Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction

Soluble guanylate cyclase (sGC) is an important enzyme in corpus cavernosum smooth muscle cells as it is one of the regulators of the synthesis of cGMP. The efficacy of sildenafil (Viagra) in the treatment of male erectile dysfunction indicates the importance of the cGMP system in the erectile response as the increased levels of cGMP induce relaxation of the corpus cavernosum. sGC is physiologically activated by nitric oxide (NO) during sexual stimulation, and its activity can be pharmacologically enhanced by several NO-donors. Agents like YC-1 can also activate sGC after binding to a novel allosteric site in the enzyme, a site different from the NO binding site. YC-1 can relax rabbit cavernosal tissue and it facilitates penile erection in vivo. This review summarizes the enzymology, biochemistry and pharmacology of this novel allosteric site and its relevance for the regulation of penile function. This type of sGC activators represent a new class of compounds with a different pharmacological profile in comparison to the classical NO-donors and they could be beneficial for the treatment of male erectile dysfunction.     

Rationale for combination therapy of intraurethral prostaglandin E(1) and sildenafil in the salvage of erectile dysfunction patients desiring noninvasive therapy

Corpus cavernosum smooth muscle relaxation and hence penile erection are regulated in part by increases in smooth muscle synthesis of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The object of this study was to determine 30-month follow-up results in motivated patients desiring noninvasive medical therapy using sildenafil citrate (Viagra) in combination with intraurethral prostaglandin E(1) (PGE(1)) (Medicated Urethral System for Erection [MUSE]). Twenty-eight patients (mean +/- s.d. age, 59 +/-7.3 y; 17 who had undergone radical prostatectomy and 11 who had a diagnosis of organic erectile dysfunction) were included in this study. Detailed history taking and physical examinations were performed and vascular risk factors noted. In these patients, treatment with either 100 mg of sildenafil citrate and/or 1000 microg of MUSE had failed. None of these patients desired intracavernosal injection. Duplex Doppler ultrasonography after redosing was carried out on all patients. Dynamic infusion corpus cavernosography/cavernosometry was obtained in 17 of 28 patients, and combination therapy was initiated using 100 mg of sildenafil citrate orally 60 min before intercourse and 500 microg of MUSE intraurethrally immediately before intercourse. Independently, either 100 mg of sildenafil citrate or 1000 microg of MUSE was not efficacious in inducing an erection sufficient for vaginal penetration in any of the 28 patients. After initiating a combination therapy, at 30 months, all 28 patients were reporting erections sufficient for vaginal penetration, with 3.6 intercourse episodes per month. None of the patients crossed over to intracavernosal therapy or penile prosthesis. During therapy, eight of 28 patients reduced the dose of sildenafil citrate to 50 mg. Combination therapy with MUSE and sildenafil may be more efficacious in the salvage of patients who desire noninvasive therapy but in whom single-treatment modalities fail. Although both cAMP- and cGMP-mediated vasodilation can lead to penile erection, combining therapies that incorporate both pathways may succeed when single therapies fail.     

Biochemical and physiological mechanisms of female genital sexual arousal

Limited studies are available concerning physiological and biochemical mechanisms involved in female sexual function and dysfunction. The paucity of physiological and biochemical data pertaining to genital sexual arousal function is attributed, in part, to lack of reliable experimental models and tools for the investigation of female sexual arousal. This review summarizes research efforts from a number of laboratories in which several experimental models have been established. These include the development of in vivo animal models, organ bath studies, and the establishment of cell cultures. The availability of such experimental model systems have facilitated efforts aimed at defining the neurotransmitters responsible for vaginal smooth muscle relaxation, the role of sex steroid hormones and their receptors in modulating genital hemodynamics, smooth muscle contractility, and neurotransmitter receptor expression. A comprehensive and integral understanding of female sexual function requires detailed investigation of the vascular, neurological (central and peripheral), and structural components of this complex physiological process.     

Pathophysiology of erectile dysfunction: the contributions of trabecular structure to function and the role of functional antagonism

Erectile dysfunction (ED) is estimated to impact more than 150 million men this year worldwide. An understanding of the pathophysiology of ED both furthers the basic scientific knowledge of disease processes and provides a rational design of pharmacotherapy. At present, there are two major views regarding the pathophysiology of ED. In the first hypothesis, the oxygen tension-dependent changes in the penis during erection are proposed to impact corpus cavernosum structure by inducing various cytokines, vasoactive factors and growth factors at the two different oxygen tensions (flaccidity and erection) which, in turn, alter smooth muscle metabolism and connective tissue synthesis. Decreases in the corpus cavernosum smooth muscle/connective tissue ratio have been correlated with an increased likelihood of diffuse venous leak and a failure of the veno-occlusive mechanism in prospective patient studies. Evidence for such a hypothesis incorporates nocturnal penile tumescence and circadian changes in oxygenation as important in maintaining erectile health. The alternate hypothesis proposes that ED is the result of a metabolic imbalance between relaxatory and contractile processes within the trabecular smooth muscle such that contractile processes predominate. Based on this hypothesis, therapy can be accomplished via drugs which shift this balance towards vasodilatation, or by gene therapy approaches to supplement the deficient components favoring smooth muscle relaxation. Both of these hypotheses predict a management strategy for ED that impacts pharmacotherapeutics. In this review of the pathophysiology of ED, each hypothesis will be examined and a synthesis devised incorporating both views. The future of research in this area as well as pharmacotherapy in ED in terms of pathophysiology is discussed including the merits and drawbacks of prophylaxis and prevention of ED. International Journal of Impotence Research (2000) 12, Suppl 4, S39-S46.     

Naloxone pharmacokinetics in the newborn.

1 Plasma naloxone levels were determined by RIA over a period of 6--36 h in three groups of neonates, (1) those given 35 microgram i.v. (n = 6), (2) those given 70 microgram i.v. (n = 6) and (3) those given 200 microgram i.m. (n = 17) naloxone HCl within 1 min of birth. 2 After intravenous administration of 35 and 70 microgram of naloxone peak levels of 4--15 ng/ml and 9--20 ng/ml respectively were reached in 5--40 min and the mean plasma half-life after both doses was 3.1 +/- 0.5 h. 3 Peak levels of 7--35 ng/ml were reached 0.5 to 2 h after intramuscular administration of 200 microgram. The fall in concentration after this was consistently biphasic with the levels declining rapidly between one and four hours and then slowly from four hours onwards. 4 Plasma levels at 24--36 h after i.m. administration were as high as they were 4 h after i.v. administration of 35 microgram and this may account for the prolonged duration of action when this route is used.     

Gallium-67 lung uptake: conjugate-view technique

A conjugate-view technique is derived for calculation of absolute gallium-67 (Ga-67) uptake from scintillation-camera images. The technique combines counts of posterior and anterior images of the lung with an attenuation correction obtained from cobalt-57 (Co-57) transmission imaging. The formulation is such that the effects of Compton scatter build-up are accounted for. Studies utilizing a canine model indicated that, normally, more activity is located in the chest wall than in the lungs. The quantitative technique must therefore accurately account for a variety of Ga-67 distributions, including that in the chest wall. Calculations were performed using a three-component model comparing results obtained with the conjugate-view approach to the actual uptake. These calculations suggest that an assumption of uniform activity distribution allows an accuracy of approximately +/- 10% over a broad range of body-part thicknesses and uptake by the lungs. It was concluded that the conjugate-view technique is necessarily approximate but can provide clinically useful results.     

Studies on a ketone reductase in human and rat liver and kidney soluble fraction using warfarin as a substrate.

The enantiomers of warfarin were reduced to warfarin alcohols on incubation with human and rat liver and kidney cytosol. The metabolism was NADPH-dependent with NADH being only one tenth as effective at supporting the reduction. R-warfarin was reduced at a greater rate than S-warfarin by each of the tissues examined. At a concentration of 2·08 mM the rate of S-warfarin reduction ranged from 5 to 50% of the rate occurring with R-warfarin in the same tissue fraction. R-warfarin (1·3 mM) was mainly reduced to warfarin alcohol 1 (RS) (77%) the remainder being warfarin alcohol 2 (RR). S-warfarin formed slightly more warfarin alcohol 2 (SS) (57%) than warfarin alcohol 1 (SR). The apparent K_m values for the reduction of R-warfarin by human and rat liver and kidney cytosol ranged from 0·54 to 1·55 mM. The human liver reductase, even 3·5–8·5 hr after death, was significantly more active (2 times) than the rat liver reductase. Stability studies using rat liver indicated that about half of the reductase activity activity may be lost during the first 6 hr after death. This would suggest that human liver had more than four times the warfarin reductase activity of rat liver.