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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 -
Microbial Cell Factories Jun 2024Computational mining of useful enzymes and biosynthesis pathways is a powerful strategy for metabolic engineering. Through systematic exploration of all conceivable...
BACKGROUND
Computational mining of useful enzymes and biosynthesis pathways is a powerful strategy for metabolic engineering. Through systematic exploration of all conceivable combinations of enzyme reactions, including both known compounds and those inferred from the chemical structures of established reactions, we can uncover previously undiscovered enzymatic processes. The application of the novel alternative pathways enables us to improve microbial bioproduction by bypassing or reinforcing metabolic bottlenecks. Benzylisoquinoline alkaloids (BIAs) are a diverse group of plant-derived compounds with important pharmaceutical properties. BIA biosynthesis has developed into a prime example of metabolic engineering and microbial bioproduction. The early bottleneck of BIA production in Escherichia coli consists of 3,4-dihydroxyphenylacetaldehyde (DHPAA) production and conversion to tetrahydropapaveroline (THP). Previous studies have selected monoamine oxidase (MAO) and DHPAA synthase (DHPAAS) to produce DHPAA from dopamine and oxygen; however, both of these enzymes produce toxic hydrogen peroxide as a byproduct.
RESULTS
In the current study, in silico pathway design is applied to relieve the bottleneck of DHPAA production in the synthetic BIA pathway. Specifically, the cytochrome P450 enzyme, tyrosine N-monooxygenase (CYP79), is identified to bypass the established MAO- and DHPAAS-mediated pathways in an alternative arylacetaldoxime route to DHPAA with a peroxide-independent mechanism. The application of this pathway is proposed to result in less formation of toxic byproducts, leading to improved production of reticuline (up to 60 mg/L at the flask scale) when compared with that from the conventional MAO pathway.
CONCLUSIONS
This study showed improved reticuline production using the bypass pathway predicted by the M-path computational platform. Reticuline production in E. coli exceeded that of the conventional MAO-mediated pathway. The study provides a clear example of the integration of pathway mining and enzyme design in creating artificial metabolic pathways and suggests further potential applications of this strategy in metabolic engineering.
Topics: Metabolic Engineering; Benzylisoquinolines; Escherichia coli; Cytochrome P-450 Enzyme System; Biosynthetic Pathways; Computer Simulation; Tetrahydropapaveroline; 3,4-Dihydroxyphenylacetic Acid
PubMed: 38879464
DOI: 10.1186/s12934-024-02453-7 -
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 -
American Journal of Obstetrics &... May 2024Catheter-balloon insertion is a cervical ripening method of labor induction. Papaverine and its derivatives are musculotropic antispasmodic drugs that directly induce...
BACKGROUND
Catheter-balloon insertion is a cervical ripening method of labor induction. Papaverine and its derivatives are musculotropic antispasmodic drugs that directly induce smooth muscle relaxation. Used during childbirth, these drugs have been suggested to shorten the duration of labor.
OBJECTIVE
We aimed to evaluate the effect of administering papaverine prior to catheter-balloon insertion on changes in Bishop-scores and on the induction-to-delivery interval.
STUDY DESIGN
This randomized double-blinded placebo-controlled trial was conducted in a single tertiary university-affiliated hospital. Participants were admitted at term for labor induction with an initial Bishop-score ≤6. Participants were randomized to receive papaverine intravenous 80 mg or saline 0.9%, within 30 minutes of Foley catheter-balloon insertion. The co-primary outcomes were the difference in Bishop-score from before catheter-balloon insertion to after removal, and the induction-to-delivery interval. Secondary outcomes included maternal pain and satisfaction-scores, delivery within 24-hours and neonatal outcome. Both intention-to-treat analysis and per protocol analysis were performed.
RESULTS
In total, 110 women were enrolled. In the intention-to-treat analysis, for the papaverine (N=55) compared to the placebo group (N=55), the median (range) difference in Bishop-score was greater: 7 (range, 4-11) vs. 6 (1-11), p=0.023; and the median range catheter insertion-to-delivery interval was shorter: 21(6-95) vs. 26 (3-108) hours, p=0.031. A higher proportion of women in the papaverine than placebo group delivered within 24-hours: 65.5% vs. 41.8%, p=0.012. Pain and satisfaction-scores, delivery and neonatal outcomes were similar between the groups. Similar results were found in the per protocol analysis.
CONCLUSIONS
Papaverine prior to Foley-catheter insertion for cervical ripening resulted in improved Bishop-scores and shorter catheter-to-delivery intervals.
PubMed: 38825005
DOI: 10.1016/j.ajogmf.2024.101388 -
ACS Pharmacology & Translational Science May 2024CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more...
CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more recently with several human cancers, in particular lung cancer. However, ATP-competitive inhibitors targeting CDK5 are poorly selective and suffer limitations, calling for new classes of inhibitors. In a screen for allosteric modulators of CDK5, we identified ethaverine and closely related derivative papaverine and showed that they inhibit cell proliferation and migration of non small cell lung cancer cell lines. Moreover the efficacy of these compounds is significantly enhanced when combined with the ATP-competitive inhibitor roscovitine, suggesting an additive dual mechanism of inhibition targeting CDK5. These compounds do not affect CDK5 stability, but thermodenaturation studies performed with A549 cell extracts infer that they interact with CDK5 . Furthermore, the inhibitory potentials of ethaverine and papaverine are reduced in A549 cells treated with siRNA directed against CDK5. Taken together, our results provide unexpected and novel evidence that ethaverine and papaverine constitute promising leads that can be repurposed for targeting CDK5 in lung cancer.
PubMed: 38751642
DOI: 10.1021/acsptsci.4c00023 -
Molecules (Basel, Switzerland) Apr 2024Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether...
Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations.
Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2-associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.
Topics: Cisplatin; Papaverine; Oxidative Stress; Animals; Rats; Inflammation; Humans; Kidney; Male; Apoptosis; Antineoplastic Agents; Protective Agents; Antioxidants; Cytokines; Computer Simulation; Biomarkers
PubMed: 38731418
DOI: 10.3390/molecules29091927 -
Joint Diseases and Related Surgery Apr 2024The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat...
OBJECTIVES
The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model.
MATERIALS AND METHODS
Forty-eight adult male Sprague-Dawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15 (early period) or 30 (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15 and 30 days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation.
RESULTS
Histopathologically, there were no significant differences among the groups on the 15 day. However, on the 30 day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05).
CONCLUSION
Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings.
Topics: Animals; Achilles Tendon; Papaverine; Rats, Sprague-Dawley; Male; Tissue Adhesions; Wound Healing; Tendon Injuries; Rats; Tensile Strength; Injections, Intraperitoneal; Biomechanical Phenomena; Disease Models, Animal
PubMed: 38727117
DOI: 10.52312/jdrs.2024.1656 -
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 -
World Journal of Clinical Cases Apr 2024Idiopathic mesenteric phlebosclerosis (IMP) is a rare type of ischemic colitis characterized by thickening of the wall of the right hemicolon and calcification,...
BACKGROUND
Idiopathic mesenteric phlebosclerosis (IMP) is a rare type of ischemic colitis characterized by thickening of the wall of the right hemicolon and calcification, sclerosis, and fibrosis of mesenteric veins. The diagnosis of IMP is based on typical clinical features and imaging findings. We report a case of IMP that was initially missed by the radiologist.
CASE SUMMARY
A 77-year-old woman was admitted to the hospital due to chronic diarrhea for over 2 months. She had been consuming Chinese patent medicines (CPM) containing fructus gardeniae for more than 15 years. Colonoscopy revealed an edematous mucosa, bluish-purple discoloration, erosions, and ulcerations throughout the colorectal area. Abdominal computed tomography (CT) showed diffuse mural thickening of the entire colorectum, with tortuous thread-like calcifications in the right hemicolon, left hemicolon, and rectum. Most of the calcifications were located in the mesenteric vein. The diagnosis of IMP was established based on medical history, colonoscopy, CT findings, and histopathological examination. The patient was treated conservatively with papaverine and rifaximin, and CPM was stopped. Her diarrhea symptoms improved, indicating the effectiveness of the treatment. Over the next several years, she took opium alkaloids for an extended period and did not require hospitalization for the aforementioned gastrointestinal disorder.
CONCLUSION
IMP is a rare gastrointestinal disease affecting Asian populations, possibly related to long-term herbal medicine intake. Accurate imaging analysis is crucial for diagnosis, but insufficient understanding of the disease can lead to misdiagnosis or missed diagnosis. Treatment strategies should be personalized.
PubMed: 38660081
DOI: 10.12998/wjcc.v12.i10.1810