Scopolamine infusion in the basolateral amygdala after saccharin intake induces conditioned taste avoidance in rats.

RATIONALE: Muscarinic receptor activity in the basolateral amygdala (BLA) is known to be involved in plasticity mechanisms that underlie emotional learning. The BLA is involved in the Attenuation of Neophobia, an incidental taste learning task in which a novel taste becomes familiar and recognized as safe. OBJECTIVE: Here we assessed the role of muscarinic receptor activity in the BLA in incidental taste learning. METHODS: Young adult male Wistar rats were bilaterally implanted with cannulas aimed at BLA. After recovery, rats were randomly assigned to either vehicle or muscarinic antagonist group, for each experiment. We tested the effect of specific and non-specific muscarinic antagonists administered either 1) 20 min before novel taste presentation; 2) immediately after novel taste presentation; 3) immediately after retrieval (the second taste presentation on Day 5 -S2-) or immediately after the fifth taste presentation on Day 8 (S5). RESULTS: Non-specific muscarinic receptor antagonist scopolamine infused prior to novel taste, while not affecting novel taste preference, abolished AN, i.e., the increased preference observed in control animals on the second presentation. When administered after taste consumption, intra-BLA scopolamine not only prevented AN but caused a steep decrease in the taste preference on the second presentation. This scopolamine-induced taste avoidance was not dependent on taste novelty, nor did it generalize to another novel taste. Targeting putative postsynaptic muscarinic receptors with specific M1 or M3 antagonists appeared to produce a partial taste avoidance, while M2 antagonism had no effect. CONCLUSION: These data suggest that if a salient gustatory experience is followed by muscarinic receptors antagonism in the BLA, it will be strongly and persistently avoided in the future. The study also shows that scopolamine is not just an amnesic drug, and its cognitive effects may be highly dependent on the task and the structure involved.

Anisocoria after scopolamine transdermal patch contamination: A case report.

RATIONALE: We report a case of anisocoria that occurred after contamination with a scopolamine transdermal patch, and introduce a diagnostic approach for anisocoria patients. PATIENT CONCERNS: A 35-year-old woman with no past ophthalmologic history presented to the ophthalmology department complaining of a dilated pupil in the right eye. Corrected visual acuities was 20/20 in both eyes, and the intraocular pressures were 20 and 18 mm Hg in the right and left eye, respectively. The anterior chambers in both eyes were unremarkable on slit-lamp examination. The pupil size was 5.0 mm in the right eye and 2.0 mm in the left eye, and the extraocular muscles of both eyes were intact. DIAGNOSIS: The patient neither did present with facial anhidrosis nor did she present with ptosis. Furthermore, as we did not observe dilatation lag in the smaller pupil, we applied 1% apraclonidine in the left eye in order to rule out Horner syndrome and did not observe dilatation of the pupil. We then applied 0.125% and 1% pilocarpine to exclude oculomotor nerve palsy; however, it could not be ruled out as constriction of pupil to 3.1 mm in the right eye was observed after applying 1% pilocarpine. Moreover, upon further investigation, we discovered that the patient had a scopolamine transdermal patch applied for 2 days prior to the clinic visit. INTERVENTIONS: Artificial tears were administered and the patient was observed and monitored. OUTCOMES: The pupil size in the right eye gradually decreased to 4.5 mm on the second day of observation and to 3.6 mm on the fourth day of observation. LESSONS: A detailed history of the use of medications such as scopolamine patches in patients with unilateral dilated pupils without vision loss is of utmost importance. We report the exclusion of important diseases using pilocarpine and apraclonidine hydrochloride. It was confirmed that improvement naturally occurs over time.

Effects of New Galantamine Derivatives in a Scopolamine Model of Dementia in Mice.

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive functions decline, is a leading cause for dementia and currently ranked as the sixth foremost cause of death. As of present, treatment of AD is symptomatic without convincing therapeutic benefits and new, effective, therapeutic agents are pursued. Due to massive loss of cholinergic neurons and decreased acetylcholine levels, cholinesterase inhibitors like galantamine, remain the backbone of pharmacological treatment of the disease. In the present study, using behavioral and biochemical methods, four newly synthesized galantamine derivatives, Gal 34, Gal 43, Gal 44, and Gal 46, were evaluated for a beneficial effect in a scopolamine model of dementia in mice. They were designed to have all the advantages of galantamine and additionally to inhibit ß-secretase and exert favorable effects on plasma lipids. Behavioral tests included step-through inhibitory avoidance, T-maze, and the hole-board test, whereas biochemical evaluations involved assessment of acetylcholinesterase activity, brain monoamines levels, lipid peroxidation, catalase, glutathione peroxidase, and superoxide dismutase activities along with measurement of total glutathione. Results show that Gal 43, Gal 44, and, in particular, Gal 46 are especially effective in improving both short- and long-term memory and in the case of Gal 46 having a significant effect on exploratory activity as well. Although Gal 34 did not show behavioral effects as convincing as those of the other three galantamine derivatives, it demonstrated persuasive antioxidant and restorative capacities, making all four galantamine derivatives promising AD treatment agents and prompting further research, especially that in many of our studies they performed better than galantamine.

A delayed treatment model for the evaluation of scopolamine for VX nerve agent intoxication.

Most research on medical countermeasures for nerve agent exposure assumes a military scenario, in which (autoinjector) treatment is envisaged to be available immediately. In a civilian setting however, treatment is delayed until arrival of first-aid responders. This may significantly affect treatment efficacy and the requirements for secondary intensive care. The aim of the current study was to develop a guinea pig model to evaluate the efficacy of delayed treatment following nerve agent exposure. We identified a trigger-to-treat based on a progressive stage of the toxidrome following VX exposure, which was associated with the subsiding of clonic movements. This paradigm resulted in treatment consistently being administered between 15 and 25 min post-exposure. Using the model, we investigated the potential for the anticholinergic scopolamine to act as a delayed treatment either as a standalone treatment, or as an adjunct to delayed treatment with Standard of Care (SOC), containing atropine, 2-PAM, and midazolam. The study provides a framework for a small animal model for evaluating the efficacy of treatment administered at a specific stage of the toxidrome, when immediate treatment is absent. As an adjunct, scopolamine treatment did not result in improved survival, but did show a beneficial effect on recovery, in terms of general posture. As a standalone treatment, scopolamine showed a significant, dose-responsive, beneficial effect on survival and recovery. These promising results warrant additional studies to investigate which observed physiological improvements are relevant for the recovery process and residual injury.

Investigation of alpha-lipoic acid effect on memory impairment considering strain-dependent differences in mice.

AIMS: Memory impairment is regarded as one of the most challenging neurological disorders. The present study aimed to investigate behavioral and biochemical differences among similar mouse strains following Scopolamine (SCO) exposure as a widespread memory disturbing agent, and a supremely potent antioxidant, alpha-lipoic acid (ALA). MATERIALS AND METHODS: Three sets of mouse strains (i.e. SW, NMRI, and NIH mice) were subjected to 2 mg/kg intraperitoneal SCO and/or 50 mg/kg ALA 30 min before each Morris Water Maze (MWM) trial for five consecutive days. Upon completion of the trials, the hippocampal region of the animals was dissected for histopathological and biochemical analyses. KEY FINDINGS: The results exhibited significant impairments caused by SCO in behavioral tests, including probe test, escape latency, and distance traveled in two strains of NMRI and NIH. Nevertheless, at swimming speed, SCO had no meaningful effect on SW and NIH strains. The level of oxidative stress parameters including MDA, ROS, and SOD increased, FRAP and TTM levels related to the hippocampus decreased. There was also a significant increase in hippocampal acetylcholinesterase levels, ADP/ATP ratio, p-NFkB, and Cyt-c. Conversely, ALA administration resulted in a significant improvement in SCO-induced spatial learning and memory impairments only in the SW and NIH mice, which was associated with a significant reduction in hippocampal AChE activity, ADP/ATP ratio, ROS and MDA levels, and SOD activity. SIGNIFICANCE: In addition of highlighting the efficacious role of ALA in cognitive functions, the findings of this study signified the behavioral dissimilarities among similar animal strains in case of different chemical exposures.

Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug "input rate" into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a "priming" dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.

Open field exposure facilitates the expression of a spatial, recognition memory.

Novelty seems to reduce the persistence of aversive memories and to modulate frustration responses, yet much less is known on how this treatment affects memories lacking hedonic or emotional content. The present study analyzed how a 5-min exposure to a novel open field modulated the expression of a spatial recognition memory. Experiment 1 indicated that male Wistar rats trained in a T-maze in which one goal arm is blocked exhibit, when tested 2 h later, preference for the novel arm. This recognition memory was impaired by the muscarinic cholinergic antagonist scopolamine. Postraining, but not pretraining, novelty exposure rescued the cognitive impairment induced by scopolamine (Experiment 2 and 3). Pretraining open field exposure alleviated the lack of memory expression, induced by imposing a 6 h delay between training and testing (Experiment 4). The study shows that a very brief exposure to novelty can improve expression of a spatial, recognition memory, a modulation that - in the case of the pretraining novelty exposure -- emerges even in spite of cholinergic blockade. The present results are consistent with research suggesting that novelty exposure can be an effective, non-pharmacological, treatment to modulate memory expression.

Evaluation of Phytochemical, Antioxidant, and Memory-Enhancing Activity of Garuga pinnata Roxb. Bark and Bryophyllum pinnatum (Lam) Oken. Leaves.

Garugapinnata Roxb. (Burseraceae) is a medium-sized tree widely available all over the tropical regions of Asia. Bryophyllum pinnatum (Lam) Oken. (Crassulaceae) is an indigenous and exotic plant grown in tropical regions. Both plants have been used for their anti-inflammatory, antioxidant, anticancer, wound healing, antidiabetic activities, etc. This investigation was designed to explore the result shown by methanolic extract of Garuga pinnata bark and Bryophyllum pinnatum leaves, on cognitive power and retention of the memory in experimental mice along with quantification of phenolic compounds and DPPH radicals neutralizing capacity. The memory-enhancing activity was determined by the elevated plus-maze method in Scopolamine-induced amnesic mice, using Piracetam as allopathic and Shankhpushpi as ayurvedic standard drugs. Two doses (200 and 400 mg/kg p.o.) of both extracts were administered to mice up to 8 consecutive days; transfer latency of individual group was recorded after 45 minutes and memory of the experienced things was examined after 1 day. DPPH assay method and the Folin-Ciocalteu method were employed to determine antioxidant potency and total phenol amount, respectively. 400 mg/kg of the methanolic B. pinnatum bark extract significantly improved memory and learning of mice with transfer latency (TL) of 32.75 s, which is comparable to that of standard Piracetam (21.78 s) and Shankhpushpi (27.83 s). Greater phenolic content was quantified in B. pinnatum bark extract (156.80 ± 0.33 µg GAE/mg dry extract) as well as the antioxidant potency (69.77% of free radical inhibition at the 100 µg/mL concentration). Our study proclaimed the scientific evidence for the memory-boosting effect of both plants.

Novel Pyridine-Containing Sultones: Structure-Activity Relationship and Biological Evaluation as Selective AChE Inhibitors for the Treatment of Alzheimer's disease.

Novel pyridine-containing sultones were synthesized and evaluated for their cholinesterase (ChE) inhibitory activity. Most of compounds showed selective acetylcholinesterase (AChE) inhibitory activity. The structure-activity relationship (SAR) showed: (i) the fused pyridine-containing sultones increase AChE inhibition, series B>series A; (ii) for series A, the effect of the 4-substituent on AChE activity, p->m- or o-; (iii) for series B, a halophenyl group increase activity. Compound B4 (4-(4-chlorophenyl)-2,2-dioxide-3,4,5,6-tetrahydro-1,2-oxathiino[5,6-h]quinoline) was identified as a selective AChE inhibitor (IC50 =8.93 µM), and molecular docking studies revealed a good fit into TcAChE via hydrogen interactions between the δ-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive (Ki =7.67 µM) AChE inhibition, nontoxicity and neuroprotective activity. In vivo studies confirmed that compound B4 could ameliorate the cognitive performance of scopolamine-treated C57BL/6 J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD.

Deciphering the scopolamine challenge rat model by preclinical functional MRI.

During preclinical drug testing, the systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used. However, it suffers important limitations, like non-specific behavioural effects partly due to its peripheral side-effects. Therefore, neuroimaging measures would enhance its translational value. To this end, in Wistar rats, we measured whisker-stimulation induced functional MRI activation after SCO, peripherally acting butylscopolamine (BSCO), or saline administration in a cross-over design. Besides the commonly used gradient-echo echo-planar imaging (GE EPI), we also used an arterial spin labeling method in isoflurane anesthesia. With the GE EPI measurement, SCO decreased the evoked BOLD response in the barrel cortex (BC), while BSCO increased it in the anterior cingulate cortex. In a second experiment, we used GE EPI and spin-echo (SE) EPI sequences in a combined (isoflurane + i.p. dexmedetomidine) anesthesia to account for anesthesia-effects. Here, we also examined the effect of donepezil. In the combined anesthesia, with the GE EPI, SCO decreased the activation in the BC and the inferior colliculus (IC). BSCO reduced the response merely in the IC. Our results revealed that SCO attenuated the evoked BOLD activation in the BC as a probable central effect in both experiments. The likely peripheral vascular actions of SCO with the given fMRI sequences depended on the type of anesthesia or its dose.

Muscarinic receptor signaling in the amygdala is required for conditioned taste aversion.

The sense of taste provides information regarding the nutrient content, safety or potential toxicity of an edible. This is accomplished via a combination of innate and learned taste preferences. In conditioned taste aversion (CTA), rats learn to avoid ingesting a taste that has previously been paired with gastric malaise. Recent evidence points to a role of cholinergic muscarinic signaling in the amygdala for the learning and storage of emotional memories. The present study tested the participation of muscarinic receptors in the amygdala during the formation of CTA by infusing the non-specific antagonist scopolamine into the basolateral or central subnuclei before or after conditioning, as well as before retrieval. Our data show that regardless of the site of infusion, pre-conditioning administration of scopolamine impaired CTA acquisition whereas post-conditioning infusion did not affect its storage. Also, infusions into the basolateral but not in the central amygdala before retrieval test partially reduced the expression of CTA. Our results indicate that muscarinic receptors activity is required for acquisition but not consolidation of CTA. In addition, our data add to recent evidence pointing to a role of cholinergic signaling in peri-hippocampal structures in the process of memory retrieval.

Antidepressant-like effect of low dose of scopolamine in the H/Rouen genetic mouse model of depression.

Rodent models of depression are useful for the investigation of cellular and neuronal mechanisms of antidepressant drugs and for the discovery of potential new targets. In this study, we examined the antidepressant-like effect of scopolamine, a non-selective muscarinic antagonist, in a genetic mouse model of depression obtained through a selective breeding strategy and called H/Rouen. In this model, we observed that scopolamine was active both in males and females at a lower dose (0.03 mg/kg) in the tail suspension test, 30 min following its administration, than observed in CD-1 mice. In addition, we showed this antidepressant-like effect was partly inhibited by an injection of 10 mg/kg of the AMPA receptor antagonist NBQX in both males and females, suggesting the antidepressant-like effect of scopolamine was mainly driven by AMPA receptors in the H/Rouen mouse line. Altogether, our results showed the high sensitivity of the H/Rouen mouse model of depression to study the antidepressant-like effects of pharmacological compounds.

Rapid acting antidepressants in the mTOR pathway: Current evidence.

Despite the growing burden of major depressive disorder (MDD) on the society, therapeutic management that is mostly based on the conventional monoaminergic mechanisms, is significantly delimited especially from low response rate and time lag for treatment response; thus, often prolonging the distress for patients. The mechanistic exploration of drug candidates that could exert antidepressant effects rapidly has highlighted the significance of modulating mammalian target of rapamycin (mTOR) pathway in MDD. Fast acting antidepressants acts at different receptors, subunits and sites, including NMDA, AMPA, m1ACh, mGluR2/3 and GluN2B to enhance mTOR function, leading to increase in synaptic protein synthesis, synaptogenesis and spine-remodeling, which in turn contribute to the rapid antidepressant effects. This review focuses on the preclinical and clinical evidences on the fast acting antidepressants that can modulate mTOR pathway. It can be understood that modulating mTOR pathway for rapid onset of antidepressant effect in MDD is not without challenges as some of the drugs have failed in advanced stages of clinical trials. However, considering the recent approval of esketamine as a breakthrough in decades, fast acting antidepressants in the mTOR pathway may have promising prospects in the drug discovery pipeline.

Chronic Administration of Scopolamine Increased GSK3ßP9, Beta Secretase, Amyloid Beta, and Oxidative Stress in the Hippocampus of Wistar Rats.

The increase of amyloid beta (Aß) release and hyperphosphorylation of Tau protein represents the main events related to Alzheimer's disease (AD). Furthermore, the sporadic type represents the most common form of AD. Therefore, the establishment of a non-transgenic animal model that resembles the characteristics of the disease is of particular importance. Scopolamine has been linked to increases in both Aß production and oxidative stress in rat and mice brains. Thus, the purpose of the present work was to identify changes in biomarkers that are related to AD after chronic administration of scopolamine (2 mg/kg i.p., during 6 and 12 weeks) to male Wistar rats. The results showed increased Aß deposition at rat hippocampus which could be due to an increase of ß-site amyloid-ß-protein precursor cleaving enzyme 1 (BACE1) expression and activity. These findings could be related to the increase of glycogen synthase kinase 3 phosphorylated (GSK3ßP9) expression. Finally, the establishment of a state of oxidative stress in groups treated with scopolamine was demonstrated by an increase in free radical content and MDA levels. The present study facilitates our understanding of the changes that occur in biomolecules related to AD in Wistar rats after the chronic administration of scopolamine.

The effect of hyoscine n- butylbromide on labor progress: A systematic review.

BACKGROUND: The objective of this systematic review and meta-analysis was to assess the effectiveness of hyoscine n-butylbromide in labor progress. METHODS: The databases including PubMed, the Cochrane Library, Science-Direct, Scopus and Web of Science were searched for studies published up to December 2019. Articles that published as randomized controlled trials (RCTs), and full-text articles published in English or other languages were included and participants were primi or multigravida women who were in active phase of labor. The intervention included HBB compared to placebo (normal saline) that was used during active phase of labor. Pooled estimates were measured using the fixed or random effect model, while the overall effect was reported in a mean difference (MD). All data were analyzed using Review Manager 5.3. RESULTS: Twenty studies involving 3108 women were included in meta-analysis. Based on subgroup analysis by parity, use of HBB significantly reduced the duration of the first stage of labor in primigravida women (MD = - 57.73; 95% CI: [- 61.48, - 53.60]) and in multigravida women (MD = - 90.74; 95% CI: [- 97.24, - 84.24]). Administering HBB could reduce the second stages of labor in primigravidas and multigravidas about 6 min and 4 min respectively. Also, HBB reduced the duration of the third stage of labor in multigravidas about 3 min. APGAR score at one and 5 min after birth was not affected. The main maternal adverse effect was tachycardia and dry mouth. Labor duration in studies in which the participants were primi-and multigravida was not presented based on separate parities except for four papers, and the route of HBB administration was not the same across all studies. CONCLUSIONS: Although, the effect of HBB was minimal when multigravidas and primigravidas women were considered together, the HBB was clinically effective in primigravida and multigravida women for shortening the first and the second stages of labor. Also, HBB could reduce the length of the third stage of labor in multigravidas.

Endogenous in-session cortisol during exposure therapy predicts symptom improvement: Preliminary results from a scopolamine-augmentation trial.

The purpose of this study was to explore whether individual differences in glucocorticoid concentrations were associated with symptom improvement following exposure therapy for patients with social anxiety disorder. To do this, 60 participants with social anxiety disorder completed a randomized-controlled trial of exposure therapy, where participants were randomized to receive scopolamine-augmentation or placebo during their 7 exposure sessions. Scopolamine is an antimuscarinic which blocks the effects of acetylcholine and reduces autonomic arousal. During sessions 1, 4, 7, and during the post-treatment extinction assessment, participants provided up to 16 saliva samples (4 in each session). Pre-treatment, post-treatment, and at 1-month follow-up, participants completed the Liebowitz Social Anxiety Scale to monitor change in fear and avoidance symptoms. Elevated endogenous in-session cortisol during exposure sessions was associated with less symptom improvement from pre- to post-treatment and at 1-month follow-up. The association between elevated endogenous in-session cortisol and attenuated symptom change was not moderated by scopolamine treatment condition. Individuals with social anxiety disorder who have elevated neuroendocrine signaling may under-benefit from exposure therapy. This is the first study, to our knowledge, to examine whether endogenous in-session cortisol concentrations predict symptom changes following exposure therapy for the treatment of social anxiety disorder. More investigation of non-invasive and reliable biological markers that explain variability in responses to effective treatments are needed.

Determination of Rate and Extent of Scopolamine Release from Transderm Scop® Transdermal Drug Delivery Systems in Healthy Human Adults.

To estimate strength of a scopolamine transdermal delivery system (TDS) in vivo, using residual drug vs. pharmacokinetic analyses with the goal of scientifically supporting a single and robust method for use across the dosage form and ultimately facilitate the development of more consistent and clinically meaningful labeling. A two-arm, open-label, crossover pharmacokinetic study was completed in 26 volunteers. Serum samples were collected and residual scopolamine was extracted from worn TDS. Delivery extent and rate were estimated by (1) numeric deconvolution and (2) steady-state serum concentration determined from graphical and non-compartmental analyses. In residual drug analyses, mean ± SD scopolamine release rate was 0.015 ± 0.002 mg/h (11% RSD), vs. 0.016 ± 0.006 mg/h (35% RSD) from numeric deconvolution, 0.015 ± 0.005 mg/h (34% RSD) from graphical analysis, and 0.015 ± 0.007 mg/h (44% RSD) from non-compartmental analysis. In residual drug analyses, total drug released was 1.09 ± 0.11 mg (10% RSD), vs. 1.12 ± 0.40 mg (35% RSD) from numeric deconvolution, 1.07 ± 0.35 mg (33% RSD) from graphical analysis, and 1.07 ± 0.45 (42% RSD) from non-compartmental analysis. Extent and rate of scopolamine release were comparable by both approaches, but pharmacokinetic analysis demonstrated greater inter-subject variability.

In silico, in vitro and in vivo studies indicate resveratrol analogue as a potential alternative for neuroinflammatory disorders.

Inflammaging is known as an imbalance between pro-inflammatory and anti-inflammatory immune mechanisms, being related to the onset of neurological disorders, such as major depression and Alzheimer's disease. Considering the known disadvantages regarding the FDA approved drug to manage such illnesses, resveratrol emerges as a natural drug candidate, despite its low bioavailability. In this study, resveratrol analogues were evaluated for their capacity of inhibiting acetylcholinesterase in silico, in vitro, and in vivo. Molecular docking simulations pointed out RSVA1 and RSVA6 as potent inhibitors, even more than resveratrol. Ellman's assay demonstrated RSVA6 as capable of inhibiting 92.4% of the enzyme activity. Further, male Swiss mice were pretreated with RSVA6 (100 mg kg-1) 60 min before receiving scopolamine (1 mg kg-1). The Novel Recognition Object (NOR), Object Location (OLT), and Buried Pellet tests (BPL) demonstrated an RSVA6 neuroprotective effect. In the second round of tests, mice received a single intraperitoneal injection of lipopolysaccharide (0.5 mg kg-1) 24 h before treatment with RSVA6 (1, 10, and 100 mg kg-1). The Open Field (OFT), Tail Suspension (TST), and Splash tests (ST) were evaluated. LPS had no significant effect on the crossing and rearing number, indicating an association between the immobility time and anhedonia observed in the TST and ST, respectively, with depressive-like behavior. RSVA6 significantly reduced the depressive-like behavior triggered by LPS in the TST and ST. Altogether, our data suggest RSVA6 as a potential drug candidate for the treatment of neuroinflammatory conditions.

A double-blind placebo-controlled randomized trial on the effect of hyosine n-butyl bromide for improving duration of labor in term pregnancies.

AIM: To compare the effectiveness of intramuscular hyocine n-butyl bromide (HBB) with placebo for shortening the duration of the first stage of labor in term pregnancies. METHODS: A double blind placebo-controlled randomized trial of parturients who presented at term in the active phase of labor was conducted. They were randomly (1:1 ratio) given intramuscular injection of either 40 mg (2 mL) of HBB or 2 mL of water for injection as a placebo. The primary outcome measures were the duration of first and second stages of labor. Subgroup analysis of primigravid and multigravid women were also performed for various outcomes. We did intention-to-treat analysis. RESULTS: Sixty-two women were randomized to each group and none were lost to follow-up. Baseline characteristics were similar between the HBB and placebo groups. The mean duration of first stage of labor was noted to be significantly shorter in the HBB group for both the primigravidas (246.6 ± 21.9 vs 391.8 ± 56.6 min for control; P < 0.001) and for multigravidas (205.9 ± 17.8 vs 323.8 ± 16.0 min for control;P < 0.001).There was also significantly shorter duration of second stage of labor in the HBB group (primigravida: P = 0.013; multigravida: P = 0.016). The duration of third stage of labor, mode of delivery and maternal and/or neonatal outcomes for both classes of parturients were not significantly different. CONCLUSION: HBB is effective in reducing the first and second stages of labor without adverse maternal or neonatal outcome. HBB does not significantly influence the duration of third stage of labor including mode of delivery. More evidence is needed to further explore the potential useful role of HBB in the active phase of labor.

A randomised, double-blind, active placebo-controlled, parallel groups, dose-response study of scopolamine hydrobromide (4-6 µg/kg) in patients with major depressive disorder.

BACKGROUND: Depressive disorders are a leading cause of disability, but current behavioural and pharmacological therapies have a slow onset of response, typically taking several weeks before achieving efficacy. Prior studies using triplicate intravenous scopolamine infusions have been shown to reduce depressive symptomologies within days compared to saline placebo infusions. However, several parameters of scopolamine's potential antidepressant effect remain unknown, such as its dose-response profile and its washout period. There is also the question as to whether the previously reported antidepressant responses were confounded by unblinding effects due to the lack of an active placebo control. Glycopyrronium bromide was selected as placebo for this trial given it has similar antimuscarinic properties to scopolamine hydrobromide but an inability to cross the blood-brain barrier, thereby hypothetically mimicking only the peripheral effects of scopolamine. METHODS/DESIGN: A parallel group trial of single intravenous scopolamine infusions at three doses (4, 5, and 6 µg/kg) along with one glycopyrronium bromide 4 µg/kg group will be administered to 40 participants with major depressive disorder in a 1:1:1:2 ratio, respectively. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 4 hours, 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks post-infusion to determine antidepressant efficacy. As a secondary measure, the Quick Inventory of Depressive Symptomatology will be administered alongside the MADRS to further track potential antidepressant responses. Other secondary measures include electroencephalography, blood samples, and Bowdle visual acuity scales recorded at baseline, 5, 10, 15, 20, 30, 60, 120, and 240 min post-infusion to determine the pharmacokinetic-pharmacodynamic profile of scopolamine in depressed participants. DISCUSSION: This trial contributes to the literature surrounding the efficacy of scopolamine as an antidepressant. Determining the dose-response profile and washout period of scopolamine's antidepressant effect will also provide important information for designing and conducting crossover trials. The use of an active placebo is important to reduce potentially confounding expectancy effects. TRIAL REGISTRATION: The trial was registered in the Australian New Zealand Clinical Trials Registry (registration number ACTRN12619000569101). Registered on 11 April 2019.