Papel da Rigidez Aórtica na Previsão da Resposta aos Inibidores da Fosfodiesterase-5 no Tratamento da Disfunção Erétil / Role of Aortic Stiffness in Predicting Response to Phosphodiesterase-5 Inhibitors in the Treatment of Erectile Dysfunction

Resumo Fundamento: Sabe-se que a rigidez aórtica (RA) aumenta em pacientes com disfunção erétil (DE). Os inibidores da enzima fosfodiesterase tipo 5 (PDE-5) são usados no tratamento da DE, e as respostas dos pacientes a esse tratamento podem variar. Objetivos: Nosso objetivo foi investigar o papel da RA na previsão da resposta de pacientes planejados para tomar inibidores da enzima PDE-5 devido à DE. Métodos: Um total de 96 pacientes do sexo masculino com DE foram incluídos no estudo. O questionário do Índice Internacional de Função Erétil (IIEF) foi utilizado para avaliar a presença e gravidade da DE e a resposta ao tratamento. A ecocardiografia transtorácica foi utilizada para avaliar RA. Resultados: Houve diferença estatisticamente significativa entre os valores de deformação aórtica e distensibilidade aórtica dos grupos de estudo (p<0,001). O escore delta IIEF apresentou alto nível de correlação positiva com a deformação aórtica (p<0,01, r=0,758) e um nível moderado de correlação positiva com a distensibilidade aórtica (p<0,01, r=0,574). Conclusão: Determinamos que em pacientes com DE, a deformação aórtica e a distensibilidade aórtica medidas de forma não invasiva por meio de ecocardiografia transtorácica são parâmetros importantes na previsão da resposta dos pacientes à terapia com inibidores da PDE-5.

Abstract Background: It is known that aortic stiffness (AS) increases in patients with erectile dysfunction (ED). Phosphodiesterase type-5 (PDE-5) enzyme inhibitors are used in the treatment of ED, and patients' responses to this treatment may vary. Objectives: We aimed to investigate the role of AS in predicting the response of patients planned to take PDE-5 enzyme inhibitors due to ED. Methods: A total of 96 male patients with ED were included in the study. The International Index of Erectile Function (IIEF) questionnaire was used to evaluate the presence and severity of ED and the response to treatment. Transthoracic echocardiography was used to evaluate AS. Results: There was a statistically significant difference between the aortic strain and aortic distensibility values of the study groups (p<0.001). The delta IIEF score had a high level of positive correlation with aortic strain (p<0.01, r=0.758) and a moderate level of positive correlation with aortic distensibility (p<0.01, r=0.574). Conclusion: We determined that in patients with ED, aortic strain and aortic distensibility measured non-invasively using transthoracic echocardiography are important parameters in predicting patients' response to PDE-5 inhibitor therapy.

[Phosphodiesterase 5 inhibitors for the treatment of heart failure: a systematic review and meta-analysis]. / Inhibidores de la fosfodiesterasa 5 para el tratamiento de la insuficiencia cardiaca: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados.

Objective: The treatment with phosphodiesterase-5 (PDE-5) inhibitors was postulated in heart failure (HF). We conducted a systematic review and a meta-analysis on their beneficial and adverse effects in patients with HF. Method: A meta-analysis of randomized trials evaluating the chronic use of PDE-5 inhibitors in patients with HF was conducted. Endpoints included death, HF hospitalizations, functional capacity, pulmonary pressures, quality of life, and adverse effects. Random-effects models were used to pool outcomes. Categorical data were summarized with relative risks (RR) and 95% confidence intervals (95%CI), and continuous data with weighted mean differences and standardized mean differences. Results: Sixteen studies (1119 participants) were included. No effect was observed on mortality (RR: 1.16; 95%CI: 0.50-2.66; I2: 0.0%) or HF hospitalizations (RR: 0.75; 95%CI: 0.41-1.37; I2: 38.7%). Treatment significantly reduced pulmonary systolic pressure (-10.64 mmHg; 95%CI: -5.14 to -16.15 mmHg; I2: 96.0%), and increased peak oxygen consumption (2.06 ml/kg/min; 95%CI: 0.40-3.72; I2: 89.6%), although with high inconsistency. There were no significant effects on quality of life (-0.15; 95%CI: -0.48-0.18; I2: 0.0%). On the other hand, the risk of headaches was increased (RR: 1.63; 95%CI: 1.11-2.39; I2: 0.0%). Publication bias was identified for HF hospitalizations. Conclusions: Current data suggest that PDE-5 inhibitors therapy does not improve prognosis or quality of life among HF patients. Hemodynamic and functional effects could be relevant, and more studies are necessary to define its role.

Objetivo: El tratamiento con inhibidores de la fosfodiesterasa 5 (iFDE-5) fue postulado en la insuficiencia cardiaca (IC). Se realizó una revisión sistemática y metaanálisis sobre sus efectos beneficiosos y adversos en pacientes con IC. Método: Metaanálisis de ensayos clínicos aleatorizados que evaluaron el uso crónico de iFDE-5 en pacientes con IC. Los criterios de valoración finales incluyeron la muerte, las hospitalizaciones por IC, la capacidad funcional, las presiones y las resistencias pulmonares, la calidad de vida y los efectos adversos. Se utilizaron modelos de efectos aleatorios para agrupar los resultados. Los datos categóricos fueron resumidos como riesgos relativos (RR) e intervalos de confianza del 95% (IC95%), y los datos continuos como diferencias de medias ponderadas y diferencias de medias estandarizadas. Resultados: Se incluyeron 16 estudios (1119 participantes). No se observaron efectos sobre la mortalidad (RR: 1,16; IC95%: 0.50-2.66; I2: 0.0%) ni sobre las hospitalizaciones por IC (RR: 0,75; IC95%: 0.41-1.37; I2: 38.7%). El tratamiento redujo significativamente la presión sistólica pulmonar (−10,64 mmHg; IC95%: −5.14 a −16.15 mmHg; I2: 96.0%) e incrementó el consumo máximo de oxígeno (2.06 ml/kg/min; IC95%: 0.40-3.72 ml/kg/min; I2: 89.6%), aunque con elevada inconsistencia. No se detectaron efectos significativos sobre la calidad de vida (−0.15; IC95%: −0.48-0.18; I2: 0.0%). Por otra parte, aumentó el riesgo de cefaleas (RR: 1.63; IC95%: 1.11-2.39; I2: 0.0%). Se identificó un sesgo de publicación para las hospitalizaciones por IC. Conclusiones: Los datos actuales sugieren que el tratamiento con iFDE-5 no mejora el pronóstico ni la calidad de vida de los pacientes con IC. Los efectos hemodinámicos y funcionales podrían ser relevantes, y son necesarios más estudios para definir su rol.

Complete study for erectile dysfunction (CompED) improving diagnosis and treatment decision-making.

Erectile dysfunction is a condition associated with increasing age. Patient evaluation and management should follow a comprehensive, stepwise approach. The aim of this article was to report our experience with the complete study for erectile dysfunction, including intracavernous injection rigidity test, biothesiometry and colour duplex Doppler ultrasound. Data were collected and analysed prospectively. The primary end point was to determine whether treatment decision-making was eased by the CompED test. Secondary end points were to establish which clinical variables prior to the study could impact the results of the CompED test, to finally improve patient selection for the study. 187 patients were recruited, 31.2% of the patients had an axial rigidity below 50%, 28.5% had a peak systolic velocity <25 cm/s, 13.2% had an end-diastolic velocity >5cm/s and 27.5% had an abnormal biothesiometry. The factors that best predicted an abnormal result in any of the tests were age >70 years, IIEF domain A < 14 points, and previous radical prostatectomy or radiotherapy. The CompED test stands as a new alternative for the evaluation of patients with erectile dysfunction, being less time consuming, aiding in a more accurate determination of the aetiology and guiding treatment decision-making.

A validated LC-MS/MS assay for the quantification of phosphodiesterase-5 inhibitors in human plasma.

Phosphodiesterase inhibitors (PDE5i) are considered the first line therapy for erectile dysfunction. All PDE5i available on the market are structurally related; their main differences relate to their pharmacokinetic parameters. For these treatments to be effective and safe, it is necessary that these drugs are in the appropriate doses and that they reach adequate concentrations in the plasma. For this purpose, it is essential to perform therapeutic monitoring using bioanalytical methods. In this way, the present work aimed to develop and validate a new bioanalytical method, based on LC-MS/MS, for the simultaneous quantification of six commercially available PDE5i (avanafil, lodenafil, sildenafil, tadalafil, udenafil, and vardenafil). For this purpose, the human plasma was extracted with diethyl ether and sulfaquinoxaline was established as an internal standard. Separation was achieved using an Xbridge C18 column at 40 °C as the stationary phase, using water and acetonitrile as the mobile phase (both with formic acid and ammonium formate) in gradient mode. The method was validated according to the current guidelines and was found to be selective, linear (from 1 to 200 ng.mL-1 for all drugs except for tadalafil which is from 5 to 200 ng.mL-1), precise, accurate, and free of residual and matrix effects. The drugs were considered stable in plasma and in solution under different conditions. The method was applied to volunteerssamples, demonstrating that the method can be used routinely and may be useful in future studies on pharmacokinetics and therapeutic monitoring.

Antinociceptive Effect of Lodenafil Carbonate in Rodent Models of Inflammatory Pain and Spinal Nerve Ligation-Induced Neuropathic Pain.

INTRODUCTION: New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models. METHODS AND RESULTS: Although no effect was detected on neurogenic phase of formalin test in mice, oral administration of lodenafil carbonate dose-dependently reduced reactivity in the inflammatory phase (200.6 ± 39.1 to 81.9 ± 18.8 s at 10 µmol/kg, p= 0.0172) and this effect was totally blocked by NO synthase inhibitor, L-Nω-nitroarginine methyl ester (L-NAME). Lodenafil carbonate (10 µmol/kg p.o.) significantly reduced nociceptive response as demonstrated by increased paw withdrawal latency to thermal stimulus (from 6.8 ± 0.7 to 10.6 ± 1.3 s, p= 0.0006) and paw withdrawal threshold to compressive force (from 188.0 ± 14.0 to 252.5 ± 5.3 g, p<0.0001) in carrageenan-induced paw inflammation model. In a spinal nerve ligation-induced neuropathic pain, oral lodenafil carbonate (10 µmol/kg) also reversed thermal hyperalgesia and mechanical allodynia by increasing paw withdrawal latency from 17.9 ± 1.5 to 22.8 ± 1.9 s (p= 0.0062) and paw withdrawal threshold from 26.0 ± 2.8 to 41.4 ± 2.9 g (p= 0.0196). These effects were reinforced by the reduced GFAP (3.4 ± 0.5 to 1.4 ± 0.3%, p= 0.0253) and TNF-alpha (1.1 ± 0.1 to 0.4 ± 0.1%, p= 0.0111) stained area densities as detected by immunofluorescence in ipsilateral dorsal horns. CONCLUSION: Lodenafil carbonate demonstrates important analgesic activity by promoting presynaptic hyperpolarization and preventing neuroplastic changes, which may perpetuate chronic pain, thus representing a potential treatment for neuropathic pain.

Cardioprotector effect of phosphodiesterase 5 inhibitors in experimental model for diabetes mellitus / Efeito cardioprotetor dos inibidores da fosfodiesterase 5 em modelo de diabetes mellitus experimental

Diabetes mellitus (DM) is considered a 21st century pandemic and is often associated with cardiovascular disease (CVD). The aim of this integrative review was to analyze the cardioprotective effects of phosdodiesterase-5 (PDE5i) inhibitors in experimental diabetes models. The articles were selected from the PubMed, SciELO and LILACS databases from 2014 to 2019. The following descriptors were used in combination with the Boolean operators: Diabetes mellitus experimental AND Phosphodiesterase 5 inhibitors; Diabetic cardiomyopathies AND Phosphodiesterase 5 inhibitors. An initial sample of 155 articles was obtained, of which six met the criteria for the synthesis of the review. The studies analyzed showed that treatment with PDE5i in experimental models, resulted in positive effects on cardiac function and metabolic parameters. Similar results have also been seen in humans. The reduction in cardiac hypertrophy, apoptosis of cardiomyocytes, pro-inflammatory factors and oxidative stress and the modulation of transcription factors involved in diabetes homeostasis, were prevalent among studies. The mechanisms of action involved in cardioprotection have not yet been fully elucidated, however the restoration of the activated cyclic guanosine monofate (cGMP) pathway by soluble guanylate cyclase (sGC) via nitric oxide (NO) was a common mechanism among the studies.

O Diabetes mellitus (DM) é considerado uma pandemia do século XXI e está frequentemente associado às doenças cardiovasculares (DCVs). O objetivo desta revisão integrativa foi analisar os efeitos cardioprotetores de inibidores da fosdodiesterase 5 (PDE5i) em modelos de diabetes experimental. Os artigos foram selecionados nas bases de dados PubMed, SciElo e LILACS no período de 2014 a 2019. Foram utilizados os seguintes descritores combinados com os operadores booleanos: Diabetes mellitus experimental AND Phosphodiesterase 5 inhibitors; Diabetic cardiomyopathies AND Phosphodiesterase 5 inhibitors. Foi obtida uma amostra inicial de 155 artigos, dos quais seis se enquadraram nos critérios para a síntese da revisão. Os estudos analisados evidenciaram que o tratamento com os PDEi5 em modelos experimentais, resultou em efeitos positivos sobre a função cardíaca e parâmetros metabólicos. Resultados semelhantes também foram observados em humanos. A redução da hipertrofia cardíaca, apoptose de cardiomiócitos, fatores pró-inflamatórios e estresse oxidativo e a modulação de fatores de transcrição envolvidos na homeostasia do diabetes, foram achados prevalentes entre os estudos. Os mecanismos de ação envolvidos na cardioproteção ainda não foram totalmente elucidados, contudo a restauração da via da guanosina monofato cíclica ativada (GMPc) pela Guanilato ciclase solúvel (GCs) via Óxido Nítrico (NO) foi um mecanismo comum entre os estudos.

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)

Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis.

PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

Phosphodiesterase-5 inhibition improves bone regeneration at the early stages of ischemic osteonecrosis of the femoral head in rats.

Posttraumatic osteonecrosis of the femoral head (ONFH) affects patients at different ages and may lead to functional limitation and joint replacement, with total hip arthroplasty, which is a costly procedure. Proposed methods to optimize ischemic tissue regeneration have been reported. Phosphodiesterase-5 inhibitors act by inhibiting the degradation of guanosine 3',5'-cyclic monophosphate in the nitric oxide pathway, increasing its bioavailability and promoting vascular endothelial growth factor (VEGF)-mediated neovascular recruitment and the induction of tissue regeneration in the traumatized bone. Thirty male Sprague-Dawley rats (6 months old) were subjected to an experimental model of traumatic ONFH divided into two groups, according to the administration of 5 mg/kg sildenafil or water (control group). Rats were then killed at 7, 14, and 21 days. Histological (Goldner's trichrome), histochemical (periodic acid-Schiff [PAS]), and immunohistochemical (VEGF and osteopontin [OPN]) techniques were used to quantify bone and vascular responses. Higher levels of VEGF (p < 0.01) and OPN (p < 0.01) immunostaining in the epiphysis, the greater formation of osteoid tissue (p < 0.01 on Day 7; p < 0.05 on Day 14), and higher levels of PAS staining (p < 0.01 on Day 7) were observed in the sildenafil-treated group. The present study demonstrated that sildenafil optimized bone tissue regeneration by increasing VEGF signaling and OPN expression, with increased bone formation (osteoid and carbohydrate macromolecule deposition) in the early stages following traumatic ischemic insult. Thus, sildenafil treatment may improve the prognosis of patients with osteonecrosis.

Pharmacological treatment and inappropriate prescriptions for patients with erectile dysfunction.

Background Erectile dysfunction is associated with old age, some morbidities and the use of certain medications. Objective To identify the treatments and drugs related to worsening sexual activity in patients with erectile dysfunction. Setting Patients diagnosed with erectile dysfunction during 2018. Methods This cross-sectional study of a population database identified all drug prescriptions of patients with erectile dysfunction during 2018. Main outcome measure The identification of other comorbidities and potentially inappropriate drugs that could worsen erectile dysfunction. Results A total of 2999 patients with erectile dysfunction (mean age 59.6 ± 12.1 years) were identified. A total of 88.2% received pharmacological treatment for erectile dysfunction, mainly tadalafil (70.5%). A total of 47.6% of all patients received at least one medication associated with worsening erectile dysfunction, especially hydrochlorothiazide (17.0%), metoprolol (7.9%) and sertraline (6.7%). Residing in Cali (OR 1.86; 95% CI 1.52-22.27) or Bucaramanga (OR 2.23; 95% CI 1.39-33.58), having 3 or more chronic comorbidities (OR 1.52; 95% CI 1.04-2.24) and presenting psychiatric (OR 5.5; 95% CI 3.70-8.17), cardiovascular (OR 3.48; 95% CI 2.79-4.33), genitourinary (OR 1.31; 95% CI 1.05-1.64) pathologies or chronic kidney failure (OR 1.84; 95% CI 1.18-2.21) elevated the probability of receiving these prescriptions. Conclusions The pharmacological treatment of erectile dysfunction was in accordance with the recommendations of clinical practice guidelines, but the high proportion of potentially inappropriate prescriptions makes it necessary to promote educational and pharmacovigilance strategies that improve the prescription habits of physicians involved in caring for this group of patients.

Do avanafil and zaprinast exert positive effects on bone tissue via the nitric oxide/cyclic guanosine monophosphate/protein kinase-G signaling pathway in rats with ovariectomy-induced osteoporosis?

Phosphodiesterase-5 inhibitors (PDE-5Is) exert positive effects on bone healing and mineralization by activation the nitric oxide/cyclic guanosine monophosphate/protein kinase-G (NO/cGMP/PKG) signaling pathway. In this study, the effects of zaprinast and avanafil, two PDE-5Is, on the NO signaling pathway, estrogen levels, selected bone formation and destruction marker levels, whole-body bone mineral density (WB-BMD), right femur trabecular bone thickness (RF-TBT) and epiphyseal bone width, angiogenesis in the bone-marrow, and selected oxidative stress parameter levels were investigated in rats with ovariectomy-induced osteoporosis. Twenty four adult rats (8 months old) were equally divided into four groups. The first group was the sham operated group. Groups 2, 3 and 4 included ovariectomized rats. At six months after ovariectomy, the 3rd and 4th groups were administered 10 mg/kg zaprinast and avanafil daily as a single dose for 60 days, respectively. Increases in the activity of the NO/cGMP/PKG signalling-pathway, C-terminal collagen peptide levels, angiogenesis in the bone marrow, RF-TBT, epiphyseal bone width and WB-BMD were observed compared to the ovariectomized positive control group (OVX), while the pyridinoline and deoxypyridinoline levels were decreased in the OVX+zaprinast and OVX+avanafil groups (p<0.05). The malondialdehyde, ubiquinone10/ubiquinol10 and 8-hydroxy-2-deoxyguanosine/106deoxyguanosine levels were also increased in the ovariectomized groups compared to the sham group (p<0.05). Based on these results, the levels of bone atrophy and some markers of oxidative stress were increased due to acute estrogen deficiency induced by ovariectomy, but zaprinast and avanafil administration significantly prevented these changes

Male sexual enhancers from the Peruvian Amazon.

ETHNOPHARMACOLOGICAL RELEVANCE: Selected Peruvian Amazon plants are macerated into sugar cane distillates to prepare alcoholic beverages used to improve male sexual performance. The tree bark from Campsiandra angustifolia Spruce ex Benth (Fabaceae), Swartzia polyphylla DC (Fabaceae), Minquartia guianensis Aubl. (Olacaceae) and Thynantus panurensis (Bureau) Sandwith (Bignoniaceae) usually are used as crude drugs in mixtures of several ingredients. AIM OF STUDY: Describe the chemical composition of the most traded traditional male enhancer beverages, namely "Levántate Lazaro" and "Siete veces sin sacarla", and their single crude drug constituents, as well as their inhibitory activity towards the enzyme phosphodiesterase-5. The presence of pro-sexual drugs such as Sildenafil® and derivatives was assessed in the samples. MATERIALS AND METHODS: Single plant constituents and the preparation mixtures were purchased in the Mercado Belen (Iquitos, Peru). Chemical profiling was carried out by HPLC-DAD-ESI-MS/MS. The extracts were assessed for phosphodiesterase-5 inhibition. The occurrence of pro-sexual drugs was determined by HPLC-DAD-ESI-MS/MS. RESULTS: Chemical profiling allowed the identification of condensed tannins as the main constituents of C. angustifolia and S. polyphylla, hydrolysable tannins for M. guianensis, and C-glycosides for T. panurensis. The traditional preparations showed similar composition compared to the crude drugs. At 200 µg/mL, the traditional preparation "Levántate Lázaro" and "Siete veces sin sacarla" inhibited the phosphodiesterase-5 by 49.88% and 27.90%, respectively. No adulterations with pro-sexual drugs were found in the samples. From the crude drugs, low effect was found for the extracts of S. polyphylla and T. panurensis and high activity for C. angustifolia which inhibited the enzyme by 89.37% and 81.32% at 200 and 100 µg/mL, respectively. CONCLUSION: The traditional preparations used to improve sexual performance in the Peruvian Amazon showed activity as phosphodiesterase-5 inhibitors. The most active ingredient of the traditional preparations was C. angustifolia, with some contribution from T. panurensis. These results encourage additional studies, including animal models to confirm the male enhancer effect of the preparations.

Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease.

BACKGROUND: Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. METHODS: We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days. RESULTS: Compared to controls, patients had elevated baseline ß-thromboglobulin (ß-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of ß-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05). CONCLUSION: In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.

Surdez súbita em paciente em uso de tadalafil: um relato de caso clínico / Sudden deafness in a patient with tadalafil use: a clinical case report

Introdução: a Surdez Súbita (SS) é uma emergência médica de baixa prevalência, porém com potencial de perda auditiva irreversível para o paciente. Possui diversos e ainda incertos mecanismos etiopatológicos. Recentemente a literatura vem trazendo a associação da SS com a classe dos inibidores da fosdodiesterase-5 (IPDE-5), a qual inclui medicamentos para tratamento de impotência sexual. Objetivo: relatar caso clínico de paciente idoso que apresentou SS após fazer uso de medicamento da classe dos IPDE-5, pesquisando na literatura qual a provável fisiopatologia. Metodologia: trata-se de estudo qualitativo, descritivo do tipo relato de caso clínico, realizado através da coleta de dados do prontuário médico, que foram comparados com literatura especializada. Resultado: paciente masculino, 72 anos, engenheiro, procurou atendimento referindo hipoacusia e plenitude aural à direita notados subitamente há três dias. Relata ter feito uso de Tadalafil 5mg, anteriormente aos sintomas. Anamnese e exame físico direcionaram para hipótese diagnóstica de SS, de modo que exames complementares foram solicitados. À audiometria evidenciou-se perda auditiva sensorioneural moderada a severa em orelha direita. Após tratamento com prednisolona oral e mesilato de codergocrina, paciente apresentou melhora, com audiometria evidenciando perda sensorioneural leve em orelha direita. Conclusão: a relação entre SS e o uso de IPDE-5 está cada vez mais evidente de acordo com a literatura. É provável que possa haver ativação de vias de estresse celular, contribuindo para patologia

Efficacy of phosphodiesterase type 5 inhibitors for the treatment of distal ureteral calculi: A systematic review and meta-analysis.

PURPOSE: To determine the efficacy of phosphodiesterase type 5 inhibitors (PDE5i) as medical expulsive therapy (MET) for the treatment of distal ureteral calculi. MATERIALS AND METHODS: A search strategy was conducted in the MEDLINE, CENTRAL, and Embase databases. Searches were also conducted in other databases and unpublished literature. Clinical trials were included without language restrictions. The risk of bias was evaluated with the Cochrane Collaboration's tool. An analysis of random effects due to statistical heterogeneity was conducted. The primary outcome was the expulsion rate of the distal ureteral calculus in 28 days. The secondary outcomes were the time to expulsion, side effects of treatment, and amount (mg) of nonopioid analgesia. The measure of the effect was the risk difference (RD) with a 95% confidence interval (CI). The planned interventions were PDE5i vs. placebo, tadalafil vs. placebo, and tadalafil vs. tamsulosin. RESULTS: Four articles were included in the qualitative and quantitative analysis. Records of 580 patients were found among the four studies. A low risk of bias was shown for the majority of the study items. The calculi expulsion rate had an RD of 0.26 (95% CI, 0.15-0.37) and a less prolonged expulsion as a secondary outcome with a mean difference of -4.39 days (95% CI, -6.69 to -2.09) in favor of PDE5i compared with the placebo. No significant difference was found for these outcomes when comparing tadalafil with tamsulosin. CONCLUSIONS: Compared with a placebo, PDE5i could be effective as MET for the treatment of distal ureter calculi.

Sildenafil (Viagra(®)) prevents and restores LPS-induced inflammation in astrocytes.

Astrocytes are effectively involved in the pathophysiological processes in the central nervous system (CNS) and may contribute to or protect against development of inflammatory and degenerative diseases. Sildenafil is a potent and selective phosphodiesterase-5 (PDE-5) inhibitor, which induces cyclic GMP accumulation. However, the mechanisms of actions on glial cells are not clear. The aim of the present work is to evaluate the role of sildenafil in lipopolysaccharide (LPS)-stimulated astrocytes. The cytoskeleton integrity and Ca(2+) waves were assessed as indicators of inflammatory state. Two main groups were done: (A) one prevention and (B) one restoration. Each of these groups: A1: control; A2: LPS for 24h; A3: sildenafil 1 or 10µM for 4h and then sildenafil 1 or 10µM+LPS for 24h. B1: control; B2: LPS for 24h; B3: LPS for 24h and then LPS+sildenafil 1 or 10µM for 24h. Cytoskeleton integrity was analyzed through GFAP immunolabeling and actin labeling with an Alexa 488-conjugated phalloidin probe. Calcium responses were assessed through a Ca(2+)-sensitive fluorophore Fura-2/AM. The results show that both preventive and restorative treatments with sildenafil (in both concentrations) reduced the Ca(2+) responses in intensity and induced a more organized actin fiber pattern, compared to LPS treated cells. This work demonstrated for the first time that astrocytes are a key part of the sildenafil protective effects in the CNS.

Psychotherapy and phosphodiesterase-5 inhibitor in early rehabilitation after radical prostatectomy: a prospective randomised controlled trial.

The aim of this study was to evaluate the impact of group psychotherapy and the use of a phosphodiesterase-5 inhibitor (PDE-5i) in the early rehabilitation stage of patients with prostate cancer undergoing radical prostatectomy (RP). Fifty-six patients undergoing RP for prostate cancer were randomised into four groups, and 53 completed the protocol: Group 1 - control (n = 11), Group 2 - group psychotherapy (n = 16), Group 3 - lodenafil 80 mg/one tablet per week (n = 12) and Group 4 - group psychotherapy + lodenafil 80 mg/one tablet per week (n = 14). The groups were individually evaluated for erectile function (IIEF-5) and quality of life - QoL (SF-36) weekly, with two meetings held a week apart before the RP and 12 weekly meetings after surgery. The ages ranged from 39 to 76 years, average 61.84. There were no significant medication side effects. Only Group 4 showed improvement in intimacy with a partner and satisfaction with their sex life (P = 0.045 and P = 0.013 respectively), and with no significant worsening of the IIEF-5 (P = 0.250) reported. All groups showed worsening in the final result of the role limitations caused by physical problems (P = 0.009) and role limitations caused by emotional problems (P = 0.002) of the SF-36, but Group 4 had a significantly higher score for the role limitations caused by physical problems (P = 0.009) than the other groups. In conclusion, precocious integral treatment involving group psychotherapy and PDE-5i before and after RP led to less deterioration of erectile function and other domains related to physical aspects (SF-36), with improvement in intimacy with their partner and satisfaction in their sex life, being superior to single treatments.