Efectividad y satisfacción del tratamiento con dosis diaria de Tadalafilo 5 mg para la disfunción eréctil / Effectiveness and satisfaction of the treatment with daily dose of Tadalafil 5 mg for erectile dysfunction

La base del tratamiento de la disfunción eréctil (DE) son los inhibidores de la fosfodiesterasa 5, disponibles mayoritariamente para dosificación a demanda. En 2008 la FDA aprobó el Tadalafilo 5 mg de uso diario. OBJETIVO: Evaluar la efectividad del Tadalafilo 5 mg de uso diario para el tratamiento de la DE y la satisfacción de los pacientes frente a su uso. PACIENTES Y METODOS: Se reclutaron pacientes con DE entre Junio de 2011 y Mayo de 2012. Se registraron datos sociodemográficos, clínicos y andrológicos. La DE se clasificó según el puntaje del cuestionario IIEF. Todos los pacientes iniciaron tratamiento diario con Tadalafilo 5 mg y fueron reevaluados luego de un mes. La satisfacción y calidad de vida se evaluó con cuestionarios validados (EDITS, SEAR y GAQ). Para el análisis estadístico se consideró significativo un P<0.05.RESULTADOS: Se reclutaron 49 pacientes con edad promedio de 59,9 +/- 8,8 años. Un 14,3 por ciento presentaba DE severa, 36,7 por ciento moderada, 36,7por ciento leve-moderada y 12,2 por ciento leve. Al mes de tratamiento, el puntaje IIEF aumentó significativamente (P<0.0005), encontrándose un 18,4 por ciento sin DE, 53,1 por ciento con DE leve, 28,6 por ciento con DE leve-moderada y ninguno con DE moderada o grave. El 87,7 por ciento de los pacientes refirió mejores erecciones y el 81,6 por ciento una mejor capacidad para mantener la relación sexual. La satisfacción global con el tratamiento fue de 64,1 por ciento. CONCLUSIÓN: El tratamiento diario con Tadalafilo 5 mg es efectivo para el manejo de la DE y se asocia a niveles adecuados de satisfacción y confianza al cabo de un mes de tratamiento.

The base of the treatment of erectile dysfunction (ED) are the phosphodiesterase-5 inhibitors, mostly available for “on demand” dosing. In 2008, the FDA approved Tadalafil 5mg for daily use. OBJECTIVE: To evaluate the effectiveness of Tadalafil 5 mg daily dose for the treatment of ED and the patient’s satisfaction with its use. PATIENTS AND METHODS: Patients with ED were enrolled between June 2011 and May 2012. Sociodemographic, clinical and andrologic data was recorded. The severity of ED was classified according to the score of the IIEF questionnaire. All patients started daily treatment with Tadalafil 5 mg and were reevaluated after one month. Satisfaction and quality of life was assessed using validated questionnaires (EDITS, SEAR and GAQ). A P<0.05 was considered significant in all statistical analysis. RESULTS: A total of 49 patients were enrolled, with mean age of 59.9 +/- 8.8 years. A 14.3 ´percent suffered severe ED, 36.7 percent moderate, 36.7 percent mild-moderate and 12.2 percent mild. After one month, the IIEF score significantly increased (P<0.0005), finding a 18.4 percent of patients without ED, 53.1 percent with mild ED, 28.6 percent with mild-moderate ED and no cases with moderate or severe ED. 87.7 percent of patients reported better erections and 81.6 percent stated a better capacity to maintain erections during. The global satisfaction rate with the treatment was of 64.1 percent. CONCLUSION: The treatment with daily dose of Tadalafil 5 mg is effective for the management of ED and is associated with adequate levels of satisfaction and confidence after one month of use.

Effect of acute administration of sildenafil to rats with detrusor overactivity induced by chronic deficiency of nitric oxide

Purpose Recently, the effect of phosphodiesterase inhibitors (PDE5i) in the lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia have been studied thoroughly. However, it remains unclear how the PDE5i improve LUTS. Therefore, the aim of the present study was to evaluate the potential of acute administration of the PDE5i sildenafil to improve detrusor overactivity (DO) induced by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), an nitric oxide sinthase (NOS) inhibitor, in rats. Materials and Methods Twenty-seven MALE adult Wistar Rats were divided into the following groups: (1) control, (2) L-NAME, (3) sildenafil alone, and (4) L-NAME + sildenafil. The NOS blocker L-NAME (20 mg/rat/day) was given in the drinking water. Sildenafil (100µg/kg) was administrated intravenously (i.v.) acutely, diluted in cremophor, propylene glycol and water. All animals underwent to anesthetized cystometograms. Results The chronic and systemic administration of L-NAME markedly increased the number of non voiding contractions (2.62 (± 0.89)), and frequency of micturition (1.97 (± 0.78)), as well increased volume threshold (2.83 mL (± 1.64)) compared with control group, the number of non voiding contractions (1.17 (± 0.75)), frequency of micturition (1.08 (± 0.65)) and volume threshold (1.16 mL (± 0.38)), p < 0.001, p = 0.01, and p = 0.04, respectively. Sildenafil infusion decreased the number of micturition cycles significantly from the baseline to end point (-0.93 (± 0.34)) in nitric oxide (NO) deficient animals compared with sildenafil infusion alone (control) in animals with normal NO level (0.13 (± 0.25)), p = 0.03. Conclusion Systemic reduction of nitric oxide causes detrusor overactivity and acute infusion of sildenafil reduces the number of micturition cycles in chronic NO-deficient rats. .

Efeitos da administração de inibidores de fosfodiesterases na reversão da hiperatividade de camundongos expostos ao etanol no período correspondente ao terceiro trimestre de gestação em humanos / Effects of phosphodiesterase inhibitors administration on reversal of hyperactivity in mice exposed to ethanol during the period corresponding to the third pregnancy trimester in humans

O consumo de etanol durante a gestação é um grave problema de saúde pública. Durante o desenvolvimento, o sistema nervoso é especialmente susceptível aos efeitos tóxicos do etanol e a exposição ao etanol durante este período pode gerar um amplo espectro de distúrbios neurocomportamentais, sendo o mais frequente, a hiperatividade. Recentemente, estudos têm sugerido que distúrbios na plasticidade neuronal podem estar relacionados com a hiperatividade. Os inibidores de PDE são drogas que agem impedindo a degradação de segundos mensageiros celulares como AMPc e GMPc, mantendo a ativação de proteínas quinases e de fatores de transcrição como o CREB, levando a expressão de genes relacionados à plasticidade. Neste trabalho, avaliamos através do teste de campo aberto se a administração de Vinpocetina ou Rolipram (inibidores de PDE) seria capaz de amenizar ou reverter a hiperatividade de camundongos Suíços expostos ao etanol no período correspondente ao terceiro trimestre de gestação humana. Para tanto, foram realizadas duas etapas: na primeira etapa, durante o período neonatal, os animais receberam injeções intraperitoneais de etanol (5g/Kg em solução salina a 25%, no 2º, 4º, 6º e 8º dias de vida pós-natal - PN2 a PN8) ou de salina, e 4 horas antes do teste comportamental no campo aberto (10 min), em PN30, receberam Vinpocetina (10mg/Kg ou 20mg/Kg diluídas em DMSO ip) ou somente DMSO ip. Na segunda etapa, os animais foram expostos ao etanol ou à salina no período neonatal nas mesmas condições da primeira etapa e no dia do teste comportamental receberam Rolipram (0,5 mg/Kg diluídas em DMSO ip ou somente DMSO ip). Posteriormente aos testes, foram coletados o córtex cerebral frontal e o hipocampo dos animais para avaliação dos níveis de AMPc. Os resultados comportamentais indicam que somente o tratamento com Vinpocetina (20mg/Kg) reverteu a hiperatividade de camundongos expostos ao etanol, resultado que não foi observado com o tratamento com Rolipram. Desta forma...

Ethanol consumption during gestation is a serious public health problem. During development, the nervous system is particularly susceptible to the toxic effects of ethanol and, in fact, ethanol exposure during perinatal development produces a range of neurobehavioral deficits, among which hyperactivity is one of the most frequently observed. There is evidence that reduced neuronal plasticity could be associated with hiperactivity. PDE inhibitors are drugs that prevent the breakdown of intracellular second-messengers such as cAMP and cGMP, maintaining the activation of protein kinases and of the CREB transcription factor, leading to the expression of plasticity-related genes. In this study we test whether Vinpocetine or Rolipram (PDE inhibitors) treatment can improve or revert hyperactivity in Swiss exposed to alcohol during the third trimester equivalent of human gestation. To that end, two experiments were carried out: In the first one, from postnatal day (PN) 2 to PN8, litters either received ethanol (5g/Kg i.p., 25% in saline solution) of an equivalent volume of saline solution every other day. On PN30, 4 h before the open field test (which lasted for 10 min) animals received Vinpocetine (10mg/Kg of 20mg/Kg diluted in DMSO i.p.) of dimethylsulfoxide (DMSO i.p.). In the second experiment animals were treated almost as before receiving Rolipram (0.5mg/Kg diluted in DMSO i.p.), instead of Vinpocetine, of DMSO i.p. After the tests, animals were sacrificed and frontal cerebral cortices and hippocampuses were dissescted and collected for the analysis of cAMP levels. Behavioral results showed that only the Vinpocetine treatment (20mg/Kg) reversed the ethanol-elicited hyperactivity, a result that was not observed for the Rolipram treatment. In this way, the dosage of cAMP levels was done only for the animals that received Vinpocetine (20mg/Kg). Ethanol neonatal exposure significantly reduced cAMP levels both in the cortex and in the hippocampus. Vinpocetine...

Freqüência de uso de inibidores de fosfodiesterase-5 por estudantes universitários / Use of phosphodiesterase-5 inhibitors by college students / Uso de inhibidores de fosfodiesterasa-5 por estudiantes universitários

O objetivo do estudo foi identificar o uso de inibidores da fosfodiesterase-5 por estudantes universitários da cidade de São Paulo (SP), em 2006. Alunos do sexo masculino (n=360) responderam questionário sobre diagnóstico de disfunção erétil, freqüência e motivo do uso, medicamento utilizado, existência de prescrição médica e relato de efeitos adversos. Os resultados mostraram que 53 (14,7 por cento) dos alunos já haviam utilizado esses medicamentos, dos quais 53 por cento relataram uso de sildenafila, 37 por cento tadalafila e 10 por cento vardenafila, adquiridos sem prescrição médica ou diagnóstico de disfunção erétil. Os principais efeitos adversos relatados foram cefaléia (23 por cento) e rubor facial (10 por cento), e as principais motivações para uso foram a curiosidade (70 por cento) e potencialização da ereção (12 por cento).

Contribuição na prevenção da isquemia cerebral pelo cilostazol, um inibidor da fosfodiesterase III: revisão de literatura / Contribution to prevention of cerebral ischemia by cilostazol, a phosphodiesterase III inhibitor: a review

Esta revisão bibliográfica objetiva expor estas pesquisas sobre as ações do cilostazol no sistema nervoso central. O cilostazol é uma droga que demonstrou exercer inibição seletiva e potente da fosfodiesterase tipo III, ocasionando o aumento de adenosina cíclica -3',5'-monofosfato nas plaquetas, nas células endoteliais e nas células musculares lisas, sendo classificado como vasodilatador, antiagregante plaquetário e antitrombótico. É o fármaco de primeira escolha na claudicação intermitente devido à doença arterial obstrutiva periférica. Além disso, há evidências de que o cilostazol é eficaz no processo aterosclerótico cerebral, promovendo aumento do fluxo e volume sangüíneos e prevenindo infartos, especialmente lacunares e recorrentes, por diminuir a morte celular devido à apoptose e ao estresse oxidativo nas substâncias branca e parda.

This literature review aims at presenting the main possibilities for the clinical application of cilostazol in the central nervous system. Cilostazol, a selective phosphodiesterase type III inhibitor, increases adenosine 3',5'-cyclic monophosphate levels on platelets, endothelial and smooth muscle cells, having vasodilatory, antiplatelet and antithrombotic properties. Currently, it is the first-choice drug for intermittent claudication, due to peripheral occlusive vascular disease. In addition, there is evidence showing that cilostazol is efficacious in cerebral atherosclerotic process, resulting in increase of blood flow and volume and preventing infarctions, especially lacunar and recurrent, since it reduces cellular death due to apoptosis and oxidative stress in white and gray substances.

Additive Antinociception between Intrathecal Sildenafil and Morphine in the Rat Formalin Test

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microliter of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

Sildenafil for pulmonary hypertension secondary to congenital heart diseases.

OBJECTIVE: The purpose of this study was to evaluate the effects of oral Sildenafil for treatment of pulmonary hypertension secondary to congenital heart diseases. METHODS & RESULTS: Twelve patients with un-repaired congenital heart diseases resulting in significant pulmonary hypertension were enrolled in a prospective trial of oral Sildenafil treatment for 12 weeks. The outcomes measured were change in the systemic oxygen saturations, 6-minute walk test distance, and New York Heart Association class. The systemic blood pressure and visual symptoms were monitored for evaluating the tolerability of Sildenafil. The mean age was 25.7+/-14.4 years. The mean pulmonary vascular resistance before treatment was 17.4 Wood units. After 12 weeks of sildenafil, an increase in oxygen saturations (87.8+/-5.3%-90.25+/-4%, p=0.04) with an associated increase of one New York Heart Association class (p=0.009) was noted. A non-statistically significant increase in the 6-minute walk test distance (310.33+/-42-333.75+/-54.6 meters, p=0.47) was also noted. Sildenafil was well-tolerated with no significant change in systemic blood pressure or visual side-effects. CONCLUSION: Oral Sildenafil is well-tolerated and produces some improvement in the oxygenation and functional status of patients with pulmonary hypertension secondary to congenital heart diseases.

Oral tadalafil in pulmonary artery hypertension: a prospective study.

BACKGROUND: Pulmonary artery hypertension is a disorder with limited treatment options and poor prognosis. We studied the effect of tadalafil, a selective phosphodiesterase type 5 inhibitor, in patients with this disease. METHODS AND RESULTS: In thirteen patients (5 males, 8 females) aged 15-70 years, with pulmonary artery hypertension (7 with congenital heart disease, 4 with chronic pulmonary thromboembolism and 2 with primary pulmonary hypertension), tadalafil was added to their baseline therapy at 10 mg OD for two weeks and if tolerated well, increased to 20 mg OD for the next two weeks. After four weeks of therapy, all thirteen patients had subjective improvement in the form of overall well being and objective improvement as measured by duration of exercise on treadmill following Bruce protocol from a baseline of 350.54+/-255.06 seconds to 479.54+/-195.00 seconds (p<0.01). There was improvement in NYHA functional class in eleven patients. Two patients, though showed no improvement in functional class, had subjective improvement in effort tolerance and objective improvement as measured by duration of exercise on TMT. Hemodynamic parameters showed a trend towards improvement, mean pulmonary artery mean pressure decreased from 63.5+/-26.2 mmHg to 62.2+/-24.8 mmHg (p>0.05), mean pulmonary blood flow increased from 3.26+/-1.04 L/min to 3.44+/-1.26 L/min (p>0.05), mean total pulmonary vascular resistance decreased from 1858.6+/-1138.9 dyne-sec.cm-5 to 1737.3+/-1017.2 dyne-sec.cm-5 (p>0.05). CONCLUSION: Oral tadalafil was well tolerated and had a beneficial effect in patients with pulmonary artery hypertension irrespective of age, sex and underlying etiology. Patient had improved effort tolerance and a trend towards improved pulmonary hemodynamics.

Sildenafil masticable, análisis prospectivo de nueva presentación farmacológica / Cheweable sildenafil: prospective analysis of a new presentation

La disfunción eréctil es una patología de alta frecuencia, especialmente en población masculina de mayor edad. La erección está dada fundamentalmente por la activación del sistema parasimpático, por acción del óxido nítrico y aumento de GMP cíclico; es así como fármacos como Sildenafil que disminuyen la eliminación de GMP cíclico al inhibir la actividad de la 5 fosfodiesterasa, potencian la mantención de dicha erección. Recientemente se lanzó al mercado la presentación masticable de este fármaco, lo que eliminaría el primer paso hepático de la presentación oral clásica. En este estudio, se analizaron 20 pacientes con disfunción eréctil sin comorbilidad asociada, los que consumieron la forma masticable; con el objetivo de evaluar eficacia clínica y efectos adversos. Los resultados obtenidos muestran que existe un alto grado de satisfacción de usuario en cuanto a forma de presentación, tiempo de administración y eficacia, y que los efectos adversos no difieren a los de la presentación tradicional. Se propone realizar estudios prospectivos comparativos de ambas presentaciones y otros inhibidores de la 5 fosfodiesterasa, para confirmar estos resultados preliminares.

Erectil dysfunction is a very frequent pathology in the elderly male. Erections are activated mainly by the parasympathic system, caused by nitric oxide and the increase of cyclic cGMP; it is because of this that drugs like Sildenafil improve partial erections by inhibiting the enzyme that facilitates the reduction of cyclic guanosine monophosphate (cGMP). Recently a chewable new form of this drug entered the market,it is deemed to avoid hepatic transformation of the drug. In this study we analyzed 20 patients witherectile dysfunction without other associated comorbidities that were treated with this drug. Results showed that patients were highly satisfied with the form of presentation, the dosage regimen, and efficacy. Side effects are no different from the other and more traditional version. We will conduct prospective comparative studies of both versions of the drugs and other inhibitors of the cGMP specific phosphodiesterase type 5,to confirm these preliminary results.

Evaluating erectile dysfunction: oral sildenafil versus intracavernosal injection of papaverine.

BACKGROUND: Intracavernosal injection of vasoactive drugs is an established method of evaluating erectile dysfunction. However, it is invasive and may be associated with pain and priapism. We investigated the use of oral sildenafil as a possible substitute for intracavernosal agents. METHODS: Men with erectile dysfunction were randomized into two groups of 25 each. One group of 25 men received injection papaverine initially followed by oral sildenafil, and another 25 received oral sildenafil followed by injection papaverine. Genital self-stimulation was used in both the groups. Penile length and circumference as well as angle of erection, before and after each medication, were recorded. Two days later, the intervention arms were crossed over. Subjective responses were obtained. The effect of medication on each outcome variable was studied by using analysis of variance models in relation to patient, period and medication. RESULTS: There was statistically significant improvement from the baseline value in both the arms, i.e injection papaverine and oral sildenafil (p<0.001, p<0.001, respectively) for both penile length and circumference. No significant difference was observed between the two medications in the outcome measures. CONCLCUSION: Oral sildenafil was as effective as injection papaverine in evaluating erectile dysfunction.

Erectile dysfunction.

With phosphodiesterase inhibitors, a safe and effective oral therapy has emerged for erectile dysfunction. Increasing awareness, particularly through the media, is inducing more men to seek help for this condition. Erectile dysfunction is defined as the persistent inability to achieve or maintain an erection adequate for satisfactory sexual activity. The prevalence increases with age. Basic and clinical research is identifying the neurovascular and humoral control of the mechanisms. The initial evaluation should differentiate erectile dysfunction from premature ejaculation and loss of libido. Myocardial insufficiency, hypogonadism and peripheral neuropathy should be looked for. Initial laboratory investigations should be restricted to identifying previously undetected medical illness that may directly contribute to erectile dysfunction. Discussing the available options with the couple is an important aspect. If erectile dysfunction is secondary to other treatable disorders these should be treated simultaneously. When other diseases that require intervention are ruled out and if there are no contraindications, therapy may be initiated with a phosphodiesterase inhibitor. In selected cases, psychosexual therapy may be beneficial. If phosphodiesterase inhibitors are contraindicated, vacuum constriction devices may be tried. Further options include intracavemosal injection, intraurethral instillation, penile revascularization and prosthesis. The availability of effective and well-tolerated oral medications has dramatically changed the clinical approach to erectile dysfunction. Pharmacotherapy is the preferred cost-effective first-line therapy in the vast majority of patients. A stepped-care approach is followed in the primary care and family practice settings. Appropriate urological, endocrine and psychiatric referrals, and shared decision-making with the couple will enable effective treatment of men with erectile dysfunction.

Management of erectile dysfunction in patients with ischemic heart disease by intracavernous injection of vasoactive drugs because of failure, complications or contraindication of sildenafil

The aim of the present study was to evaluate the effectiveness of intracavemous injection [ICI] of vasoactive drugs combination in patients with ischemic heart disease [IHD] and erectile dysfunction [ED] who were not proper cadidatefor treatment with sildenafil citrate. The study population included 122 selected patients with IHD and ED in whom sildenafil was not an option because of its failure, side effects, or presence of contraindication for its use. The ICI program consisted of two combinations of vasoactive drugs. The first combination [A] included a mixture of papaverine, phen-tolamine, and verapamil The second combination [B] included a mixture of the former 3 drugs plus prostaglandin El. Patients who failed to respond with the first combination were switched to the second combination. A positive response was defined as an erection sufficient for vaginal penetration and maintained till ejaculation. A positive response was achieved with combination [A] in 67 [54.9%] of the 122 patients and with combination [B] in 24 [43.6%] of the remaining 55 patients. The total success rate was [74.6%]. Patients with positive response [91 pts.] were followed-up for one year with 80 [87.9%] patients reported successjid coitus during this period. The remaining 11 patients [12.1%] dropped out of the program, 2 [2.2%] because of treatment failure, and 9 [9.9%] because of marital and health reasons. Adverse effects of ICI therapy included prolonged erection in 10 [11%], painful erection in 9 [9.9%], subcutaneous hematoma in 7 [7.7%], and plaque formation in 3 [3.3%]. We conclude that ICI ofvasoactive drugs is a good alternative for the treatment of ED in patients with IHD in whom stidenafil is not anoption

Physiological basis and indications of treatment of erectile dysfunction with the phosphodiesterase inhibitor sildenafil citrate

The advent of the first effective oral agent in the management of erectile dysfunction, sildenafil, has had a revolutionary impact in the medical societal and economic aspects of this field. This review will examine the clinical research and field experience with respect to efficacy and safety as well as touch on the broader societal and economic issues related to sildenafil. The following topics are extensively presented and discussed in this article: molecular pharmacology, pharmacokinetics and pharmacokinetics in special populations (geriatrics, renal insufficiency, hepatic insufficiency). The indications, contraindications and precautions. Dosage and administration, efficacy in general and in diabetic patients, spinal cord injured patients, radical prostatectomy, and according to age and severity of erectile dysfunction. The safety and the side effects are also discussed