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PloS One 2017We report information about an unpublished 1970s study ("8-way" Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
We report information about an unpublished 1970s study ("8-way" Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and dicyclomine in the management of nausea and vomiting during pregnancy. We are publishing the trial's findings according to the restoring invisible and abandoned trials (RIAT) initiative because the trial was never published.
DESIGN
Double blinded, multi-centred, randomized placebo-controlled study.
SETTING
14 clinics in the United States.
PARTICIPANTS
2308 patients in the first 12 weeks of pregnancy with complaints of nausea or vomiting were enrolled.
INTERVENTIONS
Each patient was randomized to one of eight arms: placebo, doxylamine/pyridoxine/dicylcomine, doxylamine/pyridoxine, dicylomine/pyridoxine, doxylamine, dicyclomine/pyridoxine, pyridoxine and dicyclomine. Each patient was instructed to take 2 tablets at bedtime and 1 additional tablet in the afternoon or morning if needed, for 7 nights.
OUTCOMES
Reported outcomes included the number of hours of nausea reported by patients, the frequency of vomiting reported by patients and the overall efficacy of medication as judged by physicians.
RESULTS
Data from 1599 (69% of those randomized) participants were analyzed. Based on the available summary data of physician evaluation of symptoms and ignoring missing data and data integrity issues, the proportion of participants who were "evaluated moderate or excellent" was greater in each of the seven active treatment groups when compared with placebo (57%): doxylamine/pyridoxine/dicylcomine (14% absolute difference versus placebo; 95% CI: 4 to 24), doxylamine/pyridoxine (21; 95% CI 11 to 30), dicylomine/pyridoxine (21; 95% CI 11 to 30), doxylamine (20; 95% CI 10 to 29), dicyclomine/pyridoxine (4; 95% CI -6 to 14), pyridoxine (9; 95% CI -1 to 19) and dicyclomine (4; 95% CI -6 to 14). Based on incomplete information, the most common adverse events were apparently drowsiness and fatigue. There is a high risk of bias in these previously unpublished results given the high attrition rate in a 7 day trial, the lack of prespecified outcomes or analyses, and the exclusion of some data because of questionable data integrity.
CONCLUSION
The available information about this "8-way Bendectin" trial indicates it should not be used to support the efficacy of doxylamine, pyridoxine or dicyclomine for the treatment of nausea and vomiting during pregnancy because of a high risk of bias.
TRIAL REGISTRATION
Not registered.
Topics: Cooperative Behavior; Dicyclomine; Doxylamine; Drug Combinations; Female; Humans; Nausea; Physicians; Placebos; Pregnancy; Pregnancy Complications; Publication Bias; Publications; Pyridoxine; Research Report; Risk; Vomiting
PubMed: 28052111
DOI: 10.1371/journal.pone.0167609 -
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 -
Indian Journal of Pharmaceutical... 2014Liquid chromatographic method was developed for simultaneous quantitative determination of dicyclomine hydrochloride, mefenamic acid and paracetamol in their combined...
Liquid chromatographic method was developed for simultaneous quantitative determination of dicyclomine hydrochloride, mefenamic acid and paracetamol in their combined dosage form. The separation was achieved using a C18 column (250×4.6 mm id, 5 μm) using acetonitrile:20 mM potassium dihydrogen phosphate 70:30 (v/v) adjusted to pH 4 using orthophosphoric acid as mobile phase at a flow rate of 1 ml/min and detection at 220 nm. Separation was completed within 12 min. The retention times of dicyclomine hydrochloride, mefenamic acid and paracetamol were 3.8, 9.3 and 2.5 minutes respectively. The proposed method was found to have linearity in concentration range of 10-100 μg/ml for dicyclomine hydrochloride, 0.05-10 μg/ml for mefenamic acid and 0.1-20 μg/ml for paracetamol. The developed method has been statistically validated and was found to be simple, precise, reproducible and accurate. The developed and validated method was successfully used for the quantitative analysis of commercially available dosage form.
PubMed: 25593386
DOI: No ID Found -
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 -
Indian Journal of Anaesthesia Apr 2020
PubMed: 32489212
DOI: 10.4103/ija.IJA_848_19 -
Research in Pharmaceutical Sciences Oct 2019Galantamine (GAL) is a drug for treating Alzheimer's disease which has reasonable and no significant side effects. Studies have shown that GAL possesses antioxidant,...
Galantamine (GAL) is a drug for treating Alzheimer's disease which has reasonable and no significant side effects. Studies have shown that GAL possesses antioxidant, anti-inflammatory, and cholinomimetic effects that might be beneficial for inflammatory bowel disease. Therefore, this study was aimed to investigate the anti-inflammatory effect of GAL on acetic acid-induced colitis in rats. GAL at 0.25, 1.25, 2.5 mg/kg/day was administrated orally (p.o.) to different groups of male Wistar rats 2 h before induction of ulcer with acetic acid 3% and continued for 5 consecutive days. Dicyclomine (DIC) was similarly used alone (5 mg/kg/day, p.o.) or together with GAL at doses already mentioned to delineate the impact of muscarinic pathway in probable beneficial effects of GAL on colitis. Control and reference groups received distilled water (5 mL/kg, p.o.), prednisolone (4 mg/kg/day, p.o.), or mesalazine (100 mg/kg/day, p.o.) respectively. At day 6, tissue injuries were assessed for macroscopic, histopathologic, and biochemical indices of myeloperoxidase and MPO activity. Results showed that GAL at 3 applied doses, alone or in combination with DIC diminished ulcer index, total colitis index, and MPO activity as important biomarkers of colitis. DIC alone was not effective on most parameters and its concurrent administration with GAL couldn't reverse its antiulcerative effects. Prednisolone and mesalazine were both effective in this relation. The current research indicated that GAL had anti-inflammatory and antiulcerative activities independent of its muscarinic effects. Thus the antioxidant and anti-inflammatory effects may account for its anti-inflammatory and anti-ulcerative properties. Nevertheless, further detailed studies are warranted for exact elucidation of GAL mechanism on inflammation and colitis.
PubMed: 31798655
DOI: 10.4103/1735-5362.268199