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1.
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
2.
Medicine (Baltimore) ; 99(23): e20546, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502017

RESUMO

Erectile dysfunction (ED) and depression are closely related. We sought to determine ED and depression were improved by tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, at 5 mg daily, in this case-control study.Participants were men aged 20 to 65 years with ED for >3 months, International Index of Erectile Function-5 (IIEF) score <21 points, and Zung Self-Rating Depression Scale (SDS) survey result >50 points who were willing to participate.On first visit (V1) and after 1 (V2) and 2 months (V3), clinical features were examined using IIEF-5 for diagnosing and evaluating ED, SDS for evaluating depression, and International Prostate Symptom Score and Quality of Life (IPSS/QoL) survey for examining lower urinary tract symptoms (LUTS). Tadalafil 5 mg was administered daily for 2 months.A total of 60 participants were an average age of 58.68 ± 6.71 years. Patient overall average IIEF was 8.76 ±â€Š5.98, showing mild ED symptoms, and total average IPSS 13.74 ±â€Š7.55 showed moderate LUTS. Average overall SDS index was 58.93 ±â€Š9.21, indicating moderate-to-severe findings. Average change in IIEF among all patients revealed significant improvement from V1 to V2 (-2.69 ±â€Š1.22, P = .03) and V1 to V3 (-4.38 ±â€Š1.20, P < 0.01). IPSS also significantly improved from V1 to V3 (3.48 ±â€Š1.37, P = .01), as did SDS index (V1, V2: 4.69 ±â€Š1.89, P = 0.02), (V1, V3: 5.43 ±â€Š1.89, P < .01). Patients with severe IIEF scores (group 1, n = 27) experienced significantly greater improvement in IIEF from V1 to V2 and V1 and V3, compared to those with mild-to-moderate IIEF scores. Both groups improved in SDS index from V1 to V2 and V1 to V3, with the greatest improvement between V1 and V3 for group 1 and V1 and V2 for group 2.Daily tadalafil 5 mg could be helpful for ED patients with depressive symptoms and improved LUTS and quality of life.


Assuntos
Depressão/terapia , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Tadalafila/administração & dosagem , Adulto , Idoso , Estudos de Casos e Controles , Depressão/complicações , Disfunção Erétil/complicações , Humanos , Sintomas do Trato Urinário Inferior , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
3.
Ann Rheum Dis ; 79(5): 626-634, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32161055

RESUMO

OBJECTIVES: To evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) subpopulation. METHODS: This post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling. RESULTS: The analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548). CONCLUSIONS: The benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up. TRIAL REGISTRATION NUMBER: NCT01178073.


Assuntos
Fenilpropionatos/administração & dosagem , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/epidemiologia , Piridazinas/administração & dosagem , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/epidemiologia , Tadalafila/administração & dosagem , Adulto , Comorbidade , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/tratamento farmacológico , Doenças do Tecido Conjuntivo/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Hipertensão Arterial Pulmonar/diagnóstico , Medição de Risco , Escleroderma Sistêmico/diagnóstico , Resultado do Tratamento , Vasodilatadores/administração & dosagem
4.
J Matern Fetal Neonatal Med ; 33(1): 167-170, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29886797

RESUMO

Purpose: The aim of this study is to evaluate the safety of clinical usage of tadalafil in women with preeclampsia.Materials and methods: Maternal, fetal, and neonatal adverse events were closely examined in eight preeclampsia patients receiving tadalafil treatment.Results: There were no maternal adverse events associated with 10 mg/day of tadalafil. Even at 20 mg/day, only grade 1 headaches in two cases and grade 1 palpitation in one case were observed, which resolved spontaneously within 3 days. At a dose of 40 mg/day, there was only one case of grade 1 headache. All these adverse events were grade 1 and spontaneously resolved within 3 days. There were no fetal adverse events. All observed neonatal adverse events were thought to be caused by prematurity and not related to tadalafil.Conclusion: This study shows that tadalafil treatment for preeclampsia is deemed sufficiently tolerable. Although there was a dose-dependent increase in maternal adverse events, all the adverse events were mild and deemed to be safe for the mother and fetus at all dosages.


Assuntos
Pré-Eclâmpsia/tratamento farmacológico , Tadalafila/administração & dosagem , Tadalafila/efeitos adversos , Adulto , Arritmias Cardíacas/induzido quimicamente , Peso ao Nascer/efeitos dos fármacos , Cesárea/estatística & dados numéricos , Relação Dose-Resposta a Droga , Feminino , Cefaleia/induzido quimicamente , Humanos , Gravidez , Resultado da Gravidez , Resultado do Tratamento
5.
Medicine (Baltimore) ; 98(46): e17925, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725644

RESUMO

BACKGROUND: Erectile dysfunction (ED) affects many adult men worldwide. Many studies on the brain of psychogenic ED have shown significant cerebral functional changes and reduced volume of gray matter and white matter microstructural alterations in widespread brain regions. Chaihu-Shugan-San (CHSGS) capsule has been used to treat ED from the 20th century in China. However, clinical research of CHSGS capsule in the treatment of ED was lack. We design this study to evaluate the efficacy and safety of CHSGS capsule in the treatment of patients suffering from psychogenic ED. Furthermore, we also aim to provide a new evidence as well as an innovation of the clinical treatment in psychogenic ED. METHODS: This study is designed as a multi-center, 3-arms, randomized trial. From the perspective of psychogenic ED, we will divide patients into 3 groups, which are placebo group, tadalafil group and CHSGS group. One hundred thirty-five patients will be randomly allocated to receive placebo, CHSGS capsule or tadalafil oral pharmacotherapy. After the period of 4-week treatment, the outcome of primary assessment changes in the brain MRI, IIEF-5, EHS, and QEQ total scores from baseline. Secondary assessments include the SEAR, HAMA-14, HAMD-17 scores, response rate of the patients and their partners. DISCUSSION: We designed this study based on previous research about psychogenic erectile dysfunction (ED). This study will provide objective evidences to evaluate the effects of CHSGS capsule as an adjuvant treatment for psychogenic ED. TRIAL REGISTRATION NUMBER: chictr.org.cn, ChiCTR-IOR-1800018301.


Assuntos
Disfunção Erétil/terapia , Extratos Vegetais/uso terapêutico , Tadalafila/uso terapêutico , Vasodilatadores/uso terapêutico , Adulto , Método Duplo-Cego , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Tadalafila/administração & dosagem , Tadalafila/efeitos adversos , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos , Adulto Jovem
6.
Medicina (Kaunas) ; 55(10)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640235

RESUMO

: Background and Objectives: Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine the ideal dosage to promote uterine blood flow. Materials and Methods: We recruited five pregnant women with FGR or preeclampsia before administration of tadalafil, all of which were administered tadalafil (20 mg/day, once-daily dosing). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration, and uterine blood flow was measured before tadalafil administration and 2-4 and 20-24 h after. We then analyzed the correlation between tadalafil blood concentration and uterine artery blood flow. Results: The blood concentration of tadalafil correlated with uterine artery blood flow in pregnant women. The blood concentration of tadalafil and uterine artery blood flow decreased 5 h after administration of tadalafil. Conclusions: The blood concentration of tadalafil and uterine artery blood flow fluctuate in parallel, the latter was decreased by reduced blood concentration. Thus, a study of tadalafil administered twice a day in pregnant women will be needed to stabilize uterine artery blood flow.


Assuntos
Retardo do Crescimento Fetal/tratamento farmacológico , Pré-Eclâmpsia/tratamento farmacológico , Tadalafila/administração & dosagem , Útero/irrigação sanguínea , Vasodilatadores/administração & dosagem , Adulto , Circulação Sanguínea , Esquema de Medicação , Feminino , Humanos , Gravidez/fisiologia , Tadalafila/sangue , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Artéria Uterina/efeitos dos fármacos , Útero/diagnóstico por imagem , Vasodilatadores/sangue , Adulto Jovem
7.
Mo Med ; 116(5): 400-403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31645793

RESUMO

Intracerebral hemorrhage occurs when a diseased blood vessel within the brain bursts. We present a case of 69-year-old patient with two sequential episodes of lobar intracerebral hemorrhage occurring during sexual intercourse. Both episodes were associated with the use of phosphodiesterase-5 inhibitors. This is the first case reported which is temporally associated with isolated bilateral lobar bleeds with appropriate use of phosphodiesterase-5 inhibitor on two different occasions associated with sexual intercourse.


Assuntos
Hemorragia Cerebral/etiologia , Inibidores da Fosfodiesterase 5/efeitos adversos , Citrato de Sildenafila/efeitos adversos , Tadalafila/efeitos adversos , Idoso , Hemorragia Cerebral/diagnóstico por imagem , Coito , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Inibidores da Fosfodiesterase 5/administração & dosagem , Citrato de Sildenafila/administração & dosagem , Tadalafila/administração & dosagem , Tomografia Computadorizada por Raios X
8.
Respir Res ; 20(1): 208, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31511080

RESUMO

BACKGROUND: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. METHODS: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. RESULTS: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. CONCLUSIONS: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe. Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.


Assuntos
Anti-Hipertensivos/administração & dosagem , Fenilpropionatos/administração & dosagem , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/administração & dosagem , Tadalafila/administração & dosagem , Vasodilatadores/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Eur. j. anat ; 23(5): 325-332, sept. 2019. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-183862

RESUMO

Liver ischemia reperfusion is induced during surgical procedures like liver transplantation and resection. Multiple mechanisms have been postulated to liver damage following liver ischemia reperfusion injury, such as oxidative stress and inflammatory reactions. The present study declares the possible mechanism of tadalafil, toward modulating the inflammatory response. Forty-eight rats were divided into 4 groups as follows; Sham group subjected to midline laparotomy only. Tadalafil group administered Tadalafil 10 mg/kg intraperitoneal 45 min before sham operation. I/R (Ischemiareperfusion) group, rats undergo 60 min of hepatic ischemia followed by 60 min of reperfusion. Tadalafil + I/R group rats undergo a similar pattern of I/ R after the treatment with Tadalafil 10 mg/kg, 45 min before ischemia. At the end of the reperfusion, the blood samples were collected for estimation of biochemical markers including liver enzymes using colorimetric assay method and serum: TNF-α (tumor necrosis factor-α), IL-6 (interleukin 6) levels, ICAM- 1 (Intercellular Adhesion Molecule-1) were measured. Tissues were evaluated by semiquantitative and morphometrical approaches. Tadalafil succeeded in restoring normal levels of liver enzymes and ameliorating the oxidative stress as evidenced by decreasing MDA and restoring reduced glutathione levels in liver tissue homogenate. Also, Tadalafil exhibits anti-inflammatory effects, as it significantly decreased the levels of TNF-α, IL6 and ICAM-1. The findings are supported by BCL-2, TNF-α immunomarkers. It is concluded that modulation of the inflammatory response might be one of the mechanisms of Tadalafil-mediated hepatoprotection, so it is recommended as an adjuvant therapy in liver surgery


No disponible


Assuntos
Animais , Ratos , Traumatismo por Reperfusão/veterinária , Estresse Oxidativo , Transplante de Fígado/veterinária , Apoptose/efeitos dos fármacos , Fator de Necrose Tumoral alfa , Tadalafila/administração & dosagem , Fígado/anatomia & histologia , Fígado/enzimologia , Injeções Intraperitoneais/veterinária , Imuno-Histoquímica
10.
J Vet Cardiol ; 24: 7-19, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31405557

RESUMO

INTRODUCTION: Canine pulmonary hypertension (PH) is associated with high morbidity and mortality. Tadalafil, a phosphodiesterase-5 inhibitor used commonly in humans with PH, has not been evaluated in a clinical trial in dogs with naturally occurring PH. Our objectives were to compare the efficacy of tadalafil and sildenafil on PH assessed by peak tricuspid regurgitant flow velocity, estimated systolic pulmonary arterial pressure gradient, voluntary activity, quality of life, and safety profiles in dogs with moderate to severe PH. ANIMALS: Twenty-three dogs with echocardiographic evidence of moderate to severe PH were enrolled. METHODS: A prospective short-term, randomized, double-blinded pilot study was carried out. Dogs with PH were randomly allocated to receive sildenafil or tadalafil for 2 weeks and assessed via echocardiography, activity monitors, and owner-reported outcomes. RESULTS: Collectively, phosphodiesterase-5 inhibition significantly decreased (improved) quality of life scores (p = 0.003) and visual analog score (p = 0.024) without significant between-treatment difference of these variables. Phosphodiesterase-5 inhibition did not significantly affect peak tricuspid regurgitant flow velocity (p = 0.056) or voluntary activity (p = 0.27). A total of 33% (7/21) of dogs experienced at least one adverse event during the study (tadalafil, n = 5; sildenafil, n = 2) with no significant difference between treatment type and incidence of adverse events (p = 0.36). DISCUSSION: In this pilot study, phosphodiesterase-5 inhibition led to apparent improvement in quality of life scores without documenting superiority of tadalafil over sildenafil. CONCLUSION: Tadalafil at a dose of 2 mg/kg once daily appears to be a viable alternative to sildenafil in dogs with moderate to severe PH.


Assuntos
Doenças do Cão/tratamento farmacológico , Hipertensão Pulmonar/veterinária , Inibidores da Fosfodiesterase 5/uso terapêutico , Animais , Doenças do Cão/fisiopatologia , Cães , Método Duplo-Cego , Eletrocardiografia/veterinária , Feminino , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Inibidores da Fosfodiesterase 5/administração & dosagem , Projetos Piloto , Estudos Prospectivos , Distribuição Aleatória , Índice de Gravidade de Doença , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/uso terapêutico , Inquéritos e Questionários , Tadalafila/administração & dosagem , Tadalafila/uso terapêutico , Resultado do Tratamento
11.
Andrologia ; 51(9): e13347, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231838

RESUMO

To examine the relation between NLR (neutrophil-lymphocyte ratio) and PLR (platelet-lymphocyte ratio) rates and the severity of ED (erectile dysfunction) and the effect of tadalafil 5 mg/day on these, a total of 143 patients were retrospectively evaluated. Sixty-three patients with ED who came for follow-up examinations in the 1st month of the treatment were included as the study group, and 80 men who were not diagnosed with ED were as the control group. The age and Charlson Comorbidity Indexes (CCI) of the study and control groups were compared with the IIEF 5, NLR and PLR values before and after the treatment. The mean age and median CCI were higher in the severe ED group (p < 0.05). The mean NLR and PLR values were lower in the control group (p < 0.001). In the study group, the NLR and PLR values decreased with the increase in the IIEF 5 scores (p < 0.001). The ROC curve was significant for the NLR and PLR scores (AUC = 0.779, [95% CI: 0.698-0.860]; AUC = 0.754, [95% CI: 0.670-0.838] p < 0.001). Although more prospective and randomized studies are needed, the systemic inflammation decreases and the clinical symptoms improve in patients who use tadalafil 5 mg/day.


Assuntos
Plaquetas , Disfunção Erétil/tratamento farmacológico , Linfócitos , Neutrófilos , Tadalafila/administração & dosagem , Adulto , Contagem de Células Sanguíneas , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Disfunção Erétil/sangue , Disfunção Erétil/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Ereção Peniana/efeitos dos fármacos , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Int Urol Nephrol ; 51(9): 1491-1499, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31230261

RESUMO

PURPOSE: We aimed to investigate the efficacy and safety of tadalafil, aspirin, and tadalafil + aspirin combination therapy in vascular erectile dysfunction (VED). METHODS: A total of 336 patients were randomly divided into four groups (group 1, aspirin 100 mg/day, 126 patients; group 2, tadalafil 5 mg/day, 72 patients; group 3, tadalafil 5 mg + aspirin 100 mg, 72 patients; group 4, placebo, 66 patients). In all groups, the changes from baseline to end point in erectile function scores on the International Index of Erectile Function (IIEF-EF) and the number of patients who answered "yes" to questions 2 and 3 of the sexual encounter profile(SEP) were compared statistically. RESULTS: The changes in IIEF-EF scores after treatment were 7.2 ± 4.4, 7.3 ± 4.3, 7.5 ± 4.4, and 2.0 ± 4.6 for group 1 (p < 0.0001), group 2 (p < 0.0001), group 3 (p < 0.0001), and group 4 (p = 0.0204), respectively. The change in SEP-2 ratios after treatment were 36.6%, 36.9%, 41.7%, and 9.4% for group 1 (p < 0.0001), group 2 (p < 0.0001), group 3 (p < 0.0001), and group 4 (p = 0.2925), respectively. The change in SEP-3 ratios after treatment was 46.6%, 49.2%, 53.7%, and 12.5% for group 1 (p < 0.0001), group 2 (p < 0.0001), group 3 (p < 0.0001), and group 4 (p = 0.1456), respectively. In group 2, both the number of patients who reported side effects (p < 0.0001) and stopped using the drug due to side effects (p < 0.05) were significantly higher than the control and others groups. CONCLUSIONS: Successful results were obtained by tadalafil and aspirin monotherapy and tadalafil + aspirin combination therapy in patients with VED. However, the least side effect was observed in the tadalafil + aspirin group. Aspirin can be used alone in the treatment of patients with VED, or combined with tadalafil to reduce side effects and increase success.


Assuntos
Aspirina/administração & dosagem , Impotência Vasculogênica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Tadalafila/administração & dosagem , Adulto , Combinação de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
13.
Pharm Dev Technol ; 24(9): 1083-1094, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31215307

RESUMO

This study aims at improving the bioavailability of a poorly soluble phosphodiesterase-5 inhibitor; tadalafil (TD) via developing intranasal (IN) nanoemulsions (NEs). Optimum NE ingredients were selected based on solubility studies, emulsification tests, and phase diagram construction. Both o/w and w/o NEs were selected based on their drug loading capacity. Optimum formulations were subjected to physicochemical characterization and were assessed for nasal toxicity through biochemical analysis of tumor necrosis factor-α (TNF-α) and caspase-3 in rat nasal tissues. Pharmacodynamic study was performed via biochemical analysis of cyclic guanosine monophosphate (cGMP) in rat penis 2-h post-treatment and compared with oral suspension of Cialis® tablets. Optimum o/w and w/o NEs were successfully prepared using different ratios of Capmul-MCM-EP, Labrasol:Transcutol-HP (1:1) and water. Optimized formulations exhibited more than 4000-fold increase in TD solubility compared with its aqueous solubility. Both formulations were optically isotropic with the majority of globules in the nanometric-size range. Nasal toxicity study revealed no significant difference in values of TNF-α and caspase-3 between the NE-treated groups and the control group. Both TD-NEs succeeded to achieve a significant enhancement in cGMP levels. Our findings suggested that IN administration of the developed TD-NEs could provide a safe and effective alternative to TD oral delivery.


Assuntos
Inibidores da Fosfodiesterase 5/administração & dosagem , Tadalafila/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Intranasal , Animais , GMP Cíclico/metabolismo , Emulsões/química , Masculino , Transição de Fase , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Tadalafila/química , Tadalafila/farmacocinética , Tadalafila/farmacologia , Vasodilatadores/química , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologia
14.
Chest ; 155(6): e163-e166, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174660

RESUMO

CASE PRESENTATION: A 34-year-old woman presented for evaluation of several months of a hoarse voice and dyspnea on exertion that progressed over the last 3 years. She had a clinical diagnosis of asthma that had been treated with bronchodilators and inhaled corticosteroids for a few years. She continued to use her inhalers but with minimal symptomatic improvement. The patient was a lifelong nonsmoker with no history of drug abuse. She worked as a college professor and denied any significant environmental exposures or recent travel.


Assuntos
Dispneia , Rouquidão , Laringoscopia/métodos , Pulmão/diagnóstico por imagem , Hipertensão Arterial Pulmonar , Tadalafila/administração & dosagem , Adulto , Dispneia/diagnóstico , Dispneia/etiologia , Ecocardiografia/métodos , Feminino , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Rouquidão/diagnóstico , Rouquidão/etiologia , Humanos , Administração dos Cuidados ao Paciente/métodos , Hipertensão Arterial Pulmonar/complicações , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/terapia , Artéria Pulmonar/diagnóstico por imagem , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Paralisia das Pregas Vocais/diagnóstico por imagem
15.
Clin Ther ; 41(6): 1110-1127, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060740

RESUMO

PURPOSE: Pulmonary arterial hypertension (PAH) is a life-threatening disease that typically causes shortness of breath and exercise intolerance. Combination therapy with ambrisentan and tadalafil has proven to be more effective at preventing clinical failure events in patients with PAH than either drug alone. The aim of this study was to evaluate the bioequivalence of an ambrisentan/tadalafil fixed-dose combination (FDC) compared with co-administration of the 2 monotherapies. METHODS: This 3-part, randomized, single-dose, open-label crossover study was conducted in healthy volunteers. The first part of the study consisted of a 5-way crossover that compared the relative bioavailability of 4 FDC formulations (10-mg ambrisentan + 40-mg tadalafil) with co-administered reference monotherapies. One formulation was selected and its relative bioavailability was assessed when produced in 3 different granulation sizes during the second part of the study. In the third part of the study, the bioequivalence of the candidate FDC with the reference monotherapies was evaluated for the 10-mg/40-mg dose strength, in addition to 2 other dose strengths (5 mg/20 mg and 5 mg/40 mg). For all parts of the study, blood samples were taken at regular intervals after each dose, ambrisentan and tadalafil concentrations determined, and pharmacokinetic (PK) parameters (Cmax, AUC0-∞, and AUC0-t) obtained. Test/reference ratios of the geometric means of PK parameters were used to evaluate bioequivalence. Safety and tolerability were assessed by recording adverse events and monitoring vital signs, ECGs, and clinical laboratory data. FINDINGS: Of the 174 subjects screened for eligibility, 112 were allocated to a randomized treatment sequence across all study parts, and 100 completed their full assigned treatments. All 4 FDC formulations tested during part 1 of the study yielded PK parameters similar those of the reference treatments. In part 2, granulation size was found to not affect the relative bioavailability of the selected formulation. In part 3, the selected FDC was found to be bioequivalent to co-administration of the monotherapies in both the fasted and fed states. The FDC was also found to be bioequivalent to the reference treatments at the 2 additional dose strengths. All but one of the adverse events was mild to moderate in intensity, and no serious adverse events were reported. IMPLICATIONS: An ambrisentan/tadalafil FDC was bioequivalent to concurrently administered monotherapies and therefore represents a viable alternative treatment to co-administration. Use of an FDC is likely to be associated with reduced costs and improved patient compliance. ClinicalTrials.gov identifier: NCT02688387.


Assuntos
Fenilpropionatos/farmacocinética , Piridazinas/farmacocinética , Tadalafila/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Voluntários Saudáveis , Humanos , Fenilpropionatos/administração & dosagem , Fenilpropionatos/efeitos adversos , Fenilpropionatos/sangue , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Piridazinas/sangue , Tadalafila/administração & dosagem , Tadalafila/efeitos adversos , Tadalafila/sangue , Equivalência Terapêutica
16.
Eur J Pharm Sci ; 133: 275-286, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30953751

RESUMO

Tadalafil (a phosphodiesterase-5 inhibitor) is a choice for treatment of pulmonary arterial hypertension (PAH) that is known as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest and ≥30 mmHg during exercise with reduced cardiac output. The aim of this study was to prepare inhalable tadalafil nanocomposites as a dry powder formulation by spray drying technique for increasing bioavailability and treatment efficacy, as well as decreasing systemic side effects. The D-optimal design was used for optimization of formulation parameters. Microparticle size, morphology, crystallinity, density, solubility, redispersion (%), and in-vitro inhalation performance of tadalafil nanocomposites were investigated as physicochemical characteristics. Pharmacokinetic parameters were also evaluated in plasma and lung tissue of Wistar rats after intratracheal insufflation and compared with a control group receiving an oral tadalafil marketed product (dose = 10 mg/kg). The suggested optimum formulation contained stable amorphous particles with almost rounded shape and corrugated surface that were completely redispersed in the lung simulated medium with the mass median geometric diameter of 3.2 µm, density of 1.4 g/cm3, fine particle fraction based on emitted dose (%) of 57.2 ±â€¯6.5%, and 13.7-fold enhancement in dissolution rate. In-vivo studies showed that the ratio of AUC0-24h lung/AUC0-24h plasma, achieved in the treated group after intratracheal insufflation, was significantly higher than the control group that means high local drug concentration and more efficacy. Besides, plasma data analysis indicated high value of MRT (2.3-fold) and tmax (3.7-fold) after intratracheal insufflation of tadalafil nanocomposites in comparison with the conventional oral route, indicating longer retention of tadalafil molecules in the lungs and their slower entry to the systemic blood circulation. In conclusion, it seems that inhalable tadalafil nanocomposites can be introduced as an alternative to oral tadalafil in the treatment of PAH.


Assuntos
Anti-Hipertensivos/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Nanocompostos/administração & dosagem , Inibidores da Fosfodiesterase 5/administração & dosagem , Tadalafila/administração & dosagem , Administração por Inalação , Animais , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Inaladores de Pó Seco , Pulmão/metabolismo , Masculino , Inibidores da Fosfodiesterase 5/farmacocinética , Pós , Ratos Wistar , Tadalafila/farmacocinética
17.
Acta Cir Bras ; 34(2): e201900205, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30843938

RESUMO

PURPOSE: To evaluate the impact of the combination of BRL 37344 and tadalafil (TDF) on the reduction of overactive bladder (OB) symptoms. METHODS: Thirty mice were randomized into 5 groups (G) of 6 animals each. L-NAME was used to induce DO. G1: Control; G2: L-NAME; G3: L-NAME + TDF; G4: L-NAME + BRL 37344; G5: L-NAME + TDF + BRL 37344. After 30 days of treatment, the animals were submitted to cystometry to evaluate non-voiding contractions (NVC), threshold pressure (TP), baseline pressure (BP), frequency of micturition (FM) and threshold volume (TV). Differences between the groups were analyzed with ANOVA followed by the Tukey test. RESULTS: NVC increased in G2 (4.33±2.58) in relation to G1 (1.50±0.55). NVC decreased in G3 (2.00±1.10), G4 (1.50±1.52) and G5 (2.00±1.26) compared to G2 (p<0.05). FM decreased in G3 (0.97±0.71), G4 (0.92±0.38) and G5 (1.05±0.44) compared to G2 (p<0.05). However, the combination of TDF and BRL37344 was not more effective at increasing NVC and improving FM than either drug alone. The five groups did not differ significantly with regard to TV. CONCLUSION: The combination of BRL 37344 and TDF produced no measurable additive effect on reduction of OB symptoms.


Assuntos
Etanolaminas/administração & dosagem , Tadalafila/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/administração & dosagem , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Distribuição Aleatória , Micção/efeitos dos fármacos
18.
Sex Med Rev ; 7(3): 430-441, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30711478

RESUMO

INTRODUCTION: On-demand phosphodiesterase type 5 inhibitor (PDE5i) monotherapy is a first-line treatment for erectile dysfunction (ED), but 30%-40% of patients exhibit little or no response. The success rate of alprostadil therapy is high in these patients, but this treatment requires painful intracavernosal injection. AIM: To systematically review the efficacy and safety of second-line oral pharmacologic combination therapies of ED when PDE5i monotherapy fails. METHODS: PubMed and Embase were searched to identify reports providing quantitative data on the treatment of ED in patients failing PDE5i monotherapy. MAIN OUTCOME MEASURES: The measures of erectile function were the International Index of Erectile Function (IIEF) and the Erectile Function Domain (EFD). RESULTS: Chronic treatment with the PDE5i tadalafil alone or in combination with sildenafil on demand showed similar IIEF-5 score improvements. None of the 3 randomized controlled trials (RCTs) in patients who had failed PDE5i monotherapy found a superior effect on IIEF scores from the combination of androgen plus PDE5i compared with PDE5i monotherapy. Combination therapy with androgen supplementation and PDE5i appears safe. In 1 RCT, combination therapy with PDE5i and an α1-adrenoceptor antagonist was not superior to PDE5i monotherapy. Six other studies, each with a different combination of PDE5i and another drug (eg, metformin, folic acid, 5-alpha-reductase inhibitors), were identified, but further research is required to investigate their efficacy in treating ED. CONCLUSION: For ED, chronic treatment with low-dose PDE5i can be attempted when standard on-demand regimens fail. Combination therapy with androgen supplementation and a PDE5i appears to be safe. The combination of an α1-adrenoceptor antagonist and PDE5i shows no advantageous effect on ED compared with PDE5i monotherapy. The efficacy of combining PDE5i with metformin, folic acid, or 5-alpha-reductase inhibitors is uncertain and requires further research. There is an unmet need for oral treatment of ED in nonresponders to PDE5i treatment. Munk NE, Knudsen JS, Comerma-Steffensen S, et al. Systematic Review of Oral Combination Therapy for Erectile Dysfunction When Phosphodiesterase Type 5 Inhibitor Monotherapy Fails. Sex Med Rev 2019;7:430-441.


Assuntos
Alprostadil/administração & dosagem , Disfunção Erétil/tratamento farmacológico , Ereção Peniana/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/efeitos adversos , Citrato de Sildenafila/administração & dosagem , Tadalafila/administração & dosagem , Administração Oral , Quimioterapia Combinada , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Falha de Tratamento , Resultado do Tratamento , Vasodilatadores/administração & dosagem
19.
Sci Rep ; 9(1): 234, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659198

RESUMO

We have demonstrated that tadalafil facilitates fetal growth in mice with L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia (PE) with fetal growth restriction (FGR). Tadalafil is a selective phosphodiesterase 5 inhibitor that dilates the maternal blood sinuses in the placenta, thereby facilitating the growth of the fetus. The purpose of this study was to investigate the effects of tadalafil treatment for PE and FGR on the developing brain in FGR offspring using an L-NAME-induced mouse model of PE with FGR. A control group of dams received carboxymethylcellulose (CMC). L-NAME-treated groups received L-NAME dissolved in CMC from 11 days post coitum (d.p.c.). The L-NAME-treated dams were divided into two subgroups 14 d.p.c. One subgroup continued to receive L-NAME. The other subgroup received L-NAME with tadalafil suspended in CMC. Tadalafil treatment for PE with FGR reduced the expression of hypoxia-inducible factor-2α in the placenta and in the brain of the FGR fetus. Moreover, tadalafil treatment in utero shows improved synaptogenesis and myelination in FGR offspring on postnatal day 15 (P15) and P30. These results suggest that tadalafil treatment for PE with FGR not only facilitates fetal growth, but also has neuroprotective effects on the developing brain of FGR offspring through modulating prenatal hypoxic conditions.


Assuntos
Retardo do Crescimento Fetal/prevenção & controle , Hipóxia/prevenção & controle , Pré-Eclâmpsia/tratamento farmacológico , Tadalafila/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Placenta/patologia , Gravidez , Resultado do Tratamento
20.
Neurobiol Dis ; 121: 65-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30213732

RESUMO

The nitric oxide - guanylyl cyclase-1 - cyclic guanylate monophosphate (NO-GC-1-cGMP) pathway has emerged as a potential pathogenic mechanism for glaucoma, a common intraocular pressure (IOP)-related optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. NO activates GC-1 to increase cGMP levels, which are lowered by cGMP-specific phosphodiesterase (PDE) activity. This pathway appears to play a role in both the regulation of IOP, where reduced cGMP levels in mice leads to elevated IOP and subsequent RGC degeneration. Here, we investigated whether potentiation of cGMP signaling could protect RGCs from glaucomatous degeneration. We administered the PDE5 inhibitor tadalafil orally (10 mg/kg/day) in murine models of two forms of glaucoma - primary open angle glaucoma (POAG; GC-1-/- mice) and primary angle-closure glaucoma (PACG; Microbead Occlusion Model) - and measured RGC viability at both the soma and axon level. To determine the direct effect of increased cGMP on RGCs in vitro, we treated axotomized whole retina and primary RGC cultures with the cGMP analogue 8-Br-cGMP. Tadalafil treatment increased plasma cGMP levels in both models, but did not alter IOP or mean arterial pressure. Nonetheless, tadalafil treatment prevented degeneration of RGC soma and axons in both disease models. Treatment of whole, axotomized retina and primary RGC cultures with 8-Br-cGMP markedly attenuated both necrotic and apoptotic cell death pathways in RGCs. Our findings suggest that enhancement of the NO-GC-1-cGMP pathway protects the RGC body and axon in murine models of POAG and PACG, and that enhanced signaling through this pathway may serve as a novel glaucoma treatment, acting independently of IOP.


Assuntos
GMP Cíclico/metabolismo , Glaucoma/metabolismo , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glaucoma/prevenção & controle , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Camundongos Knockout , Inibidores da Fosfodiesterase 5/administração & dosagem , Ratos Sprague-Dawley , Degeneração Retiniana/prevenção & controle , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais , Tadalafila/administração & dosagem
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