Chemical cross-linking: A feasible approach to prolong doxylamine/pyridoxine release from spray-dried chitosan microspheres.

Spray-dried chitosan microparticles have been widely exploited as vehicles for mucosal drug delivery. Despite their advantages as pharmaceutical formulations, one of the major challenges is achieving sustained drug release, which would diminish toxicity and dosage frequency. The aim of this study was to formulate mucoadhesive glutaraldehyde cross-linked chitosan microparticles loaded with doxylamine succinate and pyridoxine hydrochloride as potential nasal drug delivery systems with sustained release. Microparticle models were formulated via spray-drying technique, using glutaraldehyde in different concentrations (0.1-1.0 mg/mL) as a cross-linking agent for chitosan. The obtained particles were with spherical shape, smooth surface and median diameter of 4 µm. The drug entrapment efficiency was high (80.47%-94.25%), indicating a tendency to decrease at higher glutaraldehyde concentrations. FTIR data demonstrated that there were no chemical interactions between glutaraldehyde and the drugs. The in vitro studies showed that the cross-linking process substantially limited particles swelling. The cross-linked particles exhibited sustained drug release characteristics at pH 6.8 over a period of 5 h with an initial burst-effect in the first 30 min. Drug release followed Korsmeyer-Peppas kinetics. Although a decrease of the particles mucoadhesive properties was observed after modification, all cross-linked formulations demonstrated high in vitro adsorption of mucin. The proposed models of mucoadhesive microsphere with sustained drug release are a perspective ground for further development of a novel delivery system for nasal administration of doxylamine and pyridoxine.

A pharmacological evidence for the presence of antihistaminic and anticholinergic activities in Equisetum debile Roxb.

OBJECTIVE: The study was designed to evaluate possible antihistaminic and anticholinergic activities of Equisetum debile. MATERIALS AND METHODS: Effects of crude ethanolic (Ed.Eth) and effects of crude aqueous (Ed.Aq) extracts of E. debile 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 E. debile and also highlight its medicinal significance in the management of airway and gastrointestinal disorders.

Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy.

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.

Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting 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, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. METHODS: We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. RESULTS: Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. CONCLUSIONS: Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy. TRIAL REGISTRATION: Clinical Trial Registration No: NCT00614445 .

Enhanced histamine H2 excitation of striatal cholinergic interneurons in L-DOPA-induced dyskinesia.

Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are preferentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3(ak/ak) mutation), we chronically treated the animals with either vehicle or l-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.

A new pharmacologic treatment for nausea and vomiting of pregnancy.

Nausea and vomiting of pregnancy (NVP) affects up to 80 percent of pregnant women. This condition is usually self-limiting, but the symptoms can be distressing and interfere with work, social activities and sleep. Symptoms can often be managed by diet and lifestyle changes, but these interventions may not be successful for everyone. In April 2013, the U.S. Food and Drug Administration approved doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg (Diclegis) as the first medication to specifically treat NVP in more than 30 years. This article reviews the indications, dosage and nursing interventions associated with using doxylamine succinate/pyridoxine to treat NVP.

Factors effecting the morphology of Eudragit S-100 based microsponges bearing dicyclomine for colonic delivery.

The purpose of this study was to design microsponge-based novel colon-specific drug delivery system bearing dicyclomine. Eudragit S-100-based microsponges containing the drug in varying amount were prepared using quasi-emulsion solvent diffusion method. The microsponges were prepared by optimizing various process parameters. Differential scanning calorimetry and Fourier transform infrared studies indicated compatibility and stability of the drug in various formulations. Shape and surface morphology of the microsponges were examined using scanning electron microscopy. The formulations were subjected to in vitro release studies, and the results were evaluated kinetically and statistically. In vitro release data showed a biphasic pattern with an initial burst effect. In the first hour, drug release from microsponges was found to be between 17% and 31%. The cumulative percent release at the end of eighth hour was noted to be between 53% and 83%. The release kinetics showed that the data followed Higuchi model and the main mechanism of drug release was diffusion. The colon-specific tablets were prepared by compressing the microsponges followed by coating with pectin:hydroxypropylmethylcellulose mixture. In vitro release studies exhibited that compression-coated colon-specific formulations started releasing the drug at the sixth hour corresponding to the arrival time at colon. The study presents a new approach for colon-specific drug delivery.

Role of muscarinic M1 receptors in inhibitory avoidance and contextual fear conditioning.

The objective of the present study was to observe the effects of pre-training or post-training administration of dicyclomine, a M1 muscarinic antagonist, on inhibitory avoidance (IA) and contextual fear conditioning (CFC) and to investigate if the effects observed with the pre-training administration of dicyclomine are state-dependent. For each behavioral procedure (IA and CFC) groups of Wistar male rats were treated with saline or dicyclomine either 30 min before training (pre-training), immediately after training or 30 min before training/30 min before test (pre-training/pre-test). The animals were tested 24 h after training. The acquisition of IA and CFC was impaired by pre-training administration of dicyclomine. The consolidation of both tasks was not affected by dicyclomine given immediately after training. Pre-training/pre-test administration of dicyclomine impaired both tasks, an effect similar to that observed in the group which only received pre-training administration. Pre-test treatment induced dissociation between both tasks, impairing CFC retrieval, without interfering with the animals avoidance response. These results show that the dicyclomine did not affect IA and CFC consolidation, suggesting specific involvement of M1 muscarinic receptor only in acquisition these tasks, and these effects was not state-dependent. However, it is possible that the retrieval of these tasks may be mediated, at least in part, by different neurochemical mechanisms and may be dissociated by dicyclomine.

M1 receptors play a central role in modulating AD-like pathology in transgenic mice.

We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD.

Dose effect of dicyclomine on the reduction of peristaltic artifacts on MRI of the abdomen.

BACKGROUND: It has been demonstrated that oral administration of dicyclomine significantly reduces the noise associated with the movement of the gastrointestinal tract in abdominal magnetic resonance (MR) images. Our objective was to determine the efficacy and security of two different doses of oral dicyclomine for the reduction of the gastrointestinal noise in abdominal MR imaging. METHODS: Forty-eight patients with MR imaging of the upper abdomen were enrolled in a prospective, controlled, randomized, and double-blind study. All patients ingested barium of high density (196 g in 130 mL of tap water, 250 w/v) approximately 25 min before the MR examination. Patients were randomly distributed into three groups of 16 patients each: (a) no-drug control group, (b) 20 mg of dicyclomine chlorhydrate, and (c) 80 mg of dicyclomine chlorhydrate. Quantitative image analysis was performed with region-of-interest measurements of the signal intensity in background air posterior and lateral to the patient and in the liver. Adverse effects were counted at 2 h and 1 day after the MR examination. RESULTS: The liver and incoherent noise signal intensities were not statistically different among groups. The control group presented a gastrointestinal noise (mean and SD of the air signal intensity) that was statistically superior to that of the groups with dicyclomine (p = 0.004 and p = 0.004, respectively), although significant differences were not observed between the two dicyclomine groups. Although the differences were not significant, adverse effects were more frequently associated with the higher doses of dicyclomine. All the adverse effects (most frequently, constipation, diarrhea, and abdominal pain) were considered minor and did not require treatment. CONCLUSION: Oral dicyclomine is effective and safe for the reduction of peristaltic artifacts on abdominal MR imaging. The dose of 20 mg presents an efficacy similar to that of 80 mg, with a probably lower incidence of adverse reactions.

Different effects of an oral anticholinergic drug on gastroesophageal reflux in upright and supine position in normal, ambulant subjects: a pilot study.

OBJECTIVE: There is controversy in the literature on the effects of anticholinergic drugs on gastroesophageal reflux. Our aim was to study more extensively the effects of an oral anticholinergic drug on esophageal motility and gastroesophageal reflux in normal ambulant subjects under different circumstances: upright, supine, fed, and fasted state. METHODS: Fifteen healthy subjects (seven men, eight women), mean age 34 yr (range, 22-61 yr) underwent randomized placebo-controlled 16-h evening and overnight ambulatory esophageal motility/pH study. After a 3-day loading dose of either oral dicyclomine (Dic) 20 mg four times daily or placebo (Pla), an ambulatory esophageal motility/pH study was performed while taking medication or placebo. Each study was analyzed for meal, first and second h postprandial, upright and supine periods, and first 2 h supine after bedtime snack. RESULTS: The mean number of reflux episodes decreased with dicyclomine during the first h postprandial (Dic, 1.9 vs Pla, 2.5; p < 0.05). During the first 2 h supine, mean number of reflux episodes increased with dicyclomine (Dic, 1.4 vs Pla, 0.8; p < 0.09), as did mean percent time pH < 4 (Dic, 2.6 vs Pla, 0.5; p < 0.04), with an increase in clearance time (Dic, 0.9 vs Pla, 0.3; p < 0.05; in min). Mean peristaltic amplitude decreased with dicyclomine during the 2nd h postprandial (Dic, 48.8 vs Pla, 56.3; p < 0.04). CONCLUSIONS: Oral dicyclomine caused a decrease in early postprandial upright reflux episodes, but also significantly increased the percent time pH < 4 during the first two h supine. Therefore, its effects are dependent on body position and fasted or fed state. Our results justify additional studies with oral anticholinergic agents in patients with gastroesophageal reflux disease.

Reduction of peristaltic artifacts on magnetic resonance imaging of the abdomen: a comparative evaluation of three drugs.

BACKGROUND: Peristaltic motion is an omnipresent source of degradation in abdominal magnetic resonance (MR) imaging by blurring images and producing ghost artifacts that can mask or mimic lesions. The objective of this study was to select an effective and easy-to-administer drug to provide consistent reduction of peristaltic motion artifacts on MR images. METHODS: One hundred forty-eight adult patients with MR examinations of the abdomen were enrolled in a prospective, single-blind comparative study. Four groups were defined: (a) no-drug control group (n = 35), (b) 1 mg of intravenous (IV) glucagon (n = 19), (c) 20 mg of IV butylscopolamine (n = 28), and (d) 20 mg of oral dicyclomine (n = 66). All patients received high-density barium sulphate as a negative oral contrast medium. Quantitative image analysis was performed with operator-defined region-of-interest measurements of signal intensity. Gastrointestinal noise was measured outside the patient at the posterior part of the left hemiabdomen along the phase-encoding direction on a short inversion time inversion recovery (STIR) sequence. RESULTS: Treatment groups showed reduced gastrointestinal noise (p < 0.01). When compared with the control group, IV butylscopolamine (p < 0.05) and oral dicyclomine (p < 0.05) significantly reduced gastrointestinal noise, whereas glucagon did not. CONCLUSION: Anticholinergic drugs significantly reduced the intensity of ghost artifacts on MR imaging of the abdomen. Twenty milligrams of oral dicyclomine is an effective and safe alternative to more expensive and parenterally administered drugs such as glucagon and butylscopolamine.

Dicyclomine for medical management of persistent anal fissure with associated spasm of the internal sphincter.

The case of a 43-year-old woman with persistent anal fissure responsive to dicyclomine is described. Associated spasm of the internal sphincter had precluded fissure healing. The spasm of the internal sphincter relaxed within 24 hours of dicyclomine administration and subsequently allowed healing. Surgery was avoided.

Facilitation of amphetamine-induced rotation by muscarinic antagonists is correlated with M2 receptor affinity.

This study examined the relationship between the affinity of cholinergic drugs for muscarinic receptor subtypes and their potency in potentiating or inhibiting amphetamine-induced rotation. The ascending nigrostriatal dopaminergic pathway was unilaterally lesioned in male Wistar rats using 6-hydroxydopamine. In these rats, ipsiversive rotation induced by amphetamine sulphate (1 mg/kg, s.c.) was dose-dependently inhibited by the cholinergic agonists oxotremorine, RS86 and pilocarpine and by the acetylcholinesterase inhibitor physostigmine. In contrast the cholinergic antagonists scopolamine, secoverine and dicyclomine facilitated amphetamine-induced rotation. Agonist and antagonist potencies were then compared with M1 and M2 binding site affinities estimated by displacing [3H]pirenzepine from forebrain and [3H]QNB from brainstem homogenates. The data suggest a relationship between antagonist potency and M2 binding site affinity.

Effect of dicyclomine on intestinal absorption, disposition and biliary excretion of dexamethasone.

The effect of dicyclomine, a cholinergic blocking agent, on the in situ intestinal absorption, plasma clearance, biliary excretion of dexamethasone was examined in rats. The plasma concentrations and area under the plasma concentration-time curve (AUC) of dexamethasone after both a single and repeated oral coadministration with dexamethasone phosphate (4 mg/kg) and dicyclomine (4 mg/kg) were significantly reduced compared with those after dexamethasone alone, without the alteration of elimination rate. The in situ absorption study also indicated that the absorption of dexamethasone was reduced to about a half after repeated coadministration of the two drugs. The renal plasma flow (RPF) in coadministration group was significantly enhanced compared with that of dexamethasone alone. The biliary excretion of dexamethasone was reduced, in proportion to the plasma concentrations, by dicyclomine. Therefore, dicyclomine should be administered taking much care in the corticosteroid treatment, because of producing the decrease in absorption.

The treatment of the uninhibited bladder with dicyclomine.

Symptomatic treatment of the uninhibited bladder has presented a challenge because of the lack of an effective, well tolerated smooth muscle relaxant for the bladder that can be used during an extended interval. In a preliminary study oral dicyclomine produced resolution or significant improvement of symptoms in 24 of 27 patients and an increase in bladder capacity by an average of 137 plus or minus 26 ml. (91 plus or minus 22 per cent) after 8 weeks of therapy. Additional controlled trials definitely are warranted.

A comparison of an antacid plus antispasmodic combination and aluminium hydroxide in dyspepsia.

A single-blind, between-patient comparative study was carried out in general practice to assess the effectiveness of antacid plus antispasmodic combination tablets (240 mg dried aluminium hydroxide B.P., 144 mg magnesium hydroxide B.P.C., and 5 mg dicyclomine hydrochloride B.P.) and aluminium hydroxide B.P. tablets (500 mg) in the management of chronic dyspepsia. Twenty patients received the combination tablets and 17 the single antacid tablets. They were instructed to chew 2 tablets 3 or 4-times daily and an additional 2 tablets at night if necessary. Patients were assessed initially, and then at 2 and 4 weeks. Both preparations were effective in controlling dyspeptic symptoms. Heartburn and nausea showed an early, significantly greater (p less than 0.05) response to the combined tablet, as did night pain after 4 weeks. Tablet intake of both preparations averaged out at just under 7 tablets per day.