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Validation of Heart Failure Events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants Assigned to Doxazosin and Chlorthalidone
Linda B Piller, Barry R Davis, Jeffrey A Cutler, William C Cushman, Jackson T Wright, Jeff D Williamson, Frans HH Leenen, Paula T Einhorn, Otelio S Randall, John S Golden, L Julian Haywood, the ALLHAT Collaborative Research Group
Trials , 2002, DOI: 10.1186/1468-6708-3-10
Abstract: Baseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P < .05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67–1.38; P = 0.83).Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, two-component clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). A double-blind, active-controlled hypertension component is designed to compare the rate of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) (the primary endpoint) in high-risk hypertensive participants, aged 55 years or older, between those randomized to treatment initiated with a diuretic (chlorthalidone) and treatment initiated with each of three alternative antihypertensive drugs: a calcium-channel blocker (amlodipine), an angiotensin-converting enzyme (ACE)-inhibitor (lisinopril), or an alpha-adrenergic blocker (doxazosin). An open-label lipid-lowering component is designed to determine if lowering LDL cholesterol with pravastatin compared to "usual care" reduces all-cause mortality in a subset of moderately hypercholesterolemic patients. Randomization to the hypertension com
Hypothesis to explain poor outcomes in the ALLHAT and V-HeFT trials: decreased expression of heat shock proteins
Philip L Hooper
Trials , 2001, DOI: 10.1186/cvm-2-6-251
Abstract: The expectation that lowering blood pressure with any antihypertensive agent will have a beneficial outcome is now open to question. In particular, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) collaborative research group discontinued doxazosin from that study owing to a doubled incidence of congestive heart failure, as well as a higher rate of angina, and stroke, in patients receiving doxazosin.ALLHAT is a randomized, double blind, active-controlled trial sponsored by the National Heart, Lung, and Blood Institute that was initiated in 1994. In two arms of the four-arm study, participants were randomly assigned to receive either chlorthalidone (12.5–25 mg/day) or doxazosin (2–8 mg/day) for a planned follow-up of 4–8 years. In January 2000, the decision was made to discontinue doxazosin. However, a mechanism to explain the poor outcome of the study has not been apparent. The ALLHAT collaborators speculated that doxazosin, an α-adrenergic blocker, might increase plasma volume and norepinephrine (noradrenaline) levels, but for the most part they were puzzled by the results of their study [1]. Perhaps not coincidentally, another α-adrenergic blocker, prazosin, has similarly been associated with a higher cardiovascular mortality compared with other afterload reducers, in the Vasodilator Heart Failure Trial (V-HeFT) [2].The poor outcome of either study was not expected. In fact, α-adrenergic blockers improve patient's metabolic profile by raising high-density lipoprotein levels, lowering triacylglycerol levels and increasing sensitivity to insulin. They also improve fibrinolysis and reduce left ventricular afterload [3].A hypothesis to explain how α-adrenergic blockers confer harm on the cardiovascular system is that it lowers an important group of cytoprotective proteins, the heat shock proteins (Hsps). Hsps protect cellular elements from injury by refolding proteins, decreasing oxidation, suppressing the production and activit
ALLHAT - kritisch gesehen  [PDF]
Pilz H
Journal für Hypertonie , 2003,
Abstract: Studien bilden das Fundament der "Evidence-based Medicine" und sollten auch deshalb in ihren Aussagen unanfechtbar sein. Dennoch ist es oft angezeigt, Studienresultate zu hinterfragen, unter anderem, um nicht nachvollziehbare Interpretationen zu erkennen. Gerade in ALLHAT wurden durch ein problematisches Studiendesign sowohl die Einschlu kriterien der Studienteilnehmer als auch die Medikation betreffend die medizinischen Fakten "verzerrende" Ergebnisse erzielt. Teilweise wurden wichtige Aspekte wie z. B. die metabolischen Auslenkungen im Rahmen der Diuretikatherapie sowohl aus der Diskussion gehalten als auch in den zusammenfassenden Empfehlungen nicht entsprechend erw hnt. Auch die auf verschiedenen Ursachen beruhende unterschiedliche Blutdrucksenkung in den einzelnen Studienarmen fand wenig Beachtung, obwohl gerade dieser Parameter für die Studieninterpretation von gro er Bedeutung ist. Ein kritischer überblick über Studiendesign und Resultate von ALLHAT soll auch die Wertigkeit der aus ALLHAT abgeleiteten Empfehlungen zur antihypertensiven Therapie relativieren.
Benefits and side effects of blood pressure lowering treatment: what was wrong with doxazosin in the ALLHAT?
Irene Gavras, Haralambos Gavras
Trials , 2001, DOI: 10.1186/cvm-2-6-257
Abstract: The purpose of lowering high blood pressure is to prevent morbidity and mortality from hypertensive complications, such as heart attack, stroke, renal failure, and heart failure. The Veterans Administration studies in the 1960s proved beyond doubt that treating hypertension with thiazides and β-blockers (the drugs available at that time) significantly diminished the rates of strokes, renal failure, and heart failure, although the decrease in the rate of myocardial infarcts did not reach statistical significance. It has been estimated that a 10–15 mmHg fall in systolic blood pressure should lead to a 15% reduction in relative risk for heart attack and to a 40% reduction for stroke [1].With the advent of new classes of antihypertensive agents, the emphasis shifted from efficacy in lowering blood pressure, which is taken for granted, to potential to protect against end-organ damage. Controlled clinical trials have indicated that drugs from different classes have different neurohumoral and metabolic profiles, which might enhance or partially offset the benefits from blood pressure lowering per se. For example, thiazides and β-adrenergic blockers have been reported to further increase insulin resistance, and hence to accentuate the dysmetabolic syndrome that commonly accompanies essential hypertension [2,3]. On the contrary, α1-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors have been reported to improve insulin sensitivity and the lipid profile [4], whereas calcium-channel blockers were found to be metabolically neutral. In terms of neurohormonal changes, the stimulation of the renin–angiotensin and sympathetic systems associated with the use of diuretics and dihydropyridines should be detrimental to end organs, whereas angiotensin blockers and sympathetic blockers should be beneficial to them. Several such effects that are theoretically considered to be beneficial have been used as 'surrogate endpoints' in the absence of firm data on morbidity an
African Journal of Urology , 2002,
Abstract: Objective To evaluate the efficacy and tolerability of doxazosin tablets in elderly patients with symptomatic benign prostatic hyperplasia (BPH). Patients and Methods This study involved the use of doxazosin, a once daily alpha-1 adrenergic blocker, for the treatment of BPH in two distinct phases. Phase 1 involved a two-week dose titration, escalating from 1 mg to 8 mg depending on response and tolerability using blood pressure (BP) and pulse as a monitor to arrive at a stabilizing dose. In phase 2, the patients were maintained on the stabilized dose for 6 weeks. The International Prostate Symptom Score (IPSS) and Quality of Life Assessment (QLA) were used to evaluate the severity of the illness and the response to treatment. Twenty-six patients were enlisted while only 20 met the criteria for analysis. Mean age was 72.5 (55-90) years. Eighteen (90%) were stabilized at a doxazosin dose of 4 mg, while 2 (10%) stabilized on 2 mg. Results There was a significant improvement of symptoms (IPSS) in all the patients at the end of the titration period, and this was progressive and sustained over the 6-week study period. QLA was also significantly improved. BP did not vary significantly in the normotensives, while the hypertensives required other antihypertensives to maintain normal levels. One case had severe postural hypotension that warranted discon-tinuation of the test drug. Using the Physician Global Assessment, efficacy was excellent in 65%, good in 30% and poor in 5%, while tolerability was excellent in 95% and poor in 5%. Drug compliance was 100%. Side effects were minimal and not life threatening. Conclusion Doxazosin is effective in the treatment of BPH in elderly Nigerians. It is compatible with other drugs used in the treatment of other illnesses associated with old age. It is therefore recommended for use in elderly BPH patients. La Doxazosine dans le Traitement de lHypertrophie Bénigne de la Prostate chez les Patients Agés Objectif Evaluer lefficacité et la tolérance de la doxazosine chez des patients agés présentant des sympt mes dhypertrophie bénigne de la prostate. Patients et Méthodes Cette étude porte sur lutilisation de la doxazosine, un alpha-1 bloquant en prise unique journalière pour le traitement de lHBP en deux phases. La première phase consistait en deux semaines de recherche de la dose appropriée avec une prise progressive de 1 mg à 8 mg selon la réponse et la tolérance en mesurant la pression artérielle et le pouls jusquà arriver à une dose de stabilité. Dans la seconde phase, les patients sont maintenus à cette dose de stabilité pendant 6 semaines. Les scores internationaux des sympt mes prostatiques (IPSS) et Qualité de vie (QOL) ont été utilisés pour évaluer la sévérité de la maladie et la réponse au traitement. Sur les 26 patients enr lés, seuls 20 présentaient des critères analysables. Lage moyen était de 72,5 ans avec des extrêmes de 55 et 90 ans. La stabilisation des sympt mes a été obtenue chez 18 patients (90%) avec l
Original Articles Efficacy and Safety of Doxazosin (CARDURATM) in the Management of Benign Prostatic Hyperplasia
EA Jeje, AS Dogunro, MA Ogunjimi, KH Tijani
Nigerian Journal of Surgery , 2011,
Abstract: Objective To assess the efficacy and safety of the selective á -blocker doxazosin in black men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia. Patients and Methods An open-label study involving consecutive patients with benign prostatic hyperplasia. They were asked to complete the International Prostate Symptom Score (IPSS), with its eighth question (bother score) and perform basic uroflowmetry. The study involved the use of doxazosin for the treatment of symptomatic benign prostatic hyperplasia in three phases. Phase 1 of washout period/enrolment, a two weekly interval titration phase and a maintenance phase for four weeks. The symptom score (IPSS), bother score and uroflowmetry were used to evaluate the severity of the condition and the efficacy of the drug. Results Twenty-four patients were enrolled into the study, only 18(75%) completed the eight-week study. The ages of the patients ranged between 46 years and 82 years with a mean of 66 years. (SD, 10.0). Fourteen patients were stabilized on 4mg doxazosin while the remaining 4 patients had 2mg. There was significant improvement of the symptoms, with a remarkable sharp decline after two weeks of medication in IPSS by 8 points from baseline. The improvement was sustained over the following six weeks period. The bother score (quality of life index) was similarly observed to decline from a mean of 4.7 at baseline to 1.3 at the end of the study. The clinical trial showed a significant increase in the urine flow rate with an improvement of 4mls/second from baseline and a 24.1% increase in voided volume. There was no adverse event recorded in all the patients to warrant discontinuation of the study. Conclusion Doxazosin is an effective and well tolerated drug in the treatment of symptomatic BPH in Nigerians. Key Words: BPH, LUTS, Quality of life, IPSS, a1-blocker, Doxazosin.
The Effect of Rofecoxib / Doxazosin Treatment for Chronic Prostatitis/Chronic Pelvic Pain Syndrome in Men  [PDF]
Mutlu Ate?,Mustafa Karalar,Bünyamin Y?ld?r?m,Fatih Pekta?
Journal of Clinical and Analytical Medicine , 2012, DOI: 10.4328
Abstract: Aim: Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is a chronic disease with an unknown etiology and characterize with urinary sensibility, pelvic and genitoperineal pain. No effective treatment regime is described in the literature. In this present study, the efficacy of selective cyclooxygenase type-II (COX-II) inhibitor (rofecoxib), α-1 blocker (doxazosin) and their combination treatments were evaluated. Material and Method: Sixty-eight patients (mean age:40.3±8.2 years; range:22–54), were enrolled to the study. Twenty-four, 21 and 23 patients were treated with rofecoxib (50 mg/day), doxazosin (4 mg/day), and their combinations, respectively. The efficacies of these regimens were evaluated by comparing pre and post-treatment National Institutes of Health–Chronic Prostatitis Symptom Index (NIH-CPSI) scores as well as number of patients whose total scores decreased 25%.Results: There was significant improvement in total NIH-CPSI scores with rofecoxib treatment than doxazosin (14.3±5.3 vs. 9.5±5.8, p:0.0249). Addition of doxazosin,, to rofecoxib treatment couldn’t provide an additional benefit to rofecoxib treatment alone (13.6±5.8 vs. 14.3±5.3, p:0.9856). More than 25% improvement in total symptom score was significantly more in rofecoxib and rofecoxib+doxazosin combination than doxazosin alone (p<0.05). Discussion: Treatment with rofecoxib at CP/CPPS is effective. Addition of doxazosine to rofecoxib didn’t improve symptoms. Since 2004, COX-II inhibitors aren’t in use cause of cardiovascular side effects. We need anti-inflammatory drugs as effective as COX-II inhibitors. They can be used at patients with low cardiovascular risk, who couldn’t be treated with other several treatments. To investigate the optimal therapy for CP/CPPS further long term researches with large populations should be performed.
Doxazosin versus Finasteride for the Treatment of Large Symptomatizing Benign Prostatic Hyperplasia: A Questionnaire and Urodynamic-Based Study
MZ Shoukry, M Hassouna
African Journal of Urology , 2004,
Abstract: Objectives: To evaluate and compare the efficacy of both Finasteride and Doxazosin in the treatment of moderately symptomatizing large-sized benign prostatic hyperplasia and to correlate symptomatic changes with alterations in urodynamic values using the OCO values (Sch fer nomogram). Patients and Methods: Fifty male patients with moderately symptomatizing BPH (> 40 cc) as assessed by ultrasound, were randomized to receive either Finasteride (5 mg/day)or Doxazosin (1-4 mg/ day) for 12 months. Results: Both Finasteride and Doxazosin significantly improved the urinary flow rates. Pressure-flow studies confirmed that both Doxazosin and Finasteride were effective in decreasing the opening detrusor pressure, the detrusor pressure at maximum flow (PdetQmax) and the detrusor pressure at least flow (Pdet least). When applying the Sch fer nomogram, the OCO values were found to have improved in both treatment groups. There was, however, a significant difference between both groups with respect to the OCO values denoting a better improvement of the degree of obstruction in patients treated with Finasteride. Conclusion: The use of a compatible numerical format for grading the degree of bladder outlet obstruction would maximize the usefulness of pressure-flow studies in the evaluation of obstructed patients. Using the OCO value revealed that Finasteride was superior to Doxazosin regarding the degree of improvement in obstruction caused by benign prostatic hyperplasia. Comparaison entre le Doxazosin et le Finasteride dans le traitement des hypertrophies bénignes de la prostate très volumineuses et symptomatiques: Etude basée sur un questionnaire et des études urodynamiques Objectifs: Evaluer et comparer l'efficacité du Finastéride et du Doxazosin dans le traitement des hypertrophies bénignes de la prostate modérément symptomatiques et de grande taille et corréler les modifications de la symptomatologie avec les altérations des paramètres urodynamiques en utilisant les valeurs OCO (Normogramme de Sch fer). Patients et Méthodes: Cinquante patients présentant une hypertrophie bénigne de la prostate modérément symptomatique et de volume > 40 CC appréciée par l'échographie étaient inclus dans une étude randomisée utilisant le traitement soit par du Finastéride (5 mg/jour) soit par du Doxazosin (1-4 mg :jour) pendant 12 mois. Résultats : Aussi bien le Finastéride que le Doxazosin amélioraient significativement le débit urinaire. L'étude des pressions d'écoulement avaient confirmé qu'aussi bien le Finastéride que le Doxazosin réduisaient significativement la pression d'ouverture du détrusor, la pression du détrusor au flux maximal (Pdet Omax), et la pression du détrusor au flux minimal (Pdet least). En appliquant le normagramme de Sch fer les valeurs OCO étaient améliorées dans les deux groupes. Il y'avaient toutefois une différence significative entre les deux groupes selon les valeurs OCO, les patients sous Finastéride avaient en effet une amélioration plus nette d
The α1 Antagonist Doxazosin Alters the Behavioral Effects of Cocaine in Rats  [PDF]
Colin N. Haile,Yanli Hao,Patrick W. O'Malley,Thomas F. Newton,Therese A. Kosten
Brain Sciences , 2012, DOI: 10.3390/brainsci2040619
Abstract: Medications that target norepinephrine (NE) neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX), a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats ( n = 6–8) were administered saline, cocaine (COC, 10 mg/kg) or DOX (0.3 or 1.0 mg/kg) alone or in combination for 5 consecutive days (development). Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression). COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg), but not the low dose (0.3 mg/kg) of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.
9. Spectrophotometric and spectrofluorimetric determination of amlodipine besilate and doxazosin mesilate in bulk and in dosage forms via Hantzsch reaction  [PDF]
M.M. Ayad,H.E. Abdellatef,M.M. Hosny,Y.A. Sharaf
International Journal of Pharmaceutical and Biomedical Research (IJPBR) , 2012,
Abstract: Simple, accurate, and sensitive spectrophotometric and spectrofluorimetric methods for analysis of amlodipine besilate and doxazosin mesilate were developed and validated. Acetylacetone together with formaldehyde react with primary amines by Hantzsch reaction forming a yellow product (dihydrolutidine derivatives) that can be measured either spectrophotometrically or spectrofluorimetrically. Different variables affecting the reactions conditions were carefully studied and optimized. Under the optimum conditions, Beer's law was obeyed in the concentration range of 6-44μg/mL for amlodipine besilate and 8-36μg/mL for doxazosin mesilate, using spectrophotometric method. For the case of spectrofluorimetric method, Beer's law was obeyed in the concentration range of 1.6-7.6μg/mL and 0.02-0.22μg/mL for amlodipine besilate and doxazosin methylate, respectively. The precision of the methods were satisfactory; the values of relative standard deviation did not exceed 2%. The reaction stoichiometry was studied and the proposed methods were successfully applied for the analysis of the investigated drugs in pure and pharmaceutical dosages forms. The results obtained by the proposed methods were comparable with those obtained by the reference method.
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