Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial. OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis. METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results. RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs. CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.

Metabolite profiling and histochemical localization of alkaloids in Hippeastrum papilio (Ravena) van Scheepen.

Hippeastrum papilio (Amaryllidaceae) is a promising new source of galanthamine - an alkaloid used for the cognitive treatment of Alzheimer's disease. The biosynthesis and accumulation of alkaloids are tissue - and organ-specific. In the present study, histochemical localization of alkaloids in H. papilio's plant organs with Dragendorff's reagent, revealed their presence in all studied samples. Alkaloids were observed in vascular bundles, vacuoles, and intracellular spaces, while in other plant tissues and structures depended on the plant organ. The leaf parenchyma and the vascular bundles were indicated as alkaloid-rich structures which together with the high proportion of alkaloids in the phloem sap (49.3% of the Total Ion Current - TIC, measured by GC-MS) indicates the green tissues as a possible site of galanthamine biosynthesis. The bulbs and roots showed higher alkaloid content compared to the leaf parts. The highest alkaloid content was found in the inner bulb part. GC-MS metabolite profiling of H. papilio's root, bulb, and leaves revealed about 82 metabolites (>0.01% of TIC) in the apolar, polar, and phenolic acid fractions, including organic acids, fatty acids, sterols, sugars, amino acids, free phenolic acids, and conjugated phenolic acids. The most of organic and fatty acids were in the peak part of the root, while the outermost leaf was enriched with sterols. The outer and middle parts of the bulb had the highest amount of saccharides, while the peak part of the middle leaf had most of the amino acids, free and conjugated phenolic acids.

Synthesis and molecular docking studies of 5-trifluoromethoxy-2-indolinones as cholinesterase dual inhibitors.

Background: In Alzheimer's disease, butyrylcholinesterase (BuChE) activity gradually increases, while acetylcholinesterase (AChE) activity decreases or remains unchanged. Dual inhibitors have important roles in regulation of synaptic acetylcholine levels and progression of Alzheimer's disease. Methods: 1-(Thiomorpholin-4-ylmethyl)/benzyl-5-trifluoromethoxy-2-indolinones (6-7) were synthesized. AChE and BuChE inhibitory effects were investigated with Ellman's method. Molecular docking studies were performed for analyzing the possible binding interactions at active sites. Results: Compound 6g was the strongest inhibitor against both AChE (Ki = 0.35 µM) and BuChE (Ki = 0.53 µM). It showed higher inhibitory effects than both donepezil and galantamine. Moreover, compound 7m had a higher inhibitory effect than galantamine and the effect was comparable to that of donepezil against both AChE (Ki = 0.69 µM) and BuChE (Ki = 0.95 µM). Conclusion: The benzyl substitution compared with 1-(thiomorpholin-4-ylmethyl) group significantly increased both AChE and BuChE inhibitory effects.

Accuracy of Labeling of Galantamine Generic Drugs and Dietary Supplements.

This study examines the accuracy of labeling for galantamine products formulated as both generic drugs and dietary supplements, as well as tests for contamination with microorganisms.

Galantamine mitigates neurotoxicity caused by doxorubicin via reduced neuroinflammation, oxidative stress, and apoptosis in rat model.

OBJECTIVE: Doxorubicin (DXR) is commonly used as a drug for cancer treatment. However, there have been reports of neurotoxicity associated with chemotherapy. Galantamine (GLN) is a medication that inhibits cholinesterase activity, providing relief from the neurotoxic effects commonly seen in individuals with Alzheimer's disease. This study explored the potential ameliorative effect of GLN on brain neurotoxicity induced by DXR. MATERIALS AND METHODS: Forty rats were allocated into four separate groups for a study that lasted for a period of fourteen days. The control group was given normal saline, DXR group was given 5 mg/kg DXR every three days (cumulative dose of 20 mg/kg) through intraperitoneal injection. The GLN group was given 5 mg/kg GLN through oral gavage daily, while the DXR+GLN group was given DXR+GLN simultaneously. An analysis of brain proteins using ELISA to assess apoptosis through the concentration of inflammation and oxidative injury markers. RESULTS: The DXR treatment led to increased neuroinflammation by elevation of nuclear factor kappa B (NF-κB), and cyclooxygenase-2 (COX-2), oxidative stress by rise of malondialdehyde (MDA), and decline of superoxide dismutase (SOD), and no changes in catalase and glutathione (GSH), cell death by elevation of Bax and caspase-3 and reduced Bcl-2, and increase lipid peroxidation, impaired mitochondrial function. When GLN is administered alongside DXR, it has been observed to positively impact various biological markers, including COX-2, NF-κB, MDA, SOD, Bax, Bcl-2, and caspase-3 levels. Additionally, GLN improves lipid peroxidation and mitochondrial activity. CONCLUSIONS: DXR therapy in rats results in the development of neurotoxicity, and a combination of GLN can recover these toxicities, suggesting GLN promising evidence for mitigating the neurotoxic effects induced by DXR.

The Effect of Galantamine on Lipopolysaccharide-induced Acute Lung Injury During Neutropenia Recovery in Mice.

BACKGROUND/AIM: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice. MATERIALS AND METHODS: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration. RESULTS: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101). CONCLUSION: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.

Inhibitory effect of galantamine and donepezil combination against cholinesterase: An in silico and in vitro study.

This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease.

Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.

Galantamine mitigates testicular injury and disturbed spermatogenesis in adjuvant arthritic rats via modulating apoptosis, inflammatory signals, and IL-6/JAK/STAT3/SOCS3 signaling.

Rheumatoid arthritis (RA) affects the joints and the endocrine system via persistent immune system activation. RA patients have a higher frequency of testicular dysfunction, impotence, and decreased libido. This investigation aimed to evaluate the efficacy of galantamine (GAL) on testicular injury secondary to RA. Rats were allocated into four groups: control, GAL (2 mg/kg/day, p.o), CFA (0.3 mg/kg, s.c), and CFA + GAL. Testicular injury indicators, such as testosterone level, sperm count, and gonadosomatic index, were evaluated. Inflammatory indicators, such as interleukin-6 (IL-6), p-Nuclear factor kappa B (NF-κB p65), and anti-inflammatory cytokine interleukin-10 (IL-10), were assessed. Cleaved caspase-3 expression was immunohistochemically investigated. Protein expressions of Janus kinase (JAK), signal transducers and activators of transcription (STAT3), and Suppressors of Cytokine Signaling 3 (SOCS3) were examined by Western blot analysis. Results show that serum testosterone, sperm count, and gonadosomatic index were increased significantly by GAL. Additionally, GAL significantly diminished testicular IL-6 while improved IL-10 expression relative to CFA group. Furthermore, GAL attenuated testicular histopathological abnormalities by CFA and downregulated cleaved caspase-3 and NF-κB p65 expressions. It also downregulated JAK/STAT3 cascade with SOCS3 upregulation. In conclusion, GAL has potential protective effects on testicular damage secondary to RA via counteracting testicular inflammation, apoptosis, and inhibiting IL-6/JAK/STAT3/SOCS3 signaling.

The effects of different acetylcholinesterase inhibitors on EEG patterns in patients with Alzheimer's disease: A systematic review.

OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. The early diagnosis of AD is an important factor for the control of AD progression. Electroencephalography (EEG) can be used for early diagnosis of AD. Acetylcholinesterase inhibitors (AChEIs) are also used for the amelioration of AD symptoms. In this systematic review, we reviewed the effect of different AChEIs including donepezil, rivastigmine, tacrine, physostigmine, and galantamine on EEG patterns in patients with AD. METHODS: PubMed electronic database was searched and 122 articles were found. After removal of unrelated articles, 24 articles were selected for the present study. RESULTS: AChEIs can decrease beta, theta, and delta frequency bands in patients with AD. However, conflicting results were found for alpha band. Some studies have shown increased alpha frequency, while others have shown decreased alpha frequency following treatment with AChEIs. The only difference was the type of drug. CONCLUSIONS: We found that studies reporting the decreased alpha frequency used donepezil and galantamine, while studies reporting the increased alpha frequency used rivastigmine and tacrine. It was suggested that future studies should focus on the effect of different AChEIs on EEG bands, especially alpha frequency in patients with AD, to compare their effects and find the reason for their different influence on EEG patterns. Also, differences between the effects of AChEIs on oligodendrocyte differentiation and myelination may be another important factor. This is the first article investigating the effect of different AChEIs on EEG patterns in patients with AD.

Galantamine ameliorates experimental pancreatitis.

BACKGROUND: Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis. METHODS: The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed. RESULTS: Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase+ T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine. CONCLUSION: Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.

Quercetin-1,2,3-Triazole Hybrids as Multifunctional Anti-Alzheimer's Agents.

The number of patients with Alzheimer's disease (AD) continues to rise and, despite the efforts of researchers, there are still no effective treatments for this multifaceted disease. The main objective of this work was the search for multifunctional and more effective anti-Alzheimer agents. Herein, we report the evaluation of a library of quercetin-1,2,3-triazole hybrids (I-IV) in antioxidant, hydrogen peroxide-induced oxidative stress protection, and cholinesterases (AChE and BuChE) inhibitory activities. Hybrids IIf and IVa-d showed potent in vitro inhibitory activity on eqBuChE (IC50 values between 11.2 and 65.7 µM). Hybrid IIf, the best inhibitor, was stronger than galantamine, displaying an IC50 value of 11.2 µM for eqBuChE, and is also a competitive inhibitor. Moreover, toxicity evaluation for the most promising hybrids was performed using the Artemia salina toxicity assay, showing low toxicity. Hybrids IIf, IVb, and IVd did not affect viability at 12.5 µM and also displayed a protective effect against oxidative stress induced by hydrogen peroxide in cell damage in MCF-7 cells. Hybrids IIf, IVb, and IVd act as multifunctional ligands in AD pathologies.

Cholinesterase inhibitors and falls, syncope and injuries in patients with cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits. OBJECTIVE: To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders. METHODS: Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19 years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis. RESULTS: Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures. CONCLUSION: In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.

Do Vermicompost Applications Improve Growth Performance, Pharmaceutically Important Alkaloids, Phenolic Content, Free Radical Scavenging Potency and Defense Enzyme Activities in Summer Snowflake (Leucojum aestivum L.)?

Leucojum aestivum L. contains galanthamine and lycorine, which are two pharmaceutically valuable alkaloids. Vermicompost (VC), an organic waste product created by earthworms enhances soil quality and can improve the medicinal quality of the plant that is crucial to the pharmaceutical industry. The aim of this study was to determine the effects of four different VC concentrations (5 %, 10 %, 25 %, and 50 %) on L. aestivum growth parameters, alkaloid levels (galanthamine and lycorine), total phenol-flavonoid content, free radical scavenging potential, and defense enzyme activities (SOD and CAT) compared to control (no VC). The width, length, and fresh weight of the leaves were improved by 10 % VC treatment. The highest total phenolic content was found in the bulbs and leaves treated with 50 % VC. HPLC-DAD analysis of alkaloids showed that 10 % and 50 % VC treatments contained the most galanthamine in the bulb and leaf extracts, respectively. The application of 25 % VC was the most efficient in terms of lycorine content in both extracts. CAT activity was elevated at 10 %, 25 %, and 50 % VC. Based on the growth performance and galanthamine content of the bulbs and leaves, it can be concluded that a 10 % VC application was the most effective in the cultivation of L. aestivum.

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

Galantamine-memantine hybrids for Alzheimer's disease: The influence of linker rigidity in biological activity and pharmacokinetic properties.

Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations.

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice.

Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Leprdb/db mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-ß and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Leprdb/db mouse model.

Prevalence of treated patients with Alzheimer's disease: current trends and COVID-19 impact.

BACKGROUND: There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population. OBJECTIVE: To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic. METHODS: Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019. RESULTS: Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020. CONCLUSIONS: The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.

A combination of metformin and galantamine exhibits synergistic benefits in the treatment of sarcopenia.

Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide. Current treatments involve nonpharmacological guidelines that few subjects can abide by, highlighting the need for effective drugs. Preclinical models were employed to test the benefits of RJx-01, a combination drug composed of metformin and galantamine, on sarcopenia. In worms, RJx-01 treatment improved lifespan, locomotion, pharyngeal pumping, and muscle fiber organization. The synergistic effects of RJx-01 were recapitulated in a transgenic mouse model that displays an exacerbated aging phenotype (Opa1-/-). In these mice, RJx-01 ameliorated physical performance, muscle mass and force, neuromuscular junction stability, and systemic inflammation. RJx-01 also improved physical performance and muscle strength in 22-month-old WT mice and also improved skeletal muscle ultrastructure, mitochondrial morphology, autophagy, lysosomal function, and satellite cell content. Denervation and myofiber damage were decreased in RJx-01-treated animals compared with controls. RJx-01 improved muscle quality rather than quantity, indicating that the improvement in quality underlies the beneficial effects of the combination drug. The studies herein indicate synergistic beneficial effects of RJx-01 in the treatment of sarcopenia and support the pursuit of RJx-01 in a human clinical trial as a therapeutic intervention for sarcopenia.

Acetylcholinesterase inhibitors for autistic spectrum disorders.

BACKGROUND: Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated. OBJECTIVES: To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism. SEARCH METHODS: In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group. AUTHORS' CONCLUSIONS: Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.