Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.318
Filtrar
Más filtros

Intervalo de año de publicación
1.
Medicine (Baltimore) ; 103(38): e39753, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39312316

RESUMEN

BACKGROUND: To analyze and compare the pharmacological treatments for Alzheimer disease (AD), we will conduct a systematic review and network meta-analysis focusing on their efficacy and safety over a duration exceeding 1 year. METHODS: We searched the databases of PubMed, Scopus, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and CNKI until July 30, 2023, for randomized controlled trials (RCTs) evaluating pharmacological treatments for AD. RESULTS: Seventeen RCTs, comprising 7214 participants, investigated the efficacy of the following drugs: Donepezil, Rivastigmine, Galantamine, Memantine, Ginkgo biloba extract (EGb), Atorvastatin-calcium and Vitamin B in the treatment of AD. The network meta-analysis resulted indicated that placebo demonstrated greater effectiveness compared to Atorvastatin-calcium 80 mg (mean different [MD] = -6.93, confidence interval [CI] -11.57, -2.29) and Rivastigmine 12 mg (MD = -3.33, CI -6.56, -0.09). EGb120 mg exhibited a greater improvement in cognition compared to Atorvastatin-calcium 80 mg (MD = 7.77, CI 2.07, 13.46) and Rivastigmine 12 mg + EGb120 mg (MD = 9.92, CI 1.32, 17.22). EGb 120 mg emerged as the most efficient intervention for cognition, while placebo demonstrated the least harm over a period exceeding 1 year. CONCLUSIONS: In this network meta-analysis of studies of patients with AD and a follow-up period of at least 1 year, EGb 120 mg demonstrated cognitive benefits, while placebo posed the least harm for AD. More RCTs are required to address the uncertainty surrounding the efficacy of medication.


Asunto(s)
Enfermedad de Alzheimer , Ginkgo biloba , Metaanálisis en Red , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Atorvastatina/uso terapéutico , Rivastigmina/uso terapéutico , Extractos Vegetales/uso terapéutico , Donepezilo/uso terapéutico , Memantina/uso terapéutico , Galantamina/uso terapéutico , Resultado del Tratamiento , Extracto de Ginkgo
2.
J Mol Neurosci ; 74(3): 75, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39112893

RESUMEN

Alzheimer's disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer's disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer's disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer's disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer's disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer's disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer's disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer's disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.


Asunto(s)
Enfermedad de Alzheimer , Metilenotetrahidrofolato Reductasa (NADPH2) , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol , Rivastigmina , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Rivastigmina/uso terapéutico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Masculino , Femenino , Anciano , Irán , Receptores de Calcitriol/genética , Anciano de 80 o más Años , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores de la Colinesterasa/farmacología , Persona de Mediana Edad , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología
3.
East Asian Arch Psychiatry ; 34(2): 29-36, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38955788

RESUMEN

We conducted a systematic review evaluating the efficacy of rivastigmine augmentation for treatment-refractory posttraumatic stress disorder (PTSD). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The databases Ovid MEDLINE, PubMed, CINAHL, and EMBASE were searched using key words: 'rivastigmine' OR 'Exelon' OR 'rivastigmine augmentation' OR 'Exelon augmentation' AND 'posttraumatic stress disorder*' OR 'post-traumatic stress disorder*' OR 'PTSD' OR 'combat disorder*' OR 'post-traumatic symptoms'. The asterisk specified plural forms of the relevant word. Four papers were identified, comprising one double-blind randomised controlled trial, one non-controlled open trial, one case series (presenting three case studies), and one paper with two case studies. The randomised controlled trial found no statistically significant difference in efficacy, using the PTSD CheckList-Military Version as the relevant outcomes measure, between the active add-on rivastigmine interventions and placebo or treatment as usual. The open trial, although reporting relatively positive outcomes, had a weak study design and lacked reporting of key information, including participant sex and age and pre-rivastigmine PTSD measures. The assessment of efficacy was based on participants' reporting of subjective benefits, and clinician-rating using a Clinical Global Impression, rather than established PTSD assessments scales. Although the five case studies reported improvement in PTSD symptoms, there were confounding factors and limitations in clinical and demographic data, warranting caution regarding attributed benefits. There is a lack of methodologically robust evidence supporting the efficacy of add-on rivastigmine for the treatment of refractory PTSD. Additional research may help in further evaluating its possible clinical efficacy.


Asunto(s)
Rivastigmina , Trastornos por Estrés Postraumático , Rivastigmina/uso terapéutico , Humanos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico
5.
Arch Pharm (Weinheim) ; 357(10): e2400191, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38941614

RESUMEN

A family of new compounds with sulfonamide and amide functional groups as potential Alzheimer's disease drugs were prepared by multistep synthesis. Thermal stability measurements recorded the initial decomposition in the range of 200-220°C, close above the melting point. The final compounds were tested for their ability to inhibit acetylcholinesterase and butyrylcholinesterase, and the in vitro dissolution behavior of selected compounds was studied through both lipophilic and hydrophilic matrix tablets. All nine tested derivatives were even more active in inhibiting acetylcholinesterase than the clinically used rivastigmine. Regression analysis of the obtained dissolution profiles was performed, and the effects of the pH and the release mechanism were determined. Some substances showed remarkable biological activity and became a subject of interest for further extensive study.


Asunto(s)
Enfermedad de Alzheimer , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Sulfonamidas , Enfermedad de Alzheimer/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Relación Estructura-Actividad , Acetilcolinesterasa/metabolismo , Humanos , Solubilidad , Estructura Molecular , Rivastigmina/farmacología , Rivastigmina/síntesis química , Rivastigmina/química , Concentración de Iones de Hidrógeno
6.
Eur J Pharm Biopharm ; 201: 114382, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38942175

RESUMEN

Alzheimer's disease (ALZ) is a neurological disorder characterized by cognitive decline. Rivastigmine (RV), an acetylcholinesterase inhibitor, is commonly used to treat ALZ. Unfortunately, RV is availablein capsule form, which is associated with low drug bioavailability, and in patch form, which can lead to skin irritation upon repeated use. This study successfully fabricated a trilayer dissolving microneedle (TDMN) containing RV with adequate mechanical strength by using the molding method. In vitro release and ex vivo permeation showed that the release and permeation of RV were significantly sustained compared to control without PCL. The release and permeation percentages were 91.34 ± 11.39 % and 13.76 ± 1.49 µg/cm2, respectively. In addition, the concentration of RV in plasma and brain after 168 h was measured to be 0.44 ± 0.09 µg/mL and 1.23 ± 0.26 µg/g, respectively, which reached the minimum concentration to inhibit AcHE and BuChe. Pharmacokinetic testing revealed higher AUC values after administration of TDMN, indicating better bioavailability and RV concentrations in the brain were twice as high as those achieved with oral administration. This study suggests TDMN may enhance the bioavailability and brain delivery of RV.


Asunto(s)
Administración Cutánea , Enfermedad de Alzheimer , Disponibilidad Biológica , Encéfalo , Inhibidores de la Colinesterasa , Sistemas de Liberación de Medicamentos , Rivastigmina , Rivastigmina/administración & dosificación , Rivastigmina/farmacocinética , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/farmacocinética , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Masculino , Ratas , Agujas , Prueba de Estudio Conceptual , Ratas Sprague-Dawley , Liberación de Fármacos , Absorción Cutánea/efectos de los fármacos , Piel/metabolismo
7.
Artículo en Inglés | MEDLINE | ID: mdl-38805871

RESUMEN

Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, is considered as the first-line therapy for mild to moderate Alzheimer's disease. Asiaticoside (AS), a pentacyclic triterpenoid saponin, is well known as cognitive enhancer due to its antioxidant effect. Based on the hypothesis of their synergistic therapeutic potential, RHT and AS were co-encapsulated in niosomal formulation. A simple, precise, and accurate high-performance liquid chromatography method was developed for simultaneous quantitative analysis. The chromatographic parameters were optimized by Box-Behnken experimental design. The separation was performed on a reversed-phase Phenomenex C18 (150 mm × 4.6 mm, 5 µm) column at 30 °C under the UV detection of 210 nm. The optimized mobile phase consisted of a mixture of 20 mM potassium dihydrogen phosphate buffer (pH 2.6) and acetonitrile (72:28 % v/v) under the isocratic mode at the flow rate of 0.9 mL/min. The developed method was fully validated under the ICH guidelines and could be successfully applied for simultaneous quantitative analysis of RHT and AS in niosomal formulation.


Asunto(s)
Límite de Detección , Liposomas , Rivastigmina , Triterpenos , Cromatografía Líquida de Alta Presión/métodos , Triterpenos/análisis , Triterpenos/química , Liposomas/química , Reproducibilidad de los Resultados , Rivastigmina/análisis , Rivastigmina/química , Modelos Lineales
8.
Expert Rev Neurother ; 24(6): 607-614, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38785454

RESUMEN

INTRODUCTION: Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers. AREAS COVERED: In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments. EXPERT OPINION: While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.


Asunto(s)
Administración Cutánea , Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Donepezilo , Humanos , Donepezilo/administración & dosificación , Donepezilo/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/uso terapéutico , Parche Transdérmico , Rivastigmina/administración & dosificación , Rivastigmina/uso terapéutico , Índice de Severidad de la Enfermedad
9.
J Emerg Med ; 66(5): e589-e591, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38658202

RESUMEN

BACKGROUND: Anticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment in these patients. CASE REPORT: A 33-year-old man presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic and delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5 mg to reverse his anticholinergic delirium. Although a repeat dose was required, his delirium resolved without recurrence. Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been applied successfully here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5-6 mg, if encountering anticholinergic delirium when physostigmine is not available.


Asunto(s)
Inhibidores de la Colinesterasa , Delirio , Rivastigmina , Humanos , Rivastigmina/uso terapéutico , Masculino , Delirio/tratamiento farmacológico , Adulto , Inhibidores de la Colinesterasa/uso terapéutico , Antagonistas Colinérgicos/efectos adversos , Antagonistas Colinérgicos/uso terapéutico , Antagonistas Colinérgicos/administración & dosificación , Administración Oral , Intento de Suicidio , Servicio de Urgencia en Hospital/organización & administración
10.
Chemistry ; 30(32): e202400454, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38568868

RESUMEN

Rivastigmine is one of the several pharmaceuticals widely prescribed for the treatment of Alzheimer's disease. However, its practical synthesis still faces many issues, such as the involvement of toxic metals and harsh reaction conditions. Herein, we report a chemo-enzymatic synthesis of Rivastigmine. The key chiral intermediate was synthesized by an engineered alcohol dehydrogenase from Lactobacillus brevis (LbADH). A semi-rational approach was employed to improve its catalytic activity and thermal stability. Several LbADH variants were obtained with a remarkable increase in activity and melting temperature. Exploration of the substrate scope of these variants demonstrated improved activities toward various ketones, especially acetophenone analogs. To further recycle and reuse the biocatalyst, one LbADH variant and glucose dehydrogenase were co-immobilized on nanoparticles. By integrating enzymatic and chemical steps, Rivastigmine was successfully synthesized with an overall yield of 66 %. This study offers an efficient chemo-enzymatic route for Rivastigmine and provides several efficient LbADH variants with a broad range of potential applications.


Asunto(s)
Alcohol Deshidrogenasa , Enzimas Inmovilizadas , Levilactobacillus brevis , Rivastigmina , Rivastigmina/química , Levilactobacillus brevis/enzimología , Alcohol Deshidrogenasa/metabolismo , Alcohol Deshidrogenasa/química , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Biocatálisis , Acetofenonas/química , Acetofenonas/metabolismo , Ingeniería de Proteínas
11.
Medicine (Baltimore) ; 103(16): e37799, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38640313

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inducido químicamente , Donepezilo/uso terapéutico , Galantamina/uso terapéutico , Memantina/uso terapéutico , Simulación del Acoplamiento Molecular , Inhibidores de la Colinesterasa/uso terapéutico , Rivastigmina/uso terapéutico
12.
Brain Res Bull ; 212: 110955, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38677558

RESUMEN

In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments, while it produced a significant improvement of cognitive function when taken as monotherapy. Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. Here, we examined the effect of HMTM, given alone or in combination with the acetylcholinesterase inhibitor, rivastigmine, at the level of expression of selected pre-synaptic proteins (syntaxin-1; SNAP-25, VAMP-2, synaptophysin-1, synapsin-1, α-synuclein) in brain tissue harvested from tau-transgenic Line 1 (L1) and wild-type mice using immunohistochemistry. L1 mice overexpress the tau-core unit that induces tau aggregation and results in an AD-like phenotype. Synaptic proteins were lower in hippocampus and cortex but greater in basal forebrain regions in L1 compared to wild-type mice. HMTM partially normalised the expression pattern of several of these proteins in basal forebrain. This effect was diminished when HMTM was administered in combination with rivastigmine, where mean protein expression seemed supressed. This was further confirmed by group-based correlation network analyses where important levels of co-expression correlations in basal forebrain regions were lost in L1 mice and partially re-established when HMTM was given alone but not in combination with rivastigmine. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies.


Asunto(s)
Inhibidores de la Colinesterasa , Modelos Animales de Enfermedad , Ratones Transgénicos , Rivastigmina , Tauopatías , Animales , Tauopatías/tratamiento farmacológico , Tauopatías/metabolismo , Inhibidores de la Colinesterasa/farmacología , Rivastigmina/farmacología , Ratones , Proteínas tau/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Masculino , Azul de Metileno/análogos & derivados
13.
ACS Appl Bio Mater ; 7(5): 2710-2724, 2024 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-38591866

RESUMEN

In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.


Asunto(s)
Acetilcisteína , Materiales Biocompatibles , Ensayo de Materiales , Nanopartículas , Agujas , Tamaño de la Partícula , Impresión Tridimensional , Rivastigmina , Acetilcisteína/química , Acetilcisteína/farmacología , Rivastigmina/química , Rivastigmina/farmacología , Rivastigmina/administración & dosificación , Humanos , Nanopartículas/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Sistemas de Liberación de Medicamentos , Piel/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Supervivencia Celular/efectos de los fármacos
14.
Cells ; 13(7)2024 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-38607082

RESUMEN

Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer's disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Ratones , Animales , Lactante , Rivastigmina/farmacología , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa/metabolismo , Neuroprotección , Neuronas Colinérgicas/metabolismo , Tauopatías/tratamiento farmacológico , Colinérgicos , Ratones Transgénicos
15.
Psychopharmacol Bull ; 54(2): 15-27, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38601834

RESUMEN

The study aimed to assess Rivastigmine augmentation on positive and negative symptoms (PNSs), general psychopathology, and quality of life in patients with chronic Schizophrenia. A double-blind, parallel-design, randomized, placebo-controlled trial of 60 schizophrenia patients was conducted. Intervention group received rivastigmine 3 mg/day + Treatment as Usual (TAU) and the control group: TAU + placebo. Negative and positive symptoms, general psychopathology; and quality of life were measured using Positive and Negative Symptom Scale (PANSS) and Manchester Short Assessment of Quality of Life (MANSA). T-test, ANOVA, and the general univariate linear model tests were used for the analyses. Out of 60 participants, 52 (86.6%) were male. At baseline, no significant relationship was found for demographic and clinical characteristics between intervention and control groups. Between-group analysis indicated that all outcome measures PNSs, general psychopathology symptoms, and QoL score in rivastigmine group was significantly improved (p = 0.001). According to within-group analysis, a significant association was found between Rivastigmine and placebo groups in PNSs (p < 0.05). Rivastigmine augmentation improved PNSs and psychopathology in schizophrenia patients. However, no significant association found for improving the life quality after 8 weeks treatment.


Asunto(s)
Antipsicóticos , Esquizofrenia , Humanos , Masculino , Femenino , Esquizofrenia/tratamiento farmacológico , Rivastigmina/farmacología , Rivastigmina/uso terapéutico , Calidad de Vida , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , Quimioterapia Combinada , Método Doble Ciego
17.
Clin Toxicol (Phila) ; 62(2): 82-87, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38465631

RESUMEN

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.


Asunto(s)
Delirio , Fisostigmina , Femenino , Humanos , Adulto , Masculino , Rivastigmina/uso terapéutico , Fisostigmina/uso terapéutico , Antagonistas Colinérgicos/uso terapéutico , Antagonistas Colinérgicos/toxicidad , Inhibidores de la Colinesterasa/uso terapéutico , Delirio/inducido químicamente , Delirio/tratamiento farmacológico
18.
Int J Pharm ; 652: 123809, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38224760

RESUMEN

Alzheimer's disease (AD) is characterized by a gradual decline in cognitive function and memory impairment, significantly impacting the daily lives of patients. Rivastigmine (RHT), a cholinesterase inhibitor, is used to treat mild to moderate AD via oral administration. However, oral administration is associated with slow absorption rate and severe systemic side effects. RHT nasal spray (RHT-ns), as a nose-to-brain delivery system, is more promising for AD management due to its efficient brain delivery and reduced peripheral exposure. This study constructed RHT-ns for enhancing AD treatment efficacy, and meanwhile the correlation between drug olfactory deposition and drug entering into the brain was explored. A 3D-printed nasal cast was employed to quantify the drug olfactory deposition. Brain delivery of RHT-ns was quantified using fluorescence tracking and Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) analysis, which showed a good correlation to the olfactory deposition. F2 (containing 1% (w/v) viscosity modifier Avicel® RC-591) with high olfactory deposition and drug brain delivery was further investigated for pharmacodynamics study. F2 exhibited superiority in AD treatment over the commercially available oral formulation. In summary, the present study showed the successful development of RHT-ns with improved olfactory deposition and enhanced brain delivery. It might provide new insight into the design and development of nose-to-brain systems for the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Rivastigmina/química , Rivastigmina/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Rociadores Nasales , Administración Intranasal , Encéfalo , Inhibidores de la Colinesterasa
19.
Bioorg Chem ; 144: 107152, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38290187

RESUMEN

Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N-methyl-d-aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure-activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Ligandos , Donepezilo/uso terapéutico , Rivastigmina/uso terapéutico , Acetilcolinesterasa
20.
Eur J Neurol ; 31(2): e16142, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37975761

RESUMEN

BACKGROUND AND PURPOSE: Neuropsychiatric symptoms including depression, apathy and psychosis occur frequently in patients with Parkinson's disease. A subgroup of patients develop cognitive impairment, which may increase the risk of falls due to reduced attention. The acetylcholinesterase inhibitor rivastigmine is beneficial in Parkinson's disease dementia, but whether the use of rivastigmine is effective earlier in the disease course is unclear. The aim of this systematic review was to assess the evidence for rivastigmine in the treatment of neuropsychiatric symptoms in Parkinson's disease without dementia. METHODS: Embase, Medline, PsychINFO, Cochrane CENTRAL, NGLC, National Institute for Health and Care Excellence Evidence and medRxiv.org were searched for studies with terms relating to population (Parkinson's disease) and intervention (rivastigmine). Of 1922 references identified, 358 were duplications. Following title and abstract review, 1331 articles were excluded. After full-text review, nine articles remained. RESULTS: Outcomes were heterogenous, therefore, the results are presented in narrative form. The articles included six randomized controlled trials, two open-label trials and one case series. Outcome measures included: time to develop psychosis; frequency of rapid eye movement sleep behaviour disorder (RBD) episodes; apathy; gait variability; falls; cognitive ability; Neuropsychiatric Inventory score; and regional spontaneous brain activity. CONCLUSIONS: There is evidence that rivastigmine is beneficial for RBD and apathy in Parkinson's disease patients without dementia. There is high level evidence that rivastigmine reduces falls, which may be due to improved attention. The impact of rivastigmine on psychotic symptoms is less clear, but is supported by current theoretical models which involve acetylcholine dysfunction in the generation of visual hallucinations in Parkinson's disease.


Asunto(s)
Demencia , Enfermedad de Parkinson , Humanos , Rivastigmina/uso terapéutico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Acetilcolinesterasa , Fenilcarbamatos , Inhibidores de la Colinesterasa/uso terapéutico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA