Current Therapy of Pulmonary Hypertension

Abstract Pulmonary arterial hypertension (PAH) affects vascular proliferation and remodeling in small pulmonary arteries and results in right ventricular failure and death due to a progressive increase in pulmonary vascular resistance. Recent advances in understanding of the molecular mechanisms involved in PAH suggest that endothelial dysfunction plays a major role. Impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, accompanied with prolonged overexpression of vasoconstrictors such as endothelin-1, affects vascular tone and reinforces vascular remodeling. As the latter substances represent logical pharmacological targets, new drugs affecting these mechanisms have evolved during the past 2 decades and led to umpteen placebo-controlled trials in bygone years. Prognosis and quality of life of patients suffering from PAH seem to improve due to these new treatment strategies resulting in a reduction of mortality and morbidity, but there is still a substantial need for further long-term and head-to-head trials.     

Effect of acute in vivo sildenafil citrate and in vitro 8-bromo-cGMP treatments on semen parameters and sperm function

OBJECTIVE: To determine the effect of acute in vivo sildenafil citrate (VIAGRA) and in vitro 8-Bromo-cGMP treatments on semen parameters and sperm function. DESIGN: Prospective double-blind, placebo-controlled, crossover, two-period clinical investigation. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Twenty male volunteers with normal erectile function and normal electrocardiogram were recruited. INTERVENTION(S): In vivo: 50 mg of sildenafil citrate (VIAGRA) or placebo was administered p.o., and semen samples were collected 1 hour after administration of the test drug. In vitro: 8-Bromo-cGMP (20 microM; 60 minutes) was added to semen samples. MAIN OUTCOME MEASURE(S): Macroscopic and microscopic seminal parameters were measured and motility studies performed. Various acrosome reaction studies and sperm-zona pellucida binding studies were also done. RESULT(S): Either sildenafil citrate (VIAGRA) or 8-Bromo-cGMP treatments had no effect on both macroscopic and microscopic seminal parameters as well as the acrosome reaction. Sperm-zona pellucida binding results were however increased to 148.75% and 134%, respectively, by these treatments. Various kinematical parameters increased after treatment with the most significant increase detected in the population of rapid cells. CONCLUSION(S): VIAGRA can be used successfully to enhance sperm motility and binding to the oocyte especially during fertility treatments.     

The presence and function of phosphodiesterase type 5 in the rat myometrium

OBJECTIVE: Cyclic nucleotide phosphodiesterases (PDEs) are a diverse enzyme group with multiple regulatory properties and wide tissue distribution. Such activity includes cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) breakdown. The type 5 isoform (PDE-5, cGMP specific) is the target of specific antagonists (ie, sildenafil, Viagra). We tested the hypothesis that PDE-5 is present in rat myometrium and modulates myometrial activity. STUDY DESIGN: Full-thickness uterine wall was collected from nonpregnant (n=3) and pregnant Sprague-Dawley rats on days 10 (n=4), 17 (n=6), 22 nonlabor (n=5), and 22 during term labor (TL, n=4). Preterm labor (PTL, n=3) was induced in some animals on day 16 with 15 mg/kg mifepristone (RU 486). Tissue samples were prepared for Western blotting using a monoclonal antibody against rodent PDE-5. In a second series, cumulative doses of sildenafil (0.005, 0.05, 0.5, 5 mg/kg, intraperitoneal) were administered and the effect on uterine contractility recorded in vivo during term (TL, n=7) and preterm labor (PTL, n=6). Saline solution-injected rats provided temporal control. Uterine contractility was estimated from intrauterine pressure (IP) measured electronically with a sensor tip pressure catheter. Heart rate was recorded simultaneously using electrodes attached to the chest and connected to the same data acquisition system. RESULTS: PDE-5 immunoreactivity was present in the nonpregnant rat uterus and at all gestational times studied, although the expression was unaffected by either pregnancy or the state of labor (preterm or term). A dominant antibody-specific band was identified at 86 kd in the uterine samples, contrasting with lung where the 100-kd PDE-5 isoform was most abundant. Two additional lower molecular weight (55 and 32 kd) bands were also identified as antibody specific. Despite the lack of change in PDE-5 during pregnancy, sildenafil reduced IP during TL and PTL beginning at 0.5 mg/kg. The highest dose of sildenafil reduced IP during both TL and PTL by 45% and 59% of baseline, respectively (two-way analysis of variance, P<.01). This effect was not accompanied by changes in heart rate. CONCLUSION: PDE-5 is constitutively present in the rat uterine wall. There was no observed change in the PDE-5 protein expression throughout pregnancy. In contrast to the lung, the uterus expresses an 80-kd PDE-5 isoform. Sildenafil in pharmacologic doses inhibits mechanical uterine activity and might be of benefit if selectively used for treatment of preterm labor.     

Sildenafil (Viagra®): Is there an influence on psychological performance?

Background: Sildenafil (Viagra®) is a well-introduced medicine for erectile dysfunction; many studies about effects and side effects are published. Beside these aspects of treatment the influence of sildenafil on psychophysical performance is of interest. cGMP is one of the most important second messengers in the central nervous system(CNS), so even very small changes of the intracellular cGMP-level caused by phosphodiesterases inhibition may be relevant for CNS-function. We wanted to verify the hypothesis whether sildenfail influences human psychomotor performance, especially under the aspect of traffic safety,or not. Methods: Designed as a pilot study we tested 6 male healthy volunteers using a test battery of 7 different psychophysical performances tests. Each individual did the test battery twice, once without drug and once after a single oral dose of 100-mg sildenafil. 3persons did the first and 3 others did the second experiment under the influence of drug (UID). All results (37 parameters) were analysed by t-test for paired samples using a confidence interval of 95%. Results: Only two parameters of 2 different tests showed significant differences. In the simple choice reaction test (DR2) the mean reaction time got better in the group with sildenafil; in the multple choice reaction test with stress induction (RST3) the amount of wrong answers indicated a weak influence of performance without statistical significance, six parameters (dominantly in the speed anticipation test (DEST)) represented an increase and one other (RST3second part) showed a decrease UID. The uppermost parameters (76%of all items) stayed on equal levels for both groups. Conclusion: Sildenafil showed no important impairment of psychophysical performance, no strong improvement was found as well. With a look at the therapeutically indication of sildenafil the improvement in sexual activity may indicate no incapacity in traffic and other psychomotoric/psychophysical functions.     

口服西地那非治疗勃起功能障碍疗效和安全性的临床研究

目的：评估西地那非（艾艾可）治疗男性勃起功能障碍（ED）的有效性和安全性。方法：采用多中心，双盲，安慰剂平行随机对照,剂量可调整（25，50和100mg)方法，对628例ED患者进行为期8周的临床治疗观察。结果：西地那非使ED患者达到和维持壳起的临床总有效率为80．8％，显著高于安慰剂组的40．1％（P＜0．0001）；对心理性，器质性和混合性ED的有效率分别为80．8％，84．2％和79．4，同时对次要疗效指标评估（国际壳起功能指数中其余13个问题，记事表和总评题） 显示西地那非改善性生活的作用明显优于安慰剂，西地那非组性交成功率为69．0％，显著高于安慰剂组的27．5％，有89．2％，的西地那非组受试者认为药物改善了壳起功能，显著高于安慰剂组的37．4％，因各种原因中断研究的比例仅占2．3％，西地那非组与药物有关的不良事件发生率（28．4％）较安慰剂组高（12．2％），均为轻－中度，呈一过性。结论：西地那非是一种可治疗各种病因导致ED的安全，有效的药物，按需服用时能很好耐受。     

西地那非治疗勃起功能障碍的现状

简要介绍了西地那非的药理作用机制 ,着重阐述了该药对勃起功能障碍 (ED)的治疗效果及安全性 ,特别对高血压及服用抗高血压药物病人、心脏病病人、糖尿病病人、脊髓损伤病人、前列腺根治性手术后病人、长期透析病人等特殊人群的应用情况进行总结。西地那非对ED的治疗总体上有效、安全。     

西地那非与前列地尔治疗先天性心脏病术后肺动脉高压的疗效对比

目的比较口服西地那非(SIL)与静脉应用前列地尔(PGE1)治疗先天性心脏病(先心病)术后肺动脉高压(PH)的早期疗效。方法24例患者随机分为A、B、C三组:A组先鼻饲SIL0·35mg/kg,后静脉应用PGE120ng/(kg·min);C组顺序相反;B组为对照组。检测用药前后患者血流动力学参数、动脉血气、氧合指标及肺力学参数。结果与B组比较,两组在降低平均肺动脉压(mPAP)、mPAP/有创桡动脉压(mSAP)方面差异均具有统计学意义(P<0·01),SIL较PGE1作用更明显(P<0·05)。SIL可造成患者mSAP下降(P<0·01),但不需干预治疗;PGE1可抑制患者PaO2下降(P<0·05);两组对肺顺应性、呼吸功均无影响。结论两药均能有效降低此类患者肺动脉压力,而SIL口服使用更方便。因此,SIL可作为先心病术后治疗PH的新选择。     

2型糖尿病患者勃起功能障碍患病率及西地那非的疗效和安全性评价

目的调查内分泌门诊中糖尿病患者阴茎勃起功能障碍(ED)患病率,并评价西地那非(万艾可)在糖尿病合并ED患者中的疗效和安全性。方法多中心收集2型糖尿病男性患者6193例,入选6178例,患者签署知情同意书后,根据国际勃起功能指数表(IIEF5)患者进行自我评分。对3个月内服用3剂万艾可的患者除要求填写治疗前的IIEF5表评分外,还要求填写治疗后的总体疗效问题回答表,以评价万艾可治疗的疗效,并记录患者服药后的不良事件以评价其安全性。结果国内42家医院内分泌门诊2型糖尿病患者中ED的患病率为75.2%,其中重度、中度和轻度ED分别为9.1%、17.2%、48.9%。该受检人群中ED的知晓率为85.0%,但治疗率仅为9.4%。多因素回归分析显示患者年龄、糖尿病病程、血糖控制不佳(HbA1C>6.5%)与糖尿病患者ED的发生独立相关。共有389例患者服用万艾可治疗,治疗后患者IIEF5总评分和各问题的评分均显著高于治疗前(P<0.01);根据IIEF5评分,治疗后重、中度ED患者例数明显少于治疗前(P<0.01)。根据总体疗效评估问题的回答,给予万艾可治疗后勃起功能改善率达86.4%。对安全性评价显示服用万艾可后出现的与药物有关的不良事件主要是颜面潮红、头痛、心悸和口干等,大多为轻度。结论在2型糖尿病患者中ED是常见的合并症,万艾可治疗糖尿病合并ED疗效确切,并有良好的安全性。     

Combination of telmisartan with sildenafil ameliorate progression of diabetic nephropathy in streptozotocin-induced diabetic model

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the world. Several signaling pathways are involved in the pathogenesis of DN including elevation in level of angiotensin II, formation of advanced glycation end products (AGE), activation of protein kinase c (PKC), and lipid accumulation. These pathways activate one another mutually leading to oxidative stress, increasing expression of transforming growth factor beta-1(TGF-β 1) and release of interleukins and adhesion molecules, so the aim of this study is to interrupt more than pathogenic pathway to ameliorate the progression of DN. In the present study, white male rats (N = 48) were divided into six groups (8 rats each), the first two groups served as normal control and a control vehicle group while the remaining four groups were rendered diabetic by a single intraperitoneal injection of Streptozotocin (STZ) and being left for 4 weeks to develop DN. Thereafter, the rats were divided into DN group, DN group receiving Telmisartan or Sildenafil or Telmisartan Sildenafil combination. After the specified treatment period, urine samples were collected (using metabolic cages) to measure proteinuria, animals were then euthanized, blood and tissue samples were collected for measurement of Blood glucose,BUN, S.Cr, LDL, NO, TGF-β1, IL-1β, AGEPs, and SOD. The combination therapy showed significant decrease in BUN, S.Cr,LDL, TGF-β1, IL-1β, Proteinuria and AGEPs and significant increase in SOD and NO.The findings showed that combination therapy was able to ameliorate DN and that the effects were superior to the single drugs alone.     

The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop

A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs.