Rivastigmine-Bambuterol Hybrids as Selective Butyrylcholinesterase Inhibitors.

Selective butyrylcholinesterase inhibitors are considered promising drug candidates for the treatment of Alzheimer's disease. In this work, one rivastigmine-bambuterol hybrid (MTR-1) and fourteen of its analogues were synthesized, purified, and characterized. In vitro cholinesterase assays showed that all the compounds were more potent inhibitors of BChE when compared to AChE. Further investigations indicated that MTR-3 (IC50(AChE) > 100,000 nM, IC50(BChE) = 78 nM) was the best compound in the series, showing high butyrylcholinesterase selectivity and inhibition potency, the potential to permeate the blood-brain barrier, and longer-lasting BChE inhibition than bambuterol. These compounds could be used to discover novel specific BChE inhibitors for the treatment of Alzheimer's disease.

Efficacy of Rivastigmine Augmentation on Positive and Negative Symptoms, General Psychopathology, and Quality of Life in Patients with Chronic Schizophrenia: A Randomized Controlled Trial.

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.

Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer's-like Tauopathy Mouse Model.

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.

Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies: Interference by cholinesterase inhibitors.

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.

Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.

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.

Manifestación de una interacción farmacológica entre rivastigmina y tolterodina en un paciente geriátrico con diagnósticos de Parkinson y vejiga hiperactiva: reporte de caso / Management of the drug interaction between rivastigmine and tolterodine in one elderly patient with Parkinsonand overactive bladder

El uso conjunto de medicamentos anticolinérgicos e inhibidores de la colinesterasa no es recomendado por los fabricantes de los productos, ya que pueden afectar la función cognitiva de los pacientes, esto se ve acentuado en la población geriátrica polimedicada. Uno de los problemas relacionados a la medicación, en los que los farmacéuticos realizan con frecuencia intervenciones, es el número de interacciones farmacológicas potenciales que pueden expresarse con los distintos medicamentos que emplean los pacientes. Presentamos el caso de un paciente con diagnóstico de Parkinson y vejiga neurogénica que presentó pérdida de la concentración y memoria asociada a una interacción farmacológica entre un inhibidor directo de la colinesterasa (rivastigmina) y un anticolinérgico (tolterodina). El mecanismo descrito para la interacción es la disminución del efecto esperado de rivastigmina por efecto de inhibición de la tolterodina en los receptores colinérgicos, impidiendo la liberación de acetilcolina y quitando así el blanco terapéutico de la enzima que se inhibe por efecto de la tolterodina. La intervención oportuna y el manejo adecuado de las interacciones farmacológicas durante la atención sanitaria es de suma importancia para evitar daños en los pacientes, incluido la exacerbación de enfermedades que se encuentran controladas, debido a la adición de otros medicamentos a la farmacoterapia

The use of anticholinergic and cholinesterase inhibitors set is not recommended by drug laboratory producers, because the use of the drugs can affect the cognitive function of the patients, this is more common in the elderly and polymedicated population. For the pharmacist is a challenge to have control of the number of potential drug interactions that can express with the different drugs that the patient has in a prescription. We present a case of an expression of drug-drug interaction between anticholinergic (tolterodine) and direct cholinesterase inhibitor (rivastigmine) in a patient with Parkinson disease and overactive bladder, the outcome of this interaction is the decrease the effect of rivastigmine by inhibition of cholinergic receptors, keep the inhibition of release acetylcholine and remove the target of the enzyme that rivastigmine inhibit, the expression of the interaction in the patient is expressed in loss of concentration and memory, the management and report of this interaction is very important for the patient with control of the disease