RESUMEN
BACKGROUND AND OBJECTIVES: Terazosin, doxazosin, and alfuzosin (Tz/Dz/Az) are α-1 adrenergic receptor antagonists that also bind to and activate a key adenosine triphosphate (ATP)-producing enzyme in glycolysis. It is hypothesized that the increase in energy availability in the brain may slow or prevent neurodegeneration, potentially by reducing the accumulation of alpha-synuclein. Recent work has suggested a potentially neuroprotective effect of the use of Tz/Dz/Az in Parkinson disease in both animal and human studies. We investigated the neuroprotective effects of Tz/Dz/Az in a closely related disease, dementia with Lewy bodies (DLB). METHODS: We used a new-user active comparator design in the Merative Marketscan database to identify men with no history of DLB who were newly started on Tz/Dz/Az or 2 comparator medications. Our comparator medications were other drugs commonly used to treat benign prostatic hyperplasia that do not increase ATP: the α-1 adrenergic receptor antagonist tamsulosin or 5α-reductase inhibitor (5ARI). We matched the cohorts on propensity scores and duration of follow-up. We followed up the matched cohorts forward to estimate the hazard of developing DLB using Cox proportional hazards regression. RESULTS: Men who were newly started on Tz/Dz/Az had a lower hazard of developing DLB than matched men taking tamsulosin (n = 242,716, 728,256 person-years, hazard ratio [HR] 0.60, 95% CI 0.50-0.71) or 5ARI (n = 130,872, 399,316 person-years, HR 0.73, 95% CI 0.57-0.93). while the hazard in men taking tamsulosin was similar to that of men taking 5ARI (n = 159,596, 482,280 person-years, HR 1.17, 95% CI 0.96-1.42). These results were robust to several sensitivity analyses. DISCUSSION: We find an association in men who are taking Tz/Dz/Az and a lower hazard of DLB compared with similar men taking other medications. When combined with the literature of Tz/Dz/Az on Parkinson disease, our findings suggest that glycolysis-enhancing drugs may be broadly protective in neurodegenerative synucleinopathies. A future randomized trial is required to assess these associations for causality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that Tz/Dz/Az use reduces the rate of developing DLB in adult men.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Doxazosina , Enfermedad por Cuerpos de Lewy , Prazosina , Quinazolinas , Humanos , Masculino , Doxazosina/uso terapéutico , Anciano , Prazosina/análogos & derivados , Prazosina/uso terapéutico , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Anciano de 80 o más Años , Tamsulosina/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Persona de Mediana Edad , Estudios de CohortesRESUMEN
PURPOSE: Although it is known that alpha-adrenergic receptor antagonists have positive effects on metabolic parameters such as glucose metabolism, lipid profile, and insulin sensitivity, it is unclear whether this is a class effect. Tamsulosin is reported to have adverse effects on glucose metabolism and insulin resistance, and this may be because of its lack of glycolysis-enhancing effect compared with other alpha-adrenergic receptor antagonists with glycolysis-enhancing effects such as doxazosin, terazosin, and alfuzosin. The aim of this study was to compare the effect of tamsulosin on metabolic parameters with another alpha-1 adrenergic receptor antagonist, doxazosin. METHODS: In this prospective, observational, controlled, 12-week clinical study, a total of 60 male patients aged ≥ 40 years who were first started on tamsulosin (n = 30; 0.4 mg/day, oral; mean age, 59.20 ± 8.97 years) or doxazosin (n = 30; 4 or 8 mg/day, oral; mean age, 58.50 ± 8.93 years) for benign prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS) were enrolled. The groups were compared according to the changes in anthropometric and biochemical parameters (glycemia, lipid profile, and insulin sensitivity) at the end of treatment. RESULTS: In intragroup analyses, systolic blood pressure, diastolic blood pressure, total cholesterol, and HbA1c levels decreased significantly in the doxazosin group compared with baseline (p < 0.05 for all), while no significant change was observed in the tamsulosin group. In comparisons between groups, systolic blood pressure, total cholesterol, and low-density lipoprotein cholesterol levels showed a significant decrease in the doxazosin group compared with the tamsulosin group (percent change: - 6.68 ± 13.08 vs. 0.53 ± 11.02, p = 0.025; - 3.63 ± 9.56 vs. 4.02 ± 10.86, p = 0.005; and - 5.62 ± 18.18 vs. 5.24 ± 15.42, p = 0.015, respectively). CONCLUSION: Although these results do not support previous findings that tamsulosin has adverse effects on metabolic parameters, they suggest that doxazosin treatment may be a reason for preference in patients with BPH or LUTS accompanied by metabolic disorder.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Doxazosina , Hiperplasia Prostática , Tamsulosina , Humanos , Masculino , Doxazosina/uso terapéutico , Tamsulosina/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Anciano , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Resistencia a la Insulina , Hemoglobina Glucada/metabolismo , Sulfonamidas/uso terapéuticoRESUMEN
Liver fibrosis and cirrhosis, which are caused by chronic liver injury, represent common and intractable clinical challenges of global importance. However, effective therapeutics are lacking. Therefore, the study examines the effect of doxazosin on liver fibrosis. Carbon tetrachloride (CCl4) is injected into mice to establish a liver fibrosis model. Doxazosin (5 and 10 mg/kg) is administered daily by gavage. HE staining, Masson staining, Sirius Red staining, scanning electron microscopy, western blotting, real-time PCR, and immunofluorescence analysis are performed to estimate liver fibrosis and sinusoidal capillarization in mice. Cell Counting Kit-8 assays, western blotting, immunofluorescence analysis, tube formation, and transwell migration assays are performed on human umbilical vein endothelial cells (HUVECs) and human hepatic sinusoidal endothelial cells (HHSECs) to elucidate the potential mechanism of doxazosin. Doxazosin alleviates liver fibrosis and sinusoidal capillarization in CCl4-induced mice. Angiogenesis is attenuated by doxazosin in HUVECs and HHSECs. This study demonstrates that doxazosin attenuated liver fibrosis by alleviating sinusoidal capillarization and liver angiogenesis.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Doxazosina , Células Endoteliales de la Vena Umbilical Humana , Cirrosis Hepática , Hígado , Neovascularización Patológica , Doxazosina/farmacología , Doxazosina/uso terapéutico , Animales , Ratones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Humanos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Masculino , Hígado/efectos de los fármacos , Hígado/patología , Hígado/irrigación sanguínea , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Tetracloruro de Carbono/toxicidad , Ratones Endogámicos C57BL , Capilares/efectos de los fármacos , Capilares/patología , Modelos Animales de Enfermedad , AngiogénesisRESUMEN
PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.
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Neoplasias de las Glándulas Suprarrenales , Antagonistas de Receptores Adrenérgicos alfa 1 , Doxazosina , Paraganglioma , Feocromocitoma , alfa-Metiltirosina , Humanos , Doxazosina/uso terapéutico , Doxazosina/administración & dosificación , Femenino , Masculino , Feocromocitoma/cirugía , Feocromocitoma/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias de las Glándulas Suprarrenales/cirugía , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Estudios Retrospectivos , Paraganglioma/tratamiento farmacológico , Paraganglioma/cirugía , Adulto , Anciano , alfa-Metiltirosina/uso terapéutico , alfa-Metiltirosina/administración & dosificación , alfa-Metiltirosina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Quimioterapia Combinada , Cuidados Preoperatorios/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. METHODS: The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. RESULTS: DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. CONCLUSIONS: Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.
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Doxazosina , Neoplasias de la Mama Triple Negativas , Humanos , Línea Celular Tumoral , Proliferación Celular , Doxazosina/farmacología , Doxazosina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Células Madre Neoplásicas/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
BACKGROUND: Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and sexual AEs associated with ABs based on Eudra-Vigilance reported AEs. METHODS: Eudra-Vigilance (EV) database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We recorded the number of sexual and neuro-vascular AEs for tamsulosin, alfuzosin, silodosin, prazosin and doxazosin per category and severity until July 30th, 2022. Pooled Relative Risk (PRR) was used to compare data between drugs. RESULTS: Overall the number of AEs were 2842 for Alfuzosin, 11,086 for tamsulosin, 792 for terazosin, 572 for prazosin and 4641 for doxazosin. Different percentages of AEs were obtained for each drug and in different age groups according to EV sub-groups (≤65, 65-85, ≥85). On PRR analysis, the risk of ejaculatory disorders for Silodosin (11%) is 18.5 times higher (PRR 18.5 95%CI; 10.7-31.8; P<0.05) when compared to alfuzosin and the risk of orthostatic hypotension is 2 times lower (PRR=1,84 95%CI 1.32-2.57; P<0.05). CONCLUSIONS: Real life data is consistent with registry studies regarding side effects related to alpha-blockers. Alfuzosin is safer in terms of ejaculatory disorders while silodosin and tamsulosin in terms of orthostatic hypotension. Clinicians should consider these data when prescribing ABs especially in younger and older patients.
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Hipotensión Ortostática , Enfermedades Urogenitales , Humanos , Doxazosina/uso terapéutico , Tamsulosina/uso terapéutico , Hipotensión Ortostática/inducido químicamente , Hipotensión Ortostática/epidemiología , Hipotensión Ortostática/tratamiento farmacológico , Antagonistas Adrenérgicos alfa/efectos adversos , Prazosina/efectos adversosRESUMEN
Oral squamous cell carcinoma (OSCC), a global threatening disease, is reported mostly in the middle and elderly male population. Even though the exact cause of OSCC was not known, consumption of tobacco in any form has been reported in most of OSCC patients. OSCC is a massive invasive type of cancer which easily spreads to the distant organs. Hence treating it at appropriate time is necessary and the rate of OSCC incidence is also constantly increasing. At present, chemoradiation is the only therapy prescribed for OSCC patients which renders various side effects. Hence, the treatment with lesser side effect was of current research interest. Doxazosin (α1 adrenorecptor antagonist) had been proven to render anticancer effect in prostate, renal, hepatic, and ovarian cancers but its role in oral cancer cells was not been elucidated. Therefore, we have assessed the anticancer effect of doxazosin on oral squamous cancer cells via through the induction of apoptosis, and antioxidant property. The cytoprotective effect of doxazosin on normal Vero cells and anticancer effect on oral cancer KB cells were analyzed with MTT assay. Doxazosin antioxidant activity were analyzed by their reactivity with free radicals and metal ions by the method of FRAP, DPPH, chemilumiscence, and ORAC assay. The antioxidant levels were also assessed by TBARS, SOD, and glutathione levels, and later on apoptosis staining techniques like DCFH-DA, Rhodamine 123, and AO/EtBr stain were conducted. Apoptosis was confirmed by estimating the levels of apoptotic proteins in doxazosin-treated KB human oral cancer cells by ELISA method. The results from our study show that doxazosin is a potent antioxidant and it significantly induces apoptosis in human oral cancer by altering various cellular molecules at downstream signaling which has been depict in the results. Our study proves doxazosin as a potent anticancer drug which may be used in the treatment of oral carcinoma, if it is subjected to further research using human clinical trials.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Neoplasias de la Próstata , Animales , Chlorocebus aethiops , Humanos , Masculino , Anciano , Doxazosina/farmacología , Doxazosina/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos alfa/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Células Vero , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Apoptosis , Proliferación Celular , Línea Celular TumoralRESUMEN
Objective: The aim of this study was to determine the efficacy of doxazosin, an α1-adrenergic antagonist, for the treatment of co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD).Methods: This 12-week, double-blind, randomized controlled trial of doxazosin (16 mg/d) was conducted between June 2016 and December 2019 at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina. Participants were military veterans (N = 141) who met DSM-5 criteria for current PTSD and AUD and were randomly assigned to receive doxazosin (n = 70) or placebo (n = 71). Primary outcome measures were the Clinician Administered PTSD Scale (CAPS-5), the PTSD Checklist for DSM-5 (PCL-5), and the Timeline Follow-Back (TLFB).Results: Findings from the intent-to-treat analyses revealed that participants in both groups demonstrated statistically significant reductions in CAPS-5 and PCL-5 scores (P < .0001), but, contrary to hypotheses, no significant differences were observed between groups. Percent drinking days and percent heavy drinking days also decreased significantly during treatment, but there were no differences between groups (P < .0001). Abstinence during treatment was significantly higher in the doxazosin versus the placebo group (22% vs 7%, P = .017); however, participants in the doxazosin group consumed a greater number of drinks on drinking days (6.15 vs 4.56, P = .0096). A total of 74.5% of the sample completed the treatment phase, and there were no group differences in retention or adverse events.Conclusions: Doxazosin was safe and tolerable but was not more effective than placebo in reducing PTSD or AUD severity in this dually diagnosed sample. Clinical considerations such as heterogeneity of PTSD and AUD presentation and potential moderators are discussed in the context of future research directions.Trial Registration: ClinicalTrials.gov Identifier: NCT02500602.
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Alcoholismo , Trastornos por Estrés Postraumático , Veteranos , Humanos , Trastornos por Estrés Postraumático/complicaciones , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Doxazosina/uso terapéutico , Alcoholismo/diagnóstico , Alcoholismo/tratamiento farmacológico , Alcoholismo/epidemiología , Resultado del Tratamiento , Antagonistas de Receptores Adrenérgicos alfa 1/efectos adversos , Método Doble CiegoRESUMEN
BACKGROUND: Renal denervation (RDN) lowers blood pressure (BP) in patients with uncontrolled hypertension. Limited data exist on the effectiveness of different antihypertensive medications following RDN on BP and maladaptive cardiac phenotypes. METHODS: Eighty-nine male spontaneously hypertensive rats with continuous BP recording underwent RDN or sham operation. Ten days postsurgery, spontaneously hypertensive rats were randomized to receive no antihypertensive medication, amlodipine, olmesartan, hydrochlorothiazide, bisoprolol, doxazosin, or moxonidine for 28 days. Cardiac remodeling was determined histologically, and activation of the renin-angiotensin-aldosterone system was explored. RESULTS: Before initiation of antihypertensive drugs, RDN reduced mean arterial pressure (-12.6 mm Hg [95% CI, -14.4 to -10.8]; P<0.001). At study end, mean arterial pressure was lower in RDN compared with sham operation in drug-naïve controls (P=0.006), olmesartan (P=0.002), amlodipine (P=0.0004), hydrochlorothiazide (P=0.006), doxazosin (P=0.001), and bisoprolol (P=0.039) but not in animals receiving moxonidine (P=0.122). Compared with pooled BP change of all other drug classes, mean arterial pressure change was largest for olmesartan (-15.9 mm Hg [95% CI, -18.6 to -13.2]; P<0.001) and amlodipine (-12.0 mm Hg [95% CI, -14.7 to -9.3]; P<0.001). In drug-naïve controls, RDN reduced plasma renin activity (-5.6%¸ P=0.03) and aldosterone concentration (-53.0%; P=0.005). In the presence of antihypertensive medication, plasma renin activity and aldosterone remained unchanged after RDN. Cardiac remodeling was not affected by RDN alone. In animals receiving olmesartan after RDN, cardiac perivascular fibrosis was attenuated. Amlodipine and bisoprolol following RDN reduced cardiomyocyte diameter. CONCLUSIONS: Following RDN, treatment with amlodipine and olmesartan resulted in the largest BP reduction. Antihypertensive medications mediated heterogeneous effects on renin-angiotensin-aldosterone system activity and cardiac remodeling.
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Cardiomiopatías , Hipertensión , Animales , Masculino , Ratas , Aldosterona , Amlodipino/farmacología , Amlodipino/uso terapéutico , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Bisoprolol/farmacología , Bisoprolol/uso terapéutico , Presión Sanguínea/fisiología , Desnervación/métodos , Doxazosina/farmacología , Doxazosina/uso terapéutico , Hidroclorotiazida/farmacología , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/cirugía , Riñón , Ratas Endogámicas SHR , Renina , SimpatectomíaRESUMEN
OBJECTIVE: To develop a novel predictive model for identifying patients who will and will not respond to the medical management of benign prostatic hyperplasia (BPH). METHODS: Using data from the Medical Therapy of Prostatic Symptoms (MTOPS) study, several models were constructed using an initial data set of 2172 patients with BPH who were treated with doxazosin (Group 1), finasteride (Group 2), and combination therapy (Group 3). K-fold stratified cross-validation was performed on each group, Within each group, feature selection and dimensionality reduction using nonnegative matrix factorization (NMF) were performed based on the training data, before several machine learning algorithms were tested; the most accurate models, boosted support vector machines (SVMs), being selected for further refinement. The area under the receiver operating curve (AUC) was calculated and used to determine the optimal operating points. Patients were classified as treatment failures or responders, based on whether they fell below or above the AUC threshold for each group and for the whole data set. RESULTS: For the entire cohort, the AUC for the boosted SVM model was 0.698. For patients in Group 1, the AUC was 0.729, for Group 2, the AUC was 0.719, and for Group 3, the AUC was 0.698. CONCLUSION: Using MTOPS data, we were able to develop a prediction model with an acceptable rate of discrimination of medical management success for BPH.
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Doxazosina , Finasterida , Hiperplasia Prostática , Hiperplasia Prostática/tratamiento farmacológico , Humanos , Masculino , Finasterida/uso terapéutico , Doxazosina/uso terapéutico , Quimioterapia Combinada , Aprendizaje Automático , Inhibidores de 5-alfa-ReductasaRESUMEN
There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1-blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1-blockers as add-on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1-blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1-blockers have to be used under several considerations. Among the currently available agents, only long-acting α1-blockers, such as doxazosin gastrointestinal therapeutic system 4-8 mg daily and terazosin 2-4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1-blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1-blocker with a diuretic.
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Hipertensión , Antagonistas Adrenérgicos alfa/uso terapéutico , Anciano , Aldosterona , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Diuréticos/uso terapéutico , Doxazosina/uso terapéutico , Humanos , Hipertensión/tratamiento farmacológico , ReninaRESUMEN
BACKGROUND: Adrenergic alpha-1 receptor antagonists (alpha-1 antagonists) are frequently used medications in the management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and in the management of therapy-resistant arterial hypertension, two conditions frequently found in older adults. This systematic review aims at presenting a complete overview of evidence over the benefits and risks of alpha-1 antagonist treatment in people ≥ 65 years, and at deriving recommendations for a safe application of alpha-1 antagonists in older adults from the evidence found. METHODS: A comprehensive literature search was performed (last update March 25th 2022) including multiple databases (Medline/Pubmed, Embase, the Cochrane Library) and using the PICOS framework to define search terms. The selection of the studies was done by two independent reviewers in a two-step approach, followed by a systematic data extraction. Quality appraisal was performed for each study included using standardised appraisal tools. The studies retrieved and additional literature were used for the development of recommendations, which were rated for strength and quality according to the GRADE methodology. RESULTS: Eighteen studies were included: 3 meta-analyses, 6 randomised controlled trials and 9 observational trials. Doxazosin in the management of arterial hypertension was associated with a higher risk of cardiovascular disease, particularly heart failure, than chlorthalidone. Regarding treatment of LUTS suggestive of BPH, alpha-1 antagonists appeared to be effective in the relief of urinary symptoms and improvement of quality of life. They seemed to be less effective in preventing disease progression. Analyses of the risk profile indicated an increase in vasodilation related adverse events and sexual adverse events for some agents. The risk of falls and fractures as well as the effects of long-term treatment remained unclear. All meta-analyses and 5 out of 6 interventional studies were downgraded in the quality appraisal. 7 out of 9 observational studies were of good quality. CONCLUSIONS: It cannot be recommended to use doxazosin as first-line antihypertensive agent neither in older adults nor in younger patients. In the management of BPH alpha-1 antagonists promise to effectively relieve urinary symptoms with uncertainty regarding their efficacy in preventing long-term progression events.
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Hipertensión , Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Antagonistas de Receptores Adrenérgicos alfa 1/efectos adversos , Antagonistas Adrenérgicos alfa/efectos adversos , Anciano , Antihipertensivos/uso terapéutico , Clortalidona/uso terapéutico , Doxazosina/uso terapéutico , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Prescripción Inadecuada , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Masculino , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/tratamiento farmacológico , Calidad de VidaRESUMEN
OBJECTIVE: Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine. METHODS: We conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs. RESULTS: Twenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin. CONCLUSION: Phenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.
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Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/cirugía , Antagonistas Adrenérgicos alfa/uso terapéutico , Estudios de Casos y Controles , Doxazosina/farmacología , Doxazosina/uso terapéutico , Humanos , Fenoxibenzamina/farmacología , Fenoxibenzamina/uso terapéutico , Fenilefrina/uso terapéutico , Feocromocitoma/tratamiento farmacológico , Feocromocitoma/cirugía , Estudios ProspectivosRESUMEN
OBJECTIVE: To assess the efficacy of mirabegron in the treatment of erectile dysfunction concomitant with lower urinary tract symptoms in benign prostatic obstruction patients. METHODS: In this randomized controlled trial, 55 sexually active lower urinary tract symptoms/benign prostatic obstruction patients with concomitant erectile dysfunction were randomly allocated in two groups: the first received mirabegron 50 mg plus doxazosin 2 mg once daily (mirabegron group) and the second received tolterodine 4 mg plus doxazosin 2 mg (tolterodine group) for 12 weeks. The evaluation was based on the International Index of Erectile Function questionnaire, Erection Hardness Score questionnaire, International Prostate Symptom Score, quality of life, uroflowmetry and post-voiding residual. The therapeutic outcomes were assessed at 4 and 12 weeks compared with the baseline. RESULTS: Only the mirabegron group achieved significant improvement in sexual functions after 4 and 12 weeks. By using ≥5 points difference from the baseline as a cut-off point of change, there was a significant difference in change of direction of the International Index of Erectile Function-15 total score in favor of the mirabegron group; after 12 weeks, the International Index of Erectile Function-15 total score decreased in 0%, was unchanged in 8.3% and improved in 91.7% in the mirabegron group compared with 8.7%, 65.2% and 26.1%, respectively, in the tolterodine group (P < 0.001). Regarding the urinary characteristics, both groups showed significant improvement in the International Prostate Symptom Score, quality of life, and post-voiding residual after 4 and 12 weeks, with no significant difference among them. CONCLUSION: Mirabegron improves urinary characteristics and the associated sexual dysfunction in patients with lower urinary tract symptoms/benign prostatic obstruction.
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Disfunción Eréctil , Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Acetanilidas , Doxazosina/uso terapéutico , Disfunción Eréctil/complicaciones , Disfunción Eréctil/tratamiento farmacológico , Humanos , Síntomas del Sistema Urinario Inferior/complicaciones , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Masculino , Hiperplasia Prostática/tratamiento farmacológico , Calidad de Vida , Tiazoles , Tartrato de Tolterodina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Sexual dysfunction is a common side effect of medical therapy for benign prostatic hyperplasia (BPH), whereas prostatic urethral lift (PUL) offers safe and effective relief of lower urinary tract symptoms while preserving sexual function. OBJECTIVE: To compare the long-term impact on sexual health of PUL or daily medical therapy of doxazosin or finasteride alone or in combination in BPH patients. DESIGN, SETTING, AND PARTICIPANTS: This was a comparative analysis of sexual function outcomes from PUL studies (L.I.F.T. [n=107], Crossover [n=42], and MedLift [n=39]) and the Medical Therapy of Prostatic Symptoms (MTOPS) trial. The men included were sexually active with International Prostate Symptom Score ≥13, Qmax ≤12ml/s, and prostate volume 30-80 cm3. MTOPS subjects completed the Brief Male Sexual Function Inventory, while PUL subjects completed the International Index of Erectile Function and the Male Sexual Health Questionnaire for Ejaculatory Function. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mean percentage changes from baseline in erectile, ejaculatory, and sexual satisfaction domains were compared at 12, 24, 36, and 48 mo. RESULTS AND LIMITATIONS: PUL significantly improved erectile function through 24 mo, and ejaculatory function and sexual satisfaction across all time points. Medical therapy did not improve sexual function at any time point. Finasteride significantly decreased erectile function at 48 mo, and combined therapy significantly reduced ejaculatory function at 12 and 24 mo. Comparatively, PUL was superior to finasteride in preserving erectile function at 24 and 48 mo, and superior to doxazosin and combined therapy at 12 mo. PUL outperformed all three medical therapies at all time points in improving ejaculatory function and sexual satisfaction. Limitations include the use of distinct patient-reported questionnaires and narrowed data on comorbidities that influence male sexual function. CONCLUSIONS: Indirect comparison reveals that PUL is superior to BPH medical therapy in preserving erectile and ejaculatory function and sexual satisfaction. PATIENT SUMMARY: In our non-head-to-head study, only patients undergoing PUL for an enlarged prostate experienced improvements in sexual health. Conversely, patients on medical therapy experienced worsening of erectile and ejaculatory function.
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Disfunción Eréctil , Hiperplasia Prostática , Doxazosina/uso terapéutico , Finasterida/uso terapéutico , Humanos , Masculino , Próstata , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/tratamiento farmacológicoRESUMEN
INTRODUCTION: The aim of this study was to investigate the association of transrectal ultrasound (TRUS)-guided prostate biopsy with voiding impairment and the efficacy of doxazosin treatment. METHODS: A prospective observational study including 200 male patients undergoing TRUS-guided prostate biopsy was performed between May 2020 and December 2020. One hundred patients underwent biopsy with doxazosin (doxazosin group). The remaining 100 patients underwent biopsy without doxazosin (control group). All patients were questioned regarding post-biopsy voiding difficulty and acute urinary retention. The International Prostate Symptom Score (IPSS), maximal urinary flow rate (Qmax), and residual urine volume were recorded before biopsy and at 7 and 30 days after biopsy. RESULTS: There were no significant differences in baseline parameters between the two groups. The rate of post-biopsy voiding difficulty in the doxazosin group was significantly lower than that in the control group. Compared with baseline values, doxazosin treatment significantly improved IPSS, quality of life scores, and Qmax after biopsy (p < 0.05). The baseline values of IPSS and prostate size may be risk factors for post-biopsy voiding difficulty. CONCLUSION: TRUS-guided prostate biopsy causes transient voiding impairments, which may be improved by doxazosin treatment.
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Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Doxazosina/uso terapéutico , Biopsia Guiada por Imagen/efectos adversos , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/etiología , Próstata/patología , Ultrasonografía Intervencional , Retención Urinaria/tratamiento farmacológico , Retención Urinaria/etiología , Anciano , Humanos , Masculino , Estudios Prospectivos , Recto , Ultrasonografía Intervencional/métodosRESUMEN
INTRODUCTION: It was aimed to show the relationship between benign prostatic hyperplasia and inflammation by measuring urinary C-reactive protein values before and after alpha-blocker treatment. METHODS: A total of 71 patients with a total prostate-specific antigen <3.5 ng/mL, International Prostate Symptom Score >7, and maximum urinary flow rate <15 mL/s were included in the study. Doxazosin 4 mg p.o. once daily was started orally as an alpha-blocker treatment. Serum and urine C-reactive protein values, International Prostate Symptom Score, maximum urinary flow rate, and the post-void residual volume of patients were recorded at the first admission and in the first month of alpha-blocker treatment. RESULTS: The mean age of the patients was 59.2 ± 7.5 years. The mean serum C-reactive protein values of the patients at the first admission and follow-up were 2.62 ± 1.8 (range, 0-5) mg/L and 2.83 ± 1.6 (0-6) mg/L, respectively. The mean urine C-reactive protein values of the patients at the first admission and follow-up were 0.45 ± 0.11 (range, 0.28-0.99) mg/L and 0.14 ± 0.04 (range, 0.79-0.328) mg/L, respectively, which was statistically significantly different. In the subgroup analysis, the urine C-reactive protein level change was more prominent in severely symptomatic patients than in moderately symptomatic patients. CONCLUSION: Our results showed that C-reactive protein was detectable in urine, alpha-blocker treatment significantly reduced urine C-reactive protein levels, and the decrease was more prominent in severely symptomatic patients.
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Hiperplasia Prostática , Prostatitis , Antagonistas Adrenérgicos alfa , Anciano , Proteína C-Reactiva , Doxazosina/uso terapéutico , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Proyectos Piloto , Antígeno Prostático Específico , Hiperplasia Prostática/tratamiento farmacológicoRESUMEN
ERα and Wnt/ß-catenin pathways are critical for the progression of most endometrial cancers. We aimed to investigate the cytotoxic and apoptotic effects of tamoxifen and quinazoline derivative drugs of doxazosin and erlotinib, and their roles in ERα and Wnt/ß-catenin signaling pathways in human endometrial cancer RL 95-2 cell. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay and xCELLigence systems were performed to evaluate cytotoxicity. Furthermore, apoptotic induction was tested by Annexin V analysis. Caspase-3 and -9 activity and changes in the mitochondrial membrane potential were evaluated. The level of reactive oxygen species was measured by incubating with dichlorofluorescein diacetate. Protein ratios of p-ERα/ERα, GSK3ß/p-GSK3ß, and p-ß-catenin/ß-catenin and expression levels of ESR1, EGFR, c-Myc genes were evaluated to elucidate mechanisms in signaling pathways. We found that the tested drugs showed cytotoxic and apoptotic effects in the cells. Doxazosin significantly reduced ESR1 expression, slightly reduced the p-ß-catenin/ß-catenin ratio and c-Myc expression. Erlotinib significantly increased c-Myc expression while significantly decreasing the p-ß-catenin/ß-catenin and p-ERα/ERα ratio, and ESR1 expression. However, we observed that the cells develop resistance to erlotinib over a certain concentration, suggesting that ERα, ESR1, EGFR, and c-Myc may be a new target for overcoming drug resistance in the treatment of endometrial cancer. We also observed that erlotinib and doxazosin play an important role in the ERα signaling pathway and can act as potent inhibitors of PKA and/or tyrosine kinase in the Wnt/ß-catenin signaling pathway in RL 95-2 cell. In conclusion, doxazosin and erlotinib may have a possible therapeutic potential in human endometrial cancer.
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Antineoplásicos/uso terapéutico , Doxazosina/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Clorhidrato de Erlotinib/uso terapéutico , Receptor alfa de Estrógeno/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/efectos de los fármacos , Antineoplásicos/administración & dosificación , Doxazosina/administración & dosificación , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Clorhidrato de Erlotinib/administración & dosificación , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , beta Catenina/metabolismoRESUMEN
We aimed to identify presurgical and surgical risk factors for intraoperative complications in patients with pheochromocytomas. A retrospective study of patients with pheochromocytomas who underwent surgery in ten Spanish hospitals between 2011 and 2021 was performed. One hundred and sixty-two surgeries performed in 159 patients were included. The mean age was 51.6 ± 16.4 years old and 52.8% were women. Median tumour size was 40 mm (range 10-110). Laparoscopic adrenalectomy was performed in 148 patients and open adrenalectomy in 14 patients. Presurgical alpha- and beta-blockade was performed in 95.1% and 51.9% of the surgeries, respectively. 33.3% of the patients (n = 54) had one or more intraoperative complications. The most common complication was the hypertensive crisis in 21.0%, followed by prolonged hypotension in 20.0%, and hemodynamic instability in 10.5%. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more commonly than patients pre-treated with other antihypertensive drugs (51.1% vs 26.5%, P = 0.002). Intraoperative complications were more common in patients with higher levels of urine metanephrine (OR = 1.01 for each 100 µg/24 h, P = 0.026) and normetanephrine (OR = 1.00 for each 100 µg/24 h, P = 0.025), larger tumours (OR = 1.4 for each 10 mm, P < 0.001), presurgical blood pressure > 130/80 mmHg (OR = 2.25, P = 0.027), pre-treated with doxazosin (OR = 2.20, P = 0.023) and who had not received perioperative hydrocortisone (OR = 3.95, P = 0.008). In conclusion, intraoperative complications in pheochromocytoma surgery are common and can be potentially life-threatening. Higher metanephrine and normetanephrine levels, larger tumour size, insufficient blood pressure control before surgery, pre-treatment with doxazosin, and the lack of treatment with perioperative hydrocortisone are associated with higher risk of intraoperative complications.
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Neoplasias de las Glándulas Suprarrenales , Hipotensión , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/patología , Adrenalectomía/efectos adversos , Adulto , Anciano , Doxazosina/uso terapéutico , Femenino , Humanos , Hidrocortisona , Complicaciones Intraoperatorias/tratamiento farmacológico , Complicaciones Intraoperatorias/etiología , Complicaciones Intraoperatorias/cirugía , Metanefrina/orina , Persona de Mediana Edad , Normetanefrina , Feocromocitoma/patología , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Alpha1-adrenoceptor antagonists (α1-blockers) are first-line drugs for the treatment of lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). Doxazosin gastrointestinal therapeutic system (GITS) and tamsulosin belong to the 2 most frequently prescribed α1-blockers. This systematic review and meta-analysis was performed to compare the efficacy and tolerability of these 2 α1-blockers. METHODS: A systematic review of published randomized controlled trials in English or Chinese language was performed using the PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, and Vip databases. After data extraction and quality assessment, the meta-analysis was performed to compare clinical parameters (International Prostate Symptom Score [IPSS] total [IPSS-T], storage [IPSS-S], voiding [IPSS-V], maximum urine flow [Qmax], and postvoid residual) and adverse events (AEs) that changed after first drug intake. RESULTS: After the screening, 8 eligible randomized controlled trials with 1316 patients were identified. Doxazosin-GITS showed a significantly higher efficacy compared with tamsulosin (IPSS-T Pâ<â.001, IPSS-S Pâ<â.001, and IPSS-V Pâ<â.001). There were no significant differences between the 2 drugs for changes in Qmax (Pâ=â.477) or postvoid residual (Pâ=â.739). The overall AEs were significantly lower in the doxazosin-GITS group (risk ratio: 0.77; 95% CI: 0.54-1.08; Pâ=â.036). However, dizziness (Pâ=â.387), headache (Pâ=â.745), asthenia (Pâ=â.693), postural hypotension (Pâ=â.114), and retrograde ejaculation (Pâ=â.187) were similar between the 2 groups. CONCLUSIONS: This meta-analysis indicates that doxazosin-GITS has significantly higher efficacy and lower AEs than tamsulosin in patients with lower urinary tract symptoms/benign prostate hyperplasia.