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.

Central nervous system medication use around hospitalization.

BACKGROUND: Central nervous system (CNS) medication use is common among older adults, yet the impact of hospitalizations on use remains unclear. This study details CNS medication use, discontinuations, and user profiles during hospitalization periods. METHODS: Retrospective cohort study using electronic health records on patients ≥65 years, from three hospitals (2018-2020), and prescribed a CNS medication around hospitalization (90 days prior to 90 days after). Latent class transitions analysis (LCTA) examined profiles of CNS medication class users across four time points (90 days prior, admission, discharge, 90 days after hospitalization). RESULTS: Among 4666 patients (mean age 74.3 ± 9.3 years; 63% female; 70% White; mean length of stay 4.6 ± 5.6 days (median 3.0 [2.0, 6.0]), the most commonly prescribed CNS medications were antidepressants (56%) and opioids (49%). Overall, 74% (n = 3446) of patients were persistent users of a CNS medication across all four time points; 7% (n = 388) had discontinuations during hospitalization, but of these, 64% (216/388) had new starts or restarts within 90 days after hospitalization. LCTA identified three profile groups: (1) low CNS medication users, 54%-60% of patients; (2) mental health medication users, 30%-36%; and (3) acute/chronic pain medication users, 9%-10%. Probability of staying in same group across the four time points was high (0.88-1.00). Transitioning to the low CNS medication use group was highest from admission to discharge (probability of 9% for pain medication users, 5% for mental health medication users). Female gender increased (OR 2.4, 95% CI 1.3-4.3), while chronic kidney disease lowered (OR 0.5, 0.2-0.9) the odds of transitioning to the low CNS medication use profile between admission and discharge. CONCLUSIONS: CNS medication use stays consistent around hospitalization, with discontinuation more likely between admission and discharge, especially among pain medication users. Further research on patient outcomes is needed to understand the benefits and harms of hospital deprescribing, particularly for medications requiring gradual tapering.

Diagnoses and Treatment of Behavioral and Psychological Symptoms of Dementia Among Racially and Ethnically Diverse Persons Living with Dementia.

Background: Behavioral and psychological symptoms of dementia (BPSD) and prescribed central nervous system (CNS) active drugs to treat them are prevalent among persons living with Alzheimer's disease and related dementias (PLWD) and lead to negative outcomes for PLWD and their caregivers. Yet, little is known about racial/ethnic disparities in diagnosis and use of drugs to treat BPSD. Objective: Quantify racial/ethnic disparities in BPSD diagnoses and CNS-active drug use among community-dwelling PLWD. Methods: We used a retrospective cohort of community-dwelling Medicare Fee-for-Service beneficiaries with dementia, continuously enrolled in Parts A, B and D, 2017-2019. Multivariate logistic models estimated rates of BPSD diagnosis and, conditional on diagnosis, CNS-active drug use. Results: Among PLWD, 67.1% had diagnoses of an affective, psychosis or hyperactivity symptom. White (68.3%) and Hispanic (63.9%) PLWD were most likely, Blacks (56.6%) and Asians (52.7%) least likely, to have diagnoses. Among PLWD with BPSD diagnoses, 78.6% took a CNS-active drug. Use was highest among whites (79.3%) and Hispanics (76.2%) and lowest among Blacks (70.8%) and Asians (69.3%). Racial/ethnic differences in affective disorders were pronounced, 56.8% of white PLWD diagnosed; Asians had the lowest rates (37.8%). Similar differences were found in use of antidepressants. Conclusions: BPSD diagnoses and CNS-active drug use were common in our study. Lower rates of BPSD diagnoses in non-white compared to white populations may indicate underdiagnosis in clinical settings of treatable conditions. Clinicians' review of prescriptions in this population to reduce poor outcomes is important as is informing care partners on the risks/benefits of using CNS-active drugs.

Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Recent Advances in the Development of Pyrimidine-based CNS Agents.

BACKGROUND: In the past few decades, considerable progress has been made in CNS drug discovery, and various new CNS agents have been developed. Pyrimidine is an important scaffold in the area of medicinal chemistry. Recently, pyrimidine-containing compounds have been successfully designed as potent CNS agents. Substantial research has been carried out on pyrimidine-bearing compounds to treat different disorders of CNS in various animal models. METHODS: Utilizing various databases, including Google Scholar, PubMed, Science Direct, and Web of Science, the literature review was conducted. The specifics of significant articles were discussed with an emphasis on the potency of pyrimidines derivatives possessing CNS activity. RESULTS: Recent papers indicating pyrimidine derivatives with CNS activity were incorporated into the manuscript. (46) to (50) papers included different pyrimidine derivatives as 5-HT agonist/antagonists, (62) to (67) as adenosine agonist/antagonist, (70) to (75) as anticonvulsant agents, (80) to (83) as cannabinoid receptor agonists, (102) to (103) as nicotinic and (110) as muscarinic receptor agonists. The remaining papers (113) to (114) represented pyrimidine-based molecular imaging agents. CONCLUSION: Pyrimidine and its derivatives have been studied in detail to evaluate their efficacy in overcoming multiple central nervous system disorders. The article covers the current updates on pyrimidine-based compounds as potent CNS and molecular imaging agents and will definitely provide a better platform for the development of potent pyrimidine-based CNS drugs in the near future.

Medicalização do sofrimento psíquico na Atenção Primária à Saúde em um município do interior do Ceará / Medicalization of psychic suffering in Primary Health Care in a small town in the state of Ceara, Brazil

Resumo Este trabalho objetiva discutir como o fenômeno da medicalização do sofrimento psíquico se apresenta no discurso e na prática dos profissionais da Atenção Primária à Saúde. Foram realizadas observações sistemáticas e entrevistas semidiretivas com sete trabalhadores do município de Iguatu, Ceará, Brasil. A análise dos dados foi feita através da Análise de Conteúdo, de Bardin. Os resultados apontaram para uma centralidade no uso de medicação para atender o sofrimento psíquico que chega às unidades de saúde. Os profissionais discorreram sobre o medicamento enquanto uma estratégia rápida e eficiente, que, em consonância com a literatura pesquisada, pode ser utilizada como um dispositivo de controle do sujeito em adoecimento psíquico. Considera-se possível mobilizar, junto aos profissionais, espaços de discussão que apontem para o cuidado da pessoa com sofrimento psíquico através do uso de tecnologias leves, como escuta, vínculo e diálogo.

Abstract This paper aims to discuss how the phenomenon of the medicalization of psychological distress appears in the discourse and practice of Primary Health Care professionals. Systematic observations and semi-directive interviews were conducted with seven workers in the city of Iguatu, Ceará, Brazil. Data analysis was performed using Bardin's Content Analysis. The results pointed to a centrality in the use of medication to attend the psychological suffering that reaches the health units. The professionals spoke about the medication as a quick and efficient strategy, which, in line with the researched literature, can be used as a device to control the subject in psychic illness. It is considered possible to mobilize discussion spaces with professionals that point to the care of people with psychological distress through the use of light technologies, such as listening, bonding and dialogue.Resumo: Este trabalho objetiva discutir como o fenômeno da medicalização do sofrimento psíquico se apresenta no discurso e na prática dos profissionais da Atenção Primária à Saúde. Foram realizadas observações sistemáticas e entrevistas semidiretivas com sete trabalhadores do município de Iguatu, Ceará, Brasil. A análise dos dados foi feita através da Análise de Conteúdo, de Bardin. Os resultados apontaram para uma centralidade no uso de medicação para atender o sofrimento psíquico que chega às unidades de saúde. Os profissionais discorreram sobre o medicamento enquanto uma estratégia rápida e eficiente, que, em consonância com a literatura pesquisada, pode ser utilizada como um dispositivo de controle do sujeito em adoecimento psíquico. Considera-se possível mobilizar, junto aos profissionais, espaços de discussão que apontem para o cuidado da pessoa com sofrimento psíquico através do uso de tecnologias leves, como escuta, vínculo e diálogo.

Recent Advancements in CNS Acting Drugs: A Step Towards End of Illness.

Progressive degeneration in the morphology and functions of neuronal cells leads to multifactorial pathogenesis conditions of oxidative stress, mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity, and neuro-inflammation to mediate heterogeneous types of neurodegenerative diseases, such as Epilepsy, Alzheimer's (AD) and Parkinson's (PD), more prominently among aging populations. In this editorial, complex mechanisms, challenges, and advancements made in the discovery of new neurotherapeutics, as well as designing approaches being adopted to fabricate brain-targeted delivery systems, are discussed.

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.

Modular synthesis of 2,4-diaminoanilines as CNS drug-like non-covalent inhibitors of asparagine endopeptidase.

Asparagine endopeptidase (AEP), also called legumain, is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Recent studies showed that it possesses δ-secretase activity and that it is implicated in numerous neurological diseases such as Alzheimer's disease (AD). Following evidence of aryl-morpholines as useful asparagine endopeptidase inhibitors, a series of morpholinoanilines with diverse substituents at ortho position were synthesized in view of improving the potency and scope of this molecular scaffold, allowing to identify ethyl 2-isonipecotate-4-morpholinoaniline possessing inhibition potency in the nanomolar range. CNS MPO (CNS MultiParameter Optimization) calculations revealed that most of the compounds developed in this work show physicochemical parameters in the desirable range for CNS drug candidates.

Coronavirus Disease 2019 (COVID-19) and Its Neuroinvasive Capacity: Is It Time for Melatonin?

The world faces an exceptional new public health concern caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), subsequently termed the coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO). Although the clinical symptoms mostly have been characterized, the scientific community still doesn´t know how SARS-CoV-2 successfully reaches and spreads throughout the central nervous system (CNS) inducing brain damage. The recent detection of SARS-CoV-2 in the cerebrospinal fluid (CSF) and in frontal lobe sections from postmortem examination has confirmed the presence of the virus in neural tissue. This finding reveals a new direction in the search for a neurotherapeutic strategy in the COVID-19 patients with underlying diseases. Here, we discuss the COVID-19 outbreak in a neuroinvasiveness context and suggest the therapeutic use of high doses of melatonin, which may favorably modulate the immune response and neuroinflammation caused by SARS-CoV-2. However, clinical trials elucidating the efficacy of melatonin in the prevention and clinical management in the COVID-19 patients should be actively encouraged.

Concomitant use of direct-acting antivirals (DAA) and central nervous system drugs in patients with hepatitis C virus infection. / Uso concomitante de antivirales de acción directa (AAD) y fármacos con acción sobre el sistema nervioso central: Consideraciones en el perfil actual del paciente con hepatitis C.

Our objective was to determine potential drug interactions (DI) between pangenotypic direct-acting antivirals (pDAA) and concomitant central nervous system (CNS) medication in patients with chronic hepatitis C virus (HCV). Transversal design. Patients aged ≥ 18 years on treatment with pDAA during 2017 were included. The variables collected were comorbidity, concomitant CNS medication and potential DI. The pDAA analyzed were a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) and c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Descriptive statistical analysis. We recruited 1,170 patients (mean age 60.1 years, 56.4% male). Mean concomitant drug use was 3.2 per patient/year. The percentages of potential / possible DI between the DAAs and the concomitant drugs on the CNS were: 2.7% contraindications, 11.3% significant and 4.2% weak. By pDAA, the percentages were: SOF/VEL (2.7%; 0.0%; 4.4%), GLE/GDP (2.7%; 26.5%; 1.6%) SOF/VEL/VOX (2.7%; 6.8%; 4.4%), respectively. Concomitant CNS medication was used in one third of HCV patients. It is important to select a pDAA with a low rate of potential DI to simplify treatment. SOF/VEL is a good alternative compared with the other pDAA studied, mainly due to the concomitant use of antipsychotics and analgesics.

El objetivo fue determinar las potenciales interacciones farmacológicas (IF) entre los antivirales de acción-directa pangenotípicos (AADp) y la medicación-concomitante sobre el sistema nervioso central (SNC) asociada a los pacientes portadores del virus de la hepatitis C crónica (VHC). Se realizó un diseño transversal. Se incluyeron pacientes ≥18 años en tratamiento con AADp durante el año 2017. Las variables recogidas fueron: comorbilidad, medicación-concomitante (SNC) y potenciales IF. Los AADp analizados fueron: a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) y c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Análisis-estadístico descriptivo. Se reclutaron 1.170 pacientes; edad-media de 60,1 años y el 56,4% varones. El promedio de medicamentos-concomitantes fue de 3,2 por paciente/año. El porcentaje de potenciales/posibles IF entre los AADp y los medicamentos-concomitantes sobre el SNC fueron: 2,7% contraindicaciones, 11,3% significativas y 4,2% débiles. En función de los AADp, estos porcentajes fueron los siguientes: SOF/VEL (2,7%; 0,0%; 4,4%), GLE/PIB (2,7%; 26,5%; 1,6%) y SOF/VEL/VOX (2,7%; 6,8%; 4,4%), respectivamente. Un tercio de los pacientes con VHC muestran un uso de medicación-concomitante de acción sobre el SNC. Será importante seleccionar un AADp que tenga una baja tasa de potenciales IF para simplificar el tratamiento. SOF/VEL se presenta como una buena alternativa en comparación con los AADp seleccionados, principalmente en el uso concomitante de antipsicóticos y analgésicos.

Middle ear myoclonus: Systematic review of results and complications for various treatment approaches.

OBJECTIVE: To perform a systematic review of the diagnosis and treatment of patients with pulsatile tinnitus secondary to middle ear myoclonus. DATABASES REVIEWED: PubMed, EMBASE, and Scopus. METHODS: A systematic review was performed using standardized methodology. Computerized and manual searches were performed to identify studies of all ages (patients) who had middle ear myoclonus (intervention). All study designs were assessed. Extracted data included demographics, clinical features, duration of followup as well as the diagnosis and reversibility of symptoms with medical or surgical intervention. Studies were included if they included subjects with middle ear myoclonus. Exclusion criteria included letters/commentaries and reviews. RESULTS: Twenty articles representing 115 subjects with middle ear myoclonus were included. The mean age was 29.7 (range 6-67). The follow-up period ranged from 5 weeks to 36 months. Primary treatment consists of medical therapy utilising anxiolytics, antiepileptics, botulinum toxin and surgical treatment involving division of middle ear muscular tendon(s). In total, 60 patients underwent middle ear muscular tenotomies, with division of both stapedius and tensor tympani tendons being the most prevalent (88%). Limitations in the data arose from study design, related comorbidities such as palatal myoclonus, and concomitant drug administration. No study provided any objective criteria to diagnose this condition or evaluate post-treatment outcome. CONCLUSION: Middle ear myoclonus is an entity that is poorly assessed in the literature. There is a lack of consensus regarding the criteria and strategies for both diagnosing and treating this condition. Although level of evidence of current studies remains modest, it is felt that a stepwise approach is deemed best, with therapeutic decisions being made on an individual basis, evaluating each patient's specific circumstances and priorities.