Formulation and Evaluation of Orodispersible Tablet Containing Combination of Phosphodiesterase-5 Inhibitor and Herbal Aphrodisiac

Purpose: Sildenafil citrate is widely used drug for the treatment of Erectile Dysfunction (ED) and Ginseng is a natural aphrodisiac reported to benefit this condition. The objective of the present study was to develop orodispersible tablets (ODTs) containing combination of Sildenafil citrate and Ginseng extract to improve the bioavailability, reduce the dosing frequency and thereby maintaining the therapeutic efficacy of the drug. Methods: The ODTs were prepared using superdisintegrants such as Croscarmellose sodium (CCS), povidone, and sodium starch glycolate (SSG) at varying concentrations (2%, 4% and 6%) by direct compression. The bitter taste of Sildenafil citrate was masked by Doshion resin. The optimized formulation based on least disintegration time (DT) was chosen to reformulate using sublimating agents such as camphor, menthol or thymol at varying concentrations (1%, 2%, 3%) to further reduce the DT. The compatibility of drug with excipients was investigated and the prepared formulations were evaluated for pre and post-compression parameters. Results: The post-compression parameters such as weight variation, hardness, friability, DT and in-vitro drug release was found within specified limit. The formulation with camphor (2%) had DT of 12 sec and drug release >90% within 5 min hence was considered as optimized formulation. The accelerated stability study and kinetics modelling was performed for optimized formulation. Conclusion: The formulated Sildenafil citrate and Ginseng ODT’s were found to be promising formulation with quicker DT and drug release which will eventually have higher bioavailability and better efficacy along with averting the issues of swallowing and improving patient compliance.

Evaluation of the Effects of Aqueous Extract of Sarcocephalus latifolius on Sexual Behaviour in Male Rats

Background: Sarcocephalus latifolius, a plant of the Rubiaceae family, is found exclusively in tropical Africa, more particularly in sub-Saharan West Africa, stretching from Senegal to Zaire, but is also found as far east as Sudan (Sudan-Guinean zone). The leaves of this plant are used in traditional African medicine to treat numerous pathologies such as infertility. Aims/Objective: The present study aims to evaluate the effects of the aqueous extract of Sarcocephalus latifolius leaves on sexual parameters in male rats. Methods: The sexual parameters (latency of the mating position, latency of intromission, latency of ejaculation and mean copulation interval) were assessed by the classical method by administering distilled water, sildenafil citrate (reference molecule) called Viagra at the dose of 5 mg/kg of body weight and the aqueous extract of Sarcocephalus latifolius leaves at the dose of 1000 mg/kg of body weight per day for eight days to three batches of male rats respectively. These parameters were determined over a period of thirty minutes. Results: The results obtained show that the aqueous extract of Sarcocephalus latifolius leaves at a dose of 1000 mg/kg of body weight significantly (P < .001) decreases the latency time of mating position and the latency time of intromission, whereas this extract significantly (P < .001) increases the latency time of ejaculation and the average copulation interval. Conclusion: Aqueous extract of Sarcocephalus latifolius leaves has aphrodisiac properties which are due to sterols, flavonoids and saponosides.

Tratamiento farmacológico en la restricción del crecimiento fetal: revisión de la bibliografía / Pharmacological management for fetal growth restriction: literature review

Resumen OBJETIVO: Explorar las diferentes estrategias de tratamiento farmacológico de la restricción del crecimiento fetal propuestas a lo largo del tiempo. METODOLOGÍA: Revisión cuasi-sistemática de la evidencia científica histórica disponible acerca del tratamiento médico descrito para la atención de mujeres embarazadas con restricción del crecimiento fetal. RESULTADOS: Entre los tratamientos médicos descritos para tratar la restricción del crecimiento fetal, los donadores de óxido nítrico, las estatinas y la aspirina asociada con omega 3, han tenido desenlaces no consistentes en estudios con limitado tamaño de muestra. Por lo que se refiere a los inhibidores de la 5-fosfodiesterasa, el sildenafilo no se ha asociado con un aumento de la velocidad de crecimiento fetal pero sí con alarmas respecto de su seguridad debidas al incremento de los casos de hipertensión pulmonar fetal y mortalidad perinatal. Por su parte, el tadalafilo ha mostrado desenlaces iniciales favorables y se esperan estudios con mayor tamaño de muestra que permitan emitir recomendaciones claras con respecto a su indicación. También se esperan los desenlaces de estudios clínicos en curso, para definir la indicación de la heparina de bajo peso molecular en este escenario en virtud de sus prometedores resultados iniciales. Los procedimientos más invasivos, como la inyección de factor de crecimiento endotelial vascular y la plasmaféresis, permanecen en estudio como propuestas terapéuticas por los resultados de estudios preclínicos y clínicos con pocos pacientes. CONCLUSIÓN: Por ahora, ninguna estrategia farmacológica propuesta ha conseguido generar recomendaciones fuertes para su indicación; sin embargo, se esperan nuevos estudios con alta calidad metodológica que generen evidencia científica lo suficientemente contundente para recomendar su indicación.

Abstract OBJECTIVE: To explore the different pharmacological treatment strategies for fetal growth restriction proposed over time. METHODOLOGY: Quasi-systematic review of the available historical scientific evidence on the medical treatment described for the care of pregnant women with fetal growth restriction. RESULTS: Among the medical treatments described to treat fetal growth restriction, nitric oxide donors, statins, and aspirin associated with omega-3 have had inconsistent outcomes in studies with limited sample size. As for 5-phosphodiesterase inhibitors, sildenafil has not been associated with an increase in fetal growth velocity, but there have been alarms regarding its safety due to the increase in cases of fetal pulmonary hypertension and perinatal mortality. On the other hand, tadalafil has shown favorable initial outcomes and studies with a larger sample size are awaited to issue clear recommendations regarding its indication. The results of ongoing clinical studies are also awaited to define the indication of low molecular weight heparin in this setting, given its promising initial results. More invasive procedures, such as vascular endothelial growth factor injection and plasmapheresis, remain under study as therapeutic proposals due to the results of preclinical and clinical studies with few patients. CONCLUSION: For now, no proposed pharmacological strategy has managed to generate strong recommendations for its indication; however, new studies with high methodological quality are expected to generate scientific evidence strong enough to recommend its indication.

Effect of creatine and sildenafil citrate on the physical performance of mice / Efecto de la creatina y del citrato de sildenafil sobre el desempeño físico de ratones / Efeito da creatina e do citrato de sildenafila sobre o desempenho físico de camundongos

ABSTRACT Introduction: The use of substances to enhance sports performance among professional and amateur athletes is increasing. Such substances may either be included in the group of dietary supplements or fall into pharmacological classes. Every substance used for this purpose is called an ergogenic agent. The number of ergogenic options available increases every day, favoring overuse and use without proper guidance. Among the dietary supplements, we highlight the use of creatine, a substance widespread in sports. Among the pharmacological groups, many drugs are used. Recently the use of sildenafil citrate by professional athletes from various predominantly aerobic sports modalities was reported in the media. Objective: To compare and demonstrate the responses caused by physical training associated with the use of creatine and sildenafil citrate in mice. Methods: A swim training protocol was applied and then an electrophysiograph was used in order to obtain parameters related to contraction intensity, the area under the curve and the percentage drop. Results: The responses obtained demonstrated the ergogenic action of creatine because it altered the parameters used for measurement. The use of sildenafil citrate did not yield satisfactory results to frame the drug as an ergogenic agent. Conclusion: Creatine has an ergogenic effect, reducing the percentage drop after 10 seconds, while sildenafil demonstrated no ergogenic potential and, interestingly, resulted in weaker responses when compared to the exercise groups. Evidence level II; Comparative prospective study .

RESUMEN Introducción: El uso de sustancias con el objetivo de aumentar el rendimiento deportivo entre atletas profesionales y amateurs es creciente. Tales sustancias pueden formar parte del grupo de suplementos alimentarios o integrar clases farmacológicas. Toda sustancia empleada para ese fin es denominada agente ergogénico. El número de opciones entre los agentes ergogénicos aumenta cada día, favoreciendo así su uso excesivo y sin la debida orientación. Entre los suplementos alimentarios, se destaca el uso de creatina, sustancia muy difundida en el medio deportivo. Ya entre los grupos farmacológicos, muchas sustancias son usadas. Recientemente, fue divulgado entre los medios de comunicación el uso de citrato de sildenafil por atletas profesionales, de varias modalidades deportivas, predominantemente las aeróbicas. Objetivos: Comparar y demostrar las respuestas ocasionadas por el entrenamiento físico, asociadas al uso de creatina y citrato de sildenafil en ratones. Métodos: Se aplicó un protocolo de entrenamiento de natación y, a continuación, se usó un electrofisiógrafo con el objetivo de obtener parámetros referentes a la intensidad de contracción, al área bajo la curva y a la caída porcentual. Resultados: Las respuestas obtenidas demuestran acción ergogénica de la creatina, visto que alteraron los parámetros empleados para la medición. Ya el uso de citrato de sildenafil no presentó resultados satisfactorios para encuadrar al fármaco como agente ergogénico. Conclusión: La creatina presenta efecto ergogénico porque reduce la caída porcentual después de 10 segundos, mientras que el sildenafil no presentó potencial ergogénico y, curiosamente, demostró respuestas inferiores cuando comparado a los grupos de ejercicio. Nivel de evidencia II; Estudio prospectivo comparativo .

RESUMO Introdução: O uso de substâncias com o objetivo de aumentar o rendimento esportivo entre atletas profissionais e amadores é crescente. Tais substâncias podem fazer parte do grupo de suplementos alimentares ou integrar classes farmacológicas. Toda substância empregada para esse fim é denominada de agente ergogênico. O número de opções entre os agentes ergogênicos aumenta a cada dia, favorecendo assim o uso em demasia e sem a devida orientação. Entre os suplementos alimentares, salientamos a utilização de creatina, substância muito difundida no meio esportivo. Já entre os grupos farmacológicos, muitas substâncias são utilizadas. Recentemente, foi divulgado entre os meios de comunicação o uso de citrato de sildenafila por atletas profissionais de várias modalidades esportivas, predominantemente as aeróbicas. Objetivos: Comparar e demonstrar as repostas ocasionadas pelo treinamento físico, associadas ao uso de creatina e citrato de sildenafila em camundongos. Métodos: Aplicou-se um protocolo de treinamento de natação e, a seguir, empregou-se um eletrofisiógrafo com objetivo de obter parâmetros referentes à intensidade de contração, à área sob a curva e à queda percentual. Resultados: As respostas obtidas demonstram ação ergogênica da creatina, visto que alteraram os parâmetros empregados para a mensuração. Já a utilização de citrato de sildenafila não apresentou resultados satisfatórios para enquadrar o fármaco como agente ergogênico. Conclusão: A creatina apresenta efeito ergogênico porque reduz a queda percentual após 10 segundos, já a sildenafila não apresentou potencial ergogênico e, curiosamente, demonstrou respostas inferiores quando comparado aos grupos de exercício. Nível de evidência II; Estudo prospectivo comparativo .

Resultados Clínicos e Hemodinâmicos de Longo Prazo após o Transplante de Coração em Pacientes Pré-Tratados com Sildenafil / Long-Term Clinical and Hemodynamic Outcomes after Heart Transplantation in Patients Pre-Treated with Sildenafil

Resumo Fundamento A resistência vascular pulmonar elevada ainda é um grande problema na seleção de candidatos ao transplante cardíaco. Objetivo Nosso objetivo foi avaliar o efeito da administração de sildenafila pré-transplante cardíaco em pacientes com hipertensão pulmonar fixa. Métodos O estudo retrospectivo, de centro único, incluiu 300 candidatos a transplante cardíaco consecutivos tratados entre 2003 e 2013. Destes, 95 pacientes tinham hipertensão pulmonar fixa e, dentre eles, 30 pacientes foram tratados com sildenafila e acabaram passando pelo transplante, formando o Grupo A. O Grupo B incluiu 205 pacientes sem hipertensão pulmonar que passaram pelo transplante cardíaco. A hemodinâmica pulmonar foi avaliada antes do transplante, 1 semana e 1 ano após o transplante. A taxa de sobrevivência foi comparada entre os grupos. Neste estudo, um P valor < 0,05 foi considerado estatisticamente significativo. Resultados Após o tratamento com sildenafila, mas antes do TxC, a RVP (-39%) e a PAPs (-10%) diminuíram significativamente. A PAPs diminuiu após o TxC em ambos os grupos, mas permaneceu significativamente alta no grupo A em relação ao grupo B (40,3 ± 8,0 mmHg versus 36,5 ± 11,5 mmHg, P=0,022). Um ano após o TxC, a PAPs era 32,4 ± 6,3 mmHg no Grupo A versus 30,5 ± 8,2 mmHg no Grupo B (P=0,274). O índice de sobrevivência após o TxC 30 dias (97% no grupo A versus 96% no grupo B), 6 meses (87% versus 93%) e um ano (80% versus 91%) após o TxC não foi estatisticamente significativo (Log-rank P=0,063). Depois do primeiro ano, o índice de mortalidade era similar entre os dois grupos (sobrevivência condicional após 1 ano, Log-rank p=0,321). Conclusão Nos pacientes com HP pré-tratados com sildenafila, a hemodinâmica pós-operatória inicial e o prognóstico são numericamente piores em pacientes sem HP, mas depois de 1 ano, a mortalidade em médio e longo prazo são semelhantes. (Arq Bras Cardiol. 2021; 116(2):219-226)

Abstract 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)

Does Propolis improve sperm quality in Paroxetine-Induced Sexual Dysfunction in male Wistar rats?

@#Propolis is a resinous product collected by honey bees for construction of hives. It is locally used as remedy for several ailments including various degrees of sexual dysfunctions. This study investigated the protective property of propolis in improving sperm quality in paroxetine-induced sexually impaired male Wistar rats. Forty-two male rats were divided into 7 groups of 6 rats each. Groups I (normal saline), II (administered paroxetine only for two weeks), III (Sildenafil), IV (low dose propolis), V (moderate dose propolis), VI (high dose propolis), and group VII (propolis+sildenafil). There was significant (p< 0.05) increase in sperm count in group VI, no significant (p>0.05) change in sperm count of group VII, but significant decrease in the other groups compared to control. There was significant (p< 0.05) reduction in sperm motility of rats in groups II, III, and IV, compared to significant (p< 0.05) increase in sperm motility of rats in groups VI and VII, but there was no significant (p>0.05) change in group V. The total sperm abnormality in groups II, III and IV showed significant (p<0.05) increase, while there was significant (p<0.05) reduction in sperm abnormality of groups VI and VII compared to control, and no significant (p>0.05) difference seen in group V. The plasma testosterone levels were significantly (p<0.05) reduced in groups II, III and IV, compared to significant (p< 0.05) increase in plasma testosterone level in groups VI and VII, but no significant (p> 0.05) difference in plasma testosterone in group V. The results indicate that high doses of propolis caused significant increase in plasma testosterone, and there was improvement in sperm count and motility as was obtained by the analysis of seminal fluid (SFA).

The safety, efficacy and pharmaceutical quality of male enhancement nutraceuticals bought online: Truth versus claim / 中西医结合学报

OBJECTIVE@#Nutraceutical products are widely used for their claimed therapeutic benefits. However, falsified or adulterated nutraceuticals present a major health threat to consumers. This study investigates the pharmaceutical quality, safety and anti-inflammatory effects of six male enhancement nutraceuticals that claim to be 100% natural.@*METHODS@#Three batches of six male enhancement products were tested to detect the presence and levels of adulterants via high-performance liquid chromatography (HPLC). The pharmaceutical quality of the selected nutraceuticals was tested with near infrared spectroscopy (NIR) and SeDeM. The cytotoxic effects of these products on HepG2 cells were determined through cell proliferation (XTT) and lactate dehydrogenase (LDH) cytotoxicity assays. Lastly, the in vitro inflammatory effects of these products were investigated using murine J774 macrophages through cytokine release analysis.@*RESULTS@#HPLC analysis detected the presence of sildenafil citrate, a vasodilator, and the active ingredient in Viagra and Revatio, in all batches of the products we analyzed. Amount of sildenafil citrate ranged from 0.45 mg to 51.85 mg among different batches. NIR assessment showed inter- and intra-batch heterogeneity in product composition. Results of the XTT and LDH assays showed significant cytotoxic effects of the analyzed products. XTT analysis revealed that the viability of HepG2 treated with tested products varied from 27.57% to 41.43%. Interestingly, the male enhancement products also showed anti-inflammatory effects.@*CONCLUSION@#Despite their labeling as 100% natural, all products tested in this study contained levels of sildenafil citrate, which was not reported on the packaging. There was a lack of pharmaceutical uniformity among products of the same batch and across different batches. Additionally, the products we tested had cytotoxic effects. These study findings highlight the adulteration, poor quality and hazard of these nutraceuticals. Therefore, strict regulation of these products and standardization of the definition of nutraceuticals are urgently needed. Further, these falsely advertised products should be withdrawn from the market due to potential adverse effects on the health of their consumers.

Role of endometrial thickness in natural and stimulated cycles in infertility

Background: The endometrium plays an important role in infertility. The growth of endometrium depends on serum oestradiol level and blood flow to the uterus. A thin endometrium is defined as a lining of less than 7 mm which is associated with infertility. The endometrium is best seen on Transvaginal scan (TVS). The purpose of this study was to evaluate the role of endometrial thickness and its outcome in natural and stimulated cycles in infertile women.Methods: This prospective cohort study was conducted from June 2018 to May 2019 in LLRM Medical College Meerut, Uttar Pradesh, India. Total 150 infertile women of age less than 35 years presented with either primary or secondary infertility were enrolled. Each patient was undergoing transvaginal scan (TVS) to measure endometrial thickness follicular monitoring.Results: The endometrial thickness and pregnancy rate was higher in letrozole induced group as compared to clomiphene with estradiol valerate and clomiphene with sildenafil citrate induced group.Conclusions: Letrozole had better effect on endometrial thickness and pregnancy rate as compared to clomiphene citrate with estradiol valerate and clomiphene citrate with sildenafil citrate.

Uso de treprostinil sistémico en una paciente con hipertensión pulmonar grave, sin respuesta a la máxima terapia disponible / Use of treprostinil in a patient with a severe pulmonary arterial hypertension no responding to the maximal therapy available

En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.

In high risk Pulmonary Arterial Hypertension (PAH) patients with functional class (FC) IV, specific therapy must be combined and must include systemic prostacyclin (PGI2), meanwhile they are enlisted for double lung transplant (DLT). In Chilean Public Health System, nebulized Iloprost is the only PGI2 available to combine with Sildenafil and either Ambrisentan or Bosentan as endothelin receptor antagonist. This association is not enough for severe cases with right ventricular (RV) dysfunction. The first case from the National Institute of Thorax as a referral center is presented now in a 24 years-old lady treated with treprostinil. She has severe PAH with DLT indication. Treprostinil is a PGI2 analog, for subcutaneous use in a dose from 1 to 40 ng/kg/min. She was extremely sick, with FC IV, she walked < 300 m at 6 min walking test (6 MWT), presented pericardial effusion and severe RV dysfunction, with TAPSE (echocardiography index for RV dysfunction)=13 cm/s, ProBNP > 2,500 pg/ml. Six months after being at intensive care unit with triple therapy (Sildenafil, ambrisentan and nebulized Iloprost) plus oxygen, diuretics and milrinone, she was finally discharged after receiving a 3 weeks treprostinil course. She came back to work two months later and her condition was more stable: FC III, she walked > 440 m at 6MWT, with a significant improvement in RV function with TAPSE = 19. Although ProBNP decreased to 1,491pg/ml, it was still high, pointing out the progressive nature of her disease. However, she met a better clinical condition which allows her to reach a much better quality of life from a personal, familial and social point of view.

A retrospective interventional study for evaluation of efficacy and safety of sildenafil citrate in improving intrauterine growth restriction and oligohydramnios using ultrasound Doppler velocimetry

Background: Intrauterine growth restriction (IUGR) is one of the major reasons for neonatal morbidity and mortality. Oligohydramnios is a common finding in IUGR. In majority of these cases diminished utero-placental blood flow is observed. However, in spite of this understanding and identification of high-risk patients, the management options are limited. Sildenafil citrate, a phosphodiesterase type-5 inhibitor improves utero-placental perfusion.Methods: We present a retrospective interventional study involving 50 adult pregnant women diagnosed with early-onset IUGR (n=38) and oligohydramnios (n=12). Vaginal sildenafil citrate 25 mg t.i.d. was started from the day of diagnosis till delivery. Primary efficacy endpoints included changes in Doppler parameters i.e., amniotic fluid index (AFI), uterine artery (UA)- pulsatility index (PI), resistance index (RI) and systolic diastolic ratio (S/D ratio). Secondary endpoints included live birth, birth weight, Apgar score at birth, neonatal survival to hospital discharge and adverse maternal side effects.Results: There was a statistically significant improvement in UA-PI, RI and S/D ratios (p<0.0001) in all cases. In oligohydramnios cases, treatment showed a statistical significant increase in AFI score (2.86±1.33 cm). The mean birth weight on delivery was 2200 gm with good Apgar scores. No major adverse effects were reported by women using sildenafil citrate vaginally.Conclusions: Sildenafil citrate, by increasing utero-placental perfusion, improves uterine artery Doppler patterns, AFI, fetal weight and overall better neonatal survival rates by reducing neonatal morbidity and mortality. Sildenafil citrate may hold a promising treatment strategy for management of IUGR and oligohydramnios.

The role of sildenafil citrate in the treatment of fetal growth restriction: a randomized controlled trial

Background: This study was aimed to evaluate the effect of sildenafil citrate on Doppler velocity indices in patients with fetal growth restriction (FGR) associated with impaired placental circulation.Methods: A double-blinded, parallel group randomized clinical trial (clinicaltrials.gov NCT02590536) was conducted in Ain Shams Maternity Hospital, in the period between October 2015 and June 2017. Ninety pregnant women with documented intrauterine growth retardation at 24-37 weeks of gestation were randomized to either sildenafil citrate 25 mg orally every 8 hours or placebo visually-identical placebo tablets with the same regimen. The primary outcome of the study was the change in umbilical artery and fetal middle cerebral artery indices.Results: There was a significant improvement in umbilical and middle cerebral artery indices after sildenafil administration p<0.001. Present study observed that, sildenafil group, in comparison to placebo, has a significantly higher mean neonatal birth weight. 1783±241g vs 1570±455g (p<0.001). There was a significantly higher mean gestational age at delivery in women in sildenafil group 35.3±1.67 weeks, whereas it was lower in the placebo group 33.5±1.7 weeks. The side effects as headache, palpitation and facial flushing were significantly higher in sildenafil group compared to placebo group.Conclusions: The use sildenafil citrate in pregnancies with fetal growth restriction (FGR) improved the feto-placental Doppler indices (pulsatility index of umbilical artery and middle cerebral artery) and improved neonatal outcomes.

Transient global amnesia associated with sildenafil use: report of one case / Amnesia global transitoria asociada al uso de sildenafil: informe de un caso

ABSTRACT A 69 years old male with erectile dysfunction lasting 2 years, took 50 mg of sildenafil for having sex with his wife at about 6 o'clock in the morning. One hour later his wife detected that he had an anterograde memory impairment: this was interpreted as a confusional state. The neurological examination suggested a transient global amnesia (TGA). EEG and cerebral magnetic resonance imaging were non-informative and memory deficits resolved within 24 h. Therefore, a TGA was diagnosed. Since no other trigger was detectable, sildenafil was deemed responsible for its occurrence,

Se reporta el caso de un individuo de sexo masculino de 69 años con disfunción eréctil, que ingiere 50 mg de sildenafil con objetivo de facilitar el mantener relaciones sexuales con su esposa. Una hora después, su esposa nota que su marido presenta una alteración de su memoria anterógrada, lo que fue interpretado como un estado confusional. Evaluado clínicamente su examen neurológico es sugerente de una amnesia transitoria anterógrada. El EEG y las imágenes por resonancia magnética no muestran hallazgos significativos y el déficit de memoria remite dentro de 24 h. en vista de su evolución, se diagnostica una amnesia global transitoria. Como no se identifica otro gatillante, se consideró que el cuadro fue causado por sildenafil..

Estudio de costo-efectividad en hipertensión arterial pulmonar Grupo 1: riociguat y sildenafil / Study of cost-effectiveness in pulmonary arterial hypertension Group 1: riociguat and sildenafil / Estudo de custo-efetividade na hipertensão arterial pulmonar Grupo 1: riociguat e sildenafil

Introducción. En los últimos años se han desarrollado nuevas terapias para el tratamiento de la hipertensión arterial pulmonar (HAP); sin embargo, la adopción de estas conlleva un aumento considerable de los costos por parte de las entidades promotoras de salud. Objetivo. Evaluar la costo-efectividad de riociguat versus sildenafil en monoterapia para pacientes con diagnóstico de HAP del Grupo 1 en las clases funcionales II y III. Materiales y métodos. Se diseñó un modelo de Márkov donde todos los individuos inician en clase funcional II con alguna de las dos terapias evaluadas en monoterapia y tienen como desenlaces principales la progresión a la clase funcional IV y la muerte. Se realizó un análisis probabilístico y determinístico de sensibilidad. Resultados. Se encontró una relación de costo-efectividad de riociguat frente a sildenafil de $529.213.933; sin embargo, en el umbral de aceptabilidad para Colombia este no es costo-efectivo.Conclusión. Se aconseja la implementación de sildenafil como medicamento de primera línea

Introduction: In recent years, new therapies have been developed for the treatment of pulmonary arterial hypertension (PAH), but with considerable increase in costs for health services. Objective: To assess the cost-effectiveness of riociguat versus sildenafil monotherapy for patients diagnosed with Group 1 PAH in functional classes II and III. Materials and methods: A model of Markov was designed. All the individuals in functional class II started one of the two drugs in monotherapy. The main outcomes were the progression to functional class IV or death. A probabilistic and deterministic sensitivity analysis was made. Results: A cost-effectiveness relationship of riociguat versus sildenafil of $ 529,213,933 was found. However, at the threshold of acceptability for Colombia, this is not cost-effective.Conclusion: The implementation of sildenafil as a first line medication is advised.

Introdução. Nos últimos anos, novas terapias foram desenvolvidas para o tratamento da hipertensão arterial pulmonar (HAP); a adoção destes leva a um aumento considerável de custos por entidades promotoras da saúde. Objetivo. Avaliar a relação custo-efetividade do tratamento com riociguat versus monoterapia com sildenafil em pacientes com diagnóstico de HAP do Grupo 1 nas classes funcionais II e III. Materiais e métodos. Foi desenhado um modelo de Markov onde todos os indivíduos iniciam na classe funcional II com uma das duas terapias avaliadas em monoterapia e têm como principais desfechos a progressão para classe funcional IV e morte. Uma análise de sensibilidade probabilística e determinística foi realizada. Resultados. Uma relação de custo-efetividade de riociguat ver-sus sildenafil de $ 529.213.933 foi encontrada; No entanto, no limiar de aceitabilidade para a Colômbia, isso não é rentável.Conclusão. Recomenda-se a implementação de sildenafil como medicamento de primeira linha

No Causal Link between Phosphodiesterase Type 5 Inhibition and Melanoma

PURPOSE: To examine the association between phosphodiesterase type 5 (PDE5) inhibitor use and melanoma by 1) conducting a systematic review of observational studies; and 2) determining if low PDE5A gene expression in human melanoma correlated with decreased overall survival. MATERIALS AND METHODS: A systematic search of observational studies examining the association between PDE5 inhibitor use and melanoma was performed through ClinicalTrials.gov, the Cochrane Library, EMBASE, PubMed, and Web of Science databases, and seven eligible studies were identified. PDE5A gene expression was analyzed with RNA sequencing data from 471 human melanoma samples obtained from The Cancer Genome Atlas. RESULTS: Four studies reported a positive association between PDE5 inhibitor use and melanoma, and three studies found no correlation. RNA sequencing data analysis revealed that under-expression of the PDE5A gene did not impact clinical outcomes in melanoma. CONCLUSIONS: There is currently no evidence to suggest that PDE5 inhibition in patients causes increased risk for melanoma. The few observational studies that demonstrated a positive association between PDE5 inhibitor use and melanoma often failed to account for major confounders. Nonetheless, the substantial evidence implicating PDE5 inhibition in the cyclic guanosine monophosphate (cGMP)-mediated melanoma pathway warrants further investigation in the clinical setting.

Hipertensión pulmonar asociada al virus de la inmunodeficiencia humana en pediatría: tratamiento con sildenafil. A propósito de un caso / Pulmonary hypertension associated with the human immunodeficiency virus in children: treatment with sildenafil. A case report

La hipertensión pulmonar asociada a la infección por virus de inmunodeficiencia humana es una enfermedad sumamente infrecuente en pediatría, por lo que requiere alta sospecha clínica para llegar a su diagnóstico. Su aparición es de pronóstico desfavorable, pero el diagnóstico precoz y el tratamiento específico pueden mejorar su evolución. Se presenta el caso clínico de un paciente de 15 años con diagnóstico de infección por virus de inmunodeficiencia humana de transmisión vertical, sin tratamiento antirretroviral, con tos y disnea de esfuerzo progresiva asociadas a signos de falla cardíaca derecha en el cual se diagnosticó hipertensión pulmonar grave. Luego de descartarse otras causas, se asumió la hipertensión pulmonar asociada a la infección por virus de inmunodeficiencia humana. Se realizó el tratamiento con sildenafil y presentó buena respuesta.

Pulmonary hypertension associated with human immunodeficiency virus infection is an extremely rare disease in pediatrics; it requires a high clinical suspicion to reach a diagnosis. Its appearance poses an unfavorable prognostic, but early diagnosis and specific treatment can improve outcomes. We report the clinical case of a fifteen-year-old patient diagnosed with human immunodeficiency virus infection of vertical transmission, without antiretroviral treatment, with cough and progressive exertional dyspnea, associated with signs of right heart failure in which severe pulmonary hypertension was diagnosed. After discarding other causes, it was assumed pulmonary hypertension associated with human immunodeficiency virus infection. Treatment was performed with sildenafil with good response.

Evaluation of prophylactic and therapeutic effects of sildenafil on acute radiation proctitis in rats

Abstract Purpose: To investigate the prophylactic and therapeutical effects of sildenafil in a model of acute radiation proctitis (ARP). Methods: All experimental procedures of this study was examined by histopathological, immunohistochemical and transmission electron microscopic analysis. Results: Our histopathological evaluations indicated significant increases in lesion severity, cryptic apsis, cryptitis, cryptic distortion, reactive atypia and infiltration depth of the control (proctitis) group. While the prophylaxis group and the treatment group had significantly lower scores. High-dose group showed similar results as prophylaxis group. Histopathological findings of the prophylaxis group was more significant than the treatment group. Immunoreactivities of IL-1β, FGF-2, TNF- α and HIF-1α increased in the control group especially in the epithelial and cryptic regions. On the contrary, sildenafil application caused significant decreases of inflammatory markers in all treatment groups, specifically better results in the prophylaxis group. Conclusion: The sildenafil has anti-inflammatory effects on ARP, as well as protective effects against ARP and the protective effect of sildenafil surpasses its therapeutic effect histopathologically.

Preoperative subcutaneous sildenafil injection increases random flap survival in rats

Abstract Purpose: To investigate the effect of subcutaneous sildenafil on random flap survival. Methods: Fourteen Wistar rats, which were divided in to two groups, were used for this experimental study. Rats in the sildenafil group received subcutaneous sildenafil injections daily for seven days before flap elevation. At the end of the treatment period, 9x3 cm dorsal skin flaps were elevated and reinserted back into their place in all of the animals. Necrotic and whole flaps areas were recorded on graph papers. Seven days after the flap elevation samples for histological examination were taken and angiographies were performed to visualize the flap vascularization. Results: The calculated average percentage of necrotic flap areas were 18.29% and 42.26% in the sildenafil and control group respectively.(p=0.0233). In selected angiography images, vessels were found to be more prominent in the sildenafil group. The average number of capillary formations under light microscopy was higher in the sildenafil group (p= 0.0286). Conclusion: The subdermal high dose sildenafil has a positive effect on flap survival.

A Case of a Visual Field Defect with Optical Coherence Tomography Changes after Sildenafil Citrate Overdose

PURPOSE: A case of a transient visual field defect and a change in spectral-domain optical coherence tomography (SD-OCT) after an overdose of sildenafil citrate is described. CASE SUMMARY: A 67-year-old male with no previous medical history presented with a bluish tinge and visual field defect in both eyes. He had consumed eight tablets of sildenafil citrate (800 mg) 3 days before the visit. His best-corrected visual acuity was 14/20 in the right eye and 20/20 in the left eye. No specific finding was noted on slit-lamp examination. Fundus examination and fundus photography revealed focal foveal hypopigmentation in both eyes. He underwent SD-OCT imaging with the Cirrus HD-OCT (Carl Zeiss Meditec, Oberkochen, Germany), and thickening of the ellipsoid zone and choroid was revealed by SD-OCT scans. He was advised not to take any more sildenafil citrate and was followed for 1 week after the first visit. Central scotomas of both eyes were revealed by a visual field test, and thickening of the ellipsoid zone and choroid remained. His eyes were re-evaluated 1 and 3 months after the first visit, and although the symptoms nearly disappeared, abnormalities in the visual field test and on SD-OCT remained, albeit with some degree of improvement. He revisited us 4 months after the first visit, at which time the visual field test and SD-OCT scans showed results within normal ranges. CONCLUSIONS: Sildenafil citrate overdose can result in a color anomaly (bluish tinge), visual field defects, and thickening of the ellipsoid zone and choroid on SD-OCT scans.

Efeito redutor do Viagra (Citrato de Sildenafila) sobre a frequência de tumores epiteliais induzidos pela Doxorrubicina em Drosophila melanogaster / Viagra (Sildenafil citrate) reduced the frequency of epithelial tumors induced by doxorubicin in Drosophila melanogaster

O consumo de medicamentos está entre as principais causas de desenvolvimento do câncer. Faz-se, então, necessário investigar os efeitos de drogas amplamente consumidas no mundo, como é o caso do Viagra® (Citrato de Sildenafila - CS). O objetivo do presente estudo foi avaliar o efeito modulador do CS na carcinogênese induzida pela Doxorrubicina (DXR), por meio do Teste para Detecção de Clones de Tumores Epiteliais em Drosophila melanogaster. Foram utilizadas duas linhagens mutantes do organismo teste (wts e mwh) no intuito de obter larvas heterozigotas wts +/+ mwh, que foram tratadas com três concentrações de CS: 10 mM, 20 mM e 40 mM, isoladamente e em associação com a DXR. Constatou-se que o CS não exerceu efeito carcinogênico nas concentrações isoladamente avaliadas. Quando em associação com a DXR, propiciou efeito redutor sobre as frequências dos tumores induzidos por ela, conferindo papel anticarcinogênico ao CS. Acredita-se que este efeito seja devido a uma supra-regulação da via de apoptose dependente de caspase e ao impedimento do crescimento celular promovido pelo fármaco utilizado. As evidências obtidas comprovam o efeito protetor tumoral atribuído ao Viagra® nas condições experimentais propostas.(AU)

Drug consumption is among the leading causes of cancer development. Therefore, it is necessary to investigate the effects of drugs widely consumed in the world, as the case of Viagra® (Sildenafil Citrate - SC). The objective of the study was to evaluate the modulatory effect of SC on the carcinogenicity induced by Doxorubicin (DXR) by the Test for Detection of Epithelial Tumor Clones in Drosophila melanogaster. Two mutant lines (wts and mwh) were used in order to obtain heterozygous wts+/+mwh larvae, which were treated with three concentrations of CS: 10 mM, 20 mM and 40 mM, alone and in combination with doxorubicin. We verified that SC had no carcinogenic effect at the concentrations evaluated alone. In association with DXR, it was provided a reduced effect of tumor-induced, conferring anticarcinogenic role to SC. It is believed that this effect is due to up-regulation of the caspase-dependent apoptosis and the impediment of cell growth promoted by the drug used. Evidence obtained confirms the tumor protective effect attributed to Viagra® under experimental conditions. (AU)