Study of the electrospray ionization tandem mass spectrometry of sildenafil derivatives.

Zhong D, Xing J, Zhang S, Sun L.

Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, China. zhongdf ihw.com.cn

A detailed analysis of the product ion spectrum generated from the protonated molecule of sildenafil (Viagra(R)) under multiple tandem mass spectrometry (ESI-MS(n)) conditions using an ion-trap mass spectrometer is reported. Molecular composition data of the fragment ions were obtained with the aid of comparisons of the multiple tandem mass spectra of eight sildenafil derivatives in two series, the structures of which are identical except for some substituted alkyl groups. Attempts have been made to provide rational pathways for the formation of the fragment ions from these protonated sildenafil derivatives. The structure-fragmentation relationships will facilitate the characterization of the structures of other sildenafil analogs. Copyright 2002 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12271448&dopt=Abstract sildenafil Viagra online



What to learn about sildenafil in the treatment of erectile dysfunction from 3-year clinical experience.

Jiann BP, Yu CC, Tsai JY, Wu TT, Lee YH, Huang JK.

Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China. bpjiaan isca.vghks.gov.tw

We retrospectively assessed the clinical uses and results of sildenafil in the treatment of erectile dysfunction (ED) in daily clinical practice from a cohort of 1658 subjects at a multispecialty medical center from 1999 to 2001 through a chart review, mailed questionnaire and telephone interview. The overall follow-up rate was 77.8% (1290/1658). The mean age was 63.8 y and ED duration was 3.4 y, and 44.6% of them had one or more concomitant conditions. The mean score of the International Index of Erectile Function erectile function domain was 12.7 in 314 nonselective subjects, and 75% of them had moderate to severe ED. The average number of purchase-visits and tablets of sildenafil purchased was 2.27 and 10.8 per person, respectively, and the prescription refill rate was 58.6%. Urology accounts for 91.4% of the specialties of prescribers. The response rate was 72.0%, which was significantly lower in subjects with diabetes, ischemic heart disease and following radical pelvic surgery than those without. Subjects with psychogenic etiology had the highest response rate, while those following radical pelvic surgery the lowest. Of the nonresponders, 67% did not try the maximum dose of 100 mg and 71.1% bought no more than four tablets. Adverse events were reported in 20.1% of the subjects. No one discontinued the treatment because of the adverse events. Mortality occurred in 17 subjects and none was considered related to sildenafil use. In conclusion, sildenafil was effective and safe in the treatment of ED in clinical practice. Compared with clinical trials or prospective clinical practice based studies, lack of dose titration, less follow-up visits and inadequate attempts before giving up were the main shortfalls in daily practice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14671659&dopt=Abstract sildenafil Viagra online



Determination of a new phosphodiesterase V inhibitor, DA-8159, in plasma and urine by high-performance liquid chromatography.

Shim HJ, Lee EJ, Jung YH, Kim SH, Kim SH, Yoo M, Kwon JW, Kim WB, Lee MG.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.

A high-performance liquid chromatographic (HPLC) method using liquid-liquid extraction for sample preparation was developed for the determination of a new phosphodiesterase V inhibitor, DA-8159, in rat plasma and urine using sildenafil citrate as an internal standard. A 100 microl aliquot of 0.1 M Na(2)CO(3) (containing sildenafil citrate, 3 microg/ml as free sildenafil) and a 1 ml aliquot of ether were added to a 100 microl aliquot of biological samples (urine samples were diluted 20 times with distilled water). After vortex centrifugation at 9000 x g for 3 min, the ether layer was collected and dried under nitrogen gas. The residue was reconstituted with a 150 microl aliquot of the mobile phase, centrifuged, and a 100 microl aliquot of the supernatant was injected onto a reversed-phase column. The mobile phases, 20 mM KH(2)PO(4) (pH 4.7):acetonitrile (70:30, v/v for plasma and tissue samples, and 75:25, v/v for urine samples), were run at a flow rate of 1.0 ml/min. The column effluent was monitored by an ultraviolet detector set at 292 nm. The retention times for DA-8159 and the internal standard were approximately 10.7 and 9.1 min, respectively, in plasma and tissue samples and the corresponding values in urine samples were 47 and 33 min. The detection limits for DA-8159 in rat plasma and urine were 20 and 100 ng/ml, respectively. The coefficients of variation of the assay were generally low: below 10% for plasma and 9.9% for urine. No interferences from endogenous substances were found. Copyright 2002 Elsevier Science B.V.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12367677&dopt=Abstract sildenafil Viagra online



The cost to the United Kingdom National Health Service of managing erectile dysfunction: the impact of sildenafil and prescribing restrictions.

Wilson EC, McKeen ES, Scuffham PA, Brown MC, Wylie K, Hackett G.

York Health Economics Consortium Ltd, University of York, York, UK.

OBJECTIVE: To estimate the annual direct cost of managing erectile dysfunction (ED) to the UK National Health Service (NHS) and to examine the impact of the introduction of sildenafil in 1998 and Schedule 11 restrictions in 1999. DESIGN: A prevalence-based cost-of-illness approach was used. The period 1997 to 2000 was covered. The numbers of ED prescriptions, prosthesis implantations and general practitioner (GP) consultations were retrieved retrospectively from UK resource utilisation databases. The number of specialist consultations and psychosexual therapy sessions were estimated from NHS clinic data. National resource unit costs were applied. MAIN OUTCOMES AND RESULTS: Between 1997 and 2000 the number of men presenting with ED increased from 79,800 to 257,984. The cost to the NHS increased from pounds sterling 29.4 million to pounds sterling 73.8 million (2000 estimates). The cost per patient fell from pounds sterling 368 to pounds sterling 286. In 1997, most NHS costs came from psychosexual therapy (30.7%), specialist consultations (20.2%) and intracavernosal injections (26.6%). By 2000, NHS costs came primarily from specialist consultations (32.0%), sildenafil prescriptions (26.2%), psychosexual therapy (13.6%) and GP consultations (12.0%). The annual cost was most sensitive to the number of drug prescriptions and specialist consultations. CONCLUSIONS: The increased NHS cost of managing ED was due mainly to a three-fold increase in the number of men presenting to GPs, substantial numbers of whom were then referred for specialist consultations under Schedule 11 restrictions. This naturally resulted in the increased use of all resources including sildenafil. The cost effectiveness of transferring prescribing responsibility in cases of severe distress from specialists to GPs in primary care remains to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12381240&dopt=Abstract sildenafil Viagra online



A classification based on peak systolic velocity and end diastolic velocity predicts sildenafil citrate success.

Murad Basar M, Atan A, Tekdogan UY, Batislam E.

Department of Urology, Kirikkale University, Ankara, Turkey. gozde ada.net.tr

OBJECTIVE: To attempt to predict the success rate of sildenafil citrate in erectile dysfunction patients using penile Doppler ultrasonography (PDU) measurements of peak arterial velocity and end diastolic velocity. MATERIAL AND METHODS: A total of 212 patients (age range 27-76 years) with vascular pathologies were included in the study. Following a PDU test, the patients were divided into arterial insufficiency, veno-occlusive dysfunction and mixed vascular pathology groups. Subsequently, patients were given sildenafil citrate 50 mg and re-evaluated 1 month later to determine its efficacy. If it was ineffective, the dose was increased to 100 mg and patients were reassessed. Arterial insufficiency and veno-occlusive dysfunction patients were classified into mild, moderate and severe groups depending on peak systolic and end diastolic velocities. RESULTS: The overall response rate in patients with arterial insufficiency was 74.5%, regardless of the degree of arterial insufficiency or the dose of sildenafil. The severe arterial insufficiency group had a much better response to 100 mg compared to 50 mg doses of sildenafil. Although the 50 mg sildenafil dose was effective in patients with minimal veno-occlusive dysfunction, 100 mg was better than 50 mg to achieve adequate erection in the mild and severe veno-occlusive dysfunction groups. CONCLUSIONS: Sildenafil was ineffective in patients with severe arterial and venous insufficiency. PDU and a simple classification of PDU velocity measurements can provide some important clues to the prognosis of treatment and avoid overtreatment and unnecessary office visits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14675925&dopt=Abstract sildenafil Viagra online



Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats.

Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M.

Department of Neurology, Henry Ford Health Sciences Center, Detroit, Mich, USA.

BACKGROUND AND PURPOSE: We tested the hypothesis that sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, promotes functional recovery and neurogenesis after stroke. METHODS: Male Wistar rats were subjected to embolic middle cerebral artery occlusion. Sildenafil (Viagra) was administered orally for 7 consecutive days starting 2 or 24 hours after stroke onset at doses of 2 or 5 mg/kg per day. Ischemic rats administered the same volume of tap water were used as a control group. Functional outcome tests (foot-fault, adhesive removal) were performed. Rats were killed 28 days after stroke for analysis of infarct volume and newly generated cells within the subventricular zone and the dentate gyrus. Brain cGMP levels, expression of PDE5, and localized cerebral blood flow were measured in additional rats. RESULTS: Treatment with sildenafil significantly (P<0.05) enhanced neurological recovery in all tests performed. There was no significant difference of infarct volume among the experimental groups. Treatment with sildenafil significantly (P<0.05) increased numbers of bromodeoxyuridine-immunoreactive cells in the subventricular zone and the dentate gyrus and numbers of immature neurons, as indicated by betaIII-tubulin (TuJ1) immunoreactivity in the ipsilateral subventricular zone and striatum. The cortical levels of cGMP significantly increased after administration of sildenafil, and PDE5 mRNA was present in both nonischemic and ischemic brain. CONCLUSIONS: Sildenafil increases brain levels of cGMP, evokes neurogenesis, and reduces neurological deficits when given to rats 2 or 24 hours after stroke. These data suggest that this drug that is presently in the clinic for sexual dysfunction may have a role in promoting recovery from stroke.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411660&dopt=Abstract sildenafil Viagra online



Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development.

Sher G, Fisch JD.

Sher Institute for Reproductive Medicine, Las Vegas, Nevada, USA. gsher sherinstitute.com

OBJECTIVE: To evaluate the effects of vaginally administered sildenafil on endometrial thickness and IVF outcome in a large cohort of infertile women with poor endometrial development. DESIGN: Retrospective cohort analysis. SETTING: Private practice setting. PATIENT(S): A cohort of 105 infertile women aged <40 years, with normal ovarian reserve and at least two consecutive prior IVF failures attributed to inadequate endometrial development. INTERVENTION(S): Patients underwent IVF using a long GnRH-a protocol with the addition of sildenafil vaginal suppositories (25 mg, 4 times per day) for 3-10 days. MAIN OUTCOME MEASURE(S): Peak endometrial development, pregnancy, and implantation rates. RESULT(S): Of 105 patients, 73 (70%; Group A), attained an endometrial thickness of >/=9 mm, whereas 32 (30%; Group B) did not. Implantation and ongoing pregnancy rates were significantly higher for Group A (29% and 45%) than for Group B (2% and 0). Of 11 women in Group B who had embryos transferred in that cycle, only one conception occurred, which resulted in a miscarriage. In Group B, 59% of women had a history of endometritis, compared with 44% in Group A. CONCLUSION(S): Vaginal administration of sildenafil enhanced endometrial development in 70% of patients studied. High implantation and ongoing pregnancy rates were achieved in a cohort with a poor prognosis for success. Previous endometritis may decrease the response to sildenafil.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12413996&dopt=Abstract sildenafil Viagra online



Effects of ovariectomy and estrogen and androgen treatment on sildenafil-mediated changes in female genital blood flow and vaginal lubrication in the animal model.

Min K, Munarriz R, Kim NN, Goldstein I, Traish A.

Department of Biochemistry, Boston University School of Medicine, Mass, USA.

OBJECTIVE: Our purpose was to investigate the effects of ovariectomy and estradiol and testosterone treatment on sildenafil- induced changes in genital hemodynamics and vaginal lubrication. STUDY DESIGN: Female New Zealand White rabbits were either kept intact or underwent ovariectomy. Two weeks after ovariectomy, animals were treated with vehicle, testosterone, or a combination of estradiol and testosterone for 14 days. Genital hemodynamics and vaginal lubrication were recorded at the end of the treatment period. RESULTS: Ovariectomy caused a marked decrease in vaginal lubrication but did not significantly alter genital hemodynamics. In contrast to testosterone treatment of ovariectomized animals, estradiol treatment significantly increased genital blood flow and vaginal lubrication above that observed in control animals. Sildenafil administration caused a significant increase in genital hemodynamics irrespective of the hormonal status. CONCLUSION: This study suggests that estradiol but not testosterone modulates genital hemodynamics and that sildenafil enhances genital blood flow irrespective of hormonal status.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12439533&dopt=Abstract sildenafil Viagra online