|LE Magazine July 1998 |
Therapy for Erectile Dysfunction
Life Extension magazine republishes abstracts on health and longevity topics in each issue, drawn from research papers originally published in science and medical journals throughout the world.
Sildenafil [Viagra], a novel effective oral therapy for male erectile dysfunction
Patients and Methods:Twelve patients (aged 36-63 years) with male erectile dysfunction of no established organic cause were entered into a double-blind, randomized, placebo-controlled, crossover study which was conducted in two phases.
In the first phase (four-way crossover), treatment efficacy was evaluated by measurements of penile rigidity using penile plethysmography during visual sexual stimulation at different doses of sildenafil (10, 25 and 50 mg or placebo). In the second phase (two-way crossover), efficacy was assessed by a diary record of penile erectile activity after single daily doses of sildenafil (25 mg) or placebo for 7 days.
Results: The mean (95% confidence interval, CI) duration of rigidity of > 80% at the base of the penis was 1.3 mm (0.4-3.1) in patients on placebo, 3.5 mm (1.6-7.3; P = 0.009) on 10 mg, 8.0 mm (3.7-16.7; P = 0.003) on 25 mg and 11.2 mm (5.6-22.3; P < 0.001) on 50 mg of sildenafil. The mean (95% CI) duration of rigidity of > 80% at the tip of the penis was 1.2 mm (0.4-2.7) on placebo and 7.4 mm (2.4-8.5; P = 0.001) on 50 mg sildenafil. From the diary record of daily erectile activity, the mean (95% CI) total number of erections was significantly higher in patients receiving sildenafil: 6.1 (3.2-11.4), compared with 1.3 (0.5-2.7) in those on placebo; 10 of 12 patients reported improved erectile activity while receiving sildenafil, compared with two of 12 on placebo (P 0.018). Six patients on active treatment and five on placebo reported mild and transient adverse events which included headache, dyspepsia and pelvic musculo-skeletal pain.
Conclusion: These results show that sildenafil is a well tolerated and effective oral therapy for male erectile dysfunction with no established organic cause and may represent a new class of peripherally acting drug for the treatment of this condition.
Viagra and Erectile Dysfunction
Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.
Sildenafil (Viagra, UK-92,480) is a novel oral agent under development for the treatment of penile erectile dysfunction. Erection is dependent on nitric oxide and its second messenger, cyclic guanosine monophosphate (cGMP). However, the relative importance of phosphodiesterase (PDE) isozymes is not clear. We have identified both cGMP- and cyclic adenosine monophosphate-specific phosphodiesterases (PDEs) in human corpora cavernosa in vitro. The main PDE activity in this tissue was due to PDE5, with PDE2 and 3 also identified. Sildenafil is a selective inhibitor of PDE5 with a mean IC50 of 0.0039 microM. In human volunteers, we have shown sildenafil to have suitable pharmacokinetic and pharmacodynamic properties (rapid absorption, relatively short half-life, no significant effect on heart rate and blood pressure) for an oral agent to be taken, as required, prior to sexual activity. Moreover, in a clinical study of 12 patients with erectile dysfunction without an established organic cause, we have shown sildenafil to enhance the erectile response (duration and rigidity of erection) to visual sexual stimulation, thus highlighting the important role of PDE5 in human penile erection. Sildenafil holds promise as a new effective oral treatment for penile erectile dysfunction.
Nitric Oxide, Erectile Mechanism
Role of Nitric Oxide in The Erectile Mechanism
Nitric oxide has been identified as an Endothelium-Derived Relaxing Factor (EDRF). Non adrenergic-non cholinergic nerves synthesize and release nitric oxide, thus modulating the arterial tone. Nitric oxide synthase exists either as a constitutive enzyme in many cell types and as an inducible form expressed under immunological stimulation. Nitric oxide is also involved in the non adrenergic-non cholinergic neurotransmission that leads to smooth muscle relaxation in the corpus cavernosum. Similarly nitric oxide induces reduction of cytosolic free Ca++ as a result of activation of the soluble form of guanylyl cyclase. VIP and nitric oxide may function as co-transmitters. Relaxation of the corpus cavernosum is blocked by methylene blue which inhibits cyclic GMP synthesis; so, high flow priapism refractory to medical and surgical treatments can be managed successfully by intracavernous methylene blue. Moreover, it is suggested that enhanced alpha 1-adrenergic mediated constrictor tone and penile flaccidity in diabetic men may respond to exogenous generators of nitric oxide. We postulate that relaxation of the corpus cavernosum, started by nitric oxide in response to non adrenergic-non cholinergic neurotransmission, could be amplified and maintained by nitric oxide production as a result of platelet trapping in the corpus cavernosum during the first phase of the penile erection.
Sex, Vasodilator Responses
Sex differences in endothelial function in normal and hypercholesterolaemic subjects
Acetylcholine stimulates endothelial synthesis of nitric oxide from L-arginine. To investigate the influence of sex on endothelial function, we measured vasodilator responses to brachial artery administration of acetylcholine in hypercholesterolaemic and control men and women. Mean response to acetylcholine was impaired (55% of that in controls at 15 micrograms/minute) in hypercholesterolaemic men but not in hypercholesterolaemic women. L-arginine normalized responses to acetylcholine in hypercholesterolaemic men, but had similar effects in hypercholesterolaemic and control women. These results suggest that women are protected against adverse effects of hypercholesterolemia on the L-arginine/nitric-oxide pathway.
Nitric Oxide as Mediator
Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission.
Methods: We studied strips of corpus cavernosum tissue obtained from 21 men in whom penile prostheses were inserted because of impotence. The Smounted smooth-muscle specimens were pretreated with guanethidine and atropine and submaximally contracted with phenylephrine. We then studied the smooth-muscle relaxant responses to stimulation by an electrical field and to nitric oxide.
Conclusions: Findings support the hypothesis that nitric oxide is involved in the nonadrenergic, noncholinergic neurotransmission that leads to the smooth-muscle relaxation in the corpus cavernosum that permits penile erection. Defects in this pathway may cause some forms of impotence.