西地那非在心血管疾病患者应用的安全性研究进展

西地那非被广泛应用于治疗阴茎勃起功能障碍 (ED),由于许多ED患者同时患有心血管疾病,这类疾病患者应用西地那非治疗的安全性一直是广大医生和患者关注的问题,本文回顾分析西地那非在心血管患者应用的安全性方面的数据资料,就西地那非在心血管疾病患者应用的安全性方面的研究进展进行了综述。     

Adverse Events and Patient Tolerability of Apomorphine SL 2 and 3 mg: A Cross-Study Analysis of Phase II and III Studies

Background: In 1999, the World Health Organization (WHO) Consensus Panel recommended orally administered drugs as first-line treatment of erectile dysfunction. Apomorphine SL, a sublingually administered erectogenic agent with a favorable therapeutic index, has been studied extensively in clinical trials.Methods: The safety and tolerability of apomorphine SL 2 and 3 mg was assessed in 14 phase II and III clinical studies, in which 2908 patients received the 2 mg dose and 1331 patients received the 3 mg dose of apomorphine SL. Of the 3183 patients who received at least one dose of the 2 or 3 mg dose of apomorphine SL, 1040 received the 3 mg dose after first having been exposed to the 2 mg dose in a dose-optimizing treatment regimen. Adverse event outcomes from fixed-dose and dose-optimization studies were analyzed.Results: Across all apomorphine SL studies, the adverse events most commonly seen were nausea, headache and dizziness. The incidence of adverse events was lower with the 3 mg dose in those patients who received an initial 2 mg dose in a dose-optimizing regimen, and no individual adverse event was reported by >5% of patients in the dose-optimization cohort. Nausea, headache and dizziness occurred in 4.2%, 3.0% and 1.8% of patients, respectively, in the 3 mg dose-optimization group, and the overall incidence of any adverse event was 12.5% in these patients. Hypotension and vasovagal syncope occurred rarely at the 2 and 3 mg doses, particularly when a dose-optimization regimen was used, where 0.1% of patients reported syncope. No death, stroke, myocardial infarction, priapism, or inappropriate erection has been associated with apomorphine SL at any dose level.Conclusion: The favorable tolerability and safety profile of apomorphine SL 2 and 3 mg suggests that this drug be considered a first choice treatment for the majority of patients with erectile dysfunction.     

Clinical efficacy of Apomorphine SL in erectile dysfunction of diabetic men

Although subgroup analyses from large randomised premarketing studies have shown that Apomorphine SL enhances the percentage of erections firm enough for sexual intercourse in diabetic men, the clinical role of the drug in this patient population remains to be elucidated. The aim of the present study was to assess the efficacy of Apomorphine SL in diabetic males with erectile dysfunction (ED) and to identify factors predicting those who may benefit from the treatment. A total of 130 diabetic patients were randomised to receive either four tablets of 3 mg Apomorphine or a matching placebo. Assessments of efficacy comprised the erectile function (EF) domain of the International Index of Erectile Function (IIEF) and the one-item global efficacy question (GEQ). Patients with both a positive response to the GEQ and an improvement of at least 5 points in the EF domain of the IIEF were considered responders and subanalysed by several parameters indicative of the severity of both ED and diabetes. Response rate was 17% after placebo and 22% after Apomorphine SL. The EF domain of the IIEF and both questions 3 and 4 scores did not significantly improve in either of the two arms over the baseline. A younger age and a lower Hb1Ac were significantly linked to the status of responder in the Apomorphine arm. Apomorphine SL failed to show a statistically significant benefit over a placebo, but 22% of patients had a clinically significant erectile response. These figures seem to suggest that the drug has a limited use for ED diabetic patients.     

The Role of Apomorphine SL in the Treatment of Erectile Dysfunction

Epidemiological data indicate that erectile dysfunction (ED) affects over 140 million men worldwide, with the highest prevalence in men over 60 years. While the condition is often associated with coronary artery disease, hyperlipidemia, hypertension and diabetes, and may be a marker for these conditions, most men who present with ED for treatment have mild to moderate dysfunction. Treatment guidelines developed by an international, multidisciplinary panel of experts as a “process of care model for erectile dysfunction” recommend the implementation of oral agents as first-line therapy. Sublingual apomorphine SL is the first medication for the treatment of erectile dysfunction with a central mechanism of action. In clinical studies, apomorphine SL provides clinical erectogenic benefits at 2 and 3 mg doses particularly in those patients with mild to moderate ED. Apomorphine SL has the added advantages of a rapid onset of action, resulting in erection in less than half the time required by sildenafil, and a highly favorable tolerability and safety profile, especially in patients with coronary artery disease receiving nitrates. Apomorphine SL is an important addition to the armamentarium of primary care clinicians and urologists treating male erectile dysfunction, due to enhanced erectile function, speed of onset, convenience of dosing, and favorable side effect profile. Apomorphine SL 2 and 3 mg is an effective first-line treatment option for men presenting with mild to moderate ED, who have a degree of residual erectile function that is inadequate for satisfactory sexual performance.     

伐地那非的安全性和耐受性

本文回顾了伐地那非治疗勃起功能障碍(erectile dysfunction,ED)的安全性和耐受性,包括其总体安全性、心血管安全性和视觉安全性。临床试验和实际应用的实践经验证明,最常见的不良事件为头痛、颜面潮红和鼻充血,并且多为轻、中度和一过性。无论在一般ED人群中还是在难治性ED人群中,无论是短期还是长期应用,伐地那非均有良好的安全性和耐受性。     

Apomorphine SL: Evolution of a Centrally Acting Treatment for Erectile Dysfunction

Erectile dysfunction has been described in the medical literature since ancient times. Developments in Western medicine included the development of vascular procedures, vacuum devices, penile implants, intracavernosal and intraurethral therapies, and most recently, oral drugs: sildenafil and sublingual apomorphine. Apomorphine has a central mechanism of action, but also reinforces peripheral neuronal pathways. The hypothalamus plays a critical role in the central command of penile erection. Erectile function also depends on neurotransmitters, most notably dopamine, serotonin, norepinephrine, oxytocin, and nitric oxide. Apomorphine has predominant D₂-like dopamine receptor agonist effects and acts primarily on the paraventricular nucleus of the hypothalamus, promoting the natural erectile phenomenon and assisting in the restoration of normal autonomic balance in the control of penile function. The drug has a long history of safety in humans and is absorbed rapidly by the oral mucosa. Onset of action is rapid—usually within 20 minutes of administration. The most distinct adverse effects of the drug are nausea, dizziness and yawning. Potential drug interactions are unlikely. The drug has no addictive or analgesic properties. Clinical trials indicate that sublingual apomorphine is effective in helping men with erectile dysfunction achieve satisfactory penile erections.     

Tolerability and safety of apomorphine SL (Ixense (TM) )

Apomorphine SL (Ixense (TM) ) (apo SL) is a dopamine receptor agonist that can enhance sexual function in patients with erectile dysfunction (ED). For a patient, the ability to achieve a physiological erection, tolerability, efficacy and the speed of onset of the therapy are of considerable importance when considering ED treatment. Recent studies have focused on determining the patient's tolerability to apo SL as a therapy for ED. In addition, the cardiovascular profile of those patients that would be likely to receive apo SL in the clinic has been assessed. These studies have shown that apo SL is safe and effective in the treatment of ED and offers a new therapeutic option for the first-line treatment of patients with different concomitant diseases including cardiovascular disease and diabetes. The most frequently reported adverse events were nausea and dizziness, but no major adverse events have been noted in any of the clinical trials.     

Safety and Tolerability of Treatment for BPH

Treatment options for benign prostatic hyperplasia (BPH) include watchful waiting, pharmacologic therapy, and surgery. For individual patients, treatment choice depends on disease severity, comorbidity, patient preferences, and the comparative efficacy and adverse effects (AEs) of the available therapies. Disease-related symptoms and treatment-related factors influence health-related quality of life (HRQOL), and treatment discontinuation occurs due to lack of efficacy or the occurrence of AEs. This review explores the safety and tolerability of current treatment options. Pharmacologic therapies include α₁-adrenergic antagonists and 5α-reductase inhibitors (5ARIs). The α₁-adrenergic antagonists have comparable efficacy but tolerability profiles that differ according to vasodilatory AEs and ejaculatory abnormalities. Alfuzosin and tamsulosin are better tolerated than terazosin and doxazosin; tamsulosin causes fewer vasodilatory AEs than alfuzosin but causes more ejaculatory abnormalities. AEs associated with 5ARIs are mainly sexual (eg, erectile dysfunction, reduced libido, and gynaecomastia) and tend to be confined to the first year of therapy. Surgery has the potential for short- and long-term complications. Open surgery has been largely replaced by less invasive approaches, particularly transurethral resection of the prostate (TURP). Short-term complications of TURP include death, bleeding, clot retention, transurethral resection syndrome, urinary tract infection, and inability to void; long-term complications include failure to void, retrograde ejaculation, erectile dysfunction, incontinence, and retreatment. More recent approaches (eg, transurethral needle ablation, thermotherapy, and laser therapy) have promising efficacy and safety. Patient expectations of therapy and AEs should be considered to ensure that treatment is tailored to individual patient needs and that HRQOL is maximised.     

Safety and tolerability of apomorphine SL (Uprima)

The side effect profile of apomorphine SL (2-6 mg) has been determined in clinical studies of over 5000 patients using over 120 000 doses. Apomorphine, 2 and 3 mg, has been shown to have an excellent safety profile. The most commonly occurring side effects (<7%), nausea, headache and dizziness, tend to be mild and not compliance limiting. Neither the incidence nor the nature of the side effects is significantly affected by common co-morbidites or by the use of many concurrent medications. Over this dose range there is little evidence of vasoactivity; there is little change in haemodynamic baseline and there is no synergistic effect with nitrates. Although syncope can occur at higher doses, it is rarely observed at approved doses (<0.2%).     

伐地那非治疗抑郁症合并勃起功能障碍的有效性和安全性

勃起功能障碍 (erectiledysfunction ,ED)与抑郁症常合并存在 ,两者可相互恶化 ,给患者带来更大的痛苦 ,因而更加需要迫切、有效的治疗方法。最近的DRIVER(DepressionRelatedImprovementwithVardenafilforErectileResponse)试验结果表明 ,磷酸二酯酶 5 (PDE5 )抑制剂伐地那非不仅能改善ED合并抑郁症男性的勃起功能 ,而且能减轻抑郁症状 ,改善生活质量 ;且使用安全 ,耐受性好。     

伐地那非治疗勃起功能障碍的有效性和安全性

伐地那非是一种有效的、高选择性的口服磷酸二酯酶 (PDE5 )抑制剂。它对各种病因、各种程度、各年龄段的男性勃起功能障碍 (ED)患者均有良好疗效 ,可显著改善勃起功能。该药口服后最快 10min即可起效 ,长期使用仍能保持疗效 ,不良反应少 ,耐受性好。因此 ,伐地那非是治疗男性ED患者的有效、安全的药物。     

伐地那非的心血管安全性研究

伐地那非 (vardenafil,艾力达 )是新的选择性磷酸二酯酶 5型抑制剂 (PDE5I) ,通过选择性PDE5抑制作用(IC50 :0 .0 1nmol/L)而增强勃起功能 ,国际和国内临床研究已经表明其治疗勃起功能障碍 (ED)安全有效。艾力达和其他PDE5I一样由于具有轻度血管扩张作用 ,引起一过性头痛、头晕、颜面潮红、鼻塞等不良反应。本文对最近有关艾力达对心血管系统安全性的研究进行综述。研究显示 ,艾力达对处于心脏功能代偿期的心血管疾病患者、无活动性心绞痛或已控制好的冠心病患者ED治疗安全有效。治疗剂量的艾力达平均降低外周动脉血压幅度 <10mmHg ,除了与有机亚硝酸类药物具有协同降血压作用之外 ,与其他降压药物没有显著协同降血压作用。艾力达对心肌复极间期 (QTc)有轻微延长作用 ,但是目前临床研究没有发现艾力达引起的心律失常。 5项安慰剂对照的临床研究资料表明 ,服用艾力达后发生心血管不良事件的种类以及发生几率与安慰剂无显著差异。目前 ,研究结果表明 ,艾力达在临床治疗剂量下 ,对心血管功能具有较好的安全性和耐受性 ,是一种安全有效的治疗ED的一线药物。     

Safety and Tolerability of mRNA COVID-19 Vaccines in Kidney Transplant Recipients

BackgroundCOVID-19 mRNA vaccines have demonstrated excellent short-term safety in phase 3 trials. However, no kidney transplant recipients (KTR) were included. The aim of the study was to assess the safety and tolerability of COVID-19 mRNA vaccines in KTR.Materials and MethodsA longitudinal controlled study was conducted in 300 KTR and 143 control patients (CRL) without chronic kidney disease who had received 2-dose vaccinations with the mRNA vaccine. Solicited local and systemic reactogenicity and unsolicited adverse events were assessed with a standardized questionnaire. The toxicity grading scales were derived from the FDA guidelines.ResultsKTR (62.7% men) with a median (interquartile range) age of 53 (41-63) and transplant vintage of 7.25 (3-13) years did not differ with respect to age and sex distribution from CRL. One hundred percent CRL and 83.3% KTR were vaccinated with BNT162b2 (BionTech/Pfizer); 16.7% KTR received mRNA-1273 (Moderna) vaccine. Any local reactions were present in 84.7% (first dose) and 65.3% (second dose) KTR vs 67.1% and 60.1% CRL within 7 days after the vaccination. Any systemic reactions were reported by 26.7% (first dose) and 20.9% (second dose) KTR vs 24.7 and 35.7% CRL. The most common systemic reactions in KTR were fatigue, headache and myalgia. No serious adverse events were observed. Many systemic reactions were observed less frequently in KTR than CRL. Younger KTR (<54 years) reported any local and any systemic reactions significantly more frequently than older patients.ConclusionmRNA COVID-19 vaccines are safe and well-tolerated by KTR. The results may resolve patients' doubts and reduce their vaccine hesitancy.     

Apomorphine SL (Uprima): preclinical and clinical experiences learned from the first central nervous system-acting ED drug

An exclusive central site of action for the proerectile effect of apomorphine, including not only the brain but also the spinal cord, is supported by extensive experimental data. Assuming that the mechanisms of action of apomorphine are similar in humans and animal models, its use for the treatment of erectile dysfunction (ED) validates the emerging idea that erectile response could be enhanced by acting directly within the central nervous system (CNS). It also emphasized the key role of the dopaminergic system in the control of erection. As exemplified with the clinical development of apomorphine, targeting the CNS does not rule out the occurrence of undesirable side effects. Because the rare event of syncope induced by apomorphine is not well understood, further research should be conducted to explore its possible mechanisms. In clinical practice, however, approved doses of apomorphine SL are well tolerated. It is noteworthy that no modification of sexual desire was observed with apomorphine. Indeed, drugs acting within the CNS may more likely interact with sexual desire than peripherally acting drugs, and care should be taken to assess this point in the future. Although our knowledge of the control of penile erection by the CNS is restricted, there are many potential sites for CNS-acting ED drugs. New centrally acting therapy for ED should concentrate on receptor targets more specific to erectile command. Clinical efficacy of new centrally-acting compounds will assess the well-founded purpose of this rationalization.     

伐地那非在实际医疗模式中治疗勃起功能障碍的有效性和安全性

在研究中心进行的、固定剂量的伐地那非研究不能完全代表磷酸二酯酶(PDE)5抑制剂在临床实践中的应用情况。本文通过回顾在社区医疗环境中以及采用灵活剂量用药方案的伐地那非研究,评价了伐地那非在实际医疗模式中的有效性和安全性。结果表明,伐地那非能够改善大多数勃起功能障碍(ED)患者的勃起功能,且具有良好的安全性和耐受性。