Erythropoietin in Recurrent Anterior Ischaemic Optic Neuropathy

A 44-year-old man suffered sequential episodes of anterior ischaemic optic neuropathy in first the left and then right eye. He had suffered a previous episode of anterior ischaemic optic neuropathy in the right eye. Recent studies have shown neuroprotective properties of erythropoietin. Based on our previous studies on erythropoietin in anterior ischaemic optic neuropathy, we used intravenous erythropoietin in this patient. The patient received intravenous human recombinant erythropoietin. Visual functions significantly improved following treatment. Intravenous erythropoietin, as a neuroprotective agent, may herald a new modality of treatment in anterior ischaemic optic neuropathy.     

星状神经节阻滞联合西地那非治疗阳痿的疗效对照分析

目的比较星状神经节阻滞联合西地那非与单独西地那非治疗阳痿的疗效。方法将120例阳萎患者随机分为治疗组和对照组(各60例)。治疗组用星状神经节阻滞联合西地那非治疗,星状神经节阻滞隔日一次,15次为一疗程,西地那非首服剂量为50mg、最大为100mg,性生活前1小时服用,每周至少服用一次,两次服药间隔时间不能少于24小时,每周服药不宜超过3次,1个月为一疗程。对照组单独服西地那非,方法同治疗组。结果两组的阳痿都较疗前有明显改善,均有极显著性差异(P<0·01);两组间比较,治疗组的疗效明显优于对照组,有显著性差异(P<0·05)。结论星状神经节阻滞联合口服西地那非对阳萎的疗效明显优于单独服西地那非。     

Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo

Colorectal cancer is the third most common human cancer with frequent overexpression of the cGMP-specific phosphodiesterase 5 (PDE5). In the present study, we investigated that the anticancer effect of sildenafil on human colorectal cancer in vitro and in vivo, which is a potent and selective inhibitor of PDE5 for the treatment of erectile dysfunction and pulmonary arterial hypertension in the clinic. Sildenafil significantly induced cell growth inhibition, cell cycle arrest and apoptosis of human colorectal cancer with increased intracellular reactive oxidative specie (ROS) levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins and PARP etc. Pretreatment with ROS scavenger N-acetyl-L-cysteine could reverse sildenafil-induced ROS accumulation and cell apoptosis. Inhibition of the activity of protein kinase G with KT-5823 could enhance sildenafil-induced apoptosis. Furthermore, sildenafil caused the reduction of xenograft models of human colorectal cancer in nude mice. Overall, these findings suggest that sildenafil has the potential to be used for treatment of human colorectal cancer.     

The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects

IntroductionFemale sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as T+S.AimThe aim of this study was to compare the effect of a fed and a fasted state on the pharmacokinetics of sildenafil following administration of T+S.MethodsEighteen healthy women were administered T+S under fed and fasted conditions during 2 separate overnight visits in this randomized, open-label, balanced, 2-period, 2-treatment, 2-sequence crossover study.Main Outcome MeasuresThe pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil were determined over a 24-hour period. Total testosterone was assessed only at a limited number of time points for quality purposes, as sublingual uptake is not expected to be affected by food intake.ResultsThe observed geometric mean ratios (GMRs) and 90% confidence intervals of sildenafil were not all contained within the prespecified bounds (0.80, 1.25). The GMR (90% CI) for plasma AUC_0–last was 1.2753 (0.9706–1.6755); for AUC_0–14h, it was 1.7521 (1.0819–2.8374); and for C_max, it was 1.5591 (0.8634–2.8153). Only lower limits of the CIs fell within the bounds. For N-desmethyl sildenafil, the GMR (90% CI) for AUC_0–last was 0.8437 (0.6738–1.0564); for AUC_0–10h, it was 1.0847 (0.7648–1.5383); and for C_max, it was 1.0083 (0.6638–1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone C_max and T_max under fed and fasted conditions, which is in line with expectations for a sublingual administration.Clinical ImplicationsThe T+S combination tablet ruptures too late when taken in a fasted state and should therefore not be taken on an empty stomach.Strengths & LimitationsThis is a well-controlled study that provides important insights into the performance characteristics of the delayed-release coating of the combination tablet. The higher variability of the pharmacokinetic parameters in the fasted state was caused by severely delayed rupture in one-third of the women. A reason for this is proposed but the present data do not explain this phenomenon.ConclusionThe pharmacokinetics of sildenafil from this modified-release tablet are more robust under fed conditions as compared to the artificial fasted condition where no food is consumed 10 hours prior to and 4 hours after dosing. The dosing situation under the tested fasting condition does not represent the expected common use of this product. Patients should, however, be instructed not to take the tablet on an empty stomach.Bloemers J, Gerritsen J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Sildenafil After Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects. J Sex Med 2019; 19:1433–1443.     

枸橼酸西地那非凝胶剂基质考察及体外溶出度测定

目的:考察枸橼酸西地那非凝胶剂的基质,并对其体外溶出度进行测定.方法:建立枸橼酸西地那非含量测定高效液相色谱法,筛选了该凝胶剂的处方工艺.结果:HPLC法以pH 3.0三乙胺-甲醇-乙腈(58:25:17,V:V:V)作为流动相;采用ZORBAX SB-C18色谱柱(4.6 mm×250 mm,5μm),在5～100μg·mL-1的浓度范围内枸橼酸西地那非线性关系良好,线性方程为Y=25.58X-2.9823,r2=0.9997;通过单因素实验考察,以10％明胶-3％蔗糖作为凝胶基质的处方;通过药物含量及溶出度测定,在1～3 mg·mL-1药物浓度范围内,药物回收与投药量存在线性关系,Y=0.823X+0.053(r2=0.9989),可作为凝胶剂药物含量设定的参考;且在pH 1.0盐酸介质中,3种药物浓度的凝胶剂均有较好的溶出行为.结论:筛选出枸橼酸西地那非凝胶剂优化处方,有利于小儿服用.     

Sildenafil for pulmonary hypertension: dose-dependent improvement in exercise performance

Sildenafil has been widely used as an orphan drug for several years, mostly at a dose of 50mg tid. Since a recent randomized study showed no dose-response relationship, the target dose in future will be 20mg tid. This might, however, have a negative effect on patients being already on 50mg tid. During the past years we usually up-titrated the sildenafil dosage in monthly intervals from 12.5 to 25mg, and then finally to 50mg tid. Therefore, we wondered if a dose-response relationship could be found in a group of 23 patients, in whom we had measured a 6-min walking distance (6-MWD) at all time points. The 6-MWD was virtually unchanged during the treatment with sildenafil 12.5 and 25mg tid, respectively. However, there was a significant improvement by 34+/-63 and 26+/-47m in the 6-MWD after increasing the sildenafil dose to 50mg tid compared with baseline (p=0.015) and 25mg tid (p=0.014), respectively. In conclusion, these data suggest that sildenafil has a clinically relevant dose-response relationship with a significant improvement in 6-MWD only at a dose of 50mg tid.     

Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis

AIM： To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient （HVPG） in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown. METHODS： Ten patients with biopsy proven cirrhosis （five females/five males, mean age 54：1：8 years） and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick＇s principle, with correction for non-steady state. RESULTS： The plasma concentration of sildenafil was 222 ± 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 ±7 mmHg to 66 ± 12 mmHg, P = 0.003, while the splanchnicblood flow and oxygen consumption remained unchanged at 1.14 ± 0.71 L/min and 2.3 ± 0.6 mmol/ min, respectively. Also the HVPG remained unchanged （18 ± 2 mmHg vs 16 ± 2 mmHg） with individual changes ranging from -8 mmHg to ±2 mmHg. In seven patients, HVPG decreased and in three it increased. CONCLUSION： In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanichnic blood flow, oxygen consumption or the HVPG.