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Brain Sciences May 2023Erectile dysfunction (ED) is the inability to get and maintain an adequate penile erection for satisfactory sexual intercourse. Due to its negative impacts on men's life... (Review)
Review
Erectile dysfunction (ED) is the inability to get and maintain an adequate penile erection for satisfactory sexual intercourse. Due to its negative impacts on men's life quality and increase during aging (40% of men between 40 and 70 years), ED has always attracted researchers of different disciplines, from urology, andrology and neuropharmacology to regenerative medicine, and vascular and prosthesis implant surgery. Locally and/or centrally acting drugs are used to treat ED, e.g., phosphodiesterase 5 inhibitors (first in the list) given orally, and phentolamine, prostaglandin E1 and papaverine injected intracavernously. Preclinical data also show that dopamine D receptor agonists, oxytocin and α-MSH analogues may have a role in ED treatment. However, since pro-erectile drugs are given on demand and are not always efficacious, new strategies are being tested for long lasting cures of ED. These include regenerative therapies, e.g., stem cells, plasma-enriched platelets and extracorporeal shock wave treatments to cure damaged erectile tissues. Although fascinating, these therapies are laborious, expensive and not easily reproducible. This leaves old vacuum erection devices and penile prostheses as the only way to get an artificial erection and sexual intercourse with intractable ED, with penile prosthesis used only by accurately selected patients.
PubMed: 37239274
DOI: 10.3390/brainsci13050802 -
Indian Journal of Urology : IJU :... 2021Drug-induced priapism is well known and papaverine is the most common drug known to cause priapism. Drotaverine, an analog of papaverine, is used extensively to treat...
Drug-induced priapism is well known and papaverine is the most common drug known to cause priapism. Drotaverine, an analog of papaverine, is used extensively to treat Colicky pain. We report the first case of drotaverine.induced priapism.
PubMed: 33850364
DOI: 10.4103/iju.IJU_240_20 -
Annals of Cardiac Anaesthesia 2021
Topics: Administration, Topical; Hemodynamics; Humans; Mammary Arteries; Papaverine; Stellate Ganglion
PubMed: 33938858
DOI: 10.4103/aca.ACA_171_20 -
Proceedings of the National Academy of... Aug 2022Tetrahydropapaverine (THP) and papaverine are plant natural products with clinically significant roles. THP is a precursor in the production of the drugs atracurium and...
Tetrahydropapaverine (THP) and papaverine are plant natural products with clinically significant roles. THP is a precursor in the production of the drugs atracurium and cisatracurium, and papaverine is used as an antispasmodic during vascular surgery. In recent years, metabolic engineering advances have enabled the production of natural products through heterologous expression of pathway enzymes in yeast. Heterologous biosynthesis of THP and papaverine could play a role in ensuring a stable supply of these clinically significant products. Biosynthesis of THP and papaverine has not been achieved to date, in part because multiple pathway enzymes have not been elucidated. Here, we describe the development of an engineered yeast strain for de novo biosynthesis of THP. The production of THP is achieved through heterologous expression of two enzyme variants with activity on nonnative substrates. Through protein engineering, we developed a variant of -methylcoclaurine hydroxylase with activity on coclaurine, enabling de novo norreticuline biosynthesis. Similarly, we developed a variant of scoulerine 9--methyltransferase capable of -methylating 1-benzylisoquinoline alkaloids at the 3' position, enabling de novo THP biosynthesis. Flux through the heterologous pathway was improved by knocking out yeast multidrug resistance transporters and optimization of media conditions. Overall, strain engineering increased the concentration of biosynthesized THP 600-fold to 121 µg/L. Finally, we demonstrate a strategy for papaverine semisynthesis using hydrogen peroxide as an oxidizing agent. Through optimizing pH, temperature, reaction time, and oxidizing agent concentration, we demonstrated the ability to produce semisynthesized papaverine through oxidation of biosynthesized THP.
Topics: Biological Products; Cytochrome P-450 Enzyme System; Hydrogen Peroxide; Oxidants; Papaverine; Plant Proteins; Protein Engineering; Saccharomyces cerevisiae
PubMed: 35939674
DOI: 10.1073/pnas.2205848119 -
Molecules (Basel, Switzerland) Mar 2023The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline... (Review)
Review
The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.
Topics: Humans; Papaverine; Opium; COVID-19; SARS-CoV-2; Alkaloids; Benzylisoquinolines
PubMed: 37049912
DOI: 10.3390/molecules28073149 -
Frontiers in Pharmacology 2022Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile... (Review)
Review
Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile erection. This disorder is related to psychosocial factors such as anxiety, depression, and low self-esteem, to organic factors such as the presence of preexisting conditions like hypertension, diabetes and dyslipidemia. The pathophysiology of the disease is related to changes in the neurotransmission of the autonomic or the non-cholinergic non-adrenergic nervous system, as well as the release of local mediators, such as thromboxane A and endothelin, and hormonal action. These changes lead to impaired relaxation of cavernous smooth muscle, which reduces local blood flow and impairs penile erection. Currently, therapy is based on oral vasodilation, such as sildenafil, tadalafil, vardenafil and iodenafil, or by direct administration of these agents into the corpus cavernosum or by intraurethral route, such as alprostadil and papaverine. Despite this, studies that consolidate the understanding of its pathophysiological process contribute to the discovery of new more efficient drugs for the treatment of erectile dysfunction. In this sense, in the present work an extensive survey was carried out of the mechanisms already consolidated and the most recent ones related to the development of erectile dysfunction.
PubMed: 35865945
DOI: 10.3389/fphar.2022.895044 -
Cells Oct 2022Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits... (Review)
Review
Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits phosphodiesterase 10A (PDE10A,) resulting in the accumulation of cyclic adenosine 3', 5'-monophosphate (cAMP) that affects multiple downstream pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), a mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF). The accumulation of cAMP can further affect mitochondrial metabolism through the activation of protein kinase A (PKA), which activates the mitochondrial complex I. Literature has shown that PPV exerts anti-proliferative affects in several tumorigenic cell lines including adenocarcinoma alveolar cancer (A549) and human hepatoma (HepG-2) cell lines. Cell cycle investigations have shown varying results with the effects dependent on concentration and cell type with data suggesting an increase in cells occupying the sub-G phase, which is indicative of cell death. These results suggest that PPV may be a beneficial compound to explore for the use in anticancer studies. More insight into the effects of the compound on cellular and molecular mechanisms is needed. Understanding the effects PPV may exert on tumorigenic cells may better researchers' understanding of phytomedicines and the effects of PPV and PPV-derived compounds in cancer.
Topics: Humans; Papaverine; Phosphatidylinositol 3-Kinases; Vascular Endothelial Growth Factor A; Cyclic AMP-Dependent Protein Kinases; Cell Cycle; Neoplasms; Phosphoric Diester Hydrolases
PubMed: 36359780
DOI: 10.3390/cells11213385 -
Phytotherapy Research : PTR Jul 2022Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has a high mortality rate and transmissibility. In... (Review)
Review
Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has a high mortality rate and transmissibility. In this context, medicinal plants have attracted attention due to the wide availability and variety of therapeutic compounds, such as alkaloids, a vast class with several proven pharmacological effects, like the antiviral and anti-inflammatory activities. Therefore, this scoping review aimed to summarize the current knowledge of the potential applicability of alkaloids for treating COVID-19. A systematic search was performed on PubMed and Scopus, from database inception to August 2021. Among the 63 eligible studies, 65.07% were in silico model, 20.63% in vitro and 14.28% clinical trials and observational studies. According to the in silico assessments, the alkaloids 10-hydroxyusambarensine, cryptospirolepine, crambescidin 826, deoxynortryptoquivaline, ergotamine, michellamine B, nigellidine, norboldine and quinadoline B showed higher binding energy with more than two target proteins. The remaining studies showed potential use of berberine, cephaeline, emetine, homoharringtonine, lycorine, narciclasine, quinine, papaverine and colchicine. The possible ability of alkaloids to inhibit protein targets and to reduce inflammatory markers show the potential for development of new treatment strategies against COVID-19. However, more high quality analyses/reviews in this field are necessary to firmly establish the effectiveness/safety of the alkaloids here described.
Topics: Alkaloids; Antiviral Agents; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35355337
DOI: 10.1002/ptr.7442