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The Journal of Antibiotics Mar 2018Dicyclomine is a human muscarinic acetylcholine receptor antagonist used for the treatment of abdominal cramps. We are reporting here that dicyclomine can inhibit the in...
The human muscarinic acetylcholine receptor antagonist, Dicyclomine targets signal transduction genes and inhibits the virulence factors in the human pathogen, Candida albicans.
Dicyclomine is a human muscarinic acetylcholine receptor antagonist used for the treatment of abdominal cramps. We are reporting here that dicyclomine can inhibit the in vitro growth and virulence factors of the human pathogen Candida albicans very effectively. Dicyclomine inhibited adhesion, early biofilm, mature biofilm, and planktonic growth. Yeast to hyphal form transition of C. albicans in various inducer media such as serum, proline, glucose, and N-acetylglucosamine was inhibited. Dicyclomine also could kill C. albicans cells within 15 min of exposure. Dicyclomine appears to inhibit the yeast to hyphal conversion by affecting signal transduction pathway. The expression of selected genes associated with yeast to hyphal form transition in serum in presence of dicyclomine was studied using real-time polymerase chain reaction (RtPCR). The RtPCR analysis showed that dicyclomine targets both cAMP pathway as well as MAPK cascade. Eight genes were upregulated. Out of these, three major upregulated genes were Bcy1, Tup1, and Mig1. Dicyclomine downregulated Ume6, Ece1, and Pde2 genes which are involved in cAMP signaling pathway and also downregulated the DNA binding protein gene, Rfg1. Dicyclomine significantly upregulated the master negative regulator of hyphal formation, Tup1. Based on this study we suggest that the muscarinic acetylcholine receptor antagonist, dicyclomine could be repositioned as a potential anti-Candida albicans as well as anti-virulence agent.
Topics: Biofilms; Candida albicans; Candidiasis; Cyclic AMP; Dicyclomine; Gene Expression Regulation, Fungal; Humans; Hyphae; Mitogen-Activated Protein Kinases; Muscarinic Antagonists; Real-Time Polymerase Chain Reaction; Signal Transduction; Virulence Factors
PubMed: 29348527
DOI: 10.1038/s41429-017-0013-z -
Journal of Analytical Toxicology May 2024In forensic toxicology, the pediatric population requires special focus when evaluating positive findings because of the many toxicokinetic and toxicodynamic differences...
In forensic toxicology, the pediatric population requires special focus when evaluating positive findings because of the many toxicokinetic and toxicodynamic differences (e.g., metabolic capabilities, body size, etc.) between the pediatric and adult populations. In particular, the administration of over-the-counter (OTC) medications needs careful consideration, as dosages given to the pediatric population (0 days - 18 years), particularly those given to individuals less than five years of age, tend to be lower than those given to individuals closer to adulthood. Postmortem pediatric data from eleven years (2010-2020) was compiled. A total of 1413 positive cases contained one or more of the following common OTC medications: antihistamines (brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, and pheniramine), pain relievers (acetaminophen, naproxen, ibuprofen, and salicylates), cold/flu medications (dextro/levomethorphan, guaifenesin, ephedrine, and pseudoephedrine), gastrointestinal (GI) aids (dicyclomine and loperamide), and/or sleep aids (melatonin). Antihistamines, cold/flu medications, and pain relievers are the most common classes of drugs encountered in the postmortem pediatric population. To evaluate trends, three main age groups were created: ≤5 years old (5U, birth-5 years old), middle childhood (MC, 6-11 years old), and early adolescence (EA, 12-18 years old). When considering the data, it must be noted that many of these drugs may be co-administered in single and/or multi-drug formulations. In addition, some drugs may have a variety of uses, e.g., antihistamines may also be used as sleep aids. Of note, the prevalence of cases involving those aged 6-11 years old was far less than their younger and older pediatric counterparts. With the widespread availability of OTC medications, unintentional overdoses, recreational misuse, and suicidal overdoses can occur in the vulnerable, pediatric population.
PubMed: 38771225
DOI: 10.1093/jat/bkae042 -
The Medical Letter on Drugs and... Mar 2020
Topics: Constipation; Diarrhea; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome
PubMed: 32324172
DOI: No ID Found -
The Journal of Emergency Medicine Oct 2023Anticholinergic toxicity is a common cause of delirium in emergency department patients. The standard antidotal treatment for anticholinergic toxicity is physostigmine....
BACKGROUND
Anticholinergic toxicity is a common cause of delirium in emergency department patients. The standard antidotal treatment for anticholinergic toxicity is physostigmine. Physostigmine functions as a reversible acetylcholinesterase inhibitor that readily crosses the blood-brain barrier. Rivastigmine is another member of this class currently approved for the treatment of Alzheimer's disease and Parkinson's disease. Rivastigmine also crosses the blood-brain barrier and has been found to be effective in the management of anticholinergic toxicity in limited case reports.
CASE REPORT
A 61-year-old women presented to the emergency department via emergency medical services with altered mental status and a Glasgow Coma Scale score of 8 out of 15. She was found down near multiple medication bottles, including diphenhydramine and dicyclomine. Her physical examination was consistent with anticholinergic toxicity with mydriasis, obtundation, and warm flushed skin. In addition to standard resuscitation, she received two doses of rivastigmine 3 mg via nasogastric tube. After the second dose she was alert and oriented. She was admitted to the intensive care unit and had a rivastigmine patch applied. She was deemed back to her baseline 27 h after presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although the standard antidotal treatment for anticholinergic toxicity is physostigmine, there is a national shortage of this medication. In the absence of this standard antidote, it is reasonable for emergency physicians to use rivastigmine as an alternative treatment. This can be delivered orally or via nasogastric tube with dosing each hour until resolution of symptoms. Alternatively, in consultation with toxicology, it may be reasonable to use transdermal rivastigmine, as it provides consistent drug absorption for 24 h.
Topics: Humans; Female; Middle Aged; Rivastigmine; Physostigmine; Cholinergic Antagonists; Acetylcholinesterase; Cholinesterase Inhibitors; Antidotes; Anticholinergic Syndrome; Delirium; Transdermal Patch
PubMed: 37716903
DOI: 10.1016/j.jemermed.2023.06.008 -
Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.Cell Reports. Medicine Feb 2024Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of...
Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.
Topics: Male; Humans; Docetaxel; Receptor, Muscarinic M1; Prostatic Neoplasms, Castration-Resistant; Cell Line, Tumor; Cholinergic Agents
PubMed: 38262412
DOI: 10.1016/j.xcrm.2023.101388 -
Asian Journal of Psychiatry Feb 2020
Review
Topics: Adult; Cholinergic Antagonists; Dicyclomine; Humans; Male; Substance-Related Disorders
PubMed: 31864128
DOI: 10.1016/j.ajp.2019.101891 -
Molecules (Basel, Switzerland) Oct 2021is traditionally used in different areas of Pakistan to treat gastrointestinal, respiratory, and vascular diseases. This study evaluates the underlying mechanisms for...
is traditionally used in different areas of Pakistan to treat gastrointestinal, respiratory, and vascular diseases. This study evaluates the underlying mechanisms for traditional uses of in diarrhea, asthma, and hypertension. In vitro pharmacological studies were conducted using isolated jejunum, trachea, and aortic preparations, while the cytotoxic study was conducted in mice. Crude extract of (Pp.Cr), comprising appreciable quantities of alkaloids and flavonoids, relaxed spontaneously contracting jejunum preparation, K (80 mM)-induced, and carbachol (1 µM)-induced jejunum contractions in a concentration-dependent manner similar to dicyclomine and dantrolene. Pp.Cr showed a rightward parallel shift of concentration-response curves (CRCs) of Cch after a non-parallel shift similarto dicyclomine and shifted CRCs of Ca to rightward much likeverapamil and dantrolene, demonstrating the coexistence of antimuscarinic and Ca antagonistic mechanism. Furthermore, Pp.Cr, dicyclomine, and dantrolene relaxed K (80 mM)-induced and Cch (1 µM)-induced tracheal contractions and shifted rightward CRCs of Cch similar to dicyclomine, signifying the dual blockade. Additionally, Pp.Cr also relaxed the K (80 mM)-induced and phenylephrine (1 µM)-induced aortic contraction, similarly to verapamil and dantrolene, suggesting Ca channel antagonism. Here, we explored for the first time thespasmolytic and bronchodilator effects of Pp.Crand whether they maybe due to the dual blockade of Ca channels and muscarinic receptors, while the vasodilator effect might be owing to Ca antagonism. Our results provide the pharmacological evidence that could be a new potential therapeutic option to treat gastrointestinal, respiratory, and vascular diseases. Hence, there is a need for further research to explore bioactive constituent of as well as further investigation by suitable experimental models are required to further confirm the importance and usefulness of in diarrhea, asthma, and hypertension treatment.
Topics: Animals; Biological Products; Bronchodilator Agents; Calcium Channel Blockers; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Mice; Molecular Structure; Muscarinic Antagonists; Parasympatholytics; Parmeliaceae; Spectrum Analysis; Toxicity Tests, Acute; Vasodilator Agents
PubMed: 34770756
DOI: 10.3390/molecules26216348 -
Indian Journal of Psychiatry 2020
PubMed: 33896989
DOI: 10.4103/psychiatry.IndianJPsychiatry_562_19 -
Adolescent Medicine: State of the Art... 2016
Review
Topics: Abdominal Pain; Adolescent; Amitriptyline; Antidepressive Agents, Tricyclic; Cognitive Behavioral Therapy; Cyproheptadine; Dicyclomine; Diet Therapy; Gastrointestinal Agents; Gastrointestinal Diseases; Humans; Hyoscyamine; Muscarinic Antagonists; Quality of Life
PubMed: 27363232
DOI: No ID Found -
International Journal of Biological... Feb 2018Lipase is one of the most important groups of enzymes for industry and medicine. It breaks down triacylglycerol to glycerol and fatty acids. Some bacteria use lipase to...
Lipase is one of the most important groups of enzymes for industry and medicine. It breaks down triacylglycerol to glycerol and fatty acids. Some bacteria use lipase to degrade the extracellular matrix of the host cells to penetrate into the tissues. Dicyclomine is a muscarinic antagonist receptor that relieves the smooth muscle spasm of the gastrointestinal tract and affects the cardiovascular system. In this research, the effect of a dicyclomine on the lipase activity of Pseudomonas aeruginosa was studied. Hanes-Woolf plot showed that the drug inhibited the enzyme by competitive inhibition. The IC value (60uM) and Ki (30uM) of the drug revealed that the drug bound to enzyme with high affinity. Determination of enzyme activity in various temperature showed that the maximum activity of lipase was at 60°C both in the presence and absence of the drug. Arrhenius plot determined that the activation energy of the enzyme reaction was increased in the presence of the drug. The model of binding demonstrated that the drug entered a pocket containing 10 amino acids and interacted by hydrogen bond and hydrophobic interaction and the conformational change of the enzyme after binding of the drug was confirmed by fluorescence measurement.
Topics: Cardiovascular System; Dicyclomine; Gastrointestinal Tract; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lipase; Muscle, Smooth; Pseudomonas aeruginosa; Spasm; Temperature
PubMed: 29055706
DOI: 10.1016/j.ijbiomac.2017.10.123