Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis.

BACKGROUND: Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these medications are effective in VCI and whether there are differences between them with regard to efficacy or adverse events. OBJECTIVES: (1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI. (2) To compare the effects of different cholinesterase inhibitors on cognition and adverse events, using network meta-analysis. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 19 August 2020. SELECTION CRITERIA: We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time points using random-effects methods. We also performed a network meta-analysis using Bayesian methods. MAIN RESULTS: We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg (n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from very low to high level of certainty. For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the effect is unlikely to be clinically important (mean difference (MD) -0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95% confidence interval (CI) -1.44 to -0.40; high-certainty evidence). Donepezil 10 mg (MD -2.21 ADAS-Cog points, 95% CI -3.07 to -1.35; moderate-certainty evidence) and galantamine 16 to 24 mg (MD -2.01 ADAS-Cog point, 95%CI -3.18 to -0.85; moderate-certainty evidence) probably also improve cognition, although the larger effect estimates still may not be clinically important. With low certainty, there may be little to no effect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI -3.04 to 3.10; low-certainty evidence). Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results showed that there was probably little to no difference between donepezil 5 mg and placebo in the number of adverse events (odds ratio (OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The effect of rivastigmine 3 to 12 mg on adverse events was very uncertain (OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence). In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes. AUTHORS' CONCLUSIONS: We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to 24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain. The data suggest that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.

Galantamine protects against synaptic, axonal, and vision deficits in experimental neurotrauma.

Our goal was to investigate the neuroprotective effects of galantamine in a mouse model of blast-induced indirect traumatic optic neuropathy (bITON). Galantamine is an FDA-approved acetylcholinesterase inhibitor used to treat mild-moderate Alzheimer's disease. We exposed one eye of an anesthetized mouse to repeat bursts of over-pressurized air to induce traumatic optic neuropathy. Mice were given regular or galantamine-containing water (120 mg/L) ad libitum, beginning immediately after blast and continuing for one month. Electroretinograms and visual evoked potentials were performed just prior to endpoint collection. Histological and biochemical assessments were performed to assess activation of sterile inflammation, axon degeneration, and synaptic changes. Galantamine treatment mitigated visual function deficits induced by our bITON model via preservation of the b-wave of the electroretinogram and the N1 of the visual evoked potential. We also observed a reduction in axon degeneration in the optic nerve as well as decreased rod bipolar cell dendritic retraction. Galantamine also showed anti-inflammatory and antioxidant effects. Galantamine may be a promising treatment for blast-induced indirect traumatic optic neuropathy as well as other optic neuropathies.

Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supralethal Dose of Soman in Cynomolgus Monkeys Posttreated with Conventional Antidotes.

Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0×LD50 soman (15.08 µg/kg) in Macaca fascicularis posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-pyridine aldoxime methyl chloride (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (∼25%-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these nonhuman primates (NHPs) translate to human-equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 hours. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 hours after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline- or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.

Anti-foodborne enteritis effect of galantamine potentially via acetylcholine anti-inflammatory pathway in fish.

Foodborne enteritis has become a limiting factor in aquaculture. Plant protein sources have already caused enteritic inflammation and inhibition in growth performance. Attempts have been made to find an effective solution to foodborne enteritis. Based on the previously suggested fish cholinergic anti-inflammatory pathway, galantamine, a typical cholinesterase inhibitor, was tested for the repression of pro-inflammatory cytokines for soybean meal induced enteritis by injection into grass carp. Both the phylogenetic analysis of cholinesterase, AchR and bioinformatic prediction, indicated galantamine's potential use as an enteritis drug. The result highlighted galantamine's potential effect for anti-enteritis in fish, especially in carps. Subsequently, a 4-week feeding trail using galantamine as an additive, in a zebrafish soybean meal induced enteritis model, demonstrated the prevention of enteritis. The results demonstrated that galantamine could prevent intestinal pathology, both histologically and molecularly, and also maintain growth performance. Reflected by gene expressional analysis, all mechanical, chemical and immune functions of the intestinal barrier could be protected by galantamine supplementation, which aided molecularly in the control of fish foodborne enteritis, through down-regulating Th17 type proinflammatory factors, meanwhile resuming the level of Treg type anti-inflammatory factors. Therefore, the current results shed light on fish intestinal acetylcholine anti-inflammation, by the dietary addition of galantamine, which could give rise to protection from foodborne enteritis.

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.

Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study.

BACKGROUND: Donepezil, rivastigmine and galantamine are popular cholinesterase inhibitors used to manage the symptoms of Alzheimer disease and other dementias; regulatory agencies in several countries warn about a possible risk of rhabdomyolysis with donepezil, based on information from case reports. Our goal was to investigate the 30-day risk of admission to hospital with rhabdomyolysis associated with initiating donepezil versus other cholinesterase inhibitors. METHODS: We conducted a retrospective cohort study in Ontario, Canada, from 2002 to 2017. Participants were adults aged 66 years or older with a newly dispensed prescription for donepezil compared with rivastigmine or galantamine. The primary outcome was hospital admission with rhabdomyolysis (assessed using hospital diagnostic codes) within 30 days of a new prescription of a cholinesterase inhibitor. Odds ratios were estimated using logistic regression, with inverse probability of treatment weights calculated from propensity scores. RESULTS: The average age in our 2 groups was 81.1 years, and 61.4% of our population was female. Donepezil was associated with a higher risk of hospital admission with rhabdomyolysis compared with rivastigmine or galantamine (88 events in 152 300 patients [0.06%] v. 16 events in 68 053 patients [0.02%]; weighted odds ratio of 2.21, 95% confidence interval [CI] 1.52-3.22). Most hospital admissions with rhabdomyolysis after donepezil use were not severe, and no patient was treated with acute dialysis or mechanical ventilation. INTERPRETATION: Initiating donepezil is associated with a higher 30-day risk of admission to hospital with rhabdomyolysis compared with initiating rivastigmine or galantamine. The proportion of patients who develop severe rhabdomyolysis within 30 days of initiating donepezil is very low.

Enhancement of Galantamine HBr Skin Permeation Using Sonophoresis and Limonene-Containing PEGylated Liposomes.

This study aimed to investigate the effect of low-frequency sonophoresis (SN) and limonene-containing PEGylated liposomes (PL) on the transdermal delivery of galantamine HBr (GLT). To evaluate the skin penetration mechanism, confocal laser scanning microscopy (CLSM), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) were employed. The application of SN led to more GLT penetration into and through the skin than GLT solution alone. The liposomes also improved GLT permeation, and 2% limonene-containing PL (PL-LI2%) exhibited the highest GLT permeation, followed by PL-LI1%, PL-LI0.1%, and PL. The CLSM images of PL-LI2% resulted in the highest fluorescence intensity of fluorescent hydrophilic molecules in the deep skin layer, and the rhodamine PE-labeled liposome membrane was distributed in the intercellular region of the stratum corneum (SC). PL-LI2% induced significant changes in intercellular lipids in the SC, whereas SN had no effect on intercellular lipids of the SC. DSC thermograms showed that the greatest decrease in the lipid transition temperature occurred in PL-LI2%-treated SC. SN might improve drug permeation through an intracellular pathway, while limonene-containing liposomes play an important role in delivering GLT through an intercellular pathway by increasing the fluidity of intercellular lipids in the SC. Moreover, a small vesicle size and high membrane fluidity might enhance the transportation of intact vesicles through the skin.

A Randomized Clinical Trial of Oxytocin or Galantamine for the Treatment of Negative Symptoms and Cognitive Impairments in People With Schizophrenia.

PURPOSE/BACKGROUND: Negative symptoms and cognitive impairments tend to co-occur in people with schizophrenia. If their association with each other is due, in part, to shared pathophysiology, then this suggests that a single drug could potentially be effective for both domains. The current study was designed to examine this hypothesis. METHODS/PROCEDURES: Fifty-eight participants with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision schizophrenia or schizoaffective disorder entered into a 6-week double-blind, placebo-controlled, double-dummy, randomized clinical trial of intranasal oxytocin and galantamine. Seventeen participants were randomized to intranasal oxytocin, 20 were randomized to galantamine, and 21 were randomized to placebo. The Scale for the Assessment of Negative Symptoms total score was used to assess change in negative symptoms (the primary outcome measure for oxytocin). The MATRICS Consensus Cognitive Battery composite score was used to assess cognition (the primary outcome measure for galantamine). FINDINGS/RESULTS: There were no significant group differences for negative symptoms (oxytocin vs placebo: F2,47.4 = 0.19, P = 0.83; galantamine vs placebo: F2,52.5 = 0.41, P = 0.67). There were no significant group differences for cognitive impairments (galantamine vs placebo: t40 = 0.71, P = 0.48; oxytocin vs placebo: t40 = 0.50, P = 0.62). There were also no significant group differences for the functional capacity or ancillary symptom measures. IMPLICATIONS/CONCLUSIONS: The lack of an efficacy signal for either compound precluded our ability to test whether pharmacological treatment pathways for negative symptoms and cognitive impairments overlap or are independent.

Predicting the neural effect of switching from donepezil to galantamine based on single-photon emission computed tomography findings in patients with Alzheimer's disease.

BACKGROUND: A number of neuroimaging studies have addressed the specific effect of treatment with cholinesterase inhibitors on the frontal lobe in patients with Alzheimer's disease (AD). However, the neural effects of cholinesterase inhibitors on both apathy and executive dysfunction remain unclear. We examined whether baseline regional cerebral blood flow, as determined by using single-photon emission computed tomography, is capable of predicting changes in apathy and executive dysfunction in response to AD patients switching from donepezil to galantamine therapy. METHODS: We conducted a 24-week, prospective, open-label study of AD patients treated with galantamine who did not respond to previous treatment with donepezil. Single-photon emission computed tomography was performed at baseline, and behaviour and cognitive assessments including the Mini-Mental State Examination, the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale, the Frontal Assessment Battery, the Neuropsychiatry Inventory Brief Questionnaire Form, and the Dysexecutive Questionnaire were conducted at three time points (baseline and after 12 and 24 weeks of galantamine therapy). RESULTS: After galantamine therapy, the Neuropsychiatry Inventory Brief Questionnaire Form scores (apathy, irritability, and aberrant motor symptoms) and the Dysexecutive Questionnaire score improved significantly. The single-photon emission computed tomography findings showed that lower baseline regional cerebral blood flow values in several frontal areas, including the dorsolateral and ventrolateral prefrontal cortex, the anterior cingulate, and the orbitofrontal cortex, predicted greater reductions in the score for apathy (distress) on the Neuropsychiatry Inventory Brief Questionnaire Form and the Dysexecutive Questionnaire score after patients switched from donepezil to galantamine therapy. CONCLUSIONS: Our study suggests that galantamine therapy, unlike donepezil, is characterized by a dual mechanism of action that may increase acetylcholine and the nicotinic receptor-modulation effect within the frontal lobe, both of which are associated with apathy and executive dysfunction in AD patients.

Antidementia drug treatment in dementia networks in Germany: use rates and factors associated with treatment use.

BACKGROUND: Dementia networks in Germany constitute a specialised setting for integrated dementia care and have shown benefits on relevant outcomes, including those of drug treatment. National guidelines recommend treatment with acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) or the N-Methyl-D-Aspartate antagonist (memantine) to reduce cognitive symptoms. However, prescription rates are lower than 30 % in general practises. This study aims to describe antidementia drug treatment and the factors that are associated with the treatment in different dementia networks across Germany. METHODS: We have analysed the socio-demographic, clinical and utilisation data from 560 patients with dementia (PWD), as well as data from their caregivers, in 13 selected dementia networks in Germany. The patients and caregivers were interviewed in their homes or in the network facilities. Multiple logistic regression models were fitted to evaluate the socio-demographic and clinical factors associated with the utilisation of antidementia drug treatment in the various networks. RESULTS: In all of the networks in the study, 52 % of the participants received an antidementia drug treatment. Factors associated with the utilisation of the antidementia drug treatment were: formal diagnosis (OR = 16.81, p < 0.001), association with a physician in the network (OR = 3.69, p < 0.001), higher number of comorbidities (OR = 0.88, p = 0.039), living alone (OR = 0.51, p = 0.032) and higher age (OR = 2.97, p = 0.002). CONCLUSION: Medical treatment of PWD with antidementia drugs in dementia networks in Germany is more frequent than in primary and nursing home care settings. Our findings also suggest that participants with a formal diagnosis and a physician in the network have increased rates of receiving antidementia drug treatments. These findings suggest that dementia networks focusing on medical treatment should support diagnostic procedures and incorporate physician specialists.

Formulation and evaluation of galantamine gel as drug reservoir in transdermal patch delivery system.

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.

Galantamine attenuates reinstatement of cue-induced methamphetamine-seeking behavior in mice.

Methamphetamine (METH) dependence is becoming a serious socioeconomic health problem worldwide. The enhancement of the cholinergic nervous system is expected to greatly alleviate drug dependence. We investigated the effect of galantamine on the reinstatement of cue-induced METH-seeking behavior using a self-administration experiment. Treatment with galantamine (1 mg/kg, p.o.) 30 minutes before exposure to the cues suppressed the reinstatement of METH-seeking behavior. However, galantamine did not affect the cue-induced reinstatement of food-seeking behavior or locomotor activity. These results suggest that galantamine may be a candidate drug for treating relapses of METH-seeking behavior.

Cognitive subdomain responses to galantamine in Alzheimer's disease.

We investigated the effects of galantamine on cognitive subdomains in Alzheimer's disease (AD). Sixty-six patients with mild-to-moderate AD received open-label galantamine for 52 weeks. Cognitive function was measured using the Korean version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog-K). Response to galantamine was defined as "improvement or no deterioration" on the total scores of the ADAS-cog-K at 26 weeks. In the overall intent-to-treat sample, we found less cognitive decline during 26 and 52 weeks than the expected untreated course as predicted by Stern's equation. The operationally defined response rate at 26 weeks was 66.7%. The responders differed significantly from the nonresponders only in the memory and language domains but not in the domains of praxis or frontal/executive function or in secondary outcome measures of neuropsychiatric symptoms and activities of daily living. The subdomain analysis revealed an effect of galantamine on preservation of memory that was not apparent in the overall analysis. Failure to achieve responder status by 26 weeks was associated with no further possibility of response.

Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. MATERIALS AND METHODS: Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. RESULTS: The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. CONCLUSIONS: This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.

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.

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.

Galantamine-associated nightmares and anxiety.

BACKGROUND: This case report describes recurrent nightmares and anxiety possibly caused by the administration and rapid dose titration of galantamine. CASE SUMMARY: A 90-year-old male with Alzheimer's disease was initiated on galantamine 4 mg twice daily for 10 days, followed by 8 mg twice daily thereafter. On followup to the geriatric clinic, the patient reported complaints of nightmares and associated anxiety. The occurrences of nightmares developed after initiating galantamine and temporally increased with galantamine titration. After discontinuation of galantamine, the patient reported no further occurrences of nightmares or anxiety and memory function remained stable. CONCLUSION: Galantamine-associated nightmares are an uncommon adverse event and may have been exacerbated by rapid titration. Although such adverse events are unlikely to cause harm in the patient, such sleep abnormalities have the potential to decrease a patient's quality of life and may require the need for alternative therapy.

[Microcirculatory effects of fluctophoresis series in patient with moderate chronic periodontal disease].

The results of fluctophoresis series in 160 patients aged 35-75 years with chronic periodontal disease are discussed in the paper. It was shown that fluctophoresis may improve both clinical and rheographic values, as well and laser Doppler flowmetry rates because of improved microcirculation. Mildronat fluctophoresis influences myogenic regulation while nivaline acts as neurogenic vessel tone regulator. Acovegine fluctophoresis is effective in cases with neither myogenic nor neurogenic regulation disorder.

Synergistic effects of galantamine and memantine in attenuating scopolamine-induced amnesia in mice.

We investigated a possible drug efficacy enhancement obtained by combining inactive doses of galantamine and memantine in the scopolamine-induced amnesia model in mice. We evaluated the effects of the two drugs, either alone or in combination, using the spontaneous alternation and object recognition tasks. In both tests, combination of low doses of galantamine (0.1 mg/kg, s.c.) and memantine (0.5 mg/kg, i.p.), which were sub-active per se, rescued the memory impairment induced by scopolamine (1 mg/kg, i.p.). The results suggest that combinations of galantamine and memantine might provide a more effective treatment of memory impairments in cognitive disorders than either drug used alone.