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。     

西地那非对器质性勃起功能障碍的夜间勃起作用

目的 探讨西地那非对器质性ED夜间勃起的作用。方法 对28例器质性ED患者予以万艾可100mg睡前口服，用NEVA监测夜间勃起情况。结果 器质性ED患者的勃起参数有明显改善（P〈0．05）。结论无性刺激条件下万艾可增强器质性ED患者夜间勃起。     

西地那非治疗2型糖尿病患者勃起功能障碍疗效分析

目的 评价西地那非治疗2型糖尿病(DM)患者勃起功能障碍(ED)的临床疗效.方法 门诊筛查ED患者,符合入选标准及排除标准的ED并伴有2型DM患者42例作为实验组,另于门诊选择同期无DM的单纯ED患者40例作为对照组.按需给予西地那非治疗,3个月后随访,完善疗效评价量表.结果 实验组患者用药后IIEF-5评分,显著高于用药前两者比较差异有统计学意义(P<0.01).全球疗效问题阳性答复百分率为76.2%.与对照组患者相比差异无统计学意义(P>0.05).实验组患者按糖化血红蛋白水平(HbAlc)及DM病程(D)分为4组,其中HbAlC>7,D>5年组患者用药后IIEF-5评分为(16.00±0.82),用药前为(13.14±3.53),用药前后比较,差异具统计学意义(P<0.05).GEQ阳性答复率为42.9%,与对照组相比,差异具统计学意义(P<0.05).结论 西地那非治疗2型DM患者伴ED疗效确切.但伴有DM并发症的ED患者,效果欠佳.     

西地那非治疗勃起功能障碍的临床疗效

目的 :观察西地那非对不同年龄和病因勃起功能障碍 (ED)病人的疗效。　方法 :88例ED病人口服不同剂量的西地那非 4～ 2 2周 ,以国际勃起功能指数 5 (IIEF 5 )评分为评估标准判断疗效 ,设对照组作比较。　结果 :西地那非治疗ED病人的总疗效率为 80 .7% ,IIEF 5值上升幅度与西地那非疗效呈正相关。不同年龄ED病人的疗效无明显差异。神经性ED病人的显效率和IIEF 5值与心因性病人差异显著。　结论 :西地那非治疗ED是安全有效的 ,IIEF 5可作为评判ED疗效的可靠指标。     

西地那非对夜间勃起作用的研究

目的:探讨西地那非对夜间勃起的作用。方法:对35例勃起功能障碍(ED)患者予以西地那非100 mg睡前口服,其中器质性28例,心理性7例。用尼娃(NEVA)监测夜间勃起情况。结果:28例器质性ED患者的勃起参数有明显改善(P<0.05),7例心理性ED患者无明显改善(P>0.05)。结论:在无性刺激条件下西地那非可改善器质性ED患者夜间勃起。     

大鼠糖尿病性勃起功能障碍模型的实验研究

目的 证实链脲佐菌素(STZ)单侧腹腔注射建立大鼠糖尿病性勃起功能障碍模型的可行性.方法 45只SD大鼠随机分为对照组(15只)和实验组(30只).实验组大鼠腹腔注射STZ 60mg/kg,对照组大鼠腹腔注射相应量的柠檬酸钠-柠檬酸缓冲液,3d后测血糖确定是否成模.此后,每周测血糖1次,8周后用阿朴吗啡(APO)80μg/kg颈部皮下注射,观察大鼠阴茎勃起情况.结果 实验组糖尿病成模率为93.3%(28/30),在成模后8周的观察期间大鼠的死亡率为7.1%(2/28).实验组血糖明显高于对照组(P<0.01),体重、阴茎勃起次数、阴茎勃起率则明显低于对照组,两组间差异有统计学意义(P<0.01).结论 STZ 60mg/kg单侧腹腔内注射能安全有效地建立大鼠糖尿病模型;颈部皮下注射APO 80μg/kg可有效地筛选出大鼠糖尿病勃起功能障碍.     

西地那非治疗勃起功能障碍时间效应窗

西地那非治疗勃起功能障碍(erectiledysfunction,ED)的疗效与该药的药代动力学以及选择性行为时间密切相关。西地那非治疗ED作用的时间效应窗,包括服用西地那非治疗ED达到成功性交所需勃起硬度的最短时间、达到最佳勃起状态的时间、以及长期服用的有效性等问题随着研究的深入进一步阐明。本文对此进行综述。     

枸橼酸西地那非治疗2型糖尿病相关勃起功能障碍的疗效

糖尿病影响患者全身血管状态,是勃起功能障碍(ED)的危险因素。枸橼酸西地那非是治疗ED的有效口服药,而该药对2型糖尿病相关ED的疗效如何呢?El Sakka AI等人对466名ED患者(包括382名糖尿病和84名非糖尿病患者,平均年龄为(53±8.4)岁和(49.7±10.6)岁进行了研究[EurUrol,2004,46(     

西地那非治疗勃起功能障碍的临床进展

自1998年全球上市以来,西地那非治疗勃起功能障碍(erectiledysfunction,ED)积累了2千3百万患者的的临床应用经验,证明是有效的和安全的。本文对西地那非的作用机制、代谢过程进行回顾,对西地那非用于ED诊断、连续服用可治愈ED、规范性治疗、联合用药治疗ED、合并其他疾病时的治疗用药、循序渐进的ED治疗方案以及对视力影响的安全性等问题进行综述。     

PDE_5基因特异性siRNA改善糖尿病性勃起功能障碍大鼠勃起功能的研究

目的 探讨人鼠PDEs基因siRNA对糖尿病性勃起功能障碍(DM ED)大鼠PDE,基因表达的抑制作用及其对DMED大鼠勃起功能的影响.方法 构建可同时表达2条针对大鼠PDEs基因的shRNA重组腺病毒;50只雄性SD大鼠随机取10只作为正常对照.其余建立DM ED人鼠模型,随机分为实验组、阴性对照组和空白对照组,分别将重组腺病毒rAd-rPDEs-shRNA、腺病毒rAd-mock及生理盐水注射于阴茎海绵体.注射后第7天,电刺激盆神经测定各组大鼠阴茎海绵体内压(ICP)及平均周围动脉压(MAP),然后取海绵体组织通过RT-PCR和Western blot分别检测PDE5基因mRNA及蛋白的表达.结果 ICP/MAP实验组和正常对照组显著高于阴性对照组和窄白对照组(P＜0.05),实验组和正常对照组间无显著性差异(P＞0.05);RT-PCR和Western blot 分析,实验组大鼠PDE5基因mRNA和蛋白表达均显著低于阴性对照组和空白对照组(P＜0.05).结论 PDE5基因shRNA重组腺病毒转染可以改善DMED大鼠的勃起功能,为DMED治疗方法的探索提供了新的思路.     

Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

Recently, the relationship between advanced glycation end products (AGEs) and erectile dysfunction (ED) has been reported. The present study aimed to investigate whether a combination of an AGE cross-link breaker (alagebrium/ALT-711) and sildenafil could enhance the erectile capacity in streptozotocin (STZ) diabetic rats. Additionally, we assessed the effect of that treatment option on some molecules that have been suggested to have crucial roles in AGE-related ED pathways. Four groups of animals were utilized: (1) age-matched control rats, (2) STZ-induced diabetic rats (40 mg kg(-1) i.p.), (3) STZ rats+sildenafil (5 mg kg(-1) p.o.), (4) STZ rats treated with a combination of sildenafil (5 mg kg(-1) p.o)+alagebrium/ALT-711 (10 mg kg(-1) p.o.) for the final 1 month of the 2 months of diabetes period. At 2 months after i.p. injection of STZ, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue AGEs, MDA (malondialdehyde), cyclic guanosine monophosphate (cGMP) (ELISA), endothelial nitric oxide (NO) synthase (eNOS), inducible NO synthase (iNOS) (western blot), nuclear factor (NF)-κB, mitogen-activated protein (MAP) kinase (immunohistochemistry) and apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) analyses were performed in all groups of rats. STZ diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve) after CNS when compared with control rats (P<0.05). The increase in both ICP and area under the erectile curve of STZ diabetic rats treated with a combination of sildenafil+alagebrium/ALT-711 as well as in STZ diabetic rats treated with sildenafil alone was significantly greater than STZ diabetic rats. Additionally, combination treatment decreased AGE, MDA, iNOS, NF-κB, MAP kinase and apoptosis levels, whereas it preserved cGMP contents in diabetic penile tissue. Decreased AGE, MDA, iNOS, NF-κB, MAP kinase and increased cGMP levels at the combination (sildenafil+alagebrium/ALT-711) therapy group increased both the peak ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats. These results may explain the role of AGEs in diabetes-related ED and the effect of an AGE cross-link breaker alagebrium/ALT-711+sildenafil therapy on some critical molecules related to AGE-related ED pathways.     

Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats

Erectile dysfunction associated with diabetes mellitus is caused in part by disordered endothelial smooth muscle relaxation, neuropathy, and a decrease in cavernosal nitric oxide synthase (NOS) activity. The purpose of this study was to determine whether a combination of sildenafil and adenoviral gene transfer of endothelial NOS (eNOS) could enhance the erectile response in diabetic rats. Five groups of animals were utilized: (1) age-matched control rats, (2) streptozotocin (STZ)-induced diabetic rats (60 mg/kg i.p.), (3) STZ-rats + sildenafil (2 mg/kg i.v.), (4) STZ-rats transfected with AdCMVbetagal or AdCMVeNOS, and (5) STZ-rats transfected with AdCMVeNOS +sildenafil (2 mg/kg i.v.). At 2 months after i.p. injection of STZ, groups 4 and 5 were transfected with the adenoviruses and 1-2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Cyclic 3',5'-guanosine monophosphate (cGMP) levels were assessed in the cavernosal tissue. STZ-diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve; AUC) after CNS when compared to control rats. STZ-diabetic rats+AdCMVeNOS had a peak ICP and AUC, which were similar to control animals. STZ-diabetic rats administered sildenafil demonstrated a significant increase in peak ICP at the 5 and 7.5 V settings, while the AUC was significantly increased at all voltage (V) settings. The increase in both ICP and AUC of STZ-diabetic rats transfected with AdCMVeNOS at all V settings was greater than STZ-diabetic rats transfected with AdCMVbetagal. STZ-diabetic rats transfected with AdCMVeNOS and administered sildenafil had a significant increase in total ICP that was greater than eNOS gene therapy alone. Cavernosal cGMP levels were significantly decreased in STZ-diabetic rats, but were increased after transfection with AdCMVeNOS to values greater than control animals. In conclusion, overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the peak ICP and total ICP to CNS in the STZ-diabetic rat, which was similar to the response observed in control rats. Moreover, the total erectile response was greater in STZ-diabetic rats receiving eNOS gene therapy plus sildenafil than STZ-rats receiving sildenafil or eNOS gene therapy alone.     

Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy

Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN). However, long-term inhibition of PARP, an enzyme involved in DNA repair, can potentially result in premature aging, loss of genome stability, and other side effects. This study evaluated potential synergistic interactions between low doses of the potent and specific PARP inhibitor 1,5-isoquinolinediol (ISO) and one of two vasodilators, the ACE inhibitor lisinopril (LIS) and the beta2-adrenoceptor agonist salbutamol (SAL) in the model of early PDN. Control and streptozotocin (STZ)-induced diabetic rats were treated with either ISO plus LIS or ISO plus SAL for 2 weeks after an initial 2 weeks without treatment. ISO (intraperitoneally) and LIS and SAL (both in the drinking water) were used in subtherapeutic doses, resulting in a minor correction of diabetes-associated sciatic motor and hind-limb digital sensory nerve conduction deficits when administered as monotherapies. Both combination treatments corrected endoneurial blood flow and vascular conductance deficits in STZ-induced diabetic rats. ISO plus SAL corrected all other changes of PDN, i.e., motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) deficits as well as thermal and mechanical hyperalgesia. With ISO plus LIS, no significant correction of MNCV was observed, and the effect on thermal hyperalgesia was quite modest. SNCV and mechanical hyperalgesia were corrected. In vitro studies in human endothelial and Schwann cells showed early accumulation of poly(ADP-ribosyl)ated proteins (Western blot analysis) in response to high glucose, thus suggesting the importance of PARP activation in human PDN. In conclusion, low-dose PARP inhibitor-containing combination therapies may constitute a new approach for treatment of PDN.     

Role of poly(ADP-ribose) polymerase activation in diabetic neuropathy

Oxidative and nitrosative stress play a key role in the pathogenesis of diabetic neuropathy, but the mechanisms remain unidentified. Here we provide evidence that poly(ADP-ribose) polymerase (PARP) activation, a downstream effector of oxidant-induced DNA damage, is an obligatory step in functional and metabolic changes in the diabetic nerve. PARP-deficient (PARP(-/-)) mice were protected from both diabetic and galactose-induced motor and sensory nerve conduction slowing and nerve energy failure that were clearly manifest in the wild-type (PARP(+/+)) diabetic or galactose-fed mice. Two structurally unrelated PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, reversed established nerve blood flow and conduction deficits and energy failure in streptozotocin-induced diabetic rats. Sciatic nerve immunohistochemistry revealed enhanced poly(ADP-ribosyl)ation in all experimental groups manifesting neuropathic changes. Poly(ADP-ribose) accumulation was localized in both endothelial and Schwann cells. Thus, the current work identifies PARP activation as an important mechanism in diabetic neuropathy and provides the first evidence for the potential therapeutic value of PARP inhibitors in this devastating complication of diabetes.     

Role of poly(ADP-ribose) polymerase during vascular reconstruction

Open vascular repair of ischemic myocardium and aortic aneurysms results in a systemic inflammatory response that influences the mortality and morbidity of these procedures. Recent studies in animal models of complex vascular reconstruction indicate that the activity of poly(ADP-ribose) polymerase (PARP) may influence the mortality and morbidity of these kinds of reconstructions. PARP's activity, localized to nuclei and mitochondria, is stimulated by deoxyribonucleic acid (DNA) strand breaks. Activation of PARP results in synthesis of poly(ADP-ribose) sugar moieties, whose primary role is to protect DNA from degradation during cytotoxic stress. Paradoxically, when stressful conditions similar to those experienced during vascular reconstructions result in overactivation of PARP, depletion of cellular levels of adenosine triphosphate and nicotinamide adenine dinucleotide can result in exacerbation of tissue injury. Herein we review the role of PARP in inflammation and its relevance to cardiovascular reconstructions.     

Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats

The nuclear enzyme poly(ADP-ribose) polymerase (PARP), which has been shown to be activated following experimental traumatic brain injury (TBI), binds to DNA strand breaks and utilizes nicotinamide adenine dinucleotide (NAD) as a substrate. Since consumption of NAD may be deleterious to recovery in the setting of CNS injury, we examined the effect of a potent PARP inhibitor, GPI 6150, on histological outcome following TBI in the rat. Rats (n = 16) were anesthetized, received a preinjury dose of GPI 6150 (30 min; 15 mg/kg, i.p.), subjected to lateral fluid percussion (FP) brain injury of moderate severity (2.5-2.8 atm), and then received a second dose 3 h postinjury (15 mg/kg, i.p.). Lesion area was examined using Nissl staining, while DNA fragmentation and apoptosis-associated cell death was assessed with terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labeling (TUNEL) with stringent morphological evaluation. Twenty-four hours after brain injury, a significant cortical lesion and number of TUNEL-positive/nonapoptotic cells and TUNEL-positive/apoptotic cells in the injured cortex of vehicle-treated animals were observed as compared to uninjured rats. The size of the trauma-induced lesion area was significantly attenuated in the GPI 6150-treated animals versus vehicle-treated animals (p < 0.05). Treatment of GPI 6150 did not significantly affect the number of TUNEL-positive apoptotic cells in the injured cortex. The observed neuroprotective effects on lesion size, however, offer a promising option for further evaluation of PARP inhibition as a means to reduce cellular damage associated with TBI.     

胸段硬膜外阻滞对急性心肌梗塞大鼠心肌多聚ADP核糖聚合酶表达的影响

目的 研究胸段硬膜外阻滞（TEB）对急性心肌梗塞（AMI）大鼠心肌多聚ADP核糖聚合酶（PARP）（一种DNA修复蛋白）表达的影响。方法 65只健康雄性Wistar大鼠，随机分为3组：正常对照组（C组，n=5）、AMI组（n=30）、TEB组（n=30）。采用结扎大鼠左冠状动脉前降支制备AMI模型。TEB组行T4，5硬膜外置管，在制备AMI模型成功后，白天硬膜外注射1％利多卡因50μl，1次／2 h。AMI组和TEB组分别于结扎左冠状动脉后2 h（T1）、4 h（T2）、6 h（T3）、1周（T4）、4周（T5）、8周（T6）随机处死5只大鼠，测定坏死心肌组织PARP和DNA片段化水平。结果 AMI组、TEB组T2，3时检测到85 kD PARP，与C组比较，AMI组、TEB组T2，3时85 kD PARP水平增强（P〈0．05）;与AMI组比较，TEB组T2，3时85 kD PARP水平降低（P〈0．05），AMI组和TEB组T4-6时均未检测到85 kD PARP。AMI组T2时检测到DNA片段化，T3时其水平明显增强，TEB组T3时检测到DNA片段化，AMI和TEB组T4-6时均未检测到DNA片段化。结论 TEB可在一定程度上抑制AMI大鼠早期心肌PARP的降解，促进心肌细胞DNA的修复。     

Oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in experimental diabetic neuropathy: the relation is revisited

Poly(ADP-ribose) polymerase (PARP) activation, an important factor in the pathogenesis of diabetes complications, is considered a downstream effector of oxidative-nitrosative stress. However, some recent findings suggest that it is not necessarily the case and that PARP activation may precede and contribute to free radical and oxidant-induced injury. This study evaluated the effect of PARP inhibition on oxidative-nitrosative stress in diabetic peripheral nerve, vasa nervorum, aorta, and high glucose-exposed human Schwann cells. In vivo experiments were performed in control rats and streptozocin (STZ)-induced diabetic rats treated with and without the PARP inhibitor 3-aminobenzamide (ABA) (30 mg . kg(-1) . day(-1) i.p. for 2 weeks after 2 weeks of untreated diabetes). Human Schwann cells (HSC) (passages 7-10; ScienCell Research Labs) were cultured in 5.5 or 30 mmol/l glucose with and without 5 mmol/l ABA. Diabetes-induced increase in peripheral nerve nitrotyrosine immunoreactivity, epineurial vessel superoxide and nitrotyrosine immunoreactivities, and aortic superoxide production was reduced by ABA. PARP-1 (Western blot analysis) was abundantly expressed in HSC, and its expression was not affected by high glucose or ABA treatment. High-glucose-induced superoxide production and overexpression of nitrosylated and poly(ADP-ribosyl)ated protein, chemically reduced amino acid-(4)-hydroxynonenal adducts, and inducible nitric oxide synthase were decreased by ABA. We concluded that PARP activation contributes to superoxide anion radical and peroxynitrite formation in peripheral nerve, vasa nervorum, and aorta of STZ-induced diabetic rats and high- glucose-exposed HSC. The relations between oxidative-nitrosative stress and PARP activation in diabetes are bi- rather than unidirectional, and PARP activation cannot only result from but also lead to free radical and oxidant generation.     

Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy

Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg x kg(-1) x day(-1) i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADP-ribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.