Muscarinic Agents Research Articles

Effects of glycopyrrolate and atropine for oral secretions and perioperative hemodynamics in children undergoing tonsillectomy and adenoidectomy: a prospective, single-center, randomized, double-blind, controlled trial.

Glycopyrrolate is commonly researched as a preoperative medication or in conjunction with cholinesterase inhibitors to counteract the lingering muscarinic effects of non-depolarizing muscarinic agents. However, studies have yielded inconsistent results regarding the superiority of glycopyrrolate over other anti-cholinergic drugs, such as atropine, particularly its effect on heart rate, blood pressure (BP), and glandular secretions. This study aimed to evaluate the differences in perioperative oral secretions, hemodynamics, and recovery quality with glycopyrrolate versus those with atropine before anesthesia induction in children undergoing tonsillectomy and adenoidectomy. In this prospective, single-center, randomized, double-blind, controlled trial, a total of 103 children were randomly assigned to group A (n = 51, glycopyrrolate 0.005mg/kg) or B (n = 52, atropine 0.01mg/kg). The follow-up anesthetic induction and maintenance protocols were the same in both groups. Vital signs, duration of surgery, extubation time, degree of wetness around the vocal cords during tracheal intubation, weight of oral secretions, and perioperative complications were recorded. No significant differences were observed in the degree of wetness around the vocal cords during tracheal intubation, as well as in the weight of oral secretions, duration of surgery, or extubation time, between the two groups. The intraoperative and postoperative heart rates were lower in group A than in group B (110.18 ± 10.58 vs. 114.94 ± 11.14, p = 0.028; 96.96 ± 10.81 vs. 103.38 ± 10.09, p = 0.002). The differences observed in the intraoperative and preoperative heart rates were lower in group A than in group B (23.84 ± 9.62 vs. 29.65 ± 8.75, p = 0.002). The differences observed in the postoperative and preoperative heart rates were lower in group A than in group B (10.63 ± 9.97 vs. 18.09 ± 9.39, p = 0.000). Glycopyrrolate showed a smoother change in heart rate than atropine during and after tonsillectomy and adenoidectomy, with no effect on BP or recovery quality, and did not increase oral secretions. The findings indicate that glycopyrrolate can serve as an alternative to atropine to prevent secretions in anesthesia induction for tonsillectomy and adenoidectomy in children. Trial registration: This study was registered with the Chinese Clinical Trial Registry (Registration Number: ChiCTR2200063578; Date of Registration: 12/09/2022).

Sex-Dependent Regulation of Mucin Gene Transcription and Goblet Cell Secretion Machinery Following Intra-Airway IL-13 in Mice with Conditional Loss of Club Cell Creb1

IL-13 is an important effector molecule in allergic asthma, converting secretoglobin-positive club cells into mucin-secreting goblet cells and promoting mucin hypersecretion. IL-13-mediated conversion of club cells to goblet cells requires decreased gene expression of forkhead box A2 ( FOXA2) and increased gene expression of SAM pointed domain containing ETS transcription factor ( SPDEF). In addition, IL-13-mediated mucin hypersecretion may include modulation of purinergic and muscarinic receptors that control basal and stimulated mucus secretion, respectively. We recently found that the cAMP response element-binding protein (CREB), a ubiquitous transcription factor, directly binds to FOXA2 and modulates mucus secretion mechanisms in mice. Here we tested the hypothesis that conditional loss of club cell Creb1 in murine airways modulates the pro-mucin effects of IL-13. Loss of club cell Creb1 augmented IL-13-mediated increases in gene expression of the major gel-forming secreted mucins Muc5ac and Muc5b in male murine airways, with no effect on IL-13-mediated increases in Muc5ac and Muc5b in female murine airways. Examination of mucin secretion mechanisms revealed that IL-13 decreased muscarinic 3 receptor ( M3R) mRNA expression in male murine airways, whereas loss of club cell Creb1 prevented this, resulting in a significant treatment by genotype interaction. Interestingly, in female airways, a main effect of genotype was observed, with loss of club cell Creb1 reducing M3R mRNA expression in the airway. Examination of the purinergic receptor P2Y ( P2ry2) mRNA revealed a main treatment effect for IL-13 to increase P2ry2 expression in male murine airways with no impact of loss of club cell Creb1. In the females, IL-13 increased P2ry2 mRNA in both genotypes, with loss of club cell Creb1 significantly blunting the effect of IL-13 on P2ry2 mRNA. Lastly, we examined goblet cell density and mucin secretion mechanisms using Alcian Blue-PAS staining post in vivo stimulation with a muscarinic agent. We found no major effect of treatment or genotype in the density of goblet cells containing acidic mucins in either male or female airways. In contrast, both males and females showed IL-13-mediated increases in the density of goblet cells containing neutral mucins that was not impacted by genotype. Our preliminary findings suggest that loss of club cell Creb1 decreases molecular mucin secretion mechanisms in male and female airways, and increases Muc5ac and Muc5b mRNA in male airways, though a corresponding genotype-dependent increase in goblet cell density post cholinergic stimulation was not observed. Thus, we conclude that loss of club cell Creb1 causes changes to molecules important for IL-13-mediated mucin hypersecretion, without apparent functional benefit or detriment to the murine airway. This work was supported by the National Institutes of Health (OD026582, HL152101), the Cystic Fibrosis Foundation (REZNIKO20I0, REZNIKO19I0), the Katie Rose Foundation (AWD08203), and the University of Florida McKnight Career Accelerator Award. Angelina Bonilla was funded by the National institutes of Health (R25GM115298). Pedro Trevizan Bau receives the University of Florida McKnight Brain Institute Gator NeuroScholar Fellowship. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Muscarinic Cholinoreceptors in Skeletal Muscle: Localization and Functional Role.

The review focuses on the modern concepts of the functions of muscarinic cholinoreceptors in skeletal muscles, particularly, in neuromuscular contacts, and that of the signaling pathways associated with the activation of various subtypes of muscarinic receptors in the skeletal muscles of cold-blooded and warm-blooded animals. Despite the long history of research into the involvement of muscarinic receptors in the modulation of neuromuscular transmission, many aspects of such regulation and the associated intracellular mechanisms remain unclear. Now it is obvious that the functions of muscarinic receptors in skeletal muscle are not limited to the autoregulation of neurosecretion from motor nerve endings but also extend to the development and morphological rearrangements of the synaptic apparatus, coordinating them with the degree of activity. The review discusses various approaches to the study of the functions of muscarinic receptors in motor synapses, as well as the problems arising when interpreting experimental data. The final part of the review is devoted to an analysis of some of the intracellular mechanisms and signaling pathways that mediate the effects of muscarinic agents on neuromuscular transmission.

Feasibility of implementing a web-based tool built from pharmacy claims data (e-MEDRESP) to monitor adherence to respiratory medications in primary care

Objectives e-MEDRESP is a novel web-based tool that provides easily interpretable information on patient adherence to asthma/chronic obstructive pulmonary disease (COPD) medications, using pharmacy claims data. This study investigated the feasibility of implementing e-MEDRESP in primary care. Material and Methods In this 16-month prospective cohort study, e-MEDRESP was integrated into electronic medical records. Nineteen family physicians and 346 of their patients were enrolled. Counters embedded in the tool tracked physician use during the follow-up. Patient/physician satisfaction with e-MEDRESP was evaluated though telephone interviews and online questionnaires. The capacity of e-MEDRESP to improve adherence was explored using a pre–post analysis. Results Overall, 245 patients had at least one medical visit during follow-up. e-MEDRESP was consulted by 15 (79%) physicians for 85 (35%) patients during clinic visits. Seventy-three patients participated in telephone interviews; 84% reported discussing their medication use with their physician; 33% viewed their e-MEDRESP report and indicated that it was easy to interpret. The physicians reported that the tool facilitated their evaluation of their patients’ medication adherence (mean ± standard deviation rating: 4.8 ± 0.7, on a 5-point Likert scale). Although the pre–post analysis did not reveal improved adherence in the overall cohort, adherence improved significantly in patients whose adherence level was <80% and who were prescribed inhaled corticosteroids (26.9% [95% CI 14.3%–39.3%]) or long-acting muscarinic agents (26.4% [95% CI 12.4%–40.2%]). Conclusions e-MEDRESP was successfully integrated in clinical practice. It could serve as a useful tool to help physicians monitor their patients’ medication adherence.

Nicotine promotes the utility of short-term memory during visual search in macaque monkeys.

The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working memory (WM), the underlying mechanism remains unclear. It is widely accepted that WM consists of multiple functional modules, one storing short-term memory and the other manipulating and utilizing it. A recently developed visual search task and a relevant model can be used to assess multiple components of WM during administration of acetylcholine receptor (AChR)-related substances. The effects of systemic administration of AChR-related agents on WM and eye movements were examined during the oculomotor foraging task. Three monkeys performing the task received an intramuscular injection of saline or the following AChR-related agents: nicotine (24 or 56μg/kg), mecamylamine (nicotinic AChR antagonist, 1.0mg/kg), oxotremorine (muscarinic AChR agonist, 3.0µg/kg), and scopolamine (muscarinic AChR antagonist, 20μg/kg). The task was to find a target among 15 identical objects by making eye movements within 6s. The data were analyzed according to the foraging model that incorporated three parameters. Nicotine and mecamylamine significantly increased the utility but not the capacity of short-term memory, while muscarinic AChR-related agents did not alter any WM parameters. Further regression analyses with a mixed-effect model showed that the beneficial effect of nicotine on memory utility remained after considering eye movement variability, but the beneficial effect of mecamylamine disappeared. Nicotine improves visual search, mainly by increasing the utility of short-term memory, with minimal changes in oculomotor parameters.

Acetylcholine receptors (muscarinic) in GtoPdb v.2021.3

Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates.

Acetylcholine receptors (muscarinic) in GtoPdb v.2021.2

Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. I

Therapeutic Recommendations for the Management of Older Adult Patients with Sjögren's Syndrome.

Primary Sjögren's syndrome (SjS) is a systemic autoimmune disease most commonly diagnosed in middle-aged women. Although the disease can occur at all ages, it is diagnosed between 30 and 60years of age in two-thirds of patients. In more than 20% of cases, the people are older than 65years. In this review, we focus on the therapeutic management of primary SjS in older patients, following the recently published 2020 European League Against Rheumatism (EULAR) recommendations for the management of the disease with topical and systemic therapies. These recommendations are applicable to all patients with primary SjS regardless of age at diagnosis, although the therapeutic management in older patients requires additional considerations. Older patients are more likely to have pulmonary, liver, kidney, or heart-related comorbidities (even cognitive disturbances); caution is required when most drugs are used, including muscarinic agents, systemic corticosteroids and synthetic immunosuppressants. It is also important to monitor the use of eye drops containing steroids due to the increased risk of developing cataracts, a frequent ocular complication in the older population. In contrast, the majority of drugs that can be used topically (pilocarpine rinses, eye drops containing topical non-steroidal anti-inflammatory drugs (NSAIDs) or cyclosporine A, topical dermal formulations of NSAIDs) have shown an acceptable safety profile in older patients, as well as rituximab. A rigorous evaluation of the medical history of older patients is essential when drugs included in the EULAR guidelines are prescribed, with special attention to factors frequently related to ageing, such as polypharmacy, the existence of organ-specific comorbidities, or the enhanced susceptibility to infections.

Comparative Effectiveness of Initial LAMA versus LABA in COPD: Real-World Cohort Study

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations for the initial bronchodilator to use in newly diagnosed chronic obstructive pulmonary disease (COPD) are based on trials of patients with longstanding disease and treatment. We compared the real world effectiveness of initial treatment with long-acting muscarinic agents (LAMA) versus long-acting beta2-agonists (LABA) on the incidence of exacerbations in newly diagnosed patients. We identified a cohort of patients with COPD, new users of a LAMA or LABA (not combined with an inhaled corticosteroid (ICS)) during 2002–2018, age 50 or older, from the UK’s CPRD database, and followed for one year. The hazard ratio (HR) of exacerbation estimated using the Cox regression model, weighted by fine stratification of propensity scores. The cohort included 40,538 initiators of LAMA and 10,680 of LABA. The adjusted hazard ratio (HR) of a first moderate or severe exacerbation comparing LAMA with LABA initiation was 0.96 (95% CI: 0.90–1.02), while for severe exacerbation it was 0.92 (95% CI: 0.75–1.12). The incidence of exacerbation on LAMA was significantly lower than on LABA (HR 0.88; 95% CI: 0.80–0.96) among patients with a prior exacerbation, and the HR of exacerbation increased with percent predicted FEV1. This study in the real world clinical setting of COPD treatment found that using a LAMA or a LABA (no ICS) as the initial bronchodilator is generally as effective at reducing exacerbation incidence and frequency. However, a LAMA may be more effective in patients with prior exacerbations, which supports the GOLD recommendations for newly diagnosed COPD. The role of airway obstruction on the effectiveness of bronchodilators warrants further investigation.

The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain.

Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances, or psychosis, such as Alzheimer's disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI), and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally active dose of the M1/M4-preferring muscarinic agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high-frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high-frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.

Trends and Factors Associated with Nebulized Therapy Prescription in Older Adults with Chronic Obstructive Pulmonary Disease from 2008 to 2015.

Background: Medical management of patients with chronic obstructive pulmonary disease (COPD) includes nebulized therapy as an option for inhalational drug delivery. A broad variety of short- and long-acting bronchodilators and inhaled corticosteroids in the nebulized form are available. Despite this, limited information exists on the pattern and predictors of nebulized prescription. We examined the trend and factors associated with prescription of nebulized therapy among Medicare beneficiaries with COPD. Methods: A retrospective cross-sectional study of 5% Medicare beneficiaries with COPD (n = 66,032) who were enrolled in parts A, B, and D and received nebulized prescription from 2008 to 2015 was conducted. This sample has shown to be representative of the entire fee-for-service Medicare population. The primary outcome was a prescription of nebulized medications. Reliever nebulized medications included short-acting beta agonist (SABA), short-acting muscarinic agents (SAMAs), and a combination of SABA and SAMA, while maintenance nebulized medications included long-acting beta agonists, long-acting muscarinic agents, and corticosteroid solutions as well as combinations of these agents. The secondary outcome was prescription of other inhaler respiratory medications not administered with a nebulizer. Results: Overall, 38.9% patients were prescribed nebulized medication and their prescription significantly declined from 42.4% in 2008 to 35.1% in 2015, majority of which was related to decreased prescriptions of nebulized relievers. Factors associated with the prescription of nebulized medications include female gender (odds ratio [OR] = 1.06; 95% confidence interval [CI] = 1.02-1.09), dual eligibility or low-income subsidy beneficiaries (OR = 1.49; CI = 1.44-1.53), hospitalization for COPD in the previous year (OR = 1.29; CI = 1.25-1.34), home oxygen therapy (OR = 2.29; CI = 2.23-2.36), pulmonary specialist visit (OR = 1.24; CI = 1.20-1.27), and moderate (OR = 1.61; CI = 1.57-1.65) or high (OR = 1.52; CI = 1.46-1.59) severity of COPD. Conclusion: Between 2008 and 2015, prescriptions for nebulized therapy for COPD declined among Medicare beneficiaries, probably related to increase in use of maintenance non-nebulized medications.

Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation.

BackgroundElectrical vagal nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. This technique also remains under investigation as a specific treatment of patients with Alzheimer’s disease. Recently we discovered that VNS induced hippocampal formation (HPC) type II theta rhythm, which is involved in memory consolidation. In the present study, we have extended our previous observation and addressed the neuronal substrate and pharmacological profile of HPC type II theta rhythm induced by VNS in anesthetized rats.MethodsMale Wistar rats were implanted with a VNS cuff electrode around the left vagus nerve, a tungsten microelectrode for recording the HPC field activity, and a medial septal (MS) cannula for the injection of a local anesthetic, procaine, and muscarinic agents. A direct, brief effect of VNS on the HPC field potential was evaluated before and after medial-septal drug injection.ResultsMedial septal injection of local anesthetic, procaine, reversibly abolished VNS-induced HPC theta rhythm. With the use of cholinergic muscarinic agonist and antagonists, we demonstrated that medial septal M1 receptors are involved in the mediation of the VNS effect on HPC theta field potential.ConclusionThe MS cholinergic M1 receptor mechanism integrates not only central inputs from the brainstem synchronizing pathway, which underlies the production of HPC type II theta rhythm, but also the input from the vagal afferents in the brain stem.

Effects of a single long-acting muscarinic antagonist agent and a long-acting muscarinic antagonist/long-acting β2-adrenoceptor agonist combination on lung function and symptoms in untreated COPD patients in Japan.

BackgroundA large body of evidence suggests that long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) combinations induce a strong synergistic bronchodilatory effect in human isolated airways. Moreover, a recent post hoc analysis demonstrated clinical synergism between LABAs and LAMAs, which induces a synergistic improvement not only in lung function but also in dyspnea in COPD patients.AimThe aim of this study is to examine the baseline factors related to improvement in lung function or clinical symptoms that results from the administration of LAMA or LAMA/LABA and to compare the differences in improvement in lung function or clinical symptoms between LAMA and LAMA/LABA.MethodsAmong 829 patients with COPD who were treated with LAMA or LAMA/LABA in our hospital, 112 patients (aged 40–89 years) matched the criteria. Of these 112 patients, 71 received LAMA (LAMA group) and 41 received LAMA/LABA (LAMA/LABA group) as the initial treatment. Various examination results such as lung function test values, symptom change, and frequency of exacerbations were compared between the two groups.ResultsCompared with the monotherapy, the combination therapy significantly improved the FEV1, inspiratory capacity (IC), and total COPD assessment test (CAT) scores. Comparing the improvement in each domain of the CAT produced by the combination therapy with that of the monotherapy, larger improvements were found for the domains of going out and sleeping. The frequency of exacerbations during the 24 weeks was significantly lower in the combination therapy group than in the LAMA monotherapy group (P=0.034). Although no relationship was found between improvement in FEV1 and any pretreatment factors in the LAMA/LABA group, the improvement in the CAT score was strongly related to the baseline CAT score, smoking index, and air trapping index (P-value <1×10−4).ConclusionIn this study of clinical practice, we found that LAMA/LABA combination therapy improved the clinical symptoms of COPD and IC and that the effects of the combination therapy were consistent with those observed in previous clinical trials.

Pharmacological modulation of AMPA receptor phosphorylation by dopamine and muscarinic receptor agents in the rat medial prefrontal cortex

Two key transmitters in the medial prefrontal cortex (mPFC), dopamine and acetylcholine, are believed to interact with each other to modulate local glutamatergic transmission, although molecular mechanisms underlying their crosstalk are poorly understood. Here we investigated effects of pharmacological manipulations of dopamine and muscarinic receptors on phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat mPFC in vivo. We found that an agonist selective for Gαs-coupled dopamine D1 receptors, SKF81297, increased AMPA receptor GluA1 subunit phosphorylation at a protein kinase A-sensitive site (S845), while SKF81297 had no effect on GluA1 phosphorylation at S831. An agonist for Gαi/o-coupled dopamine D2 receptors, quinpirole, also increased S845 but not S831 phosphorylation. When coinjected, the two agonists induced an additive increase in S845 phosphorylation. The D1 receptor antagonist SCH23390 blocked the SKF81297/quinpirole-stimulated S845 phosphorylation. The D2 antagonist eticlopride also partially blocked S845 responses to SKF81297/quinpirole. VU0152100, a positive allosteric modulator selective for Gαi/o-coupled muscarinic M4 receptors, reduced the S845 phosphorylation induced by SKF81297 and quinpirole injected alone or together. In contrast, coinjection of subthreshold doses of tropicamide, an M4 antagonist, and SKF81297 facilitated S845 phosphorylation. Additionally, coadministered SFK81297 and quinpirole increased the abundance of mPFC GluA1 at extrasynaptic sites. These data reveal that both D1 and D2 receptors upregulate GluA1 phosphorylation in mPFC neurons probably via a direct and indirect mechanism, respectively. The indirect mechanism involves M4 receptors which generally counteract the effect of dopamine on GluA1 phosphorylation.

Access to affordable medicines and diagnostic tests for asthma and COPD in sub Saharan Africa: the Ugandan perspective

BackgroundEquitable access to affordable medicines and diagnostic tests is an integral component of optimal clinical care of patients with asthma and chronic obstructive pulmonary disease (COPD). In Uganda, we lack contemporary data about the availability, cost and affordability of medicines and diagnostic tests essential in asthma and COPD management.MethodsData on the availability, cost and affordability of 17 medicines and 2 diagnostic tests essential in asthma and COPD management were collected from 22 public hospitals, 23 private and 85 private pharmacies. The percentage of the available medicines and diagnostic tests, the median retail price of the lowest priced generic brand and affordability in terms of the number of days’ wages it would cost the least paid public servant were analysed.ResultsThe availability of inhaled short acting beta agonists (SABA), oral leukotriene receptor antagonists (LTRA), inhaled LABA-ICS combinations and inhaled corticosteroids (ICS) in all the study sites was 75%, 60.8%, 46.9% and 45.4% respectively. None of the study sites had inhaled long acting anti muscarinic agents (LAMA) and inhaled long acting beta agonist (LABA)-LAMA combinations. Spirometry and peak flow-metry as diagnostic tests were available in 24.4% and 6.7% of the study sites respectively. Affordability ranged from 2.2 days’ wages for inhaled salbutamol to 17.1 days’ wages for formoterol/budesonide inhalers and 27.8 days’ wages for spirometry.ConclusionMedicines and diagnostic tests essential in asthma and COPD care are not widely available in Uganda and remain largely unaffordable. Strategies to improve access to affordable asthma and COPD medicines and diagnostic tests should be implemented in Uganda.

Modification of the natural progression of epileptogenesis by means of biperiden in the pilocarpine model of epilepsy

Brain injuries are often associated with the later development of epilepsy. Evidence suggests that morphological and functional changes occur in the remaining neural tissue during a silent (or latent) period in which no seizures are expressed. It is believed that this silent (reorganization) period may provide a therapeutic window for modifying the natural history of disease progression. Here we provide evidence that biperiden, a muscarinic anticholinergic agent, is able to alter disease progression in an animal model of epilepsy. We observed that biperiden was capable of slowing the manifestation of the first spontaneous epileptic seizure and effectively reduced the severity and number of recurrent, spontaneous epileptic seizures during the animals’ lifespan. Biomolecular (microdialysis) and electrophysiological (extracellular field recordings) studies determined that biperiden was capable of elevating the threshold of hippocampal excitability, thereby making the hippocampal glutamatergic pathways less responsive to stimuli when high concentrations of potassium were used in vivo or in vitro. Notably, there was no hindrance of long-term memory or learning (a potential problem given the amnestic nature of biperiden). We conclude that biperiden has antiepileptogenic potential and may represent an opportunity for the prevention of post-traumatic epilepsy.

Sobrediagnóstico de enfermedad pulmonar obstructiva crónica en atención primaria. Prevalencia y condicionantes

IntroductionCOPD under-diagnosis is common in Primary Health Care medicine, due to the low use of spirometry, but there is less information about over-diagnosis of the disease in patients that have a clinical diagnosis of COPD. ObjectiveThe main objective of the study was to investigate the prevalence of COPD over-diagnosis in Primary Care medicine. Secondary objectives were to determine the factors associated with an incorrect clinical diagnosis of COPD and to analyse whether the pharmacological treatment is different for patients with correct or incorrect diagnosis. MethodA prospective, observational, cross-sectional study was conducted using the spirometry results of 206 patients with a clinical diagnosis of COPD, with no prior lung function testing, and who were treated with inhaled therapy. Characteristics and treatment of patients with a correct or incorrect COPD diagnosis were compared. ResultsThe prevalence of COPD over-diagnosis was 42.7% in the study population. Factors associated with an incorrect diagnosis were female sex (P<.0001), obesity (P=.009), absence of smoking history (P<.0001), lower age (P=.001), and less severe dyspnoea (P=.001). Long-acting muscarinic agents were more frequently prescribed to patients with a correct COPD diagnosis. There were no other differences regarding inhaled therapies between both groups. ConclusionsOver-diagnosis is a frequent phenomenon in patients with a clinical diagnosis of COPD managed in Primary Care medicine. There are different features between patients with a correct and incorrect diagnosis. Spirometry is an essential tool to reduce COPD over-diagnosis.

Bringing Stability to the Chronic Obstructive Pulmonary Disease Patient: Clinical and Pharmacological Considerations for Frequent Exacerbators.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are critical events associated with an accelerated loss of lung function, increased morbidity, and excess mortality. AECOPD are heterogeneous in nature and this may directly impact clinical decision making, specifically in patients with frequent exacerbations. A 'frequent exacerbator' is a sub-phenotype of chronic obstructive pulmonary disease (COPD) and is defined as an individual who experiences two or more moderate-to-severe exacerbations per year. This distinct subgroup has higher mortality and accounts for more than half of COPD-related hospitalizations annually. Thus, it is imperative to identify individuals at risk for frequent exacerbations and choose optimal strategies to minimize risk for these events. New paradigms for using combination inhalers and the introduction of novel oral compounds provide expanded treatment options to reduce the risk and frequency of exacerbations. The goals of managing frequent exacerbators or patients at risk for AECOPD are: (1) maximizing bronchodilation; (2) reducing inflammation; and (3) targeting specific molecular pathways implicated in COPD and AECOPD pathogenesis. Novel inhaler therapies including combination long-acting muscarinic agents plus long-acting beta agonists show promising results compared with monotherapy or a long-acting beta agonist inhaled corticosteroid combination in reducing exacerbation risk among individuals at risk for exacerbations and among frequent exacerbators. Likewise, oral medications including macrolides and phosphodiesterase-4 inhibitors reduce the risk for AECOPD in select groups of individuals at high risk for exacerbation. Future direction in COPD management is based on the identification of various subtypes or 'endotypes' and targeting therapies based on their pathophysiology. This review describes the impact of AECOPD and the challenges posed by frequent exacerbators, and explores the rationale for different pharmacologic approaches to preventing AECOPD in these individuals.

Benzyl quinolone carboxylic acid (BQCA) elicits positive allosteric modulation at M2‐M5 muscarinic receptors with specific mutations

The muscarinic acetylcholine receptors (mAChRs) comprise a family of G‐protein‐coupled receptors, all of which are expressed in the CNS. Physiological, behavioral, and knock‐out mouse studies all suggest that these receptors play crucial roles in many CNS functions and disorders. Unfortunately, the structures of the five subtypes of mAChRs are very highly conserved in the transmembrane regions where ACh binds; this has hampered the development of subtype‐selective agonists and antagonists. Additionally, the mAChRs also play essential roles in the autonomic system; this means that non‐selective muscarinic agents have serious dose‐limiting side effects. One approach to developing ligands with sufficient selectivity has been to target allosteric sites on the receptors, which are typically much less conserved than the orthosteric site. BQCA is a premier example of a positive allosteric modulator that is highly selective for the M1 mAChR, which is a subtype whose enhancement is likely to benefit cognitive deficits, including those of Alzheimer's Disease. BQCA enhances the potency of ACh by 100‐fold or more at M1, while having no effect at the other subtypes. Such selectivity can be due either to highly selective affinity for M1 or to neutral cooperativities at the other subtypes, and it is of significant interest to determine which mechanism is at work for this prototypical agent. We have used mutagenesis to identify residues that are key to the selective PAM activity. In agreement with others, we found that the aromatic nature of M1Y5.29 is essential (superscript numerals refer to the system of Ballesteros and Weinstein); Y=&gt;A mutation abolishes activity, while Y=&gt;F preserves it. Of the five subtypes, only M5 lacks Y or F at this site. We found that the M5Q=&gt;Y5.29 mutant displays modest PAM activity. Additionally, the PAM activity of the double mutant M1E=&gt;A7.32, E=&gt;A7.36 is markedly attenuated, whereas the M5Y5.29E7.32E7.36 mutant has PAM activity equal to M1. Unlike the case with M5, the M2E7.32E7.36, M3E7.32E7.36, and M4E7.32E7.36 mutants exhibit only moderate PAM activity, despite the Y or F present at position 5.29. Finally, the interactions between BQCA and ACh in inhibiting the binding of the labeled orthosteric antagonist [3H]N‐methylscopolamine to M1 vs M1A7.32A7.36 and M5Y5.29 vs M5Y5.29E7.32E7.36 were evaluated using a mathematical allosteric model. The mutations were found to exert marked changes in the cooperativity between BQCA and ACh, but not to alter the affinity of BQCA for the receptor. This indicates that the region near the top of TM7 that contains E7.32 and E7.36 is not part of the binding site. In agreement with this, BQCA was not found to be competitive with the allosteric modulator W84, which has previously been shown to bind within this region.Support or Funding InformationThis project is funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco CURE Funds. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Also supported by the National Institute on Aging [Grant R01AG005214] and by funds from the Department of Psychiatry, Penn State University College of Medicine

Haustral boundary contractions in the proximal 3-taeniated rabbit colon.

The rabbit proximal colon is similar in structure to the human colon. Our objective was to study interactions of different rhythmic motor patterns focusing on haustral boundary contractions, which create the haustra, using spatiotemporal mapping of video recordings. Haustral boundary contractions were seen as highly rhythmic circumferential ring contractions that propagated slowly across the proximal colon, preferentially but not exclusively in the anal direction, at ∼0.5 cycles per minute; they were abolished by nerve conduction blockers. When multiple haustral boundary contractions propagated in the opposite direction, they annihilated each other upon encounter. Ripples, myogenic propagating ring contractions at ∼9 cycles per min, induced folding and unfolding of haustral muscle folds, creating an anarchic appearance of contractile activity, with different patterns in the three intertaenial regions. Two features of ripple activity were prominent: frequent changes in propagation direction and the occurrence of dislocations showing a frequency gradient with the highest intrinsic frequency in the distal colon. The haustral boundary contractions showed an on/off/on/off pattern at the ripple frequency, and the contraction amplitude at any point of the colon showed waxing and waning. The haustral boundary contractions are therefore shaped by interaction of two pacemaker activities hypothesized to occur through phase-amplitude coupling of pacemaker activities from interstitial cells of Cajal of the myenteric plexus and of the submuscular plexus. Video evidence shows the unique role haustral folds play in shaping contractile activity within the haustra. Muscarinic agents not only enhance the force of contraction, they can eliminate one and at the same time induce another neurally dependent motor pattern.