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1.
Health Qual Life Outcomes ; 18(1): 278, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795300

RESUMO

BACKGROUND: Assessment of health-related quality of life (HRQoL) are often measured as an important patient-reported outcome (PRO) in clinical studies. Pulmonary arterial hypertension (PAH) is a common complication of atrial septal defect (ASD). This study aimed to compare the HRQoL of PAH related uncorrected secundum ASD at pre and post therapy with oral sildenafil therapy. METHODS: We conducted quasi experimental study at Sardjito General Hospital Yogyakarta since April 2016 to August 2017. Adults with PAH related uncorrected secundum ASD, listed on Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry, and met the inclusion and exclusion criteria were recruited as subject. Interview was done at pre and 12 weeks post oral sildenafil therapy 3 × 20 mg using the EQ-5D-3L questionnaire. Statistical analysis was done using Wilcoxon test and paired T-test to determine the differences of EQ-5D utility and EQ-VAS score at pre and post therapy. RESULTS: A total of 18 adult patients with PAH related to uncorrected secundum ASD were enrolled in this study (83.33% female; mean age 38.72 ± 10.81 years old). The most frequent reported problems pre therapy were pain/discomfort (83%) and anxiety/depression (78%). Wilcoxon test showed the median of EQ-5D utility score were increased after sildenafil therapy (before = 0.604, after = 0.664; Z = - 2703; p:0.007), respectively. Meanwhile, the paired T-test results showed an increase of EQ-VAS mean difference 6.67 ± 8.75 (p:0.005; 95% CI 2.32-11.02) after sildenafil therapy. CONCLUSION: The administration of oral sildenafil therapy 3 × 20 mg during 12 weeks in adult patients with PAH related uncorrected secundum ASD gives better HRQoL.


Assuntos
Hipertensão Arterial Pulmonar/tratamento farmacológico , Qualidade de Vida , Citrato de Sildenafila/administração & dosagem , Administração Oral , Adulto , Feminino , Comunicação Interatrial/complicações , Comunicação Interatrial/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/psicologia , Sistema de Registros , Inquéritos e Questionários
2.
Acta Diabetol ; 57(11): 1351-1358, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32601730

RESUMO

AIM: The study evaluated the effect of different concentrations of sildenafil-containing ointment on wound healing in healthy and streptozotocin (STZ)-induced diabetic rats. METHODS: A total of 108 Sprague Dawley male rats aged 5 months were randomly divided into two groups: healthy and diabetes-inducing rats. Following induction of diabetes by intraperitoneal STZ injection (55 mg/kg), diabetic and healthy rats were subdivided into six groups (9 rats each). Linear incisions of the dorsal backs of rats were made. Then, rats were treated twice daily with either 2%, 2% + Fucidin, 5% sildenafil-containing ointments, oral sildenafil (13.0 mg/kg), moist exposed burn ointment or vehicle. During treatment, the percent reduction of the wound area and tensile strength were measured on days 3, 7 and 10. Furthermore, histopathology was performed on the wounded skin on similar days for the assessment of collagen synthesis and proliferation of new capillary vessels. RESULTS: In healthy and STZ-induced diabetic rats, the percent reduction in wound area on day 3 was significantly higher in sildenafil-containing ointment-treated groups than all other groups, whereas on day 7 only the 5% sildenafil-containing ointment-treated group showed better response in healthy rats. Although the sildenafil-containing ointment significantly showed better tensile strength than all other groups, the 5% sildenafil-treated group significantly enhanced the tensile better than the 2% and 2% + Fucidin dose. Furthermore, the histological evaluation revealed that sildenafil-containing ointment promoted collagen synthesis and proliferation of new capillary vessels. CONCLUSION: Our results suggest that sildenafil-containing ointment can provide an advantage in wound healing by promoting wound contractions and resistance to wound breakage in healthy and diabetic conditions. Therefore, 5% sildenafil-containing ointment can be used as a support factor for wound healing in healthy and diabetic conditions; however, clinical trials are required to confirm the benefits of sildenafil in wound healing.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Citrato de Sildenafila/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/fisiopatologia , Humanos , Masculino , Pomadas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/fisiopatologia
3.
Vet Res Commun ; 44(2): 73-81, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32500313

RESUMO

BACKGROUND: Sildenafil improves autonomic dysfunction caused by pulmonary hypertension (PH) in humans, but its effect is unknown in dogs with PH. This prospective study aimed to evaluate the autonomic nervous system function of a canine model of chronic embolic PH (CEPH) and the autonomic nervous system function of a canine model of CEPH in which sildenafil was administered. METHODS: This study used five clinically healthy female beagle dogs. Evaluation parameters included hemodynamic parameters, heart rate (HR) and heart rate variability (HRV). Each evaluation parameter was compared before and after creating the CEPH model (before, BL; after, CEPHBL) and between the CEPHBL model and after the administration of sildenafil (1 mg/kg, BID) in the CEPH model dogs (CEPHSil). RESULTS: In the CEPHBL model, the hemodynamic parameters indicated cardiac hypofunction, and HR was significantly increased and HRV was significantly decreased compared with BL. Further, in the CEPHSil model, the hemodynamic parameters suggested improvement in cardiac function, and HRV was significantly increased. CONCLUSIONS: From the results of the CEPH model dogs, autonomic dysfunction was shown to occur in PH dogs. In addition, the administration of 1 mg/kg of sildenafil to CEPH model dogs may improve autonomic dysfunction.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/farmacologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Doença Crônica , Modelos Animais de Doenças , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/fisiopatologia
4.
Int J Gynaecol Obstet ; 150(1): 72-76, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32286686

RESUMO

OBJECTIVES: To investigate the role of sildenafil citrate in improving ovulation induction success rate in women with unexplained infertility. METHODS: A randomized clinical trial from January to December 2018 of 80 women with unexplained infertility randomized into two groups. Both groups received 100 mg clomiphene citrate once daily from days 3-7 of the menstrual cycle. The study group also received 25 mg oral sildenafil citrate twice daily from days 8-12 of the same cycle. Transvaginal ultrasound assessed ovulation, endometrial thickness, and number of follicles. Pregnancy was assessed 2 weeks after ovulation. Primary outcome measures were endometrial thickness, number of mature follicles, and pregnancy rates. RESULTS: Pregnancy rates (26 (65%) and 16 (40%), P=0.043) and endometrial thickness (10.4 ± 1.4 and 9.2 ± 1.9, P=0.007) were significantly higher in the study group. More women in the study group reported adverse effects compared with the control group (17 [42.5%] vs 9 [22.5%]; P=0.034), with headache the most common adverse effect in the study group, reported by 8 (20.0%) patients. CONCLUSION: Adding sildenafil citrate improved ovulation success rate and increased pregnancy rate. PAN AFRICAN CLINICAL TRIAL REGISTRY: PACTR201907658492123.


Assuntos
Fármacos para a Fertilidade Feminina/administração & dosagem , Infertilidade Feminina/tratamento farmacológico , Indução da Ovulação/métodos , Citrato de Sildenafila/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Folículo Ovariano/efeitos dos fármacos , Gravidez , Taxa de Gravidez , Citrato de Sildenafila/efeitos adversos , Citrato de Sildenafila/uso terapêutico , Adulto Jovem
5.
Br J Anaesth ; 124(6): 693-701, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32245569

RESUMO

BACKGROUND: This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg-1 i.v. over 150 min or dextrose 5% at the commencement of surgery. The primary outcome was serum creatinine measured at six post-randomisation time points. The primary analysis used a linear mixed-effects model adjusted for the stratification variables, baseline estimated glomerular filtration rate, and surgical procedure. Secondary outcomes considered clinical events and potential disease mechanisms. Effect estimates were expressed as mean differences (MDs) or odds ratios with 95% confidence intervals. RESULTS: The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 µmol L-1 [-5.82, 7.59]). There was a statistically significant increase in multiple organ dysfunction scores in the sildenafil group (MD: 0.54 [0.02, 1.07]; P=0.044). Secondary outcomes, and biomarkers of kidney injury, endothelial function, and inflammatory cell activation, were not significantly different between the groups. CONCLUSIONS: These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery. CLINICAL TRIAL REGISTRATION: ISRCTN18386427.


Assuntos
Lesão Renal Aguda/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Citrato de Sildenafila/uso terapêutico , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Glucose/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/administração & dosagem , Citrato de Sildenafila/administração & dosagem , Reino Unido
6.
J Vet Med Sci ; 82(4): 446-451, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32101822

RESUMO

Information regarding the pharmacokinetics of oral sildenafil in dogs with pulmonary hypertension is limited. In this study, we examined the pharmacokinetics of oral sildenafil in a canine model of chronic embolic pulmonary hypertension (CEPH). The CEPH model was developed by repeatedly injecting microspheres into the pulmonary arteries. The pharmacokinetics of oral sildenafil at 1, 2 and 4 mg/kg was evaluated using four dogs with pulmonary hypertension in the fasted state. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil was well tolerated in this study. Proportional increments in the maximum plasma concentration and area under the curve extrapolated to infinity at drug doses of 1, 2 and 4 mg/kg were detected using a power model analysis. No significant differences were observed among the three doses in the time to maximum plasma concentration. The mean residence time and elimination half-life were slightly but significantly higher at a dose of 4 mg/kg than at a dose of 1 mg/kg.


Assuntos
Hipertensão Pulmonar/veterinária , Citrato de Sildenafila/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Modelos Animais de Doenças , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Hipertensão Pulmonar/tratamento farmacológico , Microesferas , Citrato de Sildenafila/administração & dosagem
7.
Pharm Biol ; 58(1): 116-123, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31967915

RESUMO

Context: Clinical reports showed sildenafil beneficial therapy on severe chronic obstructive pulmonary disease (COPD) with pulmonary hypertension (PH) patients.Objective: The study investigated therapeutic effects of silenafil on pulmonary damage induced by cigarette smoke exposure and bacterial inhalation in rats.Materials and methods: Female Sprague-Dawley rats (200-250 g) were divided into control group (no exposure, n = 10) and exposure group (n = 50) suffered from cigarette smoke exposure and Klebsiella pneumonia inhalation for 8 weeks. Then rats were orally given normal saline (control group or model group), 2.0, 3.0, or 4.5 mg/kg sildenafil for 4 weeks, respectively. Pulmonary pressure, RVHI and morphological analysis of pulmonary vascular remodeling, respiratory functions assay, morphological analysis of pulmonary alveoli, and expression of PCNA and caspase-3 of epithelial cells in bronchioles wall were examined.Results: Compared to model rats, 2.0, 3.0, and 4.5 mg/kg sildenafil increased VT by -0.6 to 9.58%, PEF by 3.12 to 6.49%, EF50 by 0.81 to 6.50%, decreased mPAP by 4.43 to 25.58%, RVHI by 6.54 to 26.41%, showing a dose-dependent improvement. Furthermore, 4.5 mg/kg sildenafil significantly increased MAN by 39.70%, LA/CSA by 37.07%, decreased muscular pulmonary arteries by 48.00%, WT by 12.83%, MT by 22.89%, caspase-3 expression by 17.71%, and showed improvement on abnormality in lung interstitial and bronchioles by microscopy.Discussion and conclusion: Our results demonstrated that sildenafil decreased pathological changes in alveoli, bronchioles, interstitial tissue, and arterioles of rats with COPD and PH.


Assuntos
Pneumonia Bacteriana/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Citrato de Sildenafila/farmacologia , Fumaça/efeitos adversos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/isolamento & purificação , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/administração & dosagem , Tabaco/efeitos adversos
8.
J Surg Res ; 246: 512-518, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31630883

RESUMO

BACKGROUND: Acute mesenteric ischemia carries a significant morbidity. Measures to improve blood flow parameters to the intestine may ameliorate the disease. Sildenafil, a phosphodiesterase 5 inhibitor, increases cyclic guanosine monophosphate and has been shown to prevent the effects of ischemia when given before injury. However, its effects as a rescue agent have not been established. We therefore hypothesized that sildenafil, when given as a rescue agent for intestinal ischemia, would improve mesenteric perfusion, limit intestinal epithelial injury, and decrease intestinal leukocyte chemoattractants. METHODS: Eight to 12 wk-old-male C57BL/6J mice underwent laparotomy and temporary occlusion of the superior mesenteric artery for 60 min. Following ischemia, reperfusion was permitted, and before closing the abdomen, sildenafil was injected intraperitoneally in a variety of concentrations. After 24 h, reperfusion was reassessed. Animals were euthanized and intestines evaluated for histologic injury and leukocyte chemoattractants. RESULTS: Postischemic administration of sildenafil did not improve mesenteric perfusion following intestinal ischemia and reperfusion injury. However, sildenafil did improve histologic injury scores in dose ranges of 0.01 to 10 mg/kg. No difference was noted in histological injury with 100 mg/kg dose, and all members of the 1000 mg/kg group died within 24 h of injury. Epithelial protection was not facilitated by the leukocyte chemoattractants Regulated on Activation, Normal T Cell Expressed, and Secreted, macrophage inflammatory protein 1 alpha, monocyte chemoattractant protein, neutrophil activating protein, or granulocyte colony stimulating factor. CONCLUSIONS: Administration of sildenafil following intestinal ischemia may limit intestinal mucosal injury but does not appear to alter mesenteric perfusion or leukocyte chemoattractant influx. TYPE: Basic science. LEVEL OF EVIDENCE: N/A.


Assuntos
Mucosa Intestinal/irrigação sanguínea , Isquemia Mesentérica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Citrato de Sildenafila/administração & dosagem , Animais , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Artéria Mesentérica Superior/cirurgia , Isquemia Mesentérica/complicações , Mesentério/irrigação sanguínea , Mesentério/efeitos dos fármacos , Camundongos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Resultado do Tratamento
9.
Andrologia ; 52(1): e13414, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31692024

RESUMO

Plants and plant-derived products have a long history in the treatment of sexual disorders. Rauvolfia vomitoria is one of such plant used traditionally for the enhancement of male sexual and reproductive activity. This study was carried out to elucidate the potential activity of R. vomitoria ethanolic extract on sexual behaviour and male reproductive function. Twenty-five male rats were assigned to five groups and orally treated with distilled water (control), sildenafil citrate (standard) and R. vomitoria ethanolic extract (50, 100 and 200 mg/kg BW) for 22 days. Sexual behaviour parameters such as mount latency (ML), intromission latency (IL), ejaculation latency (EL), mount frequency (MF), intromission frequency (IF), ejaculation frequency (IF) and post-ejaculatory interval (PEI) were recorded at day 0, 1, 8, 15 and 22. The reproductive function including reproductive organ weights, testicular histology and sperm parameters was also assessed. Results showed enhancement in sexual behaviour through significant reduction (p < .01) in ML, IL and PEI and significant increase (p < .01) in EL, MF IF and EF. The extract also caused an increase in sperm count, motility and transit. Present findings demonstrate the ability of R. vomitoria ethanolic extract to improve male sexual behaviour and reproductive activity in rats.


Assuntos
Ejaculação/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Rauwolfia/química , Agentes Urológicos/administração & dosagem , Animais , Etanol/química , Feminino , Masculino , Modelos Animais , Casca de Planta/química , Extratos Vegetais/isolamento & purificação , Ratos , Comportamento Sexual Animal/efeitos dos fármacos , Citrato de Sildenafila/administração & dosagem , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Testículo/efeitos dos fármacos
10.
Eur J Clin Pharmacol ; 76(2): 219-227, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31740991

RESUMO

PURPOSE: We developed a pharmacokinetic model of intravenous sildenafil in newborns with congenital diaphragmatic hernia (CDH) to achieve a target plasma concentration of over 50 µg/l. METHODS: Twenty-three CDH newborns with pulmonary hypertension (64 blood samples) received intravenous sildenafil. Patients received a loading dose of 0.35 mg/kg (IQR 0.16 mg/kg) for 3 h, followed by a continuous infusion of 1.5 mg/kg/day (IQR 0.1 mg/kg/day). For model development, non-linear mixed modeling was used. Inter-individual variability (IIV) and inter-occasion variability were tested. Demographic and laboratory parameters were evaluated as covariates. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were used for model validation. RESULTS: A two-compartment disposition model of sildenafil and a one-compartment disposition model of desmethyl sildenafil (DMS) was observed with IIV in sildenafil and DMS clearance and volume of distribution of sildenafil. NPDE and VPC revealed adequate predictability. Only postnatal age increased sildenafil clearance. This was partly compensated by a higher DMS concentration, which also has a therapeutic effect. In this small group of patients, sildenafil was tolerated well. CONCLUSIONS: This model for sildenafil in CDH patients shows that concentration-targeted sildenafil dosing of 0.4 mg/kg in 3 h, followed by 1.6 mg/kg/day continuous infusion achieves appropriate sildenafil plasma levels.


Assuntos
Hérnias Diafragmáticas Congênitas/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Modelos Biológicos , Citrato de Sildenafila/administração & dosagem , Hérnias Diafragmáticas Congênitas/complicações , Humanos , Hipertensão Pulmonar/etiologia , Recém-Nascido , Infusões Intravenosas , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/farmacocinética , Estudos Retrospectivos , Citrato de Sildenafila/farmacocinética , Distribuição Tecidual
11.
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
12.
J Pharmacokinet Pharmacodyn ; 46(5): 499-509, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31538282

RESUMO

Sildenafil (REVATIO®) was approved for the treatment of adult Pulmonary Arterial Hypertension (PAH) in the US and the EU. A pediatric study has been performed and sildenafil was approved in the EU for pediatric PAH. The long-term extension of this study revealed good survival but also an increased mortality with the high dose of sildenafil compared to lower doses. As a consequence, FDA required Pfizer to evaluate REVATIO®'s effect on the risk of death in adults with PAH. Following FDA's rationale a survival model was developed to characterize the exposure-mortality relationship and assess its potential impact on an ongoing survival trial in adults in the context of confounding factors. Clinical trial simulations were performed to assess the design of the survival trial in adults (AFFILIATE, NCT02060487), expected to last approximately 8 years according to both assumptions: absence or presence of an exposure-mortality relationship and to quantify the impact of confounding factors on its readout. Simulations showed that the trial would be robust in most conditions. But its interpretation will depend on the number of confounding factors such as additional treatments attempting to control disease progression.Clinical trial identifier NCT00159913 for STARTS-1, NCT00159874 for STARTS-2.


Assuntos
Modelos Biológicos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/mortalidade , Citrato de Sildenafila/efeitos adversos , Adulto , Ensaios Clínicos como Assunto , Simulação por Computador , Fatores de Confusão Epidemiológicos , Feminino , Humanos , Masculino , Fatores de Risco , Citrato de Sildenafila/administração & dosagem , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Clin Drug Investig ; 39(11): 1093-1107, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31414269

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the need for oxygen therapy at 36 weeks postmenstrual age (PMA). Sildenafil has been shown to enhance the lung alveolarization and vascularization in newborn animal models after lung injury and has possible therapeutic potential for the prevention of BPD. OBJECTIVE: To perform a proof-of-concept, Phase II, pilot randomized, double-blind, clinical trial to study the efficacy of sildenafil in preventing BPD, in postnatal (< 24 h), extremely and very preterm infants. METHODS: This Phase II, pilot randomized, double-blind, clinical trial was conducted in the Neonatal Intensive Care Unit of Women's Wellness and Research Center, Doha, Qatar during 2012-2014. Infants of 240/7-296/7 weeks' gestation were eligible if they needed respiratory or oxygen support ≥ 25% at randomization, and if they were at a postnatal age of < 24 h at randomization. Forty preterm infants were randomly assigned to receive off-label oral sildenafil (0.5 mg/kg every 6 h) or a placebo solution, for one week. The primary endpoints were the incidence of BPD and death at 36 weeks PMA, and the side effects. Secondary outcomes included the incidence of BPD and the respiratory support at day 28 of life, duration of oxygen use, fraction of inspired oxygen use at 36 weeks and 28 days of life, duration of hospitalization, and the incidence of significant retinopathy of prematurity, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and late sepsis. RESULTS: No significant differences were observed between the sildenafil and placebo study groups in mortality at 36 weeks PMA (10% vs 20%, p = 1), respiratory support at 36 weeks (30% vs 25%, p = 0.57), and side effects (0% vs 0%). For all other secondary outcomes, no significant differences were detected. CONCLUSIONS: While not associated with side effects, off-label oral sildenafil did not demonstrate benefits in the prevention of BPD or death in the extreme and very preterm infants. Future studies of dosing and efficacy that target different regimens of sildenafil are warranted before sildenafil is recommended for the prevention of BPD.


Assuntos
Displasia Broncopulmonar/prevenção & controle , Recém-Nascido Prematuro , Profilaxia Pré-Exposição/métodos , Estudo de Prova de Conceito , Citrato de Sildenafila/administração & dosagem , Vasodilatadores/administração & dosagem , Displasia Broncopulmonar/diagnóstico , Método Duplo-Cego , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Masculino , Projetos Piloto , Fatores de Risco
15.
Ultrasound Obstet Gynecol ; 54(4): 506-516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364206

RESUMO

OBJECTIVES: Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). METHODS: DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. RESULTS: Lung-to-body-weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2 O; P = 0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH-sildenafil than in DH-saline lambs at 120 min. Throughout the 120-min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH-sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. CONCLUSIONS: Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.


Assuntos
Hemodinâmica/efeitos dos fármacos , Hérnias Diafragmáticas Congênitas/tratamento farmacológico , Pulmão/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Animais , Autopsia/métodos , Gasometria/métodos , Feminino , Terapias Fetais/métodos , Feto , Hérnias Diafragmáticas Congênitas/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Modelos Animais , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/sangue , Gravidez , Cuidado Pré-Natal , Troca Gasosa Pulmonar/efeitos dos fármacos , Ovinos , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/sangue
16.
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
17.
Pharm Dev Technol ; 24(10): 1218-1228, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31361185

RESUMO

Objectives: This study aims to formulate nanodispersion-based sildenafil metered-dose inhalers (MDIs) by using poloxamer 188 (P188) as a stabilizer; to evaluate their stability, aerosol characteristics, cytotoxicity, and inflammatory effects; and to investigate the effects of P188 on stability and aerosol characteristics of the MDIs. Methods: The stability and uniformity of the formulations were evaluated by high-performance liquid chromatography method. The aerosol characteristics were evaluated by the Next Generation Impactor. The cytotoxicity and inflammatory effects on respiratory epithelial cells and alveolar macrophages were evaluated by MTT assay and TNF-α, IL-1ß, and NO assay, respectively. Results: The optimal formulation was stable and well-uniform after 6 months. The fine particle fraction and mass median aerodynamic diameter (MMAD) of the formulation were 61.9% ± 2.5% and 1.69 ± 0.06 µm, respectively. The formulation was found to be nontoxic to respiratory epithelial cells and did not induce the inflammatory responses of alveolar macrophages. A positive correlation between P188 concentration and MMAD of the MDIs was observed. P188 possesses an ability to prevent the growth of sildenafil citrate monohydrate crystals in the formulations. Conclusions: The findings provided a basis for the development of sildenafil MDI as a potential candidate for the treatment of pulmonary arterial hypertension.


Assuntos
Composição de Medicamentos/métodos , Hipertensão Pulmonar/tratamento farmacológico , Inaladores Dosimetrados , Nanopartículas/química , Poloxâmero/química , Citrato de Sildenafila/administração & dosagem , Células A549 , Aerossóis , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Citocinas/metabolismo , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Células Epiteliais/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Tamanho da Partícula , Poloxâmero/toxicidade , Ratos , Citrato de Sildenafila/química , Citrato de Sildenafila/uso terapêutico , Citrato de Sildenafila/toxicidade
18.
Andrologia ; 51(9): e13371, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31347717

RESUMO

In comparison to other antidepressant drugs, erectile dysfunction (ED) is more pronounced in paroxetine use. On the other hand, orange (Citrus sinensis) peels commonly consumed in various forms are used in folkloric medicine for ED management. Thus, this study evaluated the effect of orange peels infusion on sexual behaviour, nitric oxide (NO) level and some enzymes (arginase, phosphodiesterase-5 [PDE-5], acetylcholinesterase [AChE] and adenosine deaminase [ADA]) in paroxetine-treated rats. Erectile dysfunction was induced with paroxetine (10 mg/kg body weight). The animals were grouped into five (n = 6): normal rats; paroxetine-induced rats; paroxetine-induced rats treated with sildenafil citrate (5 mg/kg); paroxetine-induced rats treated with orange peels infusion (50 mg/kg); Paroxetine induced rats treated with orange peel infusions (100 mg/kg). The results revealed a significant decrease in sexual behaviour, NO level and the activities of antioxidant enzymes, while there was a significant increase in arginase, PDE-5, AChE and ADA activities in paroxetine-induced rats. However, orange peel infusions ameliorated erectile dysfunction in paroxetine-treated rats. This study showed some possible biochemical basis underlying the use of orange peels infusion in erectile dysfunction management.


Assuntos
Antidepressivos de Segunda Geração/toxicidade , Antioxidantes/administração & dosagem , Citrus sinensis/química , Disfunção Erétil/tratamento farmacológico , Paroxetina/toxicidade , Extratos Vegetais/administração & dosagem , Acetilcolinesterase/metabolismo , Adenosina Desaminase/metabolismo , Animais , Arginase/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Modelos Animais de Doenças , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/patologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Óxido Nítrico/metabolismo , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Pênis/patologia , Ratos , Comportamento Sexual/efeitos dos fármacos , Citrato de Sildenafila/administração & dosagem , Resultado do Tratamento
19.
Arch Ital Urol Androl ; 91(2)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266280

RESUMO

Even if oral type 5 phosphodiesterase inhibitors (PDE5i) seem an effective treatment for erectile dysfunction (ED), the drop-out is high among patients. For this reason, pharmaceutical companies are encouraged to develop new administration routes, such as the orally disintegrating film. The aim of this study was to analyse the prescription habit of Italian andrologists affiliated to Italian Society of Andrology (SIA) in the era of new oro-dispersible formulation of sildenafil. A 12-items dedicated questionnaire has been distributed to 77 urologists andrologists. As a result of the questionnaire, sildenafil is still the preferred drug of Italian andrologists as it is considered the safest and the most effective. It combines the speed of action and the discretion of the intake that are very important issues for the adherence to the treatment according to the Italian sample. Physicians have also reported the positive feedback of the patients taking sildenafil film as they consider the oro-dispersible formulation either comparable or superior to the old tablet. In conclusion this new formulation has given a new life to an old molecule like sildenafil, and Italian andrologists considered this new pharmaceutical formulation as a good tool to improve the patient's adherence to the treatment and quality of life.


Assuntos
Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , Citrato de Sildenafila/administração & dosagem , Andrologia , Pesquisas sobre Serviços de Saúde , Humanos , Itália , Masculino
20.
Mayo Clin Proc ; 94(7): 1199-1209, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31272568

RESUMO

OBJECTIVE: To characterize the obese heart failure with preserved ejection fraction (HFpEF) phenotype in a multicenter cohort. PATIENTS AND METHODS: This was a secondary analysis of the randomized clinical trial RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) performed between October 1, 2008, and February 1, 2012. Patients with HFpEF were classified by body mass index (BMI) as obese (BMI≥35 kg/m2) and nonobese (BMI<30 kg/m2) for comparison. RESULTS: Obese patients with HFpEF (n=81) were younger (median age, 64 [interquartile range (IQR), 67-79] years vs 73 [IQR, 56-70] years; P<.001) but had greater peripheral edema (31% [25] vs 9% [6]; P<.001), more orthopnea (76% [56] vs 53% [35]; P=.005), worse New York Heart Association class (P=.006), and more impaired quality of life (P<.001) as compared with nonobese patients with HFpEF (n=70). Despite more severe signs and symptoms, obese patients with HFpEF had lower N-terminal pro B-type natriuretic peptide level (median, 481 [IQR, 176-1183] pg/mL vs 825 [IQR, 380-1679] pg/mL [to convert to pmol/L, multiply by 0.118]; P=.007) and lower left atrial volume index (median, 38 [IQR, 31-47] mL/m2 vs 54 [IQR, 41-63] mL/m2; P<.001). Serum C-reactive protein (median, 5.0 [IQR, 2.4-9.9] mg/dL vs 2.7 [IQR, 1.6-5.4] mg/dL [to convert to mg/L, multiply by 10-3]; P<.001) and uric acid (median, 7.8 [IQR, 6.1-8.7] mg/dL vs 6.8 [IQR, 5.5-8.3] mg/dL; P=.03) levels were higher in obese HFpEF, indicating greater systemic inflammation, than in nonobese HFpEF. Peak oxygen consumption was impaired in obese HFpEF (median, 11.1 [IQR, 9.6-14.4] mL/kg per minute vs 13.1 [IQR, 11.3-14.7] mL/kg per minute; P=.008), as was submaximal exercise capacity (6-minute walk distance, 272 [IQR, 200-332] m vs 355 [IQR, 290-415] m; P<.0001). CONCLUSION: Obese HFpEF is associated with decreased quality of life, worse symptoms of heart failure, greater systemic inflammation, worse exercise capacity, and higher metabolic cost of exertion as compared with nonobese HFpEF. Further study is required to understand the pathophysiology and potential distinct treatments for patients with the obese phenotype of HFpEF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00763867.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Obesidade/fisiopatologia , Fenótipo , Volume Sistólico/fisiologia , Idoso , Tolerância ao Exercício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Inibidores da Fosfodiesterase 5/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Citrato de Sildenafila/administração & dosagem
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