Anticholinergic Adverse Effects Research Articles

Analysis of anticholinergic adverse effects using two large databases: The US Food and Drug Administration Adverse Event Reporting System database and the Japanese Adverse Drug Event Report database.

IntroductionAnticholinergic adverse effects (AEs) are a problem for elderly people. This study aimed to answer the following questions. First, is an analysis of anticholinergic AEs using spontaneous adverse drug event databases possible? Second, what is the main drug suspected of inducing anticholinergic AEs in the databases? Third, do database differences yield different results?MethodsWe used two databases: the US Food and Drug Administration Adverse Event Reporting System database (FAERS) and the Japanese Adverse Drug Event Report database (JADER) recorded from 2004 to 2020. We defined three types of anticholinergic AEs: central nervous system (CNS) AEs, peripheral nervous system (PNS) AEs, and a combination of these AEs. We counted the number of cases and evaluated the ratio of drug–anticholinergic AE pairs between FAERS and JADER. We computed reporting odds ratios (RORs) and assessed the drugs using Beers Criteria®.ResultsConstipation was the most reported AE in FAERS. The ratio of drug–anticholinergic AE pairs was statistically significantly larger in FAERS than JADER. Overactive bladder agents were suspected drugs common to both databases. Other drugs differed between the two databases. CNS AEs were associated with antidementia drugs in FAERS and opioids in JADER. In the assessment using Beers Criteria®, signals were detected for almost all drugs. Between the two databases, a significantly higher positive correlation was observed for PNS AEs (correlation coefficient 0.85, P = 0.0001). The ROR was significantly greater in JADER.ConclusionsThere are many methods to investigate AEs. This study shows that the analysis of anticholinergic AEs using spontaneous adverse drug event databases is possible. From this analysis, various suspected drugs were detected. In particular, FAERS had many cases. The differences in the results between the two databases may reflect differences in the reporting countries. Further study of the relationship between drugs and CNS AEs should be conducted.

Anticholinergic Exposure in Elderly Complex Chronic Patients: A Cross-Sectional Study.

Elderly patients with multiple chronic conditions are closely linked to polymedication, a condition that is also highly associated with the presence of adverse effects, such as those observed by anticholinergic activity. Anticholinergic burden is defined in a very variable way and is described inconsistently using different scores and providing different interpretations of the risk of suffering from anticholinergic adverse effects. The objective is to analyse the anticholinergic risk exposure in elderly complex chronic patients. A observational multicentre study was performed for a cohort of complex chronic patients over 65 years who received treatment with at least one drug with anticholinergic activity. Anticholinergic exposure was assessed using ten scales included in the Anticholinergic Burden Calculator. 473 patients were recruited, being 67.7% with excessive polypharmacy. 80 was the total number of anticholinergic drugs with any scale, with a median of 2 drugs with anticholinergic activity per patient (IQR=2). Three scales evaluated more than 70% of the patients (Chew: 79.1%; Drug Burden Index (DBI): 77.8%; Anticholinergic Cognitive Burden (ACB): 75.9%). The percentage of different drugs with anticholinergic properties evaluated ranged from 13.8% (Anticholinergic Burden Classification (ABC)) to 57.5% (DBI) and anticholinergic drugs prescriptions oscillated from 14% (Anticholinergic Risk Scale (ARS)) to 53.3% (DBI). 71.1% of patients were at risk (moderate and high risk) according to DBI vs. 9.7% by ARS at the opposite side. Important differences of anticholinergic risk in patients with excessive polypharmacy were in ACB, ABC and DBI scales. This study has highlighted clear differences between the scales used. DBI seems to be the scale that identifies a higher number of elderly chronic complex patients at risk of developing anticholinergic adverse effects.

Real-world Safety and Efficacy of Indacaterol/Glycopyrronium in Japanese Patients with Chronic Obstructive Pulmonary Disease: A 52-week Post-marketing Surveillance.

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with chronic obstructive pulmorary disease (COPD) in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY [-6.9 (-7.8 to -6.1)]. The lung function (FEV1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Antimuscarinic use among older adults with dementia and overactive bladder: a Medicare beneficiaries study

Objectives This study examined the incidence and predictors of antimuscarinic medication use including non-selective antimuscarinics among older adults with dementia and overactive bladder (OAB). Methods The study used a new-user cohort design involving older adults (≥65 years) with dementia and OAB based on 2013–2015 Medicare data. Antimuscarinics included non-selective (oxybutynin, tolterodine, trospium, fesoterodine) and selective (solifenacin, darifenacin) medications. Descriptive statistics and multivariable logistic regression models were used to determine the incidence and predictors of new antimuscarinic use including non-selective antimuscarinics, respectively. Results Of the 3.38 million Medicare beneficiaries with dementia, over one million (1.05) had OAB (31.03%). Of those, 287,612 (27.39%) were reported as prevalent antimuscarinics users. After applying continuous eligibility criteria, 21,848 (10.34%) incident antimuscarinic users were identified (77.6% non-selective; 22.4% selective). Most frequently reported antimuscarinics were oxybutynin (56.3%) and solifenacin (21.4%). Multivariable analysis revealed that patients ≥75 years, of black race, and those with schizophrenia, epilepsy, delirium, and Elixhauser’s score were less likely to initiate antimuscarinics. Women, those with abnormal involuntary movements, bipolar disorder, gastroesophageal reflux disease, insomnia, irritable bowel syndrome, muscle spasm/low back pain, neuropathic pain, benign prostatic hyperplasia, falls/fractures, myasthenia gravis, narrow-angle glaucoma, Parkinson's disease, syncope, urinary tract infection and vulvovaginitis were more likely to initiate antimuscarinics. Further, patients with muscle spasms/low back pain, benign prostatic hyperplasia and those taking higher level anticholinergics had lower odds of receiving non-selective antimuscarinics, whereas white patients, black patients and those with schizophrenia and delirium were more likely to receive them. Conclusions Nearly one-third of dementia patients had OAB and over one-fourth of them used antimuscarinics. Majority of the incident users were prescribed non-selective antimuscarinics with several demographic and clinical factors contributing to their use. Given the high prevalence of OAB among dementia patients, there is a need to optimize their antimuscarinic use, considering their vulnerability for anticholinergic adverse effects.

Xanomeline‐trospium combination shows promise in treatment of schizophrenia

A drug combining the muscarinic receptor agonist xanomeline and the muscarinic receptor antagonist trospium resulted in greater improvement in symptoms of schizophrenia compared with placebo in a 5‐week trial. The drug was associated with a greater prevalence of cholinergic or anticholinergic adverse events, however. Study results were published in the Feb. 25, 2021 issue of the New England Journal of Medicine.

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

BackgroundThe muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor–blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.MethodsIn this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline–trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression–Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.ResultsA total of 182 patients were enrolled, with 90 assigned to receive xanomeline–trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline–trospium group and 96.6 in the placebo group. The change from baseline to week 5 was −17.4 points with xanomeline–trospium and −5.9 points with placebo (least-squares mean difference, −11.6 points; 95% confidence interval, −16.1 to −7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline–trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline–trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.ConclusionsIn a 5-week trial, xanomeline–trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline–trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.)

Less is more: Deprescribing anticholinergic medications in persons with severe mental illness.

Long-term prescribing of anticholinergic medications (ACM) for antipsychotic-associated extrapyramidal symptoms (EPS) is not recommended, yet is widely prevalent. Adverse effects of ACM include memory impairment, dry mouth, constipation, blurred vision, urinary retention, and tachycardia, which can seriously impact quality of life. This quality improvement deprescription project sought to reduce chronic ACM use in patients with serious mental illness (SMI). Education directed at psychiatrists combined with clinical pharmacy support for deprescription was used to target clinically stable patients diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder with no EPS and ACM prescriptions of ≥6 months. Scales were used to assess anticholinergic adverse effects, memory impairment, and quality of life. ACMs were tapered and discontinued over 1 to 6 months. More than 75% of targeted patients successfully tapered or discontinued ACM, which coincided with significant improvements in anticholinergic adverse effects, memory impairment, and quality of life. Approximately 10% of patients were restarted on ACM for re-emergent EPS. For most clinically stable patients with SMI without EPS, our findings suggest that gradual deprescription of chronic ACM is clinically appropriate, well tolerated, and improves quality of life. A randomized trial could provide more definitive answers.

Comparative associations between anticholinergic burden and emergency department visits for anticholinergic adverse events in older Korean adults: a nested case-control study using national claims data for validation of a novel country-specific scale

sBackgroundConsidering the limited generalizability of previous anticholinergic burden scales, the Korean Anticholinergic Burden Scale (KABS) as a scale specific to the Korean population was developed. We aimed to validate the KABS by detecting the associations between high anticholinergic burden, measured with the KABS, and emergency department (ED) visits compared to the pre-existing validated scales in older Korean adults.MethodsA nested case-control study was conducted using national claims data. The cases included the first anticholinergic ED visits between July 1 and December 31, 2016. Anticholinergic ED visits were defined as ED visits with a primary diagnosis of constipation, delirium, dizziness, fall, fracture, or urinary retention.Propensity score-matched controls were identified. Average daily AB scores during 30 days before the index date were measured. Multivariate logistic regression analyses were performed.ResultsIn total, 461,034 were included. The highest proportion of those with high AB was identified with KABS (5.0%). Compared with those who had a KABS score of 0, older adults with a score ≥ 3 were at higher risk for overall anticholinergic ED visits (aOR, 1.62, 95% CI, 1.53–1.72), as well as visits for falls/fractures (aOR: 1.54, 95% CI: 1.40–1.69), dizziness (aOR: 1.44, 95% CI: 1.30–1.59), delirium (aOR: 2.96, 95% CI: 2.28–3.83), constipation (aOR: 1.84, 95% CI: 1.68–2.02), and urinary retention (aOR: 2.13, 95% CI: 1.79–2.55). High AB by KABS showed a stronger association with overall anticholinergic ED visits and visits due to delirium and urinary retention than those by other scales.ConclusionsIn conclusion, KABS is superior to pre-existing scales in identifying patients with high AB and predicting high AB-related ED visits in older Korean adults.

Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia

BackgroundAntipsychotics are a cornerstone of pharmacological treatment of schizophrenia. Improved understanding of the dose-response relationship of antipsychotics in terms of efficacy, adverse effects, and mortality can help to optimize the pharmacological treatment of schizophrenia. MethodsThis narrative literature review summarizes current evidence on the relationship of antipsychotic dose with efficacy, adverse effects, and mortality in patients with schizophrenia. ResultsThe efficacy of antipsychotics generally appeared to be highly dose-dependent in the acute phase of schizophrenia, with each antipsychotic having a specific dose-response curve. The presence or absence of dose-dependency and its extent varied according to the type of adverse effect. Parkinsonism, hyperprolactinemia, weight gain, and neurocognitive impairment appeared to be dose-related. The following adverse effects might be at least somewhat dose-dependent: akathisia, tardive dyskinesia, osteoporosis, sexual dysfunction, diabetes mellitus, myocardial infarction, stroke, thromboembolism, QT interval prolongation, anticholinergic adverse effects, somnolence, pneumonia, hip fracture, and neuroleptic malignant syndrome. In contrast, the relationships of antipsychotic dose with dyslipidemia, hypotension, seizure, sialorrhea, and neutropenia and agranulocytosis remained unclear due to mixed findings and/or limited data. Although a higher lifetime cumulative antipsychotic dose might contribute to higher mortality, it is still difficult to conclude whether mortality increases in a dose-dependent manner. ConclusionThese findings could help clinicians to optimize antipsychotic treatment in patients with schizophrenia by balancing risks and benefits in clinical practice. However, further investigations with larger sample sizes and more robust study designs that focus on each antipsychotic agent are needed.

Imputabilité des traitements anticholinergiques dans l’exacerbation d’épisodes psychotiques : à propos d’un cas de surdosage en tropatépine

IntroductionCorrective treatments for some neurological side effects due to antipsychotic treatments can induce anticholinergic adverse effects. However, the risk of triggering or increasing psychotic symptoms induced by these drugs is unknown with only one case-report concerning the tropatepine. In addition, recommendations for the use of these drugs remain imprecise regarding the management of this type of adverse effect. Case reportWe report the case of a psychotic episode in an 18-year-old patient potentially acutised after an auto-intoxication with tropatepine. ConclusionAt high doses, anticholinergic treatments, including tropatepine, might increase psychotic episodes. In addition, the available epidemiological data reveal an inappropriate and excessive prescription of these drugs. Their use and risks should be better known and need an update of the available recommendations.

Are Beta 3 Adrenergic Agonists Now the Preferred Pharmacologic Management of Overactive Bladder?

This paper discusses the recent evidence supporting beta 3 adrenergic agonists as the preferred pharmacological management of overactive bladder syndrome. Mirabegron has a similar efficacy profile to first-line antimuscarinics with favorable adverse effects profile. Treatment of OAB with beta-3 adrenergic agonist should be favored in patients at higher risk of anticholinergic adverse events. The efficacy and tolerability of beta-3 adrenergic agonists are consistently reported in older OAB patients, whether used alone or with other antimuscarinics. Mirabegron is cost-effective in treating OAB unless the symptoms were severe or refractory. Combination therapy of mirabegron and other pharmacotherapy has proven to be efficient in controlling OAB symptoms without inducing serious add-on adverse effects. While beta-3 adrenergic agonists bear favorable advantages in OAB treatment, physicians should perform a thorough and careful pre-treatment planning to optimize treatment benefits and adherence.

Size of the associations between anticholinergic burden tool scores and adverse outcomes in older patients.

Background Several anticholinergic scales and equations to evaluate the anticholinergic burden have been previously created. Association of these instruments with the anticholinergic outcomes are usually estimated by means of hypothesis contrast tests, which ignore the size of the association effect. Objective To evaluate the effect size of the associations between the scores on cumulative anticholinergic burden instruments with peripheral or central anticholinergic adverse outcomes in older patients. Setting Internal medicine ward of a Tertiary University Hospital. Methods A case-control study was conducted in patients over 65years who were admitted to two internal medicine wards of a Portuguese university hospital. The Anticholinergic Drug Scale, Anticholinergic Risk Scale, Anticholinergic Cognitive Burden scale and Drug Burden Index were used to calculate the patients' anticholinergic burden. Peripheral (dry mouth-swab technique; dry eye-Schirmer test) and central (falls and cognitive impairment-Mini-Mental State Examination) anticholinergic adverse outcomes were investigated. The Barthel Index was used to assess overall physical functionality. The Mann-Whitney test was used to evaluate probabilistic differences in the anticholinergic scores between case and control individuals. To establish the effect size of the associations, the area under the curve of the receiver operating characteristics curve was calculated. Main outcome measure Anticholinergic adverse effects. Results A total of 250 patients (mean age 81.67years, standard deviation 7.768; 50% females) were included. In total, 148 patients (59.2%) presented with dry mouth, 85 (34%) with dry eye, 141 (56.4%) with impaired functionality, 44 (17.6%) with a history of falls and 219 (87.6%) with cognitive impairment. Significant differences (p < 0.05) were obtained for the majority of the associations between Anticholinergic Drug Scale, Anticholinergic Risk Scale, Anticholinergic Cognitive Burden and Drug Burden Index and adverse effects. Conversely, the effect sizes of these associations ranged from "fail" (area under the curve 0.5 to 0.6) to "fair" (area under the curve 0.7 to 0.8). Conclusion Although significant differences in the scores of anticholinergic burden instruments and adverse outcomes may exist, the effect sizes of these associations ranged from 'fail' to 'fair', which limits their utility in preventing anticholinergic adverse outcomes with medication review interventions.

Insights into the Management of Overactive Bladder with Transdermal Oxybutynin: A Practical Review.

Overactive bladder (OAB), clinically defined as urinary urgency, with or without incontinence, generally accompanied by an increase in urinary frequency and nocturia, after any local disease or metabolic disorder that would explain these symptoms have been ruled out, is a highly prevalent condition that affects millions of men and women worldwide. Not only can the symptoms of OAB be very bothersome, but OAB can have significant detrimental effects on many aspects of individuals’ lives, representing a particularly impactful health burden to quality of life and productivity. Besides a wide range of conservative treatments, the clinical efficacy of which remains an open issue, antimuscarinics are the mainstay of pharmacotherapy for this condition but anticholinergic troublesome side effects like dry mouth, and the patient’s perception of lack of efficacy and poor adherence, are common reasons of abandonment of treatment. An alternative to oral administration treatment, with a lower incidence of dry mouth and other anticholinergic adverse effects, might be attractive to patients and a real treatment option for physicians. Delivery of oxybutynin directly through the skin with oxybutynin transdermal (OXY-TDS) avoids the first-pass hepatic metabolism that occurs with orally administered oxybutynin and prevents the appearance of anticholinergic adverse events. OXY-TDS being equally effective than oral treatment improves adherence, persistence, and patient satisfaction. The aim of this review is to focus on evidence available of the use of OXY-TDS in the management of patients with OAB, and to help clinicians in the challenges involved in the treatment options for patients with this condition.

Cognitive Effects of Anticholinergic Load in Women with Overactive Bladder.

Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.

Intravenous Cetirizine Versus Intravenous Diphenhydramine for the Treatment of Acute Urticaria: A Phase III Randomized Controlled Noninferiority Trial

Acute urticaria is a frequent presentation in emergency departments (EDs), urgent care centers, and other clinical arenas. Treatment options are limited if diphenhydramine is the only intravenous antihistamine offered because of its short duration of action and well-known adverse effects. We evaluate cetirizine injection, the first second-generation injectable antihistamine, for acute urticaria in this multicenter, randomized, noninferiority, phase 3 clinical trial. Adult patients presenting to EDs and urgent care centers with acute urticaria requiring an intravenous antihistamine were randomized to either intravenous cetirizine 10 mg or intravenous diphenhydramine 50 mg. The primary endpoint was the 2-hour pruritus score change from baseline, with time spent in treatment center and rate of return to treatment centers as key secondary endpoints. Frequency of sedation and anticholinergic adverse effects were also recorded. Among 262 enrolled patients, the 2-hour pruritus score change from baseline for intravenous cetirizine was statistically noninferior to that for intravenous diphenhydramine (-1.6 versus -1.5; 95% confidence interval -0.1 to 0.3), and in favor of cetirizine. Treatment differences also favored cetirizine for mean time spent in treatment center (1.7 versus 2.1 hours; P=.005), return to treatment center (5.5% versus 14.1%; P=.02), lower change from baseline sedation score at 2 hours (0.1 versus 0.5; P=.03), and adverse event rate (3.9% versus 13.3%). Intravenous cetirizine is an effective alternative to intravenous diphenhydramine for treating acute urticaria, with benefits of less sedation, fewer adverse events, shorter time spent in treatment center, and lower rates of revisit to treatment center.

Combined treatment of scopolamine and group III mGluR antagonist, CPPG, exerts antidepressant activity without affecting anxiety-related behaviors

Clinical trials have revealed that the muscarinic receptor antagonist scopolamine produces a fast and potent antidepressant response. However, the anticholinergic adverse effects and the risk of psychosis at higher doses limit the widespread clinical use of scopolamine. Combination therapy of scopolamine and other antidepressants in treating depression has been suggested. Our experimentswere designed to examine the effects of the combining ineffective doses of scopolamine and a group III metabotropic glutamate receptor (mGluR) antagonist, CPPG, on depression- and anxiety-related behaviors in male NMRI mice. The forced swim test (FST) and the elevated plus maze (EPM) were selected to evaluate depression- and anxiety-related behaviors, respectively. Intraperitoneal (i.p.) administration of scopolamine (0.01-0.5 mg/kg) exerted profound antidepressive and anxiogenic effects. Intracerebroventricular (i.c.v.) administration of CPPG (12.5-50 nmol/mouse) elicited significant antidepressive and anxiolytic effects. Moreover, the ineffective dose of CPPG (12.5 nmol/mouse) plus ineffective doses of scopolamine (0.01 or 0.05 mg/kg) showed antidepressant-like effect while these combinations had no effect anxiety-related behaviors. It should be noted that none of the compounds altered locomotor activity. Results identify the combined administration of scopolamine and CPPG as a possible hopeful target in the future treatment of the depressive disorder.

Adverse drug reactions associated with amitriptyline\xa0\u2014\xa0protocol for a systematic multiple-indication review and meta-analysis

BackgroundUnwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-the-counter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals.MethodsA systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including < 100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using meta-regression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment.DiscussionWe will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations.Systematic review registrationSubmitted to PROSPERO; assignment is in progress.

The Risk Factors for Asymptomatic Pyuria Among Patients With Type 2 Diabetes

Background: Diabetic patients often develop urinary tract infections (UTI). Diabetic patients are also likely to develop mental illness, and psychotropic drugs have anticholinergic adverse effects such as urinary disturbance. We aimed to elucidate the risk factors of asymptomatic pyuria in patients with type 2 diabetes. Methods: We picked up outpatients with type 2 diabetes who visited the Department of Internal Medicine for the first time, from December 2010 to November 2012 for the treatment of diabetes and completed the questionnaire to obtain the medical history. We obtained clinical information from medical records and questionnaires. Urine leukocytes >= 10/high-power field was defined as pyuria. Comparisons such as pyuria group vs. non-pyuria group and non-mental illness group vs. mood disorder group vs. schizophrenia group were performed. Results: One hundred twenty-one patients were eligible. Sixty-nine were males, 52 were females, mean age was 63 years. There were 48 patients who had mental illness. The duration of diabetes was 5.1 years, hemoglobin A1c (HbA1c) was 8.5%. Prevalence of pyuria was 15.7%. Mean age in non-pyuria group was 62.8 years old, and 65.1 years old in pyuria group. Proportion of female (84%) in pyuria group was significantly higher than non-pyuria group. Patients with pyuria significantly more often had mental illness and psychotropic drugs prescription than patients without pyuria. Duration of diabetes in non-pyuria group was 5.3 years and that in pyuria group was 4.0 years. Coefficient of variations of R-R intervals (CVR-R) in electrocardiogram (ECG), an index of autonomic nervous dysfunction, was 3.2% in non-pyuria group and 1.8% in pyuria group. Pyuria group had significantly higher prevalence of autonomic nervous dysfunction. Coexistence of mental illness and lower CVR-R were associated with risk of pyuria in female diabetic patients. Conclusions: In addition to female sex, autonomic neuropathy and mental illness were significant risk factors for pyuria in patients with type 2 diabetes. To elucidate this association, further studies, preferably with larger numbers of subjects, will be needed. J Endocrinol Metab. 2019;9(6):193-198 doi: https://doi.org/10.14740/jem629

Promising nanoparticulate system for topical delivery of diphenhydramine hydrochloride: In-vitro and in-vivo evaluation

Diphenhydramine hydrochloride is a potent antihistaminic drug; its oral administration often leads to attention disturbance, CNS or anticholinergic adverse effects as dry mouth resulting in a less patient compliance with the therapy. The aim of the current study was to prepare diphenhydramine hydrochloride loaded nanoparticulate system, using chitosan as a natural polymer for topical application. Eight formulae were prepared adopting 23 factorial design. Diphenhydramine hydrochloride loaded nanoparticles were prepared by ionic gelation technique using chitosan and sodium tripolyphosphate (TPP). The formulae were evaluated regarding TEM, entrapment efficiency, particle size, zeta potential, in-vitro release, DSC, XRD, kinetics study, and in-vivo study regarding skin irritation test and histopathological examination using rats. The results revealed that the entrapment efficiency was significantly increased when increasing the chitosan concentration, the drug to polymer ratio and the chitosan to TPP (w/w) ratio. The particle size was significantly increased when increasing the chitosan concentration, the drug to polymer ratio but significantly decreased when increasing the chitosan to TPP (w/w) ratio. The zeta potential was significantly increased by increasing the chitosan concentration, the drug to polymer ratio and the chitosan to TPP (w/w) ratio. The in-vitro release study showed prolongation of drug release up to 6hrs. A comparison was made between the candidate formula (F8) (0.375% of diphenhydramine hydrochloride, drug to polymer 1:2, chitosan concentration 0.75% and chitosan to TPP (w/w) 5:1) and the marketed gel. The skin irritation test of F8 revealed its dermal safety and the statistical analysis revealed significant increase in its antihistaminic activity with reduction in the wheal area (from 150 mm2 ± 7.8 to 43.6 mm2 ± 4.9) when compared to the marketed gel (from 155 mm2 ± 6.1 to 82.1 mm2 ± 8.54). A value of r = 0.97704 suggested a good correlation between the in vitro-in vivo data of the candidate formula. The results revealed that the developed nanoparticles could have a potential for topical delivery of diphenhydramine hydrochloride.

An evaluation of anticholinergic adverse events with long-term use of glycopyrronium cloth, a treatment for primary axillary hyperhidrosis

An evaluation of anticholinergic adverse events with long-term use of glycopyrronium cloth, a treatment for primary axillary hyperhidrosis