Mechanism of tryptanthrin in treatment of ulcerative colitis in mice based on serum metabolomics / 中国中药杂志

This study aims to explore the effect of tryptanthrin on potential metabolic biomarkers in the serum of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) based on liquid chromatography-mass spectrometry(LC-MS) and predict the related metabolic pathways. C57BL/6 mice were randomly assigned into a tryptanthrin group, a sulfasalazine group, a control group, and a model group. The mouse model of UC was established by free drinking of 3% DSS solution for 11 days, and corresponding drugs were adminsitrated at the same time. The signs of mice were observed and the disease activity index(DAI) score was recorded from the first day. Colon tissue samples were collected after the experiment and observed by hematoxylin-eosin(HE) staining. The levels of interleukin-4(IL-4), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-8(IL-8) in the serum were measured by enzyme linked immunosorbent assay(ELISA). The serum samples were collected from 6 mice in each group for widely targeted metabolomics. The metabolic pathways were enriched by MetaboAnalyst 5.0. The results showed that compared with the model group, tryptanthrin treatment decreased the DAI score(P<0.05), alleviated the injury of the colon tissue and the infiltration of inflammatory cells, lowered the levels of proinflammatory cytokines, and elevated the levels of anti-inflammatory cytokines in the serum. The metabolomic analysis revealed 28 differential metabolites which were involved in 3 metabolic pathways including purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. Tryptanthrin may restore the metabolism of the mice with UC induced by DSS to the normal level by regulating the purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. This study employed metabolomics to analyze the mechanism of tryptanthrin in the treatment of UC, providing an experimental basis for the utilization and development of tryptanthrin.

Effects of PDE type 5 inhibitors on Left Ventricular Diastolic Dysfunction in Resistant Hypertension / Efeitos dos Inibidores da PDE do Tipo 5 sobre a Disfunção Diastólica Ventricular Esquerda na Hipertensão Arterial Resistente

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

A Hipertensão arterial resistente (HAR) é uma doença multifatorial caracterizada por níveis pressóricos acima das metas (140/90 mmHg), a despeito de tratamento farmacológico otimizado de 3 ou mais fármacos anti-hipertensivos de diferentes classes. Pacientes diagnosticados como hipertensos resistentes apresentam alta prevalência de disfunção diastólica do ventrículo esquerdo (DDVE) que proporciona risco aumentado para insuficiência cardíaca. Esta revisão reúne dados de estudos prévios avaliando os efeitos dos inibidores de fosfodiesterase-5 (PDE-5) (administração aguda de sildenafil e de curto prazo de tadalafil) na função diastólica e nos parâmetros bioquímicos e hemodinâmicos em pacientes com HAR. O estudo agudo com sildenafil demonstrou que a inibição da PDE-5 melhorou os parâmetros hemodinâmicos e de relaxamento diastólico. Além disso, o estudo curto prazo com o uso de tadalafil revelou melhora da DDVE e dos níveis de GMPc e BNP-32, independente de redução de pressão arterial. A função endotelial não apresentou alteração com ambos os tratamentos. Os resultados dos estudos agudo e de curto prazo sugerem efeitos terapêuticos potenciais dos fármacos inibidores da PDE-5 na disfunção diastólica em pacientes com HAR.

PDE5 Inhibitor Treatment Persistence and Adherence in Brazilian Men: Post-hoc Analyses from a 6-Month, Prospective, Observational Study

Purpose Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Materials and Methods Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. Results 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Conclusion Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment. .

Inibidores da fosfodiesterase do tipo 5 e perda auditiva neurossensorial subita / Phosphodiesterase Type 5 Inhibitors and sudden sensorineural hearing loss

O uso de inibidores da fosfodiesterase do tipo 5 como sildenafil, vardenafil e tadalafil tem aumentado atualmente e alguns destes pacientes vêm apresentando perda auditiva neurossensorial súbita. OBJETIVO: Apresentar dois casos de pacientes que apresentaram surdez súbita em uso eventual do medicamento e revisar estudos sobre o uso de inibidores da fosfodiesterase do tipo 5 e surdez súbita. MÉTODO: Estudo analítico de dois casos e revisão sobre o tema no banco de dados da Pubmed/ MedLine e Bireme utilizando as palavras-chave inibidores da fosfodiesterase e surdez súbita e seus correlatos na língua inglesa. RESULTADOS: Os pacientes analisados são jovens, sem comorbidades, em uso de inibidores da fosfodiesterase do tipo 5 e após terapia combinada para o tratamento da surdez súbita, apenas um deles obteve melhora auditiva. Nove estudos científicos foram encontrados. Estudos pré-clínicos e clínicos, transversais e prospectivos foram revisados. CONCLUSÃO: O aumento da ocorrência na prática clínica e relatos científicos na literatura sugerem que o uso de inibidores da fosfodiesterase do tipo 5 seja encarado como fator de risco para surdez súbita. Novos estudos com amostras maiores e grupo controle são necessários para investigar esta associação. .

Phosphodiesterase type 5 Inhibitors, such as sildenafil, vardenafil and tadalafil have been increasingly used today and some of the users have developed sudden sensorineural hearing loss. OBJECTIVE: To present two patients with sudden deafness developed after an occasional use of the drug and review studies on the use of phosphodiesterase type 5 inhibitors and sudden hearing loss. METHOD: Analytical study of two cases and review of the subject matter in the Pubmed/Medline and Bireme databases using the keywords: phosphodiesterase type 5 inhibitors and sudden deafness and its correlates in the English language. RESULTS: The patients analyzed are young without additional disorders, using phosphodiesterase type 5 inhibitors, and after combination treatment for sudden hearing loss only one had hearing improvement. We found nine scientific studies and reviewed preclinical studies, clinical trials, prospective and cross-sectional investigations. CONCLUSION: Increased occurrence in clinical practice and scientific reports in the literature suggest that the phosphodiesterase type 5 inhibitors are considered a risk factor for sudden deafness. Further studies with larger samples and control groups are needed for better assessing this association. .

Sildenafil vs. Nitroprussiato de Sódio durante Teste de Reatividade Pulmonar pré-transplante cardíaco / Sildenafil vs. sodium before nitroprusside for the pulmonary hypertension reversibility test before cardiac transplantation

FUNDAMENTO: A hipertensão pulmonar é associada ao pior prognóstico no pós-transplante cardíaco. O teste de reatividade pulmonar com Nitroprussiato de Sódio (NPS) está associado a elevados índices de hipotensão arterial sistêmica, disfunção ventricular do enxerto transplantado e elevadas taxas de desqualificação para o transplante. OBJETIVO: Neste estudo, objetivou-se comparar os efeitos do Sildenafil (SIL) e NPS sobre variáveis hemodinâmicas, neuro-hormonais e ecocardiográficas durante teste de reatividade pulmonar. MÉTODOS: Os pacientes foram submetidos, simultaneamente, ao cateterismo cardíaco direito, ao ecocardiograma e à dosagem de BNP e gasometria venosa, antes e após administração de NPS (1 - 2 µg/Kg/min) ou SIL (100 mg, dose única). RESULTADOS: Ambos reduziram a hipertensão pulmonar, porém o nitrato promoveu hipotensão sistêmica significativa (Pressão Arterial Média - PAM: 85,2 vs. 69,8 mmHg, p < 0,001). Ambos reduziram as dimensões cardíacas e melhoraram a função cardíaca esquerda (NPS: 23,5 vs. 24,8 %, p = 0,02; SIL: 23,8 vs. 26 %, p < 0,001) e direita (SIL: 6,57 ± 2,08 vs. 8,11 ± 1,81 cm/s, p = 0,002; NPS: 6,64 ± 1,51 vs. 7,72 ± 1,44 cm/s, p = 0,003), medidas pela fração de ejeção ventricular esquerda e Doppler tecidual, respectivamente. O SIL, ao contrário do NPS, apresentou melhora no índice de saturação venosa de oxigênio, medido pela gasometria venosa. CONCLUSÃO: Sildenafil e NPS são vasodilatadores que reduzem, de forma significativa, a hipertensão pulmonar e a geometria cardíaca, além de melhorar a função biventricular. O NPS, ao contrário do SIL, esteve associado a hipotensão arterial sistêmica e piora da saturação venosa de oxigênio.

BACKGROUND: Pulmonary hypertension is associated with a worse prognosis after cardiac transplantation. The pulmonary hypertension reversibility test with sodium nitroprusside (SNP) is associated with a high rate of systemic arterial hypotension, ventricular dysfunction of the transplanted graft and high rates of disqualification from transplantation. OBJECTIVE: This study was aimed at comparing the effects of sildenafil (SIL) and SNP on hemodynamic, neurohormonal and echocardiographic variables during the pulmonary reversibility test. METHODS: The patients underwent simultaneously right cardiac catheterization, echocardiography, BNP measurement, and venous blood gas analysis before and after receiving either SNP (1 - 2 µg/kg/min) or SIL (100 mg, single dose). RESULTS: Both drugs reduced pulmonary hypertension, but SNP caused a significant systemic hypotension (mean blood pressure - MBP: 85.2 vs. 69.8 mm Hg; p < 0.001). Both drugs reduced cardiac dimensions and improved left cardiac function (SNP: 23.5 vs. 24.8%, p = 0.02; SIL: 23.8 vs. 26%, p < 0.001) and right cardiac function (SIL: 6.57 ± 2.08 vs. 8.11 ± 1.81 cm/s, p = 0.002; SNP: 6.64 ± 1.51 vs. 7.72 ± 1.44 cm/s, p = 0.003), measured through left ventricular ejection fraction and tissue Doppler, respectively. Sildenafil, contrary to SNP, improved venous oxygen saturation, measured on venous blood gas analysis. CONCLUSION: Sildenafil and SNP are vasodilators that significantly reduce pulmonary hypertension and cardiac geometry, in addition to improving biventricular function. Sodium nitroprusside, contrary to SIL, was associated with systemic arterial hypotension and worsening of venous oxygen saturation.

Efecto de esfingolípidos y Agelosina B en la movilización de Ca2+ y la señalización celular en células de cáncer de mama (MCF-7) y su relación con la apoptosis / Effect of sphingolipids and Agelosin B on Ca2 + mobilization and cell signaling in breast cancer cells (MCF-7) and its relationship with apoptosis

Los esfingolípidos, como la ceramida (Cer), la ceramida-1-fosfato (C-1-P), la esfingosina (Sph) y la esfingosina-1-fosfato (S-1P) estan relacionados con la señalización intracelular en procesos como crecimiento celular, movilización intracelular de Ca+2 y apoptósis. En este trabajo se evaluó el efecto de estos esfingolípidos en la homeostasis de Ca+2 intracelular y en la apoptósis en células de cáncer de mama MCF-7. Se utilizaron fluoróforos específicos para el Ca+2 y microscopía confocal. Se demostró que en estas células, la Sph (20 uM), la Cer (10uM), la S-P (2uM) y la C--P (uM) aumentaron la concentración intracelular ce Ca+2, induciendo su liberación desde el retículo endoplasmático (RE). Además, se observo que la esfingosina abrioun canal de Ca2+ en la membrana plasmática. También se demostró que la Cer inhibe parcialmente la actividad de la Ca2+-ATPasa del RE (SERCA), de forma dosis dependiente, mientras que la ceramina, su análogo no hidrolisable la inhibe totalmente. La Sph también inhibe completamente la actividad de la SERCA, a la misma concentración que induce la liberación del Ca+2 del RE. Asimismo, se evaluó el efecto de estos esfingolípidos sobre la inducción de la apotósis en células MCF-7 evidenciando que el tratamiento con la Cer, la ceramida, la Sph inducen toxicidad. También se observo que mientras la ceramida activo la caspasa 7 y la caspasa 8, el esfingolipido natural, la Cer no tuvo ningún efecto. Por su parte, la Sph activa la caspasa 8 sin modificar la activdad de la caspasa 7. Tanto la Cer, como la ceramida y la Sph, disminuyeron la expresión de la proteína Bcl-2 amti-apoptótica, y también indujeron la fragmentación de ADN, visualizada mediante la técnica de TUNEL, demostrando que estos esfingolípidos inducen apoptósis en MCF-7. La agelasina B, toxina purificada a partir de la esponja marina Agelas clathrodes tiene un efecto citotóxico un orden de magnitud mayor en MCF-7, en comparación con fibroplastos humanos. La agelasina B induce la liberación del Ca+2 almacenado en el RE en celulas MCF-7, ademas de inhibir la actividad de la SERCA en un 100%. También se demostró que esta toxina induce apoptosis, ya que disminuye el potencial de membrana mitocondrial, activa la caspasa 8, disminuye la expresion de la proteina Bcl-2 e induce fragmentación del ADN de las células MCF-7. Este mecanismo es similar al efecto de la tapsigargina.

The effect of sildenafil on the elasticity of erythrocytes in homozygous sickle cell disease.

Purpose: One of the features of homozygous sickle cell disease (HbSS) is the impaired elasticity of the erythrocyte membrane that could impede microcirculatory blood flow and cause hypoxia and tissue damage. We investigated the effect of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor that inhibits the breakdown of cyclic guanosine monophosphate (cGMP) resulting in vasodilatation, on the elasticity of HbSS erythrocyte. Materials and Methods: Blood samples from ten HbSS patients in steady state was exposed to different doses (5, 10, 20, and 40 μg/mL) of sildenafil and the elasticity of the erythrocytes measured at native hematocrit with the BioProfiler. An equal number of subjects with normal hemoglobin (HbAA) served as the control group. Results: There was a marginal increase in elasticity with 5 μg/mL of the drug and this became significant (P < 0.05) with the 10 μg/mL dose. Thereafter, gradual nonsignificant decreases were observed with the 20 and 40 μg/mL doses. A similar trend was observed for the control group. The elasticity values for the HbSS subjects at native hematocrit were significantly (P < 0.05) less when compared with the corresponding concentrations for the HbAA controls. This was reversed at a corrected hematocrit of 45%. Conclusion: The result of this study shows that sildenafil caused an initial increase in erythrocyte membrane elasticity in both HbSS and HbAA subjects, and this later decreased with increasing concentration of the drug possibly due to the dual effect of cyclic adenosine monophosphate (cAMP).

Tratamento da hipertensão pulmonar esquistossomótica / Treatment of schistosomiasis-associated pulmonary hypertension

A esquistossomose mansoni é a terceira doença parasitária endêmica mais prevalente do mundo. Estima-se que mais de 200 milhões de pessoas estejam infectadas com uma das espécies do parasita Schistosoma. Dessas, 270.000 pessoas (4,6 por cento) são portadoras de hipertensão arterial pulmonar, que é associada à forma hepatoesplênica da doença. Essa alta prevalência coloca a hipertensão pulmonar esquistossomótica como a causa mais frequente de hipertensão pulmonar no mundo. Entretanto, o tratamento dirigido especificamente ao acometimento vascular pulmonar não está ainda estabelecido. Relatamos o caso de uma paciente portadora dessa doença que foi tratada com um inibidor de fosfodiesterase-5 (sildenafil) com resultados satisfatórios.

Schistosomiasis mansoni is the third most prevalent endemic parasitic disease in the world. It is estimated that over 200 million people are infected with parasites belonging to one of the Schistosoma species. Of those, 270,000 people (4.6 percent) suffer from pulmonary arterial hypertension, which is associated with the hepatosplenic form of the disease. This high prevalence makes schistosomiasis-associated pulmonary hypertension the leading cause of pulmonary hypertension worldwide. However, no specific treatment for the pulmonary vascular component of the disease has yet been devised. We report the case of a patient with schistosomiasis-associated pulmonary hypertension who was treated satisfactorily with a phosphodiesterase-5 inhibitor (sildenafil).

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]

Seguimento de dois anos em pacientes com hipertensão arterial pulmonar sob tratamento com sildenafila / Two-year follow-up of pulmonary arterial hypertension patients treated with sildenafil

FUNDAMENTO: Os efeitos de longo prazo das drogas desenvolvidas para o controle da hipertensão arterial pulmonar (HAP) são pouco conhecidos, já que os estudos multicêntricos em geral têm duração de 12 a 16 semanas. OBJETIVO: Avaliar a evolução de dois anos, em pacientes com HAP submetidos à monoterapia com sildenafila (inibidor da fosfodiesterase-5), com respeito à capacidade funcional. MÉTODOS: Vinte e quatro pacientes (idade entre 8 e 54 anos) com HAP idiopática (HAPI, n = 9) ou associada a cardiopatias congênitas (HAP-CCg, n = 15) foram tratados com sildenafila por dois anos, com doses diárias que variaram de 60 a 225 mg (três tomadas), por via oral. A capacidade física foi avaliada pela distância caminhada no teste de 6 minutos (DC6M) e pelo grau de dispneia ao final da caminhada (escala de Borg), sendo também registrada a saturação periférica de oxigênio (SpO(2)6M, oximetria de pulso). RESULTADOS: Nos 18 pacientes que completaram dois anos de seguimento, houve incremento progressivo e sustentado na DC6M, tanto no grupo HAPI (de 239 ± 160 m para 471 ± 66 m, p = 0,0076) como no grupo HAP-CCg (de 361 ± 144 m para 445 ± 96m, p = 0,0031), com melhora da dispneia ao final da caminhada (p < 0,05 em ambos). Não houve decréscimo na SpO(2)6M nos grupos considerados; em particular, pacientes com HAP-CCg evoluíram de 77 ± 20 por cento para 79 ± 16 por cento (p = 0,5248). Houve 5 óbitos (três no grupo HAPI) e uma perda de seguimento no período. CONCLUSÃO: Em dois anos de seguimento, a sildenafila mostrou-se útil no controle da condição funcional de pacientes com HAP, com melhora significante nas duas etiologias consideradas.

BACKGROUND: The long-term effects of drugs developed for the control of pulmonary arterial hypertension (PAH) are little known, since multicenter studies usually last 12 to 16 weeks. OBJECTIVE: To evaluate the two-year outcome of PAH patients receiving monotherapy with sildenafil (a phosphodiesterase-5 inhibitor), with regard to their functional capacity. METHODS: Twenty four patients (ages between 8 and 54 years) with idiopathic PAH (IPAH, n = 9) or congenital heart disease-associated PAH (CHD-PAH, n = 15) were treated with sildenafil for two years, with daily oral doses ranging from 60 to 225 mg (tid). Physical capacity was assessed by the distance walked in the 6-minute walk test (DW6M) and by the degree of dyspnea at the end of the walk (Borg scale); peripheral oxygen saturation was also recorded (SpO(2)6M, pulse oximetry). RESULTS: In the 18 patients who completed the two-year follow-up, there was a progressive and sustained increase in DW6M, both in the IPAH group (from 239 ± 160 m to 471 ± 66 m, p = 0.0076) and in the CHD-PAH group (from 361 ± 144 m to 445 ± 96m, p = 0.0031), with improvement of dyspnea at the end of the walk (p<0.05 for both groups). No decrease in SpO(2)6M was observed in the groups; in patients with CHD-PAH, in particular, SpO(2)6M went from 77 ± 20 percent to 79 ± 16 percent (p = 0.5248). Five deaths occurred (three in the IPAH group) and one patient was lost to follow-up during the study period. CONCLUSION: In a two-year follow-up, sildenafil proved useful in the control of the functional status of PAH patients, with significant improvement in both groups considered.

Effect of Sildenafil on Neuropathic Pain and Hemodynamics in Rats

PURPOSE: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats. MATERIALS AND METHODS: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil. RESULTS: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response. CONCLUSION: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.

Central retinal vein occlusion in a patient after being commenced on sildenafil citrate for pulmonary arterial hypertension.

A 75-year-old female was commenced on sildenafil for the treatment of pulmonary arterial hypertension (PAH) secondary to chronic obstructive pulmonary disease (COPD). She reported blurring of vision within 72 hours after starting treatment and was found to have a central retinal vein occlusion (CRVO). Such an occurrence is the second case reported to date, and we review the possible mechanisms and literature on the subject.

Acute hemodynamic effects of sildenafil in patients with idiopathic dilated cardiomyopathy.

Sildenafil, a phosphodiestrase-5 inhibitor, decreases pulmonary artery pressures (PAP) in patients with idiopathic pulmonary hypertension. There is little data pertaining to its use in unselected patients with idiopathic dilated cardiomyopathy (IDCM). A single oral dose of sildenafil (50 mg) was administered to 11 patients (mean age 44.9 +/- 7 years, 7 males) with IDCM with left ventricular ejection fraction < or = 40% in New York Heart Association class II/III at the time of right heart catheterization. There was a significant decrease in pulmonary artery systolic pressure (from 31.5 +/- 9.7 to 19.0 +/- 5.2 mmHg, p < 0.001) and pulmonary vascular resistance (PVR) (from 3.0 +/- 2.1 to 1.6 +/- 0.8 dyne/s/m(2)/cm(5), p = 0.01) following sildenafil administration. The systemic vascular resistance (SVR) and pulmonary wedge capillary pressure also significantly decreased. No significant differences in heart rate, cardiac index and PVR/SVR ratio were observed. There were no side effects documented. Sildenafil produces favorable vasodilation in both pulmonary and systemic vascular beds with decrease in left ventricular filling pressures, in stable patients with IDCM.

Rituximab, 2a línea de tratamiento en leucemia de células vellosas / Rituximab 2nd line of treatment for hairy cell leukemia

La leucemia de células vellosas (LCV) es un desorden linfoproliferativo crónico caracterizado por: esplenomegalia, pancitopenia con linfocitos vellosos e infiltración de médula ósea y de bazo. Rituximab demuestra eficacia terapéutica y en pacientes con LCV refractaria/recaída.

Sildenafil improves survival in idiopathic pulmonary arterial hypertension.

AIMS AND OBJECTIVES: Idiopathic Pulmonary Arterial Hypertension (IPAH) is a serious disorder of unknown etiology with limited therapeutic options. Sildenafil has been shown to decrease symptoms, improve hemodynamics and quality of life. Its impact on survival is uncertain. We studied the efficacy of sildenafil in improving survival in patients with IPAH. METHODS AND RESULTS: Data on survival of patients with IPAH was collected from prospectively maintained registry at our hospital from January 1999 to December 2005. Thirty nine patients who were treated with conventional therapy including digoxin, diuretics, anticoagulants and calcium channel blockers prior to January 2001 served as historical controls (control group). One hundred and thirty nine patients received sildenafil additionally from January 2001 (sildenafil group). All patients in sildenafil group showed improvement in symptoms. Survival of patients in sildenafil group was significantly better compared to historical controls receiving only conventional therapy. It was 89%, 43% and 19% in the control group Vs 93%, 75% and 54% in the sildenafil group at the end of 1, 3 and 5 years respectively (P Value=0.0002). Sildenafil was well tolerated and none of the patients had to discontinue the treatment. CONCLUSION: Sildenafil when added to conventional therapy improves symptoms as well as survival significantly compared to conventional therapy alone. Further randomized controlled trials are needed to evaluate its impact on survival when used either alone or in combination with other drugs.

Resposta pressórica de pacientes com miocardiopatia chagásica ante o uso do sildenafil / Pressure response in chagasic cardiomyopathy patients after using sildenafil

OBJETIVO: Verificar o efeito do sildenafil na pressão arterial (PA) e freqüência cardíaca (FC) de indivíduos portadores de miocardiopata chagásica (MCC) e de disfunção ventricular sistólica grave (FE<40 por cento) submetidos à atividade física. MÉTODOS: Foram avaliados 12 homens com fração de ejeção<40 por cento e MCC confirmada por sorologia. Foi realizado o Teste de 6 minutos (T6M) antes e após a ingestão de sildenafil 50 mg, com intervalo de 30 minutos. Antes e depois de cada T6M aferiram-se a freqüência cardíaca (FC) e a pressão arterial sistólica (PAS) e diastólica (PAD). Para análise estatística, o estudo foi dividido em 4 etapas: Antes do T6M realizado antes do Sildenafil (T1); após o T6M, antes do Sildenafil (T2); após o sildenafil, antes do T6M (T3); após o Sildenafil, após o T6M (T4). RESULTADOS: A idade dos participantes variou entre 47 e 68 anos (57,6±6,4). PAS e PAD após o T6M e uso do sildenafil (T4) mostraram-se menores do que antes do fármaco (T2): 134,2±15,1 versus 125,5±14,0 e 88,4±12,4 versus 83,0±10,8, respectivamente. Nenhum indivíduo referiu sintomas durante a realização do T6M. Não houve diferença na distância total percorrida no T6M antes e depois do uso do sildenafil (487,5±15,22 versus 505,3±18,45 metros, respectivamente) - p=0,056, e na FC (antes sildenafil 75,5±8,79 e 96,8±10,36 bpm e após 77,1±9,81 e 96,1 ± 12,97 bpm). CONCLUSÃO: Observou-se significante diminuição da PA após atividade física sob uso do sildenafil. Entretanto, durante o Teste de 6 minutos, não foram relatados sintomas pelos pacientes, sugerindo, então, que esse efeito parece não ser suficiente para causar manifestações clínicas entre os portadores de MCC e insuficiência cardíaca.

OBJECTIVE: To accurately verify the effect of Sildenafil on blood pressure (BP) and heart rate (HR) in individuals with Chagasic myocardiopathy (CMC) and severe systolic ventricular dysfunction (EF<40 percent) submitted to physical activity. METHODS: Twelve men with ejection fractions <40 percent and CMC confirmed by a serological test were assessed. The six-minute walk test (6MWT) was performed before and after administration of 50 mg of Sildenafil, with a 30 minute interval. Heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure were taken and compared before and after each 6MWT. For statistical analysis purposes, the study was divided into four stages: before the 6MWT and administration of Sildenafil (S1); after the 6MWT but before the administration of Sildenafil (S2); after the administration of Sildenafil but before the 6MWT (S3); and after the administration of Sildenafil and the 6MWT (S4). RESULTS: Participant ages ranged from 47 to 68 years (57.6 ± 6.4). SBP and DBP after the 6MWT and the administration of Sildenafil (S4) were lower than before taking the drug (S2): 134.2 ± 15.1 versus 125.5 ± 14.0 and 88.4 ± 12.4 versus 83.0 ± 10.8, respectively. None of the patients reported any symptoms during the 6MWT. There were no differences in the distances walked during the 6MWT before or after taking Sildenafil (487.5±15.22 versus 505.3±18.45 meters, respectively)-p=0.056, or in HR (before Sildenafil 75.5 ± 8.79 and 96.8 ± 10.36 bpm and after 77.1 ± 9.81 and 96.1 ± 12.97 bpm). CONCLUSION: Based on these results, it can be concluded that both prediction equations significantly overestimated HRmax measured during maximal GXT in Brazilian elderly women, a finding that may have important implications when prescribing exercise intensity for this population. In addition, HRmax was inversely related to the volunteers' age, suggesting that the chronotropic reserve continues to decline after age 60.