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

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

Comparative evaluation of fish oil and butter oil in modulating delivery of galantamine hydrobromide to brain via intranasal route: pharmacokinetic and oxidative stress studies.

The present study investigates the role of fish oil (FO)- and butter oil (BO)-enriched microemulsion-based system of galantamine hydrobromide (GH), an anti-Alzheimer drug, for its potential role in brain permeation enhancement and neuroprotection against oxidative stress. Microemulsion (ME)-based system of GH was prepared using water phase titration. The prepared ME was characterized by several physicochemical parameters like particle size, polydispersity index, and ex vivo drug permeation. Cell-based oxidative stress assays and pharmacokinetic studies were performed using C6 glial cell lines, and Sprague Dawley rats, respectively. The optimized ME comprised 5.3% v/v of Capmul MCM EP (as oil),15.8% v/v of Tween-80 (as surfactant), 5.3% v/v of Transcutol P (as co-surfactant), and 73.6% v/v of water (as aqueous phase). The addition of FO and BO resulted in a slight increase in the droplet size and decrease in transparency of ME. Cell-based anti-oxidative stress assays (glutathione assay, nitrite assay, and lipid peroxidation assay) showed the efficacy of formulation in the order of ME, BO ME, and FO ME, respectively. A similar trend was also observed in in vivo animal studies, wherein GH FO ME showed a comparatively higher percentage of drug reaching the brain when administered by intranasal route than by IV route. The study concluded the potential benefits of co-administering FO- and BO-enriched microemulsion is not only enhancing the permeation of drugs across BBB but also improving efficacy against lipopolysaccharide-induced oxidative stress. Graphical abstract.

Controlled Iontophoretic Delivery in Vitro and in Vivo of ARN14140-A Multitarget Compound for Alzheimer's Disease.

ARN14140 is a galantamine-memantine conjugate that acts upon both cholinergic and glutamatergic pathways for better management of Alzheimer's disease. Poor oral bioavailability and pharmacokinetics meant that earlier preclinical in vivo studies employed intracerebroventricular injection to administer ARN14140 directly to the brain. The aim of the present study was to evaluate the feasibility of using constant current transdermal iontophoresis for the noninvasive systemic delivery of ARN14140 and to quantify the amounts present in the blood and the brain. Preliminary experiments in vitro were performed using porcine skin and validated with human skin. Cumulative ARN14140 permeation across the skin increased linearly with current density and concentration. Delivery efficiency (i.e., fraction of the amount applied that is delivered) reached an exceptional 76.9%. Statistically equivalent delivery was observed after iontophoresis across human and porcine skin. In vivo studies in male Wistar rats showed that iontophoretic transport of ARN14140 could be controlled using the current density (426.7 ± 42 and 1118.3 ± 73 nmol/cm2 at 0.15 and 0.5 mA/cm2 for 6 h) and demonstrated that transdermal iontophoresis was able to deliver ARN14140 noninvasively to the brain. This is the first report quantifying drug levels in the blood and the brain following transdermal iontophoresis.

Development and in vitro evaluation of pressure sensitive adhesive patch for the transdermal delivery of galantamine: Effect of penetration enhancers and crystallization inhibition.

The transdermal route offers an attractive alternative route of drug administration especially for Alzheimer's disease patients through eliminating gastrointestinal side effects and ultimately improving compliance. In this study, we prepared an optimized matrix-type patches for the transdermal delivery of galantamine free base with ex vivo and in vitro evaluation. Four pressure sensitive adhesives with different functional groups, ten penetration enhancers and four drug loadings were tested to determine the optimized patch. The ex vivo permeation of the different formulated patches through human cadaver skin using vertical Franz diffusion cells showed that GELVA GMS 788 was the best pressure sensitive adhesive among the tested polymers. FT-IR and rheological studies done to investigate any potential interactions of the polymer with the drug and/or additives showed the possibility of hydrogen bonding between the drug and pressure sensitive adhesive (PSA), also the additives had a plasticization effect causing increased flexibility of the polymer chains. The optimized formulation had 10%w/w drug loading, 5% w/w limonene as a penetration enhancer, and 5%w/w oleic acid as a crystallization inhibitor. The combination of limonene and oleic acid increased the flux of galantamine by 2.7-fold compared to 1.7-fold when limonene was used alone. The optimized patch exhibited diffusion release kinetics and fitted well to Higuchi's model and yielded a permeation rate of 32.4 ±â€¯1.41 µg/cm2/h across human cadaver skin.

Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs.

According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found which could present sufficient experimental findings to support its clinical safety profile. It also underlines the fact that majority of work related to the nose-to-brain delivery of anti-AD drugs is limited only up to preclinical studies. In this review article, we have discussed the latest works on various novel formulations loaded with various anti-Alzheimer agents. These agents include galantamine, deferoxamine, tacrine, tarenflurbil, rivastigmine, risperidone, curcumin, quercetin, piperine, insulin, etc. and various peptides towards the development of a promising IN drug delivery system for the treatment of AD. Through this review article, we want to drag the attention of the researchers working in this field towards the challenges and hurdles of practical applicability IN delivery of anti-AD drugs. Moreover, the attention towards the clinical studies will ease the approval process for the administration of anti-Alzheimer drugs via IN route.

Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/Bcl-2 pathways.

Vagal stimulation controls systemic inflammation and modulates the immune response in different inflammatory conditions, including inflammatory bowel diseases (IBD). The released acetylcholine binds to alpha-7 nicotinic acetylcholine receptor (α7 nAChR) to suppress pro-inflammatory cytokines. This provides a new range of potential therapeutic approaches for controlling inflammatory responses. The present study aimed to assess whether galantamine (Galan) anti-inflammatory action involves α7 nAChR in a 2,4,6-trinitrobenzene sulfonic acid (TNBS) model of colitis and to estimate its possible molecular pathways. Rats were assigned into normal, TNBS, sulfasalazine (Sulfz), Galan treated (10 mg/kg), methyllycaconitine (MLA; 5.6 mg/kg), and MLA + Galan groups. Drugs were administered orally once per day (11 days) and colitis was induced on the 8th day. Galan reduced the TNBS-induced ulceration, colon mass index, colonic MDA, neutrophils adhesion and infiltration (ICAM-1/MPO), inflammatory mediators (NF-κB, TNF-α, HMGB1, and RAGE), while increased the anti-apoptotic pathway (p-Akt/Bcl-2). Mechanistic study revealed that Galan increased the anti-inflammatory cytokine IL-10, phosphorylated Jak2, while reduced the inflammation controller SOCS3. However, combining MLA with Galan abrogated the beneficial anti-inflammatory/anti-apoptotic signals. The results of the present study indicate that Galan anti-inflammatory/-apoptotic/ -oxidant effects originate from the stimulation of the peripheral α7 nAChR, with the involvement of the Jak2/SOCS3 signaling pathway.

Ascorbic acid tethered polymeric nanoparticles enable efficient brain delivery of galantamine: An in vitro-in vivo study.

The aim of this work was to enhance the transportation of the galantamine to the brain via ascorbic acid grafted PLGA-b-PEG nanoparticles (NPs) using SVCT2 transporters of choroid plexus. PLGA-b-PEG copolymer was synthesized and characterized by 1H NMR, gel permeation chromatography, and differential scanning calorimetry. PLGA-b-PEG-NH2 and PLGA-b-mPEG NPs were prepared by nanoprecipitation method. PLGA-b-PEG NPs with desirable size, polydispersity, and drug loading were used for the conjugation with ascorbic acid (PLGA-b-PEG-Asc) to facilitate SVCT2 mediated transportation of the same into the brain. The surface functionalization of NPs with ascorbic acid significantly increased cellular uptake of NPs in SVCT2 expressing NIH/3T3 cells as compared to plain PLGA and PLGA-b-mPEG NPs. In vivo pharmacodynamic efficacy was evaluated using Morris Water Maze Test, Radial Arm Maze Test and AChE activity in scopolamine induced amnetic rats. In vivo pharmacodynamic studies demonstrated significantly higher therapeutic and sustained action by drug loaded PLGA-b-PEG-Asc NPs than free drugs and drug loaded plain PLGA as well as PLGA-b-mPEG NPs. Additionally, PLGA-b-PEG-Asc NPs resulted in significantly higher biodistribution of the drug to the brain than other formulations. Hence, the results suggested that targeting of bioactives to the brain by ascorbic acid grafted PLGA-b-PEG NPs is a promising approach.

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 (Aß) 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 Aß 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 Aß binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.

An LC-MS/MS method for the simultaneous determination of lycorine and galanthamine in rat plasma and its application to pharmacokinetic study of Lycoris radiata extract in rats.

A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometry was developed for the simultaneous determination of lycorine and galanthamine, two major constituents in Lycoris radiata extract, in rat plasma. Liquid-liquid extraction with ethyl ether was carried out using diphenhydramine as the internal standard. The two bioactive alkaloids were separated on a Zorbax SB-C18 reserved-phase column (150 mm × 4.6 mm, i.d., 5 µm) by gradient elution using a mobile phase consisting of methanol with 0.1% formic acid (A) and water with 0.1% formic acid (B) at a flow rate of 0.6 mL/min. All analytes showed good linearity over a wide concentration range (r (2)>0.99) and the lower limit of quantification was 3.00 ng/mL for each analyte. The average extraction recovery of the analytes from rat plasma was more than 82.15%, and the intra-day and inter-day accuracy and precision of the assay were less than 12.6%. The validated method was successfully applied to monitoring the concentrations and pharmacokinetic studies of two Amaryllidaceous alkaloids in rat plasma after an oral administration of Lycoris radiata extract.

Highly sensitive LC-MS/MS method for determination of galantamine in rat plasma: application to pharmacokinetic studies in rats.

A rapid and highly sensitive assay method has been developed and validated for the estimation of galantamine (GLM) in rat plasma using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The assay procedure involves a simple liquid-liquid extraction of GLM and phenacetin (internal standard, IS) from rat plasma using acetonitrile. Chromatographic separation was achieved with 0.2% formic acid:acetonitrile (50:50, v/v) at a flow rate of 0.60 mL/min on an Atlantis dC18 column with a total run time 2.5 min. The MS/MS ion transitions monitored were 288.10 → 213.10 for GLM and 180.10 → 110.10 for IS. Method validation was performed as per United States Food and Drug Administration guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 0.12 ng/mL and linearity was observed from 0.12 to 525 ng/mL. The intra- and inter-day precision were in the ranges of 4.73-11.7 and 5.83-8.64%, respectively. This novel method has been applied to a pharmacokinetic study in rats.

Drugs for cognitive loss and dementia.

The drugs currently available for the treatment of Alzheimer's disease and other dementias can provide limited symptomatic improvement. The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine and the NMDA-receptor antagonist memantine have produced modest but apparently persistent improvements in cognition, activities of daily living, and behavior in patients with disease severity ranging from mild to severe. Among the acetylcholinesterase inhibitors, transdermal rivastigmine causes fewer gastrointestinal side effects than the oral formulation. Whether adding memantine to an acetylcholinesterase inhibitor is more effective than an acetylcholinesterase inhibitor alone remains to be established; clinical trial results have been mixed. None of these agents have been shown to stop or reverse the underlying neurodegenerative process.

Interaction study of acetylcholinestrase inhibitors on pharmacokinetics of memantine in rat plasma by HPLC-fluorescence method.

The present study aims to investigate the possibility of interaction of donepezil (DP) and galantamine (GAL) as acetylcholinestrase inhibitors, on memantine (MT) hydrochloride in rat plasma by HPLC-fluorescence detection. The separation of MT was achieved within 12 min without interference of DP and GAL on the chromatogram. MT levels in rat plasma with a single administration of MT (2.5 mg/kg, i.p.) and those with a co-administration of DP (5.0 mg/kg, i.p.) and GAL (3 mg/kg, i.p.) were monitored. MT concentrations determined in rat plasma ranged from 10.0 to 245.6 ng/mL. Significant difference was observed in the behavior of MT with a co-administration of DP, while no significant difference was observed with a co-administration of GAL.

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Development and in vivo evaluation of novel monolithic controlled release compositions of galantamine hydrobromide as against reservoir technology.

The objective of this study is to develop and in vivo evaluation of novel monolithic matrix mini tablets approach to control the release of galantamine hydrobromide (GAH) in comparison with desired release profile to the Innovator formulation Razadyne(®) ER capsules. The direct compression method was employed for preparation of matrix mini tablets as against reservoir multiparticulate pellets of innovator formulation. The matrix swellings, dissolution similarity, mean dissolution time and dissolution efficiency of formulations were evaluated. It was found that increase in the concentration of high viscosity hydroxypropylcellulose (HPC) results reduction in release rate. The drug release was shown to be pH dependent with faster rate at lower pH. The release of GAH followed first order shifting to dissolution dependent by increase of HPC content. The formulation showed stability of drug release. In vivo prediction was done by Wagner-Nelson method. Prediction errors were estimated for Cmax and area under curve (AUC) and found to be not exceeding 15%. In vivo study in human volunteers confirmed the similarity between test and innovator formulations and pharmacokinetic values were comparable between actual and predicted. These results suggest that novel monolithic matrix approach could be suitable technique to formulate controlled release GAH.

[New approach to gait disorders therapy in late stages of Parkinson's disease].

We conducted an open noncontrolled study of efficacy of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) combined with acetylcholinesterase inhibitor (galantamine) therapy in 30 Parkinson's disease patients with cognitive impairment and higher level of gait disorders. Galantamine dose gradually increase to maximum of 16 mg/day (8 weeks) before rTMSand after that we start rTMS for 10 consecutive days. Cognitive, neuropsychiatric and motor symptoms were assessed clinically at baseline and at end of 10 weeks combined therapy using the Mini Mental State Examination (MMSE), Freezing Of Gait (FOG), Clinical Gait And Balance Scale (GABS), Tinetti scale, the clock drawing test, the Frontal Assessment Battery (FAB), PDQ-39 and Beck Depression Inventory (BDI). The metabolism in the frontal lobes, caudate nucleus, thalamus were assessed in 9 patients at baseline and end of rTMS by [18F]FDG-PET. Changes in total point scores on the scales at the ends of 10 weeks were compared with the baseline. Results were significant in the FOG (p = 0.00002), GABS (p = 0.000006), MMSE (p = 0.0001), FAB (0 = 0.003), PDQ-39 (p = 0.00009), BDI (p = 0.00004). Improvements in gait and decreases in freezing and falls were seen in the end of study period. Our study demonstrated the beneficial effect of rTMS of the DLPFC combined with acetylcholinesterase inhibitor treatment on metabolism in the frontal lobes, caudate nucleus, thalamus ([18F]FDG-PET), improving of gait and cognitive functions in PD patients.

Investigation of formulation factors affecting in vitro and in vivo characteristics of a galantamine transdermal system.

Because of low treatment compliance with the Alzheimer disease patients, there have been clinical needs for the alternative administration route to effective and well-tolerated approaches of galantamine (Small and Dubois, 2007). In this study, drug-in-adhesive transdermal patches with galantamine were prepared and evaluated in vitro and in vivo. The in vitro permeation studies indicated that DT-2510 was the most suitable pressure-sensitive-adhesive and oleic acid was the most promising enhancer for galantamine drug-in-adhesive patch. The optimized galantamine drug-in-adhesive patch could be physicochemically stable for 28 days at 40 °C/75% RH. The in vivo studies of the optimized galantamine drug-in-adhesive patch showed high absolute bioavailability of around 80% and sustained effect on the drug plasma levels for 24 h. The in vitro and in vivo studies of galantamine drug-in-adhesive patches with different pressure-sensitive-adhesive functional groups showed a strong correlation between the skin permeation rate and the area under the curve. The results suggest that the transdermal application of galantamine drug-in-adhesive patches might be the alternative dosage form to have good efficacy and tolerability for the treatment of Alzheimer disease.

Quantification of galantamine in human plasma by validated liquid chromatography-tandem mass spectrometry using glimepride as an internal standard: application to bioavailability studies in 32 healthy Korean subjects.

A simple, rapid and selective liquid chromatography method coupled with tandem mass spectrometry is developed and validated for the quantification of galantamine in human plasma using a commercially available compound, glimepride, as an internal standard (IS). Following simple one-step liquid-liquid extraction by ethyl acetate, the analytes are separated using an isocratic mobile phase consisting of acetonitrile and 0.01M ammonium acetate (95/5, v/v) on a reverse-phase C18 column and analyzed by tandem mass spectrometry in the multiple reaction monitoring mode using the transitions of respective (M + H)(+) ions, m/z 288.22 → 213.20 and m/z 491.17 → 352.30 for the quantification of galantamine and IS, respectively. The standard calibration curves show good linearity within the range of 4 to 240 ng/mL (r(2) = 0.9996, 1/x(2) weighting). The lower limit of quantification is 4 ng/mL. The retention times of galantamine and IS are 1.1 and 0.71 min, which showsthe high throughput potential of the proposed method. In addition, no significant metabolic compounds are found to interfere with the analysis. Acceptable precision and accuracy are obtained for the concentrations over the standard curve range. The validated method is successfully applied for pharmacokinetic and bioequivalence studies of 24 mg of a galantamine hydrobromide capsule in 32 healthy Korean subjects.

Food-drug interactions: effect of capsaicin on the pharmacokinetics of galantamine in rats.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is a naturally occurring alkaloid extracted from the fruit of Capsicum plant family. It represents an important ingredient in spicy foods consumed throughout the world. However, little is known about the metabolic interactions between CAP and clinically used drugs. This study attempted to investigate the effect of CAP on the pharmacokinetics of galantamine, a competitive and reversible cholinesterase inhibitor. CAP, dexamethasone or sodium salt of carboxymethyl cellulose (CMC-Na) was given to rats for seven consecutive days and on the seventh day galantamine (10 mg/kg) was administered orally. Dexamethasone was used as a CYP inducer and CMC-Na was used as a vehicle. The results showed that the pretreatment of rats with CAP resulted in a decrease in the AUC(0-∞) of galantamine of about 49.70% (p < 0.01) compared with the control group. After oral administration of galantamine (10 mg/kg), the apparent oral clearance of galantamine was raised by 2.05-fold by pretreatment with CAP (p < 0.05). These results demonstrate that the chronic ingestion of high doses of CAP will decrease the bioavailability of galantamine to a significant extent in rats.

Evidencia sobre el tratamiento de la enfermedad de alzheimer con inhibidores de la acetilcolinesterasa y/o memantina / No disponible

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Pharmacokinetic behavior and efficiency of acetylcholinesterase inhibition in rat brain after intranasal administration of galanthamine hydrobromide loaded flexible liposomes.

Galanthamine hydrobromide (GH) has been approved for symptomatic treatment of Alzheimer's disease (AD) and vascular dementia. Hence, the effects of intranasal administration of GH loaded flexible liposomes have been investigated for the first time on the efficiency of acetylcholinesterase inhibition, as well as the pharmacokinetic behavior of GH in rat brain. The GH loaded flexible liposomes were characterized for shape, entrapment capacity, size distribution and zeta potential by transmission electron microscopy (TEM), ultracentrifugation and dynamic light scattering (DLS), respectively. The inhibition of acetylcholinesterase was investigated using rat brain homogenates as an enzyme resource and microdialysis was used to determine the pharmacokinetic behavior of GH in rats brain. The rat pheochromocytoma PC-12 cell line was used to evaluate the cytotoxicity of GH loaded flexible liposomes. The results revealed that: (i) the efficiency of acetylcholinesterase inhibition of GH was greatly enhanced by intranasal administration compared with oral administration, especially GH loaded in flexible liposomes; (ii) the C(max) and AUC(0→10) for intranasal administration of GH loaded flexible liposomes were 3.52 and 3.36 times higher than those of orally administered GH, moreover, the T(max) was greatly shortened from 1.5h for oral administration to 0.75h for intranasal administration of GH loaded flexible liposomes; and (iii) PC-12 cells viability tests showed that the flexible liposome carrier is not toxic to the cultured cells and the cytotoxicity of GH to cells was clearly decreased by loading in flexible liposomes. These results indicate that intranasal administration of GH loaded flexible liposomes could readily transport GH into brain tissues, suggesting some promise for this approach in successful brain-drug targeting in AD treatment.