Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction.

OBJECTIVES: Sildenafil has been demonstrated to be safe and effective in the treatment of men with erectile dysfunction. The role of sildenafil in treating women with sexual dysfunction has heretofore not been reported. The purpose of this preliminary study was to ascertain the response of postmenopausal women with self-described sexual dysfunction treated with sildenafil for 3 months. METHODS: Thirty-three consecutive postmenopausal women with sexual dysfunction based on history were entered in this open-label, nonrandomized study. All patients received 50 mg of sildenafil. Efficacy was assessed at weeks 4, 8, and 12 using a newly developed 9-item, self-administered Index of Female Sexual Function (IFSF) and a global efficacy question ([GEQ] Did treatment improve your sexual function?). The IFSF quantifies the domains of desire, quality of sexual intercourse, overall satisfaction with sexual function, orgasm, lubrication, and clitoral sensation. RESULTS: Of the group, 30 women (91 %) completed the study and were available for follow-up at 3 months. Mean baseline IFSF score before therapy was 24.8+/-9.8. Mean usage of sildenafil was 3.1+/-1.4 times per week for the duration of the study. The IFSF score improved to 29.5+/-7.6, 30.3+/-8.5, and 31.4+/-10.4 at 4, 8, and 12 weeks, respectively (P = 0.25). Mean scores for questions 2 (lubrication), 8 (orgasm), and 9 (clitoral sensation) improved by 23.2%, 7.4%, and 31.3%, respectively, at 12 weeks. Seven women (21%) noted improvement on the GEQ. Overall, only 6 (18.1%) of 33 patients had a significant (more than 60% improvement in IFSF score) therapeutic response. Clitoral discomfort and "hypersensitivity" occurred in 7 women (21%), 3 of whom withdrew from the study. Other side effects, which did not result in withdrawal from the study, included headache (n = 5), dizziness (n = 4) and dyspepsia (n = 3). CONCLUSIONS: The data suggest that sildenafil is well tolerated in postmenopausal women with sexual dysfunction. Overall sexual function did not improve significantly, although there were changes in vaginal lubrication and clitoral sensitivity. The role of sildenafil in treating sexual dysfunction in various cohorts of women remains to be determined.

Combination therapy using oral alpha-blockers and intracavernosal injection in men with erectile dysfunction.

OBJECTIVES: Intracavernosal injection with a combination of agents (ie, phentolamine plus papaverine or alprostadil) has been used in an effort to increase efficacy and reduce side effects compared with single agents. The purpose of this pilot study was to determine the potential role of oral alpha-blockers in combination with intracavernosal therapy in men with erectile dysfunction, for whom intracavernosal therapy alone failed. METHODS: Thirty-eight consecutive men with moderate to severe erectile dysfunction on the basis of history and examination and with minimal or no therapeutic response to intracavernosal alprostadil injection therapy were evaluated. All patients received daily doxazosin titrated to 4 mg over 3 weeks in combination with intracavernosal therapy as needed for 12 weeks. Efficacy was assessed at 4, 8, and 12 weeks after doxazosin titration using the 1 5-item, self-administered International Index of Erectile Function (IIEF) and a global efficacy question (GEQ: Did treatment improve your erections?). RESULTS: For the group, the mean baseline IIEF score before therapy was 29.7+/-9.8. After intracavernosal therapy (mean dose 34.7+/-7.3 microg), IIEF improved to 36.1+/-1 1.4 (17.7%). After addition of doxazosin, IIEF improved to 48.6+/-13.4, 46.4+/-10.9, and 51.5+/-14.3 at 4, 8, and 12 weeks, respectively (P < 0.01). The GEQ response improved from 25.7% at baseline to 81.4% at 12 weeks. Overall 22 (57.9%) of 38 patients with the combined regimen had a significant (more than 60% improvement in IIEF) therapeutic response. CONCLUSIONS: The addition of an oral alpha-blocker may have a beneficial effect in patients with erectile dysfunction for whom intracavernosal therapy alone fails. The synergistic effects of vascular dilation and blockade of sympathetic inhibition may explain this response. The potential role of alpha-blockade in synergy with other agents designed to treat erectile dysfunction remains to be determined.

Intermittent alpha-blocker therapy in the treatment of men with lower urinary tract symptoms.

OBJECTIVES: To determine the safety and efficacy of intermittent alpha-blocker therapy in men with lower urinary tract symptoms (LUTS) in a prospective study. Alpha-blockers have been demonstrated to be safe and effective in the treatment of men with LUTS. To date, the role of varying dosing regimens in responding patients has not been well studied. METHODS: Men with LUTS were entered into this prospective open label, parallel, randomized trial. In phase 1, patients were treated with alfuzosin, 2.5 mg three times daily for 3 months. In phase 2, those patients who had a significant therapeutic response were randomized into one of the following three groups: (1) maintenance of alfuzosin; (2) alfuzosin every other day; and (3) discontinuation of alfuzosin (ie, no treatment). Patients were followed up for a total of 6 months. Parameters of evaluation included the International Prostate Symptom Score (IPSS), global satisfaction, peak urinary flow rate (Qmax), and adverse events. RESULTS: At 3 months, there were 79 patients who were categorized as having obtained a therapeutic response: IPSS decreased to 7.6 +/- 3.2 and Qmax increased to 11.3 +/- 2.9 mL/s. After randomization, IPSS was 7.1 +/- 2.9 and 6.5 +/- 2.5 for group 1; 6.5 +/- 3.2 and 6.7 +/- 2.1 for group 2; and 11.4 +/- 4.8 and 12.3 +/- 4.9 for group 3 at 3 and 6 months, respectively. Qmax was 12.7 +/- 4.8 and 11.7 +/- 5.2 mL/s for group 1; 12.2 +/- 3.9 and 11.9 +/- 3.7 mL/s for group 2; and 9.7 +/- 2.5 and 9.3 +/- 2.1 mL/s for group 3 at 3 and 6 months, respectively. Global satisfaction at 6 months was the same for groups 1 and 2. There were no differences in adverse events among the three groups. CONCLUSIONS: In men with LUTS who responded to alfuzosin, changing the dosing regimen from daily to once every other day resulted in similar efficacy and safety at 3 and 6 months. By contrast, complete cessation of alfuzosin resulted in recurrence of both symptoms and impaired urinary flow. These data provide evidence that in responding patients, intermittent alpha-blocker therapy may be a reasonable therapeutic regimen. The role of intermittent alpha-blocker therapy using other agents, as well as in a large cohort of men with LUTS, remains to be determined.

Placement of a bladder neck purse-string cuff for the management of incontinence in children with myelodysplasia.

OBJECTIVES: Numerous surgical procedures have been developed in an attempt to increase bladder compliance and/or outlet resistance for the treatment of intractable incontinence in children with neurogenic lower urinary tract dysfunction. We report our experience with the development of a biocompatable purse-string cuff to increase outlet resistance by providing circumferential compression at the bladder neck. METHODS: A total of 12 children (6 boys, 6 girls) with myelodysplasia and persistent incontinence despite clean intermittent catheterization (CIC) and pharmacotherapy underwent urodynamic testing and cystoscopy that revealed neurogenic bladders with concomitant intrinsic sphincter deficiency. Through an anterior approach, the bladder neck was mobilized and wrapped with 5-mm polytetrafluoroethylene tubing. Five-millimeter woven polyester tape was then placed circumferentially within the polytetrafluoroethylene tubing lumen, purse-stringed under tension with a silicone tubing shod to appose the mucosa of the bladder neck, and secured under such tension with a surgical clip. Ten of the 12 patients underwent concomitant augmentation cystoplasty. RESULTS: Nine of 12 children (age range at time of operation 2.5 to 16 years) are continent on CIC in follow-up ranging from 6 months to 12 years. Four cuffs had to be surgically removed postoperatively. Two were removed secondary to inadvertent transvaginal placement. Two other cuffs were removed for infection. One child with persistent postoperative incontinence had the cuff retightened through a minor surgical procedure and has remained dry. Annual renal ultrasound examinations reveal stabilization of upper urinary tracts throughout the follow-up period in all but 1 patient. Postoperative urodynamic studies reveal increased bladder capacity, decreased intravesical pressures, and increased leak point pressures. CONCLUSIONS: The purse-string bladder neck cuff in combination with augmentation cystoplasty, when warranted, provides excellent, durable continence rates in children with myelodysplasia and neurogenic bladders. Attributes of the cuff are its relative low cost, ease of construction, unchanged angle of the bladder neck making catheterization easy, and potential adjustability in patients with persistent incontinence.

Lack of effect following repeated in vivo exposure of the rabbit urinary bladder to urine from interstitial cystitis patients at low infusion volumes.

We reported previously that substances in interstitial cystitis urine, when infused into the rabbit bladder, induce changes that resemble bladders of interstitial cystitis (IC) patients. Here we report our investigation of the effect of additional molecular weight subfractions of IC urine and lower infusion volume in this rabbit bladder bioassay. Urine was pooled from symptomatic IC patients, asymptomatic IC patients (in remission), and normal volunteers. Two fractions of 20x concentrated urine were obtained for each of the 3 groups: a 10-100-kD fraction and a fraction > 100 kD but <0.22 microm. Six rabbits per group were infused twice per week with 6 ml of 1 of these 6 urine fractions or saline as a control. After 6 weeks, each rabbit was cystoscoped before and after hydrodistension, bladder capacity and urea permeability were determined, and the bladder was removed for histologic examination. A questionnaire revealed a significant difference (P < 0.01) regarding voiding symptom severity between symptomatic IC patients and both normal volunteers and IC patients in remission. There was no statistically significant difference among groups of rabbits in cystoscopic bladder appearance, bladder capacity, urea permeability, or bladder histology. If a urine-borne factor is in part responsible for IC symptoms, the rabbit bladder must be filled with urine to near capacity to be able to detect a difference between IC and normal urine in this rabbit bladder bioassay.

Prejunctional M1 facilitory and M2 inhibitory muscarinic receptors mediate rat bladder contractility.

Subtype-selective muscarinic antagonists effects on carbachol-induced and electric field-stimulated contractility of rat bladder were compared in vitro. Schild plot analysis of cumulative carbachol dose-response curves in the presence of antagonists was consistent with M3-mediated bladder contractions. However, nerve-evoked contractions were inhibited 15% at 30 Hz (P < 0.01) by 10 nM pirenzepine (M1-selective antagonist), whereas 10 nM methoctramine (M2-selective antagonist) increased these contractions by 17% at 30 Hz (P < 0.01). Identical doses had no effect on carbachol-induced contractions, indicating prejunctional M1 facilitory and M2 inhibitory receptors. m1 Receptors could not be identified by subtype-selective antibodies, nor could the m1 transcript be identified by Northern hybridization. However, m1, m2, m3, and m4 transcripts were identified in rat bladder using the reverse transcriptase-polymerase chain reaction, providing support for the existence of the m1 subtype. In conclusion, strong evidence is provided for the existence of prejunctional M1 facilitory and M2 inhibitory and postjunctional M3 receptors modulating contractility in the rat urinary bladder.

Acute renal failure with thrombocytopenia after cryosurgery of the prostate.

We report three cases of transient acute renal failure accompanied by thrombocytopenia all occurring within 48 h of percutaneous transperineal cryoprostatectomy. Renal function spontaneously improved in all three patients, who currently have normal renal function and are voiding without difficulty. No known risk factor or specific etiology for the renal failure could be identified; therefore, we conclude that the renal failure is most likely secondary to the cryosurgery procedure, a common link shared by all three patients. We are currently administering intravenous mannitol before initiation of the freeze and have seen no further episodes of postcryosurgical acute renal failure in > 50 patients with prostate cancer. Because cryosurgery is currently becoming a more pervasive treatment option for localized prostate cancer, we believe it most important to report this heretofore unrecognized potential complication.

Progressive ventricular enlargement in cats in the absence of transmantle pressure gradients.

Intracranial pressure (ICP) was measured simultaneously at multiple sites in cats to determine if transmantle pressure gradients were present in progressive hydrocephalus. The cats underwent craniectomy and intracisternal injection of kaolin; 4 to 9 weeks later ICP was measured at the ventricle, cisterna magna, and convexity subarachnoid space, and in the brain tissue and the sagittal sinus. In 13 cats in which ventricular size conformed to previously established norms for duration of hydrocephalus, there were no demonstrable gradients of pressure at any of the sites of measurement according to one-way analysis of variance (p greater than 0.05). The mean (+/- standard error of the mean) peak and trough pressures (in mm Hg) at each site were: ventricle, 12.7 +/- 0.7 and 12.0 +/- 0.6; cisterna magna, 12.9 +/- 0.8 and 12.3 +/- 0.7; subarachnoid space, 12.7 +/- 0.8 and 12.1 +/- 0.7; brain tissue, 12.9 +/- 0.9 and 12.4 +/- 0.9; and sagittal sinus, 13.1 +/- 0.8 and 11.9 +/- 0.8. These results indicate that ventricular expansion can progress without measurable transmantle pressure gradients.

New ultrastructural changes of the ependyma in experimental hydrocephalus.

New ultrastructural alterations of the ependymal cells in the altered container model of experimental feline hydrocephalus are described. These include half desmosomes and a basal lamina on the apical surface of the ependymal cells, punctate adhesion-like structures between intraventricular mononuclear cells and the apical surface of the ependymal cells and unusual distortion of the ependymal cells. The significance of these previously unreported morphological alterations is unknown.