Concentrations Of Galantamine Research Articles

Galantamine Quantity and Alkaloid Profile in the Bulbs of Narcissus tazetta and daffodil cultivars (Amaryllidaceae) Grown in Israel.

Alkaloids produced by the bulbs of the Amaryllidaceae are a source of pharmaceutical compounds. The main alkaloid, galantamine, is a reversible acetylcholinesterase inhibitor and allosteric nicotinic receptor modulator, which slows cognitive and functional decline in mild to moderate dementia due to Alzheimer’s disease. Having a complex stereochemistry, the organic synthesis of galantamine for pharmaceutical uses is highly challenging and not always economically viable, and it is therefore isolated from Amaryllidaceae bulbs. In the present study, galantamine was extracted and quantified in Narcissus bulbs from five cultivars (cvs.), Fortune, Carlton, Ice Follies, Galilee and Ziva, which were grown in Israel under various conditions. Results show that the cvs. Fortune, Carlton and Ice Follies bulbs contained 285 ± 47, 452 ± 73 and 69 ± 17 µg g−1 galantamine, respectively, while the Galilee and Ziva bulbs contained relatively low concentrations of galantamine (1–20 µg g−1). Irrigation levels and pruning conditions did not affect the galantamine contents. Additionally, the alkaloids profile of the five cvs. was analyzed and characterized using LC-MS/MS showing that galantamine-type alkaloids were mainly detected in the Fortune and Carlton bulbs, lycorine-type alkaloids were mainly detected at the Galilee and Ziva bulbs and vittatine-type alkaloids were mainly detected in the Ice Follies bulbs. The present research is the first to characterize the alkaloids profile in the Narcissus bulbs of Galilee and Ziva, indigenous cvs. grown in Israel. The antiviral and anticancer alkaloids lycorine and lycorinine were the main alkaloids detected in the bulbs of those cultivars.

Galantamine plasma concentration and cognitive response in Alzheimer's disease.

BackgroundGalantamine has been approved for the treatment of Alzheimer’s disease (AD). However, there are few studies which have reported the association between cognitive responses and galantamine plasma concentration. The aim of this study was to determine the correlation between galantamine plasma concentration and the subsequent cognitive response following treatment in AD patients.MethodsAD sufferers who continuously took 8 mg/d galantamine for at least 6 months without previous exposure to other kinds of AChEI such as donepezil, rivastigmine, or memantine were included in this cohort study. The assessments included the Mini Mental Status Examination (MMSE), Clinical Dementia Rating Scale (CDR) and the Cognitive Assessment Screening Instrument (CASI). Each subdomain of the CASI assessment was conducted at baseline and after 6 months of galantamine. The plasma concentrations of galantamine were measured by capillary electrophoresis after 6 months of the treatment. Logistic regression was performed to adjust for age, gender, apolipoprotein E ε4 genotype status, and baseline score to investigate the association between galantamine plasma concentrations and the cognitive response.ResultsThe total sample consisted of 33 clinically diagnosed AD patients taking galantamine 8 mg/d for 6 months. There was no linear correlation between galantamine concentration and cognitive response in patients. However, 22 patients were responsive to the treatment in the long-term memory domain. In CASI subset domain, concentration improved during the 6 months follow up.ConclusionsIn the limited samples study, galantamine mostly benefitted the cognitive domain of long-term memory. The benefits were not related to the galantamine plasma concentration. Objective intra-individual evaluation of therapeutic response should be encouraged.

Plasma concentration of galantamine – influence of dose and body mass index in Alzheimer's disease

Background/objectives: Patients with Alzheimer’s disease (AD) are at present treated with galantamine without actual knowledge of plasma concentration levels. The aim of this presentation is to analyse the relationship between galantamine plasma concentration, dose, demographics and body mass index (BMI). Methods: A total of 84 AD patients recruited at the Memory Clinic in Malmo, Sweden, treated with galantamine were included in this study. The patients were investigated at baseline, at 2 months and every 6 months for a period of three years. Blood samples were obtained at 180 of these investigations for the analysis of plasma galantamine concentration. Efficacy measures including cognitive tests (MMSE), functional ratings (IADL) and BMI were simultaneously evaluated. The dose as well as the time from drug intake to plasma extraction was investigated. Results: The mean galantamine plasma concentration demonstrated a strong positive linear association with dose (r=0.51, p<0.001). Moreover, patients with separate doses of galantamine (8, 16 and 24 mg daily) differed significantly in plasma concentration (p<0.001). No gender differences regarding dose were observed. There was no linear relationship between galantamine plasma concentration and BMI in the entire cohort. When investigating the impact of gender, a negative linear association (r=-0.45, p=0.001) between concentration and BMI was found in the male group but not in the female. Age did not influence the plasma concentration level. In a multivariate general linear model with concentration as the dependent variable, gender (p=0.010) and BMI (p=0.038) but not age (p=0.540) were predictive factors. Conclusion: Galantamine plasma concentration demonstrated a strong relationship with dose. The dose did not differ between genders, whereas the impact of body mass index on plasma concentration was important only among the males.

Galantamine reverses scopolamine-induced behavioral alterations in Dugesia tigrina

In planaria (Dugesia tigrina), scopolamine, a nonselective muscarinic receptor antagonist, induced distinct behaviors of attenuated motility and C-like hyperactivity. Planarian locomotor velocity (pLMV) displayed a dose-dependent negative correlation with scopolamine concentrations from 0.001 to 1.0 mM, and a further increase in scopolamine concentration to 2.25 mM did not further decrease pLMV. Planarian hyperactivity counts was dose-dependently increased following pretreatment with scopolamine concentrations from 0.001 to 0.5 mM and then decreased for scopolamine concentrations ≥ 1 mM. Planarian learning and memory investigated using classical Pavlovian conditioning experiments demonstrated that scopolamine (1 mM) negatively influenced associative learning indicated by a significant decrease in % positive behaviors from 86 % (control) to 14 % (1 mM scopolamine) and similarly altered memory retention, which is indicated by a decrease in % positive behaviors from 69 % (control) to 27 % (1 mM scopolamine). Galantamine demonstrated a complex behavior in planarian motility experiments since co-application of low concentrations of galantamine (0.001 and 0.01 mM) protected planaria against 1 mM scopolamine-induced motility impairments; however, pLMV was significantly decreased when planaria were tested in the presence of 0.1 mM galantamine alone. Effects of co-treatment of scopolamine and galantamine on memory retention in planaria via classical Pavlovian conditioning experiments showed that galantamine (0.01 mM) partially reversed scopolamine (1 mM)-induced memory deficits in planaria as the % positive behaviors increased from 27 to 63 %. The results demonstrate, for the first time in planaria, scopolamine's effects in causing learning and memory impairments and galantamine's ability in reversing scopolamine-induced memory impairments.

New approach for the potentiometric-enzymatic assay of reversible-competitive enzyme inhibitors. Application to acetylcholinesterase inhibitor galantamine and its determination in pharmaceuticals and human urine

A new kinetic-potentiometric method for the characterization and analytical determination of competitive reversible enzyme inhibitors was developed. The method is based on a mathematical approach, assuming that the reaction proceeds at the steady state, which permits calculation of a tentative substrate concentration to be used to determine low inhibitor concentrations and to obtain the value of inhibition constant corresponding to the inhibitor. The mathematical approach predicts a linear relationship between the inverse of the relative inhibition and the inverse of the inhibitor concentration. The method developed is applied to the acetylcholinesterase inhibitor galantamine, using an acetylcholine-selective electrode. A linear relationship for galantamine concentration from 2×10−8 to 1×10−6M and a limit of detection of 5.4×10−9M was found. A value for KIGal of 2.0×10−7±0.1×10−7M was obtained. The effect of several other drugs and of the main galantamine metabolite excreted in urine was studied. The method was satisfactorily applied to the determination of galantamine in pharmaceuticals and human urine.

Protective Effect of Galantamine Against Oxidative Damage Using Human Lymphocytes: A Novel In Vitro Model

Neurodegenerative disorders such as Alzheimer's disease are characterized in the initial stages by an increase in reactive oxygen species that trigger apoptosis or programmed cell death. It has been suggested that the synthetic alkaloid galantamine may offer protection against this cell loss. This investigation sought to assess the protective effect of galantamine against oxidative damage induced by hydrogen peroxide (H2O2) using human lymphocytes cultured invitro as a model. Cell death can be measured indirectly using cell viability testing with trypan blue. Determination of the galantamine concentrations used was made possible by thenegative correlation found between galantamine concentration and average mitotic index (MI). Average viability of lymphocytes treated with low and medium concentrations of galantamine was significantly higher than the control. Galantamine does indeed demonstrate a protective capacity against cell damage induced by hydrogen peroxide. This finding supports the possible use of the drug in treatment of neurodegenerative diseases related to oxidative stress.

Dose and plasma concentration of galantamine in Alzheimer's disease - clinical application

IntroductionPatients with Alzheimer's disease (AD) are currently treated with cholinesterase inhibitors, such as galantamine, without actual knowledge of its concentration in plasma. Our objective was to analyse potential relationships between galantamine concentration, galantamine dose, socio-demographic characteristics, body weight, body mass index (BMI), and treatment response.MethodsEighty-four patients with AD recruited from the Memory Clinic, Malmö, Sweden, and treated with galantamine were included in the study. Efficacy measures, including cognition (Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog)) and instrumental activities of daily living (IADL), were evaluated at baseline, 2 months after treatment initiation (MMSE only) and semi-annually over 3 years. At these assessments, blood samples were obtained for the analysis of the galantamine concentration, and body weight, BMI, drug dose and time from drug intake were recorded.ResultsAll patients had a measurable concentration of galantamine at all assessments. The mean plasma concentration of the drug exhibited a positive linear association with dose (r = 0.513, P < 0.001). The dose did not differ between sexes. Negative linear associations between the galantamine plasma concentration and BMI (r = -0.454, P = 0.001) or body weight (r = -0.310, P = 0.034) were found exclusively in the male group. When mixed-effects models were used, the dose of galantamine (P < 0.001), time from drug intake (P < 0.001), and BMI (P = 0.021) or weight (P = 0.002) were factors that predicted the concentration, whereas sex, age, and cognitive and functional changes were not.ConclusionsHigh compliance to galantamine treatment was found among all patients in this naturalistic AD study. The impact of BMI or body weight on the plasma concentration of galantamine was important only among males. No relationship was observed between concentration and short-term treatment response or progression rate in terms of cognitive and functional abilities.

Synergistic neuroprotective effect of combined low concentrations of galantamine and melatonin against oxidative stress in SH-SY5Y neuroblastoma cells

Melatonin is a potent free radical scavenger, antioxidant and neuroprotective drug. On the other hand, galantamine is a cholinergic drug with antioxidant and neuroprotective properties linked to inhibition of acetylcholinesterase and allosteric modulation of nicotinic receptors. This investigation evaluated a possible synergistic neuroprotective effect of subeffective concentrations of combined galantamine and melatonin. Human neuroblastoma SH-SY5Y cells were subjected to a mitochondrial oxidative stress, by blockade of mitochondrial complexes I and V with rotenone and oligomycin-A (R/O); cells were treated for 24 hr with R/O. This caused 40% of the cell to die as measured by lactate dehydrogenase (LDH) release. Cell incubation with increasing concentrations of galantamine (10-300 nm) or melatonin (0.3-10 nm) for 24 hr, followed by a 24-hr period with R/O, caused a concentration-dependent protection; maximum protection was achieved with 300 nm galantamine (56% protection) and 10 nm melatonin (50% protection). Combination of subeffective concentrations of melatonin (0.3 nm) and galantamine (30 nm) caused a synergistic and significant protection that was similar to the maximum protection afforded by effective concentrations of melatonin or galantamine alone. This protective effect was completely reversed when nicotinic and melatonin receptors were blocked respectively by mecamylamine and luzindole. The neuroprotective effect was prevented by chelerythrine, LY294002, and Sn (IV) protoporphyrin IX dichloride (SnPP), indicating the participation of the PKC/PI3K/Akt activation and induction of the antioxidant enzyme heme oxygenase-1. The synthesis of novel multitarget compounds having in a single molecule the combined neuroprotective properties of galantamine and melatonin could be a new strategy for potential therapeutic agents in neurodegenerative diseases.

Galantamine reduces striatal degeneration in 3-nitropropionic acid model of Huntington's disease

The acetylcholinesterase inhibitor (AChEI) galantamine is currently used to treat mild to moderate Alzheimer's disease (AD), and it has been suggested to have several neuroprotective effects. To investigate the potential application of this drug to the treatment of Huntington's disease, we examined whether galantamine can reduce the striatal degeneration induced by the mitochondrial toxin, 3-nitropropionic acid (3NP). 3NP (63mg/kg/day) was delivered to Lewis rats by osmotic pumps for 5 consecutive days, and the rats received intraperitoneal administration of either different concentrations of galantamine (1mg/kg/day or 10mg/kg/day, twice daily) or vehicle (saline) throughout the experiment. Galantamine attenuated the 3NP-induced neurologic deficits on days 2–5. Galantamine-treated rats showed smaller striatal lesion volumes measured by Nissl staining and lower numbers of TUNEL+ apoptotic cells when compared to the vehicle-treated rats. Galantamine failed to reduce the striatal lesion volume when co-administered with mecamylamine, a nicotinic acetylcholine receptor antagonist. Our data indicate that galantamine can attenuate neurodegeneration in a Huntington's disease model by modulating nAChR.

PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD

The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients’ cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16–24 mg/day) and 6 patients the placebo, and this was followed by 9 months’ galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity ( 11C-PMP) and 11C-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30–40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical 11C-nicotine binding was observed during the study. 11C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and 11C-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and 11C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.

Pharmacokinetics and Bioequivalence Studies of Galantamine Hydrobromide Dispersible Tablet in Healthy Male Chinese Volunteers

ABSTRACTA randomized, two-way, crossover study was conducted in 18 healthy male Chinese volunteers to compare pharmacokinetics profiles of galantamine hydrobromide dispersible tablet with that of conventional tablet. A single oral dose of 10 mg galantamine was administrated to each volunteer. Plasma concentrations of galantamine were determined by a validated high-performance liquid chromatography (HPLC) method with fluorescence detection, which allowed 1 ng/mL to be assayed as the lowest quantifiable concentration. From plasma concentrations, AUC0→t (the area under the plasma concentration-time curve from time 0 to the last sampling time, 32 hr), AUC0→∞ (the area under the plasma concentration-time curve from time 0 to infinity), t½ (elimination of half-life of the terminal log linear phase), Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were evaluated through noncompartmental pharmacokinetic analysis. AUC0→t and AUC0→∞ were calculated by the linear-log trapezoidal rule method. Cmax and Tmax were obtained directly from the plasma concentration-time curve. Analysis of variance was carried out using logarithmically transformed AUC0→t, AUC0→∞ and Cmax. As far as AUC0→t, AUC0→∞ and Cmax were concerned, there was no statistically significant difference between the test and reference formulations. Ninety percent confidence intervals (90% CI) for the ratio of AUC0→t, AUC0→∞ and Cmax values for the test and reference formulations were 100.4–107.8%, 99.0–107.2% and 87.5–111.3%, respectively. As the 90% CIs of AUC0→t, AUC0→∞ and Cmax were entirely within 80–125%, two formulations were considered bioequivalent.

Effect of galantamine on the human α7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity

1. Various types of anticholinesterasic agents have been used to improve the daily activities of Alzheimer's disease patients. It was recently demonstrated that Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human alpha4beta2 neuronal nicotinic receptor activity. We explored its effect on the human alpha7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes. 2. Galantamine, at a concentration of 0.1 microM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human alpha7 nAChR expressed in Xenopus oocytes, but caused inhibition at higher concentrations. The maximum effect of galantamine, an increase of 22% in the amplitude of ACh-induced currents, was observed at a concentration of 250 microM Ach. 3. The same enhancing effect was obtained in oocytes transplanted with Torpedo nicotinic acetylcholine receptor (AChR) isolated from the electric organ, but in this case the optimal concentration of galantamine was 1 microM. In this case, the maximum effect of galantamine, an increase of 35% in the amplitude of ACh-induced currents, occurred at a concentration of 50 microM ACh. 4. Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 microM, quantal spontaneous events, recorded in a cholinergic synapse, increased their amplitude, an effect which was independent of the anticholinesterasic activity associated with this compound. The anticholinesterasic effect was recorded in preparations treated with a galantamine concentration of 10 microM. 5. In conclusion, our results show that galantamine enhances human alpha7 neuronal nicotinic ACh receptor activity. It also enhances muscular AChRs and the size of spontaneous cholinergic synaptic events. However, only a very narrow range of galantamine concentrations can be used for enhancing effects.

Galantamine Pharmacokinetics, Safety, and Tolerability Profiles Are Similar in Healthy Caucasian and Japanese Subjects

The aim of this study was to compare the pharmacokinetics of galantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups of healthy Japanese (n = 13; 6 males and 7 females)and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses of galantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses of galantamine (4 and 8 mg), and there was an approximate dose proportionality of galantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (+/- SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC)0-infinity) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CII = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI= 90-127) and 108% (90% CI= 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit of bioequivalence. Analysis of variance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because of adverse events. No consistent or clinically relevant pattern of blood chemistry, hematology, or cardiovascular changes was seen. These results suggest that the pharmacokinetic profiles of galantamine after single-dose administration are not statistically significantly different between Caucasian and Japanese groups. Galantamine was well tolerated. The safety and tolerability of galantamine were very similar in the two ethnic groups.

Miniature endplate currents of muscle fibers from rat diaphragm during galantamine-induced acetylcholinesterase inhibition

Miniature endplate currents (MEPC) were recorded in muscle fibers of rat diaphragm using voltage clamp technique during acetylcholinesterase (AChE) inhibition induced by various concentrations of galantamine. Their amplitude and time course began to increase at a galantamine concentration of 3.16·10−8 g/ml. Increased concentrations of galantamine produced a greater effect. Maximum amplitude and time course were reached at a concentration of 10−6 g/ml. The input resistance of muscle fibers increased under the effects of galantamine. In all cases MEPC fell exponentially. At a concentration of 10−5 g/ml galantamine produced a curarelike effect; amplitude and time course of decay increased to a lesser extent than at a concentration of 10−6 and the decay in MEPC became biphasic. Following washout of galantamine (10−5 g/ml) the time course of MEPC first rose, then fell, returning to the initial level in 3 h, and decay again became exponential. Changes in MEPC parameters under the effects of different concentrations of galantamine and washout were closely correlated. A positive correlation was found between the time course of decay and MEPC amplitude both in the presence and absence of AChE inhibition. It is postulated that the functional importance of synaptic AChE in repressing the postsynaptic action of acetylcholine is limited and that parameters of postsynaptic response may therefore be used to evaluate its action.