-
The American Journal of Gastroenterology Aug 2021Chronic abdominal pain is a common gastrointestinal (GI) symptom that characterizes many functional GI disorders/disorders of gut-brain interaction, including irritable... (Review)
Review
Chronic abdominal pain is a common gastrointestinal (GI) symptom that characterizes many functional GI disorders/disorders of gut-brain interaction, including irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome. The symptoms of abdominal pain in these highly prevalent disorders are often treated with antispasmodic agents. Antispasmodic treatment includes a broad range of therapeutic classes with different mechanisms of action, including anticholinergic/antimuscarinic agents (inhibition of GI smooth muscle contraction), calcium channel inhibitors (inhibition of calcium transport into GI smooth muscle), and direct smooth muscle relaxants (inhibition of sodium and calcium transport). The aim of this review article was to examine the efficacy and safety of antispasmodics available in North America (e.g., alverine, dicyclomine, hyoscine, hyoscyamine, mebeverine, otilonium, pinaverium, and trimebutine) for the treatment of chronic abdominal pain in patients with common disorders of gut-brain interaction. For the agents examined, comparisons of studies are limited by inconsistencies in treatment dosing and duration, patient profiles, and diagnostic criteria employed. Furthermore, variability in study end points limits comparisons. Risk of selection, performance, detection, attrition, and reporting bias also differed among studies, and in many cases, risks were considered "unclear." The antispasmodics evaluated in this review, which differ in geographic availability, were found to vary dramatically in efficacy and safety. Given these caveats, each agent should be considered on an individual basis, rather than prescribed based on information across the broad class of agents.
Topics: Abdominal Pain; Chronic Pain; Humans; North America; Parasympatholytics
PubMed: 33993133
DOI: 10.14309/ajg.0000000000001266 -
JNCI Cancer Spectrum Mar 2023Incidence rates of colorectal cancer (CRC) are increasing among adults born in and after the 1960s, implicating pregnancy-related exposures introduced at that time as... (Review)
Review
BACKGROUND
Incidence rates of colorectal cancer (CRC) are increasing among adults born in and after the 1960s, implicating pregnancy-related exposures introduced at that time as risk factors. Dicyclomine, an antispasmodic used to treat irritable bowel syndrome, was initially included in Bendectin (comprising doxylamine, pyridoxine, and dicyclomine), an antiemetic prescribed during pregnancy in the 1960s.
METHODS
We estimated the association between in utero exposure to Bendectin and risk of CRC in offspring of the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in Oakland, CA, between 1959 and 1966 (n = 14 507 mothers and 18 751 liveborn offspring). We reviewed prescribed medications from mothers' medical records to identify those who received Bendectin during pregnancy. Diagnoses of CRC in adult (aged ≥18 years) offspring were ascertained by linkage with the California Cancer Registry. Cox proportional hazards models were used to estimate adjusted hazard ratios, with follow-up accrued from birth through cancer diagnosis, death, or last contact.
RESULTS
Approximately 5% of offspring (n = 1014) were exposed in utero to Bendectin. Risk of CRC was higher in offspring exposed in utero (adjusted hazard ratio = 3.38, 95% confidence interval [CI] = 1.69 to 6.77) compared with unexposed offspring. Incidence rates of CRC were 30.8 (95% CI = 15.9 to 53.7) and 10.1 (95% CI = 7.9 to 12.8) per 100 000 in offspring exposed to Bendectin and unexposed, respectively.
CONCLUSIONS
Higher risk of CRC in offspring exposed in utero may be driven by dicyclomine contained in the 3-part formulation of Bendectin used during the 1960s. Experimental studies are needed to clarify these findings and identify mechanisms of risk.
Topics: Adult; Female; Humans; Pregnancy; Antiemetics; Colorectal Neoplasms; Dicyclomine; Mothers; Prenatal Exposure Delayed Effects
PubMed: 36895101
DOI: 10.1093/jncics/pkad021 -
Dementia & Neuropsychologia 2023Anticholinergics (ACs) are among the most prescribed drugs. Investigating the impaired cognitive domains due to individual ACs usage is associated with controversial... (Review)
Review
UNLABELLED
Anticholinergics (ACs) are among the most prescribed drugs. Investigating the impaired cognitive domains due to individual ACs usage is associated with controversial findings.
OBJECTIVE
The objective of this study was to investigate the effects of individual ACs on different aspects of cognitive function based on clinical trial studies.
METHODS
This systematic review was conducted following the PRISMA statement. A systematic search was performed in Embase, PubMed, Cochrane Library, Scopus, and Web of Science databases. Risk of bias (RoB) was assessed by the Joanna Briggs Institute checklists and the meta-analysis was performed using the CMA software.
RESULTS
Out of 3,026 results of searching, 138 studies were included. A total of 38 studies that assess the cognitive impacts of scopolamine were included in the meta-analysis. Included studies reported cognitive effects of scopolamine, mecamylamine, atropine, biperiden, oxybutynin, trihexyphenidyl, benzhexol, and dicyclomine; however, glycopyrrolate, trospium, tolterodine, darifenacin, fesoterodine, tiotropium, and ipratropium were not associated with cognitive decline. Based on the meta-analyses, scopolamine was associated with reduced recognition (SDM -1.84; 95%CI -2.48 to -1.21; p<0.01), immediate recall (SDM -1.82; 95%CI -2.35 to -1.30; p<0.01), matching to sample (SDM -1.76; 95%CI -2.57 to -0.96; p<0.01), delayed recall (SDM -1.54; 95%CI -1.97 to -1.10; p<0.01), complex memory tasks (SDM -1.31; 95%CI -1.78 to -0.84; p<0.01), free recall (SDM -1.18; 95%CI -1.63 to -0.73; p<0.01), cognitive function (SDM -0.95; 95%CI -1.46 to -0.44; p<0.01), attention (SDM -0.85; 95%CI -1.38 to -0.33; p<0.01), and digit span (SDM -0.65; 95%CI -1.21 to -0.10; p=0.02). There was a high RoB in our included study, especially in terms of dealing with possible cofounders.
CONCLUSION
The limitations of this study suggest a need for more well-designed studies with a longer duration of follow-up on this topic to reach more reliable evidence.
PubMed: 37261256
DOI: 10.1590/1980-5764-DN-2022-0053 -
Gastroenterology and Hepatology From... 2022As few randomized clinical trials have verified the efficacy of selective and norepinephrine reuptake inhibitors in IBS, the current study made an inclusive comparison...
AIM
As few randomized clinical trials have verified the efficacy of selective and norepinephrine reuptake inhibitors in IBS, the current study made an inclusive comparison between them, and their effectiveness in IBS-C was proven.
BACKGROUND
Irritable bowel syndrome with constipation (IBS-C) is a functional bowel disorder characterized by changes in bowel movements and abdominal pain in the absence of identifiable structural abnormalities. Despite much progress in the treatment of other types of IBS, limited treatments are available for IBS-C.
METHODS
The study population comprised 182 IBS-C patients who were randomly divided into 3 groups according to treatment type. One group was given 20 mg of dicyclomine and fluoxetine, the second group received dicyclomine along with duloxetine hydrochloride, and the third group received dicyclomine only for two months. The severity of symptoms was recorded by questionnaire at the beginning and end of the treatment.
RESULTS
The average age and BMI of the patients were 28.5 ± 5.2 years and 25.2 ± 2.4 kg/m2, respectively. Duloxetine was more effective than fluoxetine in reducing flatulence (=0.043), abdominal pain intensity (≤0.046), and duration (≤0.003), in increasing the quality of life (≤0.046), and the frequency of fecal excretion in patients (≤0.004).
CONCLUSION
Based on the study findings, fluoxetine and duloxetine had greater therapeutic effects on all symptoms of IBD than dicyclomine, with duloxetine, specifically, being more effective than fluoxetine. Further studies on larger groups are suggested to determine the best dosage and identify any potential side effects of these drugs.
PubMed: 35611252
DOI: No ID Found -
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 -
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 -
ELife May 2020Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments....
Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.
Topics: Animals; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Female; Fluconazole; High-Throughput Screening Assays; Humans; Meningitis, Cryptococcal; Mice; Mycoses; Structure-Activity Relationship
PubMed: 32367801
DOI: 10.7554/eLife.54160 -
Evidence-based Complementary and... 2020Aqueous-methanolic crude extracts of Flaxseed (Fs.Cr) and Flaxseed oil were tested against 6% acetic acid- (AA-) induced colitis in BALB/c mice. Microscopic damage...
MATERIALS AND METHODS
Aqueous-methanolic crude extracts of Flaxseed (Fs.Cr) and Flaxseed oil were tested against 6% acetic acid- (AA-) induced colitis in BALB/c mice. Microscopic damage parameters of the hematoxylin and eosin-stained and periodic acid-Schiff-alcian blue-stained sections of the colon were scored to be assessed. Possible antispasmodic mechanism was studied on isolated rabbit jejunum, while antibacterial activity was assessed for microbes implicated in IBD.
RESULTS
In AA-induced colitis, Flaxseed oil was found to be more effective in reducing mortality and colonic ulcers than Fs.Cr at 500 mg/kg dose. Fs.Cr was more efficacious in increasing mucin content as compared to oil, exhibiting slightly greater anti-inflammatory effect (50% vs 35%) and reducing depth of lesion (55% vs 42.31%, respectively). Antispasmodic activity of Fs.Cr (0.03 and 0.1 mg/ml) was mediated by phosphodiesterase inhibitors (PDEI, possibly PDE-4 subtype) with a resultant increase in cAMP levels. Flaxseed oil PDEI activity was mild (1 and 3 mg/ml). Fs.Cr (0.1 and 0.3 mg/ml) was potent in exhibiting anticholinergic activity, similar to dicyclomine, whereas Flaxseed oil showed anticholinergic effect at 1 and 3 mg/ml. Flaxseed oil (9 and 14 g/ml) was bactericidal against enteropathogenic (EPEC), enterotoxigenic (ETEC), and enteroaggregative (EAEC), whereas Fs.Cr exhibited bactericidal effect against EPEC at 100 g/ml.
CONCLUSIONS
Results of this study, taken together with previous studies, suggest that Flaxseed possesses anti-inflammatory, antibacterial, and antispasmodic action through multiple pathways and thus offers promising potential to be developed for IBD.
PubMed: 32765633
DOI: 10.1155/2020/7974835