Neonatal therapy after maternal central neurotropic drug exposure-a retrospective cohort study.

OBJECTIVE: Evaluation of neonatal morbidity after maternal central neurotropic drug exposure. METHODS: Retrospective single-center level-III neonatology cohort analysis of neonates after CND from 2018 to 2021. Control group of neonates born to mothers without CND cared for at the maternity ward. RESULTS: Significantly more frequent therapy need of neonates with CND [OR 23 (95% CI: 7.8-62); RR 14 (95% CI: 5.4-37); p < 0.01]. Neonates after CND had lower Apgar-scores LM 1 [CND 8.1; CG 8.6; p < 0.05]; LM 5 [CND 9; CG 9.7; p < 0.01]; LM 10 [CND 9.6; CG 9.9; p < 0.05]. The first symptom occurred in 95.35% within 24 h (mean: 3.3 h). CND group showed significantly more often preterm delivery [OR 3.5; RR 3.2; p < 0.05], and especially cumulative multiple symptoms [OR 9.4; RR 6.6; p < 0.01] but no correlation to multiple maternal medication use (p = 0.3). CONCLUSIONS: Neonates exposed to CND are at increased risk for postnatal therapy, often due to multiple symptoms. Neonates should be continuously monitored for at least 24 h.

Longitudinal effects of using and discontinuing central nervous system medications on cognitive functioning.

PURPOSE: To investigate the longitudinal effect of using and discontinuing central nervous system (CNS) medications on cognitive performance. METHODS: Using longitudinal cognitive data from population representative adults aged 25-100 years (N = 2188) from four test waves 5 years apart, we investigated both the link between use of CNS medications (opioids, anxiolytics, hypnotics and sedatives) on cognitive task performance (episodic memory, semantic memory, visuospatial ability) across 15 years, and the effect of discontinuing these medications in linear mixed effects models. RESULTS: We found that opioid use was associated with decline in visuospatial ability whereas using anxiolytics, hypnotics and sedatives was not associated with cognitive decline over 15 years. A link between drug discontinuation and cognitive improvement was seen for opioids as well as for anxiolytics, hypnotics and sedatives. CONCLUSIONS: Although our results may be confounded by subjacent conditions, they suggest that long-term use of CNS medications may have domain-specific negative effects on cognitive performance over time, whereas the discontinuation of these medications may partly reverse these effects. These results open up for future studies that address subjacent conditions on cognition to develop a more complete understanding of the cognitive effects of CNS medications.

Growing Role of Gabapentin in Opioid-Related Overdoses Highlights Misuse Potential and Off-label Prescribing Practices.

This Medical News article discusses a trend of gabapentin misuse and harms, including fatal overdoses.

Short-Term Risk of Unintentional Poisoning After New Initiation of Central Nervous System Medications in Swedish Older Adults: A Register-Based Case-Crossover Study.

INTRODUCTION: Medications acting on the central nervous system (CNS) are common causes of medication-related unintentional poisoning. Little is known about the short-term effects of CNS medications on unintentional poisoning. OBJECTIVE: This study aims to determine the short-term association between newly prescribed CNS drugs and unintentional poisoning. METHODS: We conducted a register-based case-crossover study of 9354 patients (age ≥ 50 years) with first-time hospitalization for unintentional poisoning in Sweden between 1 July, 2006 and 30 September, 2018. Newly initiated CNS medication was identified based on dispensations from the Swedish Prescribed Drug Register during 28 days prior to the unintentional poisoning event and compared with dispensations during an equally long control period. Conditional logistic regression was used to estimate the odds ratio and 95% confidence intervals. RESULTS: After a newly initiated CNS treatment, we found an increased risk of unintentional poisoning during the following 2 weeks with an odds ratio (95%) being 2.52 (1.98-3.21) and 1.47 (1.08-2.00) for the first and second week, respectively. The risk was elevated in all sub-groups but to a different degree with odds ratio ranges of 1.73-2.47 by age, 1.91-2.21 by sex, 1.40-2.30 by Charlson Comorbidity Index, 2.00-2.07 by neuropsychiatric comorbidity, and 1.63-2.82 by number of other medications. CONCLUSIONS: The risk of unintentional poisoning doubles in 2 weeks following a new initiation of CNS drugs and the risk is increased across a range of population groups. Clinicians should carefully monitor signs of poisoning after such initiation among not only multimorbid older adults but also those with less comorbidity and polypharmacy.

De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

Change in central nervous system-active medication use following fall-related injury in older adults.

BACKGROUND: Central nervous system (CNS)-active medication use is an important modifiable risk factor for falls in older adults. A fall-related injury should prompt providers to evaluate and reduce CNS-active medications to prevent recurrent falls. We evaluated change in CNS-active medications up to 12 months following a fall-related injury in community-dwelling older adults compared with a matched cohort without fall-related injury. METHODS: Participants were from the Adult Changes in Thought study conducted at Kaiser Permanente Washington. Fall-related injury codes between 1994 and 2014 defined index encounters in participants with no evidence of such injuries in the preceding year. We matched each fall-related injury index encounter with up to five randomly selected clinical encounters from participants without injury. Using automated pharmacy data, we estimated the average change in CNS-active medication use at 3, 6, and 12 months post-index according to the presence or absence of CNS-active medication use before index. RESULTS: One thousand five hundred sixteen participants with fall-related injury index encounters (449 CNS-active users, 1067 nonusers) were matched to 7014 index encounters from people without fall-related injuries (1751 users, 5236 nonusers). Among CNS-active users at the index encounter, those with fall-related injury had an average decrease in standard daily doses (SDDs) at 12 months (-0.43; 95% CI: -0.63 to -0.23), and those without injury had a greater (p = 0.047) average decrease (-0.66; 95% CI: -0.78 to -0.55). Among nonusers at index, those with fall-related injury had a smaller increase than those without injury (+0.17, 95% CI: +0.13 to +0.21, vs. +0.24, 95% CI: +0.20 to +0.28, p = 0.005). CONCLUSIONS: The differences in CNS-active medication use change over 12 months between those with and without fall-related injury were small and unlikely to be clinically significant. These results suggest that fall risk-increasing drug use is not reduced following a fall-related injury, thus opportunities exist to reduce CNS-active medications, a potentially modifiable risk factor for falls.

Relationship between use of sleep medication and accidental falls during hospitalization.

Falls are common in elderly patients, and prevention of fall is important for safety and for reduction of health care costs. Sleep medications are among many potential causes of fall. In this study, we examined relationship of sleep medication with fall from January 2017 to December 2017. 726 falls occurred in 442 patients, and the average age at the time of fall was 60.7 ± 23.8 years. Fall was most common in patients with neurological disease, followed by gastroenterological, ophthalmological, respiratory, and orthopedic conditions. Sleep medication was used in 223 falls (31%). Fall occurred at all times of day, but with a different distribution in patients with and without use of sleep medication. Thus, the rate of falls from 22:00 to 6:00 was significantly higher in patients using sleep medication (62% vs. 18%, p<0.01). There was also a significantly higher rate of multiple falls in patient using sleep medication (p<0.01). Zolpidem (25%, n=63), a non-benzodiazepine, was the most frequently used sleep medication, followed by brotizolam (16%, n=41) and etizolam (13%, n=32), which are both benzodiazepines. Multiple falls from 22:00 to 6:00 occurred significantly more frequently in patients using ≥2 types of sleep medications compared to one (53% vs. 17%, p<0.01). Taking multiple sleeping pills makes it easier to fall, and even drugs with a short half-life, which are considered to be safe, can cause falls at night in elderly patients. The results of this study show that careful selection of sleep medications is required to prevent fall in elderly patients.

Risk of fall-related injury and all-cause hospitalization of select concomitant central nervous system medication prescribing in older adult persistent opioid users: A case-time-control analysis.

BACKGROUND: Concomitant use of central nervous system (CNS) medications frequently occurs in older adults with persistent opioid use. The risks of adverse outcomes associated with combinations of opioids, sedative hypnotics, or skeletal muscle relaxants have not been sufficiently described in this population. OBJECTIVE: To compare the overall and incremental risk of (1) fall-related injury and (2) all-cause hospitalization associated with sedative hypnotics and skeletal muscle relaxants among older persistent opioid users. METHODS: A case-time-control study was conducted using administrative claims of adults ages ≥66 years with a history of persistent (≥90 days) opioid use. Cases included those with first (1) emergency department, hospital, or outpatient visit for a fall-related injury, or (2) all-cause hospitalization. Exposure to CNS medications prior to the case event versus earlier periods, and the risk associated with CNS drug class combinations and sequence of use, was estimated using conditional logistic regression, adjusted for time trends and time-varying covariates. RESULTS: Among 140,101 older persistent opioid users, 20,723 experienced fall-related injury and 39,444 were hospitalized during follow-up. Skeletal muscle relaxant use was associated with an increased risk of fall-related injury (Odds ratio [OR] 1.28) and all-cause hospitalization (OR 1.11). Statistically significant associations were observed for the joint effects of interactions involving skeletal muscle relaxants on fall-related injury (with opioid: OR 1.25; with sedative hypnotic: OR 1.24), and interactions involving opioids on all-cause hospitalization (with sedative hypnotic: OR 1.10; with skeletal muscle relaxant: OR 1.17). The addition of a skeletal muscle relaxant to an opioid regimen was associated with a 25% increased risk of fall-related injury. Additions of other CNS medications did not have apparent incremental effects on the risk of all-cause hospitalization. CONCLUSION: The excess risks of fall-related injury and hospitalization associated with various combinations of CNS medications among older persistent opioid users should be considered in therapeutic decision making. Further research is needed to confirm these findings.

Increasing diversion of prescribed benzodiazepines and Z-drugs to new psychoactive substances.

ABSTRACT: Over the last few years reports have indicated an increase in the number, type and availability of new psychoactive substances belonging to the benzodiazepine class. These molecules may pose high risks to users, since the majority have never undergone clinical trials or tests so their pharmacology and toxicology is largely unknown. However the new drug scenario emerging from the COVID-19 global pandemic seems to play a role in increasing the diversion of prescribed benzodiazepines and Z-drug. A brief presentation of this phenomenon is hereby presented. The awareness and response activities at national and international levels related to this issue should be enforced.

Potentially inappropriate prescriptions to Brazilian older people with Alzheimer disease: A cross-sectional study.

ABSTRACT: Older adults are the leading users of medications, where this can be associated with a high number of potentially inappropriate medications (PIMs) and of potentially inappropriate prescribing (PIP) and consequent harm to health. No Brazilian study evaluating potentially inappropriate prescribing in older patients with Alzheimer's disease (AD) was found. This study determined and analyzed the prevalence of PIP and PIM prescribed for older people with AD.A cross-sectional study was carried out at the Specialty Drugs Pharmacy in the city of Sorocaba, São Paulo State, Brazil. The MEDEX system provided the register in older people with AD and data were collected during interviews with patients and/or caregivers between June and September 2017. The PIMs were identified according to the 2019 Beers Criteria. The association between PIMs and independent variables was analyzed by Poisson regression.This study included 234 older patients with AD. The prevalence of PIP prescribed was 66.7% (n = 156). Of the 1073 medications prescribed, 30.5% (n = 327) were inappropriate with most affecting the central nervous system or cardiovascular, particularly quetiapine (12.8%) and acetylsalicylic acid (11.6%), respectively. Around 45.2% of the PIMs should be avoided in older people, especially sertraline (14.2%) and clonazepam (7.4%). After adjusted analysis, the PIMs were associated with the diagnosis of depression (P = 0.010) and the number of comorbidities (P = 0.005).There was a high number of PIMs among older people, a substantial number of which should have been avoided in this population. Health care professionals can apply these findings to improve safety in the use of medications for treating patients with AD.

Novel test strategies for in vitro seizure liability assessment.

INTRODUCTION: The increasing incidence of mental illnesses and neurodegenerative diseases results in a high demand for drugs targeting the central nervous system (CNS). These drugs easily reach the CNS, have a high affinity for CNS targets, and are prone to cause seizures as an adverse drug reaction. Current seizure liability assessment heavily depends on in vivo or ex vivo animal models and is therefore ethically debated, labor intensive, expensive, and not always predictive for human risk. AREAS COVERED: The demand for CNS drugs urges the development of alternative safety assessment strategies. Yet, the complexity of the CNS hampers reliable detection of compound-induced seizures. This review provides an overview of the requirements of in vitro seizure liability assays and highlights recent advances, including micro-electrode array (MEA) recordings using rodent and human cell models. EXPERT OPINION: Successful and cost-effective replacement of in vivo and ex vivo models for seizure liability screening can reduce animal use for drug development, while increasing the predictive value of the assays, particularly if human cell models are used. However, these novel test strategies require further validation and standardization as well as additional refinements to better mimic the human in vivo situation and increase their predictive value.

Neuropharmacological potentials of ß-carboline alkaloids for neuropsychiatric disorders.

Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. ß-Carboline (ßC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the ßC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that ßC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.

Identification of Optimal Measures of Human Abuse Potential: A Post Hoc Assessment of 19 Studies.

BACKGROUND: Human abuse potential studies include multiple measures to assess the subjective effects of central nervous system-active drugs. In this retrospective analysis, measurement properties of commonly used measures were assessed, and factor analysis was conducted to identify a core battery of measures. METHODS: Measures of positive, negative and other effects, for example, bipolar "at-the-moment" Drug Liking visual analog scale (VAS), were derived for active controls and placebo from 19 studies in recreational drug users (N = 570). Distribution, placebo response, variability, convergent/discriminant validity, parameter effect sizes (eg, maximum effect [Emax], time-averaged area under the effect curve), and predictive validity were evaluated. A factor analysis was conducted with 9 studies. RESULTS: Most parameters were not normally distributed. Bipolar VAS exhibited the lowest variability. Drug Liking VAS Emax was very sensitive, showed large effect sizes (>1.0), and was moderately to strongly correlated with Emax of other positive effects measures (r > 0.5), but weaker with less specific scales (eg, high, Any Effects VAS); time-averaged area under the effect curve showed higher variability and lower effect sizes. Maximum effect at any dose (EmaxD) was significantly correlated with Emax across all selected measures and showed higher effect sizes. In the overall factor analysis, factors could be categorized into positive effects/euphoria (77% of variance), negative effects (17.9%), and pharmacologic effects (5%). For predictive validity, effect sizes for Drug Liking VAS Emax/EmaxD were moderately correlated with postmarket adverse events related to abuse (R = 0.52). CONCLUSIONS: A core battery of 7 subjective measures was proposed, with additional measures added based on pharmacologic effects.

Botulinum Toxin and Neuronal Regeneration after Traumatic Injury of Central and Peripheral Nervous System.

Botulinum neurotoxins (BoNTs) are toxins produced by the bacteria Clostridiumbotulinum, the causing agent for botulism, in different serotypes, seven of which (A-G) are well characterized, while others, such as H or FA, are still debated. BoNTs exert their action by blocking SNARE (soluble N-ethylmale-imide-sensitive factor-attachment protein receptors) complex formation and vesicle release from the neuronal terminal through the specific cleavage of SNARE proteins. The action of BoNTs at the neuromuscular junction has been extensively investigated and knowledge gained in this field has set the foundation for the use of these toxins in a variety of human pathologies characterized by excessive muscle contractions. In parallel, BoNTs became a cosmetic drug due to its power to ward off facial wrinkles following the activity of the mimic muscles. Successively, BoNTs became therapeutic agents that have proven to be successful in the treatment of different neurological disorders, with new indications emerging or being approved each year. In particular, BoNT/A became the treatment of excellence not only for muscle hyperactivity conditions, such as dystonia and spasticity, but also to reduce pain in a series of painful states, such as neuropathic pain, lumbar and myofascial pain, and to treat various dysfunctions of the urinary bladder. This review summarizes recent experimental findings on the potential efficacy of BoNTs in favoring nerve regeneration after traumatic injury in the peripheral nervous system, such as the injury of peripheral nerves, like sciatic nerve, and in the central nervous system, such as spinal cord injury.

Polypharmacy in patients with epilepsy: A nationally representative cross-sectional study.

OBJECTIVE: The objective of the study was to characterize the prevalence of polypharmacy and central nervous system (CNS)-acting medications in patients with epilepsy, and particular types of medications. METHODS: This was a retrospective cross-sectional study using data from the nationally representative National Health and Nutrition Examination Survey (NHANES). We included patients who reported taking at least one prescription medication in order to treat seizures or epilepsy during NHANES survey years 2013-2016. We assessed the number and types of drugs and predictors of total number of medications using a negative binomial regression. We then assessed prevalence of polypharmacy (≥5 medications), CNS polypharmacy (≥3 CNS-acting medications) and additional CNS-acting medications, and drugs that lower the seizure threshold (i.e., bupropion and tramadol), and extrapolated prevalence to estimated affected US population. RESULTS: The NHANES contained 20,146 participants, of whom 135 reported taking ≥1 antiseizure medication (ASM) for seizures or epilepsy representing 2,399,520 US citizens using NHANES's sampling frame. Patients reported taking a mean 5.3 (95% confidence interval (CI): 4.3-6.3) prescription medications. Adjusting for race, sex, and uninsurance, both age and number of chronic conditions predicted increased number of medications (incident rate ratio (IRR) per decade: 1.16, 95% CI: 1.04-1.28; IRR per chronic condition: 1.19, 95% CI: 1.11-1.27). Polypharmacy was reported by 47% (95% CI: 38%-57%) of patients, CNS polypharmacy by 34% (23%-47%), benzodiazepine use by 21% (14%-30%), opioid use by 16% (11%-24%), benzodiazepine plus opioid use by 6% (3%-14%), and 6% (2%-15%) reported a drug that lowers the seizure threshold. Twelve percent (7%-20%) took an opioid with either a benzodiazepine or gabapentinoid. CONCLUSIONS: Polypharmacy is common in patients with epilepsy. Patients taking ASMs frequently reported also taking other CNS-acting medications (i.e., opioids, benzodiazepines, seizure threshold-lowering medications), and medication combinations with black box warnings. Central nervous system polypharmacy poses health risks. Future research is needed to explore drivers of polypharmacy and strategies to help mitigate potentially harmful prescription use in this high-risk population.

Therapeutic potential of pharmacological agents targeting TRP channels in CNS disorders.

Central nervous system (CNS) disorders like Alzheimer's disease (AD), Parkinson disease (PD), stroke, epilepsy, depression, and bipolar disorder have a high impact on both medical and social problems due to the surge in their prevalence. All of these neuronal disorders share some common etiologies including disruption of Ca2+ homeostasis and accumulation of misfolded proteins. These misfolded proteins further disrupt the intracellular Ca2+ homeostasis by disrupting the activity of several ion channels including transient receptor potential (TRP) channels. TRP channel families include non-selective Ca2+ permeable channels, which act as cellular sensors activated by various physio-chemical stimuli, exogenous, and endogenous ligands responsible for maintaining the intracellular Ca2+ homeostasis. TRP channels are abundantly expressed in the neuronal cells and disturbance in their activity leads to various neuronal diseases. Under the pathological conditions when the activity of TRP channels is perturbed, there is a disruption of the neuronal homeostasis through increased inflammatory response, generation of reactive oxygen species, and mitochondrial dysfunction. Therefore, there is a potential of pharmacological interventions targeting TRP channels in CNS disorders. This review focuses on the role of TRP channels in neurological diseases; also, we have highlighted the current insights into the pharmacological modulators targeting TRP channels.

In vivo near-infrared fluorescent optical imaging for CNS drug discovery.

INTRODUCTION: In vivo imaging technologies have become integral and essential component of drug discovery, development, and clinical assessment for central nervous system (CNS) diseases. Near-infrared (NIR) fluorescence imaging in the range of 650-950 nm is widely used for pre-clinical in vivo imaging studies. The recent expansion of NIR imaging into the shortwave infrared (SWIR, 1000-1700 nm) window enabled improvements in tissue penetration and resolution required for anatomical, dynamic, and molecular neuroimaging with high potential for clinical translation. AREAS COVERED: This review focuses on the latest progress in near-infrared (NIR)-fluorescent optical imaging modalities with an emphasis on the SWIR window. Advantages and challenges in developing novel organic and inorganic SWIR emitters, with special attention to their toxicology and pharmacology, are discussed. Examples of their application in preclinical imaging of brain function and pathology provide a platform to assess the potential for their clinical translation. EXPERT OPINION: Propelled through concomitant technological advancements in imaging instrumentation, algorithms and new SWIR emitters, SWIR imaging has addressed key barriers to optical imaging modalities used in pre-clinical studies addressing the CNS. Development of biocompatible SWIR emitters and adoption of SWIR into multi-modal imaging modalities promise to rapidly advance optical imaging into translational studies and clinical applications.

Interrupted time series analysis to assess changes in prescription filling around conception and implications for exposure misclassification.

PURPOSE: Medication exposures in pregnancy are often defined by one or more prescription fills. Harmful effects could be underestimated if rapid discontinuation of use after pregnancy recognition is common. We used conception, a critical biological period, as an intervention in a novel application of interrupted time series analysis (ITSA). METHODS: Among 645 049 pregnancies from the Medical Birth Registry (2005-2015) linked to the Norwegian Prescription Database, we modeled the total number of prescription fills in the 12 weeks before and after estimated conception date with ITSA. We examined psychostimulants, antidepressants, antipsychotics, and antiepileptics (AEDs; separated by use for epilepsy or other indications). We used relative measures (%) to compare model coefficients. We also compared number of pregnancies defined as exposed when the earliest fill considered was 30 days before the last menstrual period (LMP -30 days), LMP, or estimated conception date (LMP +14 days). RESULTS: We observed a sudden decline in prescription fills from 2 weeks after conception and decreasing fills thereafter for psychostimulants, antidepressants, AEDs for other indications, and antipsychotics excluding incident users. Fills for AEDs for epilepsy did not fall after conception. Only 77% of pregnancies with fills for psychostimulants from LMP and 58% with fills from LMP -30 days had fills from conception. Similar figures for AEDs for epilepsy were 99% and 96%. CONCLUSIONS: This application shows that ITSA can help researchers understand rapid changes in patient behavior around conception that have consequences for exposure misclassification in pregnancy drug safety studies. ITSA results can help pharmacoepidemiologists guide study exposure definitions.