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Indian Journal of Pharmacology 2017The study was designed to evaluate possible antihistaminic and anticholinergic activities of . (Comparative Study)
Comparative Study
OBJECTIVE
The study was designed to evaluate possible antihistaminic and anticholinergic activities of .
MATERIALS AND METHODS
Effects of crude ethanolic (Ed.Eth) and effects of crude aqueous (Ed.Aq) extracts of were studied using isolated guinea pig ileum, rabbit jejunum, and rabbit trachea. Tissue responses were recorded using isotonic and isometric transducers, connected with PowerLab data acquisition system.
RESULTS
A dose-dependent (0.1-0.3 mg/ml) rightward shift was demonstrated in histamine concentration-response curves. Whereas a complete relaxation of carbachol (1 μM)-induced contractions in isolated rabbit jejunum (3 mg/ml) and tracheal (10 mg/ml) preparations was observed, similar to dicyclomine at 1 and 3 μM, respectively. However, no significant difference between the effects of Ed.Eth and Ed.Aq was observed.
CONCLUSION
Study provides pharmacological evidence for the presence of antihistaminic and anticholinergic activities in crude extracts of and also highlight its medicinal significance in the management of airway and gastrointestinal disorders.
Topics: Animals; Cholinergic Antagonists; Dicyclomine; Dose-Response Relationship, Drug; Equisetum; Female; Guinea Pigs; Histamine Antagonists; Ileum; Jejunum; Male; Plant Extracts; Rabbits; Trachea
PubMed: 28458431
DOI: 10.4103/0253-7613.201017 -
BMJ (Clinical Research Ed.) Jan 2017
Topics: Antiemetics; Clinical Trials as Topic; Dicyclomine; Doxylamine; Drug Approval; Drug Combinations; Female; Humans; Morning Sickness; Pregnancy; Pyridoxine
PubMed: 28069575
DOI: 10.1136/bmj.j132 -
PloS One 2017We report information about an unpublished 1970s study ("8-way" Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and...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We report information about an unpublished 1970s study ("8-way" Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and dicyclomine in the management of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 -
Physiology & Behavior Feb 2017Several studies have investigated the transition of consolidation of recent memory to remote memory in aversively motivated tasks, such as contextual fear conditioning...
Several studies have investigated the transition of consolidation of recent memory to remote memory in aversively motivated tasks, such as contextual fear conditioning (CFC) and inhibitory avoidance (IA). However, the mechanisms that serve the retrieval of remote memories, has not yet been fully understood. Some evidences suggest that the central cholinergic system appears be involved in the modulation of these processes. Therefore, the present study aimed to investigate the effects of a pre-test administration of dicyclomine, a high-affinity M1 muscarinic receptor antagonist, on the retrieval of remote memories in fear conditioning and IA tasks. Male Wistar rats were trained, and after 1 or 28days, the rats received dicyclomine (16 or 32mg/kg, intraperitoneally, i.p.) and were tested in CFC, tone fear conditioning (TFC) and IA tasks. At both time intervals, 32mg/kg dicyclomine induced impairment of CFC. In TFC task only the performance of the rats 28days after training was impaired. The IA task was not affected in any of the studied intervals. These findings suggest a differential contribution of muscarinic receptors on recent and remote memories retrieval revealing a more generalized role in remote memory.
Topics: Acoustic Stimulation; Analysis of Variance; Animals; Avoidance Learning; Conditioning, Classical; Dicyclomine; Dose-Response Relationship, Drug; Fear; Male; Mental Recall; Muscarinic Antagonists; Rats; Rats, Wistar; Receptor, Muscarinic M1; Time Factors
PubMed: 27940145
DOI: 10.1016/j.physbeh.2016.12.008 -
BMC Pregnancy and Childbirth Nov 2016Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (Diclegis®) for NVP, based in part, on the results of a phase III randomized trial demonstrating the efficacy of this drug combination [study drug marketed under the trade name Diclectin® in Canada and Diclegis® in the United States] compared to placebo in pregnant women. Study drug dosing occurred for 14 days, which is substantially longer than what has been performed in similar studies. The objective of this study was to evaluate, through secondary analysis, whether the primary measure of efficacy can be demonstrated after five days of treatment.
METHODS
Women suffering from NVP were randomized to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from two to four tablets a day, based on a pre-specified titration protocol. The primary efficacy endpoint was the change in the validated Pregnancy-Unique Quantification of Emesis (PUQE) score at baseline versus Day 15 between Diclegis®-treated and placebo-treated women. For the present study, the change in PUQE score between baseline and Day 15 (end of the study) was compared to the changes observed for Days 3, 4, and 5.
RESULTS
The use of delayed-release doxylamine succinate and pyridoxine hydrochloride tablets show improved NVP symptom control as compared to placebo on Days 3,4 and 5, with sustained efficacy until the end of the trial.
CONCLUSION
A four day study drug dosing trial with Diclegis® is sufficient to document efficacy, as the results are similar to those achieved after 14 study drug dosing days. The benefit seen at the earlier time validates drug efficacy and minimizes the natural course of improvement.
TRIAL REGISTRATION
CTR No. NCT006 14445 2007.
Topics: Antiemetics; Delayed-Action Preparations; Dicyclomine; Doxylamine; Drug Combinations; Female; Humans; Morning Sickness; Pregnancy; Pyridoxine; Time Factors
PubMed: 27881103
DOI: 10.1186/s12884-016-1172-9 -
Journal of Ethnopharmacology Dec 2016Seeds of Sisymbrium irio Linn has been used traditionally in different regions of Pakistan for the treatment of gastrointestinal, airways and vascular system ailments....
Anti-cholinergic and Ca-antagonist mechanisms explain the pharmacological basis for folkloric use of Sisymbrium irio Linn. in gastrointestinal, airways and vascular system ailments.
ETHNOPHARMACOLOGICAL RELEVANCE
Seeds of Sisymbrium irio Linn has been used traditionally in different regions of Pakistan for the treatment of gastrointestinal, airways and vascular system ailments. To insight the pharmacological basis, in vitro study was conducted in order to validate its folkloric uses.
MATERIAL AND METHODS
70% aqueous-methanolic extract of seeds from S. irio (Si.MEs) was tested on isolated rabbit aorta, jejunum and trachea strip hanged in tissue bath having physiological solutions aerated with carbogen and their responses were measured and recorded via Power Lab.
RESULTS
The Si.MEs exhibited the transient spasmogenic effect (0.01-1.0mg/mL) on spontaneous jejunum contractions, followed by the spasmolytic effect. The addition of atropine resulted in blocking in spasmogenic effect while the spasmolytic effect was originated, suggesting the presence of an antimuscarinic effect. Likewise verapamil, Si.MEs (0.03-5mg/mL) repressed the high concentration K(80mM)-induced contraction and also drifted the Ca concentration-response curves toward right (0.3-3.0mg/mL), possibly signifying the Ca channel blockade. Furthermore, Si.MEs exhibited nonspecific relaxant effect on carbachol (1µM)- and high concentration K(80mM)-induced tracheal contractions in a way comparable to dicyclomine, suggesting the coexistence of Ca-antagonistic and/or antimuscarinic properties. Additionally, Si.MEs also relaxed the phenylephrine(1µM)- and high concentration K(80mM)-induced aortic contraction (0.01-3mg/mL), suggesting blockade of Ca channel. Moreover, oral administration of Si.MEs, as high as 6g per kg, did not produce lethality among the treated groups of mice.
CONCLUSIONS
Aqueous-methanolic extract of seeds from S. irio (Si.MEs) exhibited the bronchodilator and gut modulator (spasmogenic and spasmolytic) activities, probably through dual blockade of muscarinic receptors and Ca channels, whereas, vasodilator effect may be due to Ca channels blockade.
Topics: Animals; Aorta; Brassicaceae; Bronchodilator Agents; Calcium Channel Blockers; Cholinergic Antagonists; Dose-Response Relationship, Drug; Ethnobotany; Ethnopharmacology; Female; Folklore; Gastrointestinal Agents; Gastrointestinal Motility; In Vitro Techniques; Jejunum; Male; Methanol; Mice; Muscle Contraction; Phytotherapy; Plant Extracts; Plants, Medicinal; Rabbits; Seeds; Solvents; Trachea; Vasoconstriction; Vasodilator Agents
PubMed: 27693774
DOI: 10.1016/j.jep.2016.09.028 -
The Cochrane Database of Systematic... Sep 2016Infantile colic is a common disorder in the first months of life, affecting somewhere between 4% and 28% of infants worldwide, depending on geography and definitions... (Review)
Review
BACKGROUND
Infantile colic is a common disorder in the first months of life, affecting somewhere between 4% and 28% of infants worldwide, depending on geography and definitions used. Although it is self limiting and resolves by four months of age, colic is perceived by parents as a problem that requires action. Pain-relieving agents, such as drugs, sugars and herbal remedies, have been suggested as interventions to reduce crying episodes and severity of symptoms.
OBJECTIVES
To assess the effectiveness and safety of pain-relieving agents for reducing colic in infants younger than four months of age.
SEARCH METHODS
We searched the following databases in March 2015 and again in May 2016: CENTRAL, Ovid MEDLINE, Embase and PsycINFO, along with 11 other databases. We also searched two trial registers, four thesis repositories and the reference lists of relevant studies to identify unpublished and ongoing studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of pain-relieving agents given to infants with colic.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures of The Cochrane Collaboration.
MAIN RESULTS
We included 18 RCTs involving 1014 infants. All studies were small and at high risk of bias, often presenting major shortcomings across multiple design factors (e.g. selection, performance, attrition, lack of washout period).Three studies compared simethicone with placebo, and one with Mentha piperita; four studies compared herbal agents with placebo; two compared sucrose or glucose with placebo; five compared dicyclomine with placebo; and two compared cimetropium - one against placebo and the other at two different dosages. One multiple-arm study compared sucrose and herbal tea versus no treatment. Simethicone. Comparison with placebo revealed no difference in daily hours of crying reported for simethicone at the end of treatment in one small, low-quality study involving 27 infants. A meta-analysis of data from two cross-over studies comparing simethicone with placebo showed no difference in the number of of infants who responded positively to treatment (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.73 to 1.23; 110 infants, low-quality evidence).One small study (30 participants) compared simethicone with Mentha piperita and found no difference in crying duration, number of crying episodes or number of responders. Herbal agents. We found low-quality evidence suggesting that herbal agents reduce the duration of crying compared with placebo (mean difference (MD) 1.33, 95% CI 0.71 to 1.96; three studies, 279 infants), with different magnitude of benefit noted across studies (I² = 96%). We found moderate-quality evidence indicating that herbal agents increase response over placebo (RR 2.05, 95% CI 1.56 to 2.70; three studies, 277 infants). Sucrose. One very low-quality study involving 35 infants reported that sucrose reduced hours spent crying compared with placebo (MD 1.72, 95% CI 1.38 to 2.06). Dicyclomine. We could consider only one of the five studies of dicyclomine (48 infants) for the primary comparison. In this study, more of the infants given dicyclomine responded than than those given placebo (RR 2.50, 95% CI 1.17 to 5.34). Cimetropium bromide. Data from one very low-quality study comparing cimetropium bromide with placebo showed reduced crying duration among infants treated with cimetropium bromide (MD -30.20 minutes per crisis, 95% CI -39.51 to -20.89; 86 infants). The same study reported that cimetropium increased the number of responders (RR 2.29, 95% CI 1.44 to 3.64).No serious adverse events were reported for all of the agents considered, with the exception of dicyclomine, for which two of five studies reported relevant adverse effects (longer sleep 4%, wide-eyed state 4%, drowsiness 13%).
AUTHORS' CONCLUSIONS
At the present time, evidence of the effectiveness of pain-relieving agents for the treatment of infantile colic is sparse and prone to bias. The few available studies included small sample sizes, and most had serious limitations. Benefits, when reported, were inconsistent.We found no evidence to support the use of simethicone as a pain-relieving agent for infantile colic.Available evidence shows that herbal agents, sugar, dicyclomine and cimetropium bromide cannot be recommended for infants with colic.Investigators must conduct RCTs using standardised measures that allow comparisons among pain-relieving agents and pooling of results across studies. Parents, who most often provide the intervention and assess the outcome, should always be blinded.
PubMed: 27631535
DOI: 10.1002/14651858.CD009999.pub2 -
Anti-cancer Drugs Jan 2017Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the...
Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 µg/ml of dicyclomine. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer.
Topics: Cell Line, Tumor; Cell Proliferation; Dicyclomine; Humans; Male; Pirenzepine; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptors, Androgen; Signal Transduction
PubMed: 27606721
DOI: 10.1097/CAD.0000000000000432 -
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