Paracetamol orodispersible tablets: a risk for severe poisoning in children?

Purpose: Childhood paracetamol (acetaminophen) ingestion with subsequent risk of hepatotoxicity is a major medical problem. The aim of this study was to investigate the risk of high-dose ingestion of orodispersible, fast-disintegrating paracetamol tablets in children. Methods: A retrospective single-center case study of all accidental selfadministrations of solid or orodispersible 500-mg paracetamol tablets occurring in children ≤ 6 years, reported to the Swiss Toxicological Information Centre between June 2003 and August 2009. Results: We found 187 cases with ingestion of solid 500-mg paracetamol tablets and 16 cases with ingestion of orodispersible 500-mg tablets. The mean ingested dose in the orodispersible-tablet group was 59% higher than in the solid-tablet group (p = 0.085). Administration of activated charcoal and/or N-acetylcysteine because of ingestion of a potentially hepatotoxic paracetamol dose ( ≥ 150 mg/kg body weight) was recommended in 32 patients (17.1%) in the solid-tablet group and in five (31%) in the orodispersible-tablet group. Conclusions: Orodispersible paracetamol formulations may represent an important risk factor for severe paracetamol poisoning in children. Over-the-counter availability may contribute to increasing the use of this galenic formulation and eventually the number of poisonings in childre

Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database

Purpose: Tizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue. Methods: We conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication. Results: In 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13-85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported. Conclusion: Despite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided. Keywords: Adverse reaction; Cytochrome P450; Drug interaction; Pharmacokinetics; Sirdalu

Prefrontal Interneurons: Populations, Pathways, and Plasticity Supporting Typical and Disordered Cognition in Rodent Models

Prefrontal cortex (PFC) inhibitory microcircuits regulate the gain and timing of pyramidal neuron firing, coordinate neural ensemble interactions, and gate local and long-range neural communication to support adaptive cognition and contextually tuned behavior. Accordingly, perturbations of PFC inhibitory microcircuits are thought to underlie dysregulated cognition and behavior in numerous psychiatric diseases and relevant animal models. This review, based on a Mini-Symposium presented at the 2022 Society for Neuroscience Meeting, highlights recent studies providing novel insights into: (1) discrete medial PFC (mPFC) interneuron populations in the mouse brain; (2) mPFC interneuron connections with, and regulation of, long-range mPFC afferents; and (3) circuit-specific plasticity of mPFC interneurons. The contributions of such populations, pathways, and plasticity to rodent cognition are discussed in the context of stress, reward, motivational conflict, and genetic mutations relevant to psychiatric disease

Atypical antipsychotic poisoning in young children: a multicentre analysis of poisons centres data

Although paediatric patients frequently suffer from intoxications with atypical antipsychotics, the number of studies in young children, which have assessed the effects of acute exposure to this class of drugs, is very limited. The aim of this study was to achieve a better characterization of the acute toxicity profile in young children of the atypical antipsychotics clozapine, olanzapine, quetiapine, and risperidone. We performed a multicentre retrospective analysis of cases with atypical antipsychotics intoxication in children younger than 6years, reported by physicians to German, Austrian, and Swiss Poisons Centres for the 9-year period between January 1, 2001 and December 31, 2009. One hundred and six cases (31 clozapine, 29 olanzapine, 12 quetiapine, and 34 risperidone) were available for analysis. Forty-seven of the children showed minor, 28 moderate, and 2 severe symptoms. Twenty-nine cases were asymptomatic. No fatalities were recorded. Symptoms predominantly involved the central nervous and cardiovascular systems. Minor reduction in vigilance (Glasgow Coma Scale score >9) (62%) was the most frequently reported symptom, followed by miosis (12%) and mild tachycardia (10%). Extrapyramidal motor symptoms were observed in one case (1%) after ingestion of risperidone. In most cases, surveillance and supportive care were sufficient to achieve a good outcome, and all children made full recovery. Conclusions: Paediatric antipsychotic exposure can result in significant poisoning; however, in most cases only minor or moderate symptoms occurred and were followed by complete recovery. Symptomatic patients should be monitored for central nervous system depression and an electrocardiogram should be obtained