[Sensitivity to change and minimally important diference of the Spanish version of the Life-Satisfaction questionnaire LISAT-8 in male patients with erectile dysfunction.]

[Article in Spanish]

Rejas J, Gil A, San Isidro C, Palacios G, Carrasco P.

Departamento de Farmacoepidemiologia y Farmacovigilancia. Unidad Medica. Pfizer S.A. Madrid. Spain.

Background and objective: We determined the sensitivity to change and minimally important difference (MID) of the Spanish version of the life-satisfaction check list LISAT-8. Patients and method: We included a random sample obtained from an open, naturalistic, prospective and multicenter study, which assessed the effectiveness of sildenafil as erectile dysfunction (ED) therapy. A total of 537 patients, males older than 18 years, with ED and > active sexual desire, received flexible and at demand doses of sildenafil for 10 weeks. IIEF and LISAT-8 questionnaires were used. MID was determined from the patient's classification according to change in erectile function domain of the IIEF after treatment as follows: no change (< 5 pts), small change (6 to 10 pts), moderate change (11 to 15 pts) and big change (> 15 pts). Results: Sildenafil significantly modified the baseline punctuation of the LISAT 8 from a crude value of 30.2 (5.9) pts (mean [standard deviation]), at baseline, to 34.7 (5.6) pts after treatment., and from 55.4% (14.7%) to 66.8% (14.3%) in standardized punctuation (p < 0.0001 in both cases). Sildenafil responders showed a response increase of the total punctuation which was significantly higher than non-responders: 12.5% versus 4.3% (p < 0.001). MID was 3.2 pts as crude punctuation, and 8.1% in normalized score. Statistically significant correlations were found between changes in LISAT-8 and changes in IIEF. Conclusions: The Spanish version of the LISAT-8 showed to be responsive to change in male ED patients. Meaningful MID was 3.1 pts (crude) and 8.1% (normalized).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15725366&dopt=Abstract sildenafil Viagra online



Recreational use and misuse of phosphodiesterase 5 inhibitors.

Smith KM, Romanelli F.

Drug Information Center, College of Pharmacy, University of Kentucky, Lexington, 40536-0293, USA. ksmit1 email.uky.edu

OBJECTIVE: To characterize the rationale for and extent of phosphodiesterase (PDE) 5 inhibitor use in recreational settings, describe risks from such misuse, and discuss postexposure clinical management strategies. DATA SOURCES: Published articles identified by searches through Medline, EMBASE, International Pharmaceutical Abstracts, and Toxline, from 1990 to March 2004, using the search terms sildenafil, tadalafil, vardenafil, phosphodiesterase inhibitor, abuse, overdose, adverse effects, recreational, and street drugs. Additional references identified within articles and information from the Internet were included. STUDY SELECTION: Clinical trials, epidemiologic reviews, case reports, and news releases concerning the misuse of sildenafil. DATA EXTRACTION: By the authors. DATA SYNTHESIS: PDE5 inhibitors, indicated for treatment of erectile dysfunction, can produce several adverse effects, including potentially fatal cardiovascular events. Reports of recreational use and misuse of sildenafil appear in the medical literature and the media. The potential for abuse also exists for the two more recently approved drugs in this class, vardenafil and tadalafil. Increasing access to these drugs via the Internet may facilitate such misuse. Use in social settings has gained popularity, both in young, healthy patients, as well as those with chronic medical conditions, including human immunodeficiency virus infections. In these settings, the PDE5 inhibitors are sometimes used concomitantly with "club drugs" such as ketamine and amyl nitrite, leading to potentially harmful or fatal drug interactions. CONCLUSION: Pharmacists should be cognizant of the potential for PDE5 inhibitors to be misused, particularly in patients who are at greater risk of cardiovascular complications, and should advise patients and other health care professionals accordingly.

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Pro-erectile effect of vardenafil: in vitro experiments in rabbits and in vivo comparison with sildenafil in rats.

Giuliano F, Bernabe J, Alexandre L, Niewoehner U, Haning H, Bischoff E.

Pelvipharm Laboratories, CNRS Bat 5, 1 avenue de la Terrasse, 91140 Gif-sur-Yvette, France. giuliano cyber-sante.org

OBJECTIVES: To assess pro-erectile responses to vardenafil, a new selective PDE5 inhibitor, in vitro in isolated rabbit corpora cavernosa, and in vivo in anaesthetized rats. METHODS: Rabbit cavernosal strips were precontracted with 10 microM phenylephrine. Dose-response relaxation curves to cumulative dosings of vardenafil (1 nM-10 microM) were constructed alone and in the presence of 10 mM L-NAME. Relaxation responses to electrical field stimulation (EFS) (2 Hz, 2 ms, 10 V) were compared in control preparations and in the presence of vardenafil (1-10 nM). Male Sprague-Dawley rats were anaesthetized with urethane and prepared for measurement of blood pressure and intracavernous pressure. Erectile responses (ICPmax/dBP x 100) to cavernous nerve submaximal stimulation (10 Hz, 1 ms, 0.45-1.6 V) were determined before, and 3, 10 and 23 min after i.v. administration of saline, vardenafil or sildenafil (0.1, 1 mg/kg). RESULTS: Vardenafil was effective in relaxing precontracted rabbit cavernosal strips (IC50 54 +/- 18 nM). This relaxing activity was partially antagonized with 10 mM L-NAME, increasing the IC50 to 620 +/- 81 nM. Vardenafil significantly increased (more than 4 times) relaxation of precontracted rabbit cavernosal strips to EFS at 10 nM. In anaesthetized rats, erectile responses were significantly facilitated 3 and 13 min after 0.1 and 1 mg/kg vardenafil was administered. In contrast, 1 mg/kg sildenafil only significantly increased erectile responses at 3 min post-injection. CONCLUSIONS: Vardenafil relaxes rabbit corpus cavernosum in vitro and is effective at a lower dose than sildenafil in facilitating erectile responses to cavernous nerve stimulation in anaesthetized rats.

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Sildenafil reverses O2 constriction of the rabbit ductus arteriosus by inhibiting type 5 phosphodiesterase and activating BK(Ca) channels.

Thebaud B, Michelakis E, Wu XC, Harry G, Hashimoto K, Archer SL.

Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.

Oxygen constriction causes functional closure of the ductus arteriosus (DA) at birth. Although DA closure is crucial for postnatal adaptation, patency of the DA is critical for survival of newborns with duct-dependent cardiac malformations. In these cases, DA patency is achieved by i.v. infusion of prostaglandin E1, which, though effective, is often associated with complications. We hypothesized that sildenafil, a specific phosphodiesterase type 5 inhibitor, is an effective DA vasodilator. In isolated DA rings from term (d 30) fetal rabbits, sildenafil (10(-6)-10(-4) M) and diethylamine NONOate (10(-7)-10(-5) M) induced dose-dependent relaxation of oxygen-constricted DA (-52 +/- 4% and -51 +/- 6%, respectively) that was inhibited by the soluble guanylyl-cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5 x 10(-5) M). Sildenafil increased cyclic GMP levels. Iberiotoxin (200 nM), an inhibitor of calcium-sensitive potassium channels, decreased the vasodilatory effect of sildenafil and diethylamine NONOate (-30 +/- 2% and -27 +/- 4%, respectively). Oxygen inhibition of whole-cell K+ current and membrane depolarization were partially restored by sildenafil, and this was inhibited by iberiotoxin. Immunohistochemistry and immunoblotting confirmed the presence of phosphodiesterase type 5 and calcium-sensitive potassium channels in the DA smooth muscle cells. This is the first study to demonstrate that sildenafil dilates the DA by increasing soluble guanylyl-cyclase-derived cGMP levels and thereby activating calcium-sensitive potassium channels, causing membrane hyperpolarization. Sildenafil, already approved for human usage, might be an alternative or a useful adjunct to prostaglandin E1 as a bridge to cardiac surgery.

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Effects of sildenafil on erectile activity in mice lacking neuronal or endothelial nitric oxide synthase.

Cashen DE, MacIntyre DE, Martin WJ.

Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey, NJ 07065, USA.

1. Using an in vivo model of erectile activity, the effects of sildenafil were studied in mice lacking neuronal or endothelial nitric oxide synthase (nNOS and eNOS, respectively). 2. Under pentobarbitone anaesthesia, intracavernous pressure (ICP) and mean arterial pressure (MAP) were monitored continuously in wild-type, nNOS-/- and eNOS-/- mice. The magnitude of erectile activity was quantified as the ratio of ICP to MAP. 3. No differences in basal ICP or MAP were observed amongst wild-type, eNOS-/- and nNOS-/- mice. Electrical stimulation of the cavernous nerve (ESCN; 4.0 V, 16 Hz, 1 ms, 30 s) evoked increases in ICP and ICP/MAP as well as penile tumescence. Responses to ESCN were reduced in nNOS-/-, but not in eNOS-/- mice. 4. L-NAME (50 mg kg(-1), i.v.) significantly increased MAP and attenuated erectile responses in both wild-type and eNOS-/- mice. 5. Sildenafil (1 mg kg(-1), i.v.) augmented electrically-evoked erectile activity in a voltage-dependent manner in wild-type mice and facilitated erectile responses in eNOS-/- mice. By contrast, sildenafil failed to augment the diminished erectile responses in mice lacking the nNOS isoform. 5. These data reveal the relative importance of nNOS, compared to eNOS, as the critical NOS isoform in the control of erectile function and illustrate that the nNOS isoform is required for sildenafil-induced facilitation of erectile responses in vivo in mice.

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Sildenafil test: changes in the diagnostic and therapeutic management of erectile dysfunction.

Perimenis P, Athanasopoulos A, Gyftopoulos K, Barbalias G.

Department of Urology, Medical School, University of Patras, Greece. perimenis internet.gr

OBJECTIVE: To assess the efficacy of sildenafil as a first-step diagnostic and therapeutic tool for erectile dysfunction (ED) and to evaluate the consequent changes in the management of male sexual insufficiency. MATERIALS AND METHODS: Sildenafil in titrating doses up to 100 mg was prescribed to 50 men presenting to a sexual dysfunction clinic with medically documented ED. They had not undergone any specific diagnostic test before starting sildenafil. RESULTS: Of the 50 men, 24 (48%) responded to sildenafil. Of these, 8 (33.3%) responded to 50 mg and 16 (66.7%) to 100 mg of sildenafil. Of the responders, 9 representing 18% of all studied men were discharged achieving spontaneous erections in a mean follow-up of 5.3 months. Men with no medical history, men with hypertension and men with mild coronary artery disease responded better. CONCLUSIONS: The sildenafil test revealed that 48% of men responded to this therapy with no requirement for more invasive tests and that 18% of men required no further treatment at all. In addition this test reduced the overall cost of the diagnostic investigation. It is proposed that the sildenafil test should be used in cases with no significant medical history or in men with hypertension or mild coronary artery disease although almost all men with ED could be categorized as sildenafil-responders or sildenafil-resistant. It is also suggested that the sildenafil test would result in the ability for more men with ED to be managed exclusively in the primary care sector.

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The effect of sildenafil on oesophageal motor function in healthy subjects and patients with nutcracker oesophagus.

Lee JI, Park H, Kim JH, Lee SI, Conklin JL.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. hjpark21 yumc.yonsei.ac.kr

Type 5 phosphodiesterase terminates the action of nitric oxide (NO) induced 3',5'-cyclic monophosphate (cGMP). Sildenafil inhibits this phosphodiesterase, increases cellular cGMP concentrations and enhances NO-induced smooth muscle relaxation. We investigated the effect of sildenafil on the oesophageal motor function of healthy subjects and patients with nutcracker oesophagus. Eight healthy volunteers and nine patients with nutcracker oesophagus participated in this study. The participants underwent oesophageal manometries on two separate days after either 20 mL of distilled water or 0.8 mg kg-1 sildenafil dissolved in 20 mL of water was infused into the stomach. Lower oesophageal sphincter (LOS) resting pressure, the duration of LOS relaxation and the amplitudes of oesophageal pressure waves were examined before, and 7.5, 15, 30 and 60 min after either placebo or sildenafil. In both healthy subjects and patients with nutcracker oesophagus, sildenafil decreased resting LOS pressure and the amplitude of peristaltic pressure waves at 3, 8 and 13 cm above LOS. Sildenafil also prolonged the duration of LOS relaxation. It had no effect on the velocity of peristalsis or the amplitude of peristaltic pressure waves 18 cm above LOS. Sildenafil may be considered as an alternative treatment in nutcracker oesophagus although there are several limitations to be overcome.

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Clinical efficacy and safety of sildenafil citrate (Viagra) in a multi-racial population in Singapore: A retrospective study of 1520 patients.

Lim PH, Li MK, Ng FC, Chia SJ, Consigliere D, Gooren L, Ng KK, Munisamy M, Perianan M.

Department of Urology, Changi General Hospital, Urology Center, National University Hospital, Singapore. tphphc1 pacific.net.sg

BACKGROUND: Sildenafil citrate (Viagra), a selective inhibitor of cGMP-specific phosphodiesterase type-5, has been used as an oral therapeutic drug for erectile dysfunction. The present paper is a clinical study of the success rate and side-effects of the use of sildenafil in a multi-racial population in Singapore. METHODS: From April 1999 to May 2000, 1520 patients were given sildenafil citrate. Of these, 912 patients (mean age, 54.6 years; age range, 22-99 years) were followed up and evaluated for clinical efficacy and safety of the drug. The mean duration of erectile dysfunction (ED) and follow-up periods were 31.5 and 3.0 months, respectively. RESULTS: Satisfactory erections assessed by single global efficacy question (GEQ) occurred in 83% of patients, major side-effects in the form of flushing (3.48%), headache (1.97%), blurred vision (1.25%), giddiness (1.18%), warmth (1.11%) and others (4.92%) were recorded in 127 patients (13.9%). Racially, Chinese men with ED had higher efficacy (85.7%), compared to Indian men (74.2%) and Malay men (72.8%). With respect to comorbid profiles, an efficacy of 77.8% (n = 271), 83.9% (n = 292), 86.4% (n = 44) and 83.3% (n = 199) was recorded in diabetic, hypertensive, ischemic heart disease patients and in benign prostatic hyperplasia patients, respectively. Patients who smoked (n = 135) and drank alcohol (n = 118) showed an efficacy of 80%. Baseline hormonal profiles of luteinizing hormone, follicle stimulating hormone, testosterone and prolactin did not affect the success rates of sildenafil citrate. Many patients had earlier received other forms of treatment (medicated urethral suppository for erection (MUSE; 84.9%); vacuum devices (86.8%), traditional medicines (100%) and other oral medications (89.2%)), but this did not influence the success rate of sildenafil citrate. But patients previously treated with prostaglandin-E intracavernosal injections were less successful on sildenafil citrate (77.3%). In the total cohort, 50 mg sildenafil citrate was an effective dose in 49% of patients and 46.5% patients needed 100 mg sildenafil citrate, while 4.1% of the total cohort needed only 25 mg sildenafil citrate. CONCLUSION: Oral sildenafil citrate has been shown to be an effective, safe and well tolerated drug in Singaporean men with ED, as in men from other parts of the world.

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