Treatment of erectile dysfunction with chronic dosing of tadalafil.
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Carbolines↗
Biomedical subjects
Chris G McMahon
Publications and source records attributed to Chris G McMahon.
Efficacy of type-5 phosphodiesterase inhibitors in the drug treatment of premature ejaculation: a systematic review.
This review examines the role of nitric oxide (NO) as a neurotransmitter involved in the central and peripheral control of ejaculation, the methods of phosphodiesterase type 5 inhibitor (PDE5I) drug treatment studies for premature ejaculation (PE), the adherence of methods to the contemporary consensus of ideal PE drug trial design, the impact of methods on treatment outcomes and the role of PDE5Is in the treatment of PE. NO/cGMP transduction is involved in both the central and peripheral control of emission, but evidence for a direct central or peripheral effect of PDE5Is on ejaculation is speculative. Thirteen of the 14 studies reviewed failed to fulfil the evidence-based medicine criteria for ideal PE drug trial design. Limitations of the studies include inadequately defined study populations, the lack of a double-blind placebo-controlled study design, and the absence of consistent objective physiological measures or sensitive, validated outcome assessment instruments as study endpoints. The broad range of intravaginal ejaculatory latency time (IELT) fold-increases reported with PDE5Is, on-demand selective serotonin re-uptake inhibitor (SSRI) drugs, and combined PDE5I/on-demand SSRIs is testament to the unreliability of data and conclusions from methodologically flawed studies. The one study that fulfilled the evidence-based medicine criteria of an ideal clinical trial design reported that treatment with sildenafil failed to significantly increase baseline IELT, supporting our conclusion that there is no convincing evidence to support any role for PDE5Is in the treatment of men with lifelong PE and normal erectile function. However, there is limited evidence to support a potential role for PDE5Is alone or combined with daily or on-demand SSRIs in the treatment of acquired PE in men with comorbid erectile dysfunction. Further controlled studies adhering to the contemporary consensus of ideal clinical trial design are required to clarify the role of PDE5Is in this subgroup of men with acquired PE.
Ejaculation↗
Tolerance to the therapeutic effect of tadalafil does not occur during 6 months of treatment: A randomized, double-blind, placebo-controlled study in men with erectile dysfunction.
INTRODUCTION: Tolerance can cause a decrease in drug efficacy during chronic therapy, possibly leading to treatment failures. AIM: The aim of this article is to determine whether tolerance developed to the effects of tadalafil on erectile function (EF) over a 6-month treatment period. METHODS AND MAIN OUTCOME MEASURES: Post hoc analysis of data from a multicenter, double-blind, randomized, placebo-controlled, parallel group study was performed. Men (> or =18 years of age) with erectile dysfunction (ED) were randomized to treatment with placebo (N = 47) or 20-mg tadalafil (N = 93) taken as needed for 6 months. This report focuses on efficacy assessed with the Sexual Encounter Profile (SEP) diary (diaries were collected after a 4-week treatment-free run-in period [baseline], and monthly for 6 months), and with the International Index of Erectile Function (IIEF) (administered at baseline, and at 3 and 6 months). RESULTS. The mean per-patient percentage "yes" response on SEP question 3 (SEP3, successful intercourse) was 33 +/- 4% at baseline, 74 +/- 4% after 1 month, and 78 +/- 4% after 6 months of tadalafil treatment. The IIEF EF domain score was 16.2 +/- 0.7 at baseline, 24.3 +/- 0.8 after 3 months, and 24.3 +/- 0.9 after 6 months of tadalafil treatment. In a subgroup of patients who took tadalafil > or =3 times per week (N = 24), the SEP3 score was 87 +/- 4% after 1 month and 93 +/- 3% after 6 months of treatment, and the IIEF EF domain score was 27.3 +/- 0.9 after 3 months and 28.5 +/- 0.4 after 6 months. Of 16 tadalafil-treated patients who discontinued, three cited a lack of efficacy. CONCLUSIONS: Tadalafil treatment significantly improved SEP3 and IIEF EF domain scores. The efficacy of tadalafil, taken as needed, was maintained over a 6-month treatment period in men with ED.
Adult↗
The etiology and management of premature ejaculation.
Premature ejaculation (PE) is a common male sexual disorder. Normative data suggest that men with an intravaginal ejaculatory latency time of less than 1 min have 'definite' premature ejaculation, while men with intravaginal ejaculatory latency times of between 1 and 1.5 min have 'probable' premature ejaculation. Although there is insufficient empirical evidence to identify the etiology of PE, there is correlational evidence to suggest that men with PE have high levels of sexual anxiety and altered sensitivity of central 5-hydroxytryptamine receptors. Pharmacological modulation of the ejaculatory threshold using daily or on-demand selective serotonin reuptake inhibitors offers patients a high likelihood of achieving improved ejaculatory control within a few days of initiating treatment, leads to improvements in sexual desire and other sexual domains, and is well tolerated.
Algorithms↗
Efficacy of sildenafil citrate (Viagra) in men with premature ejaculation.
OBJECTIVES: Premature ejaculation (PE) is the most common ejaculatory dysfunction. We assessed the efficacy of sildenafil to increase the time to ejaculation, improve ejaculatory control, and decrease the postejaculatory erectile refractory time in men with PE. DESIGN AND METHODS: The main study was an 8-week, double-blind, placebo-controlled, parallel group study in men between 18 and 65 years of age with diagnosed PE. A substudy was also conducted using a subset of patients (two-way crossover, one center) before entry to the main study. The primary study measured intravaginal ejaculatory latency (IELT) and responses to the Index of Premature Ejaculation (IPE) questionnaire. The substudy measured vibrotactile stimulation ejaculatory latency time (VTS-ELT) and postejaculatory erectile refractory time. Differences between treatment groups were determined by ancova at the 5% level of significance. RESULTS: The change in IELT (1.6 +/- 6.08 vs. 0.6 +/- 2.07 minutes) and VTS-ELT (2.9 +/- 0.4 vs. 2.4 +/- 0.4 minutes) were higher after taking sildenafil, compared with placebo, but did not reach statistical significance. However, patients who took sildenafil (vs. placebo) reported significantly (P < 0.05) increased ejaculatory control (1.8 +/- 0.3 vs. 1.5 +/- 0.3), increased ejaculatory confidence (2.2 +/- 0.2 vs. 1.9 +/- 0.2), and improved overall sexual satisfaction scores (3.1 +/- 0.2 vs. 2.8 +/- 02) on the IPE, and had a decreased postejaculatory erectile refractory time (3.2 +/- 0.7 vs. 6.4 +/- 0.7 minutes). The most common adverse events for sildenafil (vs. placebo) were headache (15% vs. 1%), flushing (15% vs. 0%), dyspepsia (5% vs. 1%), abnormal vision (5% vs. 0%), and rhinitis (5% vs. 0%). CONCLUSIONS: Although IELT and VTS-ELT were not significantly improved, sildenafil increased confidence, the perception of ejaculatory control, and overall sexual satisfaction, and decreased the refractory time to achieve a second erection after ejaculation in men with PE.
Adolescent↗
Disorders of orgasm and ejaculation in men.
INTRODUCTION: Ejaculatory/orgasmic disorders, common male sexual dysfunctions, include premature ejaculation, inhibited ejaculation, anejaculation, retrograde ejaculation and anorgasmia. AIM: To provide recommendations/guidelines concerning state-of-the-art knowledge for management of ejaculation/orgasmic disorders in men. METHODS: An International Consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a 2-year period. Concerning the Disorders of Ejaculation/Orgasm in Men Committee, there were nine experts from six countries. MAIN OUTCOME MEASURE: Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. RESULTS: Premature ejaculation management is dependent upon etiology. When secondary to ED, etiology-specific treatment is employed. When lifelong, initial pharmacotherapy (SSRI, topical anesthesia, PDE5 inhibitors) is appropriate. When associated with psychogenic/relationship factors, behavioral therapy is indicated. When acquired, pharmacotherapy and/or behavioral therapies are preferred. Retrograde ejaculation, diagnosed with spermatozoa and fructose in centrifuged post-ejaculatory voided urine, is managed by education, patient reassurance, pharmacotherapy or bladder neck reconstruction. Men with anejaculation or anorgasmia have a biologic failure of emission and/or psychogenic inhibited ejaculation. Men with age-related penile hypoanesthesia should be educated, reassured and be instructed in revised sexual techniques which maximize arousal. CONCLUSIONS: More research is needed in understanding management of men with ejaculation/orgasmic dysfunction.
Anesthetics, Local↗
Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses.
PURPOSE: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg up to a maximum of once daily [DOSAGE ERROR CORRECTED] in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of "yes" responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question. RESULTS: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Patients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in International Index of Erectile Function erectile function domain score from baseline (p <0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p <0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p <0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events. CONCLUSIONS: Tadalafil was effective and well tolerated in this patient population.
3',5'-Cyclic-GMP Phosphodiesterases↗
Topiglan MacroChem.
MacroChem is developing Topiglan, a topical gel containing prostaglandin E1 (PGE1 or alprostadil) and its patented through-the-skin absorption enhancer excipient (SEPA), for the potential treatment of erectile dysfunction. By September 2000, it was in phase III clinical trials [382682]. By October 2000, MacroChem expected to file an NDA for Topiglan in late 2002 [387433]. In January 2002, at the JP Morgan Hambrecht & Quist 20th Annual Healthcare Conference in San Francisco, CA, MacroChem stated that further phase III studies were planned, including a reformulation that could reduce initation and increase dosage, as well as providing new packaging that improves dose consistency These studies should be underway by the third quarter of 2002, with a potential launch in late 2003 or early 2004 [436390]. The company's patented SEPA technology used in Topiglan is an absorption enhancer for transdermal delivery that has the potential to effectively increase the passage of therapeutic agents through the skin. The application of SEPA alone to the skin of carcinogenic-sensitive rats did not cause the development of tumors attributable to the SEPA [357621]. The company received a US notice of allowance of all patent claims covering Topiglan in February 1999. The patent (US-05942545) was issued in August 1999 [316028], [337720]. Further patent applications are pending in Canada, Europe and Japan [337720]. In February 2000, MacroChem filed further patent applications in 13 countries in Europe, Asia and Latin America and with the EPO [355947].
Adjuvants, Pharmaceutic↗