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Biomedical subjects

J P Mulhall

Publications and source records attributed to J P Mulhall.

At least 19 recordsLinked to original sources
PubMed2001

Should all infertile males undergo urologic evaluation before assisted reproductive technologies? Two cases of testicular cancer presenting with infertility.

OBJECTIVE: To report two cases of testicular cancer in patients presenting with infertility. DESIGN: Case reports. SETTING: University-affiliated urology practice. PATIENT(S): Two men presenting with infertility. INTERVENTION(S): Complete history and physical, hormonal assays, semen analysis, scrotal ultrasound, radical orchiectomy. MAIN OUTCOME MEASURE(S): Testicular pathology specimens. RESULT(S): Testicular cancer was diagnosed in two men sent to a urology clinic for infertility treatment. CONCLUSION(S): A thorough evaluation should be completed in all males in couples presenting with infertility.

Adult↗
PubMed2001

Improving the accuracy of vascular testing in impotent men: correcting hemodynamic alterations using a vasoactive medication re-dosing schedule.

PURPOSE: Arteriogenic or venogenic vascular insufficiency is the most common pathophysiology of organic erectile dysfunction. While vascular insufficiency may be suspected on history and physical examination, the definitive diagnosis is made by vascular testing. Dynamic infusion cavernosometry is a recognized technique for evaluating the hemodynamics of erection. Assigning the correct vascular diagnosis during testing is important. Complete corporeal smooth muscle relaxation is essential for obtaining accurate data. Previously others have suggested that repeat dosing with vasoactive medication may improve the diagnostic accuracy of vascular testing. We investigated the hemodynamic effect of repeat doses of medication. MATERIALS AND METHODS: Data were prospectively obtained on men undergoing dynamic infusion cavernosometry. When veno-occlusive parameters were abnormal, the intracavernous vasoactive agent dose was repeated to a maximum of 3 doses. Standard dynamic infusion cavernosometry criteria were used for diagnosing arteriogenic and venogenic erectile dysfunction. We analyzed the proportion of men in whom the vascular diagnosis was altered using this regimen. RESULTS: Of 420 men undergoing dynamic infusion cavernosometry, 70% warranted re-dosing based on abnormal veno-occlusive parameters. Of these 294 men veno-occlusive values were corrected by repeat medication in 32% and, therefore, they would have been falsely diagnosed with venous leakage during vascular evaluation. Half of all corrections occurred with the second dose, while half of the patients required a third dose of medication. CONCLUSIONS: These data should encourage clinicians to consider re-dosing during the vascular evaluation of men in whom incomplete corporeal smooth muscle relaxation is suspected. In this way a false diagnosis of venous leakage may be avoided in a significant number of cases.

Adult↗
PubMed2001

Analysis of the consistency of intraurethral prostaglandin E(1) (MUSE) during at-home use.

OBJECTIVES: To determine the consistency of a successful response to intraurethral prostaglandin E(1) (MUSE), an effective treatment for a proportion of patients with erectile dysfunction, during at-home use in men who had a successful response in the office, to define the factors that correlated with the consistency of the response, and to determine whether patients continued long-term use. METHODS: The study group consisted of men with documented erectile dysfunction who had a successful response (grade 3 or 4 erection) to MUSE during an initial in-office dose. All enrollees completed a home diary assessing the treatment success during at least five medication administrations. Factors such as patient age, vascular risk factor status, and degree of in-office response were prospectively evaluated as correlates of response consistency. Finally, patient follow-up was conducted in an attempt to define how many patients were continuing to use this medication as a long-term treatment modality. RESULTS: Two hundred twelve patients underwent screening and 72 (34%) patients had in-office success. The overall per patient at-home consistency rate was 51%. None of the aforementioned factors correlated with the consistency of the response. At a mean of 9 months after beginning treatment, only 31% of the in-office responders were continuing to use MUSE. CONCLUSIONS: Although MUSE is an appropriate and safe treatment for many patients with erectile dysfunction, the lack of consistency is a significant consideration. Clinicians should pay close attention to patient education in an effort to promote realistic expectations for MUSE therapy. Furthermore, the lack of consistency may significantly lower the patient's interest in continuing this treatment long term.

Adult↗
PubMed2001

An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction.

BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Administration, Sublingual↗
PubMed2001

Comparison of in-patient and out-patient penile prosthesis surgery.

Between December 1996 and December 1998, 79 inflatable penile implant insertions have been performed at our institution by a single surgeon. The objective of this analysis was to compare our in-patient and out-patient experience with penile prosthesis insertion with respect to ease of performance and complication profiles. Data was collected in a prospective manner for both groups (in-patient, n = 33 and out-patient, n = 46). The two groups were compared with respect to intra-operative blood loss, operative time, time lost from work, narcotic use and complication rates. Both groups of patients experienced similar operative blood loss, essentially identical operative times, time lost from work and narcotic use. Most importantly, overall complication rates were 6% for the in-patient group and 4% for the out-patient group. Inflatable penile implant surgery is feasible in an ambulatory surgical setting. There is no difference in complication rates, loss of time from work, or intra-operative and post-operative course. Furthermore, there is a significant saving at our institution by performing the procedure in an out-patient fashion. In-patient prosthetic surgery is reserved for secondary procedures following a prior implant infection or primary implants in men with significant co-morbidities that require in-patient postoperative monitoring.

Aged↗
PubMed2001

Development of a mathematical model for the prediction of the area of venous leak.

Erectile dysfunction (ED) is an increasingly prevalent medical problem, affecting up to 50% of men aged between 40 and 70-y-old. Many cases are vasculogenic and some of these stem from the inability of the penis to store blood during erection due to leak into the venous system, termed corporo-venocclusive dysfunction (CVOD). The area of leakage during erection could be the most direct measure of erectile function but has not been investigated before. We have developed a simple mathematical model to determine the area of leak during erection and have tested it on data from both normal men (n=3) and men with venogenic impotence (n=16) undergoing dynamic infusion cavernosometry (DIC). The area of leak in the impotent group is significantly greater than in normal men at intracorporal pressures above 30 mmHg and reaches a plateau between 60 and 90 mmHg. Based on this study, we suggest that it may be necessary only to perform DIC at intracorporal pressures between 60 and 90 mmHg.

Capillary Permeability↗
PubMed2001

Perturbation of cell cycle regulators in Peyronie's disease.

Peyronie's disease is a fibromatosis of the tunica albuginea, characterized by development of a plaque consisting primarily of collagen. It has been suggested that trauma to the erect penis is the inciting event. More recent research has focused on the cellular events leading to the dysregulated wound healing and plaque formation. Previous work has shown chromosomal aneusomies and this combined with an increased S-phase in plaque derived cell cultures suggests a perturbation in the cell cycle in this condition. The p53 protein has been shown to be an important cell cycle regulator and pro-apoptotic factor. Aberrant p53 function leading to cell immortalization and proliferation has been implicated in several human malignancies. We hypothesized that abnormal p53 function may explain the high proliferative ability of fibroblasts derived from Peyronie's plaques. This study was undertaken to study the presence and function of p53 and its downstream elements (p21, mdm-2) in Peyronie's disease cell cultures. Plaque-derived fibroblasts have been established in culture and characterized. These cells and control neonatal foreskin fibroblasts were subjected to 5 Gy of gamma radiation to induce DNA damage. After fixation, antibodies to p53 and its transcriptional elements were used to stain irradiated and non-irradiated cells and levels of p53, p21 and mdm-2 were quantified using combined immunofluorescence and flow cytometry. Non-irradiated plaque fibroblasts demonstrated the presence of p53, p21 and mdm-2 at baseline. In control foreskin fibroblasts no p53 or mdm-2 were detectable at baseline. In irradiated foreskin-derived cells significant changes in all elements were demonstrated indicating a fully functional p53 pathway and cell cycle checkpoint system in these cells. In contrast, plaque-derived cells showed no such alterations in levels of cell cycle regulators following irradiation. This is highly suggestive of an aberration of the p53 pathway in plaque-derived fibroblasts. Peyronie's plaque-derived fibroblasts demonstrated stabilization and defunctionalization of p53 protein combined with appropriate responses of its transcriptional elements. These findings may explain the high cell proliferation rates in these cells and suggests a role for perturbation of the p53 pathway in the pathogenesis of Peyronie's disease.

Cell Cycle↗
PubMed2001

Basic fibroblast growth factor expression in Peyronie's disease.

PURPOSE: Peyronie's disease is a fibromatosis resulting in scarring of the tunica albuginea. While the inciting event is believed to be trauma to the erect penis, little is understood about the cascade of cellular events that leads to the formation of the plaque. Dysregulated wound healing serves as a paradigm for the study of this condition. Previous work has demonstrated a role for fibrogenic cytokines in wound healing, fibromatoses, including Peyronie's disease. We analyze the expression of the fibrogenic cytokine, basic fibroblast growth factor (FGF), by fibroblasts derived from Peyronie's disease tissue. MATERIALS AND METHODS: Patients with Peyronie's disease undergoing either penile prosthesis insertion or Nesbit penile plication surgery had biopsy specimens removed from the plaque and from normal tunical tissue remote from the plaque. Cell cultures were derived from these specimens. Cultured cells were characterized using immunofluorescence staining and immunosorbent digital imaging. The cell culture supernatants were analyzed using an enzyme-linked immunosorbent assay for the production of basic FGF. Foreskin tissue from men without Peyronie's disease was used as control cells. RESULTS: Five independent cell lines were established from plaque tissue and 4 independent cell lines were established from normal tunica from the same subjects. Intracellular antigen expression was consistent with the cells being myofibroblasts. Production of basic FGF by the plaque derived myofibroblasts was significantly greater compared to production by normal tunical myofibroblasts and foreskin fibroblasts. CONCLUSIONS: These data demonstrate the successful establishment of cell lines from plaque tissue and normal tunica from men with Peyronie's disease. The findings indicate a potential role for basic FGF over expression in the tunical fibrosis that occurs in this condition. This information may allow a better understanding of the basic mechanisms involved in the development of this disease. Furthermore, it may permit the elaboration of therapeutic strategies to prevent or reduce tunical scarring and plaque formation.

Cells, Cultured↗
PubMed2000

Inhibition of Peyronie's plaque fibroblast proliferation by biologic agents.

Peyronie's disease is a fibromatosis of the tunica albuginea which affects up to 2% of men. Plaque development is believed to result, at least in part, from fibroblast proliferation and excess collagen deposition. Numerous oral and intralesional therapies have been used, including verapamil, colchicine and steroids. The purpose of this study was to investigate the in vitro effects of prostaglandin-E1 (PGE1), verapamil and colchicine on the proliferation rates of fibroblasts derived from Peyronie's disease tissue. Using tissue culture, multiple cell lines comprising fibroblasts from Peyronie's plaque, normal tunica and foreskin were established. Cells of low passage were removed from the parent culture and incubated with varying concentrations of PGE1 (0.1-10 mg/ml), verapamil (10-1000 mg/ml), and colchine (2.5 mg/ml). Proliferation was assessed at 48, 72 and 96 hours using the Vybrant MTT cell proliferation and then compared to control cells. Six plaque lines and 5 normal tunical cell lines were established. These cell lines exhibited excellent linear growth in culture media alone. Co-culture wih PGE1 resulted in no significant inhibition at 0.1 and 1 mg/ml, but a mean inhibition of 60.6+/-11.5% at a concenrtation of 10 mg/ml was noted. Similar inhibition was noted with verapamil at 100 and 1000 mg/ml with a mean inhibition of 65.2+/-10.6%. Colchicine resulted in a mean inhibition of 28% at a concentration of 2.5 mg/ml. Maximum inhibition occurred at 96 hours in all cases. There was no statisitically significant difference in proliferation rates between plaque and normal tunical cell lines. We have developed an in vitro model to assess the effects of biologically active agents on the growth of fibroblasts derived from Peyronie's disease tissue. Our data suggests that PGE1, verapamil, and colchicine inhibit in vitro proliferation of fibroblasts at specific concentrations. Refinement and application of this knowledge may allow the development of useful pharmacologic strategies for men with PD.

Alprostadil↗
PubMed2000

Current concepts in erectile dysfunction.

As the population ages, the prevalence of sexual dysfunction has steadily increased. Erectile dysfunction (ED) is defined as the consistent inability to obtain and/or maintain an erection sufficient for satisfactory sexual relations. Complete ED is defined as the absolute inability to participate in penetrative relations at any stage. Results from the Massachusetts Male Aging Study of 1300 men between the ages of 40 and 70 years show 52% of men--1 in 2--have some degree of ED; 5% of 40-year-olds and 25% of 75-year-olds have complete ED. Taking a detailed medical history and performing a thorough physical examination are essential for the safe and effective treatment of men with ED. This article reviews the physiology and pharmacology of ED. Although effective therapies are available, including surgery, external devices, and subcutaneous penile injections, many find those modalities unacceptable. The oral agent sildenafil is now widely used but not without concern about specific health risks as well as lifestyle issues. This article also reports clinical trial results for new oral agents that will soon offer new options for men who cannot use or are dissatisfied with other therapies.

Administration, Oral↗
PubMed1999

Medical treatment of erectile dysfunction.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. Data from the Massachusetts Male Aging Study have indicated that the prevalence of erectile dysfunction of any degree is 39% in 40-year old men, and 67% in those aged 70 years. Effective therapy has been available for some time, but it has commonly involved surgery, external devices or penile self-injection. For many men, these represent unacceptable barriers to seeking therapy. Recently, however, an effective oral medication has become available. This article reviews the physiology and pharmacology of ED. The literature currently available on the effectiveness and safety of various drugs used for ED is summarized, with particular attention to newly available oral agents. Guidelines for work-up and drug treatment of patients with ED are given. Detailed history and physical examination are crucial to the safe and effective treatment of men with erectile impotence. An extensive review of the literature shows that based on safety, effectiveness and ease of use, oral sildenafil citrate is an excellent choice for first-line therapy. Patients who use organic nitrates of any kind in any capacity should not be offered sildenafil. Based solely on effectiveness intracavernosal injection therapy remains the golden standard and should also be offered as an option for first-line therapy for the appropriate patients. Many alternatives are available for men who cannot use sildenafil or injection therapy. A thorough knowledge of existing medications is essential for proper treatment of ED.

Adrenergic alpha-Antagonists↗
PubMed1999

The causes of patient dropout from penile self-injection therapy for impotence.

PURPOSE: Penile self-injection therapy, a second line treatment for erectile dysfunction, is the most efficacious means of reestablishing functional erections when first line therapies fail and the patient wants to avoid penile prosthesis implantation. Despite high efficacy rates, injection therapy has high dropout rates. To our knowledge studies to date analyzing patient attrition have reviewed small numbers of patients followed for only short periods. We elucidate the main reasons for patient dropout in a large penile self-injection program with long-term followup. MATERIALS AND METHODS: A questionnaire was mailed to 1,424 patients who completed the office training and home use phases of a penile self-injection program. RESULTS: The overall attrition rate was 31% of the 720 men who completed the questionnaire, with a mean followup of 38 months. The main reasons for dropout were cost of therapy, patient and partner problems with the concept of penile injection, lack of partner availability and spontaneous improvement in erections. Lack of efficacy of therapy was the primary reason for only 1 of 7 dropouts. Furthermore, adverse effects of penile injections (priapism, penile nodules, pain) appeared to be only minor contributors to dropout. CONCLUSIONS: To our knowledge this study is the largest published, single center cohort of patients treated with injection and followed for an analysis of dropout rates. Based on study data a reduction in dropout rates may be achieved by keeping the cost of therapy low, and ensuring patient and partner education as well as continued support throughout treatment.

Adult↗
PubMed1997

Intracavernosal forskolin: role in management of vasculogenic impotence resistant to standard 3-agent pharmacotherapy.

PURPOSE: We investigated forskolin, a direct adenylate cyclase activator, as an intracavernosal vasoactive agent in management of vasculogenic impotence. MATERIALS AND METHODS: Concentration responses for forskolin and prostaglandin E1 induced relaxation of phenylephrine precontracted strips of human corpus cavernosum smooth muscle were constructed in vitro. Cyclic adenosine monophosphate (cAMP) synthesis was determined with papaverine, phentolamine, prostaglandin E1 and forskolin in human corpus cavernosum smooth muscle cell cultures. Dose-dependent hemodynamic responses to intracavernosal forskolin (5 to 20 micrograms) were evaluated in a New Zealand White rabbit model. Safety and efficacy outcome data were obtained in vasculogenically impotent patients who signed informed consent and met strict inclusion and exclusion criteria that included having had standard self-injection therapies fail. RESULTS: In vitro forskolin and prostaglandin E1 alone caused concentration dependent relaxation with an EC50 of approximately 200 nm. and 16 nm., respectively. When the 2 agents were combined, the concentration response curve for relaxation shifted to the left. cAMP production was highest in cells treated with prostaglandin E1 and forskolin and was unaffected by papaverine or phentolamine. In 3 animals, equilibrium intracavernosal pressure and duration of erection had a dose dependent increase. Clinical investigation in 31 patients showed no adverse events with a mean of 14 +/- 4, range 11 to 18 months of followup. Overall 61% reported improvement in rigidity and/or erection duration using intracavernosal forskolin (98 micrograms./ml.), papaverine (29 mg./ml.), phentolamine (0.98 mg./ml.) and prostaglandin E1 (9.8 micrograms./ml.). CONCLUSIONS: Forskolin is a United States Food and Drug Administration nonapproved vasoactive agent that acts in synergism with prostaglandin E1 to induce smooth muscle relaxation. In combination with other vasoactive agents, forskolin has demonstrated preliminary safety and efficacy in patients with vasculogenic impotence resistant to standard 3-agent pharmacotherapy.

Alprostadil↗