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The Journal of Sexual Medicine Dec 2023Phosphodiesterase type 5 (PDE5) inhibitor labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism...
BACKGROUND
Phosphodiesterase type 5 (PDE5) inhibitor labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism occurring.
AIM
We explored the risk of priapism and prolonged erections in men in our post-radical prostatectomy (RP) penile injection program who were using regular PDE5 inhibitor and intracavernosal injections (ICIs) as part of their rehabilitation program.
METHODS
The study cohort included men on penile injection therapy who (1) were taking tadalafil 5 mg daily or taking sildenafil 25 mg on noninjection days, (2) had an RP, (3) were using their respective PDE5 inhibitor regularly at the time of penile injection training, and (4) complied with the program instructions regarding penile injection use. Demographics, comorbidity details, PDE5 inhibitor dose and utilization, and injection dose and utilization data were collected. All patients underwent in-office injection training and used trimix (papaverine/phentolamine/prostaglandin E1) as the intracavernosal medication.
OUTCOMES
Priapism was defined as a patient self-reported penetration hardness erection ≥4 hours in duration, while prolonged erection was defined as a penetration hardness erection lasting ≥2 hours.
RESULTS
A total of 112 tadalafil users and 364 sildenafil users were compared. Mean age and duration post-RP were 62 ± 14 years and 5.2 ± 12 months, respectively, and there was no difference between tadalafil and sildenafil groups. The mean trimix dose was tadalafil 24 ± 24 units and sildenafil 31 ± 37 units (P < .05). Priapism occurred in 2 (1.7%) of 112 tadalafil users and 5 (1.4%) of 364 sildenafil users (P = .47). Excluding those men experiencing priapism on any occasion, those with any reported penetration hardness erection lasting ≥2 hours were 7 (6.3%) of 112 tadalafil users and 12 (3.3%) of 364 sildenafil users (P < .01). A total of 53% of these prolonged erections occurred within the first 6 injections at home (no difference between tadalafil and sildenafil groups).
CLINICAL IMPLICATIONS
We emphasize the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events in ICI and PDE5 inhibitor combination therapy.
STRENGTHS & LIMITATIONS
This study has a relatively large patient population with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. However, there are some limitations, such as social desirability, confounding factors, and recall bias.
CONCLUSION
There is no significant difference in the incidence of priapism in an ICI program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase.
Topics: Male; Humans; Middle Aged; Aged; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil; Erectile Dysfunction; Priapism; Reproducibility of Results; Piperazines; Purines; Penile Erection; Prostatectomy
PubMed: 37973393
DOI: 10.1093/jsxmed/qdad144 -
Journal of Biomolecular Structure &... Nov 2023The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A...
The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A emerges as a relevant pharmacological drug target for neurological conditions such as psychosis, schizophrenia, Parkinson's, Huntington's disease, and other memory-related disorders. In the current study, we subjected a set of 1,2,3-triazoles to be explored as PDE10A inhibitors using diverse computational approaches, including molecular docking, classical molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, steered MD, and umbrella sampling simulations. Molecular docking of cocrystallized ligands papaverine and PFJ, along with a set of in-house synthesized molecules, suggested that molecule 3i haded the highest binding affinity, followed by 3h and 3j. Furthermore, the structural stability studies using MD and MM-PBSA indicated that the 3h and 3j formed stable complexes with PDE10A. The binding free energy of -240.642 kJ/mol and -201.406 kJ/mol was observed for 3h and 3j, respectively. However, the cocrystallized ligands papaverine and PFJ exhibited comparitively higher binding free energy values of -202.030 kJ/mol and -138.764 kJ/mol, respectively. Additionally, steered MD and umbrella sampling simulations provided conclusive evidence that the molecules 3h and 3j could be exploited as promising candidates to target PDE10A.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Phosphodiesterase Inhibitors; Papaverine; Phosphoric Diester Hydrolases; Molecular Docking Simulation; Nervous System Diseases; Molecular Dynamics Simulation
PubMed: 36336960
DOI: 10.1080/07391102.2022.2141895 -
The Journal of Sexual Medicine May 2024Intracavernosal injection therapy (ICI) is a well-established therapeutic strategy for men with erectile dysfunction. Complications are often related to patient error...
BACKGROUND
Intracavernosal injection therapy (ICI) is a well-established therapeutic strategy for men with erectile dysfunction. Complications are often related to patient error when performong ICI.
AIM
The objective of this study was to examine patient errors in an established patient training program for performing ICI and identify factors that could predict major errors.
METHODS
Patients enrolled in our ICI program are trained on technical aspects, and dose titration is begun. Patients are given explicit instructions during training, both verbally and in written form. Records were reviewed for men using ICI for ≥6 months. Multivariable analysis was used to define predictors of major errors.
OUTCOMES
Errors were listed as minor (zero-response injection, penile bruising, expired medication) and major (errors potentially leading to priapism: dose self-titration, double injecting).
RESULTS
Overall, 1368 patients met the inclusion criteria and were included in the analysis. The mean patient age was 66 ± 22 (range 29-91) years. Regarding education, 41% of patients had graduate-level education, 48% had college education, and 11% high school education. Mean follow-up was 3.2 ± 7.6 (range 0.5-12) years. The agents used were trimix (62%), bimix (35%), papaverine (2%), and prostaglandin E1 monotherapy (1%). At least 1 error occurred during self-administration in 42% of patients during their time in the program. Errors included zero response to medication due to technical error (8% of patients), penile bruising (34%), use of an expired bottle (18%), self-titration (5%), and double injecting (4% of patients); 12% of men committed ≥1 error during their time in the program. On multivariable analysis, independent predictors of the occurrence of a major error included: young age, graduate-level education, and <12 months of injection use.
CLINICAL IMPLICATIONS
To the best of our knowledge, this is the first reported study to investigate ICI errors and risk factors. The identification of factors predictive of major errors allows for more tailored and intensive training in this subset of patients.
STRENGTHS AND LIMITATIONS
Strengths of this study include a large patient population (1386 men) with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions, enhances the accuracy and reliability of the results. Despite the strengths of the study, recall bias may be a limitation concern.
CONCLUSION
The majority of patients were error free, and the majority of the errors were minor in nature. Major errors occurred in <10% of patients. Younger age, graduate-level education, and less experience with ICI were independent predictors of major errors.
Topics: Humans; Male; Adult; Middle Aged; Aged; Erectile Dysfunction; Aged, 80 and over; Injections; Patient Education as Topic; Vasodilator Agents; Medication Errors; Papaverine; Penis; Medical Errors; Priapism
PubMed: 38660738
DOI: 10.1093/jsxmed/qdae031 -
International Journal of Microbiology 2023Breast cancer is a lethal disease in females worldwide and needs effective treatment. Targeting cancer cells with selective and safe treatment seems like the best...
Breast cancer is a lethal disease in females worldwide and needs effective treatment. Targeting cancer cells with selective and safe treatment seems like the best choice, as most chemotherapeutic drugs act unselectively. Papaverine showed promising antitumor activity with a high safety profile and increased blood flow through vasodilation. At the same time, it was widely noticed that virotherapy using the Newcastle disease virus proved to be safe and selective against a broad range of cancer cells. Furthermore, combination therapy is favorable, as it attacks cancer cells with multiple mechanisms and enhances virus entrance into the tumor mass, overcoming cancer cells' resistance to therapy. Therefore, we aimed at assessing the novel combination of the AMHA1 strain of Newcastle disease virus (NDV) and nonnarcotic opium alkaloid (papaverine) against breast cancer models in vitro and in vivo. In vitro experiments used two human breast cancer cell lines and one normal cell line and were treated with NDV, papaverine, and a combination. The study included a cell viability MTT assay, morphological analysis, and apoptosis detection. Animal experiments used the AN3 mouse mammary adenocarcinoma tumor model. Evaluation of the antitumor activity included growth inhibition measurement; the immunohistochemistry assay measured caspase protein expression. Finally, a semiquantitative microarray assay was used to screen changes in apoptotic proteins. In vitro, results showed that the combination therapy induces synergistic cytotoxicity and apoptosis against cancer cells with a negligible cytotoxic effect on normal cells. In vivo, combination treatment induced a significant antitumor effect with an obvious regression in tumor size and a remarkable and significant expression of caspase-3, caspase-8, and caspase-9 compared to monotherapies. Microarray analysis shows higher apoptosis protein levels in the combination therapy group. In conclusion, this study demonstrated the role of papaverine in enhancing the antitumor activity of NDV, suggesting a promising strategy for breast cancer therapy through nonchemotherapeutic drugs.
PubMed: 37720338
DOI: 10.1155/2023/3324247 -
Pharmacoepidemiology and Drug Safety Jan 2024To explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal...
PURPOSE
To explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs).
METHODS
We queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the adverse drug reactions (ADR) with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the reporting odds ratio (ROR) of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients.
RESULTS
From a total of 133 819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n = 550, 0.41%; intracavernousal drugs: n = 82, 9.92%). Priapism disproportionality signals from intracavernousal drugs were 25 times stronger than PDE5is (ROR = 34.7; confidence interval [CI] 95%: 27.12-43.94 vs. ROR = 1.38; 95% CI: 1.24-1.54). For all PDE5i agents, the 12-17 years age group had the highest ROR (9.49, 95% CI: 3.76-19.93) followed by 2-11 years (4.31, 95% CI: 1.57-9.4). Disproportionality signals for consumers under 18 for both all PDE5is as a whole (ROR = 4.57, 95% CI: 2.48-7.73) and sildenafil (ROR = 4.89, 95% CI: 2.51-8.62) were stronger than individuals 18 or older (ROR = 1.06, 95% CI: 0.93-1.21 and ROR = 1.08, 95% CI: 0.91-1.26, respectively).
CONCLUSIONS
PDE5i use shows disproportionate priapism signals which are higher in young patients.
Topics: Male; Humans; Child, Preschool; Child; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Priapism; Erectile Dysfunction; Tadalafil; Drug-Related Side Effects and Adverse Reactions
PubMed: 37909414
DOI: 10.1002/pds.5721 -
Current Research in Pharmacology and... 2024Cholestasis is a hepatobiliary condition that manifests as acute or chronic and results from disruptions in the bile flow, formation, or secretion processes. The...
Cholestasis is a hepatobiliary condition that manifests as acute or chronic and results from disruptions in the bile flow, formation, or secretion processes. The Farnesoid X receptor (FXR) is a vital target for the therapy of cholestasis since it regulates BA homeostasis. Despite the discovery of multiple active FXR agonists, there are still no effective treatments for cholestasis. Papaverine is identified as an FXR agonist.This study investigates papaverine's efficacy and probable mechanism in protecting against alpha naphthylisothiocyanate (ANIT) induced cholestasis. Thirty male albino rats were divided into three groups, each with ten rats. Group I (control) rats were administered 1 mL/kg corn oil 48 h before sacrifice; group II rats were orally administered 100 mg/kg ANIT. Group III received a 200 mg/kg dosage of papaverine over seven consecutive days. A single dose of ANIT at a concentration of 100 mg/kg was orally administered on the fifth day; group II and III animals were euthanized 48 h after inducing cholestasis, and serum concentrations of liver function tests and total bile acid (TBA) were measured. Besides measuring the inflammatory mediator's tumor necrosis factor-alpha (TNF-α) and interleukin 1 (IL-1β), antioxidant markers such as superoxide dismutase (SOD) and glutathione (GSH) were also assessed. The findings indicated the enhancement in the liver function test and total bile acids, as well as in liver histology; papaverine significantly lowered TNF-α and IL-1β while SOD and GSH significantly increased. Additionally, papaverine upregulates gene expression, bile salt export pump (), small heterodimer partner (), hepatocyte nuclear factor 1α (), nuclear factor erythroid 2-related factor (), heme oxygenase (), NAD(P)H quinone oxidoreductase 1 (). Furthermore, papaverine increased protein expressions of Sirtuin1. (SIRT 1), FXR, HO-1, and BSEP levels in the rats' livers. The protective effects of papaverine may be attributed to the activation of FXR signaling pathways. These findings revealed that papaverine protects against ANIT-induced Cholestasis.
PubMed: 38322817
DOI: 10.1016/j.crphar.2024.100177 -
Mini Reviews in Medicinal Chemistry Jun 2024Alpha-synuclein (α-syn) aggregation products may cause neural injury and several neurodegenerative disorders (NDs) known as α-synucleinopathies. Alkaloids are...
BACKGROUND
Alpha-synuclein (α-syn) aggregation products may cause neural injury and several neurodegenerative disorders (NDs) known as α-synucleinopathies. Alkaloids are secondary metabolites present in a variety of plant species and may positively affect human health, particularly α-synucleinopathy-associated NDs.
AIM
To summarize the latest scientific data on the inhibitory properties of alkaloids in α- synucleinopathies, especially in Parkinson's disease.
METHODS
Literature search was performed using web-based databases including Web of Science, PubMed, and Scopus up to January 2024, in the English language.
RESULTS
Harmala alkaloids, caffein, lycorine, piperin, acetylcorynoline, berberin, papaverine, squalamine, trodusquemine and nicotin have been found to be the most active natural alkaloids against synucleinopathy. The underlying mechanisms that contribute to this effect would be the inhibition of α-syn aggregation; elimination of formed aggregates; improvement in autophagy activation; promotion of the activity and expression of antioxidative enzymes; and prevention of oxidative injury and apoptosis in dopaminergic neurons.
CONCLUSION
The findings of the present study highlight the inhibitory activities of alkaloids against synucleinopathy. However, no clinical data supports the reported activities in humans, which calls attention to the need for conducting clinical trials to elucidate the efficacy, safety, proper dosage, unwanted effects and pharmacokinetics aspects of alkaloids in humans.
PubMed: 38874050
DOI: 10.2174/0113895575306884240604065754 -
Molecular and Cellular Biochemistry Jul 2023This research aimed to investigate the effect of PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target protein of rapamycin) signaling...
Effect of PI3K/AKT/mTOR signaling pathway-based clustered nursing care combined with papaverine injection on vascular inflammation and vascular crisis after replantation of severed fingers.
This research aimed to investigate the effect of PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target protein of rapamycin) signaling pathway-based clustering care combined with papaverine injection on vascular inflammation and vascular crisis after finger amputation and replantation. 100 patients admitted in General Hospital of Ningxia Medical University from April 2022 to December 2022 for replantation of severed fingers were selected and divided into a control group (n = 50) and an observation group (n = 50) using the randomized grouping principle. The control group received a papaverine injection and general nursing care, the observation group received a papaverine injection and clustered care. The pain score; constipation incidence; replantation finger survival rate; physician, nurse, and patient satisfaction; serum inflammatory factors; vascular crisis parameters; and occurrence of adverse reactions were compared between the two patient groups. Enzyme-linked immunosorbent assay was performed to detect PI3K, AKT, and mTOR protein concentrations in the venous blood of the two groups, and statistical analysis of the data was performed. On postoperative day 7, the pain score and incidence of constipation in the observation group were lower than those in the control group (P < 0.05); the survival rate of reimplanted fingers in the observation group was 88.00%, which was higher than that in the control group 80.00% (P < 0.05); the satisfaction of doctors, nurses, and patients in the observation group was higher than that in the control group; the concentrations of interleukin-1 (IL-1), tumor necrosis factor (TNF-α), blood flow resistance index (RI), and arterial pulsatility index (PI) in the observation group were lower than those in the control group, while the concentration of interleukin-10 (IL-10), vascular diameter, and Vm (mean blood flow velocity) were higher in the observation group than those in the control group; the differences were statistically significant (P < 0.05). The difference in the incidence of adverse reactions between the two groups was not statistically significant (P > 0.05). The concentrations of PI3K, AKT, and mTOR proteins in the observation group were higher than those in the control group (P < 0.05). The concentrations of PI3K, AKT, and mTOR proteins in the observation group were higher than those in the control group (P < 0.05). Overall, these findings suggest that clustered care combined with papaverine injection reduces vascular inflammatory symptoms and vascular crisis in the treatment of severed finger replantation through the PI3K/AKT/mTOR signaling pathway.
PubMed: 37490177
DOI: 10.1007/s11010-023-04796-y -
International Journal of Impotence... Jun 2024Clinically, collagen fleece patching of the penile tunica albuginea (TA) has been successful. However, the histopathological and hemodynamic outcomes are not known. We...
Clinically, collagen fleece patching of the penile tunica albuginea (TA) has been successful. However, the histopathological and hemodynamic outcomes are not known. We studied in vivo TachoSil® patching in two beagle dogs weighing 16.8 (16.7-16.9) Kg. Bilateral intracavernous pressures (ICP) response to 10 mg papaverine hydrochloride were measured. A full-thickness defect was created on the left side in TA 1 × 0.5 cm, and four transverse incisions 1 cm long were made on the right side, placed 0.5 cm apart, and covered with TachoSil®. Six months later, ICP measurements were repeated, and the penis was excised for histopathology. Grossly, the graft site was indistinguishable. The mean baseline ICP was 19.3 ± 2.98 mmHg and increased after papaverine injection to a mean peak ICP of 122 ± 26.1 mmHg. The ICP measurement before and after grafting did not show a significant difference in the baseline (p = 0.068) or the peak pressure (p = 0.465). Histologically, minimal foreign body reaction was seen, and the TA was completely regenerated. The underlying cavernous tissue did not show inflammation or necrosis. The study is the first to show the long-term histopathologic regeneration of TA after collagen fleece patching while maintaining the hemodynamic response to papaverine.
PubMed: 38886595
DOI: 10.1038/s41443-024-00934-2 -
Cardiovascular Revascularization... Mar 2024This prospective cross-sectional study evaluated the correlation between physiological assessment (PA) and minimum lumen area (MLA) by intravascular ultrasound (IVUS)...
BACKGROUND
This prospective cross-sectional study evaluated the correlation between physiological assessment (PA) and minimum lumen area (MLA) by intravascular ultrasound (IVUS) during drug-coated balloon (DCB) treatment for femoropopliteal (FP) diseases.
METHODS
A total of 51 limbs of 44 patients undergoing endovascular treatment with DCB for de novo FP disease were examined from April 2022 to February 2023. PA was conducted at baseline, after balloon dilatation, and after DCB treatment. PA was measured before (pressure ratio; PR) and after vasodilation (peripheral flow fractional flow reserve; pFFR) with the administration of 30 mg papaverine through a guiding catheter. The correlation of PA with percent diameter stenosis (%DS) and MLA was examined, and factors correlated with higher pFFR after balloon dilatation were evaluated in a multivariate analysis.
RESULTS
At baseline, there were correlations between pressure ratio (PR) and %DS (coefficients: 0.641 [p < 0.001]) and between pFFR and %DS (0.666 [p < 0.001]). After balloon dilatation, there was no correlation between PR and %DS (coefficients: 0.33 [p = 0.27]) or between pFFR and %DS (0.41 [p = 0.71]). At baseline, PR and MLA were correlated (coefficients: 0.757 [p < 0.001]) as were pFFR and MLA (0.762 [p < 0.001]). After balloon dilatation, PR and MLA were correlated (coefficients: 0.524 [p < 0.001]) as were pFFR and MLA (0.601 [p < 0.001]). Balloon/EEM ratio, calcification >270°, and chronic total occlusion were associated with pFFR after balloon dilatation.
CONCLUSION
After balloon dilatation, PA was correlated with MLA by IVUS but not with %DS based on angiography.
Topics: Humans; Coronary Angiography; Fractional Flow Reserve, Myocardial; Prospective Studies; Cross-Sectional Studies; Treatment Outcome; Angioplasty, Balloon; Peripheral Arterial Disease; Ultrasonography, Interventional; Femoral Artery; Popliteal Artery
PubMed: 37739885
DOI: 10.1016/j.carrev.2023.09.004