Sildenafil como tratamiento de la restricción de crecimiento intrauterino, revisión sistemática de la literatura / Sildenafil as a treatment for blood restriction fetal growth, systematic review of the literature

INTRODUCCIÓN Y OBJETIVO: La restricción del crecimiento intrauterino (RCIU), expresión insuficiente del potencial genético de crecimiento fetal, complica el 5-8% de los embarazos, con unas altas tasas de morbimortalidad perinatal. De origen multifactorial, puede ser causada por patologías maternas, fetales o placentarias. El tratamiento es limitado, optándose por un seguimiento riguroso con eventual interrupción del embarazo según la evolución. Se han utilizado diferentes estrategias terapéuticas para su prevención y manejo, surgiendo el citrato de sildenafil (CS), inhibidor de la fosfodiesterasa tipo 5, como fármaco que podría mejorar el flujo sanguíneo uteroplacentario y ofrecer mejores resultados perinatales en fetos con RCIU. Se propone realizar una revisión de la literatura disponible en relación al CS como tratamiento del RCIU. MÉTODO: Se realizó una búsqueda de literatura en inglés y español. De 105 artículos seleccionados, se excluyeron 94. La información obtenida fue clasificada y utilizada como soporte para la realización de esta revisión, siguiendo el modelo PRISMA. RESULTADOS: Se encontraron 11 estudios que contrastan el uso de placebo y CS en pacientes con RCIU. Respecto al aumento de peso al nacimiento, solo dos estudios demostraron evidencia significativa. Se reportaron 40 casos de muerte fetal/neonatal asociada al tratamiento con CS. CONCLUSIONES: No se encontró evidencia suficiente que justifique el uso sistemático de CS en casos de RCIU. Aún es necesario realizar estudios con muestras de mayor tamaño y posterior metaanálisis para confirmar el beneficio farmacológico en cuanto al aumento de peso de nacimiento, la prolongación del embarazo y los posibles efectos adversos a largo plazo.

INTRODUCTION AND OBJECTIVE: Intrauterine growth restriction (IUGR) is an insufficient expression of the genetic potential for fetal growth, complicates 5-8% of pregnancies and represents high rates of perinatal morbidity and mortality. Of multifactorial origin, it can be caused by pathologies at the maternal, fetal or placental level. The treatment is limited, opting for a rigorous follow-up with eventual interruption of the pregnancy according to evolution. Different therapeutic strategies have been used for its prevention and management, emerging sildenafil citrate (CS), inhibitor of phosphodiesterase type 5, as a drug that could improve the uteroplacental blood flow and offer better perinatal results in fetuses with IUGR. A review of the available literature on CS as a treatment for IUGR is proposed. METHOD: A search was conducted for literature in English and Spanish. Out of 105 selected articles, 94 were excluded. The information obtained was classified and used as support for this review, following the PRISMA model. RESULTS: We found 11 studies that contrast the use of placebo and CS in patients with IGR. Regarding birth weight gain, only two studies showed significant evidence. Forty cases of fetal/neonatal death associated with CS treatment were reported. CONCLUSIONS: Not enough evidence was found to justify the routine use of CS in IUGR cases. Studies with larger samples and subsequent meta-analysis are still necessary to confirm the benefit of this drug in terms of birth weight gain, prolongation of pregnancy and possible long-term adverse effects.

Ressecção anterior do reto vs prostatectomia radical. Existem diferenças na reabilitação sexual? / Anterior resection of the rectum vs radical prostatectomy. Are there any differences in sexual rehabilitation?

RESUMO Objetivo: O objetivo deste estudo foi avaliar o impacto da reabilitação peniana na recuperação da função erétil em pacientes submetidos a ressecção anterior do reto (RAR) ou a prostatectomia radical (PR), comparando os resultados entre esses dois grupos. Materiais e Métodos: Foi realizado estudo de coorte retrospetivo unicêntrico, em pacientes avaliados na nossa consulta multidisciplinar de oncosexologia, entre janeiro de 2015 e janeiro de 2018, submetidos a PR ou RAR (homens) com disfunção sexual. Avaliamos as características oncológicas dos pacientes, idade, estado civil, tipo de disfunção sexual, Índice Internacional de Função Erétil (IIEF-5) na primeira e última consulta e terapêutica utilizada. Foi realizada análise estatística. Resultados: Foram incluídos 55 pacientes, 60% (33) realizaram RAR e 40% (22) PR. Em relação à disfunção sexual após a cirurgia, a disfunção erétil (DE) foi encontrada na maioria dos pacientes (> 95%). Na pontuação inicial do IIEF-5, os pacientes com RAR e PR apresentaram, com maior frequência, DE moderada ou grave (escore 5-11), em 78,8% e 59,1% dos casos, respetivamente. Ao reavaliar a pontuação do IIEF-5 de cada paciente durante o acompanhamento, verificou-se melhoria em 69,7% dos pacientes com RAR e 72,7% dos pacientes com PR (p = 0,81). Quanto à abordagem terapêutica, 84,8% dos pacientes com RAR foram medicados com inibidores da fosfodiesterase-5 (PDE5I) exclusivamente e 3% com injeção de Alprostadil. Os pacientes com PR foram medicados com PDE5I em 63,6% e com injeção de Alprostadil em 31,8% (p <0,05). Conclusões: Apesar das diferenças técnicas destas cirurgias, do ponto de vista sexual, os pacientes se beneficiaram com a reabilitação peniana.

ABSTRACT Purpose: The aim of this study was to evaluate the impact of penile rehabilitation in restoring erectile function in patients submitted to anterior resection of the rectum (ARR) or radical prostatectomy (RP), comparing the results between these two groups. Materials and Methods: We performed a unicenter retrospective cohort study, on patients evaluated in our multidisciplinary oncosexology consultation, between January 2015 and January 2018, submitted to RP or ARR (males) and presenting sexual dysfunction. We evaluate the patient and oncologic characteristics, the type of sexual dysfunction, marital status, assessed the International Index of Erectile Function (IIEF-5) on the first and last consultation and the therapeutic approach. A statistical analysis was performed. Results: A total of 55 patients were included, 60% (33) performed ARR and 40% (22) RP. Regarding the sexual dysfunction after surgery, erectile dysfunction (ED) was found in the majority of patients (>95%). On the initial IIEF-5 scoring, ARR and RP patients had, most frequently, severe or moderate ED (score 5-11), 78.8% and 59.1% respectively. When reassessed the IIEF-5 scoring of each patient during follow-up, there was an improvement in 69.7% of ARR patients and 72.7% of RP patients (p=0.81). Regarding the therapeutic approach, 84.8% of ARR patients used phosphodiesterase-5 inhibitors (PDE5I) exclusively, 3% used Alprostadil injection, while RP patients used 63.6% and 31.8%, respectively (p<0.05). Conclusions: Despite the technical differences of these surgeries, from the sexual point of view these patients benefit with a penile rehabilitation.

Medida computadorizada da evolução da área cicatricial tratada com ultrassom terapêutico e citrato de sildenafila / Computerized measurement of the evolution of cicatricial area treated with ultrasound and sildenafil citrate

Objetivou-se comparar a evolução da cicatrização de feridas cirúrgicas com cinco protocolos de tratamento através de análise planimétrica. Grupos de 12 ratos Wistar, foram alocados em cinco estudos experimentais: A- controle negativo; B- ferida cirúrgica, tratada com ultrassom terapêutico (UST) desligado ; C- ferida tratada somente com citrato de sildenafila ; D- ferida tratada com citrato de sildenafila e UST e grupo E-ferida tratada somente com UST. A evolução cicatricial foi acompanhada diariamente e avaliada por imagem fotográfica computadorizada aos sete, 14 e 21 dias. A aplicação do UST pulsado, com doses 1MHZ e 0,4Wcm2 reduziu o tempo de cicatrização epitelial em condições experimentais, favorecendo precocemente a reparação tecidual com efeitos qualitativos superiores ao tratamento com citrato de sildenafila (CS). A mensuração computacional para evolução da cicatrização de ferida dérmica mostrou-se um recurso de fácil aplicação sendo de baixo custo e eficiente para a aplicabilidade na rotina médica veterinária.

This study aimed at comparing the evolution of healing of surgical wounds with five treatment protocols through planimetric measurement. Groups of 12 Wistar rats were allocated in five experimental studies: A ­ negative control; B ­ surgical wound treated with therapeutic ultrasound turned off; C ­ surgical wound treated with sildenafil citrate; D ­ wound treated with sildenafil citrate and therapeutic ultrasound; and group E ­ wound treated only with therapeutic ultrasound. The healing progress was monitored daily and assessed by computed photographic image at seven, 14 and 21 days. It was concluded that the application of pulsated therapeutic ultrasound on surgical wounds at 1 MHz and 0.4Wcm2 doses reduces the epithelial healing time in experimental conditions, favoring the early repair of tissue with qualitative effects superior than the ones found in the treatment with sildenafil citrate (SC). The computational measurement for the evolution of the dermal wound healing proved to be an easy-to-apply resource, with a low cost and great efficiency for the applicability in the veterinary medical routine.

Adding a vacuum erection device to regular use of Tadalafil improves penile rehabilitation after posterior urethroplasty / 亚洲男科学杂志(英文版)

This study aimed to evaluate whether adding a vacuum erection device (VED) to regular use of Tadalafil could achieve better penile rehabilitation following posterior urethroplasty for pelvic fracture-related urethral injury (PFUI). Altogether, 78 PFUI patients with erectile dysfunction (ED) after primary posterior urethroplasty were enrolled and divided into two treatment groups: VED combined with Tadalafil (Group 1, n = 36) and Tadalafil only (Group 2, n = 42). Changes in penile length, testosterone level, International Index of Erectile Function-5 (IIEF-5) questionnaire, Quality of Erection Questionnaire (QEQ), and nocturnal penile tumescence (NPT) testing were used to assess erectile function before and after 6 months of ED treatment. Results showed that the addition of VED to regular use of Tadalafil preserved more penile length statistically (0.4 ± 0.9 vs -0.8 ± 0.7 cm, P < 0.01). IIEF-5 score and QEQ score in Group 1 were higher than Group 2 (both P < 0.05). After treatment, 21/36 (58.3%) Group 1 patients and 19/42 (45.2%) Group 2 patients could complete vaginal penetration. Group 1 patients also had markedly improved testosterone levels (P = 0.01). Unexpectedly, there was no significant difference in NPT testing between two therapies. For PFUI patients with ED after posterior urethroplasty, the addition of VED to regular use of Tadalafil could significantly improve their conditions - improving erection and increasing penile length - thus increasing patient satisfaction and confidence in penile rehabilitation.

The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction / 亚洲男科学杂志(英文版)

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg-1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg-1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg-1 LIMK2i and 20.0 mg kg-1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

Evaluation of the long-term safety and effectiveness of tadalafil once daily in Chinese men with erectile dysfunction: interim results of a multicenter, randomized, open-label trial / 亚洲男科学杂志(英文版)

Once-daily tadalafil administration has been well established; however, studies about tadalafil once-daily treatment in the Chinese population are lacking. In this phase 4, postmarketing study, we ascertained the long-term safety and effectiveness of tadalafil 2.5 mg and 5.0 mg once daily in Chinese men with erectile dysfunction (n = 635). The primary endpoint of the study was safety at 12 months as assessed by the proportion of patients experiencing at least one treatment-emergent adverse event (serious or nonserious). The secondary endpoints included safety and effectiveness, measured by the International Index of Erectile Function-Erectile Function (IIEF-EF) domain scores. Similar adverse events to the known safety profile of tadalafil, such as nasopharyngitis, upper respiratory tract infection, headache, and dizziness, were detected. No new cardiovascular safety concerns were observed. After 3 months of treatment, significant increases in IIEF-EF domain scores were detected for both 2.5-mg (least squares [LS] mean change: 6.3; 95% confidence interval [CI]: 5.4-7.1; P < 0.001) and 5.0-mg (LS mean change: 7.4; 95% CI: 6.8-7.9; P < 0.001) tadalafil doses, and significance was maintained up to 12 months. In addition, approximately 40% of patients regained normal erectile function (IIEF-EF ≥26) following 1 year of tadalafil once-daily treatment. The findings in this study provide evidence for the extended effectiveness and tolerability of tadalafil, demonstrating no new safety concerns, in a Chinese population and make once-daily tadalafil administration a viable option for improving sexual performance and satisfaction in Chinese men with erectile dysfunction.

Prevalence of erectile dysfunction oral drugs use in a city of southern Brazil / Prevalência do uso de drogas orais para disfunção erétil em uma cidade do sul do Brasil

Abstract The last decade has seen a breakthrough in the treatment of erectile dysfunction (ED) with the advent of phosphodiesterase-5 inhibitors. There are few population-based observational studies on the prevalence of use of these drugs. We conducted a cross-sectional population-based study in the city of Pelotas (Brazil). Our sample comprised 1,082 men aged 20 years or older who answered a confidential and self-administered questionnaire. Prevalence of EDD use was 5% (IC95% = 4%;7%). ED and advanced age were strongly associated with a higher prevalence of EDD use. ED prevalence in men who used EDD was 68%, which was much higher than the one found in the entire sample (27%). The use of EDD was more frequently reported among separated men, respondents with higher level of education and those without ED. A high proportion of respondents (68%) did not seek medical advice on the use of EDD. Sildenafil was the most commonly used drug (38%) but non-regulated and non-evidence-based drugs were also frequently used (14%). Prevalence of EDD use is higher among individuals with ED, opposing to the notion of recreational use of EDD.

Resumo Na última década houve um grande avanço no tratamento da disfunção erétil (DE), com o advento dos inibidores da fosfodiesterase-5. Existem poucos trabalhos sobre a prevalência de uso destas drogas. Foi realizado um estudo transversal de base populacional na cidade de Pelotas. A amostra foi composta por 1.082 homens com 20 anos ou mais de idade que responderam um questionário confidencial e auto-aplicado. A prevalência do uso de medicamentos estimulantes da ereção (MEE) foi de 5%(IC95% = 4%-7%). Idade avançada e DE foram fortemente associados a uma maior prevalência de uso de MEE. A prevalência foi também maior em indivíduos com ensino superior e aqueles separados. A prevalência de DE em homens que usaram MEE foi de 68%, sendo maior do que a prevalência encontrada em toda a amostra (27%). A maioria dos indivíduos não teve aconselhamento médico para o uso de MEE (68%). Sildenafil foi a droga mais utilizada (38%), seguida por aquelas não regulamentadas (14%). A prevalência do uso de MEE é maior em indivíduos com disfunção erétil, opondo-se à noção de uso "recreativo" de EDD.

Tadalafil: protective action against the development of multiple organ failure syndrome

Abstract Introduction: Multiple organ failure syndrome (MOFS) is a pathology associated to unspecified and severe trauma, characterized by elevated morbidity and mortality. The complex inflammatory MOFS-related reactions generate important ischemia-reperfusion responses in the induction of this syndrome. Nitric oxide elevation, through the activation of cyclic guanosine monophosphate (cGMP), has the potential of counteracting the typical systemic vasoconstriction, and platelet-induced hypercoagulation. Tadalafil would possibly act protectively by reducing cGMP degradation with consequent diffuse vasodilatation, besides reduction of platelet-induced hypercoagulation, thus, preventing multiple organ failure syndrome development. Methods: The experimental protocol was previously approved by an institution animal research committee. Experimental MOFS was induced through the stereotaxic micro-neurosurgical bilateral anterior hypothalamic lesions model. Groups of 10 Wistar rats were divided into: a) Non-operated control; b) Operated control group; c) 2 hours after tadalafil-treated operated group; d) 4 hours after tadalafil-treated operated group; e) 8 hours after post-treated operated group. The animals were sacrificed 24 hours after the neurosurgical procedure and submitted to histopathologic examination of five organs: brain, lungs, stomach, kidneys, and liver. Results: The electrolytic hypothalamic lesions resulted in a full picture of MOFS with disseminated multiple-organs lesions, provoked primarily by diffusely spread micro-thrombi. The treatment with tadalafil 2 hours after the micro-neurosurgical lesions reduced the experimental MOFS lesions development, in a highly significant level (P<0.01) of 58.75%. The treatment with tadalafil, 4 hours after the micro-neurosurgically-induced MOFS lesions, also reduced in 49.71%, in a highly significant level (P<0.01). Finally, the treatment with tadalafil 8 hours after the neurosurgical procedure resulted in a statistically significant reduction of 30.50% (P<0.05) of the experimentally-induced MOFS gravity scores. Conclusion: The phosphodiesterase 5 inhibitor, tadalafil, in the doses and timing utilized, showed to protect against the experimentally-induced MOFS.

The effect of tadalafil therapy on kidney damage caused by sepsis in a polymicrobial septic model induced in rats: a biochemical and histopathological study

ABSTRACT Introduction Sepsis is an inflammatory reaction to bacteria involving the whole body and is a significant cause of mortality and economic costs. The purpose of this research was to determine whether tadalafil exhibits a preventive effect on sepsis in a septic model induced in rats with cecal ligation and puncture (CLP). Materials and Methods Rats were randomly separated into groups, 10 rats in each: (i) a sham (control) group, (ii) an untreated sepsis group, (iii) a sepsis group treated with 5mg/kg tadalafil and (iv) a sepsis group treated with 10mg/kg tadalafil. A polymicrobial sepsis model was induced in rats using CLP. Rats were sacrificed after 16h, and blood and kidney tissues were collected for biochemical and histopathological study. Results Levels of the inflammatory parameter IL-6 decreased significantly in the sepsis groups receiving tadalafil in comparison with the untreated sepsis group (p<0.05). In terms of histopathology, inflammation scores investigated in kidney tissues decreased significantly in the sepsis groups receiving tadalafil compared to the untreated sepsis group (p<0.05). In addition, levels of creatinine and cystatin C measured in septic rats receiving tadalafil were lower by a clear degree than in septic rats (p<0.05). Conclusion In this study, tadalafil exhibited a preventive effect for sepsis-related damage by suppressing inflammation in serum and kidney tissue of septic rats in a polymicrobial sepsis model induced with CLP.

Current status of penile rehabilitation after radical prostatectomy

Although disease-free survival remains the primary goal of prostate cancer treatment, erectile dysfunction (ED) remains a common complication that affects the quality of life. Even though several preventive and therapeutic strategies are available for ED after radical prostatectomy (RP), no specific recommendations have been made on the optimal rehabilitation or treatment strategy. Several treatment options are available, including phosphodiesterase-5 inhibitors, vacuum erection devices, intracavernosal or intraurethral prostaglandin injections, and penile prostheses. Urologists must consider more effective ways to establish optimal treatments for ED after RP. ED is an important issue among patients with prostate cancer, and many patients hope for early ED recovery after surgery. This review highlights the currently available treatment options for ED after RP and discusses the limitations of each.

Esclerose sistêmica e fenômeno de Raynaud: manejo terapêutico / Systemic sclerosis and Raynaud's phenomenon: therapeutic management

O fenômeno de Raynaud (FRy) caracteriza- se por episódios reversíveis de vasoespasmos de extremidades, que ocorrem usualmente após estresse ou exposição ao frio. O FRy pode ser primário ou secundário a uma série de condições, principalmente a doenças do espectro da esclerose sistêmica (ES). Na ES o FRy costuma ser mais grave, e lesões isquêmicas de extremidades são frequentes. Nos últimos anos, avanços no estudo da fisiopatologia do FRy e da doença vascular na ES propiciaram o surgimento de novas opções terapêuticas para esta manifestação. Os bloqueadores de canal de cálcio devem ser utilizados como tratamento de primeira escolha para o FRy. Novas drogas, como os inibidores da fosfodiesterase V e os prostanoides, podem ser utilizadas em pacientes com FRy grave, e a bosentana (antagonista do receptor da endotelina-1) é indicada para a prevenção de úlceras digitais recorrentes.

Raynaud?s phenomenon (RP) is characterized by episodic vasospasm of the extremities, usually in response to stress or cold exposure. It can be primary or secondary to several conditions, especially systemic sclerosis-related diseases. In systemic sclerosis (SSc), RP is usually more severe and digital ischemic lesions are a frequent problem. In recent years, advances in the understanding of the pathophysiology of RP and of SSc vasculopathy led to the development of new therapeutic options for this condition. Calcium-channel blockers are the first choice for the treatment of RP. New drugs, including phosphodiesterase type V inhibitors and prostanoids, can be used for severe RP, and bosentan (endothelin-1 receptor antagonist) for prevention of recurrent digital ulcers.

Sildenafil improves six-minute walk distance in chronic obstructive pulmonary disease: A randomised, double-blind, placebo-controlled trial.

Background. Sildenafil has been found to improve exercise capacity and haemodynamic parameters in patients with various pulmonary disorders. This study was undertaken to evaluate its efficacy in severe chronic obstructive pulmonary disease (COPD). Methods. In this double-blind, randomised, placebo-controlled study, 37 patients with severe COPD received either sildenafil or placebo for 12 weeks. Distance covered in six-minute walk test (6MWD) was taken as primary end-point. Pulmonary artery pressure (PAP) was measured as secondary end point. Results. Thirty-three patients (15 in sildenafil arm and 18 in placebo arm) completed the study. Non-parametric tests were used for comparison. There was significant increase in 6MWD from baseline after three months of follow-up in sildenafil users (median change in distance covered in six-minute walk test (Δ6MWD)=190m) as compared to placebo users (Δ6MWD=0m, p< 0.05). The PAP decreased significantly (χ2=14.94, p<0.05) in sildenafil group after three months, while it did not change significantly among placebo group (χ 2=3.84, p>0.05). Conclusion. Sildenafil improved 6MWD and PAP in patients with severe COPD. This trial has been registered with Indian Council of Medical Research (ICMR) Trial Registry. [CTRI Registry Number: CTRI/ 2009/091/000017]