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Femoral blood concentrations are usually used in postmortem toxicology to assess possible toxic effects of drugs. This includes QT-prolongation and other cardiac dysrhythmia, which could have been the cause of death. However, blood concentration is only a surrogate for the active site concentration, and therefore cardiac tissue concentration may provide a more accurate toxicological interpretation. Thus, cardiac tissue and femoral and cardiac blood concentrations were examined for eight frequently used QT-prolonging drugs (QTD) and their metabolites in a mentally ill population. In total, 180 cases were included from the Danish autopsy-based forensic study SURVIVE. The concentrations were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry utilizing stable isotopically labeled internal standards. The results showed that the cardiac tissue concentrations were significantly higher compared to femoral and cardiac blood concentrations, with two exceptions. The median cardiac tissue-to-femoral blood concentration ratio (Kb) ranged from 2.2 (venlafaxine) to 15 (nortriptyline). The inter-individual fold difference between the minimum and maximum Kb ranged from 2.6-fold (Z-hydroxynortriptyline) to 61 (venlafaxine). For 12 compounds, postmortem redistribution appeared to be minimal, whereas four compounds displayed some degree of postmortem redistribution. Citalopram and quetiapine were selected for in-depth analysis of the relation between the toxicological interpretation and femoral blood/cardiac tissue concentrations. Within this dataset, citalopram displayed a wide overlap in cardiac tissue concentrations (~50%) between non-toxic and toxic citalopram cases, as estimated from femoral blood concentrations. In contrast, quetiapine displayed no overlap in cardiac tissue concentrations between non-toxic and toxic quetiapine cases based on femoral blood concentrations. The implication of the citalopram finding is that possible intoxications can be overlooked when only considering femoral blood concentrations. Based on the present findings, non-toxic cardiac tissue 10th-90th percentile concentration ranges were estimated for citalopram (0.93-4.4 mg/kg) and quetiapine (0.0073-0.60 mg/kg).

Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB, direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors, oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or parenchyma overcomes this obstacle. Clinical experience with direct CNS administration of small molecule therapies suggests that this approach may be efficacious for the treatment of neurodegenerative disorders using biological therapies. Risks of administration into the brain tissue or cerebrospinal fluid include local damage from implantation of the delivery system and/or administration of the therapeutic and reactions affecting the CNS. Preclinical safety studies on CNS administered compounds must differentiate between the effects of the test article, the delivery device, and/or the vehicle, and assess exacerbations of reactions due to combinations of effects. Animal models characterized for safety assessment of CNS administered therapeutics have enabled human trials, but interpretation can be challenging. This manuscript outlines the challenges of preclinical intrathecal/intracerebroventricular/intraparenchymal studies, evaluation of results, considerations for special endpoints, and translation of preclinical findings to enable first-in-human trials. Recommendations will be made based on the authors' collective experience with conducting these studies to enable clinical development of CNS-administered biologics., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: To shorten the time required to bring new treatments to clinics, recent efforts have focused on repurposing existing Food and Drug Administration (FDA)-approved drugs with established safety data for new indications. We hypothesized that adverse effect profiles might aid in prioritizing compounds for investigation in central nervous system (CNS) applications by providing an indication of their abilities to cross the blood-brain barrier., Methods: Data were drawn from an investigation of similarity of adverse effect profiles, utilizing pre- and post-marketing data. A panel of known CNS-active drugs was utilized to estimate aggregate similarity profiles for all other FDA drugs in the database. Permutations were used to test whether similarities for any given drug exceeded that expected under the null hypothesis. To estimate the performance of algorithms using such profiles, manually-curated lists of known CNS-active and -inactive medications were classified using logistic regression. Algorithms with and without this similarity data were compared for prediction of CNS penetrance., Results: Models incorporating adverse effect similarity data exhibited greater discrimination of brain-penetrant and non-penetrant drugs than models without this data. A visualization tool was developed to allow any medication to be evaluated for adverse effect similarity to the CNS panel or a custom panel., Conclusions: Consideration of adverse effect profiles allows in silico prioritization of compounds for follow-up investigation for CNS indications. In concert with chemical screening approaches, this may accelerate repurposing efforts for putative CNS-active medications., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Introduction: drugs acting on the central nervous system (CNS) increase falls risk. Most data on CNS drugs and falls are in women/mixed-sex populations. This study assessed the relationship between CNS drugs and falls in men aged 60-75 years., Methods: a questionnaire was sent to randomly selected Danish men aged 60-75 years. Cross-sectional data on CNS drugs and falls in the previous year were available for 4,696 men. Logistic regression investigated the relationship between falls and CNS drugs., Results: the median age was 66.3 (IQR = 63.1-70.0) years; 21.7% were fallers. The following were associated with fallers (OR; 95% CI): opiates (2.4; 1.5-3.7), other analgesics (1.7; 1.4-2.1), antiepileptics (2.8; 1.5-5.1), antidepressants (2.8; 1.9-4.1) and anxiolytics/hypnotics (1.5; 0.9-2.6). Effects of opiates interacted strongly and significantly with age, with a marked association with falls in the older half of the subjects only. No significant associations were found between antipsychotics and fallers. Selective serotonin reuptake inhibitors and tricyclics were significantly associated with fallers (3.1; 2.0-5.0 and 2.2; 1.0-4.7, respectively)., Conclusion: several CNS drug classes are associated with an approximately 2-3-fold increase risk of falls in men aged 60-75 years randomly selected from the population. Further longitudinal data are now required to confirm and further investigate the role of CNS drugs in falls causation in men.

Purpose: The association between fall risk and inpatient medications was evaluated., Methods: A retrospective, case-control study was performed to compare the medication use of patients sustaining at least one fall during hospitalization (case group) with a control group of patients who did not fall. Data were collected from medical records and generated reports. A fall was defined by the hospital as an event in which the patient comes to rest on the floor from a lying, standing, or sitting position. Adult patients (≥18 years of age) admitted between January 1 and December 31, 2006, experiencing a fall at least 48 hours after hospital admission were included in the case group. Each case was matched with one control by age (within five years), sex, admission date (within 30 days), patient care unit, and length of stay. Medications administered within 48 hours before the fall for the case group or designated fall date and time for the control group were documented., Results: Of the 414 documented fall events, 209 patients met the inclusion criteria. Of those patients, 96 matched control patients on all criteria. Significantly more case patients received a greater number of central nervous system (CNS) agents compared with matched control patients (p = 0.017). There was no statistically significant difference in the number of medications from all other drug classes or the total number of medications received by the groups., Conclusion: In a sample of hospitalized patients, CNS agents were significantly associated with falls.

Objectives: To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, ≥ 50 years or <50 years., Methods: All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database., Results: Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥ 50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups., Conclusions: The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and response.

Cognition has become increasingly important as an outcome measure in studies of medication. Traditional neuropsychological assessment is limited in its ability to detect subtle, medication-related changes and it is not suitable for the rapid serial assessment required in most clinical trials. Thus, investigators have turned to computerized neuropsychological assessment for its repeatability, sensitivity to subtle cognitive changes, and ease of administration. The automated neuropsychological assessment metrics (ANAM) is one such computerized battery that has been used to measure the effects of numerous CNS-active drugs. This paper is an exhaustive review of studies that have used ANAM to measure cognitive changes associated with pharmacological treatments. The benefits and limitations of using ANAM in clinical trials are discussed.

The potential use of weapons of mass destruction has recently become a real threat even in the areas of ongoing armed conflicts. Mass casualty victims can suffer from psychological and physical trauma. The exposure of physically injured patients to a toxic substance, in a scenario of mass injury, has recently gained major attention among planners of future protocols for emergency medical services. Because rapid deterioration and multiorgan involvement are to be expected after physical injuries, proper organization and complex but efficient acute medical care systems must be organized and deployed to ensure a maximal number of saved lives. These victims will inevitably require urgent surgical intervention and prolonged perioperative care. Understanding the interdependence between the toxic and traumatic occurrences and the drugs used to prevent or treat nerve agent intoxication (pyridostigmine bromide, a reversible inhibitor of acetylcholinesterase; atropine, a muscarinic receptor antagonist that is one of the on-site, first aid, pharmacological resuscitation drugs; and oxime-like pralidoxime chloride or obidoxime chloride, acetylcholinesterase reactivators) is vital. In addition, the administration of anesthesia and emergency surgery pose further unpredictable threats to the central nervous system, the cardiovascular system, and respiratory function, all of which may be compromised after chemical intoxication and physical trauma. It is noteworthy that information concerning the effects of nerve agent intoxication among human subjects is derived largely from reports of incidents of intentional terrorist attacks or of accidental exposure to organophosphate pesticides, compounds that are chemically related to nerve agents.

Purpose: Medication errors identified through solicited error reports in general medicine and specialty units of a major tertiary care teaching hospital were studied to identify prevalent patterns and causes., Methods: Medication error reports by a multidisciplinary team of eight clinicians at adult medical and surgical, hematology and oncology, bone marrow transplantation, and medical and cardiac intensive care units were collected prospectively over a three-month period. The reports were validated in terms of clinical significance, causality, and true presence of an error by two independent reviewers. Cluster analysis of valid reports (reports accepted by both reviewers) was used to identify prominent error patterns., Results: Of 321 medication error reports, 240 were included in the analysis. Of these, 95 represented manifested errors and the rest near misses (not manifested [94] or averted [51]). Most manifested errors involved uncontrolled infections associated with prescribed underdoses of antiinfectives (23%), renal failure associated with prescribed overdoses of antiinfectives (4%), central-nervous-system drug intoxication following prescribed overdoses (4%), or uncontrolled pain associated with prescribed underdoses (4%). Most errors were initiated during prescribing (72%) and were associated with deficits in pharmacotherapy knowledge (39%) or with failure to consider critical patient information (18%). Errors initiated during dispensing and administration were mostly associated with performance deficits (e.g., accidental slips and lapses)., Conclusion: A limited number of prevalent medication-error patterns described more than half of all reported errors in a hospital and suggested excellent areas for quality improvement. Error causes varied with the node of the medication-use process where they arose and suggested the need for tailored interventions to improve clinicians' performance.

Drugs have been associated with the development of delirium in the elderly. Successful treatment of delirium depends on identifying the reversible contributing factors, and drugs are the most common reversible cause of delirium. Anticholinergic medications, benzodiazepines, and narcotics in high doses are common causes of drug induced delirium. This article provides an approach for clinicians to prevent, recognise, and manage drug induced delirium. It also reviews the mechanisms for this condition, especially the neurotransmitter imbalances involving acetylcholine, dopamine, and gamma aminobutyric acid and discusses the age related changes that may contribute to altered pharmacological effects which have a role in delirium. Specific interventions for high risk elderly with the goal of preventing drug induced delirium are discussed.

Correspondence analysis (CA) and some of its uses in pharmacy practice are described. CA is a multivariate and graphic form of exploratory data analysis that reduces a multidimensional contingency table to a two-dimensional plot with minimal loss of information. An exploratory association between medication use and the number and severity of falls among the elderly living at home is used to illustrate the process of CA. Row profiles are constructed by dividing the count data in each cell by the total of the corresponding row, converting frequency data into relative frequencies. A graph of the data can be made by recalculating the frequencies to illustrate how the data might appear in a three-dimensional space with the axes defined by the three categories of falling (minimum, moderate, and major). For example, the number of patients using central nervous system (CNS) agents is plotted using the relative frequencies as vectors to locate a position in the three-dimensional space. All drug profiles and the average profile will lie exactly in a triangular plane defined by the terminal points of each axis. In this manner, data with three dimensions can be projected onto a two-dimensional space. Transferring the vectors named by pharmacologic class onto the plot requires creating two axes that cross at a common point or the origin. This point locates the average profile and defines an important reference for making comparisons. CA revealed that CNS agents may be associated with moderate to major falls, psychotherapeutic agents with moderate falls, and anticoagulants with moderate to minimum falls. CA has widespread uses in pharmacy practice. It can identify patients at risk for serious but preventable drug-related complications, enabling pharmacists to allocate pharmacy resources to the areas in most need and suggest hypotheses for future research. Clinicians can also use CA to analyze vast amounts of patient-related data to uncover hard-to-detect associations. The use of CA in pharmacy practice will allow new strategies for improved patient care to be more readily appreciated and implemented.

In a study of 843 independent-living men and women aged between 60 and 87 in Perth, Western Australia, stepwise multiple regression, after correction for initial levels of systolic blood pressure, showed that postural fall in systolic blood pressure was positively related to alcohol intake of more than 20 ml/day, the use of sleeping tablets and higher levels of anxiety on the Spielberger state-trait scale, and negatively related to body mass index. Postural fall in blood pressure was not significantly related to treatment for hypertension, age, sex, patterns of usual physical activity, tea or coffee drinking, or the diagnosis of diabetes mellitus. This analysis is the first to examine the relationship between lifestyle factors and the magnitude of the fall in systolic blood pressure on standing after adjustment for the association between the change in a variable and its initial level. Our analysis suggests the need for further study of the possible role of lifestyle factors such as the use of sleeping tablets and alcohol in postural hypotension in the elderly.