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Clinics (Sao Paulo, Brazil) 2024Summarize the evidence on drug therapies for obstructive sleep apnea. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Summarize the evidence on drug therapies for obstructive sleep apnea.
METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed, Embase, Scopus, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched on February 17th, 2023. A search strategy retrieved randomized clinical trials comparing the Apnea-Hypopnea Index (AHI) in pharmacotherapies. Studies were selected and data was extracted by two authors independently. The risk of bias was assessed using the Cochrane Risk of Bias tool. RevMan 5.4. was used for data synthesis.
RESULTS
4930 articles were obtained, 68 met inclusion criteria, and 29 studies (involving 11 drugs) were combined in a meta-analysis. Atomoxetine plus oxybutynin vs placebo in AHI mean difference of -7.71 (-10.59, -4.83) [Fixed, 95 % CI, I2 = 50 %, overall effect: Z = 5.25, p < 0.001]. Donepezil vs placebo in AHI mean difference of -8.56 (-15.78, -1.33) [Fixed, 95 % CI, I2 = 21 %, overall effect: Z = 2.32, p = 0.02]. Sodium oxybate vs placebo in AHI mean difference of -5.50 (-9.28, -1.73) [Fixed, 95 % CI, I2 = 32 %, overall effect: Z = 2.86, p = 0.004]. Trazodone vs placebo in AHI mean difference of -12.75 (-21.30, -4.19) [Fixed, 95 % CI, I2 = 0 %, overall effect: Z = 2.92, p = 0.003].
CONCLUSION
The combination of noradrenergic and antimuscarinic drugs shows promising results. Identifying endotypes may be the key to future drug therapies for obstructive sleep apnea. Moreover, studies with longer follow-up assessing the safety and sustained effects of these treatments are needed.
PROSPERO REGISTRATION NUMBER
CRD42022362639.
Topics: Humans; Sleep Apnea, Obstructive; Atomoxetine Hydrochloride; Donepezil; Norepinephrine
PubMed: 38341903
DOI: 10.1016/j.clinsp.2024.100330 -
Biosensors Feb 2024Neurodegenerative diseases and Alzheimer's disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a... (Review)
Review
Neurodegenerative diseases and Alzheimer's disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a reduction in the presynaptic markers of the cholinergic system. These consequences can be compensated by the inhibition of acetylcholinesterase (AChE) followed by a decrease in the rate of acetylcholine hydrolysis. For this reason, anticholinesterase drugs with reversible inhibition effects are applied for the administration of neurodegenerative diseases. Their overdosage, variation in efficiency and recommendation of an individual daily dose require simple and reliable measurement devices capable of the assessment of the drug concentration in biological fluids and medications. In this review, the performance of electrochemical biosensors utilizing immobilized cholinesterases is considered to show their advantages and drawbacks in the determination of anticholinesterase drugs. In addition, common drugs applied in treating neurodegenerative diseases are briefly characterized. The immobilization of enzymes, nature of the signal recorded and its dependence on the transducer modification are considered and the analytical characteristics of appropriate biosensors are summarized for donepezil, huperzine A, rivastigmine, eserine and galantamine as common anti-dementia drugs. Finally, the prospects for the application of AChE-based biosensors in clinical practice are discussed.
Topics: Humans; Alzheimer Disease; Cholinesterase Inhibitors; Acetylcholinesterase; Pharmaceutical Preparations; Piperidines; Indans
PubMed: 38392012
DOI: 10.3390/bios14020093 -
Frontiers in Pharmacology 2023Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer's disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is...
Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer's disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is essential for its safe and rational administration. This study aimed to evaluate the correlation between different ChEIs and TdP/QT prolongation. All ChEIs related TdP/QT prolongation cases were retrieved from the FAERS database using standard MedDRA query (SMQ) from the first quarter of 2004 to the third quarter of 2022. Disproportionality and sensitivity analysis were used to determine the signal of TdP/QT prolongation related to ChEIs. 557 cases of TdP/QT prolongation related to 3 ChEIs were searched by SMQ. The patients were mostly elderly people, with markedly more female than male. The signals of TdP/QT prolongation for ChEIs were detected by disproportionality analysis, and the signal of Donepezil was the strongest. The sensitivity analysis results indicate a robust and stable correlation between these signals with ChEIs. TdP/QT prolongation usually occurs within 1 month after taking ChEIs. The drug with the highest frequency of combination with donepezil and galantamine is citalopram, and the drug with the highest frequency of combination with rivastigmine is atorvastatin. The signals of TdP/QT prolongation related to ChEIs were strong and stable. It is necessary to be vigilant about the TdP/QT prolongation of various ChEIs, especially in elderly women, the initial stage after taking ChEIs, and when ChEIs combining with drugs that could prolong the QT interval.
PubMed: 38273821
DOI: 10.3389/fphar.2023.1343650 -
International Journal of Molecular... Aug 2023A synthesis procedure and aggregation properties of a new homologous series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments...
A synthesis procedure and aggregation properties of a new homologous series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments (N,N'-dialkyl-N,N'-bis(2-(ethylcarbamoyloxy)ethyl)-N,N'-dimethyldodecan-1,6-diammonium dibromide, n-12-n(Et), where n = 10, 12, 14) were comprehensively described. The critical micelle concentrations of gemini surfactants were obtained using tensiometry, conductometry, spectrophotometry, and fluorimetry. The thermodynamic parameters of adsorption and micellization, i.e., maximum surface excess (Г), the surface area per surfactant molecule (A), degree of counterion binding (β), and Gibbs free energy of micellization (∆G), were calculated. Functional activity of the surfactants, including the solubilizing capacity toward Orange OT and indomethacin, incorporation into the lipid bilayer, minimum inhibitory concentration, and minimum bactericidal and fungicidal concentrations, was determined. Synthesized gemini surfactants were further used for the modification of liposomes dual-loaded with α-tocopherol and donepezil hydrochloride for intranasal treatment of Alzheimer's disease. The obtained liposomes have high stability (more than 5 months), a significant positive charge (approximately + 40 mV), and a high degree of encapsulation efficiency toward rhodamine B, α-tocopherol, and donepezil hydrochloride. Korsmeyer-Peppas, Higuchi, and first-order kinetic models were used to process the in vitro release curves of donepezil hydrochloride. Intranasal administration of liposomes loaded with α-tocopherol and donepezil hydrochloride for 21 days prevented memory impairment and decreased the number of Aβ plaques by 37.6%, 40.5%, and 72.6% in the entorhinal cortex, DG, and CA1 areas of the hippocampus of the brain of transgenic mice with Alzheimer's disease model (APP/PS1) compared with untreated animals.
PubMed: 37569687
DOI: 10.3390/ijms241512312 -
Alzheimer's Research & Therapy Aug 2023Although hypertension is a critical risk factor for dementia, the association between primary aldosteronism (PA) and dementia has been scarcely reported. We aimed to...
BACKGROUND
Although hypertension is a critical risk factor for dementia, the association between primary aldosteronism (PA) and dementia has been scarcely reported. We aimed to investigate whether the risk of dementia in patients with PA was elevated compared with patients with essential hypertension (EH).
METHODS
From the National Health Insurance Claim database in Korea (2003-2017), 3,687 patients with PA (adrenalectomy [ADX], n = 1,339, mineralocorticoid receptor antagonist [MRA] n = 2,348) with no prior dementia were age- and sex-matched at a 1:4 ratio to patients with EH (n = 14,741). The primary outcomes were all-cause dementia events, including Alzheimer's disease, vascular dementia, or other dementia combined with a prescription of one or more medications for dementia (donepezil, galantamine, memantine, or rivastigmine). Multivariable Cox regression models were used to evaluate the hazard ratios (HRs) and 95% confidence intervals for the outcome incidence rates between patients with PA and their EH matches.
RESULTS
During a median follow-up of 5.2 years, there were 156 cases of all-cause dementia (4.2%), 140 cases of Alzheimer's disease (3.8%), and 65 cases of vascular dementia (1.8%). Compared with EH, the risk of all-cause dementia was increased in treated PA (unadjusted hazard ratio [HR] 1.26; p < 0.011). Among PA, MRA group had higher risks of all-cause dementia, especially vascular dementia, adjusted for age, sex, income, comorbidities, and concurrent medication (adjusted HR 1.31; p = 0.027 and adjusted HR 1.62; p = 0.020, respectively) compared to EH. ADX group seemed to have a lower dementia risk than the EH group, but there was no statistical significance after full adjustment. This trend became more prominent when the dementia risks were evaluated from the time of hypertension diagnosis rather than treatment initiation for PA.
CONCLUSION
The findings of this cohort study suggest that PA, especially the MRA group, is associated with an increased risk of dementia. Monitoring cognitive function in PA patients even after treatment initiation might be warranted to prevent dementia.
Topics: Humans; Cohort Studies; Alzheimer Disease; Dementia, Vascular; Hyperaldosteronism; Essential Hypertension; Hypertension; Mineralocorticoid Receptor Antagonists
PubMed: 37568223
DOI: 10.1186/s13195-023-01274-x -
European Psychiatry : the Journal of... Feb 2024A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the '...
BACKGROUND
A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer's disease. Hence, we aimed to shorten the ' (ADAS-Cog) and test its use as an efficacy measure.
METHODS
Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer's disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups.
RESULTS
Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34).
CONCLUSIONS
IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.
Topics: Humans; Alzheimer Disease; Donepezil; Cognition Disorders; Cognition
PubMed: 38389390
DOI: 10.1192/j.eurpsy.2024.14 -
Frontiers in Pharmacology 2023Total saponins from Maxim (TSTT), a bioactive component of local natural herbs in the Enshi area, China, have been demonstrated to have functions of restoring cognitive...
Total saponins from Maxim (TSTT), a bioactive component of local natural herbs in the Enshi area, China, have been demonstrated to have functions of restoring cognitive capacity and promoting axonal regeneration post-stroke, but the mechanism of this process remains unclear. The hippocampus is a critical tissue for controlling learning and memory capacity, and the sonic hedgehog (Shh) signaling pathway plays a major role in the patterning and synaptic plasticity of hippocampal neural circuits. Therefore, we aimed to investigate whether TSTT could restore learning and cognitive functions by modulating the Shh pathway in rats with post-stroke cognitive impairment (PSCI). The ischemia model was established by permanent middle cerebral artery occlusion (MCAO) in 100 Sprague-Dawley (SD) rats, and the model rats were administered using TSTT (100 mg/kg) or donepezil hydrochloride as the positive control (daily 0.45 mg/kg, DON) for 4 weeks after the operation. As assessed by the Morris water maze test, the cognitive function of PSCI rats was significantly improved upon TSTT treatment. Meanwhile, the cerebral infarct volume reduced with TSTT, as shown by HE and TTC staining, and the number of Nissl bodies and dendritic spine density were significantly increased, as shown by Nissl and Golgi staining. In addition, TSTT upregulated PSD-95, SYN, and GAP-43, and inhibited neuronal apoptosis, as evidenced by increased Bcl-2 levels along with decreased Bax and caspase-3 expression. TSTT could also significantly upregulate Shh, Ptch1, Smo, and Gli1 proteins, indicating the activation of the Shh signaling pathway. Therefore, TSTT can protect PSCI rats by inhibiting apoptosis and promoting neuronal synaptic remodeling. The Shh pathway is also involved.
PubMed: 37745057
DOI: 10.3389/fphar.2023.1255560 -
Rambam Maimonides Medical Journal Oct 2023Movement disorders associated with donepezil have been only rarely reported. Herein, we describe an older woman who developed myoclonus secondary to donepezil. A...
Movement disorders associated with donepezil have been only rarely reported. Herein, we describe an older woman who developed myoclonus secondary to donepezil. A 61-year-old female presented with brief involuntary twitching. The patient reported that she consulted a general practitioner about 1 month before due to memory complaints. A diagnosis of mild cognitive impairment was made. Donepezil was started. After 4 weeks, she presented to our emergency department due to significant twitching. Multifocal myoclonus was observed. These movements occurred during rest and voluntary movement. Laboratory exams and cerebrospinal fluid analysis were normal. A cranial computed tomography and brain magnetic resonance imaging were unremarkable. Electroencephalography did not show epileptic activity. Electromyography revealed burst durations varying between 50 and 100 ms. Diazepam intravenous was started, which improved her abnormal movement within 1 hour. On the next day, she developed the same clinical symptoms of presentation. Donepezil was discontinued, and clonazepam was started. The patient had a complete recovery from her myoclonus. To the authors' knowledge, there are six reports of myoclonus secondary to donepezil/galantamine. There is no report of rivastigmine-induced myoclonus. The most frequent presentation was multifocal myoclonus. The management was the discontinuation of the acetylcholinesterase inhibitor. All the individuals recovered within 3 weeks.
PubMed: 37917866
DOI: 10.5041/RMMJ.10510 -
CNS Drugs Jul 2023Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular... (Review)
Review
Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer's disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer's disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer's disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches.
Topics: Humans; Alzheimer Disease; Cholinergic Agents; Brain; Aphasia; Acetylcholine
PubMed: 37341896
DOI: 10.1007/s40263-023-01017-4 -
Neuroreport Dec 2023Alzheimer's disease (AD) is a degenerative disorder characterized by cognitive dysfunction and BDNF/TrkB is a well-conceived anti-AD signaling. Cynomorium songaricum...
Total flavonoids of Cynomorium songaricum attenuates cognitive defects in an Aβ 1-42 -induced Alzheimer's disease rat model by activating BDNF/TrkB signaling transduction.
Alzheimer's disease (AD) is a degenerative disorder characterized by cognitive dysfunction and BDNF/TrkB is a well-conceived anti-AD signaling. Cynomorium songaricum Rupr. ( C. songaricum ) is a herb with promising neuroprotective effects and the function is majorly attributed to flavonoids. The current study attempted to explore the effects of total flavonoids of C. songaricum (CS) on AD model by focusing on changes in BDNF/TrkB axis. AD model was induced in rats via transcranial injection of Aβ 1-42 and AD symptoms treated with CS of three doses. Donepezil was used as the positive control. Changes in rat memory and learning abilities, brain histological, apoptosis, production of neurotransmitters, BDNF/TrkB axis, and apoptosis-related markers were measured. The injection of Aβ 1-42 induced cognitive dysfunction in AD rats. The integrity of brain tissue structure was destructed and apoptosis was induced in AD rats, in which was found the increased production of AChE and Aβ 1-42 , and decreased production of ChAT, ACH. At the molecular level, the expression of BDNF, TrkB, and Bcl-2 was suppressed, while the expression of Bax, caspase-3, and caspase-9 was induced. After the administration of CS, the memory and learning abilities of rats were improved, the production of neurotransmitter was restored, ordered arrangement of pyramidal cells was retained, and neuron apoptosis was inhibited. The attenuation of Aβ 1-42 -indcued impairments was associated with the activation of BDNF/TrkB axis and blockade of apoptosis-related pathways. Collectively, CS can improve learning and memory abilities in Aβ 1-42 -induced AD model rats. which may depend on the activation of the hippocampal BDNF/TrkB signaling pathway.
Topics: Rats; Animals; Alzheimer Disease; Brain-Derived Neurotrophic Factor; Cynomorium; Amyloid beta-Peptides; Flavonoids; Cognitive Dysfunction; Signal Transduction; Hippocampus; Cognition
PubMed: 37851367
DOI: 10.1097/WNR.0000000000001960