Galantamine Research Articles

Detecting the neurogenesis effect of erythropoietin and galantamine in the dentate gyrus and spatial memory in Alzheimer's experimental rat model

Background: Alzheimer’s disease is neurodegenerative disorder develops unreversed causing memory and behavior impairment. It is estimated that 35.5 million people are living with Alzheimer’s disease worldwide. The early symptoms of Alzheimer’s are short-term memory weakness and it develops gradually causing death. There is no curing medication for Alzheimer’s rather than some drugs that improve memory defects for a period of time. Many studies proved that erythropoietin (EPO) and galantamine (GAL) could improve neurogenesis in hippocampus, which is promising in finding a cure for Alzheimer’s. Aims and Objectives: In this study, we compared neurogenesis effect of GAL and EPO and its effect on spatial memory. Materials and Methods: We used Wistar rats to make Alzheimer’s rat model by bilateral intracerebroventricular injection of streptozotocin. We used a dose of EPO 5000 IU/Kg intraperitoneal every other day for 14 days, and GAL group was treated with intraperitoneal daily dose of 5 mg/kg. Then, all groups were tested by Morris water maze test to compare spatial memory. Then, all rats were anesthetized and decapitated for immunohistochemical study by KI67 kit to investigate proliferated cells in dentate gyrus of hippocampus. Results: The results driven from the histological study showed that both EPO and GAL significantly increase neuronal proliferation in dentate gyrus of hippocampus, but EPO has better effect on neurogenesis, whereas GAL could improve spatial memory more than EPO in Morris water maze test. Conclusion: GAL has better effect on spatial memory in short period study, but EPO increases proliferation more than GAL.

An analytical review on method development and validation of drugs used for alzheimers disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by progressive memory defeat and impairment in behavior, language, and visuospatial skills. Current approved drugs for the treatment of Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, galantamine and rivastigmine,) and the NMDA receptor antagonist memantine. These drugs can provide a symptomatic relief but they poorly affect the progression of the disease. There are several risk factors for the development of Alzheimers disease which include factors like age, genetic factor family history, Downs syndrome, head injury and cardiovascular diseases. Cardio vascular risk factors may include blood pressure, cholesterol, diabetes, obesity and smoking. People may experience cognitive mental illness, difficulty in understanding and thinking, forgetting things easily, making things complicated, mental confusion, difficulty in concentrating, inability to create old memories, inability to do simple things, or inability to recognize common things. The main objective of this review is discussion on various analytical methods used, different solvents used as mobile phase and their retention time. This review includes method development and validation of cholinesterase inhibitors like Donepezil, Galantamine, Rivastigmine and Tacrine combination of drugs which include cholinesterase inhibitors like Donepezil and NMDA receptor antagonist Memantine. The review is a collection of data including various analytical methods used, the different columns used, mobile phase used, flow rate, different detectors and detection wavelength and retention time. This review includes discussion on method development and validation of Alzheimers drugs and newly developed compounds which have lesser side effects and are proving more efficient for treatment of Alzheimers disease.

Galantamine attenuates N,N-dimethyl hydrazine induced neoplastic colon damage by inhibiting acetylcholinesterase and bimodal regulation of nicotinic cholinergic neurotransmission

The present study reveals the effect of galantamine (GAL) against 1, 2-dimethylhydrazine (DMH) induced colon cancer. Wistar albino rats were arbitrarily divided into four groups (n = 8). Group 1 served as normal control (normal saline, 3ml/kg/day, p.o.); group 2, 3 and 4 received DMH (20mg/kg/week, s.c.), for 6 weeks; groups 3 and 4 also received GAL (2 and 4mg/kg/day, p.o) for 6 weeks. DMH treated rats showed decreased heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), increased thiobarbituric acid reactive substances (TBARs) along with the decrease in the enzymatic activity of superoxide dismutase (SOD) and catalase. Increased levels of inflammatory marker cyclooxygenase (COX) and lipoxygenase (LOX) was also evident in DMH treated animals. The colonic surface architecture was studied using scanning electron microscopy revealed aberrant crypts(X500) and neoplastic nodules (X2000). GAL treatment helped to minimize the ACF count, restored oxidative stress and inflammatory markers favorably. To further validate our results, our study was directed to define the effect of GAL on acetylcholine neurotransmission using a simple model organism, Caenorhabditis elegans (C. elegans). Increased synaptic cholinergic transmission by GAL (32µM) was evident in the worms when studied through aldicarb assay. However, GAL (32µM) treatment negatively modulated α7 nicotinic acetylcholine receptor (α7nAch receptor), when evaluated using the levamisole assay. GAL (32µM) treatment down regulated the genomic expression of ace-1, ace-2 along with unc-29, unc-38, and unc-50 (essential components of α7 nAch receptor). GAL by inhibiting AchE and regulating Alpha7nACh activity can improve cholinergic neurotransmission.

Rehabilitative Success After Brain Trauma by Augmenting a Subtherapeutic Dose of Environmental Enrichment With Galantamine

Background. Environmental enrichment (EE) confers benefits after traumatic brain injury (TBI) when provided daily for > 6 hours, but not 2 or 4 hours, which more accurately reflects the daily amount of clinical rehabilitation. The lack of benefit with sub-therapeutic EE suggests that augmentation with galantamine (GAL), which enhances cognition after TBI, may be indicated to confer benefits. Objective. To test the hypothesis that 2 and 4 hours of EE paired with GAL will provide benefits comparable to 24 hours of EE alone. Moreover, all EE groups will perform better than the standard (STD)-housed GAL group. Methods. Anesthetized rats received a TBI or sham injury and then were randomized to receive intraperitoneal injections of GAL (2 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 hours after surgery and once daily while receiving EE for 2, 4, or 24 hours. Motor and cognitive assessments were conducted on postoperative days 1-5 and 14-19, respectively. Results. Motor function was significantly improved in the TBI + 24-hour EE group versus the TBI + STD + VEH and TBI + STD + GAL groups (P < .05). Cognitive performance was enhanced in all EE groups as well as in the TBI + STD + GAL versus TBI + STD + VEH (P < .05). Moreover, the 2- and 4-hour EE groups receiving GAL did not differ from the 24-hour EE group (P > .05) and performed better than GAL alone (P < .05). Conclusions. The findings support the hypothesis and have clinical relevance because, often, only brief rehabilitation may be available in the clinic and, thus, augmenting with a pharmacotherapy such as GAL may lead to outcomes that are significantly better than either therapy alone.

In vitro anticholinesterase activity and molecular docking studies of coumarin derivatives isolated from roots of Heptaptera cilicica

The chloroform extract of the roots of Heptaptera cilicica (Boiss. & Bal.) Tutin (Apiaceae) was investigated in terms of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects by Ellman method. Afterwards, a new furocoumarin: trichoclin angelate with five known coumarin derivatives: umbelliprenin, badrakemone, badrakemin, badrakemin acetate and prunate were isolated from this extract. Their structures were identified by means of spectroscopic methods (1D, 2D-NMR and HRESIMS). The next step of our study was determining AChE and BuChE inhibitory activities of the compounds by molecular docking and in vitro methods. According to the results, prunate was found to be the most potent compound, which exhibited significant inhibitory potency against acetylcholinesterase (IC50 = 1.76 ± 0.003 µM) and butyrylcholinesterase (IC50 = 0.21 ± 0.002 μM) as compared with the reference compound, galantamine hydrobromide.

Canagliflozin prevents scopolamine-induced memory impairment in rats: Comparison with galantamine hydrobromide action

Canagliflozin (CAN) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated to improve glycemic control in adults with type 2 diabetes mellitus. There is a little information about its effect on the cholinergic system that proposed mechanism for memory improvement occurring by SGLT2 drugs. This study aimed to estimate the effect of CAN as compared to galantamine (GAL) treatments for two weeks on scopolamine hydrobromide (SCO)-induced memory dysfunction in experimental rats. Animals divided into six groups; control (CON), CAN, GAL, SCO, SCO + CAN and SCO + GAL. Results indicated significant decrease in body weights of the CAN groups as compared to control values. Moreover, in the SCO + CAN and SCO + GAL the number of arm entry and number of correct alternation in Y maze task increased and showed improvement in the water maze task, acetylcholinesterase (AChE) activities decreased significantly, while monoamines levels significantly increased compared with the SCO group values. Results also recorded acetylcholine M1 receptor (M1 mAChR) in SCO + CAN or SCO + GAL groups in comparison with the SCO group. The study suggested that canagliflozin might improve memory dysfunction induced by scopolamine hydrobromide via cholinergic and monoamines system.

Design and synthesis of 2,6-di(substituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as α-glucosidase and α-amylase inhibitors, co-relative Pharmacokinetics and 3D QSAR and risk analysis

Ten fused heterocyclic derivatives bearing the 2,6-di(subsituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as central rings were synthesized and structures of the compounds were established by analytical and spectral data using FTIR, EI-MS, 1H NMR and 13C NMR techniques. In vitro inhibitory activities of synthesized compounds on α-amylase, α-glucosidase and α-burylcholinesterase (α-BuChE) were evaluated using a purified enzyme assays. Compound 5c demonstrated strong and selective α-amylase inhibitory activity (IC50=1.1μmol/g). 5g exhibited excellent inhibition against α-glucosidase (IC50=1.2μmol/g) when compared with acarbose (IC50=4.7μmol/g) as a positive reference. Compound 5i was found to be most potent derivative against α-BuChE with the IC50 of 1.5μmol/g which was comparable to the value obtained for (4.7μmol/g) positive control (i.e. galantamine hydrobromide). Molecular dockings of synthesized compounds into the binding sites of human pancreatic α-amylase, intestinal maltase-glucoamylase and neuronal α-butrylcholinesterase allowed to shed light on the affinity and binding mode of these novel inhibitors. Preliminary structure–activity relationship (SAR) studies were carried out to understand the relationship between molecular structural features and inhibition activities of synthesized derivatives. These data suggested that compounds 5c, 5g and 5i are promising candidates for hitto- lead follow-up in the drug-discovery process for the treatment of Alzheimer’s disease and hyperinsulinamia.

Novel dehydroabietylamine derivatives as potent inhibitors of acetylcholinesterase

Nowadays, the inhibition of acetylcholinesterase is one of the main pharmacological strategies for the treatment of Alzheimer’s disease. Therefore, a set of thirty-four derivatives of the diterpenoid dehydroabietylamine has been synthesized and screened in colorimetric Ellman’s assays to determine their ability to inhibit the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). A systematic variation of the substitution of dehydroabietylamides enabled an approach to analogs showing a remarkable inhibition potency for AChE. Particularly N-benzoyldehydroabietylamines 11, 12 and 13 were excellent inhibitors for AChE, showing inhibition rates comparable to standard galantamine hydrobromide.

Significance of the nicotinic alpha7 receptor in cognition and antipsychotic-like behavior in the rat

Schizophrenic (SCH) patients show cognitive impairment in attentional performance. Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) such as the Alzheimer’s drug galantamine (GAL) and PAM-2 are documented to have pro-cognitive properties. However, it is not well established if these properties would be lost, or may hamper antipsychotic efficacy, when given as an adjunct to an antipsychotic which is needed for managing psychotic symptoms. Using adult male Wistar rats, we here investigated the effects of: a) GAL, alone or co-administered with the antipsychotic risperidone (RISP), on acute phencyclidine (PCP)-induced deficits in the attentional set-shifting (ASST) test; b) PAM-2, alone and co-administered with RISP, in the conditioned avoidance response (CAR) test for antipsychotic activity.Acute PCP produced selective and significant SCH-like impairment in extra dimensional shift (EDS) performance, which was completely reversed by GAL. The ability of GAL to reverse PCP-induced EDS impairment was not prevented when co-administered with RISP, suggesting that the combination of GAL and low doses of RISP may be used to improve the cognitive impairment in SCH. Pretreatment with methyllycaconitine (MLA), a selective α7 nAChR antagonist, completely prevented the reversal elicited by GAL, supporting the concept that α7 nAChRs are involved in this process. On the other hand, PAM-2 alone had no effects on CAR, but enhanced, although not significantly, the antipsychotic-like effect of RISP when administered together. In conclusion, α7 PAMs, in addition to alleviate the cognitive impairments observed in SCH patients, may enhance the antipsychotic efficacy of atypical antipsychotics.

New Bioactive Heteroleptic Copper(II) Carboxylates: Structure, Enzymatic and DNA-Binding Studies.

Two new binuclear O-bridged copper(II) carboxylates with chemical formulas [Cu2(3-ClC6H4CH2COO)4(phen)2] (1) and [Cu2(3-ClC6H4CH2COO)4(bipy)2] (2) where phen = 1,10-phenanthroline and bipy = 2,2'-bipyridine have been synthesized and characterized by FT-IR, UV-Visible spectroscopy, CHN analysis and single crystal XRD. The results revealed distorted square pyramidal geometry around each copper atom of 1 and 2. The DNA interaction studies showed strong binding with Kb = 5.07 × 103 and 4.62 × 103 M-1 for 1 and 2, respectively. Both complexes showed strong enzyme inhibition, i.e., 70% and 90% for α-glucosidase with IC50 = 34.6 and 30.1 μM for 1 and 2, respectively, where acarbose was employed as control. However, both the complexes were found inactive against α-amylase. Using galantamine hydrobromide as control, 1 showed moderate inhibition activity (47%) with IC50 = 179.4 μM for acetylcholine esterase whereas 2 showed strong inhibition activity (76%) with IC50 = 95.8 μM for butyrylcholine esterase. The data reflects active anti-diabetic and anti-Alzheimer's nature of the synthesized complexes.

Docking-based design and synthesis of galantamine-camphane hybrids as inhibitors of acetylcholinesterase.

Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aβ) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Aβ aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω-loop of Aβ binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.

Optimization of Galantamine Loaded Bovine Serum Albumin Nanoparticles by Quality by Design and Its Preliminary Characterizations

Alzheimer’s disease is a progressive neurodegenerative disorder having a severe socio-economical and medical burden all over the world. The objective of this work was to develop nanoparticulate drug delivery system for Galantamine Hydrobromide (GAL) with the aid of Quality by Design (QbD) for intranasal administration to improve its targeting to brain. Bovine Serum Albumin (BSA) nanoparticles were prepared by desolvation process. Quality Target Profile and Critical Quality Attribute was set, proper risk identification and risk analysis was conducted using the Failure Mode and Effect Analysis. After proper risk assessment, optimization of the formulation was done using the Box-Behnken Design. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were conducted. The characterization was done by studying the entrapment efficiency, particle size, zeta potential, transmission electron microscopy and atomic force microscopy. Drug amount, pH of aqueous phase, addition rate of desolvating agent was identified as parameters for Box-Behnken Design. The DSC of GAL nanoparticles did not show any peak at the melting point of GAL, proving its entrapment. Entrapment efficiency upto 78% could be achieved. A negative zeta potential was observed for GAL nanoparticles, ranging from -13 mV ± 0.25 to -11 mV ± 0.32. Nanoparticles were spherical, uniform in size with less than 200 nm. The surface was smooth with few undulations, may be due to GAL particles adsorbed on the surface during ionic interaction between GAL and BSA. Therefore, GAL nanoparticles were formulated employing a very simple, cost effective desolvation method.

A novel one-step electrochemical preparation of silver nanoparticles/poly(3-methylthiophene) nanocomposite for detection of galantamine in human cerebrospinal fluid and narcissus

In this research, the manufacturing of highly sensitive and effective electrochemical sensor is presented. It is based on silver nanoparticles/poly(3-methylthiophene) (Ag–NPs/P3MT) nanocomposite for the detection of galantamine hydrobromide (Gal). In this process, Ag–NPs/P3MT modified electrode was fabricated by electro-polymerization of 3-methylthiophene (3MT) in the presence of silver nitrate on the surface of the glassy carbon electrode (GCE). Scanning electron microscopy (SEM), field emission scanning electron microscopy (FE–SEM) and energy dispersive X–ray (EDX) analysis were employed to characterize the constructed sensor. Compared with unmodified and P3MT modified electrodes, the Ag–NPs/P3MT modified electrode demonstrated superb electrochemical catalytic activity and significantly enhanced the oxidation peak current of Gal. The experimental parameters, such as supporting electrolyte and its pH, the number of cycles for the electro-polymerization and the scan rate for the sensor preparation were optimized. Under the optimal conditions, the proposed electrode exhibited excellent sensing performance for detecting of Gal using differential pulse voltammetry over the concentration range of 1.0 to 700μM and a detection limit of 0.18μM. Finally, the excellent results showed that the modified electrode can be successfully applied to quantitatively measure of Gal in human cerebrospinal fluid (CSF), Narcissus and pharmaceutical real samples with satisfactory consequences.

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined.

Environmental enrichment (EE) enhances cognition after traumatic brain injury (TBI). Galantamine (GAL) is an acetylcholinesterase inhibitor that also may promote benefits. Hence, the aims of this study were to assess the efficacy of GAL alone (standard [STD] housing) and in combination with EE in adult male rats after TBI. The hypothesis was that both therapies would confer motor, cognitive, and histological benefits when provided singly, but that their combination would be more efficacious. Anesthetized rats received a controlled cortical impact or sham injury, then were randomly assigned to receive GAL (1, 2, or 3 mg/kg; intraperitoneally [i.p.]) or saline vehicle (VEH; 1 mL/kg; i.p.) beginning 24 h after surgery and once daily for 21 days (experiment 1). Motor (beam-balance/walk) and cognitive (Morris water maze [MWM]) assessments were conducted on post-operative Days 1-5 and 14-19, respectively. Cortical lesion volumes were quantified on Day 21. Sham controls were better versus all TBI groups. No differences in motor function or lesion volumes were observed among the TBI groups (p > 0.05). In contrast, GAL (2 mg/kg) enhanced MWM performance versus VEH and GAL (1 and 3 mg/kg; p < 0.05). In experiment 2, GAL (2 mg/kg) or VEH was combined with EE and the data were compared with the STD-housed groups from experiment 1. EE alone enhanced motor performance over the VEH-treated and GAL-treated (2 mg/kg) STD-housed groups (p < 0.05). Moreover, both EE groups (VEH or GAL) facilitated spatial learning and reduced lesion size versus STD + VEH controls (p < 0.05). No additional benefits were observed with the combination paradigm, which does not support the hypothesis. Overall, the data demonstrate that EE and once daily GAL (2 mg/kg) promote cognitive recovery after TBI. Importantly, the combined therapies did not negatively affect outcome and thus this therapeutic protocol may have clinical utility.

Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques.

Galantamine hydrobromide and (-)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID50) was 4.1ug/kg for huperzine, 362ug/kg for galantamine, and 30.9ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile.

Repurposing N,N'-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases

Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.

Preparation and evaluation of novel galantamine hydrobromide sustained-release capsule

In present study, a novel galantamine hydrobromide sustained-release capsule was prepared with the extrusion-spheronization method and the optimized preparative formulation. The release studies were performed using marketed capsules (Razadyne ER) as a reference and data were analyzed in terms of cumulative release amounts as a function of time. Furthermore, fiber-optic real time detection was adopted to monitor the release process. Results demonstrated that our developed formulation had superior properties, worked better as sustained-release carriers and lasted longer time to release compared with the marketed product. The in vitro release characteristics of different batches of preparations were quite similar with each other, the total release proportions of galantamine hydrobromide from sustained-release capsules reached higher than 90% within 12 hours. Similar factors f2 of two preparations were all higher than 50, the release profile of drugs from capsules fitted to Higuchi model with the equation of Q% = 0.2681t1/2 + 0.0684 (r = 0.9966). Pharmacokinetics profile and parameters in beagle dogs after oral administration also revealed the superior release performances of new capsules being consistent with the in vitro study. The developed sustained-release formulation may be a promising alternative dosage form for treatment of related diseases.

Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer’s disease management

Purpose: Nasal galantamine hydrobromide (GH)/chitosan complex nanoparticles (CX-NP2) could have an improved therapeutic potential for managing Alzheimer’s disease (AD). The current study aimed to investigate if the complexation reaction between GH and chitosan altered the pharmacological and toxicological profiles of the parent drug; GH.Methods: The nasal administration of CX-NP2 to male Wistar rats for 12 consecutive days was compared to negative control group, and oral and nasal GH solutions treated groups in 3 mg/kg daily GH dose. Brain acetylcholinesterase (AChE) protein level and activity were assessed. The in vivo toxicity of CX-NP2 was evaluated via monitoring the clinical signs throughout the study. Histopathological examination of brain sections was performed. The intracellular localization of CX-NP2 within brain neurons was investigated using transmission electron microscopy.Results: GH/chitosan complexation did not negatively alter the pharmacological efficiency of GH. Intriguingly, nasal CX-NP2 exhibited a significant decrease of AChE protein level and activity in rat brains compared to the oral and nasal GH solutions. No toxicity signs or histopathological manifestations were noticed. The nanoparticles were found intracellularly in the brain neurons.Conclusion: The pharmacological efficacy and in vivo safety of nasal CX-NP2 confirm their promising potential to contribute to the management of AD intranasally.

Réactions cutanées graves au bromhydrate de galantamine (Reminyl® et génériques)

La pemphigoïde bulleuse (PB) touche principalement le sujet âgé. Elle est souvent associée à des maladies neurologiques, qui représentent un facteur de risque connu de PB. L’objectif de cette étude rétrospective était de déterminer si les maladies neurologiques, notamment la démence, influençaient le pronostic vital et l’évolution de la PB.Tous les patients hospitalisés pour PB dans notre service de dermatologie entre 1997 et 2011 ont été inclus. Les données cliniques et immunologiques, le traitement, le nombre de récidives et la survie globale ont été comparés en fonction de la coexistence d’une maladie neurologique et en particulier d’une démence.Parmi les 178 patients inclus, 84 (47,2 %) avaient une maladie neurologique, dont 43 (24,2 %) une démence, au moment du diagnostic de la PB. Les patients avec démence associée étaient plus âgés et avaient un indice de Karnofsky plus bas. Soixante-quatre malades (37,8 %) ont présenté au moins une rechute clinique de PB, principalement dans les 18 premiers mois. L’existence d’une maladie neurologique, en particulier d’une démence, au moment du diagnostic de la PB n’était pas associée à une plus grande fréquence de rechute de PB (respectivement p = 0,55 et p = 0,54), contrairement au caractère multi-bulleux initial de la PB (p = 0,008). L’existence d’une maladie neurologique ou d’une démence au moment du diagnostic de la PB était associée à une mortalité plus élevée (p = 0,03 et p < 0,001), mais ne modifiait pas le type ou la durée totale de traitement de la PB.La présence initiale d’une démence ou d’une maladie neurologique augmente significativement le risque de décès et raccourcit la durée de suivi des patients atteints de PB, limitant ainsi l’analyse de leur influence sur l’évolution de la PB elle-même.Bullous pemphigoid (BP) mainly affects elderly patients. It is often associated with neurological disorders, which constitute a major risk factor of the disease. The aim of our study was to determine whether neurological disorders, particularly dementia, influence outcome and mortality in BP patients.We conducted a retrospective study of all patients with BP seen in our dermatology department consecutively between 1997 and 2011. Clinical, immunological and therapeutic data, number of relapses and survival status were compared according to the presence at diagnosis of neurological disorders, particularly dementia.Among the 178 patients included, an associated neurological disease was present in 84 (47.2%) and dementia in 43 (24.2%) at the time of diagnosis of BP. Patients with associated dementia were older and had a lower Karnofsky index. Sixty-four patients (37.8%) had had at least one clinical relapse of BP, chiefly within the first 18 months after starting therapy. Coexistent neurological disease was not associated with BP relapse (P = 0.55) contrary to an extensive BP phenotype at diagnosis (P = 0.008). Coexistent neurological disease and/or dementia were associated with higher mortality (P = 0.03 and P < 0.001, respectively), but did not modify the type or the total duration of BP treatment.A coexistent neurological disease or dementia at the time of diagnosis of BP significantly increase the risk of mortality and shortens the duration of clinical follow-up of patients with BP, thus limiting the analysis of their influence on the outcome of BP itself.

Galantamine protects against lipopolysaccharide-induced acute lung injury in rats.

Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.