Spray-dried co-amorphous Tadalafil ternary mixtures: a promising platform towards the enhancement of solubility and bioavailability

Abstract Tadalafil (Tad) is a poorly water-soluble drug (BCS class II) that is used for the treatment of erectile dysfunction. An enhancement of aqueous solubility is vital to accelerate its onset of action and subsequently enhance its therapeutic effect. Binary and ternary mixtures of Tad with different amino acids (histidine, valine, alanine or arginine) and other excipients (mannitol and SLS) were prepared and then spray dried. The solubilizing efficiency and physicochemical characterization of all spray dried mixtures of Tad were studied. The optimum formulation was investigated in male rats to determine the onset of erection and the pharmacokinetic parameters of Tad. In general terms, the drug solubility of spray-dried formulae was enhanced compared to the crystalline form of the drug as a result of the formation of co-amorphous structures. The final result revealed that the Tad/alanine/mannitol spray-dried mixture (F10) showed the highest solubility and an improvement in its physicochemical characteristics. Moreover, F10 showed a significantly faster erection in rats with an improvement in Tad pharmacokinetic parameters when compared to the crystalline drug. Thus, F10 is selected as a promising formulation that successfully enhanced the bioavailability and the therapeutic efficacy of Tad.

Morphological and molecular analysis of apoptosis in the corpus cavernosum of rats submitted to a chronic alcoholism model

Abstract Purpose To evaluate the effect of chronic alcoholism on morphometry and apoptosis mechanism and correlate with miRNA-21 expression in the corpus cavernosum of rats. Methods Twenty-four rats were divided into two experimental groups: Control (C) and Alcoholic group (A). After two weeks of an adaptive phase, rats from group A received only ethanol solution (20%) during 7 weeks. The morphometric and caspase-3 immunohistochemistry analysis were performed in the corpus cavernosum. The miRNA-21 expression was analyzed in blood and cavernous tissue. Results Chronic ethanol consumption decreased cavernosal smooth muscle area of alcoholic rats. The protein expression of caspase 3 in the corpus cavernosum was higher in A compared to the C group. There was no difference in the expression of miRNA-21 in serum and cavernous tissue between the groups. Conclusion Chronic ethanol consumption reduced smooth muscle area and increased caspase 3 in the corpus cavernosum of rats, without altered serum and cavernosal miR-21 gene expression.

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.

The relationship between histological prostatitis and lower urinary tract symptoms and sexual function

ABSTRACT This prospective analysis assessed the effect of histological prostatitis on lower urinary tract functions and sexual function. The patients were separated into two groups as histologically observed prostatitis (Group A) and no prostatitis (Group B) according to the biopsy outcomes. International prostate symptom score, international index of erectile function-5 scores, maximal and average flow rate, and residual urine volumes were compared statistically between groups. There was no significant difference (P>0.05) in baseline age (t=0.64), body mass index value (t=0.51), prostate volume (t=0.87), prostate-specific antigen levels (t=0.43), maximal (t=0.84) and average flow rate (t=0.59), and post-void residual urine volume (t=0.71). Mean international prostate symptom score in patients with prostatitis was numerically but not significantly higher than that in those without prostatitis (t=0.794, P=0.066). Mean international index of erectile function-5 score in the prostatitis group was significantly lower than that in those without prostatitis (t=1.854, P=0.013). Histological prostatitis notably affected sexual function of patients and may serve as a major risk factor for sexual dysfunction while having little effect on lower urinary tract symptoms.

Papel da disfunção erétil como manifestação sentinela e marcador de risco para doença coronariana / Role of erectile dysfunction as a sentinel event and risk marker for coronary disease

INTRODUÇÃO: A doença cardiovascular é a causa mais comum de morte em todo o mundo. Em homens, 50% das mortes por doença arterial coronariana ocorre em indivíduos sem história prévia de doença cardiovascular. Disfunção erétil e doença arterial coronariana têm uma relação estreita, já que ambas são consequências de disfunção endotelial, levando a limitações no fluxo sanguíneo. A associação entre severidade da disfunção erétil e a extensão das lesões da doença arterial coronariana ao exame angiográfico sugere que homens com disfunção erétil sejam considerados sob risco aumentado de doença arterial coronariana. OBJETIVO: Avaliar o papel da disfunção erétil como manifestação sentinela e/ou marcador de risco para doença arterial coronariana. MÉTODOS: Realizou-se uma análise secundária com dados previamente coletados em dois projetos (“Projeto Avaliar” e “Projeto Ampliar”). Pacientes do sexo masculino, com idade >18 anos, foram convidados a participar das duas pesquisas sobre disfunção erétil ao comparecerem a uma consulta médica ambulatorial em 2002-2003 (Projeto Avaliar) e em 2003-2004 (Projeto Ampliar)...

INTRODUCTION: Cardiovascular disease is the most common cause of death worldwide. In men, 50% of deaths due to coronary artery disease occur among those without previous history of cardiovascular disease. Erectile dysfunction and coronary artery disease are closely related, since they are both consequences of endothelial dysfunction, leading to restrictions on the blood flow. The association between the severity of erectile dysfunction and the angiographic extension of coronary artery disease suggests that men with erectile dysfunction be considered at increased risk for coronary artery disease. OBJECTIVES: To evaluate the role of erectile dysfunction as a sentinel sign and/or surrogate of risk for coronary artery disease. METHODS: We performed a secondary analysis on data previously collected in two research projects (“Projeto Avaliar” e “Projeto Ampliar”). Male patients, age 18 years old or more, were invited to participate in two surveys about erectile dysfunction while attending a routine office visit or consultation in 2002-2003 (Projeto Avaliar) and in 2003-2004 (Projeto Ampliar)...

Disfunção erétil: um marcador precoce de doenças cardiovasculares / Erectile dysfunction: an early marker of cardiovascular diseases

A disfunção erétil tem fatores de risco similares aos das doenças cardiovasculares, mas também pode ser um fator de risco independente para tais doenças. As evidências atuais consideram a disfunção erétil como uma desordem primordialmente de origem vascular e, mais do que isso, como um marcador precoce das doenças cardiovasculares. Apesar disso, o potencial da disfunção erétil como um sinal para alertar os médicos para uma possível manifestação precoce de doenças cardiovasculares mais graves tem sido pouco explorado na prática clínica diária.

Avaliação da qualidade de vida e disfunções sexuais em pacientes com insuficiência renal crônica em tratamento dialítico em hospital / Evaluation of quality of life and sexual dysfunctions in chronic renal failure patients undergoing hemodialysis in a hospital

Disfunção erétil é definida como a incapacidade persistente de obter e/ou manter uma ereção suficiente paraum desempenho sexual satisfatório, com prevalência de 52% em homens com idade de 40 a 70 anos, segundoo Massachusetts Male Aging Study. É uma condição bastante prevalente em pacientes portadores deinsuficiência renal crônica em tratamento dialítico, tendo como etiologia múltiplos fatores orgânicos epsicológicos, e que se manifesta fundamentalmente no homem por diminuição da libido e disfunção erétil. Oobjetivo desse estudo foi avaliar a qualidade de vida de pacientes do sexo masculino, com disfunção erétil,portadores de insuficiência renal crônica em hemodiálise no Hospital de Base de São José do Rio Preto –FAMERP. Foram analisados prontuários de 13 pacientes, coletando-se valores laboratoriais de testosteronasérica livre, creatinina sérica e respostas de questionário sobre qualidade de vida e o Índice Internacional deFunção Erétil (IIFE). A média de idade foi de 45,69 ± 12,12 anos, o valor médio da testosterona sérica foi de9,51 pg/ml ± 3,17, e o valor médio de creatinina sérica foi de 12,43 mg/dL ± 2,97. A Disfunção Erétil foi severaem 23%, moderada em 23% e leve em 54%. Todos os pacientes avaliados apresentavam desejo sexualpreservado, embora não com a mesma intensidade. Em relação ao questionário sobre qualidade de vida, 47%sentiriam-se muito insatisfeitos, 38% um pouco insatisfeitos e 15% nem satisfeitos nem insatisfeitos casopermanecessem com a função erétil que possuíam para o resto da vida. A Disfunção Erétil ocorre independentedos níveis séricos de testosterona livre, o que é justificado pela permanência do desejo sexual. É justificada,portanto, pela interação dos distúrbios orgânicos, emocionais e da condição a que o doente é submetido,com conseqüente agravo na qualidade de vida.

Erectile Dysfunction is defined as the incapacity to obtain and/or maintain an effective erection for asatisfactory sexual performance, affecting 52% of men aged 40 to 70 years, according to the MassachusettsMale Aging Study. It is a prevalent condition in patients with chronic renal failure undergoing hemodialysis.It has as etiology multiple organic and psychological factors, which finds expression mainly in the erectiledysfunction and reduction of men’s libido . The objective of this study was to evaluate the quality of life ofmale patients with erectile dysfunction, carriers of chronic renal failure in hemodialisys in Hospital de Base deSão José do Rio Preto - FAMERP. Medical charts of 13 patients have been analyzed, collecting laboratorialvalues of free serum testosterone, serum creatinine and answers of a questionnaire on quality of life and theInternational Index of Erectile Function (IIEF). The average age was 45.69 ± 12.12 years, the average value ofthe serum testosterone was 9.51 pg/ml ± 3.17, and the average value of serum creatinine was 12.43 mg/dL ±2.97. The Erectile Dysfunction was severe in 23%, moderate in 23% and mild in 54%. All the evaluatedpatients presented preserved sexual desire, even though with no same intensity. In relation to thequestionnaire on quality of life, 47% felt very unsatisfied, 38% a little unsatisfied and 15% neither satisfiednor unsatisfied in case that they could remain with the present erectile function for the rest of their life. TheErectile Dysfunction occurs independently from the serum levels of free testosterone; that is, by thepermanence of the sexual desire. It is justified, therefore, by the interaction of the organic and emotionaldisorders, and by the condition that the patient is submitted, worsening their quality of life.

Evaluación de la respuesta al sildenafil 50 mg en pacientes con disfunción eréctil sin tratamientos previos en la práctica cotidiana / Evaluation of the response to sildenafil 50 mg in patients with erectil dysfunction without previous treatment during the current practice

Nuestro estudio corrobora la elevada eficacia del Sildenafil para el tratamiento de la Disfunción Sexual Eréctil en el contexto de la práctica diaria de consultorio. El Sildenafil mostró ser un fármaco seguro, aun en pacientes con patologías concomitantes, debiendo pocos pacientes suspender la medicación por efectos secundarios severos. El Sildenafil mejoró no sólo la actividad sexual de los pacientes sino también su calidad de vida.

Histomorphometry of penile smooth muscle fiber in severe erectile dysfunction

CONTEXTO E OBJETIVO: A fibra muscular lisa apresenta fundamental importância no mecanismo de ereção e alterações em sua função ou em sua quantidade podem estar associadas à disfunção erétil. O objetivo do estudo é analisar a proporção de fibras musculares lisas em pacientes com disfunção erétil grave. TIPO DE ESTUDO E LOCAL: Estudo clínico, realizado no Grupo de Disfunção Erétil da Universidade Federal de São Paulo (Unifesp) e no Laboratório de Anatomia e Urologia da Universidade Estadual do Rio de Janeiro (UERJ). MÉTODOS: 20 pacientes com disfunção erétil grave de acordo com o Indice Internacional de Função Erétil e Teste de Ereção Fármaco-Induzida divididos em dois grupos de 10 pacientes, sendo um com fluxo arterial normal (44 a 78 anos, média @ 63 anos) e o outro com fluxo arterial alterado (38 a 67 anos, média @ 56,2 anos) ao duplex ultra-som. Os resultados são comparados com um grupo formado por 10 cadáveres de 18 a 25 anos (média @ 21,6 anos) presumidamente potentes. A quantificação das fibras musculares lisas foi realizada a partir de estudo imunoistoquímico com anticorpo anti-actina e análise computadorizada da imagem pelo sistema HSL (matiz, saturação e luminosidade). RESULTADOS: A proporção de fibras musculares lisas encontradas foi de 41,15 por cento para o grupo controle. Os pacientes com disfunção erétil apresentaram 27,24 por cento de fibras musculares lisas para o grupo com fluxo arterial normal e 25,74 por cento para o grupo com fluxo arterial insuficiente. Com exceção de apenas um paciente (do grupo com fluxo arterial normal), 19 pacientes apresentavam ao menos uma doença crônica ou fator de risco para disfunção erétil, destacando-se diabetes mellitus, hipertensão arterial sistêmica e tabagismo, nesta ordem. CONCLUSAO: Nos pacientes com disfunção erétil grave, o fluxo arterial isoladamente não apresenta interferência na proporção de fibras musculares lisas, pois os resultados foram semelhantes. Nestes pacientes com disfunção grave, a diminuição das fibras musculares lisas em relação ao grupo controle pode decorrer das doenças crônicas e de seu potencial aterosclerótico.