Pharmacologic treatment of erectile dysfunction

Penile erection occurs in response to cavernous smooth muscle relaxation, increased blood flow to the penis, and restriction of venous outflow. These events are regulated by a spinal reflex relying on visual, imaginative, and olfactory stimuli generated within the central nervous system (CNS) and on tactile stimuli to the penis. Drugs can have a facilitatory or inhibitory effect either on the nerves regulating this reflex or on the cavernous smooth muscle. A balance between contractile and relaxant factors governs flaccidity/rigidity within the penis. Drugs that raise cytosolic calcium either prevent or abort erection. Conversely, drugs that lower cytosolic calcium relax smooth muscle and can initiate penile erection. Efficacy in treating erectile dysfunction (ED) with phosphodiesterase inhibitors, especially type 5; alpha-adrenergic-receptor antagonists; and dopamine agonists exploit these mechanisms within the penis or CNS. Recent advances in our understanding of the pharmacology of penile erection are being translated into effective therapies for ED.     

Nonpharmacologic treatment of erectile dysfunction

Nonpharmacologic treatment for erectile dysfunction (ED) includes sex therapy, the use of vacuum erection devices, penile prosthesis implantation, and penile vascular surgery. Sex therapy is indicated for psychogenic ED and is at times a useful adjunct for other treatments in men with mixed psychogenic and organic ED. Vacuum erection devices produce usable erections in over 90% of patients; however, patient and partner acceptability is an issue. Three-piece inflatable penile prostheses create flaccidity and an erection that comes close to that which occurs naturally. Penile vascular surgery has shown greatest efficacy in young men with vasculogenic ED resulting from pelvic or perineal trauma.     

3-Thio-quinolinone maxi-K openers for the treatment of erectile dysfunction

A series of Maxi-K openers for the treatment of erectile dysfunction based on the 3-thio-quinolinone core is described. Significant levels of channel opening (up to 550% of control) are seen in transfected oocytes. Functional activity in rabbit corpus cavernosum tissue strips confirms the potential to effect therapy for ED, the effect being maximal for the 3-amino-2-hydroxy thiol side chain.     

SAR development of polycyclic guanine derivatives targeted to the discovery of a selective PDE5 inhibitor for treatment of erectile dysfunction

Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).     

Future strategies for treating erectile dysfunction

Erectile dysfunction affects over half of all men between 50 and 70 years of age, and by the age of 40, about 40% of men may suffer from some form of erectile dysfunction. Many disease states, such as diabetes, hypertension, depression, and vascular disease, are associated with the condition, which may occur many years prior to the onset of these disorders. The phenomenal success of sildenafil in improving erections in men with erectile dysfunction is due to the fact that the drug, as a phosphodiesterase inhibitor, improves the relaxation of smooth muscle cells, which become dysfunctional with the aging process. However, not everyone responds to this medication, mainly because the efficacy of the drug is directly dependent on the release of nitric oxide from the nerve terminals of the cavernosal nerve, and this may become defective with aging/certain disease states. The goal of gene therapy for organic impotence is to allow the patient to sustain physiologically elicited erections without resorting to pharmacological treatment immediately prior to the sexual act. Experimental efforts in gene therapy for erectile dysfunction are likely to continue intensively in a series of directions, some specific to the nature of the selected gene to be manipulated or the physiology of the corpora cavernosa itself, and others extrapolatable from the advancement of gene therapy in general.     

Novel thiophene derivatives for the treatment of benign prostatic hyperplasia

The syntheses and biological activities of a novel series of 2,4- and 2,5-disubstituted thiophenes are reported. These analogues have shown excellent affinity and selectivity against alpha(1)-adrenoreceptor subtypes.     

Hyperprolactinemia and erectile dysfunction

Hyperprolactinemia from a pituitary adenoma is a rare cause of erectile dysfunction. Men with erectile dysfunction who are found to have a low testosterone level should have a measurement of their prolactin level. Treatment consists of lowering the prolactin level by medication or surgery, or both. Bromocriptine, a dopamine agonist, is efficacious in lowering elevated prolactin levels and can simultaneously shrink these pituitary tumors. With large tumors, transphenoidal surgery may be used to debulk/remove the tumor. Post-treatment prolactin levels can be used to monitor the efficacy of treatment.     

Novel cinnamaldehyde-based aspirin derivatives for the treatment of colorectal cancer

Colorectal cancer (CRC) is a leading cause of mortality worldwide. Current treatments of CRC involve anti-cancer agents with relatively good efficacy but unselectively target both cancer and non-cancer cells. Thus, there is a need to discover and develop novel CRC therapeutics that have potent anti-cancer effects, but show reduced off-target cell effects. Here, a novel series of cinnamaldehyde-based aspirin derivatives were designed and synthesized. Biological evaluation indicated that the most active compound 1f exhibited more than 10-fold increase in the anti-proliferation efficacy in HCT-8 cells compared to the parent compounds. Its effects were similarly reproduced in another CRC cell line, DLD-1, but with 7- to 11-fold less inhibitory activity in non-tumorigenic colon cells. Flow cytometry analysis showed that 1f induced cell cycle arrest and apoptosis, which was further validated with immunoblot analysis of the relative protein levels of cleaved caspase 3 and PARP as well as the ROS production in CRC cells. More so, 1f significantly inhibited the growth of implanted CRC in vivo in mouse xenograft model. Taken together, our results show that cinnamaldehyde-based aspirin derivatives such as 1f show promise as novel anti-CRC agent for further pharmaceutical development.     

Evaluation of vitamin E in the treatment of erectile dysfunction in aged rats

AimsThe present study aims to elucidate the role of oxidative stress in erectile dysfunction associated with aging and to investigate the effect of treatment with vitamin E in this respect.Main methodsRats were divided into four groups: young (3-month-old), aged rats (18-month-old), aged rats given 80 IU of vitamin E/rat/day for 21-days, aged rats given 5 mg/kg of sildenafil/day for 21-days. Intracavernosal pressure/mean arterial pressure (ICP/MAP), nitric oxide production, TBARS, GSH levels and SOD activity in corpus cavernosum were measured.Key findingsSignificant decrease in ICP/MAP was observed in aged rats at both low and high frequency of stimulation. Significant increase in ICP/MAP was observed in aged rats treated with vitamin E over the range of 0.8 to 5 Hz but young control values were not restored. Percentage potentiation of ICP/MAP than aged group at 0.8 Hz was 326 ± 41.3% and 897 ± 72.2% for vitamin E and sildenafil respectively. Decreased levels of NO₂/NO₃ and SOD activity in the penile tissue observed with aging were elevated back to control by either vitamin E or sildenafil. Penile concentration of TBARS was 20.86 ± 0.83 for aged rats vs. 11.39 ± 0.79 nmol/g tissue for young controls. Both vitamin E and sildenafil reduced penile TBARS in aged rats.SignificanceThis study proves that antioxidant therapy with vitamin E ameliorates the age-associated erectile dysfunction. Sildenafil may exert some antioxidant properties which add to the advantages of its long-term use. The effect of combinations of low-dose sildenafil and vitamin E on age-associated erectile dysfunction merits to be studied.     

The role of prostaglandins in the aetiology and treatment of erectile dysfunction.

Both animal and human penile tissue synthesize prostaglandins (PGs). Furthermore, intracavernous injection of certain PGs elicits erection in men with erectile dysfunction (ED). It is also well established that PGs are involved in the pathophysiology of atherosclerosis and diabetes mellitus (DM). Since atherosclerosis and DM are major risk factors for ED, it has been suggested that the disruption of PG synthesis in penile tissues and related vasculature may play a role in the pathogenesis of ED. In this review, we discuss the role of PGs in normal penile erection as well as on the pathophysiology and treatment.     

Antiretroviral (HIV-1) activity of azulene derivatives

The antiretroviral activity of azulene derivatives was detected for the first time. A series of eighteen diversely substituted azulenes was synthesized and tested in vitro using HIV-1 based virus-like particles (VLPs) and infectious HIV-1 virus in U2OS and TZM-bl cell lines. Among the compounds tested, the 2-hydroxyazulenes demonstrated the most significant activity by inhibiting HIV-1 replication with IC₅₀ of 2–10 and 8–20 μM for the VLPs and the infectious virus, respectively. These results indicate that azulene derivatives may be potentially useful candidates for the development of antiretroviral agents.     

The effect of erectile dysfunction on quality of life following treatment for localized prostate cancer

All forms of prostate cancer therapy carry significant risk of erectile dysfunction, but patients value sexual function so highly that they are often willing to choose a therapy that offers a shorter life expectancy but better potency following treatment. Advances in research methodology now allow reliable collection of meaningful data regarding patients' health-related quality of life, including both objective evaluation of patients' functional status and their perceptions of their own health and its impact on their existence. In the past decade, several validated and reliable questionnaires have been developed that are specifically designed to measure HRQOL in men with prostate cancer. Studies using these instruments have found that function and perceived bother may not be correlated; patients may express satisfaction with their therapy despite loss of sexual function. Erectile aids, including sildenafil, can be helpful for patients following treatment for localized prostate cancer.     

Oral and non-oral combination therapy for erectile dysfunction

An estimated 30 million men in the United States suffer from varying degrees of erectile dysfunction. Increasing age and comorbidities are likely to increase the number of men who are initially refractory or become refractory to phosphodiesterase (PDE)-5 inhibitors, the most popular oral therapy. Combination therapy, a concept well proved in other areas of medicine, is therefore of increasing importance. Combination oral and non-oral (intracavernosal injection and intraurethral application) therapies have been shown to salvage monotherapy. The early introduction of combination therapy has been shown to expedite both the return of natural function and PDE-5 inhibitor responsiveness in post-prostatectomy patients with no reports of serious adverse events. Larger controlled studies are needed to corroborate those encouraging findings.     

Biweekly intracavernous administration of papaverine for erectile dysfunction.

To determine the efficacy of the intracavernous administration of papaverine hydrochloride every 2 weeks to treat male impotence, we recruited 50 patients from a sexual dysfunction clinic. Of these, 8 did not complete the course of papaverine therapy. A total of 8 had complications, including priapism in 3 and ecchymoses or urethral bleeding in 5. In 30 patients who had substantial vasculogenic disease, there was a notable improvement in the penile blood pressure after papaverine treatment, although only 9 reported successful sexual intercourse. The penile blood pressure in the remaining 12 patients without substantial vascular disease increased modestly after therapy, and 5 persons reported satisfactory sexual activity. We conclude that administering papaverine intracavernosally every 2 weeks improves sexual potency in a subset of sexually impotent patients. Those with severe vasculogenic disease and a penile-brachial pressure index of less than 0.65 are not good candidates for this regimen.     

Postprostatectomy erectile dysfunction: the role of penile rehabilitation

Radical prostatectomy has become the gold standard for the treatment of prostate cancer in patients who have a longer than 10-year life expectancy. Surgical treatment has led to severe quality-of-life issues in these patients, especially urinary incontinence and erectile dysfunction (ED). This article reviews the etiology and pathophysiology of postprostatectomy ED, and current management strategies for these patients.