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1.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670094

RESUMO

Unapproved ingredients included in herbal medicines and dietary supplements have been detected as adulterated synthetic drugs used for erectile dysfunction. Extraction from a dietary supplement was performed to isolate the compounds by HPLC analysis. The structural characterization was confirmed using mass spectrometry (ESI-TOF/MS and LC-MS/MS), 1H NMR, and 13C NMR spectroscopy techniques. Results identified the thus-obtained compound to be sulfoaildenafil, a thioketone analogue of sildenafil. The biological activities of this active compound have been focused for the first time by the experimental point of view performance in vitro. The results revealed that sulfoaildenafil can affect the therapeutic level of nitric oxide through the upregulation of nitric oxide synthase and phosphodiesterase type 5 (PDE5) gene expressions. This bulk material, which displays structural similarity to sildenafil, was analyzed for the presence of a PDE5 inhibitor using a theoretical calculation. These unique features of the potential activity of PDE5 protein and its inhibitors, sildenafil and sulfoaildenafil, may play a key consideration for understanding the mode of actions and predicting the biological activities of PDE5 inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Suplementos Nutricionais , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/química , Cromatografia Líquida de Alta Pressão , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/efeitos dos fármacos , Disfunção Erétil/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Medicina Herbária , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/química , Piperazinas/uso terapêutico , Citrato de Sildenafila/química , Citrato de Sildenafila/uso terapêutico , Sulfonas/química , Sulfonas/uso terapêutico
3.
Arq Bras Cardiol ; 116(2): 219-226, 2021 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33656068

RESUMO

BACKGROUND: Elevated pulmonary vascular resistance remains a major problem for heart transplant (HT) candidate selection. OBJECTIVE: This study sought at assess the effect of pre-HT sildenafil administration in patients with fixed pulmonary hypertension. METHODS: This retrospective, single-center study included 300 consecutive, HT candidates treated between 2003 and 2013, in which 95 patients had fixed PH, and of these, 30 patients were treated with sildenafil and eventually received a transplant, forming Group A. Group B included 205 patients without PH who underwent HT. Pulmonary hemodynamics were evaluated before HT, as well as 1 week after and 1 year after HT. Survival was compared between the groups. In this study, a p value < 0.05 was considered statistically significant. RESULTS: After treatment with sildenafil but before HT, PVR (-39%) and sPAP (-10%) decreased significantly. sPAP decreased after HT in both groups, but it remained significantly higher in group A vs. group B (40.3 ± 8.0 mmHg vs 36.5 ± 11.5 mmHg, p=0.022). One year after HT, sPAP was 32.4 ± 6.3 mmHg in group A vs 30.5 ± 8.2 mmHg in group B (p=0.274). The survival rate after HT at 30 days (97% in group A versus 96% in group B), at 6 months (87% versus 93%) and at one year (80% vs 91%) were not statistically significant (Log-rank p=0.063). After this first year, the attrition rate was similar among both groups (conditional survival after 1 year, Log-rank p=0.321). CONCLUSION: In patients with severe PH pre-treated with sildenafil, early post-operative hemodynamics and prognosis are numerically worse than in patients without PH, but after 1 year, the medium to long-term mortality proved to be similar. (Arq Bras Cardiol. 2021; 116(2):219-226).


Assuntos
Transplante de Coração , Hipertensão Pulmonar , Hemodinâmica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento
4.
JAMA Netw Open ; 4(2): e2036337, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33599772

RESUMO

Importance: Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. Objective: To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. Data Sources: Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. Study Selection: Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. Data Extraction and Synthesis: Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. Results: A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. Conclusions and Relevance: This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.


Assuntos
Antioxidantes/uso terapêutico , Equipamentos e Provisões , Disfunção Erétil/terapia , Tratamento por Ondas de Choque Extracorpóreas , Inibidores da Fosfodiesterase 5/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Terapia Combinada , Quimioterapia Combinada , Ácido Fólico/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Tadalafila/uso terapêutico , Resultado do Tratamento , Complexo Vitamínico B/uso terapêutico
5.
BMJ Case Rep ; 14(1)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504532

RESUMO

About 10% of term neonates present with respiratory distress at birth. The most common aetiologies include transient tachypnoea of the newborn, pneumonia and meconium aspiration syndrome (MAS). Hyaline membrane disease (HMD) in a term infant occurs either as primary HMD, secondary surfactant deficiency or congenital surfactant dysfunction. A detailed history supported with appropriate radiological and laboratory investigations can help a clinician reach a diagnosis. We report a case of surfactant dysfunction disorder which presented as severe MAS and persistent pulmonary hypertension of the newborn. In the infant described, the significant history of a sibling death with severe neonatal respiratory disease led us to think of diffuse developmental lung diseases especially surfactant dysfunction syndromes. Exome sequencing detected a heterozygous missense variation in exon 21 of the ATP binding cassette protein member 3 (ABCA3) gene. Based on the clinical picture supported with the exome sequencing, a diagnosis of surfactant dysfunction disorder (ABCA3 deficiency) was confirmed.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Síndrome de Aspiração de Mecônio/diagnóstico , Síndrome da Persistência do Padrão de Circulação Fetal/diagnóstico , Transportadores de Cassetes de Ligação de ATP/genética , Broncodilatadores/uso terapêutico , Diagnóstico Diferencial , Evolução Fatal , Humanos , Recém-Nascido , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/terapia , Masculino , Óxido Nítrico/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Respiração Artificial , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/uso terapêutico
6.
Urologiia ; (6): 38-43, 2020 Dec.
Artigo em Russo | MEDLINE | ID: mdl-33377677

RESUMO

AIM: To study the efficacy and safety of using sildenafil in patients with erectile dysfunction (ED) and concomitant cardiovascular diseases (CVD) who underwent transurethral resection of the prostate (TURP). MATERIAL AND METHODS: A total of 59 patients (age from 50 to 75 years) with a diagnosis of benign prostatic hyperplasia (BPH), requiring surgical treatment due to inefficiency of drug therapy, I-PSS score more than 20 points), who were sexually active, but had erectile dysfunction (IIEF score < 21), coronary heart disease (NYHA class I) and stage 1-2 hypertension with stable blood pressure. All patients underwent bipolar TURP. From the first day after the TURP, therapy was prescribed as following: tamsulosin 0.4 mg once a day for 90 days, ciprofloxacin 500 mg twice a day for 10 days. In addition, the patients received treatment for comorbidities. In the main group (n=30), men additionally received sildenafil (EFFEX Sildenafil Evalar) 50 mg daily for 60 days, starting from the 30th day postoperatively. We have chosen this drug from an economic standpoint. RESULTS: At baseline, all patients in both groups had hemodynamic and microcirculatory disorders in the prostate, which got worse in the early postoperative period. During the long-term follow-up, hemodynamic and microcirculatory impairments decreased. This effect was more pronounced in patients who received sildenafil. In addition, patients had an improvement in sexual function. During follow-up, there was no adverse effects of sildenafil on hemodynamic parameters (blood pressure, heart rate). CONCLUSION: Our results allow to recommend sildenafil in order to restore sexual function postoperatively in patients with BPH, including those with concomitant cardiovascular disorders.


Assuntos
Disfunção Erétil , Hiperplasia Prostática , Ressecção Transuretral da Próstata , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Humanos , Masculino , Microcirculação , Hiperplasia Prostática/complicações , Hiperplasia Prostática/cirurgia , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento
7.
Chirurgia (Bucur) ; 115(6): 783-791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378637

RESUMO

Background: Ischeamia reperfusion injury is a frequent challenge during tissue reconstruction. Atorvastatin and Sildenafil, have been studied for their protective and/or therapeutic effects on various organ systems subjected to IRI. The aim of the present study was to compare a single dose of Atorvastatin and Sildenafil pretreatment on acute oxidative/nitrosative stress and the subsequent dermal flap necrosis. Materials and Methods: Forty-five Sprague-Dawley rats, were randomly allocated into three equal groups(n=15): Group A: Control rats treated with intraperitoneal saline, Group B: Sildenafil group, and Group C: atorvastatin group. All rats underwent flap elevation and inferior epigastric artery occlusion thirty minutes after drug administration. Myeloperoxidase activity, malondialdehyde levels and inducible nitric oxide synthase activity were evaluated 12 hours after reperfusion. Flap survivability was analysed 7 days after the procedure. Results: Statistically significant reduction was detected in sildenafil and atorvastation. Measurements of myelopyroxidase followed a similar pattern, interestingly malonadehyde levels measured to be significantly lower in the sildenafil group. Contrary, iNOS activity atorvastatin was significantly elevated in atorvastatin group. Conclusion: The single dose of atorvastatin or sildenafil increase flap survivability almost equally, however only atorvastatin enhances significantly iNOS expression.


Assuntos
Atorvastatina/farmacologia , Óxido Nítrico , Traumatismo por Reperfusão/tratamento farmacológico , Citrato de Sildenafila/farmacologia , Pele/irrigação sanguínea , Vasodilatadores/farmacologia , Animais , Atorvastatina/uso terapêutico , Modelos Animais de Doenças , Sobrevivência de Enxerto/efeitos dos fármacos , Necrose/etiologia , Necrose/prevenção & controle , Óxido Nítrico/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Citrato de Sildenafila/uso terapêutico , Pele/efeitos dos fármacos , Pele/patologia , Retalhos Cirúrgicos/irrigação sanguínea , Retalhos Cirúrgicos/patologia , Resultado do Tratamento , Vasodilatadores/uso terapêutico
8.
Int Heart J ; 61(5): 1084-1087, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921661

RESUMO

Diazoxide, a drug used to treat hyperinsulinemic hypoglycemia (HH), is associated with pulmonary hypertension (PH), as reported by the US Food and Drug Administration. However, no report has detailed the association between diazoxide dose and PH development. We report a case of an infant with HH, subsequently complicated by diazoxide-induced PH. When diazoxide was introduced, PH did not appear initially, but it developed during increased dosing. We monitored PH via regular echocardiography examinations. PH gradually improved with tapering of the diazoxide dose and disappeared after drug discontinuation. Our case suggests a diazoxide dose threshold might induce PH. Therefore, close echocardiography examinations should accompany diazoxide treatment.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Hipertensão Pulmonar/induzido quimicamente , Fator Natriurético Atrial/sangue , Síndrome de Beckwith-Wiedemann/complicações , Cateterismo Cardíaco , Hiperinsulinismo Congênito/etiologia , Desprescrições , Diazóxido/administração & dosagem , Diuréticos/uso terapêutico , Relação Dose-Resposta a Droga , Ecocardiografia , Eletrocardiografia , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/tratamento farmacológico , Lactente , Recém-Nascido , Masculino , Peptídeo Natriurético Encefálico/sangue , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/uso terapêutico
9.
AAPS PharmSciTech ; 21(6): 221, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32748291

RESUMO

Sildenafil citrate causes vasodilatation, relaxation of the smooth muscle, and reduction of pulmonary arterial pressure. The latter property makes sildenafil citrate efficient for the treatment of cardiovascular diseases, including pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension are more susceptible to errors in drug administration than adults because of a lack of suitable drug dosages. Thus, the purpose of this study was to develop stable (chemically and microbiologically) sildenafil citrate drop liquid formulation, suitable for pediatric patients (including diabetics), ensuring safety during preparation and storing and improving palatability by using milk as a carrier for administration. The significant factors that affect the sildenafil solubility were evaluated by applying a Plackett-Burman design using two levels with six variables. The experiment showed that the type of buffer and glycerin content influenced the sildenafil solubility. The developed formulations proved to be stable for 6 months at all three assayed conditions (40± 2°C, 75 ± 5% RH; 25± 2°C, 60 ± 5% RH; and 4 ± 2°C). The microbiological tests fit with the requirement of the pharmacopeia at day 0 and 90 and even more at day 180. Finally, the palatability assay showed that 0.82 mL of the formulation containing buffer phosphate, 20% glycerin, and 4 mg mL-1 of sildenafil citrate diluted in 4.8 mL milk (which fits the medium pediatric dose) presented similar palatability to milk alone, and no precipitate or turbidity was observed. Graphical abstract.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Citrato de Sildenafila/química , Adulto , Criança , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Pessoa de Meia-Idade , Citrato de Sildenafila/uso terapêutico , Solubilidade , Soluções
10.
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
11.
Life Sci ; 257: 118001, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634428

RESUMO

AIMS: Pulmonary hypertension (PH) is a severe and prevalent complication of chronic obstructive pulmonary disease (COPD), with low quality of life and poor prognosis. This study was designed to evaluate the efficacy and safety of Sildenafil in the treatment of PH caused by COPD (COPD-PH) and provide reference for clinical treatment. MATERIALS AND METHODS: We systematically searched PubMed, EMBASE, Cochrane Library, Clinical Trials.gov databases, Wanfang Data and CNKI for comprehensive literature reporting Sildenafil for randomized controlled trials (RCT) of COPD-PH. Quality assessment, data analysis used the modified Jadad scale and RevMan5.3 software. KEY FINDINGS: A total of 9 RCTs involving 579 patients were included in our study. The primary outcome measure was Six minutes walking distance (6MWD). Secondary observations were Pulmonary artery systolic pressure (PASP), Borg dyspnea index, and Survey scale (SF-36). Our data demonstrate that Sildenafil can improve 6WMD [29.64, 95% CI (13.78, 45.50), P < 0.00001] and PASP [-7.86, 95% CI (-11.26, -4.46) P < 0.00001] of COPD-PH, compared with the control group. However, SF-36 [2.64, 95% CI (-6.85, 12.14) P = 0.59] and Borg dyspnea index [-0.28, 95% CI (-1.08, 0.52) P = 0.49] have no significant difference between those two groups. Adverse reactions in the Sildenafil treatment group were tolerated headaches and digestive symptoms, which were relatively safe. SIGNIFICANCE: Available clinical evidence indicates that Sildenafil seems to be safe and effective for COPD-PH and can improve the patients' 6WMD. However, large-sample, high-quality multicenter RCTs are still needed to provide stronger evidence-based medical evidence.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Citrato de Sildenafila/metabolismo , Resultado do Tratamento
12.
JAMA Netw Open ; 3(6): e205323, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585017

RESUMO

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.


Assuntos
Peso ao Nascer , Término Precoce de Ensaios Clínicos , Retardo do Crescimento Fetal/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Doenças Placentárias/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Retardo do Crescimento Fetal/etiologia , Idade Gestacional , Humanos , Hipertensão Pulmonar/induzido quimicamente , Recém-Nascido , Doenças do Recém-Nascido/induzido quimicamente , Doenças do Recém-Nascido/prevenção & controle , Análise de Intenção de Tratamento , Masculino , Artéria Cerebral Média/fisiologia , Mortalidade Perinatal , Inibidores da Fosfodiesterase 5/efeitos adversos , Doenças Placentárias/fisiopatologia , Pré-Eclâmpsia/etiologia , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Fluxo Pulsátil , Citrato de Sildenafila/efeitos adversos , Artérias Umbilicais/fisiologia
14.
Med Hypotheses ; 143: 109851, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32534175

RESUMO

PURPOSE: Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. HYPOTHESIS: A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID-19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin, and/or nutraceuticals that have been published to support immune function including glutathione, vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and "cytokine storm syndrome" with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to "acute respiratory distress syndrome" (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NF-κB and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione with associated anti-viral effects should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID-19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. CONCLUSION AND IMPLICATIONS: A three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with ivermectin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NF-κB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.


Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Acetazolamida/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticoagulantes/uso terapêutico , Técnicas de Laboratório Clínico , Infecções por Coronavirus/tratamento farmacológico , Dietoterapia , Humanos , Sistema Imunitário , Inflamação , Ivermectina/uso terapêutico , Programas de Rastreamento , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Alocação de Recursos , Risco , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento
16.
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
18.
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
19.
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
20.
Cochrane Database Syst Rev ; 4: CD004198, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251534

RESUMO

BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review. OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials. MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low. AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.


Assuntos
Anemia Falciforme/complicações , Dietilestilbestrol/uso terapêutico , Estrogênios não Esteroides/uso terapêutico , Priapismo/tratamento farmacológico , Vasoconstritores/uso terapêutico , Adrenérgicos/efeitos adversos , Adrenérgicos/uso terapêutico , Efedrina/efeitos adversos , Efedrina/uso terapêutico , Etilefrina/efeitos adversos , Etilefrina/uso terapêutico , Humanos , Masculino , Priapismo/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Citrato de Sildenafila/uso terapêutico , Taquicardia/induzido quimicamente , Vasoconstritores/efeitos adversos , Adulto Jovem
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