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A 4-year update on the safety of sildenafil citrate (ViagraS)1
Abstract
Clinical studies have demonstrated that sildenafil citrate (Viagra) is an effective and well-tolerated oral treatment for erectile dysfunction. Despite its established safety profile, concern about its cardiovascular safety persists among some physicians and the general public. This concern has stemmed primarily from sporadic reports of adverse events published in the literature and sensationalized by the media. However, the only absolute contraindication for sildenafil is concurrent use of nitrates. Because sildenafil has been on the market for 4 years and under clinical investigation for even longer, we can now evaluate its long-term safety in men who have been taking the drug for several years. We review this issue from 3 perspectives. First, we reassess the overall safety profile of sildenafil by reviewing the initial controlled clinical trials and open-label studies. We present new data from patients who have been exposed to sildenafil for up to 4.5 years. We also evaluate the results from independent postmarketing studies. Second, we review the cardiovascular-specific results from the clinical trials, long-term extension, and postmarketing studies. Lastly, we review the specific effects on the visual system based on findings from studies conducted during drug development and post marketing.
... Still, the safety of this drug in people with ischemic heart disease and users of antihypertensive drugs is well established. 35 The adverse cardiovascular outcomes of sildenafil are more observed in the following conditions: ...
... However, orthostatic hypotension due to the simultaneous administration of alpha-blockers and PDE5Is has led to warnings in their use since 2005. 41 Drugs affecting CYP3A4, including erythromycin, ritonavir, saquinavir, ketoconazole, itraconazole, or cimetidine, are more likely to interfere with sildenafil than drugs affecting CYP2C9 and CYP2D6 ( Table 2) 35 One of the CYP3A inhibitors is grapefruit juice, which effectively increases exposure to sildenafil. 43 High levels of NO and cGMP can cause severe hypotension and even death. ...
Abstract
Introduction: Erectile dysfunction (ED) is one of the most common urologic problems in men worldwide, with an approximately high incidence
rate, significantly affecting patients’ quality of life and their sexual partners.
Objectives: Due to the association of this disorder with essential diseases such as cardiovascular disease and diabetes, its prevention and
treatment are vital for overall human physiologic and psychological health. Along with reviewing the history of treatment and current methods,
we seek new approaches to curb this issue in the future.
Methods: In this review, investigations were based on the focus of each section’s content or conducted on an ad hoc basis. Searches were
performed in Scopus and PubMed.
Results: In recent years, many treatments for ED have been reported besides oral administration of phosphodiesterase 5 inhibitors such as
sildenafil and tadalafil (approved by the Food and Drug Administration). Common oral medications, intracavernous injections, herbal therapies
(eg, herbal phosphodiesterase 5 inhibitors), and topical/transdermal medications are routine ED treatment approaches. Moreover, some novel
medications are innovative candidates for completing ED’s treatment protocols: stem cell injection, low-intensity extracorporeal shock wave
therapy, platelet-rich plasma injection, gene therapy, amniotic fluid matrices, rho-kinase inhibitors, melanocortin receptor antagonists, maxi-K
channel activators (ie, large-conductance calcium-activated potassium channels), guanylate cyclase activators, and nitric oxide donors.
Conclusion: Due to the importance of this complicated problem in men’s society, a faster course of treatment trends toward new methods is
needed to increase efficiency. Combining the mentioned treatments and attentively examining their efficacy through programmed clinical trials
can be a big step toward solving this global problem.
... %, between 1 and 6%). [3][4][5][6][7] In these studies, there was no priapism, and the percentage of dropouts due to NB was similar to that of placebo (2.5% vs. 2.3%). Most are due to fear that the exertion of sexual activity will precipitate another myocardial infarction, but 10% to 15% is due to organic causes of impotence. ...
... Padma-Nathan et al. [6] review AAs in 13 published series and post-marketing, in 5,295 patients. Most of the problems were mild. ...
Sildenafil is a medication used to treat male erectile dysfunction. It is an inhibitor of one of the phosphodiesterases, and during clinical studies, it was found to be more effective in the treatment of impotence. Sildenafil is active in 70% of the subjects with the impotence of diverse etiology. The objective of the study is to determine the interactions of the drug vs. nitrogenous bases (NBs). The Hyperchem Professional software was used the parametric semi-empirical parametric method 3 (SE-PM3). It was found that the interactions of the pure NBs and the drug have a very high probability that they occur. The interactions of the pairs of BNs and sildenafil also have a very high probability that they will occur. In both cases, it can be predicted that this drug brings many health problems including mutations.
... They do not increase the patients' cardiovascular risk and will not pose a particular risk unless used with nitrates. 67 Sildenafil can also cause a sharp drop in blood pressure if taken with alpha-adrenergic blockers such as doxazosin. 65,68 Alpha-adrenergic blockers are mainly used to treat benign prostatic hyperplasia (BPH). ...
Introduction
Due to the prevalence of erectile dysfunction and impotence among men in recent years, several pharmacotherapies have been considered for such problems. Systemic drug therapies in the treatment of erectile dysfunction have significant issues, including drug interactions and contraindications in a wide range of diseases, which makes researchers seek to design drugs and dosage forms with fewer side effects, interactions, and contraindications with maintained efficacy.
Objectives
5-Phosphodiesterase inhibitors (5-PDEIs or PDE5Is), previously used systemically to treat erectile malfunction, are now appropriate candidates for topical application with considerable potency and fewer complications.
Methods
We sought to investigate the recent findings on the current subject in order to provide a comprehensive overview of the issue using an extensive literature search to pinpoint the latest scientific reports on this subject.
Results
In the present review, the function of 5-Phosphodiesterase inhibitors as topical formulations was evaluated with details including formulation type, adsorption, and comparative efficacy in all recent studies as an acceptable alternative therapy to systemic drugs.
Conclusions
Due to the fact that the influential factors in erectile dysfunction interact with many diseases and delinquent treatments, the use of topical therapeutic agents can be promising in mild to moderate cases. The utilization of 5-PDEIs through novel topical and transdermal drug delivery techniques plays a vital role in improving this effectiveness.
Hamzehnejadi M, Tavakoli MR, Abiri A, et al. A Review on Phosphodiesterase-5 Inhibitors as a Topical Therapy for Erectile Dysfunction. Sex Med Rev 2021;XX:XXX–XXX.
... In terms of side effects, daily use yielded a lower incidence than did ondemand use, and a fundamental change in the plasma concentration was expected. Considering these factors, the optimal administration methods can be considered In terms of safety, most studies have raised concerns on cardiovascular safety, although some studies have reported that PDE5-Is can have beneficial effects on the cardiovascular system (39)(40)(41)(42)(43). Because cardiovascular safety is directly linked to survival, it should be considered differently from other factors, even if it is less frequent. ...
Background:
Nerve-sparing radical prostatectomy (NSRP) had to be performed because approximately 94% of patients are diagnosed with localized prostate cancer (PCa). Although NSRP is generally done to improve functional outcomes, erectile dysfunction (ED) is one of the most prevailing complications after radical prostatectomy (RP). Phosphodiesterase type 5 inhibitors (PDE5-Is) are the most well-known treatment agent for postoperative ED. This study aimed to assess the efficacy of PDE5-Is in patients with ED after NSRP.
Methods:
In this systematic literature review, randomized controlled trials on the efficacy and safety of PDE5-Is in patients who underwent NSRP were searched in MEDLINE, EMBASE, and the Cochrane Controlled Trials Register using the OVID platform. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Review Methods. The quality of the evidence of the outcome data was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.
Results:
A total of 14 trials involving 2,822 patients were included. Significant improvements in the International Index of Erectile Function-Erectile Function (IIEF) domain score [mean difference (MD) =4.93; 95% confidence interval (CI): 4.14-5.71; P<0.00001] and erectile function recovery events [odds ratio (OR) =2.06; 95% CI: 1.45-2.94; P<0.0001] were observed after PDE5-I treatment. A higher positive response to Sexual Encounter Profile (SEP) question 2 (OR =2.27; 95% CI: 1.80-2.86; P<0.00001) and question 3 (OR =2.78; 95% CI: 1.97-3.91; P<0.00001) was also found after PDE5-I treatment. However, the incidence of treatment-emergent adverse events (TEAEs) was higher after PDE5-I treatment than after placebo treatment (OR =2.91; 95% CI: 1.84-4.61). Furthermore, the incidence of headache (OR =3.38; 95% CI: 2.40-4.75) and flushing (OR =9.44; 95% CI: 4.30-20.70) was also significantly higher after PDE5-I treatment (P<0.00001). In terms of the quality of the evidence of the outcome data, inconsistency problems were detected in all outcomes and imprecision problems in most outcomes.
Discussion:
PDE5-I treatment was more effective to placebo treatment in patients with ED after NSRP. No clinically serious complications were found in spite of the incidence of TEAEs being higher after PDE5-I treatment.
... The molecule is well known even outside of chemical circles. Apart from this it works to alleviating distress for an underserved cohort [30]. This wonderful molecule has been an significant contributor of Pfizer's revenues since 1998 [31] ( Fig. 1). ...
Medicines are the imperative constituent in the present day lifestyle and their consumption for different cause’s increases day by day. Synthesis of most of the drugs involves use of toxic chemicals and hazardous solvents, tedious workup or lengthy strategies. The needs of environment friendly procedures are the prerequisites of current environment concern. The known drug candidates Sildenafil citrate and Celecoxib are selected for the investigation and study for improved synthetic opportunities. It is found that several alterations are useful in the synthesis of these biological active profiles and they are adopted for large scale production of the compound in pharmaceutical industries. The old and new synthetic strategies are discussed in this case study based article.
... Side effects of sildenafil include headache, flushing, dizziness, visual disturbance and hypotension, especially in patients with cardiovascular disease [1]. The recommended dose is 50 mg which may be increased to a maximum approved dose of 100 mg [2][3][4]. ...
The phosphodiesterase (PDE)-5 inhibitor sildenafil is a commonly used drug to treat erectile dysfunction. As its vascular relaxation effects might affect not only the corpus cavernosum, but as well vasculature in general, an association with bleeding incidents has been discussed. We report on a 55-year-old patient presenting with thunderclap headache due to perimesencephalic subarachnoid hemorrhage (SAH) after ingestion of a very high dose (200 mg) of sildenafil. No aneurysm or other vascular abnormality was found as a cause of the bleeding. We discuss possible mechanisms by which sildenafil might alter intracranial blood coagulation, e.g. via acting on the PDE-1 and PDE-2 enzymes and via affecting platelet aggregation. In conclusion, Sildenafil may cause or intensify extra- and intracranial hemorrhage. Thus, careful discussion and indication are mandatory. On the other hand, sildenafil is also addressed as a potential option in the prevention and treatment for cerebral vasospasm as complication of SAH.
... [23] In recent discussions about potency-enhancing drugs such as sildenafil, health hazards associated with sexual activity have attracted increased attention. [24][25][26] Sildenafil citrate is a useful tool for the treatment of erectile dysfunction because it selectively inhibits phosphodiesterase type 5 (PDE-5), wich inactivates cyclic guanine monophosphate (cGMP), the mediator of smooth muscle relaxation in the corpus cavernosum. [27] By selectively inhibiting cGMP catabolism in cavernosal smooth cells, sildenafil citrate can restore the natural erectile response to sexual stimulation without causing erections in the absence of such stimulation. ...
... Безопасность силденафила стала предметом большого количества исследований, в ходе которых было доказано, что этот препарат повышает способность получить и удер-жать эрекцию у мужчин со стабильной ИБС [29], не приво-дит к увеличению риска развития сердечно-сосудистых осложнений и инфаркта миокарда и даже может умень-шить его [30], не снижает способность переносить физи-ческую нагрузку и не влияет на сократимость миокарда и потребление им кислорода, а также может приводить к увеличению основного и резервного кровотока в коро-нарных артериях [31]. Силденафил хорошо совместим с лекарственными препаратами, которые чаще всего назна-чают мужчинам с ЭД по поводу имеющихся у них сопут-ствующих заболеваний [32]. ...
... 6 Accumulating evidence from numerous double-blind placebo-controlled and open-label trials suggests that sildenafil is well tolerated and effective for the treatment of ED of diverse etiology. 7,8 Further, successful treatment of ED may be associated with improved measures of quality of life (QoL). 5 However, correlations between successful ED treatment and changes in psychosocial measures have been difficult to determine because QoL is difficult to define and contains multiple components. ...
Erectile dysnfuntion (ED) can significantly impact a man´s relationships and well-being
... Sildenafil citrate, Vardenafil, and Tadalafil, and a number of published studies have supported their efficacy and tollerability in treatment of ED. In fact, they are currently prescribed oral agents (8)(9)(10)(11). In physiological conditions one of the principal mediators of erection is nitric oxide (NO), constitutively produced from eNOS, expressed in endothelial cells lining the smooth muscle cells ofthe cavernous sinus and the elicine arteries in response to sheer stress from agonist-induced activation of acetylcholine-released from cholinergic terminals. NO is also produced by the activity of nNOS, which is involved in the signalling mechanism that regulates the neurotransmission and vascular tone of the penis (12). ...
Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Numerous physical and psychological factors are involved in normal erectile function, including neurological, vascular, hormonal and cavernous functions. The current therapy for the condition is pharmacological and psychotherapeutic which regulates the erectile function and amplifies the NO-mediated response. The aim of this work is to test the action of three common phosphodiesterase inhibitors: Tadalafil, Sildenafil Citrate and Vardenafil at 0.05 μM on human monocytes, analyzing the expression of iNOS protein and mRNA by Western blot and rt-PCR, and production of NO by conversion of L-(2,3,4,5)-[³H]Arginine to L-(³H) citrulline. We also tested the efficiency of the antioxidant network by spectrophotometer (SOD, CAT, GPx and Gr), under normal conditions and after stimulation with LPS. The results showed an increase in ROS levels, similar for all the molecules with regard to the antioxidant enzymes. In all cases the treatment determines a response to the limited efficiency, arriving at a situation in which phosphodiesterase inhibitors + LPS clearly show oxidative stress.
... Эти явления носили слабый и преходящий характер и не требовали отмены препарата [20]. Учащения и утяжеления побочных эффектов не было при четырехлетнем применении препарата [21]. В отсутствие эффекта на дозе в 100 мг/сут ее можно повысить, но это ведет к учащению развития побочных явлений, включая изменение цветового восприятия и повышение чувствительности к свету (возможно, в связи с ингибированием простагландина Е6). ...
Prostate stands in close anatomical and functional relations with urethra, genital glands and other pelvic organs. Inflammatory process in prostate is almost universally associated with inflammation in other genitourinary organs as well as sexual dysfunction, abnormal spermogram, psycho-emotional disorders and, in elderly men, with benign prostatic hyperplasia. Sildenafil (phosphodiesterase-5 inhibitor) is effective in the treatment of erectile dysfunction, testicular insufficiency and depression which may persist after the standard therapy of chronic prostatitis and is recommended as add-on to rehabilitation procedures after chronic prostatitis therapy.
... Recentemente uma meta-análise envolvendo os oito subtipos dos inibidores do PDE5 disponíveis no mercado farmacêutico mundial demonstrou que o principal efeito colateral é a cefaléia 8 . Dependendo destes estudos a prevalência da cefaléia variou entre 4,6 à 30,4% dos pacientes utilizando esta classe de medicamento [9][10][11][12][13][14] . ...
Cefaleia secundaria ao uso de medicamentos e frequente e subdiagnosticada na pratica medica. Relatamos o caso de um paciente que apos o uso de tadalafila desenvolveu uma cefaleia relacionada com atividade sexual. Discutimos os aspectos semiologicos das cefaleias relacionadas com o uso de drogas, com atividade sexual e finalmente comentamos aspectos relacionados com a cefaleia thunderclap primarias e secundarias.
... Although sexual intercourse may slightly increase the risk of an ischemic cardiac event, 23 current evidence suggests that sildenafil does not increase cardiovascular risk in certain groups of patients with cardiovascular disease, and an algorithm has been proposed as an aid to decision making in the treatment of ED among patients with cardiovascular disease. 24,25 In these patients, the risk of myocardial infarction or unstable angina does not seem to increase with sildenafil treatment. 22,26 -28 In a recent study involving 23 patients with clinically stable congestive heart failure, sildenafil was considered to improve exercise capacity, reducing heart rate and probably improving O 2 consumption. ...
Background
The aim of this study was to establish the prevalence of erectile dysfunction (ed) in hypertensive patients in specialized care hypertension units (SCHUs) and to assess the effectiveness and tolerability of sildenafil treatment.
Methods
This was a multicenter, prospective, open, observational pharmacoepidemiology study conducted in 25 Spanish SCHUs. A total of 2130 men with essential hypertension under treatment were recruited. In a second phase, 291 subjects with a score ≤ 21 in the Sexual Health Inventory for Men (SHIM) received sildenafil (50 mg/day) as required 30 to 60 minutes before sexual activity, and were evaluated by the International Index of Erectile Function (IIEF).
Results
A total of 975 subjects (45.8%) had a score ≤ 21 in the SHIM. In the second phase, sildenafil improved the score in the erectile function domain in 232 patients (83.2%). Severity of ED significantly improved (P < .001); severe (22.3% to 7.7%), moderate (23% to 5.6%), and mild impairment (36.3% to 44.8%). The IIEF was normalized in 39.1% of patients who completed post-treatment IIEF. In all, 33 subjects (11.8%) failed to complete the study: two (0.7%) because of lack of efficacy, two (0.7%) intercurrent disease, 10 (3.6%) failure to return to the visits, three (1.1%) fear of therapy, four (1.4%) adverse effects requiring treatment discontinuation, and 12 (4.3%) protocol violations. No statistically significant association was found between the prevalence of adverse effects and antihypertensive treatment with single drug or combination therapy.
Conclusions
A high incidence of ED was found in hypertensive patients from Spanish SCHUs. Sildenafil showed an excellent response and safety profile.
Am J Hypertens 2004;17:139–145 © 2004 American Journal of Hypertension, Ltd.
... Należą do nich bóle głowy, uderzenia gorąca, zaburzenia widzenia i uczucie "zatkania" nosa. Przy dłuższym stosowaniu leków obserwuje się tendencje do ustępowania objawów ubocznych [29]. ...
Streszczenie Zaburzenia erekcji (ED) to utrwalona (ponad 6 miesięcy) niezdolność do uzyskania lub utrzymania erekcji, wystarczającej do odbycia satysfakcjonującego stosunku płciowego. Szacuje się, że na zaburzenia erekcji cierpi ponad 100 milionów mężczyzn na świecie, w tym ponad 1,5 miliona w Polsce. Najczęściej zaburzenia erekcji wys-tępują u pacjentów chorujących na cukrzycę, nadciśnienie tętnicze oraz w zaburzeniach lipidowych i chorobach naczyń obwodowych. Jest też efektem ubocznym działania wielu leków. Częstość występowania ED zwiększa się istotnie wraz z wiekiem, wpływając istotnie na pogorszenie jakości życia. Obecnie podkreśla się istotny wpływ związanego z wiekiem obniżania się stężenia testosteronu – " andropauzy " – w etiopatogenezie ED. Długotrwały niedobór testosteronu prowadzi do zmniejszenia uwalniania tlenku azotu (NO) z zakończeń nerwów jamistych, zmniejsza się też podatność mięśniówki gładkiej ciał jamistych na czynniki relaksacyjne. W obecnej chwili dzięki postępom nauki dostępne są skuteczne metody leczenia ED. Lekami pierwszego rzutu są inhibitory fosfodiesterazy typu 5 (PDE-5). Są to leki bardzo skuteczne i stosunkowo bezpieczne. U mężczyzn z andropauzą lub u pacjentów nieskutecznie leczonych inhibitorami PDE-5 skuteczne może być wyrównywanie niedoboru testosteronu, często łącznie z inhibitorami PDE-5. Geriatr Pol 2007; 1: 203-208. Słowa kluczowe: zaburzenia erekcji, etiopatogeneza, leczenie, testosteron, inhibitory PDE-5 Summary Erectile dysfunction (ED) has been defined as the persistent (at least 6 months) inability to obtain and maintain an erection sufficient to permit satisfactory sexual performance. It is estimated, that over 100 milion men worldwide as well as up to 1.5 milion in Poland experience erectile dysfunction. ED are closely connected and common complication of diabetes mellitus, hypertension, lipid disturbances and peripheral vascular diseases. There is a strong connection between erectile dysfunction and quality of life. The prevalence of ED increases progressivly with advanced age. Actually the late onset hypogonadism in elderly men – andropause – is recognized as important factor in pathogenesis of erectile dysfunction. Long-lasting deficiency of testosterone leads to limited nitric oxide (NO) secretion from cavernous nerves endings and diminished relaxation of corpora cavernous smooth muscles. The progress of medical sciences resulted in discovering efficacy drugs and methods of treatment of ED. The first line drugs are inhibitors of phosphodiesterase type 5 (PDE-5), very efficacy and relative safety. In patients with andropause or in cause of insufficiency of PDE-5 inhibitors, testosterone replacement therapy can be efficacy, alone or together with PDE-5 inhibitors. Geriatr Pol 2007; 1: 203-208.
... Los 3 I PDE5 son eficaces en el 50 -80% de pacientes, presentando una mejor respuesta en los casos psicológicos y neurológicos y peor en la diabetes y en la prostatectomía radical (18)(19)(20). La seguridad cardiovascular esta bien demostrada (21)(22)(23)(24) y los efectos adversos, que oscilan entre el 20 y el 40%, son los debidos a la vasodilatación (rubor, cefalea, rinitis, etc.) y a la inhibición de otras PDE. Las alteraciones visuales y los dolores de espada, aunque poco frecuentes, pueden observarse en los pacientes tratados con sildenafilo y tadalafilo respectivamente. ...
Resumen La disfunción eréctil (DE) tiene una alta prevalencia fundamentalmente en las últimas décadas de la vida y se halla relacionada con una gran cantidad de factores como los tras-tornos psicológicos, las enfermedades cardiovasculares y sus factores de riesgo (hiper-lipidemia, tabaco, obesidad. etc.), la diabetes, trastornos neurológicos y hormonales, así como con gran cantidad de tratamientos médicos y quirúrgicos. El diagnóstico de la DE se basa fundamentalmente en la anamnesis, exploración física y la determinación analítica. En determinados casos es preciso realizar estudios de objetivación de la erección (inyección intracavernosa de fármacos vasodilatadores, registro de erecciones nocturnas), estudios vasculares (ecoDoppler) y valoración psicológica con el objetivo de poder realizar un tra-tamiento etiológico. Si este no es posible o fracasa, debe indicarse el tratamiento sintomático de primer nivel con inhibidores de la 5 fosfodiesterasa (I PDE5). El sildenafilo, el tadalafilo y el vardenafilo han demostrado en los ensayos clínicos y en la práctica clínica ser eficaces y seguros, debiéndose conocer sus características farmacológicas para aplicar el más adecuado para cada paciente. El tratamiento sintomático de segundo nivel lo constituye la inyección intracavernosa de fármacos vasodilatadores y los mecanismos de erección por vacío. El im-plante de una prótesis peneana constituye la última alternativa terapéutica. En el proceso diagnóstico y terapéutico no puede obviarse que la DE puede ser un primer síntoma de un proceso cardiovascular que debe intentar detectarse y establecer las medidas necesarias (control de las enfermedades, dieta, ejercicio físico, eliminación de tóxicos, etc.) para evitar su progresión. Introducción La disfunción eréctil (DE) se define como la incapa-cidad persistente o recurrente para conseguir o man-tener una erección suficiente para permitir una relación sexual satisfactoria. De acuerdo a diferentes criterios de valoración, la DE afecta entre el 10 y el 70% de hombres (1-3), con una clara tendencia a incrementarse debido a la mayor longevidad del hombre y a una mejora de la calidad de vida (4). La DE es mas prevalente en las últimas décadas de la vida, aunque, de manera preo-cupante, cada vez afecta a hombres mas jóvenes por factores fundamentalmente psicógenos y ligados al estilo actual de vida. Desde la perspectiva clínica la DE puede dividirse en 5 grados: 1. ausencia absoluta de erección, 2. sólo tumes-cencia, 3. rigidez peneana incompleta que no permite la penetración, 4. rigidez peneana incompleta que permite la penetración y 5. rigidez peneana completa o incompleta que se pierde antes o después de realizar la penetración.
... A high prevalence of ED has been reported in many studies, and the situation could be even worse in the coming years, particularly in developing countries [3,4]. Although the release of phosphodiesterase type 5 inhibitors (PDE5-i) highly improved the treatment of ED patients with almost all kinds of pathophysiological causes, the high discontinuation rate of PDE5 inhibitors make it still essential to seek the causes for disease diagnosis and treatment [2,[5][6][7]. ...
Background
The simplified International Index of Erectile Function (IIEF-5) is a convenient, reliable and validated diagnostic tool for erectile dysfunction (ED). However, few studies focused on IIEF-5 in ED patients with different pathophysiological causes. ,We aim to compare the IIEF-5 score among ED patients with specific pathophysiologies in this study.
Methods
The IIEF-5 score of 3,327 ED patients (median age 39 years) was analyzed. The primary causes of ED were determined by comprehensive diagnostic procedures in the urology/andrology clinics in five training hospitals. Patients with uncertain pathophysiologic cause were excluded.
Results
176 patients were excluded, 3151 patients with ED history between 0.5 year and 20 years, were enrolled. The causes of ED was classified as psychogenic (59.2%), vasoculogenic (21.3%), neurogenic (4.1%), anatomical/structural (2.8%), hormonal (7.1%) or drug-induced (5.5%). A significant difference was detected in the median IIEF-5 score between psychogenic ED and organic ED (15 (IQR 13, 17) versus 12 (IQR 9.5, 14.5), P < 0.001). There was no significant difference of IIEF-5 scores among the organic groups (P = 0.073), or between arteriogenic and venogenic groups (13 (IQR 10.5, 15.5) versus 13 (IQR 11–15), P = 0.912 (adjusted α = 0.017)). However, the median IIEF-5 score of those with a mixed vascular cause was the lowest among vasculogenic patients (11 (IQR 8.5-13.5), scores for the three groups: P = 0.003.).
Conclusions
The IIEF-5 scores of men with psychological ED are higher than those with organic causes, but there is no difference among patients with different organic pathophysiologies. Our data indicate that IIEF-5 is not a definitive diagnostic tool to discriminate the pathophysiological causes of ED.
... Along with similar analogues such as tadalafil (Cialis ® ; Lilly, Indianapolis, IN, US) and vardenafil (Levitra ® ; Bayer, Wayne, NJ, US), these drugs are now first-line treatment for erectile dysfunction worldwide. 1 In addition to their therapeutic use, PDE5 inhibitors are popular recreational drugs owing to their perceived ability to enhance sexual performance. 2 In recent years, there has been an exponential increase in the availability of prescription-only medication via websites. ...
The internet provides the public with unregulated access to a wide range of medications. We present the case of a 43-year-old man who purchased oral tadalafil gel on the internet and injected it into his left radial artery. He presented 48 hours after injection with signs of ischaemia distal to the injection site requiring a combination of medical and surgical treatment. This unique case highlights the potential dangers of unregulated access to medication and the consequences of intravascular injection of oral gels.
... Most studies raised concern over cardiovascular safety [36][37][38] even though some studies reported that PDE5-Is may have a beneficial effect on cardiovascular system [39,40]. In our systematic review, no trial reported severe cardiovascular AEs. ...
Prostate cancer is relatively common cancer occurring in males. Radical prostatectomy (RP) is the most effective treatment for a localized tumor but erectile dysfunction (ED) is common complication, even when bilateral nerve-sparing RP (BNSRP) is performed. Clinical trials have shown varied effectiveness of phosphodiesterase type-5 inhibitors (PDE5-Is) for treatment of post-BNSRP ED, but there remains controversy over the application of this treatment and no formal systematic review and meta-analysis for the use of PDE5-Is for this condition has been conducted. This review was to systematically assess the efficacy and safety of oral PDE5-Is for post-BNSRP ED. A database search was conducted to identify randomized controlled trials (RCTs). The comparative efficacy of treatments was analyzed by fixed or random effect modeling. Erectile function was measured using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) question-2, 3 and the Global Assessment Question (GAQ). The rate and incidence of adverse events (AEs) were determined. The quality of included studies was appraised using the Cochrane Collaboration bias appraisal tool. Eight RCTs were included in the analyses. PDE5-Is were effective for treating post-BNSRP ED compared to placebo when erectile function was determined using the IIEF score [mean difference (MD) 5.63, 95% confidence interval (CI) (4.26-6.99)], SEP-2 [relative risk (RR) 1.63, 95% CI (1.18-2.25) ], SEP-3 [RR 2.00, 95% CI (1.27-3.15) ] and GAQ [RR 3.35, 95% CI (2.68-4.67) ]. The subgroup analysis could find a trend that longer treatment duration, higher dosage, on-demand dosing, sildenafil and mild ED are associated with more responsiveness to PDE5-Is. PDE5-Is were overall well tolerated with headache being the most commonly reported AE. Our data provides compelling evidence for the use of PDE5-Is as a primary treatment for post-BNSRP ED. However, further studies are required to optomize usage parameters (such as dosage and duration of treatment).
... The rate was much lower than that for sildenafil. 27 These observed AE data for avanafil might be correlated with its favorable pharmacokinetic profile and greater selectivity for PDE5. Avanafil has a higher selectivity (120-fold) against PDE6 than sildenafil (16-fold) and vardenafil (21-fold), as well as a much higher selectivity (>10 000-fold) against PDE1 than sildenafil (380-fold) or vardenafil (1000-fold). ...
Avanafil, a potent new selective phosphodiesterase type 5 (PDE5) inhibitor, has been developed for the treatment of erectile dysfunction (ED). We carried out a systematic review and meta-analysis to assess the efficacy and safety of this drug for the treatment of ED. A literature review was performed to identify all published randomized, double-blind, placebo-controlled trials of avanafil for the treatment of ED. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Four publications, involving a total of 1381 patients, were used in the analysis, including four randomized controlled trials (RCTs) that compared avanafil with a placebo. Among the co-primary efficacy end points indicating that avanafil 100 mg was more effective than a placebo were successful vaginal penetration (SEP2) (the odds ratio (OR) =5.06, 95% confidence interval (CI) =3.29-7.78, P< 0.00001) and successful intercourse (SEP3) (OR = 3.99, 95% CI = 2.80-5.67, P< 0.00001). Men randomized to receive avanafil were less likely than those receiving the placebo to drop out due to an adverse event (AE) (OR = 1.48, 95% CI = 0.54-4.08, P= 0.44). Specific AEs with avanafil included headache and flushing, which were significantly less likely to occur with placebo. This meta-analysis indicates that avanafil 100 or 200 mg is an effective and well-tolerated treatment for ED. Compared with avanafil 100 mg, patients who take avanafil 200 mg are more likely to experience headaches.
Mit einer Gesamtprävalenz zwischen 30 und 40 % und einem Leidensdruck von 90 % ist die ED bei Männern >50 Jahre die häufigste Sexualstörung. Das ED-Risiko (Odds Ratio) liegt mit zwischen 2,2 und 4,3 für Männer mit Herz-Kreislauf-Erkrankungen, Diabetes, Neuropathien, BPH/LUTS sowie Operationen und Bestrahlungen im kleinen Becken am höchsten. Während bei Männern <40 Jahre psychogene Faktoren mit Versagensängsten und erhöhtem adrenergen Tonus am häufigsten für eine ED verantwortlich zeichnen, sind dies bei Männern >40–50 Jahre vaskuläre (endotheliale Dysfunktion), hormonelle (Hypogonadismus, Hyperprolaktinämien), neurogene und medikamentöse/iatrogene Faktoren. Die Diagnostik der ED beinhaltet eine detaillierte Sexualanamnese mit Erfassung auch anderer simultaner Sexualstörungen sowie Fokussierung auf die Partnerschaft, eine detaillierte Allgemeinanamnese inkl. der Risikofaktoren und derzeitigen Medikationen, eine fokussierte körperlich-genitale Untersuchung und Labordiagnostik inkl. BZ/HbA1C-Wert, Cholesterin und Testosteron sowie ggf. Prolaktin und TSH. Neben dem positiven Effekt der Beeinflussung von Lifestyle-und Risikofaktoren auf eine ED wie Gewichtsabnahme, Medikamentenselektion, Cholesterinsenkung, Nikotinabstinenz und T-Substitution bei T-Werten <3,2 ng/ml besteht die First-Line-Therapie der ED in der oralen Medikation mit den derzeit 4 verfügbaren PDE-5-Hemmern Avanafil, Sildenafil, Tadalafil und Vardenafil, wobei Avanafil am schnellsten (15–30 min) wirkt und die wenigsten Nebenwirkungen aufweist, Tadalafil hingegen die längste (>36 h) Wirkdauer aufweist und auch als tägliche Dosierung für die ED mit/ohne BPH zur Verfügung steht. Für Non-Responder auf PDE-5-Hemmer (ca. 30–40 % aller ED-Patienten) steht die intraurethrale PGE 1-Behandlung mit MUSE, die Schwellkörperinjektionstherapie mit PGE1 (Alprostadil), Papaverin/Phentolamin oder der Trimix-Kombination aus PGE1/Papaverin/Phentolamin Aviptadil(VIP)/Phentolamin zur Verfügung, in schweren Fällen evtl. auch in Kombination mit PDE-5-Hemmern angewandt. Für Patienten, bei welchen medikamentöse Therapien nicht erfolgreich sind, steht seit langem die Vakuumapparatetherapie sowie jetzt auch bei organischen ED Formen die extrakorporale Schock(Stoß)wellentherapie (ESWT) zur Verfügung.Neue Therapieansätze für die Zukunft stellen die intrakavernöse Platelet Rich Plasma (PRP) Therapie, die intrakavernöse Stammzellentherapie sowie die intrakavernöse Botoxtherapie dar.
Sildenafil citrate is a selective oral phosphodiesterase 5 (PDE5) inhibitor, a widely used drug for erectile dysfunction that acts by elevating cGMP levels and causing smooth muscle relaxation. It also has 10% activity against PDE6, a key enzyme in phototransduction cascade in the retina. Recent ocular imaging developments have further revealed the influence of sildenafil on ocular hemodynamics, particularly choroidal perfusion. Choroidal thickness is increased, and choroidal perfusion is also enhanced by autoregulatory mechanisms that are further dependent on age and microvascular abnormalities. Studies demonstrating high intraocular pressure via a "parallel pathway" from increased choroidal volume and blood flow to the ciliary body have challenged previous concepts. Another new observation is the effect of sildenafil on bipolar cells and cyclic-nucleotide gated (CNG) channels. We discuss potential deleterious effects (central serous chorioretinopathy, glaucoma, ischemic optic neuropathy, and risks to recessive carriers of retinitis pigmentosa), potential beneficial effects (ameliorate choroidal ischemia, prevent thickening of Bruch membrane, and promote recovery of the ellipsoid zone) in macular degeneration, as well as potential drug interactions of sildenafil.
Background: Sildenafil, a phosphodiestrate-5 (PDE-5) inhibitor is used in the treatment of erectile dysfunction. There have been reports of adulteration of herbal products with PDE-5 inhibitors without considering its deleterious consequences to public safety. Objectives: To evaluate the presence of sildenafil as an undeclared adulterant in herbal products marketed in northwest Nigeria by TLC/IR Spectroscopy. Methods: A survey of herbal aphrodisiac products marketed in four Northwestern Nigerian states was carried out. A sample size (50) representative of the total products surveyed was collected for this study. A simple, rapid thin layer chromatographic (TLC) method was employed for the identification of sildenafil adulterant in herbal aphrodisiac samples. Presence of sildenafil from the suspected products was confirmed by Fourier transform Infrared (FTIR) analysis. Results: TLC method revealed 16 out of 50 herbal aphrodisiac samples to contain sildenafil which was affirmed by Infrared spectroscopy. Conclusion: About 32% of the market products sampled were adulterated with sildenafil. The use of such products poses a serious threat to public safety. RESUME Contexte: Le sildénafil, un inhibiteur du phosphodiestrate-5 (PDE-5) est utilisé dans le traitement de la dysfonction érectile. Il y a eu des rapports d'adultération de produits à base de plantes avec des inhibiteurs de PDE-5 sans tenir compte de ses conséquences délétères pour la sécurité publique. Objectifs: Évaluer la présence de sildénafil comme adultérant non déclaré dans les produits à base de plantes commercialisés dans le nord-ouest du Nigéria par spectroscopie TLC/IR. Méthodes: Une enquête sur les produits aphrodisiaques à base de plantes commercialisés dans quatre États du nord-ouest du Nigéria a été menée. Une taille d'échantillon (50) représentative du total des produits enquêtés a été recueilliepour cette étude. Une méthode de chromatographie en couche mince (TLC) simple et rapide a été utilisée pour identifier l'adultérant au sildénafil dans des échantillons aphrodisiaques à base de plantes. La présence de sildénafil dans les produits suspects a été confirmée par l'analyse infrarouge à transformée de Fourier (FTIR). Résultats: La méthode TLC a révélé que 16 des 50 échantillons aphrodisiaques à base de plantes contiennent du sildénafil, ce qui a été confirmé par spectroscopie infrarouge. Conclusion: Environ 32 % des produits du marché échantillonnés étaient frelatés au sildénafil. L'utilisation de ces produits constitue une grave menace pour la sécurité publique. Mots-clés: Aphrodisiaques à base de plantes, sildénafil, adultération, TLC, FTIR. Détection TLC et IR du sildénafil comme adultérant non déclaré dans certains produits aphrodisiaques à base de plantes commercialisés dans le nord-ouest du Nigéria
Background:
The phosphodiesterase-5 (PDE5) inhibitors that have been available for nearly 20 years are highly effective in treating erectile dysfunction and have been consistently shown to be safe when used according to package insert instructions.
Aim:
To review the cardiovascular (CV) safety of PDE5 inhibitors used to treat erectile dysfunction.
Methods:
PubMed, the Derwent Drug File, and Embase were searched to identify papers published from 1990-2016 presenting CV safety data for PDE5 inhibitors.
Outcomes:
This narrative review focuses mainly on papers published in the last 10 years with CV safety data for sildenafil, tadalafil, or vardenafil.
Results:
Similar to earlier studies, newer studies demonstrate that PDE5 inhibitors do not show an increased incidence of serious CV adverse events such as cardiac death or myocardial infarction. There are drug-drug interactions with PDE5 inhibitors that for the most part are now commonly known, and PDE5 inhibitors are generally safe to use with other commonly used drugs including antihypertensive agents.
Conclusion:
PDE5 inhibitors are a class of drugs that when used appropriately demonstrate a favorable CV safety profile and present some encouraging signals for new CV indications, which will require additional study. Kloner RA, Goldstein I, Kirby MG, et al. Cardiovascular Safety of Phosphodiesterase Type 5 Inhibitors After Nearly 2 Decades on the Market. Sex Med Rev 2018;XX:XXX-XXX.
Product placement can be presented through edutainment. A drug such as Viagra is introduced or impotence is branded in movies and TV series in different ways to raise awareness of impotence disorder and Viagra as a solution.
This study aims to analyze strategies of framing and branding Viagra and impotence disorder, based on a qualitative method analysis of 40 movies and TV series.
Findings show that Viagra is shown as not only for older men but also for young and healthy men. Out of 40 movies and TV series in the study sample, in 14 (32.5%), the age of the target audience ranged from 20 to 40 years, in 12 (31.6%) movies and series, the age of the target audience was over 40, and in 12 (31.6%) movies and series, the target audience was very old (over 70). Viagra is shown as not only treating impotence but is presented as a wonder drug that provides a solution for psychological and social needs. The movies show usage instructions, side effects, and risks, and how to store the drug.
We recommend that the viewing audience be educated for critical viewing of movies/series in order to empower viewers and give them tools for their decision-making processes concerning their health.
Sexual activity affects the quality of life of patients with cardiovascular disease (CVD). The purpose of this document is to highlight the fact that sexual activity of patients with stable forms of CVD and moderate exercise tolerance is safe. Delaying resumption of sexual activity is not justified and could have a negative impact on the patient's mental status and the quality of partner life. Vasculogenic erectile dysfunction is considered an independent risk factor for coronary heart disease.
The past decade has been witness to dramatic advances in drug therapy for erectile dysfunction. Multiple therapeutic targets along the physiologic pathway essential for normal erection have been exploited. While phosphodiesterase inhibitors are the “poster child” for this therapeutic field, are well tolerated oral therapies other delivery pathways and agents exist that hold great promise as well. A multitude of intracavernosal agents have been studied with varying success, including vasoactive and gene-based approaches. Topical and intraurethral therapies are also available with merits and limitations of their own. The future is bright, armed with an enhanced understanding of erectile physiology, new targets and approaches for therapies are being developed.
Die Bedeutung der Sexualität für eine Partnerschaft nimmt zwar mit zunehmendem Alter ab, ist aber auch noch in fortgeschritteneren Altersgruppen für ca. die Hälfte der Befragten von Bedeutung, wie eine repräsentative Umfrage aus Australien in einer 75–95 Jahre alten Population (n = 2783) zeigt (Tab. 1, Hyde et al. 2010)
Erectile dysfunction (ED) is a disease marker for cardiovascular disease. Men with ED should be properly assessed and investigated before starting treatment. The PDE5 inhibitors, including sildenafil, proved to be safe and effective treatment for this disorder.
1.
Der Wunsch nach sexuellen Kontakten und die Fähigkeit, Sexualität zu erleben, sind auch in der Lebensphase ab 60 Jahren bei Mann und Frau unverändert vorhanden.
2.
Der Phasen des sexuellen Reaktionszyklus laufen protrahierter ab.
3.
Die Möglichkeit Sexualität zu erleben hängt wesentlich von dem Vorhandensein einer stabilen Partnerschaft sowie dem Auftreten von chronischen Erkrankungen und deren medikamentöser Therapie ab.
4.
Ein manifester Hypogonadismus sollte bei fehlenden Kontraindikationen aufgrund der Gefahr eines okkulten Prostatakarzinoms mit kurzfristig absetztbaren Testosteronpräparaten (Pflaster oder Gel) erfolgen. Zur Vermeidung von Nebenwirkungen sollte der Testosteronspiegel bei der Substitution niemals in supraphysiologische Bereiche angehoben werden.
5.
Die Häufigkeit der erektilen Dysfunktion nimmt ab dem 60. Lebensjahr progredient zu. Besonders die Einführung der Phosphodiesterase-V-Inhibitoren hat eine wesentliche Erweiterung der Therapieoptionen erbracht.
Erectile dysfunction (ED) is a clinical condition affecting nearly one-third of men ages 40–70 yr (1). Since the release of sildenafil in 1998, more than 10 million men with ED have received this agent (2). Double-blind and postmarketing studies have demonstrated the safety of sildenafil in men with ED (3). However, there is concern among the public and the medical profession that patients undergoing treatment with sildenafil may experience acute myocardial infarction (MI) and death related to sexual activity. This concern prompted a multidisciplinary conference in 1999 at Princeton, New Jersey, that considered the risks associated with sexual activity and developed guidelines for evaluating the risk of heart attack after sexual activity (4).
Landmark studies by Muller, Mittleman, Tofler and others have suggested that acute myocardial infarctions (MIs) may be triggered by certain phenomena (1–4). It is believed that these triggers, often initiated by an increase in catecholamines and sympathetic nervous system activity, ultimately lead to a disruption of the vulnerable atherosclerotic plaque. Increases in sympathetic vascular tone and sympathetic/catecholamine-related increases in heart rate, blood pressure, ventricular contractility, platelet aggregability, hematocrit, and reductions in fibrinolysis may all contribute (2). For example, an increase in ventricular contractility with changes in dP/dT (change in ventricular pressure over time) and an increase in coronary tone can increase the sheer-stress of blood flowing across a vulnerable atherosclerotic plaque. These mechanical forces may then contribute to rupture of a thin fibrous cap overlying the lipid pool of the plaque. Lipid, foam cells, and tissue factors escape into the lumen of the artery, contributing to platelet aggregation, fibrin deposition, and thrombus, which can then obstruct flow through the coronary artery, causing acute MI and/or sudden death. Reduction in flow also results from an increase in stimulation of alpha sympathomimetic receptors. Increases in heart rate and blood pressure during emotional or physical stress increase oxygen demand, and if O2 supply is limited by coronary stenosis, coronary artery vasospasm, or flow limiting intra-coronary thrombus, ischemia will be worsened.
Oral phosphodiesterase-5 (PDE5) inhibitors have been shown to be effective oral agents for the treatment of organic, psychogenic, and mixed erectile dysfunction (ED). There are numerous PDE isoforms throughout the body (1). PDE5 is concentrated in genitalia but is also found in systemic arteries and veins throughout the body as well as in smooth muscle cells in the gastrointestinal tract and platelets (2–4).
Sildenafil citrate (Viagra™; Pfizer, Inc., New York, NY) is the first of a series of orally active phosphodiesterase (PDE) type-5 inhibitors that have and will continue to transform the treatment of erectile dysfunction (ED) (1). Initially advocated as a potential alternative to oral nitrates for the treatment of stable angina pectoris, sildenafil’s short half-life and its modest nitrate-like hemodynamic properties were not seen as a clinical advance. Sildenafil’s role in the treatment of ED follows from erections in healthy volunteers being recorded as “adverse events.” The subsequent recognition that vascular disease accounts for greater than 70% of ED cases and that cardiac disease, either documented or silent, is a frequent cause of ED refocused attention on sildenafil’s hemodynamic properties, initially in the context of safety but more recently as a form of therapy (2). Therefore, because PDE5 is present in smooth muscle cells throughout the vasculature, the potential for PDE5 inhibition reducing the degradation of guanosine monophosphate has widespread implications throughout the vascular system.
Erectile dysfunction (ED) is a very common disorder with a deep impact on quality of life on both patients and partners. Several options are available for treating ED: oral pharmacotherapy with phosphodiesterase 5 (PDE5) inhibitors currently represents the first-line option for many patients with ED. Alprostadil, a prostaglandin, has been marketed for many years as a urethral stick and an intracavernous injection for the treatment of ED. It is now available in the form of a cream (Vitaros/Virirec), a noninvasive treatment which combines an active drug (alprostadil, a synthetic prostaglandin E1) with a skin enhancer improving its local absorption directly at the site of action. Alprostadil has a favourable pharmacodynamic profile and is poorly absorbed in systemic circulation, which makes it suitable in a lot of circumstances and results in a reduced risk of adverse effects (AEs). Systemic AEs are reported in only 3% of the treated population. Clinical efficacy has been demonstrated in both phase II and III trials, showing a global efficacy up to 83% with the 300 μg dose in patients with severe ED, significantly better than placebo. Its fast onset of action and lack of interactions with other drugs makes alprostadil cream a possible first-line therapeutic option for some patients with ED: individuals who are reluctant to take systemic treatments or have AEs, patients who do not respond, cannot tolerate, or do not accept PDE5 inhibitor therapy, and patients treated with nitrates. Therefore, this new treatment for ED can be offered to patients and could help address the needs unmet by other treatments.
Heart failure is a condition, often called congestive heart failure (CHF), defined as the inability of the heart to pump enough blood throughout the body due to any structural or functional disorders (Hunt et al. 2009). CHF occurs as a result of myocardial infarction (MI) and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy (Dickstein et al. 2008). In spite of several advances in therapy for CHF and MI, the prevalence of this disease is expected to still rise and predicted to reach 10 million patients by the year 2037 (Rich 1997). Even though several new drugs have been introduced to treat CHF condition and symptoms, still there is a pressing need for new effective drugs and treatment options for patients who may remain symptomatic despite optimal therapy. The inhibitors of phosphodiesterase (PDE) enzymes emerge as a class of cardioprotective drugs for their use in the adjunctive therapy in patients with decompensated heart failure (Cvelich et al. 2011). The main role of the cyclic nucleotide PDE enzymes is to hydrolyze the phosphodiester bonds in the second messenger molecules such as the cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) (Mullershausen et al. 2003). The cyclic nucleotides, cAMP and cGMP (Kass et al. 2007; Movsesian et al. 2009), influence functions, gene expression, and morphology of heart and hence play a central role in the cardiovascular regulation (Kass et al. 2007). The actions of epinephrine on the heart are regulated by cAMP (Eckly-Michel et al. 1997; Maurice 2005; McConnachie et al. 2006; Movsesian and Bristow 2005; Muller et al. 2000; Murray 1990), whereas cGMP is an important mediator of the physiological actions of nitric oxide (NO) (Hofmann et al. 2006; Lohmann and Walter 2005; Pilz and Casteel 2003; Potter et al. 2006).
Mit einer Gesamtprävalenz zwischen 30 und 40 % und einem Leidensdruck von 90 % ist die ED bei Männern >50 Jahre die häufigste Sexualstörung. Das ED-Risiko (Odds Ratio) liegt mit zwischen 2,2 und 4,3 für Männer mit Herz-Kreislauf-Erkrankungen, Diabetes, Neuropathien, BPH/LUTS sowie Operationen und Bestrahlungen im kleinen Becken am höchsten. Während bei Männern <40 Jahre psychogene Faktoren mit Versagensängsten und erhöhtem adrenergen Tonus am häufigsten für eine ED verantwortlich zeichnen, sind dies bei Männern >40–50 Jahre vaskuläre (endotheliale Dysfunktion), hormonelle (Hypogonadismus, Hyperprolaktinämien), neurogene und medikamentöse/iatrogene Faktoren. Die Diagnostik der ED beinhaltet eine detaillierte Sexualanamnese mit Erfassung auch anderer simultaner Sexualstörungen sowie Fokussierung auf die Partnerschaft, eine detaillierte Allgemeinanamnese inkl. der Risikofaktoren und derzeitigen Medikationen, eine fokussierte körperlich-genitale Untersuchung und Labordiagnostik inkl. BZ/HbA1C-Wert, Cholesterin und Testosteron sowie ggf. Prolaktin und TSH. Neben dem positiven Effekt der Beeinflussung von Lifestyle-und Risikofaktoren auf eine ED wie Gewichtsabnahme, Medikamentenselektion, Cholesterinsenkung, Nikotinabstinenz und T-Substitution bei T-Werten <3,2 ng/ml besteht die First-Line-Therapie der ED in der oralen Medikation mit den derzeit 4 verfügbaren PDE-5-Hemmern Avanafil, Sildenafil, Tadalafil und Vardenafil, wobei Avanafil am schnellsten (15–30 min) wirkt und die wenigsten Nebenwirkungen aufweist, Tadalafil hingegen die längste (>36 h) Wirkdauer aufweist und auch als tägliche Dosierung für die ED mit/ohne BPH zur Verfügung steht. Für Non-Responder auf PDE-5-Hemmer (ca. 30–40 % aller ED-Patienten) steht die intraurethrale PGE1-Behandlung mit MUSE, die Schwellkörperinjektionstherapie mit PGE1 (Alprostadil), Papaverin/Phentolamin oder der Trimix-Kombination aus PGE1/Papaverin/Phentolamin zur Verfügung, in schweren Fällen evtl. auch in Kombination mit PDE-5-Hemmern angewandt. Für Patienten, bei welchen medikamentöse Therapien nicht erfolgreich sind, steht seit langem die Vakuumapparatetherapie oder jetzt auch neu die extrakorporale Schockwellentherapie (ESWT) zur Verfügung.
Erectile dysfunction (ED) associated with cancer therapy is commonly encountered whenever surgical interventions, radiotherapy, or systemic chemotherapy compromise the pelvic blood vessels or nerves. Currently, available treatment modalities frequently achieve long-term cancer remissions, and as a consequence, with advancing age patients are likely to face sexual dysfunctions and suffer their devastating effects on quality of life (QoL) long after the cancer treatment has been completed. The diagnosis of cancer is tough to overcome, but when its therapy results in alteration of basic bodily functions, it can be hard to deal with for patients and their partners.
The relaxing effect of the phosphodiesterase type 5 (PDE5) inhibitors on vascular smooth muscle has attracted much attention, especially in persons with cardiovascular disease. The results of early studies showed that sildenafil slightly reduces systolic and diastolic blood pressures and has no effect on heart rate, while being safe and well tolerated. Studies also indicate that sildenafil does not contribute to the development of myocardial infarction or ischemia. Similar benign effects on hemodynamics and cardiac events have also been demonstrated for tadalafil and vardenafil. None of the PDE5 inhibitors adversely affects total exercise time or time to ischemia during exercise testing in men with stable angina, it is key to avoid concomitant administration of nitrates with any of the PDE5 inhibitors because this combination can cause increased vasodilation and a subsequent drop in blood pressure. Sildenafil has an alpha-blocker precaution; tadalafil is contraindicated with alpha blockers except for 0.4 mg tamsulosin; vardenafil is contraindicated with alpha blockers.
IntroductionPsychogenic FactorsCardiovascular Risk FactorsDiabetes MellitusMedical DisordersIatrogenic DisordersPost-traumatic EDEndocrine FactorsLower Urinary Tract Symptoms (LUTS)Etiologies and Co-morbidities in Relation to Prevalence of EDConclusion
IN BRIEF
Erectile dysfunction affects ∼ 30 million men in the United States to some extent. It may indicate the presence of a serious underlying medical condition, such as cardiovascular disease, diabetes, or depression. It compromises multiple aspects of a patient's life, including overall quality of life and interpersonal relationships.
Hypoxic pulmonary vasoconstriction is a fundamental physiologic mechanism, optimizing perfusion–ventilation matching in periods of regional hypoventilation of the lung (19). However, during global alveolar hypoxia, whether due to lung disease or environmental conditions such as high altitude, this mechanism results in pulmonary hypertension and enhanced right-heart load. These effects were consistently reproduced in the healthy volunteers in our study, who developed substantial pulmonary hypertension both under experimental hypoxia at sea level and at high altitude in the Mount Everest base camp. Moreover, a marked further increase in pulmonary hypertension was noted during hypoxic exercise in participants taking placebo; median systolic pulmonary artery pressure was 42.9 mm Hg at low altitude and 33.6 mm Hg at high altitude. Of note, this pulmonary hypertensive response was observed in persons not previously characterized as sensitive to pulmonary edema at high altitudes. This finding is consistent with the notion that exercise enhances even moderate forms of pulmonary hypertension (20). The Doppler echocardiographic technique used to assess systolic pulmonary artery pressure in our study has been extensively evaluated in different types of pulmonary hypertension and is closely correlated with right-heart catheterization in healthy participants (21–23).
Aiming to verify the procedure that intensive care professionals and students adopt for oral intake in acute neurologic patients after mechanical ventilation, a questionnaire was applied to health care professionals (Intensive Care medical and nursing staff, and neurologists), medical residents and medical students in a public teaching hospital. The survey contained questions about food texture criteria, and questions to choosing the best oral diet for patients with neurologic acute diseases. The survey was answered by 14 doctors, 9 residents, 13 medical students and 21 nursing professionals. It was made descriptive statistics, with univariated analysis. The most cited parameters to indicate oral intake were: proper consciousness level, effectiveness of swallowing, and gastrointestinal stability. Food textures most frequently elected to oral intake were soft and semisoft. However, there were several contradictory answers about food texture, mainly about fluids. There is no agreement about oral intake procedures in the acute neurocritical patient among intensive care professionals, mainly about selecting food texture to be tested.
Erectile dysfunction affects more than 150 million men worldwide and is increasingly prevalent. Elderly men are at increased risk for erectile dysfunction, which is, in part, owing to medical comorbidities associated with erectile dysfunction. Slidenafil, the first US FDA-approved, oral phosphodiesterase type-5 inhibitor, has revolutionized the treatment of erectile dysfunction since its approval in 1998. High treatment success rates and low number of adverse events, in addition to significant improvements in psychosocial parameters, have resulted in increased patient and physician satisfaction with sildenafil, and increased usage. Safety has been demonstrated in patients with stable cardiovascular disease, and rates of discontinuation owing to adverse effects remains low.
Sildenafil citrate (Revatio) is approved for pediatric pulmonary arterial hypertension (PAH) in the European Union. A new pediatric formulation, 10 mg/mL sildenafil citrate powder for oral suspension (POS), was developed for pediatric PAH patients. Bioequivalence among the POS suspension (20 mg), the Revatio 20-mg commercial tablet, and the sildenafil citrate 2 × 10-mg clinical trial tablets was assessed. In this randomized, open-label study, 42 healthy adult volunteers received the 3 different sildenafil treatments, each in a single 20-mg oral dose, using a 3-way crossover design. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax, AUClast, and AUC∞) were evaluated for bioequivalence using a mixed-effects model. Results were used to estimate relative bioavailability and construct 90% confidence intervals (CIs). Bioequivalence was concluded if the 90% CIs for Cmax, AUClast, and AUC∞ were wholly contained within 80% to 125%. All 90% CIs for the ratios of adjusted geometric means of Cmax, AUClast, and AUC∞ were within 80% to 125%, the prespecified bioequivalence criteria. All 3 formulations were well tolerated. In conclusion, the POS suspension, the commercial 20-mg Revatio tablet, and the 10-mg sildenafil tablets were all bioequivalent to one another when given at the equal doses.
Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.
Erectile dysfunction is common in the patient with cardiovascular disease. It is an important component of the quality of life and it also confers an independent risk for future cardiovascular events. The usual 3-year time period between the onset of erectile dysfunction symptoms and a cardiovascular event offers an opportunity for risk mitigation. Thus, sexual function should be incorporated into cardiovascular disease risk assessment for all men. A comprehensive approach to cardiovascular risk reduction (comprising of both lifestyle changes and pharmacological treatment) improves overall vascular health, including sexual function. Proper sexual counselling improves the quality of life and increases adherence to medication. This review explores the critical connection between erectile dysfunction and cardiovascular disease and evaluates how this relationship may influence clinical practice. Algorithms for the management of patient with erectile dysfunction according to the risk for sexual activity and future cardiovascular events are proposed.
An association between diminution in the quality of male sexual function and ischemic coronary disease has been suggested. Patients with ischemic heart disease who underwent coronary angiography participated in this study which aimed to document the impact of the extent of coronary disease upon sexual function in 40 patients (mean age 56.6 y). The 11-questions accepted questionnaire addressing sexual drive, erectile function, and ejaculation was used. Information regarding, age, medications, hypertension, diabetes, relevant risk factors, medical history, and the number of occluded coronary vessels was retrieved from the patients' records. A statistically significant correlation was demonstrated between erectile function and the number of coronary vessels involved. Patients with one-vessel disease had more (P < 0.04) and firmer erections (P < 0.001) with fewer difficulties in achieving an erection (P < 0.007) than men with two- or three-vessel disease. Age, diabetes, and hypertension also had a negative effect on the quality of the erection (P < 0.05) in all patients.
Sildenafil citrate has been shown to be effective in a wide range of patients with erectile dysfunction and has been approved in the United States for this indication. The overall clinical safety of oral sildenafil, a potent inhibitor of phosphodiesterase type 5, in the treatment of erectile dysfunction was evaluated in more than 3700 patients (with a total of 1631 years of exposure worldwide). Safety and tolerability data were analysed from a series of double-blind, placebo-controlled studies and from 10 open-label extension studies of sildenafil in the treatment of erectile dysfunction. A total of 4274 patients (2722 sildenafil, 1552 placebo; age range 19-87 y) received double-blind treatment over a period of up to six months' duration, and 2199 received long-term, open-label sildenafil for up to 1 y. The most commonly reported adverse events (all causes) were headache (16% sildenafil, 4% placebo), flushing (10% sildenafil, 1% placebo), and dyspepsia (7% sildenafil, 2% placebo) and they were predominantly transient and mild or moderate in nature. These adverse events reflect the pharmacology of sildenafil as a phosphodiesterase type 5 inhibitor. No cases of priapism were reported. The rate of discontinuation due to adverse events (all causes) was comparable for patients treated with sildenafil (2.5%) and placebo (2.3%). In open-label extension studies, 90% of patients completed long-term sildenafil treatment, with only 2% withdrawing due to adverse events. Sildenafil is a well-tolerated oral treatment for erectile dysfunction.
To clarify the determinants of contemporary trends in mortality from coronary heart disease (CHD), we conducted surveillance of hospital admissions for myocardial infarction and of in-hospital and out-of-hospital deaths due to CHD among 35-to-74-year-old residents of four communities of varying size in the United States (a total of 352,481 persons in 1994). Between 1987 and 1994, we estimate that there were 11,869 hospitalizations for myocardial infarction (on the basis of 8572 hospitalizations sampled) and 3407 fatal coronary events (3023 sampled).
The largest average annual decrease in mortality due to CHD occurred among white men (change in mortality, -4.7 percent; 95 percent confidence interval, -2.2 to -7.1 percent), followed by white women (-4.5 percent; 95 percent confidence interval, -0.7 to -8.2 percent), black women (-4.1 percent; 95 percent confidence interval, -10.3 to +2.5 percent), and black men (-2.5 percent; 95 percent confidence interval, -6.9 to +2.2 percent). Overall, in-hospital mortality from CHD fell by 5.1 percent per year, whereas out-of-hospital mortality declined by 3.6 percent per year. There was no evidence of a decline in the incidence of hospitalization for a first myocardial infarction among either men or women; in fact, such hospital admissions increased by 7.4 percent per year (95 percent confidence interval for the change, +0.5 to +14.8 percent) among black women and 2.9 percent per year (95 percent confidence interval, -3.6 to +9.9 percent) among black men. Rates of recurrent myocardial infarction decreased, and survival after myocardial infarction improved.
From 1987 to 1994, we observed a stable or slightly increasing incidence of hospitalization for myocardial infarction. Nevertheless, there were significant annual decreases in mortality from CHD. The decline in mortality in the four communities we studied may be due largely to improvements in the treatment and secondary prevention of myocardial infarction.
Sildenafil (Viagra®), the anti-impotence drug, was originally developed as an antihypertensive agent. Its action is mediated by inhibiting the breakdown of cyclic guanosine monophosphate (c-GMP) by a type 5 c-GMP phosphodiesterase. The elevated levels of c-GMP cause smooth muscle relaxation, resulting in arteriolar dilation (hypotension), and corpora cavernosal engorgement (erection). The side effects of sildenafil: headache, facial flushing, nasal congestion, dyspepsia, and visual disturbances, are related to the vasodilatatory actions. Recently, concerns over the potential cardiovascular complications of sildenafil have been raised. Whether this relationship is causal or confounding remains uncertain. We report the case of a 66 year old man who developed an acute anterior myocardial infarction shortly after taking sildenafil.
Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that function to terminate the action of the hormone.
Background: The cardiovascular effects of sildenafil (Viagra), a selective inhibitor of phosphodiesterase type 5 (PDE5), have been extensively studied. However, its effect on human retinal arteries and veins has not yet been investigated. The effect of a single dose administration of sildenafil on the retinal vessel diameters of healthy subjects was evaluated.
Methods: Sildenafil 50 mg was administered to 10 healthy subjects (male:female = 4:6; mean age 31 (SD 6) years). The diameters of retinal arteries and veins were measured by means of a retinal vessel analyser (RVA) immediately before and at 30, 60, 90, and 120 minutes after sildenafil uptake. Blood pressure, heart rate, and intraocular pressure were monitored in parallel.
Results: A significant increase of 5.8% (p<0.001) in both retinal arterial and venous diameters was found 30 minutes after sildenafil uptake. The diameters returned to baseline after 120 minutes. A mild systemic hypotensive response was seen. Changes in heart rate and intraocular pressure were not observed.
Conclusion: Sildenafil causes a significant dilatation of retinal arteries and veins in healthy subjects. A possible role for PDE5 in the regulation of retinal blood flow is implicated.
Purpose:
Erectile dysfunction continues to be a significant problem for men after radical retropubic prostatectomy despite nerve sparing techniques. Sildenafil citrate (Viagra) has proved effective for erectile dysfunction in many men. We determine the efficacy of sildenafil in men with erectile dysfunction after radical retropubic prostatectomy and examine variables that may impact the response to treatment.
Materials and methods:
A total of 84 men were prescribed sildenafil after radical retropubic prostatectomy and asked to complete a series of questionnaires, including the International Index of Erectile Function (IIEF), on erectile function before and after sildenafil administration. The importance of factors, such as patient age, time since surgery, degree of cavernous nerve sparing, preoperative prostate specific antigen, Gleason score, clinical and pathological stage, and baseline postoperative erectile function, was examined.
Results:
Of the 84 patients 45 (53%) had improved erections and 34 (40%) had improved ability for intercourse while taking sildenafil. Mean IIEF score for the erectile function domain increased from 9 to 14 (p <0.001). Orgasmic function (p = 0.004) and intercourse satisfaction (p = 0.009) also significantly improved. The degree of nerve sparing and baseline postoperative erectile dysfunction had a significant impact on the ability of sildenafil to improve erectile function (p = 0.010 and p <0.001, respectively) and total IIEF questionnaire responses (p = 0.031 and p <0.001, respectively). Age and pathological stage also appeared to have a significant effect.
Conclusions:
Sildenafil improved erectile function and the ability to have intercourse in more than half of men after radical retropubic prostatectomy. Baseline postoperative erectile function, which is dependent on the degree of nerve sparing technique, significantly impacts the likelihood that patients will respond to sildenafil.
During the last two decades, significant advances have been made in the understanding of male sexual dysfunction. Concomitantly, a marked increase in both clinical and research activity in the field of male erectile dysfunction has led to a better evaluation and more treatment options. The prevalence and incidence are dependent on the definitions used, the diagnostic tolls, and the treatment options. Using standard definitions as suggested by the NIH Consensus Conference and improving our diagnostic and treatment options will have a major impact on the epidemiology of ED. A summary of the risk factors for ED is presented in Table 3. Still more epidemiologic research is essential to further understand the distribution as well as the prevalence of ED in certain ethnic groups, chronic conditions, and as a result of surgery and trauma. These studies will help us improve our diagnostic skills as well as our therapeutic options.
The pharmaceutical preparation sildenafil citrate (Viagra) is being widely prescribed as a treatment for male erectile dysfunction, a common problem that in the United States affects between 10 and 30 million men. The introduction of sildenafil has been a valuable contribution to the treatment of erectile dysfunction, which is a relatively common occurrence in patients with cardiovascular disease. This article is written to appropriately caution and not to unduly alarm physicians in their use of sildenafil in patients with heart disease. Reported cardiovascular side effects in the normal healthy population are typically minor and associated with vasodilatation (ie, headache, flushing, and small decreases in systolic and diastolic blood pressures). However, although their incidence is small, serious cardiovascular events, including significant hypotension, can occur in certain populations at risk. Most at risk are individuals who are concurrently taking organic nitrates. Organic nitrate preparations are commonly prescribed to manage the symptoms of angina pectoris. The coadministration of nitrates and Viagra significantly increases the risk of potentially life-threatening hypotension. Therefore, Viagra should not be prescribed to patients receiving any form of nitrate therapy. Although definitive evidence is currently lacking, it is possible that a precipitous reduction in blood pressure with nitrate use may occur over the initial 24 hours after a dose of Viagra. Thus, for patients who experience an acute cardiac ischemic event and who have taken Viagra within the past 24 hours, administration of nitrates should be avoided. In the event that nitrates are given, especially within this critical time interval, it is essential to have the capability to support the patient with fluid resuscitation and α- adrenergic agonists if needed. In patients with recurring angina after Viagra use, other nonnitrate antianginal agents, such as β-blockers, should be considered. Other patients in whom the use of Viagra is potentially hazardous include those with active coronary ischemia; those with congestive heart failure and borderline low blood volume and low blood pressure status; those with complicated, multidrug, antihypertensive therapy regimens; and those taking medications that may affect the metabolic clearance of Viagra. With respect to patients following complicated multidrug, antihypertensive programs, the randomized studies included a large number of hypertensive patients. However, most patients were controlled with 1 antihypertensive agent, and only a small number were controlled with 3 antihypertensive agents. Until adequate studies are done in these subgroups of patients, sildenafil should be prescribed with caution. Viagra acts as a selective inhibitor of cyclic GMP (cGMP)-specific phosphodiesterase type 5, resulting in smooth muscle relaxation, vasodilatation, and enhanced penile erection. Although the cardiovascular effects of sildenafil reported in available randomized, controlled clinical trials were relatively minor, heart disease patients represented only a small fraction of studied patients, and patients with heart failure, patients with myocardial infarction or stroke within 6 months, or patients with uncontrolled hypertension were not included in these studies. Thus, there are possible problems in the use of Viagra in these patients that have not been adequately studied. Given the increasing reports of deaths in which the use of Viagra may be implicated, clinicians need to exercise caution when advising their patients with heart disease about taking this medication. Specific recommendations regarding sildenafil (Viagra) and the cardiac patient are summarized in the following Table.
To determine the efficacy of sildenafil for the treatment of erectile dysfunction (ED) in a clinical practice setting; to evaluate the correlation between patient and partner perceptions of treatment outcomes; and to assess the relation between the severity of ED and response to treatment.
Among the first 100 men to receive sildenafil in a urology practice setting, 74 (mean + SD age 64+/-11 years) completed a validated sexual function questionnaire (International Index of Erectile Function [IIEF]) before and after a 4 to 6-week treatment period. A modified version of the same questionnaire was independently completed by partners. ED was categorized into a severity class of I to IV.
Sildenafil treatment improved erections by 71% to 95%, according to responses in key IIEF questions 3 and 4. Overall, 57 (77%) of 74 patients desired to continue treatment after the test period. Patient score on the IIEF was correlated with partner score on the modified questionnaire before and after treatment (r = 0.67 to 0.81, P <0.01). IIEF scores were reflected in a simple severity classification system. Men with the best preservation of erections (severity class I) exhibited the best responses to sildenafil, whereas men with no erections (severity class IV) were much less likely to respond to the drug and desire continuation of treatment (P <0.01). Patients with a radical prostatectomy were relatively refractory to sildenafil, except for 2 of 5 who had undergone a nerve-sparing operation.
In clinical practice, sildenafil is an effective treatment of ED, according to partner-validated questionnaire responses; and the results of treatment are predictable with an ED severity classification system.
Men on antihypertensive medications (anti-HTNs) often have erectile dysfunction (ED). We evaluated the safety of VIAGRA® (sildenafil citrate) in men with ED and taking >2 anti-HTNs.568 men (≥18 years) with ED and taking ≥2 anti-HTNs were randomized to receive sildenafil (50-mg starting dose) or placebo for a 6-week, double-blind (DB) flexible dose phase followed by a 6-week, open-label (OL) extension. Patients completing DB were eligible for OL. Patients started OL with 50-mg sildenafil. Observed/volunteered adverse events (AEs) and suspected causality were recorded.At week 6, 40% of sildenafil- and 26% of placebo-treated patients experienced at least 1 AE (any cause). 95% of patients completed the study; 4 (1.4%) in each group discontinued due to AEs. Two patients (0.7%) in each group had serious adverse events (SAEs). The most common AEs in sildenafil- versus placebo-treated patients were headache (10% vs 4%), flushing (6% vs 0.4%), dyspepsia (5% vs 1%), dizziness (4% vs 0.4%), and abnormal vision (3% vs 0%). At the end of OL (week 12), 36% and 40% of patients who took DB sildenafil and placebo, respectively, experienced AEs. The most common OL AEs are listed in the table. AEs associated with changes in blood pressure were (sildenafil vs placebo): hypotension (0.7% vs 0%), postural hypotension (0.4% vs 0.4%), and dizziness (2% vs 2%). 3 DB placebo patients (1.1%) discontinued due to AEs during OL. There were no SAEs.Sildenafil was well tolerated among men with ED who were taking multiple anti-HTNs. The incidence of AEs was similar in men taking 2 (n=307) and 3+ (n=222) anti-HTNs and consistent with that previously reported. Less than 2% of patients discontinued because of AEs. Thus, men who are taking multiple anti-HTNs are not at increased risk for more frequent or severe AEs while taking sildenafil for ED.
Oral sildenafil is an effective treatment for erectile dysfunction (ED), which is a common complaint for patients with hypertension and those taking antihypertensive agents. This post hoc subanalysis assessed the efficacy and safety of sildenafil in men with ED who were receiving concomitant antihypertensive medication. Efficacy was assessed in 3414 men (1218 of whom were taking antihypertensive medication) who received sildenafil (5 to 200 mg) or placebo for 6 weeks to 6 months in 10 double-blind, placebo-controlled studies. The significant improvements in erectile function demonstrated by sildenafil-treated patients were comparable in patients taking and those not taking antihypertensive medication. Safety was assessed in 3975 men (1094 of whom were taking one or more antihypertensive agent, classified as a diuretic, β-blocker, α1-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker), who received sildenafil or placebo in 18 double-blind, placebo-controlled studies. For patients taking sildenafil and antihypertensive medication, the incidence of treatment-related adverse events (34%) was similar to that for sildenafil-treated patients not taking any antihypertensive agent (38%). The incidences of the most common adverse events and of adverse events potentially related to blood pressure decreases (eg, hypotension, dizziness, and syncope) were similar in both sildenafil groups. The number of antihypertensive medications taken from among the five classes had no effect on the adverse event profile of sildenafil. Sildenafil is an effective and well-tolerated treatment for ED in patients taking concomitant antihypertensive medication, including those on multidrug regimens.
OBJECTIVES: The purpose of the present study is to describe changes over two decades (1975 to 1995) in the incidence, in-hospital and long-term case-fatality rates associated with acute myocardial infarction (AMI) from a multihospital community-wide perspective.
BACKGROUND: Despite the magnitude of, and mortality associated with acute myocardial infarction (AMI), relatively limited population-based data are available to describe recent and temporal trends in the attack and case-fatality rates associated with AMI from a representative population-based perspective.
METHODS: The community-based study included 5,270 residents of the Worcester, Massachusetts, metropolitan area hospitalized with confirmed initial AMI in all metropolitan Worcester, Massachusetts, hospitals (1990 census population = 437,000) in 10 one-year periods between 1975 and 1995.
RESULTS: The age-adjusted incidence rates of initial AMI increased between 1975 (244 per 100,000) and 1981 (272 per 100,000), after which time these rates declined through 1995 (184 per 100,000). The crude and multivariable-adjusted in-hospital case-fatality rates exhibited a consistent decline between 1975/1978 (17.8%), 1986/1988 (17.0%) and 1993/1995 (11.7%). Although there were no statistically significant differences in the unadjusted long-term case-fatality rates of discharged hospital survivors over the periods under study, declines in the multivariable-adjusted risk of dying within the first year after hospital discharge were observed between the earliest and most recently discharged patients with AMI.
CONCLUSIONS: The results of this population-based study of patients with validated initial AMI provide encouragement for efforts directed at the primary and secondary prevention of AMI given declining incidence and case-fatality rates.
The optic disc appearance in the normal fellow eye of 126 patients with nonarteritic anterior ischemic optic neuropathy (n-AION) was compared with the discs in 23 patients with arteritic AION (a-AION) and 122 normal subjects. The number of discs with no cup was significantly greater (P less than 0.001) and the number of discs with a large cup was significantly fewer (P less than 0.001) in the n-AION group compared to the other two groups. No significant differences were found in cup size between the a-AION and normal groups. The pathogenesis of n-AION appears to be multifactorial. There is overwhelming evidence that ischemia is the primary factor. The size of the optic disc also plays a role, probably through a compressive effect at the level of the lamina cribrosa on axons subjected to ischemia. In contrast, a-AION occurs from posterior ciliary artery occlusion and disc size is not a factor.
The Food and Drug Administration maintains an adverse drug reaction reporting system. Physicians report suspected adverse reactions that occur while a patient is taking a drug; reporting is voluntary and spontaneous. Data from spontaneous adverse drug reaction reporting systems are designed to signal that rare, unsuspected adverse reactions exist as a result of using a specific drug. Problems arise when attempts are made to use such data for other purposes. Specifically, spontaneous adverse drug reaction data, such as those published by the Food and Drug Administration, are inappropriate for calculating actual adverse drug reaction rates for specific drugs or for making safety comparisons among drugs. This is because these data are subject to numerous biases that can be easily identified and described but not easily corrected. As a result, data from spontaneous adverse drug reaction reporting systems bear little relationship to the actual incidence of adverse drug reactions.
Cup-disc ratios in the fellow eyes of 26 patients with unilateral, nonarteritic, anterior ischemic optic neuropathy were compared with the ratios in fellow eyes of 29 patients with unilateral idiopathic or demyelinative optic neuritis. The ratios in both groups were also compared with the ratios of a large group of normal subjects evaluated in a population survey. Observers measured the cup-disc ratio by viewing color stereophotographs. The cup-disc ratios of the fellow eyes of patients with anterior ischemic optic neuropathy were significantly smaller on average than were those of the fellow eyes of patients with optic neuritis and the normal subjects. Eyes with small cup-disc ratios may be more vulnerable to infarction than are eyes with large cup-disc ratios.
We provide current, normative data on the prevalence of impotence, and its physiological and psychosocial correlates in a general population using results from the Massachusetts Male Aging Study. The Massachusetts Male Aging Study was a community based, random sample observational survey of noninstitutionalized men 40 to 70 years old conducted from 1987 to 1989 in cities and towns near Boston, Massachusetts. Blood samples, physiological measures, socio-demographic variables, psychological indexes, and information on health status, medications, smoking and lifestyle were collected by trained interviewers in the subject's home. A self-administered sexual activity questionnaire was used to characterize erectile potency. The combined prevalence of minimal, moderate and complete impotence was 52%. The prevalence of complete impotence tripled from 5 to 15% between subject ages 40 and 70 years. Subject age was the variable most strongly associated with impotence. After adjustment for age, a higher probability of impotence was directly correlated with heart disease, hypertension, diabetes, associated medications, and indexes of anger and depression, and inversely correlated with serum dehydroepiandrosterone, high density lipoprotein cholesterol and an index of dominant personality. Cigarette smoking was associated with a greater probability of complete impotence in men with heart disease and hypertension. We conclude that impotence is a major health concern in light of the high prevalence, is strongly associated with age, has multiple determinants, including some risk factors for vascular disease, and may be due partly to modifiable para-aging phenomena.
Sildenafil, an inhibitor of cGMP-specific phosphodiesterase 5 (PDE5), is currently undergoing evaluation as an oral therapy for penile erectile dysfunction. The aims of this study were to investigate the mechanism of action of sildenafil on the neurogenic relaxation of human corpus cavernosum (HCC) in vitro and to determine the activity of sildenafil against a full range of PDE isozymes.
Strips of HCC tissue were precontracted with phenylephrine. Relaxation responses resulting from electrical field stimulation (EFS) were then determined in the presence and absence of sildenafil. The effects of sildenafil on PDE1 to 5 prepared from human tissues and PDE6 from bovine retina were determined by measuring the conversion of [3H]-cGMP or [3H]-cAMP to their respective [3H]-5'-mononucleotides.
Sildenafil (0.001 to 1 microM) enhanced the EFS-induced, nitric oxide (NO) dependent, relaxation of HCC in a concentration-dependent manner to a maximum of 3 times the pretreatment level at 1 microM sildenafil. Compared with zaprinast, an early PDE5 inhibitor, sildenafil was approximately 240-fold more potent, inhibiting PDE5 from HCC with a geometric mean IC50 of 3.5 nM. For sildenafil, IC50 values for inhibition of PDE1 to 4 were 80 to more than 8500 times greater than that for PDE5 and the IC50 for PDE6 (33 nM) was approximately 9-fold greater.
The data support the proposal that enhancement of penile erection by sildenafil in patients with erectile dysfunction involves potentiation of the NO-stimulated cGMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. Sildenafil is a potent inhibitor of PDE5 from HCC, with high selectivity for PDE5 relative to other PDE isozymes.
To report unilateral pupil-sparing third nerve palsy after use of sildenafil citrate (Viagra).
Case report.
A 56-year-old man with a history of tobacco abuse was treated for erectile dysfunction. Viagra, 50 mg, was taken once without adverse effect. Three weeks later, the patient took a second dose of Viagra (50 mg); 36 hours later he experienced a complete pupil-sparing third nerve palsy. Erythrocyte sedimentation rate, blood glucose level, magnetic resonance imaging, and magnetic resonance angiography were normal.
In a patient with microvascular disease, use of sildenafil may be associated with pupil-sparing third nerve palsy.
To determine whether the response to the new oral medication, sildenafil citrate (Viagra), was influenced by the presence or absence of the neurovascular bundles, as recent reports on its success did not specify the efficacy of the drug in patients with erectile dysfunction after radical prostatectomy.
Baseline and follow-up data from 28 healthy patients presenting with erectile dysfunction after radical prostatectomy were obtained. Patients receiving any neoadjuvant/adjuvant hormones or adjuvant radiation therapy were excluded. Patients reported what their erectile status was before surgery, before sildenafil therapy, and after using a minimum of four doses of sildenafil. Both the patients and their spouses were interviewed using the Cleveland Clinic post-prostatectomy questionnaire, which includes questions about response to therapy, duration of intercourse, spousal satisfaction, side effects, and related topics. The patients were compared on the basis of the type of surgical procedure they had undergone-nerve sparing or non-nerve sparing. A positive response to sildenafil was defined as erection sufficient for vaginal penetration.
Of the 15 patients who had bilateral nerve-sparing procedures, 12 (80%) had a positive response to sildenafil, with a mean duration of 6.92 minutes of vaginal intercourse. These 12 patients also reported a spousal satisfaction rate of 80%. All 12 of the responders had a positive response within the first three doses, and 10 of the 12 responded with the first or second dose. None of the 3 patients who had undergone a unilateral nerve-sparing procedure responded, nor did any of the 10 patients who had undergone a non-nerve-sparing procedure. The two most common side effects of the drug were transient headaches (39%) and abnormal color vision (11%). No patients discontinued the medication because of side effects.
Successful treatment of erectile dysfunction in a patient after prostatectomy with sildenafil citrate may depend on the presence of bilateral neurovascular bundles. No patient who had undergone a non-nerve-sparing procedure responded. Whether patients who undergo unilateral nerve-sparing procedures will respond to sildenafil is still unclear because of the small number of patients in our study. These findings should encourage urologists to continue to perform and perfect the nerve-sparing approach. The ability to restore potency with an oral medication after radical prostatectomy will impact our discussion with the patient on the surgical morbidity of radical prostatectomy.
Erectile dysfunction is a common condition in men with cardiovascular disease, probably as a result of shared factors that impair hemodynamic mechanisms in the penile and ischemic vasculature. Sildenafil citrate, an orally active, selective inhibitor of phosphodiesterase type 5 (PDE5), has demonstrated excellent efficacy and safety profiles in men with erectile dysfunction of various etiologies. Sildenafil administration is contraindicated in patients who are taking nitrates or nitric oxide donors. This retrospective subanalysis of data from double-blind, placebo-controlled studies assessed the efficacy (9 studies) and safety (11 studies) of sildenafil in patients with erectile dysfunction and ischemic heart disease who were not taking nitrates. Of 3,672 patients randomized to receive sildenafil (5-200 mg) or placebo for 4-24 weeks in 11 double-blind, placebo-controlled studies, 357 (10%) reported a history (past or present) of ischemic heart disease and were not taking nitrates. Efficacy was assessed using end-of-treatment responses to Question 3 (ability to achieve an erection) and Question 4 (ability to maintain an erection) of the International Index of Erectile Function (IIEF), scores for the 5 domains of male sexual function assessed by the IIEF (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), and responses to a global efficacy question ("Did the treatment improve your erections?"). The responses to the 2 IIEF questions were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with a score of 0 indicating no attempt at sexual intercourse. At the end of treatment, the mean scores for Question 3 and Question 4 of the IIEF for patients with erectile dysfunction and ischemic heart disease were significantly higher for the sildenafil group than for the placebo group (p <0.0001). Mean end-of-treatment scores for the IIEF domains also demonstrated significant increases for sildenafil-treated patients compared with those receiving placebo (p <0.05). At the end of treatment, improved erections were reported by 70% of patients who received sildenafil and by 20% of those in the placebo group p <0.0001). For the sildenafil group, the incidences of the most common adverse events (headache 25%, flushing 14%, and dyspepsia 12%) for patients with ischemic heart disease were similar to those in patients without this concomitant illness (21%, 15%, and 10%, respectively). Moreover, the overall incidence of cardiovascular adverse events other than flushing was comparable in patients with and without ischemic heart disease for both treatment groups. Since there is a degree of cardiac risk associated with sexual activity, clinicians should consider the patient's cardiovascular status before initiating any treatment for erectile dysfunction. Physicians should be aware that patients with underlying cardiovascular disease could be adversely affected by the vasodilator effects of sildenafil, especially in combination with sexual activity. The results of the present subanalysis indicate that oral sildenafil significantly improves erectile function and is well tolerated in patients with erectile dysfunction and ischemic heart disease who are not taking nitrate therapy.
Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p < or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p <0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)
Nitric oxide (NO) induces the formation of intracellular cyclic guanosine monophosphate (cGMP) by guanylate cyclase. Sildenafil, which selectively inhibits phosphodiesterase type 5 (PDE5) found predominantly in the corpora cavernosa of the penis, effectively blocks the degradation of cGMP and enhances erectile function in men with erectile dysfunction. The NO-cGMP pathway also plays an important role in mediating blood pressure. It is, therefore, possible that the therapeutic doses of sildenafil used to treat erectile dysfunction may have clinically significant effects on human hemodynamics. Three studies were undertaken to assess the effects of intravenously, intra-arterially, and orally administered doses of sildenafil on blood pressure, heart rate, cardiac output, and forearm blood flow and venous compliance in healthy men. A fourth study evaluated the hemodynamic effects of intravenous sildenafil in men with stable ischemic heart disease. In healthy men, significant (p <0.01) decreases in supine systolic and diastolic blood pressures were observed with intravenous sildenafil (20, 40, and 80 mg) at the end of the infusion period when plasma levels of sildenafil were highest (mean decreases from baseline of 7.0/6.9 and 9.2/6.7 mm Hg, for the 40- and 80-mg doses, respectively). These changes were transient and not dose related. Modest reductions in systemic vascular resistance also were observed (maximum decrease 16%), although heart rate was not affected by sildenafil administration when compared with placebo. Single oral doses of sildenafil (100, 150, and 200 mg) produced no significant changes in cardiac index from 1-12 hours postdose between placebo- and sildenafil-treated subjects. The approved dosage strengths of sildenafil citrate are 25 mg, 50 mg, and 100 mg. The 80-mg intravenous dose and the 200-mg oral dose of sildenafil produced comparable plasma levels at twice the maximum therapeutic dose (recommended range, 25-100 mg). After brachial artery infusion of sildenafil (up to 300 microg/min), there was a modest vasodilation of resistance arteries and a reversal of norepinephrine-induced preconstriction of forearm veins. These hemodynamic effects were similar to but smaller in magnitude than those of nitrates. In a small pilot study of men with ischemic heart disease, decreases from baseline in pulmonary arterial pressure (-27% at rest and -19% during exercise) and cardiac output (-7% at rest and -11% during exercise) were observed after 40-mg intravenous doses of sildenafil. Sildenafil was well tolerated by subjects and patients in all studies, with headache and other symptoms of vasodilation the most commonly reported adverse effects of treatment. Modest, transient hemodynamic changes were observed in healthy men after single intravenous or oral doses of sildenafil even at supratherapeutic doses. In men with stable ischemic heart disease, sildenafil produced modest effects on hemodynamic parameters at rest and during exercise.
We assess the clinical efficacy of sildenafil citrate and predictors of satisfactory outcome.
All patients treated with sildenafil citrate within the first 6 weeks of its release were evaluated with a self-administered questionnaire before and at completion of therapy to assess etiology of erectile dysfunction, level of sexual function, libido, response to previous therapies, response to therapy with sildenafil citrate and quality of life. Sexual function was measured before and during therapy using an abbreviated version of the International Index of Erectile Function, with a successful outcome defined as a level of satisfaction of 4 or 5 on a 5-point scale.
Followup was obtained in 267 of the 308 patients who entered the study. Mean age plus or minus standard deviation was 61+/-9.6 years and duration of erectile dysfunction was 4.1+/-3 years. Overall satisfaction with sildenafil citrate for the entire patient population was 65% and response to prior therapies did not affect satisfaction. There was a significant positive correlation between baseline sexual function and response to sildenafil citrate but even patients with severe erectile dysfunction had a 41% satisfaction rate. Etiology of erectile dysfunction had a significant impact on satisfaction rate, with neurogenic causes of erectile dysfunction (diabetes, prostate surgery and so forth) having significantly lower rates than psychogenic or vasculogenic erectile dysfunction.
Sildenafil citrate is a highly effective oral agent for the treatment of erectile dysfunction in clinical practice. The best predictors for response to sildenafil citrate therapy are baseline sexual function and etiology of erectile dysfunction. However, we could not identify any patient characteristic that would predict absolute failure for sildenafil citrate therapy. Therefore, all patients with erectile dysfunction who do not have specific contraindications should be considered for sildenafil citrate therapy.
Erectile dysfunction continues to be a significant problem for men after radical retropubic prostatectomy despite nerve sparing techniques. Sildenafil citrate (Viagra) has proved effective for erectile dysfunction in many men. We determine the efficacy of sildenafil in men with erectile dysfunction after radical retropubic prostatectomy and examine variables that may impact the response to treatment.
A total of 84 men were prescribed sildenafil after radical retropubic prostatectomy and asked to complete a series of questionnaires, including the International Index of Erectile Function (IIEF), on erectile function before and after sildenafil administration. The importance of factors, such as patient age, time since surgery, degree of cavernous nerve sparing, preoperative prostate specific antigen, Gleason score, clinical and pathological stage, and baseline postoperative erectile function, was examined.
Of the 84 patients 45 (53%) had improved erections and 34 (40%) had improved ability for intercourse while taking sildenafil. Mean IIEF score for the erectile function domain increased from 9 to 14 (p <0.001). Orgasmic function (p = 0.004) and intercourse satisfaction (p = 0.009) also significantly improved. The degree of nerve sparing and baseline postoperative erectile dysfunction had a significant impact on the ability of sildenafil to improve erectile function (p = 0.010 and p <0.001, respectively) and total IIEF questionnaire responses (p = 0.031 and p <0.001, respectively). Age and pathological stage also appeared to have a significant effect.
Sildenafil improved erectile function and the ability to have intercourse in more than half of men after radical retropubic prostatectomy. Baseline postoperative erectile function, which is dependent on the degree of nerve sparing technique, significantly impacts the likelihood that patients will respond to sildenafil.
To assess the acceptability, feasibility, and early results of sildenafil (Viagra) in a nonselected cohort of 316 patients (median age 58 years) who sought treatment for male sexual dysfunction during a 10-week period.
Erectile status and activity were evaluated by questionnaire; erectile function was assessed by pharmacologic testing and visual sexual stimulation. Cardiovascular contraindications were assessed. Patients selected for the trial received treatment for 2 months. Results based on the possibility of penetration and individual satisfaction (scale from 0 to 10) were classified as good, fair, or bad. Multifactorial analysis was performed to define factors influencing the response to sildenafil.
Twenty-five percent of the patients from the initial cohort refused or did not meet the criteria for oral treatment; 25% of the remaining had a cardiovascular contraindication. At the end of the trial, 157 patients (88.7%) had completed the study; the efficacy of and satisfaction with sildenafil were considered good for 50 (31.84%), fair for 46 (29.29%), and bad for 61 (38.85%). Spontaneous nocturnal erections, organic etiologies, especially cavernovenous impotence, and previous treatment with self-intracavernous injections were significant factors influencing responses to oral treatment. Finally, 32% of the patients after completing the trial (17.2% of the initial cohort) were using sildenafil as their sole treatment, 34% chose self-intracavernous injections, and 25% decided to alternate between oral and local therapy.
In the present study, sildenafil had a 60% efficacy rate and was chosen as the sole treatment by only 30% of the patients tested. We propose pretreatment tests to help to predict the response to this medication.
EXECUTIVE SUMMARY
• Sexual activity is no more stressful to the heart when compared with a number of other natural daily activities, e.g. walking one mile on the level in 20 minutes.
• The cardiac risk of sexual activity in patients diagnosed with cardiovascular disease is minimal in properly assessed and advised patients.
• Erectile dysfunction (ED) is common, affecting 10% of men aged 40‐70 years and increases in frequency with age.
• ED and cardiovascular disease share many of the same risk factors and often coexist.
• ED in the diagnosed cardiovascular patient should be identified by routine questioning in general practice. Modern therapies can restore a sexual relationship in the majority of patients with ED and can lead to a substantial improvement in quality of life.
• The majority of patients assessed to be at low or intermediate cardiac risk, as defined later in this paper (Table 4), can be effectively managed in primary care. Primary care treatment for ED in patients defined as high risk can be initiated following a specialist opinion and/or confirmation that the patient's cardiovascular condition is stabilised.
• There is no evidence that currently licensed treatments for ED add to the overall cardiovascular risk in patients with or without diagnosed cardiovascular disease.
To date, sildenafil citrate (Viagra) gives every evidence of being a safe drug for the eye despite a series of expressed concerns. A review of how its ocular safety profile has been identified offers insights into the strengths and weaknesses of present systems and resources for judging the ocular safety of Viagra or, for that matter, of any new drug. Such insights include: The great value of careful, informed assessment of preclinical information gleaned from laboratory experiments. By and large, such assessments point the way toward appropriate clinical evaluation. For Viagra, early in its development it was noted that besides exerting a major inhibitory effect on the intended target, the vascular-associated enzyme phosphodiesterase 5 (PDE5), the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6, located in the retina. For this reason, preclinical evaluation of the drug included electroretinography plus postmortem histology. In addition, an extended eye examination was incorporated into clinical protocols. The often chaotic but invaluable information stream that becomes available once marketing approval has been gained and large populations begin to use a drug. False alarms, misattribution, and erroneous information are the order of the day. Nevertheless, as information accumulates, patterns of response clarify and the true nature of special susceptibility for subpopulations, if any, becomes apparent. A role for the astute clinician remains: Subtle changes or unusual risks for subpopulations can be missed entirely for long periods of time. A manifest need for improvement in evaluation of postmarketing side-effects. This need has led to the establishment of a new discipline: pharmacoepidemiology. In ophthalmology, the National Registry of Drug Induced Ocular Side-Effects maintains a constant and invaluable surveillance. Examples are supplied to illustrate each of these major points: Our presentation will include data gleaned from clinical trials plus postmarketing information on the incidence, duration, and type of color vision defects observed at different doses of Viagra.
The cardiovascular effects of sildenafil are important because of the frequent presence of underlying cardiac disease in men with erectile dysfunction and reports indicating serious cardiac events temporally associated with the use of this drug.
We assessed the systemic, pulmonary, and coronary hemodynamic effects of oral sildenafil (100 mg) in 14 men (mean [+/-SD] age, 61+/-11 years) with severe stenosis of at least one coronary artery (stenosis of >70 percent of the vessel diameter) who were scheduled to undergo percutaneous coronary revascularization. Blood-flow velocity and flow reserve were assessed with a Doppler guidewire in 25 coronary arteries, including 13 severely diseased arteries (mean stenosis, 78+/-7 percent) and 12 arteries without stenosis, used as a reference; maximal hyperemia was induced (to assess flow reserve) with the intracoronary administration of adenosine both before and after sildenafil.
Oral sildenafil produced only small decreases (<10 percent) in systemic arterial and pulmonary arterial pressures, and it had no effect on pulmonary-capillary wedge pressure, right atrial pressure, heart rate, or cardiac output. There were no significant changes in average peak coronary flow velocity, coronary-artery diameter, volumetric coronary blood flow, or coronary vascular resistance. Coronary flow reserve at base line was lower in the stenosed arteries (1.26+/-0.26) than in the reference arteries (2.19+/-0.44) and increased about 13 percent in both groups of arteries combined after the administration of sildenafil (from 1.70+/-0.59 to 1.92+/-0.72, P=0.003). The ratio of coronary flow reserve in coronary arteries with stenosis to that in the reference arteries (0.57+/-0.14) was not affected by sildenafil.
No adverse cardiovascular effects of oral sildenafil were detected in men with severe coronary artery disease.
To the Editor: Mild, transient visual changes such as increased sensitivity to light and color-tinge alterations occur in 3 percent of men who take sildenafil.1–3 We therefore assessed whether sildenafil could alter ocular perfusion. We studied the right-eye responses in 12 normal adults (10 men and 2 women; mean [±SD] age, 36±3 years) before and after the oral administration of 50 mg of sildenafil (Viagra, Pfizer, New York). We measured intraocular pressure and pulsatile ocular blood flow by analyzing five consecutive tonometric ocular pulse waves (tonometer, OBF Laboratories, Malmesbury, United Kingdom), retinal microcirculation by Doppler velocimetry (HRF flowmeter, Heidelberg . . .
To assess the short-term effects of sildenafil citrate on intraocular pressure in healthy male volunteers and participants in clinical trials.
Intraocular pressure and pupil diameter were measured in two placebo-controlled studies. Oral doses of sildenafil citrate (VIAGRA; Pfizer Inc, New York, New York) ranged from 10 mg to 150 mg.
No major changes in intraocular pressure or pupillometry were detected at any time (1.0-24 hours) after administration of sildenafil. Additionally, of 36 subjects with a medical history of increased intraocular pressure in the sildenafil safety database, none were reported to have a clinically significant increase of their intraocular pressure. During clinical trials, two glaucoma cases were listed as serious adverse events, but were not considered treatment related.
No clinical abnormalities were observed in intraocular pressure or pupil diameter in subjects receiving sildenafil. Currently, no evidence suggests that long-term treatment with sildenafil has an effect on intraocular pressure or is associated with the development or worsening of glaucoma.
Cardiovascular risk factors are commonly associated with erectile dysfunction and should be identified and treated. Patients with cardiovascular diseases should be assessed and counselled regarding their fitness for sexual activity. The danger of concurrent use of sildenafil and nitrates under any circumstances, regardless of age and sex, must be highlighted at all levels of the community. Sildenafil is absolutely contraindicated in patients receiving treatment with long-acting nitrates for ischaemic heart disease. Patients who need sublingual short-acting nitrates infrequently should not be precluded from taking sildenafil, provided they are aware that sildenafil is not to be taken within 24 h of taking the nitrate.
Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.
Sildenafil citrate (Viagra) has been shown to be an effective treatment for erectile dysfunction. Initial studies reported a high tolerability and low incidence of certain characteristic adverse reactions. We sought to evaluate the incidence of side effects of sildenafil citrate, independent of industry support and constraints, utilizing a heterogeneous cohort of patients from a university-based practice.
A prospective, open-label, flexible-dose study of 256 patients treated with sildenafil citrate for erectile dysfunction was performed at a single institution. The patients were questioned explicitly about the occurrence of headache, flushing, dyspepsia, nasal congestion, visual changes, and other side effects.
The adverse reactions most commonly observed were flushing (30.8%), headache (25. 4%), nasal congestion (18.7%), and heartburn (10.5%). All events were short lived and mild in nature. In the present study, 31.6% of patients experienced one or more adverse events. However, no one withdrew from the study because of the severity of these events. There was a significant association between higher doses and the occurrence of side effects.
The incidence of adverse events attributable to sildenafil citrate may be higher than initially reported, but an explanation may be the methodology of data collection and the industry-independent nature of this study. The side-effect profile is dose related and mild. Sildenafil citrate remains a safe and well-tolerated treatment for erectile dysfunction.
Editor,— Sildenafil is the oral treatment for erectile dysfunction and was licensed throughout Europe in September 1998. It is a potent, selective inhibiter of the isoenzyme phosphodiesterase type 5 (PDE 5). Inhibition of PDE5 leads to prolongation of cyclic guanosine monophosphate (cGMP) activity in erectile tissue and increases the natural vasodilatory actions of nitric oxide on the cavernosal smooth muscle, facilitating the erectile response in men with erectile dysfunction.1 Whereas many ocular adverse effect of sildenafil have been reported,2-5 we present, to the best of our knowledge, the first case report of branch central retinal artery occlusion following the use of sildenafil.
### CASE REPORT
A 69 years old man presented with a sudden painless loss of vision in the left eye 2 days previously. The patient was fit and …
We assessed the efficacy and safety of sildenafil citrate as treatment for erectile dysfunction.
A total of 433 completely evaluated men with chronic erectile dysfunction were treated with sildenafil citrate. Response was assessed prospectively by baseline and followup physician interviews, and by a patient self-administered 15-item questionnaire on the domains of patient treatment response and satisfaction, partner treatment satisfaction, comparative previous treatment satisfaction, adverse effects, and patient and partner quality of life.
Of the 304 men (70.2%) who completed the questionnaire 278 received sildenafil, including 186 who previously had undergone treatment for erectile dysfunction, principally involving intracavernous injection therapy. A response was elicited by a median dose of 100 mg. in 188 patients (67.6%) who achieved erection suitable for sexual intercourse. Those with psychogenic erectile dysfunction responded significantly better than those with organic dysfunction (p <0.001). Erection suitable for intercourse was attained by 30.8% of patients with erectile dysfunction after radical prostatectomy and 80% with cavernous veno-occlusive dysfunction. Of previous intracavernous injection responders 29.9% were refractory to sildenafil, while 33. 3% of previous intracavernous injection nonresponders responded to sildenafil. The sildenafil response was considered inferior to the intracavernous injection response by 43.6% of the men who previously responded to intracavernous injection, of whom 51.5% continued to receive intracavernous injection as the only treatment (19.5%) or as an alternative to sildenafil (32%). Adverse effects in 53.6% of cases were assessed as mild in 56.4%, moderate in 38.3% and severe in 5.3%. Multiple adverse effects were reported by 62.4% of patients, while 17 (6.1%) discontinued sildenafil as a direct result of intolerable adverse effects. The most common adverse effects were facial flushing in 33.5% of cases, headaches in 23.4%, nasal congestion in 12.6%, dyspepsia in 10.1% and dizziness in 10.8%. Baseline patient and partner quality of life scores significantly improved after sildenafil treatment (p <0.001), while significantly improved quality of life was noticed by 51.5% and 43.1%, respectively.
Sildenafil citrate is effective oral first line treatment for erectile dysfunction. Although more than 50% of men reported adverse effects, most were considered mild and rarely resulted in treatment cessation. There was a trend in those on intracavernous injection who responded to sildenafil to continue intracavernous injection as the only therapy or as an alternative to sildenafil. Also, we noted that some cases refractory to sildenafil responded to intracavernous injection. These findings imply that intracavernous injection remains an effective erectile dysfunction treatment option.
The long-term efficacy and safety of oral Viagra (sildenafil citrate), a selective phosphodiesterase 5 inhibitor, and the effect of withdrawing treatment were evaluated in men with erectile dysfunction (ED). In 233 men with ED of psychogenic or mixed organic/psychogenic aetiology, 16 weeks of open-label, flexible-dose sildenafil treatment (10-100 mg) was followed by eight weeks of double-blind, fixed-dose, randomised withdrawal to placebo or continued treatment with sildenafil. Sildenafil was taken as needed (not more than once daily) approximately 1 h prior to sexual activity. The main outcome measures were a global efficacy question, a sexual function questionnaire, an event log of erections, and adverse event recording. In the open-label phase, 200 of 216 patients (93%) reported improved erections with sildenafil; 28 patients (12%) discontinued treatment. In the double-blind phase, the significant improvements in the frequency and duration of erections were maintained in the sildenafil group but returned to pre-treatment values in patients on placebo (P values < 0.0001 versus placebo). The most frequent adverse events in the sildenafil group during the double-blind phase were flushing (7%), headache (6%), and dyspepsia (5%). Of the 192 patients enrolled in the 1-y extension, 90% completed the study; only two patients (1%) were withdrawn due to lack of efficacy. In men with ED of psychogenic or mixed aetiology, oral sildenafil is effective and well-tolerated both at the initiation of therapy and during long-term treatment. For most patients, sildenafil treatment must be continued for improvements in erectile function to be maintained.
To study the effects of sildenafil on blue-on-yellow and white-on-white Humphrey visual field (HVF).
Healthy subjects, ages 20 to 38 years, were prospectively randomized to active drug (n = 5) or placebo (n = 3) groups. Blue-on-yellow and white-on-white HVF testing was performed before and 1 hour after masked dosing of sildenafil 200 mg or placebo. Changes in mean deviation (MD) were compared between groups.
Three of three placebo and four of five sildenafil subjects had no change on HVF. One of five sildenafil subjects had a decrease in MD of 17.9 dB and 4.7 dB on blue-on-yellow and white-on-white HVF testing, respectively. This subject reported more systemic side effects than other subjects.
Sildenafil has no effect on HVF testing in most persons; however, sildenafil caused an acute abnormality of HVF testing in one subject, who experienced pronounced non-visual systemic symptoms; this effect was greater on blue-on-yellow than white-on-white HVF.
To assess the acute effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication.
Post-hoc subanalysis of five, 12- or 24-week, prospective, randomized, double-blind, placebo-controlled studies.
Private-practice and academic urology clinics.
A total of 1685 men with erectile dysfunction of > or = 6 months duration, of whom 667 (sildenafil n = 406, placebo n = 261) were taking antihypertensive medication (diuretic, beta-blocker, alpha-blocker, angiotensin converting enzyme inhibitor, and/or calcium antagonist). Of the patients taking antihypertensive medication, 608 (91%) completed the studies (374 of 406 receiving sildenafil, 234 of 261 receiving placebo).
The last dose of oral sildenafil (25-200 mg) or placebo was taken at home on the morning of the final clinic visit. Patients taking antihypertensive medication maintained usual dosing schedules.
Sitting systolic (SBP)/diastolic blood pressure (DBP) and heart rate at baseline and after dosing with sildenafil or placebo (end-of-treatment visit).
Mean changes from baseline in SBP/DBP for men taking antihypertensive medication were -3.6/-1.9 mmHg for those receiving sildenafil and -0.8/-0.1 mmHg for those receiving placebo compared with -2.2/-2.0 mmHg and -0.1/0.4 mmHg, respectively, for men not taking antihypertensive medication. Mean changes from baseline in heart rate for men taking antihypertensive medication were -0.6 beats/min after sildenafil and 0.9 beats/min after placebo compared with 0.4 beats/min and -0.6 beats/min, respectively, for patients not taking antihypertensive medication. Differences in SBP, DBP, and heart rate between the patients taking and those not taking antihypertensive medication were small.
The acute, short-term effects of oral sildenafil on blood pressure and heart rate in men with erectile dysfunction were small and not likely to be clinically significant in those taking concomitant antihypertensive medication.