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1.
Int J Nanomedicine ; 15: 10099-10112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363369

RESUMO

Background: Gastric ulcer is a prevalent disease with various etiologies, including non-steroidal anti-inflammatory drugs and alcohol consumption. This study aimed to explore the dual gastric protection effect of tadalafil and limonene as a self-nanoemulsifying system (SNES)-based orodispersible tablets. Methods: Tadalafil-loaded limonene-based SNES was prepared, and the optimum formula was characterized in terms of particle size (PS), polydispersity index (PDI), and zeta potential (ZP) then loaded on various porous carriers to formulate lyophilized orodispersible tablets (ODTs). The ODTs were evaluated via determining hardness, friability, content uniformity, wetting, and disintegration time. The selected ODT was examined for its gastric ulcer protective effect against alcohol-induced ulcers in rat model. Ulcer score and ulcer index were computed for rats stomachs that were inspected macroscopically and histopathologically. Results: The prepared SNES had droplet size of 104 nm, polydispersity index of 0.2, and zeta potential of -15.4 mV. From the different ODTs formulated, the formula with superior wetting time: 23.67 s, outstanding disintegration time: 28 s, accepted hardness value: 3.11 kg/cm2 and friability: 0.6% was designated. A significant gastroprotective effect of the unloaded and tadalafil-loaded ODTs was recognized compared to the omeprazole pre-treated group. Moreover, the histopathological analysis displayed very mild inflammation in the limonene-based ODTs group and intact structure in the tadalafil-loaded pre-treated animals. Conclusion: Limonene gastroprotective effect functioned along with tadalafil in the form of SNES-incorporated ODTs could serve as a promising revenue for better efficacy in gastric ulcer prevention.


Assuntos
Composição de Medicamentos , Limoneno/química , Substâncias Protetoras/farmacologia , Estômago/efeitos dos fármacos , Tadalafila/administração & dosagem , Tadalafila/farmacologia , Administração Oral , Animais , Sistemas de Liberação de Medicamentos , Emulsões/química , Liofilização , Dureza , Masculino , Porosidade , Ratos Wistar , Solubilidade , Estômago/patologia , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Comprimidos , Tadalafila/uso terapêutico , Termodinâmica , Água/química
2.
PLoS One ; 15(11): e0241509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33166302

RESUMO

OBJECTIVES: Infertility is a global health problem with about 15 percent of couples involved. About half of the cases of infertility are related to male-related factors. A major cause of infertility in men is oxidative stress, which refers to an imbalance between levels of reactive oxygen species (ROS) and antioxidants. Erectile dysfunction drugs (EDD), known as phosphodiesterase inhibitors (PDEIs), have been used for the treatment of ED. It has been shown that oxidative stress plays an important role in the progression of erectile dysfunction. Oxidative stress can be alleviated or decreased by non-antioxidants and antioxidant enzymes. The present study was undertaken to determine if these compounds could have a role in the incidence of infertility, especially after long-term use. Therefore, the present study aims to investigate the effect of EDD on the activities of antioxidant enzymes, free radical levels as well as the protein expression of different cytochrome P450 isozymes involved in the steroidogenesis of different hormones. In addition, the activity of both 17ß-hydroxysteroid dehydrogenase and 17-ketosteroid reductase were assayed. The architectures of both livers and testes cells were investigated under the influence of EDD. METHODS: A daily dose of Sildenafil (1.48 mg/kg), Tadalafil (0.285 mg/kg) and Vardenafil (0.285 mg/kg) were administered orally to male rabbits for 12 week. Western immunoblotting, ELISA, spectrophotometric and histopathological techniques were used in this study. RESULTS: The present study showed that Sildenafil, Vardenafil, and Tadalafil treatments significantly decreased the levels of glutathione and free radicals in both livers and testes of rabbits. Also, Vardenafil and Sildenafil induced the activity of superoxide dismutase and catalase whereas, glutathione S-transferase, glutathione reductase, and glutathione peroxidase activities inhibited in livers of rabbits. The protein expression of cytochrome P450 isozymes (CYP 11A1, 21A2, and 19C) which are involved in the steroidogenesis was markedly changed in both livers and testes of rabbits after their treatments for 12 weeks. After the treatment of rabbits with these medication, the protein expression of CYP11A1 was slightly down-regulated in both livers and testes except Sildenafil up-regulated such protein expression. In addition, the protein expressions of CYP11A1 and CYP 19C in both livers and testes were down-regulated after treatment of rabbits with Sildenafil, Vardenafil, and Tadalafil for 12 weeks. Also, these drugs inhibited the activity of both 17ß-hydroxysteroid dehydrogenase and 17-ketosteroid reductase in testes of rabbits. Moreover, Sildenafil, Vardenafil, and Tadalafil-treated rabbits showed a decrease in spermatocytes and the number of sperms in the testes. CONCLUSIONS: It is concluded that ED drugs induced the activities of both SOD and catalase which consequently decreased MDA level. Decrement in MDA levels and oxidative stress could therefore sustain the erection for a long period of time. On the other hand, it is not advised to use these drugs for a long-term since the protein expressions of CYP isozymes involved in steroidogenesis as well as the numbers of spermatocytes in testes were decreased.


Assuntos
Antioxidantes/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Disfunção Erétil/tratamento farmacológico , Estresse Oxidativo , Esteroides/biossíntese , Animais , Glutationa/metabolismo , Isoenzimas/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Coelhos , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Testículo/efeitos dos fármacos , Testículo/patologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Dicloridrato de Vardenafila/farmacologia , Dicloridrato de Vardenafila/uso terapêutico
3.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 234-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093789

RESUMO

Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Piridazinas/uso terapêutico , Sarcoidose Pulmonar/complicações , Tadalafila/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Resultado do Tratamento
4.
Medicine (Baltimore) ; 99(34): e21849, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846835

RESUMO

INTRODUCTION: Patent ductus venosus (PDV) is a rare and critical disease, and the majority of patients present with pulmonary arterial hypertension (PAH) or hepatopulmonary syndrome due to congenital portosystemic shunt. We reported that both PAH and hypersplenism were major complications of PDV in this case. This case report can assist the treatment and recovery of the patients with similar symptoms. PATIENT CONCERNS: A 4-year-old male patient presented to our institution with a history of recurrent respiratory infections accompanied by leukocytopenia, thrombocytopenia and presented with tachypnoea. upon mild exertion. DIAGNOSIS: A wide communication, 10 mm in diameter, between the portal vein and inferior vena cava was identified in the subcostal echocardiogram and computed tomography images. Echocardiography showed an estimated systolic pulmonary artery pressure of 106 mm Hg. Right-sided cardiac catheterization indicated a mean pulmonary arterial pressure of 30 mm Hg and a pulmonary vascular resistance of 3 Wood units. Chest X-ray revealed cardiomegaly with a prominent pulmonary segment. INTERVENTIONS: The patient was treated with combination pharmacotherapy of bosentan and tadalafil and PDV ligation. OUTCOMES: A year later, the boy showed normal exercise tolerance and weight gain. Liver and spleen parameters, liver function, blood cells and the general condition of the boy improved. CONCLUSION: Initial combination therapy of bosentan and tadalafil is safe and effective in children with PAH associated with PDV. When PDV banding test shows normal portal pressure, PDV ligation is considered acceptable in children with PAH and hypersplenism associated with PDV.


Assuntos
Hiperesplenismo/etiologia , Ligadura/métodos , Veia Porta/anormalidades , Hipertensão Arterial Pulmonar/etiologia , Malformações Vasculares/cirurgia , Assistência ao Convalescente , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Bosentana/administração & dosagem , Bosentana/uso terapêutico , Cardiomegalia/diagnóstico por imagem , Pré-Escolar , Terapia Combinada/métodos , Ecocardiografia/métodos , Humanos , Masculino , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Hipertensão Arterial Pulmonar/fisiopatologia , Radiografia Torácica/métodos , Tadalafila/administração & dosagem , Tadalafila/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Malformações Vasculares/complicações , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/tratamento farmacológico , Resistência Vascular/fisiologia , Vasodilatadores/administração & dosagem , Vasodilatadores/uso terapêutico
6.
Neurourol Urodyn ; 39(7): 1994-2002, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32648985

RESUMO

AIMS: To compare the efficacy of cernitin pollen extract (cernitin) or tadalafil for treating persistent chronic pelvic pain despite α1-blocker monotherapy in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and lower urinary tract symptoms (LUTS). METHODS: A total of 100 patients with refractory CP/CPPS despite ongoing α1-blocker monotherapy were randomized to receive add-on therapy with either cernitin (4 capsules/day) or tadalafil (5 mg/d) for 12 weeks. At week 12, changes from baseline in the patients' CP/CPPS, LUTS, and voiding function, as assessed using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the International Prostate Symptom Score (IPSS), and uroflowmetry, respectively, were compared between the groups. RESULTS: The final analysis included 42 and 45 patients in the cernitin and tadalafil groups, respectively. Although the NIH-CPSI total, NIH-CPSI pain sub-score, and NIH-CPSI quality of life sub-score significantly improved in both groups, the cernitin (vs tadalafil) group showed significantly greater improvements in the NIH-CPSI total score (-6.8 vs -4.6; P = .02) and NIH-CPSI pain sub-score (-4.1 vs -1.5; P < .001). Half (50%) of the patients in the cernitin group showed a reduction greater than 50% in their NIH-CPSI pain sub-score; in the tadalafil group, only four patients (8.9%) showed ≥50% improvement (P < .001). In contrast, the improvement in LUTS was significantly superior in the tadalafil group. CONCLUSION: Both cernitin and tadalafil significantly ameliorated chronic pelvic pain in patients with refractory CP/CPPS. The add-on of cernitin was more effective than tadalafil for pelvic pain and discomfort.


Assuntos
Dor Pélvica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pólen/química , Prostatite/tratamento farmacológico , Tadalafila/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Idoso , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Urodinâmica
7.
Med Hypotheses ; 143: 110129, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721814

RESUMO

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Estrogênios/fisiologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Inflamação , Interleucinas/fisiologia , Modelos Animais , Modelos Biológicos , Óxido Nítrico/uso terapêutico , Obesidade/complicações , Obesidade/fisiopatologia , Uso Off-Label , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/fisiologia , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Pneumonia Viral/complicações , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico
8.
PLoS One ; 15(6): e0232870, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555695

RESUMO

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.


Assuntos
Teste de Esforço , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Adolescente , Criança , Simulação por Computador , Progressão da Doença , Teste de Esforço/métodos , Seguimentos , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Fármacos Neuromusculares/uso terapêutico , Prognóstico , Tamanho da Amostra , Tadalafila/uso terapêutico , Caminhada
9.
Life Sci ; 256: 117960, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534033

RESUMO

BACKGROUND: Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS: 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS: Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION: Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.


Assuntos
Constipação Intestinal/complicações , Constipação Intestinal/fisiopatologia , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/fisiopatologia , Peptídeos/uso terapêutico , Tadalafila/uso terapêutico , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Colo/fisiopatologia , Constipação Intestinal/tratamento farmacológico , GMP Cíclico/metabolismo , Fezes/química , Trânsito Gastrointestinal/efeitos dos fármacos , Hipocampo/metabolismo , Intestino Grosso/metabolismo , Masculino , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Reflexo/efeitos dos fármacos , Natação , Tadalafila/farmacologia , Água
10.
Proc Natl Acad Sci U S A ; 117(25): 14386-14394, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513693

RESUMO

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine ß-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.


Assuntos
Disfunção Erétil/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Envelhecimento/fisiologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Reposicionamento de Medicamentos , Disfunção Erétil/complicações , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Modelos Moleculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteoporose/complicações , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/uso terapêutico , Cultura Primária de Células , Tadalafila/química , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Dicloridrato de Vardenafila/química , Dicloridrato de Vardenafila/farmacologia , Dicloridrato de Vardenafila/uso terapêutico
11.
Neurourol Urodyn ; 39(5): 1378-1386, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32383533

RESUMO

AIMS: To characterize the epidemiology and treatment patterns of adult men (≥40 years) diagnosed with, or treated for, overactive bladder (OAB) and/or benign prostatic hyperplasia (BPH). METHODS: This retrospective observational study used data extracted from the IBM MarketScan Commercial Claims and Encounters database and the Medicare Supplemental Coordination of Benefits database. Men with BPH and/or OAB were identified and observed to assess treatment and diagnostic patterns. RESULTS: Within the entire study sample (N = 462 400), BPH diagnosis (61.5%) and BPH treatment (73.7%) were more common than the corresponding values for OAB (25.8% and 7.0%, respectively). Notably, among diagnosed individuals, the dispensation of a corresponding treatment was more likely in individuals diagnosed with BPH (183 672 out of 284 416 = 64.6%) compared with OAB (16 468 out of 119 236 = 13.8%). Among newly diagnosed and/or treated patients (n = 196 576), only 60.3% received treatment. Among treated patients, most experienced only a single type of treatment (93.4%), 6.6% went on to receive a secondary treatment and 3.5% a tertiary. The most common primary treatment was alpha-blocker monotherapy (76.9%) followed by tadalafil monotherapy (16.4%). Among those untreated at first diagnosis, the median time between diagnosis and treatment initiation was 128 days. CONCLUSIONS: Diagnosis and management of OAB among males are challenging given the inherent overlap in symptoms observed with BPH. Unsurprisingly, we found that BPH is diagnosed and treated more frequently than OAB; but the differences between diagnosis and treatment patterns for the two conditions highlight the potential undertreatment of OAB and misdirection of therapy for men with a combination of voiding and storage symptoms.


Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Hiperplasia Prostática/complicações , Tadalafila/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Humanos , Masculino , Medicare , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Bexiga Urinária Hiperativa/etiologia , Micção
12.
Int Heart J ; 61(2): 413-418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32224603

RESUMO

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.


Assuntos
Anticorpos Antinucleares/imunologia , Centríolos/imunologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Vasodilatadores/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Bosentana/uso terapêutico , Cateterismo Cardíaco , Quimioterapia Combinada , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Feminino , Volume Expiratório Forçado , Humanos , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Capacidade de Difusão Pulmonar , Pirimidinas/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Sulfonamidas/uso terapêutico , Tadalafila/uso terapêutico , Tomografia Computadorizada por Raios X
13.
Biomed Res Int ; 2020: 1419520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309423

RESUMO

Purpose: The purpose of this study was to compare the relative safety and efficacy of different types of phosphodiesterase type 5 inhibitors (PDE5-Is) with tamsulosin for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostate hyperplasia (BPH) (BPH-LUTS) with or without erectile dysfunction (ED). Methods: We use the Stata version 13.0 to conduct the network meta-analysis (NMA) with a random effects model of the Bayesian framework. The International Prostate Symptom Score (IPSS), Maximum Urinary Flow Fate (Q max), International Index of Erectile Function (IIEF), and their credible intervals (CI) were used to compare the efficacy and safety of every medical intervention, including sildenafil plus tamsulosin, tadalafil plus tamsulosin, and vardenafil plus tamsulosin. Results: Seven RCTs including 531 participants with seven interventions were analyzed. The results of NMA SUCRA showed that compared with different doses or types of PDE5-Is combined with tamsulosin (0.4 mg qd), the sildenafil (25 mg qd) combined with tamsulosin (0.4 mg qd) group had the greatest probabilities of being the best in the achievement of improving IIEF. The sildenafil (25 mg 4 days per week) combined with tamsulosin (0.4 mg qd) group had the greatest probabilities of being the best in the achievement of improving Q max, whereas sildenafil (25 mg qd) combined with tamsulosin (0.4 mg qd) ranked the best for the safety outcomes. Conclusions: This meta-analysis indicates that sildenafil combined with tamsulosin is the best effective and tolerated treatment option for BPH-LUTS with or without ED. Further RCTs are strongly required to provide more direct evidence.


Assuntos
Disfunção Erétil/complicações , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Hiperplasia Prostática/complicações , Segurança , Tansulosina/uso terapêutico , Teorema de Bayes , Bases de Dados Factuais , Quimioterapia Combinada , Humanos , Sintomas do Trato Urinário Inferior/complicações , Masculino , Metanálise em Rede , Citrato de Sildenafila/uso terapêutico , Tadalafila/uso terapêutico , Resultado do Tratamento
14.
Neurourol Urodyn ; 39(4): 1087-1097, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32150290

RESUMO

AIMS: To evaluate the impacts of hydrogen sulfide (H2 S) donor, sodium hydrogen sulfide (NaHS), and phosphodiesterase type-5 inhibitor (PDE5i), tadalafil per se and their combination treatment on partial bladder outlet obstruction (PBOO)-induced erectile dysfunction (ED). METHODS: Sprague-Dawley rats were equally divided into five groups: (a) sham-operated control; (b) PBOO; (c) PBOO-treated with NaHS (5.6 mg/kg/day, ip); (d) PBOO-treated with tadalafil (2 mg/kg/day, oral); and (e) PBOO-treated with combination of NaHS and tadalafil. The obstruction was created by urethral ligation for 6 weeks. In vivo erectile responses, in vitro relaxant and contractile responses in penile tissue as well as protein expression of nitric oxide synthases (NOS), H2 S synthesis enzymes, oxidative stress, hypoxia, fibrosis markers, and the smooth muscle/collagen ratio and apoptosis were analyzed. RESULTS: Combined treatment entirely returned increased bladder mass, reduced erectile responses, relaxation responses to acetylcholine, and electrical field stimulation in obstructed rats, while partial amelioration was observed after mono-treatment. Decreased neuronal NOS and 3-mercaptopiruvate transferase enzyme expressions in penile tissue from obstructed rats were also entirely restored by the combined treatment. Mono-treatment partially improved increased hypoxia, oxidative stress, fibrosis markers, decreased smooth muscle mass, and H2 S levels, while combined therapy completely recovered. CONCLUSIONS: The combination therapy with H2 S donor and PDE5i had positive effects on erectile responses through the improvement of ischemia-induced morphological and functional penile alterations in obstruction. H2 S and NO may likely play a synergistic role in the regulation of erectile function and have constructive effects on clinical outcomes in male patients with ED and benign prostatic hyperplasia/lower urinary tract symptoms.


Assuntos
Disfunção Erétil/tratamento farmacológico , Sulfeto de Hidrogênio/uso terapêutico , Ereção Peniana/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/uso terapêutico , Tadalafila/uso terapêutico , Obstrução do Colo da Bexiga Urinária/complicações , Animais , Modelos Animais de Doenças , Disfunção Erétil/etiologia , Hidrogênio/metabolismo , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Sulfeto de Hidrogênio/farmacologia , Masculino , Músculo Liso/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Ratos Sprague-Dawley , Tadalafila/farmacologia , Resultado do Tratamento
15.
Sci Rep ; 10(1): 4182, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144403

RESUMO

We evaluated pathophysiological characteristics of the lower urinary tract dysfunction in a streptozotocin (STZ)-induced diabetic rat model. STZ (60 mg/kg) was injected intraperitoneally into male Wistar rats. In vitro bladder muscle strip experiments, in vivo cystometry, and simultaneous recordings of bladder pressure + urethral perfusion pressure (BP + UPP) with or without intravenous administration of L-arginine (300 mg/kg) or tadalafil (0.03 mg/kg) were performed at several time points. In vitro muscle strip experiments demonstrated that diabetic rats had significantly higher contractile responses to carbachol at 4-16 weeks, and a tendency for higher contractile responses to electrical field stimulation at 4-12 weeks, but this was reversed at 16 weeks. Diabetic rats had significant increases in voided volume, residual volume, bladder capacity, maximal voiding pressure, and amplitude and frequency of non-voiding contractions at 16 weeks. Tadalafil decreased the residual volume in diabetic rats. Diabetic rats had significantly higher UPP nadir and mean UPP during high-frequency oscillation at 16 weeks, which were reversed by tadalafil or L-arginine administration. The present results suggest that urethral relaxation failure, probably related to impairment of the NO/cGMP signalling pathway, rather than bladder contractile dysfunction may be a prominent cause for voiding dysfunction in STZ-induced chronic diabetic rats.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Estreptozocina/toxicidade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Animais , Arginina/uso terapêutico , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Ratos , Ratos Wistar , Volume Residual/efeitos dos fármacos , Tadalafila/uso terapêutico
17.
J Sex Med ; 17(5): 941-948, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32144034

RESUMO

BACKGROUND: While phosphodiesterase type-5 inhibitors (PDE5Is) are highly effective for the treatment of erectile dysfunction (ED) and well tolerated, updated data on prescription patterns have been limited in real-world settings. AIM: To describe men in the United States who are prescribed PDE5Is for ED treatment and to evaluate patterns of initiation, switching, and treatment overlap. METHODS: This retrospective claims study used MarketScan Commercial and Medicare Supplement Databases from January 1, 2010, to December 31, 2015, to identify initial PDE5I claims (index date) for sildenafil, tadalafil, and/or vardenafil. Adults aged ≥18 years with ED were identified between July 1, 2010, and December 31, 2014, allowing for a 6-month preindex and 12-month follow-up period from the index date. OUTCOMES: Outcomes included patient demographics and treatment-related patterns after treatment initiation. RESULTS: A total of 106,206 identified patients met all inclusion criteria. Of these, 51,694, 40,193, and 14,319 had initial claims for sildenafil, tadalafil, and vardenafil, respectively. Mean age was 50.35 years, and comorbidities included dyslipidemia (44.17%), hypertension (43.09%), diabetes (15.32%), and depression (10.61%). More patients (48.67%) initiated on sildenafil than tadalafil (37.85%) or vardenafil (13.48%). Rate of switching was lower in the 60 days after the end of day supply of the initial prescription in the sildenafil cohort (2.71%) compared with the tadalafil (2.81%) and vardenafil (3.88%) cohorts (P < .001 for sildenafil vs tadalafil or vardenafil). Treatment overlap was lower in the sildenafil cohort (0.35%) than in the tadalafil (0.75%) and vardenafil (0.62%) groups (P < .001 for sildenafil vs tadalafil or vardenafil). CLINICAL IMPLICATIONS: These findings provide insight into updated patterns of PDE5I prescriptions in the United States and may aid in clinical decision-making. STRENGTHS & LIMITATIONS: Strengths include the large sample size, long data coverage period, and the real-world nature of the study. Limitations include the retrospective study design, use of data collected with a primary focus of claims, and lack of further details regarding reasons that drive switching. Actual rates of ED and impact on prescription patterns may be underestimated because the claims database only captured patients electing to visit a health-care provider. CONCLUSION: Among men with ED in the United States, rates of switching and treatment overlap were low for all PDE5Is but were found to be the lowest for sildenafil compared with tadalafil and vardenafil. Mulhall JP, Chopra I, Patel D, et al. Phosphodiesterase Type-5 Inhibitor Prescription Patterns in the United States Among Men With Erectile Dysfunction: An Update. J Sex Med 2020;17:941-948.


Assuntos
Disfunção Erétil , Inibidores da Fosfodiesterase 5 , Adulto , Idoso , Carbolinas , Disfunção Erétil/tratamento farmacológico , Humanos , Imidazóis , Masculino , Medicare , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/uso terapêutico , Diester Fosfórico Hidrolases , Piperazinas , Prescrições , Purinas , Estudos Retrospectivos , Citrato de Sildenafila/uso terapêutico , Sulfonas , Tadalafila/uso terapêutico , Triazinas/uso terapêutico , Estados Unidos , Dicloridrato de Vardenafila/uso terapêutico
18.
Medicine (Baltimore) ; 99(3): e18712, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011446

RESUMO

BACKGROUND: Drug therapy for lower urinary tract symptoms (LUTS) secondary to benign prostate hyperplasia (BPH) is a major and popular method. However, the therapeutic strategy is still not clear enough up to now. The purpose of this study was to compare the relative safety and efficacy of different types of phosphodiesterase type 5 inhibitors (PDE5-Is) with tamsulosin for the treatment of LUTS secondary to BPH. METHODS: Databases including PubMed, OpenGrey, Embase, Cochrane Library, and Web of Science will be searched to identify qualified studies. We will use the Stata version 13.0 to conduct the network meta-analysis (NMA) with a random or fixed effects model of Bayesian framework. International prostate symptom score (IPSS), maximum urinary flow fate (Qmax) and their credible intervals (CI) will be used to compare every medical intervention with the efficacy and safety, including sildenafil plus tamsulosin, tadalafil plus tamsulosin, vardenafil plus tamsulosin. And the ranking of probability of different interventions will be estimated by comparing the surface under the cumulative ranking curve (SUCRA). RESULTS: A high quality-synthesis of the current evidence for comparing with different doses or types of PDE5-Is combined with tamsulosin to the treatment of LUTS secondary to BPH will be provided. CONCLUSIONS: This NMA and systematic review will generate evidence to help choose the best combination for treatment of LUTS secondary to BPH.PROSPERO registration number: PROSPERO CRD 42019139062.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Tansulosina/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Teorema de Bayes , Quimioterapia Combinada , Humanos , Masculino , Metanálise em Rede , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Citrato de Sildenafila/uso terapêutico , Tadalafila/uso terapêutico , Tansulosina/administração & dosagem , Tansulosina/efeitos adversos , Dicloridrato de Vardenafila/uso terapêutico
19.
BJU Int ; 125(5): 718-724, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32012409

RESUMO

OBJECTIVE: To compare the efficacy and safety of tamsulosin vs the combination of tamsulosin and tadalafil in male lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: This was a double-blinded, parallel-arm randomised controlled trial. Men aged >45 years with moderate LUTS and a maximum urinary flow rate (Qmax ) of 5-15 mL/s were included. One arm received 0.4 mg tamsulosin only (Group-A), while the second received 5 mg tadalafil with tamsulosin (Group-B). The primary outcome was the International Prostate Symptom Score (IPSS). Secondary outcomes were IPSS quality of life (QoL) score, five-item version of the International Index of Erectile Function (IIEF-5) score, Qmax , and post-void residual urine (PVR). Block randomisation was used. Placebo was used for blinding and allocation concealment. Intention-to-treat analysis was used for outcome measures. RESULTS: Of the 183 men screened, 140 were randomised (71 in Group-A, 69 in Group-B); 116 (82.85%) (61 in Group-A, 55 in Group-B) completed the study. Baseline characteristics were comparable. The improvements in the IPSS, IPSS QoL score, IIEF score and Qmax were -1.69 (95% confidence interval [CI] -1.4 to -2.0), -0.70 (95% CI -0.60 to -0.80), 3.8 (95% CI 3.4-4.2) and 1.8 mL/s (95% CI 1.1-2.4) respectively, in favour of the combination group. The difference in PVR was not significant. There were no serious adverse events (AEs). The dropout rate due to AEs was 2.85%. Myalgia (five patients) was the commonest AE in the combination group. CONCLUSION: The combination of tamsulosin and tadalafil produced significantly better improvements in LUTS, QoL, erectile function and Qmax compared to monotherapy with tamsulosin, without an increase in AEs.


Assuntos
Sintomas do Trato Urinário Inferior/tratamento farmacológico , Qualidade de Vida , Tadalafila/uso terapêutico , Tansulosina/uso terapêutico , Micção/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Seguimentos , Humanos , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
20.
J Sex Med ; 17(4): 688-694, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32007430

RESUMO

BACKGROUND: Erectile dysfunction (ED) after radical prostatectomy (RP) still represents a major issue. Considering the benefits recently described regarding the application of low-intensity extracorporeal shockwave therapy (LiESWT) in vasculogenic ED, questions arise about its role in the scenario of penile rehabilitation. AIM: To compare the early introduction of phosphodiesterase-5 inhibitor (PDE5i) with a combination therapy enrolling both early PDE5i use and LiESWT in patients submitted to RP. METHODS: This study is a randomized clinical trial, open-label, with 2 parallel arms and an allocation ratio of 1:1. The study was registered in ReBEC (ensaiosclinicos.gov.br) Trial: RBR-85HGCG. Both arms started tadalafil at a dose of 5 mg/day right after the removal of the transurethral catheter, and the experimental group received 2,400 shocks/session-week distributed on 4 different penile regions. The full treatment consisted of 19,200 impulses across 8 weeks. OUTCOMES: The primary clincal end point was ≥4-point difference favoring the experimental group considering the mean International Index of Erectile Function short form (IIEF-5) at last follow-up. Any statistical difference in the IIEF-5 score between the arms was stated as the primary statistical end point. RESULTS: Between September 25, 2017, and December 3, 2018, 92 men were enrolled in the study. At last follow-up, we assessed 77 patients, 41 in the control group and 36 in the intervention group. A difference between groups was detected when accessing the final median IIEF-5 score (12.0 vs 10.0; P = .006). However, the primary clinical endpoint considering a difference ≥4-point between the arms has not been reached. When performing an exploratory analysis comparing the proportion of those individuals with an IIEF-5 score ≥17, no difference between groups was noted (17.1% vs 22.2%; P = .57). CLINICAL IMPLICATIONS: So far, the benefits arising from LiESWT for penile rehabilitation after RP have been uncertain. STRENGTHS & LIMITATIONS: This is the first trial assessing the role of LiESWT on erectile function after RP. Our study protocol included only one session per week for the experimental group, raising a query if a more intensive application could achieve better results once a statistically significant difference was found between groups. We discontinue the PDE5i use at the last session, which may have interfered in the penile vascular rehabilitation, maybe compromising the results too. CONCLUSION: After therapy with 19,200 impulses therapy across 8 weeks, we found an improvement of the IIEF-5 score, but it was not enough to be considered clinically significant. More studies are warranted before any recommendation on this topic. Baccaglini W, Pazeto CL, Corrêa Barros EA, et al. The Role of the Low-Intensity Extracorporeal Shockwave Therapy on Penile Rehabilitation After Radical Prostatectomy: A Randomized Clinical Trial. J Sex Med 2020;17:688-694.


Assuntos
Disfunção Erétil/terapia , Tratamento por Ondas de Choque Extracorpóreas , Prostatectomia/efeitos adversos , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Ereção Peniana , Pênis/fisiopatologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Tadalafila/uso terapêutico , Resultado do Tratamento
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