-
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 -
Expert Opinion on Therapeutic Targets 2023Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity.... (Review)
Review
INTRODUCTION
Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy.
AREAS COVERED
Triphenylphosphonium cation (TPP)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies.
EXPERT OPINION
TPP-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
Topics: Humans; Mice; Animals; Mitochondria; Oxidative Phosphorylation; Neoplasms; Drug Delivery Systems; Antineoplastic Agents
PubMed: 37736880
DOI: 10.1080/14728222.2023.2261631 -
Journal of Clinical Neurophysiology :... Jul 2021The autonomic nervous system is a complex neural network that controls several organ systems. Its assessment includes a detailed history of autonomic functions, clinical... (Review)
Review
The autonomic nervous system is a complex neural network that controls several organ systems. Its assessment includes a detailed history of autonomic functions, clinical examination, and autonomic tests. Most widely used is a battery of tests that assess cardiovascular reflex autonomic and sudomotor tests, which include deep breathing (assesses parasympathetic function), Valsalva maneuver, tilt test (both assess parasympathetic and adrenergic functions), and sudomotor testing for the evaluation of postganglionic sudomotor fibers. These basic tests represent a foundation of autonomic testing. Nevertheless, the autonomic nervous system also controls organ systems not directly assessed by basic tests. This review describes a number of auxiliary autonomic tests that can be used in addition to basic autonomic tests or can be used independently to explore particular autonomic functions or to answer a specific clinical question. The auxiliary tests described in this review evaluate cardiovascular, thermoregulatory, gastrointestinal, genitourinary, eye, and exocrine functions. These tests are cold pressor test, sustained handgrip maneuver, reverse tilt test, venoarteriolar reflex, laser Doppler flare imaging, microneurography, neck suction, lower body negative pressure, venous occlusion plethysmography, pharmacologic assessment of postganglionic sympathetic outflow, plasma norepinephrine, sympathetic skin response, video cinefluoroscopic swallowing test, esophageal manometry test, small bowel manometry test, wireless motility capsule test, urodynamic studies, penile plethysmography, intracavernosal papaverine injection, infrared video pupillography, corneal confocal microscopy, pupillary response to dilute pilocarpine and hydroxyamphetamine, Schirmer test, tear osmolarity test, and salivary secretion test. The protocol of each test is described in detail. This review can be used as a quick reference for the auxiliary autonomic tests.
Topics: Autonomic Nervous System; Autonomic Nervous System Diseases; Diagnostic Techniques, Neurological; Hand Strength; Heart Rate; Humans; Reflex; Tilt-Table Test; Valsalva Maneuver
PubMed: 34009848
DOI: 10.1097/WNP.0000000000000626 -
Phosphodiesterase type 10A inhibitor attenuates lung fibrosis by targeting myofibroblast activation.IScience May 2023Pulmonary fibrosis (PF) is a fatal and irreversible respiratory disease accompanied by excessive fibroblast activation. Previous studies have suggested that cAMP...
Pulmonary fibrosis (PF) is a fatal and irreversible respiratory disease accompanied by excessive fibroblast activation. Previous studies have suggested that cAMP signaling pathway and cGMP-PKG signaling pathway are continuously down-regulated in lung fibrosis, whereas PDE10A has a specifically expression in fibroblasts/myofibroblasts in lung fibrosis. In this study, we demonstrated that overexpression of PDE10A induces myofibroblast differentiation, and papaverine, as a PDE10A inhibitor used for vasodilation, inhibits myofibroblast differentiation in human fibroblasts, Meanwhile, papaverine alleviated bleomycin-induced pulmonary fibrosis and amiodarone-induced oxidative stress, papaverine downregulated VASP/β-catenin pathway to reduce the myofibroblast differentiation. Our results first demonstrated that papaverine inhibits TGFβ1-induced myofibroblast differentiation and lung fibrosis by VASP/β-catenin pathway.
PubMed: 37138780
DOI: 10.1016/j.isci.2023.106586 -
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 -
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 -
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