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Biochemical Pharmacology Nov 2023Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous...
Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous research has revealed that IBD patients often have a deficiency of choline and its metabolites, including acetylcholine (ACh) and phosphatidylcholine (PC), within the colon. However, a comprehensive study linking these three substances and their mechanistic implications in IBD remains lacking. This study aimed to investigate the efficacy and underlying mechanism of cytidine diphosphate (CDP)-choline (citicoline), an intermediate product of choline metabolism, in a mouse model of IBD induced by dextran sulfate sodium salt (DSS). The results demonstrated that CDP-choline effectively alleviated colonic inflammation and deficiencies in choline, ACh, and PC by increasing the raw material. Further detection showed that CDP-choline also increased the ACh content by altering the expression of high-affinity choline transporter (ChT1) and acetylcholinesterase (AChE) in DSS-induced mice colon. Moreover, CDP-choline increased the expression of alpha7 nicotinic acetylcholine receptor (α7 nAChR) and activated the cholinergic anti-inflammatory pathway (CAP), leading to reduced colon macrophage activation and proinflammatory M1 polarization in IBD mice, thus reducing the levels of TNF-α and IL-6. In addition, CDP-choline reduced intestinal ecological imbalance and increased the content of hexanoic acid in short-chain fatty acids (SCFAs) in mice. In conclusion, this study elucidates the ability of CDP-choline to mitigate DSS-induced colon inflammation by addressing choline and its metabolites deficiencies, activating the CAP, and regulating the composition of the intestinal microbiome and SCFAs content, providing a potential prophylactic and therapeutic approach for IBD.
Topics: Humans; Mice; Animals; Cytidine Diphosphate Choline; Gastrointestinal Microbiome; Acetylcholinesterase; Choline; Colitis; Inflammation; Acetylcholine; Inflammatory Bowel Diseases; Nicotinic Antagonists; Colon; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37827341
DOI: 10.1016/j.bcp.2023.115845 -
The Cochrane Database of Systematic... Oct 2023Overactive bladder (OAB) is a common chronic and bothersome condition. Bladder training is widely prescribed as a first-line treatment for OAB, but the efficacy has been... (Review)
Review
BACKGROUND
Overactive bladder (OAB) is a common chronic and bothersome condition. Bladder training is widely prescribed as a first-line treatment for OAB, but the efficacy has been systematically evaluated for urinary incontinence rather than OAB alone.
OBJECTIVES
To evaluate the benefits and harms of bladder training for treating adults with OAB compared to no treatment, anticholinergics, β3-adrenoceptor agonists, or pelvic floor muscle training (PFMT) alone or in combination.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 6 November 2022.
SELECTION CRITERIA
We included randomized controlled trials involving adults aged 18 years or older with non-neurogenic OAB. We excluded studies of participants whose symptoms were caused by factors outside the urinary tract (e.g. neurologic disorders, cognitive impairment, gynecologic diseases).
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were 1. participant-reported cure or improvement, 2. symptom- and condition-related quality of life (QoL), and 3.
ADVERSE EVENTS
Secondary outcomes included 4. participant-reported satisfaction, 5. number of incontinence episodes, 6. number of urgency episodes, and 7. number of micturition episodes. For the purpose of this review, we considered two time points: immediately after the treatment (early phase) and at least two months after the treatment (late phase). We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS
We included 15 trials with 2007 participants; participants in these trials were predominantly women (89.3%). We assessed the risk of bias of results for primary and secondary outcomes, which across all studies was similar and predominantly of high risk of bias, and none were at low risk of bias. The certainty of evidence was low to very low, with some moderate, across measured outcomes. Bladder training versus no treatment: three studies involving 92 participants compared bladder training to no treatment. The evidence is very uncertain about the effects of bladder training on cure or improvement at the early phase (risk ratio (RR) 17.00, 95% confidence interval (CI) 1.13 to 256.56; 1 study, 18 participants; very low-certainty evidence). Bladder training may reduce the number of incontinence episodes (mean difference (MD) -1.86, 95% CI -3.47 to -0.25; 1 study, 14 participants; low-certainty evidence). No studies measured symptom- and condition-related QoL, number of adverse events, participant-reported satisfaction, number of urgency episodes, or number of micturition episodes in the early phase. Bladder training versus anticholinergics: seven studies (602 participants) investigated the effects of bladder training versus anticholinergic therapy. Bladder training may be more effective than anticholinergics on cure or improvement at the early phase (RR 1.37, 95% CI 1.10 to 1.70; 4 studies, 258 participants; low-certainty evidence). The evidence is very uncertain about the effects of bladder training on symptom- and condition-related QoL (standardized mean difference (SMD) -0.06, 95% CI -0.89 to 0.77; 2 studies, 117 participants; very low-certainty evidence). Although the evidence is very uncertain, there were fewer adverse events in the bladder training group than in the anticholinergics group (RR 0.03, 95% CI 0.01 to 0.17; 3 studies, 187 participants; very low-certainty evidence). The evidence is very uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.36, 95% CI -0.27 to 1.00; 2 studies, 117 participants; very low-certainty evidence), the number of urgency episodes per 24 hours (MD 0.70, 95% CI -0.62 to 2.02; 2 studies, 92 participants; very low-certainty evidence), and the number of micturition episodes per 24 hours (MD -0.35, 95% CI -1.90 to 1.20; 3 studies, 175 participants; very low-certainty evidence). No studies measured participant-reported satisfaction in the early phase. Bladder training versus PFMT: three studies involving 203 participants compared bladder training to PFMT. The evidence is very uncertain about the different effects between bladder training and PFMT on symptom- and condition-related QoL at the early phase (SMD 0.10, 95% CI -0.19 to 0.40; 2 studies, 178 participants; very low-certainty evidence). There were no adverse events in either group at the early phase (1 study, 97 participants; moderate-certainty evidence). The evidence is uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.02, 95% CI -0.35 to 0.39, 1 study, 81 participants; low-certainty evidence) and very uncertain about the number of micturition episodes per 24 hours (MD 0.10, 95% CI -1.44 to 1.64; 1 study, 81 participants; very low-certainty evidence). No studies measured cure or improvement, participant-reported satisfaction, or number of urgency episodes in the early phase. Although we were interested in studies examining bladder training versus β3-adrenoceptor agonists, in combination with β3-adrenoceptor agonists versus β3-adrenoceptor agonists alone, and in combination with PFMT versus PFMT alone, we did not identify any eligible studies for these comparisons.
AUTHORS' CONCLUSIONS
This review focused on the effect of bladder training to treat OAB. However, most of the evidence was low or very-low certainty. Based on the low- or very low-certainty evidence, bladder training may cure or improve OAB compared to no treatment. Bladder training may be more effective to cure or improve OAB than anticholinergics, and there may be fewer adverse events. There may be no difference in efficacy or safety between bladder training and PFMT. More well-designed trials are needed to reach a firm conclusion.
Topics: Female; Adult; Humans; Male; Urinary Bladder, Overactive; Quality of Life; Electric Stimulation Therapy; Urinary Bladder; Pelvic Floor; Urinary Incontinence; Cholinergic Antagonists; Receptors, Adrenergic
PubMed: 37811598
DOI: 10.1002/14651858.CD013571.pub2 -
The Journals of Gerontology. Series A,... Aug 2023Polypharmacy is associated with poor outcomes in older adults. Targeted deprescribing of anticholinergic and sedative medications may improve health outcomes for frail... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Polypharmacy is associated with poor outcomes in older adults. Targeted deprescribing of anticholinergic and sedative medications may improve health outcomes for frail older adults. Our pharmacist-led deprescribing intervention was a pragmatic 2-arm randomized controlled trial stratified by frailty. We compared usual care (control) with the intervention of pharmacists providing deprescribing recommendations to general practitioners.
METHODS
Community-based older adults (≥65 years) from 2 New Zealand district health boards were recruited following a standardized interRAI needs assessment. The Drug Burden Index (DBI) was used to quantify the use of sedative and anticholinergic medications for each participant. The trial was stratified into low, medium, and high-frailty. We hypothesized that the intervention would increase the proportion of participants with a reduction in DBI ≥ 0.5 within 6 months.
RESULTS
Of 363 participants, 21 (12.7%) in the control group and 21 (12.2%) in the intervention group had a reduction in DBI ≥ 0.5. The difference in the proportion of -0.4% (95% confidence interval [CI]: -7.9% to 7.0%) provided no evidence of efficacy for the intervention. Similarly, there was no evidence to suggest the effectiveness of this intervention for participants of any frailty level.
CONCLUSION
Our pharmacist-led medication review of frail older participants did not reduce the anticholinergic/sedative load within 6 months. Coronavirus disease 2019 (COVID-19) lockdown measures required modification of the intervention. Subgroup analyses pre- and post-lockdown showed no impact on outcomes. Reviewing this and other deprescribing trials through the lens of implementation science may aid an understanding of the contextual determinants preventing or enabling successful deprescribing implementation strategies.
Topics: Humans; Aged; Polypharmacy; Frail Elderly; Deprescriptions; Cholinergic Antagonists; Frailty; COVID-19; Communicable Disease Control; Hypnotics and Sedatives
PubMed: 36692224
DOI: 10.1093/gerona/glac249 -
Drug Development Research Dec 2023Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying... (Review)
Review
Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aβ aggregation.
Topics: Humans; Rivastigmine; Carbamates; Acetylcholinesterase; Pharmacophore; Cholinesterase Inhibitors; Alzheimer Disease
PubMed: 37694498
DOI: 10.1002/ddr.22113 -
Aging Clinical and Experimental Research Dec 2023Sleep disorders are a frequent health problem in older patients with diabetes mellitus (DM). There has been no study investigating the factors associated with excessive...
OBJECTIVES
Sleep disorders are a frequent health problem in older patients with diabetes mellitus (DM). There has been no study investigating the factors associated with excessive daytime sleepiness (EDS) in older diabetic patients. We aimed to investigate the prevalence and associated factors of EDS.
METHODS
We performed a retrospective cross-sectional study in older diabetic patients. The Epworth Sleepiness Scale score of ≥ 11 points indicated EDS. All patients underwent comprehensive geriatric assessment including demographic characteristics, blood pressures, comorbid diseases, cognitive and nutritional states, basic and instrumental daily living activity indexes, lower urinary tract symptoms, and laboratory values.
RESULTS
Of 227 patients, 73.1% were females, with a mean age of 78.8 ± 6.5. The prevalence of EDS was 19.8%. Patients with EDS were mostly males with dementia and used significantly more medication with more anticholinergic drug burden, falls, urge incontinence, and nocturia (p < 0.05). They had higher SARC-F and lower Barthel index, Lawton-Brodie, Tinetti, MMSE scores, and high-density lipoprotein than the patients without EDS (p < 0.05). After adjusting for age, sex, and dementia, all parameters that were significant in univariate analysis remained associated with EDS, except for falls, and MMSE scores.
CONCLUSION
The EDS was found in one in five older diabetic patients. There was a significant relationship between EDS and drug use, anticholinergic drug burden, impaired excretory functions, sarcopenia, decreased functional capacity, falls, gait-balance disorder, and cognitive dysfunction. The recognization of EDS and the implementation of interventions may be helpful in the management of geriatric syndromes.
Topics: Male; Female; Humans; Aged; Aged, 80 and over; Cross-Sectional Studies; Prevalence; Retrospective Studies; Diabetes Mellitus; Dementia; Disorders of Excessive Somnolence; Cholinergic Antagonists
PubMed: 38064108
DOI: 10.1007/s40520-023-02602-9 -
International Journal of Geriatric... Dec 2023Several studies have investigated that anticholinergic drugs cause cognitive impairment. However, the risk of dementia associated with anticholinergics has not been...
OBJECTIVES
Several studies have investigated that anticholinergic drugs cause cognitive impairment. However, the risk of dementia associated with anticholinergics has not been extensively investigated in the super-aging society of Japan. We conducted this study to assess the association between anticholinergic drugs and the risk of dementia in older adults in Japan.
METHODS
This nested case-control study used data from the Longevity Improvement & Fair Evidence Study, which includes claim data in Japan from 2014 to 2020. We included 66,478 cases of diagnosed dementia and 328,919 matched controls aged ≥65 years, matched by age, sex, municipality, and cohort entry year. Primary exposure was the total cumulative anticholinergic drugs prescribed from cohort entry date to event date or matched index date, which was the total standardized daily doses for each patient, calculated by adding the total dose of different types of anticholinergic drugs in each prescription, divided by the World Health Organization-defined daily dose values. Odds ratios for dementia associated with cumulative exposure to anticholinergic drugs were calculated using conditional logistic regression adjusted for confounding variables.
RESULTS
The mean (standard deviation) age at index date was 84.3 (6.9), and the percentage of women was 62.1%. From cohort entry date to event date or matched index date, 18.8% of the case patients and 13.7% of the controls were prescribed at least one anticholinergic drug. In the multivariable-adjusted model, individuals with anticholinergic drugs prescribed had significantly higher odds of being diagnosed with dementia (adjusted odds ratio, 1.50 [95% confidence interval, 1.47-1.54]). Among specific types of anticholinergic drugs, a significant increase in risk was observed with the use of antidepressants, antiparkinsonian drugs, antipsychotics, and bladder antimuscarinics in a fully multivariable-adjusted model.
CONCLUSIONS
Several types of anticholinergic drugs used by older adults in Japan are associated with an increased risk of dementia. These findings suggest that the underlying risks should be considered alongside the benefits of prescribing anticholinergic drugs to this population.
Topics: Humans; Female; Aged; Cholinergic Antagonists; Dementia; Case-Control Studies; Japan; Antidepressive Agents
PubMed: 38041399
DOI: 10.1002/gps.6029 -
Geriatrics & Gerontology International Mar 2024Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant... (Review)
Review
Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant concern in the management of older adults. The accuracy of the anticholinergic burden rating may be increased by considering pharmacokinetic and pharmacodynamic factors such as biophase drug concentrations, the pharmacologically active metabolites formed after drug administration, and muscarinic receptor-mediated effects. Therefore, a pharmacological evidence-based burden scale that considers pharmacokinetic and pharmacodynamic factors is expected to be a more optimal tool for precisely assessing the anticholinergic burden, specifically risk reductions in anticholinergic adverse events in the poly-medicated elderly. Geriatr Gerontol Int 2024; 24: 81-87.
Topics: Humans; Aged; Cholinergic Antagonists; Pharmaceutical Preparations; Drug-Related Side Effects and Adverse Reactions; Polypharmacy
PubMed: 37872832
DOI: 10.1111/ggi.14706 -
CNS Drugs Apr 2024Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are... (Review)
Review
Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.
Topics: Humans; Aged; Dystonia; Cholinergic Antagonists; Psychomotor Agitation; Movement Disorders; Tardive Dyskinesia; Antipsychotic Agents; Neuroleptic Malignant Syndrome; Dystonic Disorders
PubMed: 38502289
DOI: 10.1007/s40263-024-01078-z -
Kyobu Geka. the Japanese Journal of... Sep 2023The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung...
The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung cancer and mediastinal tumors is increasing every year. It is also true that the indications for surgery have been expanding as surgery itself has become less invasive, such as thoracoscopic and robotic surgery. However, it is not uncommon for patients over 80 years of age to have some organ dysfunction and many comorbidities. Therefore, when performing surgery for lung cancer and other diseases, it is important to assess the patient's ability to tolerate surgery, including respiratory and cardiac functions, and to perform risk management. To prevent postoperative complications and improve the accuracy of perioperative management, respiratory rehabilitation should be conducted before and after surgery, and not only smoking cessation instruction but also inhalation training using incentive spirometry( IS), breathing exercises, and the use of inhalers such as long-acting β2 agonist (LABA)/long-acting muscaring antagonist (LAMA) for patients with chronic obstructive pulmonary disease( COPD) are useful.
Topics: Humans; Aged, 80 and over; Aged; Muscarinic Antagonists; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Respiratory Therapy; Pulmonary Disease, Chronic Obstructive; Lung Neoplasms; Drug Therapy, Combination
PubMed: 38056855
DOI: No ID Found -
Indian Pediatrics Dec 2023
Topics: Humans; Cyclopentolate
PubMed: 38087795
DOI: No ID Found