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For the determination of Galantamine Hydrobromide in bulk and produced extended formulation, a new sensitive and quick HPLC technique was developed and validated according to ICH guidelines. The HPLC analysis was carried out using a waters system with a Thermo Scientific C18 (steel column (5 µm, 250mm × 4.6 mm)) column and a mobile phase of 0.1M phosphate buffer: Acetonitrile (40:60V/V) pH adjusted to 4.5 with orthophosphoric acid, at a flow rate of 1.0 mL/min. The detection was done at a wavelength of 203 nm, and galantamine hydrobromide had a retention time of 8.0 minutes. Over the concentration range of 1-10 g/ml, the calibration plot revealed a linear relationship. The accuracy of the proposed method was determined by recovery studies and was found to be near to 100 and % RSD value was found less than 2. The repeatability testing for both standard and sample solutions showed that the method is precise within the acceptable limits. RSD % of the determination of precision was

Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer’s disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. In the present research work, Galantamine hydrobromide is formulated as proniosome gel by Coacervation phase separation method using different surfactants such as Tweens and Spans. Overall eight formulations were developed and evaluated for various parameters. The prepared gels were viewed by naked eye to observe the colour of gel. Microscopical observations of the gels showed vesicles of optimum size from 3.030 mm (P2) - 3.735 mm (P5). The gel also showed optimum rate of spontaneity in the range 9.60 mm3x1000 (P7) to 11.80 mm3x1000 (P4) and entrapment efficiency of vesicles in the range 66.15% (P5) to 86.92% (P3). The gels had pH in suitable range of skin (5.92-6.9). The in vitro drug diffusion studies revealed that the drug diffusion was affected by the various surfactants used. The rank order of surfactant effect on in-vitro drug diffusion was Tween 80 > Tween 60 > Tween 40 >Tween 20 > Span 80 > Span 60 > Span 40 > Span 20. The proniosomal gel containing Tween 80 showed maximum drug diffusion (99.24%) and the gel containing Span 20 showed minimum drug diffusion (71.74%). FT-IR studies of optimized proniosome gel P8 revealed the absence of any chemical interactions between drug and carriers used. Keywords: Galantamine hydrobromide, Proniosome gel, Coacervation phase separation method, Surfactants, in vitro drug diffusion 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.

Natural alkaloid galantamine is widely used for the treatment of Alzheimer’s disease and various other memory impairments. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solution. However, oral delivery of GH can cause side effects, such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery is one possible way to avoid such unwanted effects and is also patient friendly, especially for unconscious patients, patients with swallowing difficulties, and patients with mental disturbances. In this work, thermoresponsive copolymer networks based on poly(N-isopropylacrylamide) were studied as new platforms for potential transdermal GH delivery. Series of networks of varied structure and composition were synthesized and investigated by applying swelling kinetics and different spectroscopic and thermal methods. The network films were drug loaded in GH aqueous solution and main characteristics of the obtained GH delivery systems were evaluated. The GH release kinetic profiles in BS at 37 °C were established and discussed.

A series of benzamide derivatives 1–12 with various functional groups (–H, –Br, –F, –OCH3, –OC2H5, and –NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure–activity relationship showed that the substitution of –Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 1–12 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3–4, and 7–8 showed a mixed mode of inhibition against BCHE, while compounds 2, 5–6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many others.

Alzheimer's disease is a common cause of dementia in the elderly. Galantamine hydrobromide (GH) is an anti-Alzheimer cholinesterase inhibitor that has an intrinsic antioxidant effect. In a previous study, GH was complexed with chitosan to prepare intranasal GH/chitosan complex nanoparticles (CX-NP2). The nanoparticles were located in rat brains 1 h after nasal administration and showed pharmacological superiority to GH nasal solution without showing histopathological toxicity.This study aimed to investigate whether the long-term administration of CX-NP2 leads to biochemical toxicity in rat brains compared to GH nasal solution.CX-NP2 dispersion and GH solution were administrated intranasally to male Wistar rats for 30 days (3 mg/kg/day). Malondialdehyde (MDA), lipid peroxidation marker, glutathione (GSH), superoxide dismutase (SOD) activity and tumor necrosis factor-α (TNF-α) were assessed in the brain extracts in all groups.There was statistically insignificant difference between the CX-NP2 and GH nasal solution treated groups in all biochemical toxicity parameters assessed. Interestingly, MDA and TNF-α levels in the CX-NP2-treated group significantly decreased compared to the control group. Also, GSH level and SOD activity were significantly enhanced in CX-NP2 treated group compared to the control group.CX-NP2 did not induce a statistically significant oxidative stress or neuroinflammation in rat brains after 30-day treatment, they rather elicited neuroprotective potentials.HighlightsIntranasal GH/chitosan complex nanoparticles (CX-NP2) show promising potential as a brain targeting carrier.Compared to GH nasal solution, nasal CX-NP2 formulation did not exert oxidative stress nor neuroinflammation when administered for 30 days.

Patient’s poor compliance and the high risk of toxic effects limit the clinical use of galantamine hydrobromide. To overcome these drawbacks, the sustained-release galantamine pamoate microspheres (GLT-PM-MS) were successfully developed using an oil/water emulsion solvent evaporation method in this study. Physicochemical properties of GLT-PM-MS were carefully characterized, and the in vitro and in vivo drug release behaviors were well studied. Results showed that the morphology of optimized microspheres were spherical with smooth surfaces and core-shell interior structure. Mean particle size, drug loading and entrapment efficiency were 75.23 ± 1.79 μm, 28.01 ± 0.81% and 87.12 ± 2.71%, respectively. The developed GLT-PM-MS were found to have a sustained release for about 24 days in vitro and the plasma drug concentration remained stable for 17 days in rats. These results indicated that GLT-PM-MS could achieve the sustained drug release purpose and be used in clinical trial.

The paper presents a comparative analysis of information content of methods for assessing the copulatory behavior of male rats with the introduction of compounds that have a stimulating effect on the sexual activity of animals. The social significance of the problem of sexual dysfunctions determines the relevance of the development of various experimental models of sexual behavior that allow assessing the effectiveness and safety of new drug. The probability of detecting the activating effect of pharmacological agents on sexual activity directly depends on the correct choice of the experimental model. The drugs of the central mechanism of action – galantamine hydrobromide (1 mg/kg) and loxidan (1,7 mg/kg), were used as pharmacological agents; drugs of peripheral action were yohimbine hydrochloride (2,6 mg/kg) and vardenafil hydrochloride (1,7 mg/kg). It has been shown that the determination of the stimulating effects of compounds of the central mechanism of action is possible using methods with different testing duration (from 15 to 180 min). Thus, the introduction of galantamine enhances the sexual activity of males in terms of the «copulation rate», «the number of perfect ejaculations» and «the duration of the post-ejaculatory refractory period», loxidan – in terms of the «total number of intromissions» and «relative rest time» in tests of limited duration. In the test showing the completed sexual cycle of males, the stimulating effects of galantamine are shown in terms of «the number of completed copulatory series» and «the number of completed ejaculations». To assess the activating effects of compounds of the peripheral mechanism of action, the expediency of using experimental models with a test duration of 30 minutes or more was shown. The most informative test is the test of paired interaction between a male and a female until the male reaches the state of «sexual exhaustion». A method with high information content is presented, which provides a high probability of detecting the activating effect of compounds on the sexual function of male rats. Determination of the stimulating effects of compounds of the central mechanism of action is possible using methods with different test duration

The study aims to prepare a smart copolymeric for controlled delivery of Galantamine hydrobromide. The synthesis of the hydrogel was executed through free radical polymerization using HPMC (Hydroxypropyl methylcellulose) and pectin as polymers and acrylic acid as monomer. Cross-linking was performed by methylene bisacrylamide (MBA). HPMC-pectin-co-acrylic acid hydrogel was loaded with Galantamine hydrobromide (antidementia drug) as a model drug for treatment of Alzheimer based dementia. Formulated hydrogels (SN1&ndash, SN9) were characterized for Fourier transform-infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, and energy dispersive X-ray. Drug loading efficiency, gel fraction, measurements of porosity, and tensile strength were reported. Swelling and release studies were performed at pH 1.2 and 7.4. Drug liberation mechanism was evaluated by applying different release kinetic models. Galantamine hydrobromide was released from prepared hydrogels by Fickian release mechanism. Swelling, gel fraction, porosity, and drug release percentages were found to be dependent on hydroxypropyl methylcellulose, pectin, acrylic acid, and methylene bisacrylamide concentrations. By increasing HPMC amount, swelling was increased from 76.7% to 95.9%. Toxicity studies were conducted on albino male rabbits for a period of 14 days. Hematological and histopathological studies were carried out to evaluate safety level of hydrogel. Successfully prepared HPMC-pectin-co-acrylic acid hydrogel showed good swelling and release kinetics, which may help greatly in providing controlled release drug effect leading to enhanced patient compliance for dementia patients.

Objetivo: Avaliar comparativamente o perfil farmacocinético do bromidrato de galantamina presente no medicamento teste (8 mg de bromidrato de galantamina em cápsula gelatinosa dura de liberação prolongada, Aché Laboratórios Farmacêuticos S.A.) e do medicamento de referência (8 mg de bromidrato de galantamina em cápsula gelatinosa dura de liberação prolongada, Janssen Ortho LLC). Métodos: Foram realizados dois estudos de bioequivalência, um em estado de jejum e outro pós-prandial. Ambos os estudos foram realizados em desenho cruzado, randomizado, aberto, dois períodos, com participantes de pesquisa saudáveis (n = 74 participantes idade: 18-50 anos) após administração de dose única dos medicamentos teste e referência. Para concluir pela equivalência farmacocinética entre os tratamentos, a razão das médias geométricas dos parâmetros farmacocinéticos deveria estar compreendida entre 80% e 125%, assim como o intervalo de confiança de 90%. Resultados: Os valores médios obtidos para os parâmetros farmacocinéticos Cmáx e ASC0-t, tanto para o estudo em jejum quanto para o estudo conduzido sob alimentação padronizada, estavam dentro da faixa determinada para conclusão de bioequivalência (Cmáx 106,65% - 120,14% para o estudo em jejum e 101,41% - 112,40% para o estudo pós-prandial e ASC0-t 91,96% - 99,23% no estudo em jejum e 93,88% - 101,31% no estudo alimentado). O poder do teste foi de 100% em todos os casos e os intervalos de confiança estão dentro dos limites de aceitação de bioequivalência. Conclusões: Considerando os resultados obtidos, foi possível observar que os medicamentos avaliados são bioequivalentes tanto em jejum quanto em condição pós-prandial e, portanto, intercambiáveis na prática médica.

In this study, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives were synthesized from betulin, oleanolic, ursolic and glycyrrhetinic acids aiming to develop new cholinesterase inhibitors. Azepanobetulin, azepanoerythrodiol and azepanouvaol were modified to give amide and tosyl derivatives, while azepano-anhydrobetulines and azepano-glycyrrhetols were obtained for the first time. Oleanane and ursane type 3-amino-3,4-seco-4(23)-en triterpenic alcohols were synthesized by reducing the corresponding 2-cyano-derivatives accessible from Beckmann type 2 rearrangements. The compounds were screened in colorimetric Ellman’s assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). While most of these compounds were only moderate inhibitors for AChE, several of them were shown to be inhibitors for BChE acting as mixed-type inhibitors. Azepanobetulin 1, its C28-amide derivatives 7 and 8, azepano-11-deoxo-glycyrrhetol 12 and azepanouvaol 18 held inhibition constants Ki ranging between 0.21 ± 0.06 to 0.68 ± 0.19 μM. Thus, they were approximately 4 to 10 times more active than standard galantamine hydrobromide. For all of the compounds reasonably high docking scores for BChE were obtained being in good agreement with the experimental results from the enzymatic studies. As a result, A-ring azepano-triterpenoids were found to be new scaffolds for the development of BChE inhibitors.

A rapid, sensitive and reliable LC-MS/MS method for the determination of galantamine in plasma was developed and validated for the pharmacokinetic study of galantamine hydrobromide 8 mg prolonged-release capsules. The plasma sample was prepared by simple liquid-liquid extraction with dichloromethane. Chromatographic separation was performed on a Hypurity C4 (150 x 4.6 mm, particle size 5.0 µm) using isocratic acetonitrile: 10 mM ammonium formate (90:10) as a mobile phase at a flow rate of 0.8 mL/min. Galantamine was detected by mass spectrometry using the electrospray ion source in the selected reaction monitoring mode. Carbamazepine was used as an internal standard (IS). The extraction recovery was 105.45–111.84% for galantamine and 107.35% for IS. Linearity was found within the calibration range of 0.39–62.5 ng/mL. The intra-day and inter-day accuracy were achieved with the mean concentrations of the quality control samples as 91.92–100.97% and 94.29–102.07%, respectively. The intra-day and inter-day precision were expressed as %CV of 1.34–6.11% and 3.31–5.01%. The long-term stability study showed that galantamine was stabled in plasma for at least 50 days at −30°C. This validated method was proven to be useful for the pharmacokinetic study of galantamine hydrobromide in healthy Thai volunteers. After the oral administration of one tablet in fasting conditions, Tmax and Cmax were found to be 5.61 ± 1.71 hours and 25.96 ± 4.18 ng/mL, respectively, whereas T1/2 was found to be 9.89 ± 1.48 hours.

Optimizing the microenvironment of MOF pore is an effective strategy to improve the sensitivity of MOF-based electrochemical biosensors. In this work, a series of isomorphic 3D chiral Ni-MOFs with different pore sizes were prepared and used to construct acetylcholinesterase (AChE) biosensors for the electrochemical detection of chiral drug inhibitor galantamine hydrobromide (GH). The combination of the dense metal nodes with intrinsic oxidase-like activity and the high active AChE, creates synergistic catalysis hydrolysis of acetylthiocholine chloride (ATCl) to produce fast sensing response. The more matched size and chirality of MOF pore significantly enhance the host–guest interactions between the substrate and biosensor, which allows the optimum AChE/L-Ni-BPY/DpAu/GCE platform to exhibit highly sensitive detection of GH, with a lowest detection limit of 0.31 pM and a wide linear range of 1 × 10−12 ~ 1 × 10−6 M among the reported pharmaceutical AChE inhibitor sensing systems. Such matching effect is identified and quantified with accurate apparent energy through the detailed microcalorimetry investigations, which well illustrates the structure–activity relationship of the as-synthesized biosensors. The thermodynamically-guided assembling strategy provides new insights into the development of practical MOF-based electrochemical sensors.

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.

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.

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.

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.

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.

Bu tez çalışmasında, Alzheimer hastalığının semptomatik tedavisinde kullanılan FDA (U.S. Food and Drug Administration) tarafından onaylı bir asetilkolinesteraz inhibitörü Galantamin hidrobromür (GAL) etken maddesinin kontrollü salımı için mini emülsiyon polimerizasyon yöntemi ile p(HEMA-MAPA) nanopolimerleri sentezlenmiştir. Sentezlenen nanopolimerlerin morfolojik özelliklerini ve yüzeydeki elementlerin miktarını belirlemek için SEM-EDS analizi yapıldı. Kimyasal yapılarının tespit edilmesi için FTIR analizi yapıldı ve partikül boyutu Zeta-Sizer cihazı ile belirlendi. SEM analizi sonucunda nanopolimerlerin yüzey morfolojisinin küresel olduğu görülmüş, Zeta-sizer analizine göre ortalama partikül boyutunun 113,3 nm olduğu bulunmuştur. Nanopolimerlerin spesifik yüzey alanı ise 844,38 m2/g olarak hesaplanmıştır. GAL'in nanopolimerlere optimum adsorpsiyon koşulları altında maksimum adsorpsiyon miktarının 1:39 polimer-ilaç oranında, 25 oC'de, 120 dakika temas süresinde, pH 5,5'te, 250 μg/mL GAL konsantrasyonunda 109,29 mg/g olduğu bulunmuştur. GAL'in p(HEMA-MAPA) ile adsorpsiyonunun Langmuir izotermi ile uyumlu olduğu bulunmuştur. Optimum koşullarda nanopolimere yüklenen GAL'in in vitro kontrollü salım çalışmaları için pH ve sıcaklık denemeleri ise diyaliz yöntemi ile yapılmıştır., In this thesis, p(HEMA-MAPA) nanopolymers were synthesized by mini emulsion polymerization method for controlled release of an acetylcholinesterase inhibitor Galantamine hydrobromide (GAL) approved by the FDA (U.S. Food and Drug Administration) which is used in the symptomatic treatment of Alzheimer's disease. SEM-EDS analysis was performed to determine the amount of elements on the surface and morphological properties of the synthesized nanopolymers. FTIR analysis was performed to determine chemical structures and particle size was determined by Zeta-Sizer device. As a result of SEM analysis, the surface morphology of the nanopolymers was found to be spherical. The specific surface area of the nanopolymers was calculated as 844.38 m2/g. The maximum adsorption amount was found to be 109.29 mg/g at a 1:39 polymer-drug ratio, 25 ̊C, 120 minutes contact time, pH 5.5, 250 μg/mL GAL concentration under the optimization of the adsorption conditions of GAL to nanopolymers. Langmuir isotherm was found to be fitted best with the adsorption of GAL onto p(HEMA- MAPA). In vitro controlled release studies of GAL loaded on nanopolymer under optimum conditions were done by dialysis method.

The aim of the present work was to prepare floating tablets of galantamine HBr using sodium alginate and xanthan gum as matrix forming carriers. Galantamine HBr is used for the treatment of mild to moderate Alzheimer's disease and various other memory impairments, in particular those of vascular origin. The matrix tablet formulations were prepared by varying the concentrations of sodium alginate and xanthan gum. The tablets were prepared by direct compression technique using PVP K-30 as a binder and sodium bicarbonate for development of CO2. The prepared matrix tablets were evaluated for properties such as hardness, thickness, friability, weight variation, floating lag time, compatibility using DSC and FTIR. In vitro dissolution was carried out for 12 hrs in 0.1N HCl at 37±0.5 ºC using USP paddle type dissolution apparatus. It was noted that, all the prepared formulations had desired floating lag time and constantly floated on dissolution medium by maintaining the matrix integrity. The drug release from prepared tablets was found to vary with varying concentration of the polymers, sodium alginate and xanthan gum. From the study it was concluded that floating drug delivery system for galantamine HBr can be prepared by using sodium alginate and xanthan gum as a carrier.

Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer’s disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman’s assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of Ki = 4.29 μM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing Ki = 1.72 µM and Ki′ = 1.28 μM, respectively.

Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer’s disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system.

International audience; We report on highly-sensitive ion-selective electrodes (ISEs) for potentiometric determining of galantamine hydrobromide (GB) in physiological fluids. Galantamine hydrobromide (GB) was selected for this study due to its previous medical importance for treating Alzheimer's disease. Three different types of ISEs were investigated: PVC membrane electrode (PVCE), carbon-paste electrode (CPE), and coated-wire electrode (CWE). In the construction of these electrodes, galantaminium-reineckate (GR) ion-pair was used as a sensing species for GB in solutions. The modified carbon-paste electrode (MCPE) was prepared using graphene oxide (MCPE-GO) and sodium tetrakis (trifluoromethyl) phenyl borate (MCPE-SIFPB) as ion-exchanger. The potentiometric modified CPEs (MCPE-GO and MCPE-SIFPB) show an improved performance in term of Nernstian slope, selectivity, response time, and response stability compared to the unmodified CPE. The prepared electrodes PVCE, CWE, CPE, MCPE-GO and MCPE-STFPB show Nemstian slopes of 59.9, 59.5, 58.1, 58.3 and 57.0 mV/conc. decade, and detection limits of 5.0 x 10(-6), 6.3 x 10(-6), 8.0 x 10(-6), 6.0 x 10(-6) and 8.0 x 10(-6) mol L-1, respectively. The prepared ISEs also show high selectivity against cations (i.e. Na+, K+, NH4+, Ca2+, Al3+, Fe3+), amino acids (i.e. glycine, L-alanine alanine), and sugars (i.e. fructose, glucose, maltose, lactose). The prepared ISEs are applicable for determining GB in spiked serums, urines, and pharmaceutical preparations, using a standard addition and a direct potentiometric method. The fast response time (

Introduction: Delayed encephalopathy due to carbon monoxide (CO) poisoning can even occur in patients with mild symptoms of acute CO poisoning. Some cases taking conventional hyperbaric oxygen (HBO) therapy or steroid-pulse therapy may be insufficient, and AchEI may be effective. Patient Concerns and Diagnoses: We report two cases of delayed encephalopathy after acute CO poisoning involving two women aged 69 (Case 1) and 60 years (Case 2) whose cognitive function improved with acetylcholinesterase inhibitor (AchEI) treatment. Delayed encephalopathy occurred 25 and 35 days after acute CO poisoning in Case 1 and Case 2, respectively. Both patients demonstrated cognitive impairment, apathy, and hypokinesia on admission. Interventions and Outcomes: Although hyperbaric oxygen therapy did not yield any significant improvements, cognitive dysfunction improved substantially. This was evidenced by an improved Mini-Mental State Examination score ffom 9 to 28 points in Case 1 and an improved Hasegawa's dementia rating scale score from 4 to 25 points in Case 2 after administration of an AchEI. In Case 1, we administered galantamine hydrobromide, which was related with improved white matter lesions initially detected on brain magnetic resonance imaging. However, in Case 2 white matter lesions persisted despite AchEI treatment. AchEI treatment may result in improved cognitive and frontal lobe function by increasing low acetylcholine concentrations in the hippocampus and frontal lobe caused by decreased nicotinic acetylcholine receptor levels in delayed encephalopathy after CO poisoning. Conclusion: Physicians should consider AchEIs for patients demonstrating delayed encephalopathy due to CO poisoning.

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.

Summary Galantamine hydrobromide was subjected to oxidative stress degradation using hydrogen peroxide and analyzed as per the chromatographic conditions described in European Pharmacopoeia. The drug showed considerable degradation at ambient temperature resulting in the formation of two degradation products at relative retention times (RRTs) 0.63 and 2.52. The minor degradant at RRT 0.63 was identified as galantamine N-oxide. The principal degradant formed at RRT 2.52 was found to be unknown and has not been reported previously. The unknown impurity was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by isolation using semi-preparative high-performance liquid chromatography (HPLC). The isolated impurity was characterized using one-dimensional, two-dimensional nuclear magnetic resonance spectroscopy (1D and 2D NMR) and elemental analysis (EA). The principal degradant was found to be formed due to the generation of bromine and subsequent attack on the aromatic ring via in s...

Gypsogenin (1) was obtained by acidic hydrolysis from its saponin. While the parent compound 1 acted as a selective inhibitor for butyrylcholinesterase (from equus) possessing a moderate mixed-type inhibition of the enzyme, Ki values as low as 2.67 ± 0.59 μM were determined for (3β,4α) 3-O-acetyl-olean-12-ene-23,28-dinitrile (11) and acetylcholinesterase (AChE, from electric eel). Thus, 11 possesses one-fifth of the inhibitory activity of the "gold standard" galantamine hydrobromide; this compound is one of the first pentacyclic triterpenoids described as a potent AChE-selective inhibitor.

Alzheimer&rsquo, s disease (AD), a neurodegenerative disease, is the most common form of dementia. Inhibition of acetylcholinesterase (AChE) is a common strategy for the treatment of AD. In this study, aqueous, hydro-methanolic, and methanolic extracts of five potent herbal extracts were tested for their in vitro anti-AChE activity. Among all, the Tinospora cordifolia (Giloy) methanolic fraction performed better with an IC50 of 202.64 &micro, g/mL. Of the HPLC analyzed components of T. cordifolia (methanolic extract), palmatine and berberine performed better (IC50 0.66 and 0.94 &micro, g/mL, respectively) as compared to gallic acid and the tool compound &ldquo, galantamine hydrobromide&rdquo, (IC50 7.89 and 1.45 &micro, g/mL, respectively). Mode of inhibition of palmatine and berberine was non-competitive, while the mode was competitive for the tool compound. Combinations of individual alkaloids palmatine and berberine resulted in a synergistic effect for AChE inhibition. Therefore, the AChE inhibition by the methanolic extract of T. cordifolia was probably due to the synergism of the isoquinoline alkaloids. Upon molecular docking, it was observed that palmatine and berberine preferred the peripheral anionic site (PAS) of AChE, with &pi, interactions to PAS residue Trp286, indicating that it may hinder the substrate binding by partially blocking the entrance of the gorge of the active site or the product release.

In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC50 values for BuChE of around 16.5 and 16.4 µM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins.

Objectives The present study emphasizes the prolonged effects of an anti-Alzheimer's drug, Galantamine hydrobromide (GHB) on morphometric, behavioural and cholinergic system in mice in the absence of the disease, AD. Methods One month old male albino mice, Mus musculus (20 ± 2 g) were selected as experimental model and GHB as the test drug. The ED50 dose (5 mg/kg body weight) was given to experimental mice once in a day up to 180 days continuously. Results Observations on the morphometric aspects such as weight, size and also changes in the behaviour pattern of both control and experimental mice were recorded with help of the Morris water maze technique. Various constituents of the cholinergic system viz. acetylcholine content and acetylcholinesterase level were estimated in different regions of brain such as Olfactory Lobe, Hippocampus, Cerebral Cortex, Cerebellum, Pons-medulla and Spinal cord on selected days during the entire treatment schedule lasting for 180 days through standard biochemical assay techniques. From the results, it was evident that GHB exerted severe perturbations in the cholinergic system in all regions of brain on chronic exposure, thus eventually leading to behavioural changes. Conclusions From this, it was concluded that GHB, even though exerted positive effects on all the above mentioned parameters which were of course short-lived and during later stages, GHB exerted ill effects. In view of this, particularly, children are cautioned not to consume indiscriminately any kind of memory enhancing drugs or any formulated health drinks containing these chemicals either directly or indirectly for improvement of their cognitive skills.

Aim: To develop a simple, accurate, sensitive, rapid and precise method for the determination of galantamine hydrobromide in bulk drug and pharmaceutical dosage form. Material and Methods: The method employs wavelength detection and determination of galantamine hydrobromide at excitation wavelength 282 nm and emission wavelength 607 nm in a solution of simple distilled water. Result and Conclusion: The method was found to be linear in the range of 2-14 μg/ml having r 2 = 0.9999. The mean accuracy was found to be 98.12% to 99.67%. The intraday and interday precision was found to be 0.18-0.35% and 0.13-0.46%, respectively. The limit of detection was found to be 0.29 μg/ml. The limit of quantification was found to be 0.89 μg/ml. The method was successfully applied for the determination of galantamine hydrobromide in bulk drug as well as pharmaceutical dosage form.

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 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/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 3–16 days. 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.