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A new method for simultaneous determination of phentermine and topiramate by liquid chromatography/electrospray tandem mass spectrometry (LC/MS/MS) operated in positive and negative ionization switching modes was developed and validated. Protein precipitation with acetonitrile was selected for sample preparation. Analyses were performed on a liquid chromatography system employing a Kromasil 60-5CN column (2.1 mm × 100 mm, 5 μm) and an isocratic elution with mixed solution of acetonitrile-20mM ammonium formate containing 0.3% formic acid (40:60, v/v), at a flow rate of 0.35 mL/min. Doxazosin mesylate and pioglitazone were used as the internal standard (IS) respectively for quantification. The determination was carried out on an API 4000 triple-quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode using the following transitions monitored simultaneously: positive m/z 150.0/91.0 for phentermine, m/z 452.1/344.3 for doxazosin, and negative m/z 338.3/77.9 for topiramate, m/z 355.0/41.9 for pioglitazone. The method was validated to be linear over the concentration range of 1-800 ng mL(-1) for phentermine, 1-1000 ng mL(-1) for topiramate. Within- and between-day accuracy and precision of the validated method at three different concentration levels were within the acceptable limits of <15% at all concentrations. Blood samples were collected into heparinized tubes before and after administration. The simple and robust LC/MS/MS method was successfully applied for the simultaneous determination of phentermine and topiramate in a pharmacokinetic study in healthy male Chinese volunteers.
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Blood pressure displays appreciable predictable-in-time circadian variation. The chronotherapy of hypertension takes into account the clinically relevant features of the 24-h pattern of blood pressure, e.g. the accelerated morning rise and nighttime decline during sleep, plus potential administration circadian time determinants of the pharmacokinetics and dynamics of antihypertensive medications.
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A prospective randomized study including 150 patients presented with LUTS caused by BPH in association with clinically diagnosed ED, with age equal or more than 45 years from April 2010 to April 20011. They were categorized into three comparative groups each one containing 50 patients. These groups were comparable regarding pretreatment international prostate symptoms score (IPSS) and international index of erectile function (IIEF). The patients of the first group were given sildenafil 50 mg as monotherapy, those of the second group were given doxazosin 2 mg and those of the third group were given combination of both drugs for 4 months for each group. The main post-treatment parameters for assessment and comparison include assessment of patient's symptoms by repeated IPS Sand IIEF, uroflowmetry and assessment of PVR. The statistics was done by use of the Qui--square test.
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ED is a symptom very often associated to BPH, even in relatively young men. Doxazosin appears to have a beneficial effect in ED improvement, particularly in the younger patients.
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The purpose of this study was to determine the contribution of the adrenergic system in mediating hypertension in obese and lean patients. Thirteen obese, hypertensive patients with a body mass index (BMI) > or =28 kg/m2 (obese) and nine lean patients with a BMI < or =25 kg/m2 (lean) were recruited. After a 1-week washout period, participants underwent daytime ambulatory blood pressure monitoring (ABPM). Participants were then treated with the alpha-adrenergic antagonist doxazosin, titrating to 4 mg QHS in 1 week. In the next week, the beta-adrenergic antagonist atenolol was added at an initial dose of 25 mg/day and titrated to 50 mg/day within 1 week. One month after the addition of atenolol, all patients underwent a second ABPM session. There were no differences between the obese and lean subjects in baseline systolic (SBP), diastolic (DBP), or mean arterial pressures (MAP) measured by office recording or ABPM. However, obese subjects had higher heart rates than lean subjects (87.5+/-2.4 v 76.8+/-4.9 beats/min). After 1 month of treatment with the adrenergic blockers, obese patients had a significantly lower SBP (130.0+/-2.5 v 138.9+/-2.1 mm Hg, P = .02) and MAP (99.6+/-2.3 v 107.0+/-1.5 mm Hg, P = .02) than lean patients. Obese patients also tended to have a lower DBP than lean patients (84.3+/-2.5 v 90.9+/-1.6 mm Hg, P = .057), but there was no significant difference in heart rate after 1 month of adrenergic blockade. These results indicate that blood pressure is more sensitive to adrenergic blockade in obese than in lean hypertensive patients and suggest that increased sympathetic activity may be an important factor in the maintenance of hypertension in obesity.
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We evaluated the effects of treatment for 12 weeks with 10 mg/kg/day of either losartan or doxazosin on vascular function in senescent spontaneous hypertensive rats (SHR). Both doxazosin and losartan reduced blood pressure, although the former was more effective. In contrast, both drugs reduced relative aortic weight and increased plasma nitrates to a similar extent. Losartan, but not doxazosin, increased the magnitude of the response to acetylcholine (10(-9) to 10(-5) mol/L). Both treatments increased relaxations to sodium nitroprusside (10(-10) to 10(-6) mol/L). These data show that losartan may possess advantages over doxazosin in improving vascular function in senescent SHR. This report emphasizes the importance of angiotensin II in vascular function alterations induced by aging in SHR.
The antihypertensive effect and safety of doxazosin once-daily was compared with that of atenolol once-daily in 40 patients with mild to moderate hypertension. During the first 4 weeks all patients received placebo therapy. During the subsequent 10 weeks patients were randomized to doxazosin or atenolol treatment. Treatment was initiated with 1 mg doxazosin or 50 mg atenolol once-daily. The dose could be doubled biweekly until a final dose of 16 mg doxazosin or 100 mg atenolol was reached. The average final dose of doxazosin was 6.4 +/- 0.8 mg (SEM) and that of atenolol 66.7 +/- 5.7 mg. During the 10 weeks of active treatment, the systolic and diastolic blood pressure tended to be lower (p less than 0.05) in patients on atenolol, this difference was however not significant for the standing blood pressure. Recumbent and standing heart rate were lower (p less than 0.01) during atenolol. Multiple regression analysis showed that in the doxazosin group the recumbent systolic blood pressure after 10 weeks of treatment was significantly (p less than 0.05) and independently related to age, recumbent systolic blood pressure at randomization, and the changes in recumbent heart rate. In neither group severe adverse reactions were observed. However, two patients on doxazosin dropped out of the study: one because of blurred vision and persistent high blood pressure, and one because of fatigue and palpitations. No patient dropped out of the atenolol group during the study.
Thirty patients with hypertension were enrolled in this study, 13 had non-insulin-dependent diabetes mellitus (NIDDM) and 17 were nondiabetic. Patients were treated with doxazosin for approximately 4 months, and blood pressure fell significantly (P < .001) in both nondiabetics (149/96 to 134/85 mm Hg) and in those with NIDDM (154/96 to 143/84 mm Hg). In the nondiabetic group, doxazosin treatment was associated with significant improvement in insulin-mediated glucose disposal (P < .05) and lower plasma insulin (P < .001), and triglyceride (P < .001) concentrations measured at hourly intervals from 8 AM to 4 PM (breakfast at 8 AM and lunch at noon). In addition, fasting total plasma (P < .001) and VLDL cholesterol (P < .01), and total plasma (P < .05), VLDL (P < .08), LDL (P < .01), HDL (P < .01) triglyceride concentrations were lower following doxazosin treatments in the nondiabetic group, as was the ratio of total to HDL cholesterol (P < .001). Finally, apoprotein B concentrations fell with doxazosin in the nondiabetic group (P < .01). Significant changes seen in the group with NIDDM included a decrease in the ratio of total to HDL cholesterol (P < .001) and a fall in apoprotein B concentration (P < .05). However, values for all other variables did not change significantly with treatment in this group. Thus, doxazosin treatment of nondiabetic subjects with high blood pressure was associated with a series of changes in glucose, insulin, and lipoprotein metabolism that should decrease risk of coronary heart disease (CHD) in these individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
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The study subjects comprised 281 patients (60 with diabetes and 221 non-diabetics with clinically diagnosed BPH) who were treated with alpha1-blockers (doxazosin, terazosin, alfuzosin and tamsulosin). The international prostate symptom score (IPSS), bother score, maximum flow rate (Q(max)) and post-void residual urine volume (PVR) were determined at baseline and after treatment for a minimum of 6 months.
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Studies have shown that alpha 1-adrenergic blockade reduces intimal hyperplasia in the rabbit aorta. In this study a selective alpha 1-adrenergic antagonist, doxazosin, has been used to examine whether this effect is persistent and dose dependent. Forty-eight New Zealand White rabbits underwent endothelial denudation of the abdominal aorta using a Fogarty balloon catheter. Test rabbits were given low-dose (2 mg) or high-dose (8 mg) doxazosin daily and all animals killed at either 1 or 12 weeks after the procedure. The aortas were harvested after fixation in situ with 4 per cent glutaraldehyde and neointimal hyperplasia was measured, using an x-y digitizer, as the percentage reduction in luminal cross-sectional area. At 1 week after surgery, rabbits receiving the low dose had a median area reduction of 7.7 per cent and those receiving the high dose a reduction of 8.2 per cent; both had significantly less intimal hyperplasia than control rabbits, which had a median area reduction of 14.8 per cent (P < 0.01). However, at 12 weeks, when compared with the 32.6 per cent reduction in the control group, only those rabbits receiving high-dose doxazosin had significantly less intimal hyperplasia, with a reduction of 5.5 per cent (P < 0.001). It is concluded that selective alpha 1-adrenergic blockade significantly reduces neointimal hyperplasia, that this effect is dose dependent, and that it persists for at least 3 months.
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Male white New Zealand rabbits were fed by an atherogenic diet for 4 weeks. 8 rabbits whose serum TC <10 mmol/L were confirmed as normal diet group and were fed normally. 40 rabbits whose serum TC >10 mmol/L were randomly divided into 4 groups (n=10): atherogenic diet group, atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (+/-)DOX group, which were intraperitoneally injected with (-)DOX, (+)DOX and (+/-)DOX for 9 weeks respectively. Normal and atherogenic diet group were intraperitoneally injected with double distilled water. After 9 weeks administration of (+/-)doxazosin and its enantiomers, effects of the three agents on serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were observed.
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In order to investigate an association between systemic blood pressure and restitution of normal visual function in dim illumination after photostress, macular recovery time and blood pressure were measured in two groups: 1) 90 young and healthy military pilots and applicants for military pilot training; and 2) 10 hypertensive patients before and after 12 weeks of antihypertensive treatment. Young normotensive subjects (20/20 vision) with low diastolic blood pressure performed less well (longer macular recovery time) than those with higher pressure (r = -0.42, p less than or equal to 0.05). Among the hypertensive patients three were given doxazosin, three, prazosin, and four, placebo. The treatment period produced significant fall in blood pressures, a small reduction in intraocular pressure (p less than or equal to 0.03) and a lengthening of initial monocular recovery period (p = 0.04) in addition to reduced monocular (p = 0.015) and binocular (p = 0.022) macular recovery in the remaining part of the 2-min test period. This observation may be important for antihypertensive treated patients whose occupation requires fast visual adjustment to changing stimuli in dim light.
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In 2003, 3.3% (408,375) of all 12,513,584 drug prescriptions for patients 65 years and older which were analyzed included a PIM from the Beers list. In 2004, it was 2.9% (297,524) of 10,126,809 (p < 0.001). The most frequently prescribed PIMs were short-acting nifedipine (13.4%), indomethacin (12.3%) and diazepam (11.8%) in 2003, and diazepam (14.6%) followed by indomethacin (13.7%) and doxazosin (10.9%) in 2004. 21.7% (119,482) and 18.2% (98,465) of patients 65 years or older received at least one prescription of a PIM in 2003 and 2004, respectively (p < 0.001). In a multivariate logistic regression model female gender and a higher number of prescribed drugs were significantly associated with an increased frequency of receiving a PIM in both years.
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There is evidence that doxazosin is effective in the treatment of posttraumatic stress disorder (PTSD). Doxazosin is a "me-too" drug of prazosin. Doxazosin has an improved absorption profile and this likely minimizes the risk for unintended adverse hypotensive effects. The availability of doxazosin in the gastrointestinal therapeutic system (GITS) form permits a higher initial daily dose (4 mg/day) while avoiding significant first-dose side effects. The treatment of PTSD with prazosin has several disadvantages due to its short duration of action (6-8 hours), which results in multiple doses being required. Prazosin may wear off and this may lead to nightmares in the latter half of the sleep. Doxazosin has significant advantages over prazosin in clinical practice because it has a long half-life and requires only once-daily dosing. This may lead to better adherence and greater effectiveness in the treatment of PTSD.
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To investigate the effect of doxazosin on orthostatic blood pressure changes with daily activity, the relationship among blood pressure, physical position and physical activities using an ambulatory multibiomedical monitoring system(TM2425) were studied. The subjects were 22 patients with essential hypertension(EHT group), 23 patients with diabetic mellitus(DM group) and 17 healthy volunteers for the control. Patients were administered doxazosin at 2-8 mg/day for 0.5 month to 12 months. Twenty-four-hour blood pressure, posture and activity were monitored. Systolic blood pressure was higher in the standing position than that in the sitting position in the control group, but there were no differences between these values in the EHT group and DM groups. During the awake, sleep, and standing periods, doxazosin significantly decreased blood pressure in the EHT group; however, it significantly decreased only the standing systolic blood pressure in the DM group. Absolute changes in blood pressure after the administration of doxazosin were not significantly different between the standing and sitting periods in each group. These findings suggest that doxazosin decreases the blood pressure of both patients with essential hypertension and patients with diabetic mellitus without an excessive decrease in standing blood pressure.
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Objective: Centrally active α-1-adrenergic-receptor antagonists such as prazosin are effective in the treatment of nightmares in patients with posttraumatic stress disorder (PTSD). A pharmacological alternative is doxazosin, which has a longer half-life and fewer side effects. However, doxazosin is currently being used without solid empirical evidence. Furthermore, no study so far has assessed the effects of α-1-antagonists on nightmares in patients with borderline personality disorder (BPD). We retrospectively assessed the effectiveness of doxazosin on nightmares in PTSD and BPD. Method: A retrospective chart review of patients treated with doxazosin for trauma-associated nightmares in our clinic was performed. As in previous prazosin studies, the B2 score of the Clinician-Administered PTSD Scale (CAPS) was used as the primary outcome measure. Furthermore, the Pittsburgh Sleep Quality Index-Addendum for PTSD (PSQI-A) and sleep logs were analyzed. Results: We identified 51 patients with PTSD and/or BPD (mean age 35.7 years, 92.3% women) who received doxazosin for nightmares. Of these, 46 patients continued doxazosin over a 4-week period and 31 patients over a 12-week period. Within the 12-week period, doxazosin treatment significantly reduced nightmares regardless of PTSD/BPD. 25 percent of patients treated for 12 weeks had full remission of nightmares. PSQI-A scores indicated that additional trauma-associated sleep symptoms improved over 12 weeks. Furthermore, recuperation of sleep improved with doxazosin within the first 4 weeks of treatment. Conclusion: Doxazosin might improve trauma associated nightmares and more general sleep parameters in patients with PTSD and BPD. Randomized controlled trials are warranted.
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Not only androgen variabilities but also alterations in sympathetic neurotransmission with age could have important implications for pathophysiological prostate growth. The combination of finasteride and alpha1-ARA is not superior to alpha1-ARA therapy with their similar epithelial and stromal apoptotic effects with unaffected cell proliferation.
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Minimally invasive adrenalectomy for pheochromocytoma (PCC) is a complex surgical procedure especially because of the haemodynamic instability due to the excessive secretion of cathecolamines, which may result in a considerable risk of conversion and complications.
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Currently available data and clinical observations which suggest that there is a pathogenetic relationship between hypertension, diabetes mellitus, and atherosclerosis have provided a concept of the X syndrome, by which hypertensive patients, mainly males, have impaired insulin tolerance along with hyperinsulinemia and concurrent atherogenic disorders of lipid metabolism. The paper discussed the specific pathogenetic mechanisms, clinical manifestations, and prospects for drug correction of the metabolic syndrome. The treatment of arterial hypertension with the calcium antagonist Lomir has indicated there are no negative changes as a control of non-insulin-dependent diabetes mellitus in the presence of effective correction of arterial hypertension and atherogenic dyslipidemias. With the monotherapy of essential hypertension concurrent with hypercholesterolemia with the alpha 1-adrenoblocker Doxazosin, in addition to the agent's high antihypertensive effects, the authors noted its favourable action on lipid spectral parameters and platelet functional activity. There is abundant evidence for the use of specific hypolipidemic agents in patients with essential hypertensive refractory to current antihypertensive drugs. The data obtained with the use of Lescol (fluvastatin) in patients with hypertensive disease and hypercholesterolemia suggest that by substantially reducing the levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and its transport protein apo B does not deteriorate the quality of correction of arterial hypertension in this group of patients.
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Taken together, our findings demonstrate the ability of the quinazoline alpha-blockers, terazosin and doxazosin, but not the sulphonamide, tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. These studies underwrite the durability of the response seen in long-term studies with terazosin, and suggest the potential of this drug in the treatment of prostate carcinoma.
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Mechanical stress increases myocardial myostatin expression. However, the expression of myostatin in chronic heart failure resulting from volume-overload and after treatment with beta-blockers is little known. The authors hypothesize that myostatin plays a role in the failing myocardium because of volume-overload.
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On the basis of a 1-year double-blind comparative study of doxazosin and atenolol in hypertensive patients, we have previously described sustained and significantly different drug effects on the blood lipid profile. The present paper presents a retrospective analysis of the smoking subgroups for each drug regimen, for both the original 12-month double-blind period and for a further 12-month open-label period. The changes in blood lipids were qualitatively and quantitatively similar in both the smoking subgroup and in the full study population (smokers and non-smokers). In the hypertensive smokers doxazosin increased high-density lipoprotein (HDL) cholesterol (+9.4%) and decreased triglycerides (-10.9%) whereas atenolol had the opposite effect, decreasing HDL cholesterol (-5.6%) and increasing triglycerides (+20.7%). The antihypertensive effects of doxazosin (n = 24) and atenolol (n = 23) were comparable over 24 months of treatment. Eighteen (75%) doxazosin and 17 (73.9%) atenolol patients reached the blood pressure goal (sitting diastolic blood pressure less than or equal to 90 mmHg with at least a 5-mmHg reduction, or a greater than or equal to 10-mmHg reduction from baseline). As a consequence of the lowered blood pressure and favourable lipid changes, doxazosin decreased the risk of coronary heart disease (as calculated from the Framingham risk equation) by -24.4% (P less than 0.05). However, the calculated risk was not significantly reduced by atenolol (-2.1%). It is concluded that the smoking status of the patient has no obvious implications for the safety, efficacy or metabolic effects of doxazosin.
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For various reasons, the alpha 1-receptor blocker prazosin has been used infrequently as initial therapy for hypertension. The introduction of additional agents of this class with properties different from prazosin provides slower onset of action, which should reduce the degree of first-dose and postural hypotension and a longer duration of action, which allows for once-a-day dosage. A summary of the published data on efficacy, side effects, and special properties of this class of agents indicates that they will probably be used more extensively, particularly because of their ability to improve lipid and glucose-insulin metabolism.