative treatment. Propofol with nitrous oxide-oxygen-sevoflurane and epidural anesthesia were used for excision of the tumor, and the procedure was performed without any marked changes in hemodynamics. Although ectopic ACTH-producing pheochromocytoma is a very rare disease, it can be managed safely by appropriate preoperative treatment for pheochromocytoma and Cushing's syndrome.
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Doxazosin gastrointestinal therapeutic system (GITS) or placebo was added to the antihypertensive therapy of uncontrolled hypertensive patients in a prospective, randomized, double-blind trial. Patients received doxazosin GITS 4 mg/d (n=89) or placebo (n=86) for 6 weeks in addition to entry antihypertensive medication. Doxazosin GITS was increased to 8 mg/d after 2 or 4 weeks if patients did not respond (sitting blood pressure <140/90 mm Hg and 10/10-mm Hg decrease from baseline). Reductions from baseline in sitting and standing blood pressures were greater with doxazosin GITS than placebo at all time points (p=0.017) except Week 1 sitting systolic pressure (p=0.068). The response rate was greater in the doxazosin GITS group (37.3%) than the placebo group (10.7%; p<0.001). With the exception of postural hypotension (7% compared with 0.0%), the frequency of adverse events was similar for doxazosin GITS and placebo. Doxazosin GITS was effective as combination antihypertensive therapy with the major classes of antihypertensive agents.
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Essential hypertension is characterized by an insulin-resistance state that may be responsible for the increased atherogenesis typical of this disease. To investigate the effect on glucose and insulin metabolism of doxazosin, an antihypertensive drug whose favorable impact on lipid metabolism is well known, 10 newly diagnosed essential hypertensive patients of the same age and body mass index (BMI) were selected for our study. They underwent an oral glucose tolerance test (OGTT) with measurement of plasma insulin levels before and after a 6-month treatment period with doxazosin. In this period of time, they took no other drugs and followed no diets, nor did their weights vary. The daily dose of doxazosin was increased (maximum, 8 mg) to achieve a normotensive blood pressure (< 140/90). At the end of treatment, total and low-density lipoprotein (LDL) cholesterol levels (225 +/- 18 v 200 +/- 16 and 177 +/- 8 v 150 +/- 7 mg/dL, respectively; P < .05) were decreased, confirming the lipid-lowering effect of the drug. The OGTT showed a significant decrease of plasma insulin (16.04 +/- 1.8 v 10.99 +/- 0.9 mU/mL.min, P < .05) and blood glucose (22.54 +/- 1.6 v 20.83 +/- 1.6 g/dL.min, P < .05) areas. The glucose to insulin ratio, also known as the insulin sensitivity index, increased (1.56 +/- 0.15 v 1.95 +/- 0.12, P < .05). These findings seem to provide evidence of a favorable effect of doxazosin on insulin action.
Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.
After 12 weeks of treatment, both groups showed significant improvements in IPSS scores (total, obstructive and irritative subscores, QoL score) from baseline (p < 0.0001). However, the doxazosin-GITS group showed significantly greater improvements in total IPSS and obstructive subscore than the tamsulosin group in the early period (p < 0.05). Improvements in irritative subscore (within 4 weeks) and QoL score (during 12 weeks) were not significantly different between the groups. The incidences of AEs were similar between the groups.
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The purpose of this study was to compare prescriber monitoring for safety and efficacy of medication classes used to treat benign prostatic hyperplasia (BPH).
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The efficacy and tolerability of doxazosin and atenolol in the management of mild and moderate hypertension were compared in a multicentre, parallel study, the first year of which was randomized and double-blind. Patients who completed this first year were invited to enter a two-year extension phase; the results after the first year are presented. A total of 228 patients entered the double-blind phase (118 received atenolol). A reduction in dose was required by 4% in each group; eight patients on doxazosin and 11 on atenolol were withdrawn due to adverse effects. Ninety-three of the 100 doxazosin patients and 88 of the 104 atenolol patients who completed the double-blind phase agreed to participate in the open extension study. At 24 months, the mean dose of doxazosin was 5.2 mg/day, and of atenolol 66.7 mg/day. From baseline levels of BP of 158/104 mmHg in the doxazosin group and 161/103 mmHg in the atenolol group, average reductions at 24 months were -16/-14 and -19/-15 mmHg respectively. Neither drug had a significant effect on total cholesterol levels. At all four points of measurement over the two years, doxazosin decreased blood triglyceride levels and increased high density lipoprotein (HDL) cholesterol and the HDL: total cholesterol ratio. Atenolol had the opposite effect on each of these lipid values with the differences between the treatment groups being significant. Doxazosin was well tolerated and was shown to be effective as monotherapy in mild and moderate hypertension. Its effect on blood lipids was potentially favourable, and it should therefore be regarded as an alternative first-line drug in hypertensive patients.
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The effect of the drugs on albumin and total protein excretion, beta-2-microglobulin, proximal tubular enzyme markers and renal haemodynamics.
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These findings suggest that the treatment of BPH with finasteride is cost-effective compared to placebo in the Brazilian public health system perspective.
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In Protocol 1, a significant relationship was observed between the following: trait anxiety and plasma norepinephrine (r = 0.32, P < .01); plasma norepinephrine and ROS formation by MNC (r = 0.36, P < .01); and plasma norepinephrine and systolic, diastolic, and mean BP (r = 0.17, P = .04; r = 0.26, P = .02; r = 0.23, P < .01, respectively). In Protocol 2, subtherapeutic doxazosin treatment (1 mg/day) had no significant effect on BP. However doxazosin significantly decreased ROS formation by MNC compared with placebo (P < .01).
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Fifteen male Wistar rats were treated subcutaneously with 10 mg/Kg doxazosin during 15 days and fifteen controls were treated with the vehicle only. After the treatment period, prostate was removed to obtain soluble and membrane-bound fractions. Soluble and membrane-bound IRAP specific activities were assayed fluorometrically using leucyl-ß-naphthylamide as substrate. Prostate OT content was assayed by enzyme immunoassay.
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We conducted ambulatory BP monitoring three times (twice at baseline and after nighttime dosing of the alpha1-blocker doxazosin) in 98 elderly hypertensive patients in whom the presence of silent cerebral infarcts (SCI) was assessed by brain magnetic resonance imaging. The morning BP surge (MBPS) was calculated as the mean systolic BP during the 2 h after waking minus the mean systolic BP during 1 h that included the lowest sleep BP. The alpha-adrenergic MBPS was calculated as the reduction of MBPS by doxazosin.
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The acute effects of selective alpha 1 inhibition with doxazosin (0.5-0.7 mg intravenously) and beta 1-blockade with atenolol (0.1 mg/kg body weight, intravenously) on smoking-induced peripheral vasoconstriction were investigated in 24 hypertensive habitual smokers. Forearm blood flow was measured by venous occlusion plethysmography and skin blood flow was estimated by thermography and laser doppler flowmetry. After the patients had smoked two cigarettes, plasma adrenaline elevations were similar under basal conditions and after drug administration; plasma noradrenaline remained unchanged. The smoking-induced increase in the heart rate was attenuated by atenolol compared with basal values. The smoking-induced increase in systolic blood pressure was more marked after atenolol and doxazosin (P less than 0.05) than before the drug administration. The smoking-induced increase in diastolic blood pressure was enhanced by atenolol (P less than 0.05) but unchanged by doxazosin. Smoking increased forearm vascular resistance under basal conditions (P less than 0.05) and after atenolol (P less than 0.01) but not after doxazosin. Similarly, skin temperature was significantly reduced by smoking under basal conditions and after the administration of atenolol (P less than 0.001) but not doxazosin. The smoking-induced reduction in skin blood flow was attenuated by doxazosin compared with atenolol (P less than 0.05). Thus, smoking-induced muscular and cutaneous vasoconstriction was inhibited by doxazosin as opposed to atenolol in hypertensive habitual smokers. This may reflect unmasked beta-adrenoceptor mediated vasodilation in addition to attenuated alpha 1-adrenoceptor mediated vasoconstriction.
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Randomised controlled trials of at least one anti-hypertensive treatment against placebo, or two anti-hypertensive medications against each other, with interventions lasting at least one month. Trials had to include patients with symptomatic PAD.
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Clinical trials of alpha-blockers in men with enlarged prostate have reported improvements in total symptom scores of 10% to 20% compared with placebo; however, these agents were not shown to reduce the risk of long-term complications or disease progression. Studies of the 5ARIs have reported significant reductions compared with placebo in the relative risk for AUR and enlarged prostate-related surgery, slowing of disease progression, and relief of symptoms. In studies of dutasteride, improvements in symptom scores were greater after 4 years of therapy compared with 2 years (-6.4 vs -4.3 points, respectively) and flow rates were better (2.6 vs 2.3 mL/sec). Six-year data for finasteride showed maintenance of the decreased risk for AUR and enlarged prostate-related surgery. Use of combination therapy with an alpha-blocker and a 5ARI may be of benefit in patients who require immediate relief of symptoms, with discontinuation of the alpha-blocker after several months of therapy. 5ARIs were generally well tolerated, with sexual dysfunction the most frequently reported adverse effect, although in only a small proportion of men (1%-8%).
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1. The effects of the alpha(1)-adrenoceptor antagonists doxazosin (0.1 -- 2 mg kg(-1)), RS-100329 (alpha(1A); 0.01 -- 1 mg kg(-1)), RS-513815 (Ro 151-3815, alpha(1B); 0.3 -- 3 mg kg(-1)) and BMY 7378 (alpha(1D); 0.1 -- 1 mg kg(-1)), the 5-HT(1A) receptor agonist, 8-OH-DPAT (0.03 -- 0.3 mg kg(-1)) and antagonist WAY-100635 (0.03 -- 0.3 mg kg(-1)) were investigated (i.v.) on the 'micturition reflex' in the urethane anaesthetized male rat. 2. Reflex-evoked urethra contractions were most sensitive to the inhibitory action of RS-100329, followed by doxazosin, BMY 7378 and WAY-100635 and then RS-513815. The maximum inhibition was 66, 63, 54, 46 and 22% at doses of 0.3, 0.5, 0.3, 0.3 and 3 mg kg(-1) respectively. 3. BMY 7378 and 8-OH-DPAT decreased, while WAY-100635 increased, the pressure threshold to induce bladder contraction. WAY-100635 (0.01 mg kg(-1)) blocked the effects of BMY 7378 (1 mg kg(-1)) on bladder pressure and volume threshold. 4. Doxazosin, RS-100329 and BMY 7378 had a similar potency in inducing a fall in arterial blood pressure while WAY-100635 only caused a fall at the highest dose. 5. Therefore, reflex-evoked urethral contraction involves the activation of alpha(1A/1D)-adrenoceptors, as BMY 7378 and RS-100329 are similarly potent in attenuating this effect. The ability of WAY-100635 to attenuate this contraction may suggest that 5-HT(1A) receptors are also involved. However, as this inhibition occurred at the highest dose of WAY-100635, which also caused a fall in arterial blood pressure; this effect is considered to be due to blockade of alpha(1)-adrenoceptors not 5-HT(1A) receptors. Nevertheless the initiation of the 'micturition reflex' involves the activation of 5-HT(1A) receptors.
The attenuation of cyclic guanosine 5'-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade with antioxidant properties.
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Benign prostatic hyperplasia (BPH) is highly prevalent in the male population beyond the age of 60. Impairment of urinary flow due to prostate enlargement gives rise to symptoms of 'prostatism' that have a detrimental impact on the quality of life. The current trend in the management of symptomatic BPH favours pharmacotherapy as a first line option, while the number of surgical procedures being performed has experienced a steady decline during the last ten years. Among the pharmacological treatments, the use of alpha1-adrenoceptor blockers has demonstrated to be an effective treatment option for BPH. These agents reduce the adrenergic tone to the prostate and increase urinary flow, with a concomitant reduction of lower urinary tract symptoms. The alpha1-blockers currently approved include compounds such as alfuzosin, terazosin and doxazosin, originally developed for the treatment of hypertension, and more recently tamsulosin, an alpha1-subtype selective drug. The blockade of alpha1-adrenoceptors present in vascular smooth muscle is largely responsible for the most prominent side effects of current drugs, which can be severe and require patients dose titration. The limitation imposed by side effects naturally raises the possibility that complete blockade of prostatic alpha1 receptors is not attained at the maximum tolerated dose. The extensive efforts by the pharmaceutical industry towards the development of uroselective alpha1-blockers, is the subject of this review. Advances in the molecular cloning of genes encoding three alpha1-adrenoceptors led to the identification of the alpha1A-subtype as the predominant receptor responsible for the contraction of prostate smooth muscle. In preclinical animal models, selective alpha1A-antagonists have consistently been found to have minimal cardiovascular effects, thus providing a pharmacological rationale for uroselectivity. It has also become apparent, however, that uroselectivity can emerge in a poorly understood manner from the pharmacodynamic properties of compounds without alpha1A-subtype selectivity. Clinical experience with tamsulosin, an alpha1A/alpha1D selective drug, has failed to demonstrate a significant improvement in efficacy beyond that demonstrated for non-subtype selective alpha1-blockers, and gives support to the notion that alpha1A-selective antagonists might achieve greater efficacy for the treatment of BPH. Given the demonstrated uroselectivity of alpha1A-selective antagonists in preclinical models, it is anticipated that third generation alpha1-blockers will exhibit improved urinary flow efficacy and be better tolerated than tamsulosin. The extent to which the improvement in urinary flow will translate to the relief of symptoms of prostatism, however, remains to be demonstrated in randomised placebo-controlled clinical trials of alpha1A-selective antagonists.
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Data were extracted by one author (DAL) and checked by the other (GYHL). Potentially eligible studies were excluded when the results presentation prevented adequate extraction of data and enquiries to authors did not yield raw data.
These data show that the low subdepressor dose ACE inhibitor with an alpha- or beta-adrenergic receptor antagonist provides beneficial cardiovascular effects in SHR.
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A study was conducted to determine whether sympathetic nerve activity, one of the main regulators of blood pressure, is involved in high blood pressure in the night-time and morning. Twenty-seven untreated hypertensive subjects, in whom hypertension was diagnosed by ambulatory blood pressure (ABP) measurement, who showed a 24 h systolic ABP value over 140 mmHg and/or 24 h diastolic ABP over 90 mmHg were recruited. They also showed a night-time systolic ABP value of over 130 mmHg and/or a night-time diastolic ABP of over 80 mmHg. They were divided into two groups: "dippers (D)" whose night-time ambulatory blood pressure fell by more than 10% of the day-time blood pressure, and "non-dippers (ND)" in whom this phenomenon was absent. We examined the effect of a long-acting alpha 1-blocker (doxazosin) on diurnal blood pressure variation in these subjects with essential hypertension. Baseline casual blood pressure and 24 h systolic ABP were not significantly different between the two groups. However, both night-time and morning ABP in ND were higher than those in D. Administration of doxazosin (mean 73 +/- 13 (SE) d) significantly decreased casual blood pressure, and 24 h, day-time, night-time and morning systolic ABP in the whole cohort. When subjects were divided into D and ND, the day-time and morning systolic ABP decreased significantly after doxazosin treatment in both groups, whereas the night-time systolic ABP decreased significantly only in ND but not in D. These results suggest that sympathetic nerve activity involved in elevating blood pressure during the night may differ between D and ND.