Jeremy P. W. Heaton

Recovery of erectile function by the oral administration of apomorphine

OBJECTIVES Apomorphine has been reported to be effective in causing erections in animals and man when administered parenterally. The side effects, notably nausea, have seriously limited its clinical usefulness. We formulated apomorphine for controlled sublingual absorption and herein report on four preliminary studies evaluating efficacy and side effects in men with no documentable organic cause of erectile dysfunction. METHODS Patients complaining of erectile dysfunction underwent a careful evaluation. Those with measurable organic dysfunction or known organic factors were excluded. Men with primarily psychogenic impotence were tested with one of four protocols of an apomorphine preparation (preliminary sublingual liquid, preliminary 5 mg tablet, aqueous nasal spray, and new 3 and 4 mg controlled absorption tablets). The erectile response of these men to the drug with visual erotic or sexually neutral stimulation was studied with the Rigiscan. RESULTS Seven of 10 evaluable patients responded to the sublingual liquid preparation but the majority experienced significant nausea. The preliminary 5 mg tablet and aqueous forms did not produce useful responses free of side effects. The newly formulated controlled absorption 3 and 4 mg tablets were tested in 12 men. Eight of 12 (67%) developed erections in response to apomorphine. Erectile activity was seen during sexually neutral visual stimulation to a significantly greater extent than with placebo. Home trial use was found to be successful and sustained by 7 of 11 (64%) patients. CONCLUSIONS We have shown that apomorphine will act as an erectogenic agent when absorbed through the oral mucosa. In a carefully selected group of impotent patients with no documentable organic causes of erectile dysfunction, but with proven erectile potential, 67% will experience significantly durable erections with a dose of 3 or 4 mg of apomorphine when formulated for controlled absorption. The results in these small groups appear to justify larger clinical studies of this proprietary formulation.

Testosterone Supplementation for Hypogonadal Impotence: Assessment of Biochemical Measures and Therapeutic Outcomes

PURPOSE Although hypogonadism is a rare cause of erectile failure, impotent men are frequently treated with supplemental androgens. The results of such treatment and the individual merits of available formulations remain controversial. A series of hypogonadal men participated in a trial of oral testosterone undecanoate to assess the effectiveness of the medication, and use of biochemical and clinical outcome measures. MATERIALS AND METHODS A consecutive sample of 23 hypogonadal impotent men received testosterone undecanoate orally for no less than 60 days. Serum levels of gonadotropins, testosterone, estrogens and sex hormone-binding globulin were measured before, during and after the trial. Sexual response and feeling of well-being were measured by daily diaries and visual analogue scales. RESULTS Testosterone undecanoate produced restoration of plasma testosterone levels in all patients but a measurable improvement in sexual attitudes and performance in only 61%. Visual analogue scores were effective discriminants of the therapeutic response but none of the conventional biochemical measures predicted or correlated with clinical outcome. CONCLUSIONS Testosterone undecanoate is an effective agent for treating hypogonadism. In hypogonadal impotent patients the most appropriate outcome measure for androgen supplementation is individual response to therapy, while conventional biochemical hormone determinations lack predictive value and fail to correlate with response.

Central neuropharmacological agents and mechanisms in erectile dysfunction: the role of dopamine

Central nervous system processes are fundamental to sexual function. Considerable progress has been made in our understanding of the neuroanatomical and neuropharmacological bases for erection. Based largely on rat models, there is adequate understanding presently of the general anatomical areas of the brain that relate to sexual function, including the medial amygdala, medial preoptic area, paraventricular nucleus, the periaqueductal gray, ventral tegmentum and others. There is also a burgeoning body of evidence implicating nitric oxide, dopamine, serotonin and oxytocin as critical central neurotransmitters involved in various aspects of sexual function. The role of dopamine, in particular, appears fundamental in the mediation of erectile responses in both animals and man. Additionally, clinical research with apomorphine, a D1/D2 agonist, has shown significant promise in improving erections in men with a wide range of erectile difficulties. Finally, a new classification matrix has been proposed for existing treatments for erectile dysfunction based upon the putative site and mechanism of action. Implications for the further development of neuropharmacological agents in this area are discussed.

The Characterization of a Bio-Assay of Erectile Function in a Rat Model

The investigation of biological phenomena in impotence using an animal system requires a determination of the erectile capabilities of the animal. Rats respond reliably to apomorphine by the exhibition of a phenomenon of erections and yawns. This property has been used to form the basis of a bio-assay of erectile integrity in the rat. We compared rats treated with placebo alone, sham operated rats, rats rendered surgically impotent and castrated rats with and without testosterone. Rats did not respond to placebo. The sham operated rats remained normal in all measured respects (2.66 erections/rat/30 minutes). Surgically impotent rats yawned normally but had no erections. Castrated rats did not have erections and had diminished yawning (3.21 yawns/rat/30 minutes vs. 7.7 for controls p less than .001) but responded normally after testosterone administration. The bio-assay is useful as a standard test of erectile function in the rat.

Oxygen-mediated Regulation of Tumor Cell Invasiveness INVOLVEMENT OF A NITRIC OXIDE SIGNALING PATHWAY

Tumor hypoxia is associated with a poor prognosis for patients with various cancers, often resulting in an increase in metastasis. Moreover, exposure to hypoxia increases the ability of breast carcinoma cells to invade the extracellular matrix, an important aspect of metastasis. Here, we demonstrate that the hypoxic up-regulation of invasiveness is linked to reduced nitric oxide signaling. Incubation of human breast carcinoma cells in 0.5% versus 20% oxygen increased their in vitro invasiveness and their expression of the urokinase receptor, an invasion-associated molecule. These effects of hypoxia were inhibited by nitric oxide-mimetic drugs; and in a manner similar to hypoxia, pharmacological inhibition of nitric oxide synthesis increased urokinase receptor expression. The nitric oxide signaling pathway involves activation of soluble guanylyl cyclase (sGC) and the subsequent activation of protein kinase G (PKG). Culture of tumor cells under hypoxic conditions (0.5% versus 20% oxygen) resulted in lower cGMP levels, an effect that could be prevented by incubation with glyceryl trinitrate. Inhibition of sGC activity with a selective blocker or with the heme biosynthesis inhibitor desferrioxamine increased urokinase receptor expression. These compounds also prevented the glyceryl trinitrate-mediated suppression of urokinase receptor expression in cells incubated under hypoxic conditions. In contrast, direct activation of PKG using 8-bromo-cGMP prevented the hypoxia- and desferrioxamine-induced increases in urokinase receptor expression as well as the hypoxia-mediated enhanced invasiveness. Further involvement of PKG in the regulation of invasion-associated phenotypes was established using a selective PKG inhibitor, which alone increased urokinase receptor expression. These findings reveal that an important mechanism by which hypoxia increases tumor cell invasiveness (and possibly metastasis) requires inhibition of the nitric oxide signaling pathway involving sGC and PKG activation.

Bacterial Biofilm in Persistent Penile Prosthesis-Associated Infection

The ultrastructural microbiology of 2 cases of infection associated with rigid penile prostheses was studied. The persistence of these infections appeared to be related to the mode of growth of the bacteria in protected biofilms adherent to the inert surface of the prosthesis.

Dietary patterns and risk of prostate cancer in Ontario, Canada

Dietary patterns reflect combinations of dietary exposures, and here we examine these in relation to prostate cancer risk. In a case‐control study, 80 incident primary prostate cancer cases and 334 urology clinic controls were enrolled from 1997 through 1999 in Kingston, Ontario, Canada. Food‐frequency questionnaires were completed prior to diagnosis and assessed intake in the 1‐year period 2–3 years prior to enrollment. Among controls, dietary intake was used in principal components analyses to identify patterns that were then evaluated with all subjects in relation to prostate cancer risk using unconditional logistic regression, controlling for age. Four dietary patterns were identified: Healthy Living, Traditional Western, Processed and Beverages. Increased prostate cancer risk is apparent in relation to the Processed pattern, composed of processed meats, red meats, organ meats, refined grains, white bread, onions and tomatoes, vegetable oil and juice, soft drinks and bottled water. The OR for the highest tertile compared to baseline is 2.75 (95% CI 1.40–5.39), with a dose–response pattern (trend test p < 0.0035). Our results suggest that a dietary pattern including refined grain products, processed meats and red and organ meats contributes to increased prostate cancer risk. Since dietary information was collected before subjects knew their diagnosis, recall bias was avoided.

Effects of castration and exogenous testosterone supplementation in an animal model of penile erection.

The dependence of erectile behavior on androgen functioning is well established. Castration produces loss of both libido and potency in man and animals. The present study, using an animal model for potency, demonstrates the dependence of centrally induced erectile behavior on an intact androgen milieu. Castrated rats failed to produce an erection in response to apomorphine, an agent shown to produce erection in nearly all normal rats. Administration of exogenous testosterone propionate in dosages exceeding 60 micrograms./kg. produced a significant increase in erectile behavior. Yawning, an essentially parallel phenomenon to the stimulation of the erectile response, was also decreased following castration and responded similarly to increasing amounts of exogenous testosterone, demonstrating the influence of androgen functioning on the central nervous system. It was concluded that testosterone is a necessary prerequisite for the maintenance of a centrally induced erectile and yawning response. In an animal model of penile erection, testosterone increases the number of erections in a dose-dependent manner in castrated rats. The dependence of the erectile response on testosterone is, at least in part, centrally mediated.

Phase II study of nitric oxide donor for men with increasing prostate-specific antigen level after surgery or radiotherapy for prostate cancer.

OBJECTIVES To evaluate the effect of low-dose glyceryl trinitrate (GTN) on men with biochemical recurrence of prostate cancer after primary therapy. Preclinical, proof-of-principle studies have demonstrated that nitric oxide signaling plays a significant role in the hypoxia-induced progression of prostate cancer. METHODS A prospective, open-label clinical trial of men with an increasing prostate-specific antigen (PSA) level after surgery or radiotherapy was conducted. Men with PSA recurrence were enrolled in a 24-month trial investigating the effect of a low-dose, slow-release transdermal GTN patch. The PSA doubling time (PSADT) was compared before and after treatment initiation, as well as with a matched control group that received no immediate treatment for their PSA recurrence. RESULTS A total of 29 patients were enrolled in the study. Of the 29 patients, 62% completed the 24-month protocol, with 10% experiencing clinical disease progression. The calculated PSADT of the treatment group before initiating GTN was 13.3 months, not significantly different from that of the matched control group at 12.8 months. In an intention-to-treat analysis, the end-of-study PSADT for the treatment group was significantly different at 31.8 months (P < .001). CONCLUSIONS We report the first clinical trial of a GTN patch in patients with prostate cancer. The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study.

Predictive validity of five comorbidity indices in prostate carcinoma patients treated with curative intent.

Comorbidity is important to consider in clinical research on curative prostate carcinoma because of the role of competing risks. Five chart‐based comorbidity indices were assessed for their ability to predict survival.