High performance liquid chromatography coupled with mass spectrometry for simultaneous determination of rivastigmine and its metabolite in rat plasma

Several studies on the pharmacokinetic parameters of antidementia drugs have reported that plasma concentration is linked to the drugs’ efficacy and adverse effects. At present, there is no quantitation method that is highly sensitive and can be applied to simultaneous monitoring of the pharmacokinetics of rivastigmine and its metabolites (NAP 226-90) in rat plasma. No methods fulfilling the assay validation requirements of the US Food and Drug Administration and the European Medicines Agency was also established. Therefore, this study developed a quantitative method for measuring rivastigmine and NAP 226-90 concentrations using high-performance liquid chromatography and tandem mass spectrometry, examining plasma samples after rivastigmine administration. Rat plasma samples were prepared via the protein precipitation method. The methods for measuring rivastigmine and NAP 226-90 concentrations showed good fit over wide ranges of 1–100 ng mL−1 and 0.5–50 ng mL−1, with lower limits of quantification at 1 ng mL−1 and 0.5 ng mL−1, respectively. The plasma concentrations of rivastigmine and NAP 226-90 in six healthy rats were successfully determined, demonstrating the feasibility of applying the developed method. Thus, this research has successfully developed a sensitive, selective method, to simultaneously quantify rivastigmine and NAP 226-90 concentrations in rat plasma and be applicable to a pharmacokinetic study.

Pharmacological Investigations in Glia Culture Model of Inflammation

Astrocytes and microglia are the main cell population besides neurons in the central nervous system (CNS). Astrocytes support the neuronal network via maintenance of transmitter and ion homeostasis. They are part of the tripartite synapse, composed of pre- and postsynaptic neurons and perisynaptic astrocytic processes as a functional unit. There is an increasing evidence that astroglia are involved in the pathophysiology of CNS disorders such as epilepsy, autoimmune CNS diseases or neuropsychiatric disorders, especially with regard to glia-mediated inflammation. In addition to astrocytes, investigations on microglial cells, the main immune cells of the CNS, offer a whole network approach leading to better understanding of non-neuronal cells and their pathological role in CNS diseases and treatment. An in vitro astrocyte-microglia co-culture model of inflammation was developed by Faustmann et al. (2003), which allows to study the endogenous inflammatory reaction and the cytokine expression under drugs in a differentiated manner. Commonly used antiepileptic drugs (e.g., levetiracetam, valproic acid, carbamazepine, phenytoin, and gabapentin), immunomodulatory drugs (e.g., dexamethasone and interferon-beta), hormones and psychotropic drugs (e.g., venlafaxine) were already investigated, contributing to better understanding mechanisms of actions of CNS drugs and their pro- or anti-inflammatory properties concerning glial cells. Furthermore, the effects of drugs on glial cell viability, proliferation and astrocytic network were demonstrated. The in vitro astrocyte-microglia co-culture model of inflammation proved to be suitable as unique in vitro model for pharmacological investigations on astrocytes and microglia with future potential (e.g., cancer drugs, antidementia drugs, and toxicologic studies).

Polypharmacy in elderly patients with falls

Background: Falls in elderly–a multifactorial syndrome. One of the modifiable factors is polypharmacy. STOPP/START criteria are used for correction of polypharmacy in geriatrics.Aim: Assessment of the prevalence of polypharmacy, analysis and correction of pharmacotherapy using STOPP/START criteria in patients with falls.Materials and methods: The study included 655 patients hospitalized in the geriatric department over 60 years of age, who were divided into two groups. Group 1 (n=332, 50.7%)–patients with 1 or more falls, group 2 (n=323,49.3%)–patients without falls. The analysis of the received therapy before hospitalization was performed. After that, based on the indications, contraindications and STOPP/START criteria, drug therapy was corrected in patients with falls.Results: Patients of group 1 took 4.5±2.18 drugs, group 2–4.3±2.6. Polypharmacy was diagnosed in 150 (45.2%) patients with falls and in 122 (37.8%) patients without falls. Patients with falls were more likely to receive sleeping pills, NSAIDs. Univariate analysis showed that falls were associated with NSAIDs (OR 2.15, 95% CI 1.38–3.35, p=0.001) and sleeping pills (OR 2.03, 95% CI 1.02–4.02, p=0.047). An audit and correction of therapy was performed: in 108 (32.5%) patients the number of prescribed drugs was reduced. Patients with falls were prescribed statins, antidementia drugs, anticonvulsants and antidepressants as components of therapy for chronic pain syndrome, chondroitin sulfate and glucosamine sulfate for the treatment of osteoarthritis, calcium and antiresorbtive therapy, antianemic drugs, vitamin D. Antiplatelet agents, digoxin, sleeping pills and NSAIDs were less frequently prescribed. STOPP/START criteria and their frequency in patients with falls were analyzed. 141 cases of potentially non-recommended but prescribed medications were identified. STOPP criteria were for the administration of NSAIDs (n=53, 37.6%) and acetylsalicylic acid (n=62, 44%). There were 458 cases of potentially recommended but not prescribed medications. The most common START criteria were not for the administration of vitamin D and statins.Conclusion. Half of elderly patients with falls have polypharmacy. These patients are more likely to take sleeping pills and NSAIDs. STOPP criteria most often concerned the appointment of NSAIDs and acetylsalicylic acid, and the START criteria revealed the absence of the appointment of vitamin D and statins.

Increased risk for dementia in neurofibromatosis type 1

Purpose To determine the risk for dementia in neurofibromatosis type 1 (NF1) using a Finnish nationwide cohort of individuals with NF1, and data from national registries. Methods A Finnish cohort of 1,349 individuals with confirmed NF1 according to the US National Institutes of Health (NIH) diagnostic criteria was compared with a control cohort of 13,870 individuals matched for age, sex, and area of residence. Dementia-related hospital visits were retrieved from the Finnish Care Register for Health Care using International Classification of Diseases, 10th revision (ICD-10) diagnosis codes G30 and F00–F03. Purchases of antidementia drugs were queried with Anatomical Therapeutic Chemical (ATC) classification code N06D from the drug reimbursement register maintained by the Social Insurance Institution of Finland. The follow-up spanned 1998–2014. Results Totals of 16 and 165 individuals with at least two dementia-related diagnoses or drug purchases were identified in the NF1 and control cohorts, respectively. The hazard ratio for dementia in NF1 was 1.67 (95% confidence interval [CI] 1.00–2.80, P = 0.050). In an analysis stratified by the type of dementia, the risk for Alzheimer disease was increased in NF1 compared to controls with a hazard ratio of 2.88 (95% CI 1.47–5.66, P = 0.002). Conclusion Dementia and especially Alzheimer disease are previously unrecognized neurological complications of NF1.

Medications in Patients with Dementia and Behavioral Disturbance

Background: Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population. Objective: To describe real-world medications use in this population. Methods: A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015–Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Results: A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23%to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). A list of 60 unique medications were suggested to be the commonly used drugs in dementia patients with BD. Conclusion: In dementia patients with BD, anti-dementia medications, antidepressants, anticonvulsants, hypnotics and antipsychotics were the most used drug classes. Antidepressants and antipsychotics use were more frequent after a BD event, which suggests a need for safe drugs targeting BD in dementia patients.

Potentially Inappropriate Prescriptions of Antipsychotics for Patients With Dementia

Dementias are neurodegenerative and progressive diseases of the central nervous system. The objective of this study was to determine the frequency of potentially inappropriate prescriptions of antipsychotics in a group of patients diagnosed with dementia in Colombia. This was a cross-sectional study based on a population database for drug dispensing that identified prescriptions of antidementia drugs, antipsychotics, and other drugs for patients with a diagnosis of dementia. Descriptive statistics and bivariate and multivariate analyses were performed. A total of 11,372 patients with dementia were identified; 66.6% were women, and the mean age was 80.5 ± 9.6 years. Alzheimer’s disease was the most frequent diagnosis (76.6%). A total of 69.0% of patients received antidementia drugs. A total of 37.1% of patients received some antipsychotic, especially atypical antipsychotics (31.0%). Increased age, being treated with memantine, simultaneously presenting with anxiety, depression, and psychotic disorders, and concomitantly receiving anticonvulsants, bronchodilators and benzodiazepines were associated with a greater probability of being prescribed antipsychotics. More than one-third of patients with dementia received antipsychotic prescriptions, which are considered potentially inappropriate because they can worsen cognitive decline and favor the occurrence of adverse events.

Use of psychotropic drugs and drugs with anticholinergic properties among residents with dementia in intermediate care facilities for older adults in Japan: a cohort study

ObjectivesTo evaluate the prescription and discontinuation of psychotropic drugs (PD) and drugs with anticholinergic properties (DAP) in residents with dementia admitted to Roken, a major type of long-term care facility in Japan.DesignCohort study.SettingA nationwide questionnaire survey across 3598 Roken in Japan in 2015 (up to five randomly selected residents per facility).ParticipantsThis study included 1201 residents from 343 Roken (response rate: 10%). We determined the presence and severity of dementia using a nationally standardised measure.Primary and secondary outcome measuresPrescriptions of PD and DAP at admission and 2 months after admission were evaluated. Multivariable logistic regression was used to evaluate the associations of residents’ baseline characteristics with prescriptions or discontinuation.ResultsPrescription rates decreased for antidementia drugs (19.4% to 13.0%), hypnotics (25.1% to 22.6%) and anxiolytics (12.3% to 10.7%), whereas those for other PD, such as antipsychotics (13.2% to 13.6%), antidepressants (7.4% to 6.7%), antiepileptic drugs (7.1% to 7.8%) and DAP (35.2% to 36.6%) did not statistically significantly decrease. Some factors were associated with the prescriptions, for example, for antipsychotics, older age (≥85 years) (adjusted OR (aOR), 0.60; 95% CI 0.43 to 0.85) and being bedridden (aOR 0.67; 95% CI 0.47 to 0.97) were associated with a lower use of antipsychotics, whereas severe dementia was associated with a higher use of antipsychotics (aOR 3.26; 95% CI 2.26 to 4.70). At an individual level, a quarter of residents prescribed PD or DAP at admission had discontinued at least one PD or DAP, respectively, 2 months after admission. Antidementia drug use in severe dementia (aOR 1.86; 95% CI 1.04 to 3.31) and PD use in older age (aOR 1.61; 95% CI 1.00 to 2.60; in residents with disabling dementia) were associated with discontinuation.ConclusionsThere is possible scope for deprescribing PD and DAP in Roken residents with dementia to mitigate the risks of adverse events.

Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, β-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

Management of the predementia stage of Alzheimer’s disease, complicated with hypoactive delirium

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in elderly population leading to the development of dementia. The emergence of modern diagnostic approaches makes possible reveal AD at predementia stage and study new drugs with pathogenetic and neuroprotective properties before severe cognitive impairment (dementia) arises. We present a description of patient with amnestic type of mild cognitive impairment with subsequent follow-up for more than two years. AD presence in mentioned patient was confirmed by evaluation of specific clinical, laboratory and instrumental biomarkers. Therapy with akatinol memantine (one of the main antidementia drugs in AD) at dose 20 mg/day was accompanied by cognitive defect stabilization. After two years of therapy acute severe decompensation related to hypoactive delirium due to respiratory infection was observed, which was followed by marked cognitive status deterioration. Daily dose of akatinol memantine was increased to 30 mg with subsequent restoration of baseline cognitive status. Possible mechanisms of akatinol memantine action and its effects in management of geriatric patients with AD including role in delirium therapy are discussed.