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Biomedical subjects

Andrew McCullough

Publications and source records attributed to Andrew McCullough.

11 recordsLinked to original sources
PubMed2006

PLP1 alternative splicing in differentiating oligodendrocytes: characterization of an exonic splicing enhancer.

Proteolipid protein (PLP) and DM20 are generated by alternative splicing of exon 3B of PLP1 transcript in differentiating oligodendrocytes. We investigated the role of exonic splicing enhancers (ESE) in the selection of PLP 5' donor site, focusing on putative ASF/SF2, and SC35 binding motifs in exon 3B on the basis of mutations that cause disease in humans. Mutations in a putative ASF/SF2 binding motif (nucleotides 406-412) reduced PLP 5' donor site selection, whereas a mutation in a putative SC35 binding motif (nucleotides 382-389) had no effect. UV crosslinking and immunoprecipitation (IP) assays using an antibody to ASF/SF2 showed that the ASF/SF2 protein specifically binds to the ESE (nucleotides 406-412). The single nucleotide mutations that reduced PLP splice site selection greatly diminished ASF/SF2 protein binding to this motif. We next tested the effect of overexpressed ASF/SF2 on PLP 5'splice selection in differentiating oligodendrocytes. ASF/SF2 positively regulates PLP splice site selection in a concentration-dependent manner. Disruption of the putative ASF/SF2 binding site in exon 3B reduced the positive effect of ASF/SF2 on PLP splicing. We conclude that an ESE in exon3B regulates PLP 5' donor site selection and that ASF/SF2 protein participates in the regulation of PLP alternative splicing in oligodendrocytes.

Alternative Splicing↗
PubMed2006

Single-blind, multicenter, placebo controlled, parallel study to assess the safety and efficacy of intralesional interferon alpha-2B for minimally invasive treatment for Peyronie's disease.

PURPOSE: We investigated the efficacy and safety of intralesional interferon alpha-2b for the treatment of Peyronie's disease. MATERIALS AND METHODS: A total of 117 consecutive patients with a mean age of 55.1 years who had Peyronie's disease were enrolled in a single-blind, multicenter, placebo controlled, parallel study to determine the efficacy and safety of intralesional interferon alpha-2b therapy (Schering, Kenilworth, New Jersey), including 62 who received placebo and 55 who received interferon alpha-2b. Saline (10 ml) in controls and interferon alpha-2b (5 x 10(6) U) were administered biweekly for 12 weeks. Each patient was evaluated for penile curvature, plaque size and density, penile pain, erectile function and penile hemodynamics before and after study completion. Improvement in these parameters was statistically compared between the groups. RESULTS: A total of 53 patients in the control arm and 50 in the interferon alpha-2b arm completed the study. Improvement in penile curvature, plaque size and density, and pain resolution was significantly greater in patients treated with interferon alpha-2b vs placebo. The increase in mean International Index of Erectile Function scores was not significantly different between the groups. Penile blood flow improvement was observed in interferon alpha-2b treated patients but not in those who received placebo. The decrease in the number of penile vascular pathologies was significantly higher in interferon alpha-2b cases. Side effects, mostly flu-like symptoms, which were frequently noted in patients on interferon alpha-2b, were mild to moderate in degree and of short duration. CONCLUSIONS: This single-blind, multicenter, placebo controlled, parallel study demonstrates that intralesional interferon alpha-2b at a dose of 5 x 10(6) units biweekly for 12 weeks is effective and safe as minimally invasive therapy for Peyronie's disease.

Adult↗
PubMed2006

hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial.

Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patients each were given 500, 1000, and 5000 microg, and two patients were given 7500 microg, of hMaxi-K and monitored for 24 weeks. The primary objectives of this phase I study were safety and tolerability of escalating hMaxi-K doses as assessed by clinical evaluations and laboratory tests. Secondary efficacy objectives were measured primarily by use of the International Index of Erectile Function (IIEF) scale. Patient responses were validated by partner responses. There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry, and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function (EF) as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 microg and one given 7500 microg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study. Efficacy conclusions cannot be drawn from results of a phase I trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of ED and that further studies investigating the efficacy of hMaxi-K in patients with ED should be performed.

Adult↗
PubMed2005

The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results.

OBJECTIVE: To test the safety of a single intracavernous injection of a plasmid vector (hMaxi-K) that expresses the hSlo gene, that encodes the alpha-subunit of the Maxi-K channel, for the treatment of erectile dysfunction (ED). METHODS: Six men, thus far have fulfilled the entry criteria of the protocol and had gene transfer with hMaxi-K. Three received a dose of 500 microg and three received a dose 1000 microg of the gene product, injected intracavernously as naked DNA. Dosing at 5000 microg and higher is planned. RESULTS: The primary end point of the phase I trial is safety. No drug-related adverse events or significant laboratory changes have occurred after the gene transfer. Moreover, there is no evidence of the gene in semen at the one copy per mug total DNA in any of the participants. CONCLUSION: Preliminary results indicate that, in a single dose escalation study, ion channel gene transfer with hMaxi-K can be administered safely to men with ED without adverse events.

Erectile Dysfunction↗
PubMed2005

Efficacy of sildenafil citrate in men with erectile dysfunction following radical prostatectomy: a systematic review of clinical data.

INTRODUCTION: Radical prostatectomy is a frequently used treatment option for prostate cancer; however, prostatectomy is often associated with significant morbidity, including erectile dysfunction (ED). AIM: To analyze the efficacy of sildenafil citrate in treating ED after radical prostatectomy. MATERIALS AND METHODS: MEDLINE and CANCERLIT (1998 to January 2004) were searched for English language articles using the key words prostatectomy, sildenafil, and phosphodiesterase inhibitors. Eleven studies fulfilled the inclusion criteria: primary, discrete data sets of postprostatectomy patients with ED treated with sildenafil monotherapy. RESULTS: Sample sizes ranged from 13 to 198 (mean age, 61 +/- 3 years). Treatment durations were 4 weeks (or more than four doses) to 1 year, and sildenafil dosing was in the recommended range (25-100 mg). Seven studies reported a response rate (range, 14%-53%) for an end point consistent with the primary analysis outcome (erection sufficient for vaginal intercourse); the combined estimate of probability of response was 35% (95% confidence interval [CI], 24%-48%). There was strong evidence for a lower response rate after non-nerve-sparing (range, 0%-15%) versus nerve-sparing surgery (range, 35%-75%; combined odds ratio [OR] = 12.1; 95% CI, 5.5-26.6) but not after unilateral (range, 10%-80%) versus bilateral nerve-sparing surgery (range, 46%-72%; combined OR = 2.21; 95% CI, 0.75-6.54). CONCLUSIONS: The results of these studies demonstrate that with sildenafil, more than one third of patients with postprostatectomy ED achieved erection sufficient for intercourse. The odds of responding improved 12-fold with preservation of at least one neurovascular bundle. Early treatment failure does not necessarily imply lack of efficacy in the future, and patients should be encouraged to continue trying sildenafil, titrating up to 100 mg as needed.

Erectile Dysfunction↗
PubMed2004

Erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy: comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies.

Postprostatectomy erectile dysfunction appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Phosphodiesterase-5 (PDE-5) inhibitor therapy is the current cornerstone of erectile dysfunction (ED) therapy in this population. Although no head-to-head trials have been performed with sildenafil, vardenafil, and tadalafil in this population, there are numerous studies in the general ED population. The results of these studies demonstrate that neither of the new PDE-5 inhibitors met statistical noninferiority to sildenafil. Sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. In this novel approach, it effected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation. This effect appears to be mediated by properties unique to sildenafil that include improved endothelial function and neuronal regeneration and neuroprotection. In primary prevention, unlike ED therapy, one has only "one shot" by definition. Therefore, it is even more critical to apply evidence-based medicine.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial.

PURPOSE: We evaluated the efficacy and safety of tadalafil 20 mg, taken on demand, in men with erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy (BNSRRP). MATERIALS AND METHODS: This randomized, double-blind, placebo controlled multicenter study consisted of a 4-week treatment-free run-in period (baseline) followed by 12 weeks of treatment. A total of 303 men (mean age 60 years) with preoperative normal erectile function who had undergone a BNSRRP 12 to 48 months before study were randomized (2:1) to tadalafil (201) or placebo (102). The 3 co-primary end points were changes from baseline in the International Index of Erectile Function erectile function domain score, and the percentage of positive responses to Sexual Encounter Profile questions 2 (successful penetration) and 3 (successful intercourse). The Global Assessment Question and the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire were secondary end points. We defined a priori a subgroup of 201 patients reporting evidence of postoperative tumescence, defined as 50% or greater "yes" responses to Sexual Encounter Profile question 1 (ability to achieve at least some erection) during baseline intercourse attempts and stratified randomization based on this criterion. RESULTS: Patients receiving tadalafil reported greater improvement on all primary and secondary end points (p <0.001) compared to placebo. For all randomized patients and for the subgroup with evidence of postoperative tumescence, the mean International Index of Erectile Function erectile function domain score increased for patients receiving tadalafil (mean +/- SEM 5.3 +/- 0.5 and 5.9 +/- 0.7, respectively, p <0.001 vs placebo for both). For all randomized patients who received tadalafil, the mean percentage of successful penetration attempts was 54% and the mean percentage of successful intercourse attempts was 41%. For the subgroup with evidence of postoperative tumescence these values were 69% and 52%, respectively. Of all patients randomized to tadalafil 62% and of the subgroup patients randomized to tadalafil 71% reported improved erections. Patients receiving tadalafil reported greater treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction than those receiving placebo. Headache (21%), dyspepsia (13%) and myalgia (7%) were the most commonly reported adverse events. CONCLUSIONS: Tadalafil 20 mg, taken on-demand, was an efficacious and well tolerated treatment for erectile dysfunction following BNSRRP.

Carbolines↗
PubMed2004

Pharmacotherapy for erectile dysfunction.

INTRODUCTION: Advances in understanding of the biochemistry and physiology of penile erection have led to breakthroughs in pharmacotherapy of erectile dysfunction. AIM: To provide recommendations/guidelines concerning state-of-the-art knowledge for the putative molecular and cellular mechanisms of action of centrally and peripherally acting drugs currently utilized in pharmacotherapy of erectile dysfunction. 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 two-year period. Concerning the Pharmacotherapy for Erectile Dysfunction Committee there were 25 experts from 10 countries. MAIN OUTCOME MEASURE: Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. RESULTS: Selective and potent oral PDE5 inhibitors have significantly more affinity than cGMP and form broader molecular interactions with multiple amino acids, thereby blocking access to cGMP in the catalytic sites of the PDE5 enzyme. PDE5 inhibitors, which vary as to biochemical potency, selectivity and pharmacokinetics, lead to cGMP elevation and relaxation facilitation of penile corpus cavernosum smooth muscle cells following sexual stimulation. Various centrally acting drugs influence sexual behaviour. In particular, the dopaminergic substance apomorphine is a central enhancer that acts in the paraventricular nucleus of the hypothalamus as a dopamine (D2) receptor agonist, induces and increases penile erection responses via disinhibition, following sexual stimulation. CONCLUSIONS: There is a need for more research in the pharmacotherapeutic development of central and peripheral agents for safe and effective erectile dysfunction treatment.

Apomorphine↗
PubMed2004

Self-reported premature ejaculation and aspects of sexual functioning and satisfaction.

BACKGROUND: Although premature ejaculation (PE) is a common male sexual dysfunction, its relevant parameters have not been adequately studied in large community-based samples. OBJECTIVE: To examine the diagnostic utility of two self-report questions based on the DSM-IV-TR definition of PE and to investigate the relationship between self-identified PE, sexual functioning, and sexual satisfaction in men. METHODS: An Internet survey of general health and aspects of sexual functioning and satisfaction was conducted in 2,056 males. Subjects were classified as having "probable" or "possible" PE, or as "non-PE" by survey responses. RESULTS: A total of 1158 men met the selection criteria (sexually active in a stable heterosexual relationship), and 189 (16.3%) were classified as having probable PE by reporting they ejaculated before they wished and indicating it was "very much" or "somewhat" a problem. Another 188 (16.2%) men reported ejaculating before they wished but rated their distress lower and were classified as having possible PE. Compared to non-PE men, those with probable and possible PE reported significantly worse sexual functioning in 6 of 8 study measures. Concern about partner satisfaction was high in all groups. The importance of ejaculatory control and the ability to have intercourse for the desired time was significantly higher in men with PE as compared to non-PE men (P < 0.01). CONCLUSIONS: PE was a common problem, was characterized by a lack of ejaculatory control, and was associated with significant effects on sexual functioning and satisfaction. Additional research on the sensitivity and specificity of these self-report questions should be pursued.

Adult↗
PubMed2003

Case scenarios in androgen deficiency.

Deciding whether to choose androgen replacement for a particular patient is one of the many tasks facing the urologist. Factors including androgen levels, medical history, symptom profile, current medications, and prostate cancer risk all need to be considered when making this decision. However, the role each of these factors plays in arguing for or against androgen replacement remains controversial and more research is needed in many of these areas before the outstanding issues can be resolved. This article presents three cases involving patients who may require androgen supplementation. The cases describe (1) partial androgen deficiency syndrome, (2) testosterone deficiency in an anorchic man after bilateral orchiectomy for seminoma, and (3) a patient with sildenafil-refractory erectile dysfunction following treatment of localized prostate cancer with radiation therapy and androgen ablation. These cases illustrate some of the dilemmas and controversies surrounding androgen replacement that face the practicing urologist.

Case Reports↗