vardenafil-dihydrochloride and Priapism

Highly selective inhibitors of phosphodiesterase type 5 (PDE5I) have been commercially available for over a decade. Our knowledge of these drugs continues to expand.. To review developments within the past 18 months on the utilization of PDE5I in preclinical studies and clinical practice. The focus of this article is on updates on regular dosing regimens of PDE5I other than the newly approved daily dose tadalafil.. PubMed search utilizing the terms "phosphodiesterase type 5 inhibitor," PDE5 inhibitor,""sildenafil,""vardenafil," and "tadalafil." Articles were screened based on whether or not they addressed issues of routine dosing of PDE5I. Manuscripts on the newly approved daily dose tadalafil for erectile dysfunction (ED) were deferred for analysis in a separate manuscript in this series.. Peer reviewed publications on routine dosing of PDE5I published in the medical literature since 2007.. There have been numerous publications in the past 2 years regarding routine dosing of PDE5I for three major urological indications; penile rehabilitation, stuttering priapism, and management of lower urinary tract symptoms (LUTS). Evidence from basic science investigations has indicated that daily dose PDE5I may improve erectile function and exert a number of beneficial tissue effects on the penis. Unfortunately, data from human series of routine dose PDE5I for penile rehabilitation after radical prostatectomy are conflicting, with the two largest studies showing no benefit to daily dose therapy in the post-radical prostatectomy and the general ED populations. PDE5I are generally helpful at reducing symptoms of LUTS, particularly when given in conjunction with alpha blockers. Routine dosing of PDE5I has also been utilized successfully for management of stuttering ischemic priapism and several other medical indications.. PDE5I given as routine doses have clinical promise. Further research is required to clarify their safety and efficacy for various indications.

Topics: Humans; Imidazoles; Impotence, Vasculogenic; Male; Penis; Phosphodiesterase Inhibitors; Piperazines; Priapism; Prostatectomy; Purines; Secondary Prevention; Sildenafil Citrate; Sulfones; Triazines; Urologic Diseases; Vardenafil Dihydrochloride; Vasodilator Agents

Despite their efficacy and general safety, rare but devastating adverse drug reactions have been associated with phosphodiesterase type 5 inhibitors.. To determine the safety profile of oral phosphodiesterase type 5 inhibitors with a particular focus on priapism and malignant melanoma.. In this case-non-case study, we queried the individual case safety reports for phosphodiesterase type 5 inhibitors within the World Health Organization global database of individual case safety reports (VigiBase) between 1983 and 2021. We included all individual case safety reports for sildenafil, tadalafil, vardenafil, and avanafil in men. For comparison, we also extracted the safety data from the Food and Drug Administration trials for these drugs. We assessed the safety profile of phosphodiesterase type 5 inhibitors by disproportionality analysis by measuring reporting odds ratio for their most commonly reported adverse drug reactions, once for all phosphodiesterase type 5 inhibitor reports and once for reports of oral phosphodiesterase type 5 inhibitor use in adult men (≥18 years old) with sexual dysfunction.. A total of 94,713 individual case safety reports for phosphodiesterase type 5 inhibitors were extracted. A total of 31,827 individual case safety reports were identified relating to adult men taking oral sildenafil, tadalafil, vardenafil, or avanafil for sexual dysfunction. The most common adverse drug reactions included poor drug efficacy (42.5%), headache (10.4% vs. 8.5%-27.6% [Food and Drug Administration]), abnormal vision (8.4% vs. ≤4.6% [Food and Drug Administration]), flushing (5.2% vs. 5.1%-16.5% [Food and Drug Administration]), and dyspepsia (4.2% vs. 3.4%-11.1% [Food and Drug Administration]). Priapism showed significant signals for sildenafil (reporting odds ratio = 13.81, 95% confidence interval: 11.75-16.24), tadalafil (reporting odds ratio = 14.54, 95% confidence interval: 11.56-18.06), and vardenafil (reporting odds ratio = 14.12, 95% confidence interval: 8.36-22.35). Comparing with other medications in VigiBase, sildenafil (reporting odds ratio = 8.73, 95% confidence interval: 7.63-9.99) and tadalafil (reporting odds ratio = 4.25, 95% confidence interval: 3.19-5.55) had significantly higher reporting odds ratios for malignant melanoma.. Phosphodiesterase type 5 inhibitors show significant signals correlating with priapism among a large international cohort. Further clinical study is needed to elucidate whether this is from proper or inappropriate use or other confounding conditions, as analysis of pharmacovigilance data does not allow for quantifying the clinical risk. Also, there appears to be a relationship between phosphodiesterase type 5 inhibitor use and malignant melanoma, which warrants additional study to better understand causation.

Topics: Adolescent; Adult; Erectile Dysfunction; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Pharmacovigilance; Phosphodiesterase 5 Inhibitors; Priapism; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride; World Health Organization

Nitrergic neurons are important for erectile responses in the corpus cavernosum and impaired signalling results in erectile dysfunction, today treated successfully by oral administration of the selective phosphodiesterase 5 (PDE 5) inhibitors sildenafil, tadalafil and vardenafil. Although the importance of nitrergic neurons in urogenital function has become evident, it has not been investigated if the PDE 5 inhibitors affect the nerve-induced release of nitric oxide (NO). In a previous study we found that the soluble guanylate cyclase (sGC)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway might modulate nerve-induced release of NO in isolated cavernous tissue.. Electrical field stimulation (EFS 5 Hz, 40 V, 0.3 ms pulse duration, 25 pulses at intervals of 2 min) of rabbit isolated cavernous tissue elicited reproducible, nerve-mediated relaxations in the presence of scopolamine (10(-5) M), guanethidine (10(-5) M) and phenylephrine (3 x 10(-6) M). In superfusion experiments, nerve stimulation (20 Hz, 40 V, 1 ms) of the cavernous tissue evoked release of NO/NO2-, measured by chemiluminescence.. Sildenafil, tadalafil and vardenafil decreased the muscular tone and prolonged the relaxations to nerve stimulation. The evoked release of NO decreased to 72+/-11%, 55+/-16% and 61+/-14% of control, respectively after addition of sildenafil, tadalafil or vardenafil (all 10(-4) M, n=6-8, p<0.05).. Selective PDE 5 inhibitors influence the nerve-induced release of NO, probably via cGMP-mediated negative feedback. This negative feedback might explain why priapism is not seen during monotherapy with the PDE inhibitors.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Imidazoles; In Vitro Techniques; Male; Muscle, Smooth; Nitrergic Neurons; Nitric Oxide; Penis; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Rabbits; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride