Expert Opinion on Drug Metabolism & Toxicology最新文献

Introduction: Antipsychotics (APs), during treatment or overdose, may be associated with respiratory aspiration.

Areas covered: A PubMed search on 30 September 2022, provided 3 cases of respiratory aspiration during clozapine therapy and 1 case during an AP overdose. VigiBase records of respiratory aspiration associated with APs from inception until 5 September 2021, were reviewed. VigiBase, the World Health Organization's global pharmacovigilance database, uses a statistical signal for associations called the information component (IC).

Expert opinion: The ICs (and IC₀₂₅) were 2.1 (and 2.0) for APs, 3.2 (and 3.0) for clozapine, 2.6 (and 2.4) for quetiapine, and 2.5 (and 2.2) for olanzapine. Cases of respiratory aspiration associated with APs included: 137 overdose/suicide cases (64 fatal) and 609 cases during treatment (385 fatal) including 333 taking clozapine (238 fatal). In logistic regression models of fatal outcomes, the odds ratios, OR, and (95% confidence intervals, CI) of significant independent variables were: a) 2.3-2.6 for clozapine in 3 samples of AP treatment of varying size, b) 1.9 (CI 1.0 to 3.5) for geriatric age in 284 patients on clozapine treatment, and c) 1.8 (CI 1.1-3.2) for antidepressant co-medication in 276 patients on non-clozapine APs. Multiple AP pharmacological mechanisms may explain respiratory aspiration.

Introduction: Despite many research efforts, current data on the safety of medicines during breastfeeding are either fragmented or lacking, resulting in restrictive labeling of most medicines. In the absence of pharmacoepidemiologic safety studies, risk estimation for breastfed infants is mainly derived from pharmacokinetic (PK) information on medicine. This manuscript provides a description and a comparison of the different methodological approaches that can yield reliable information on medicine transfer into human milk and the resulting infant exposure.

Area covered: Currently, most information on medicine transfer in human milk relies on case reports or traditional PK studies, which generate data that can hardly be generalized to the population. Some methodological approaches, such as population PK (popPK) and physiologically based PK (PBPK) modeling, can be used to provide a more complete characterization of infant medicine exposure through human milk and simulate the most extreme situations while decreasing the burden of sampling in breastfeeding women.

Expert opinion: PBPK and popPK modeling are promising approaches to fill the gap in knowledge of medicine safety in breastfeeding, as illustrated with our escitalopram example.

Introduction: Acute poisoning is a significant global health burden, and the causative agent is often unclear. The primary aim of this pilot study was to develop a deep learning algorithm that predicts the most probable agent a poisoned patient was exposed to from a pre-specified list of drugs.

Research design & methods: Data were queried from the National Poison Data System (NPDS) from 2014 through 2018 for eight single-agent poisonings (acetaminophen, diphenhydramine, aspirin, calcium channel blockers, sulfonylureas, benzodiazepines, bupropion, and lithium). Two Deep Neural Networks (PyTorch and Keras) designed for multi-class classification tasks were applied.

Results: There were 201,031 single-agent poisonings included in the analysis. For distinguishing among selected poisonings, PyTorch model had specificity of 97%, accuracy of 83%, precision of 83%, recall of 83%, and a F1-score of 82%. Keras had specificity of 98%, accuracy of 83%, precision of 84%, recall of 83%, and a F1-score of 83%. The best performance was achieved in the diagnosis of single-agent poisoning in diagnosing poisoning by lithium, sulfonylureas, diphenhydramine, calcium channel blockers, then acetaminophen, in PyTorch (F1-score = 99%, 94%, 85%, 83%, and 82%, respectively) and Keras (F1-score = 99%, 94%, 86%, 82%, and 82%, respectively).

Conclusion: Deep neural networks can potentially help in distinguishing the causative agent of acute poisoning. This study used a small list of drugs, with polysubstance ingestions excluded.Reproducible source code and results can be obtained at https://github.com/ashiskb/npds-workspace.git.

Introduction: Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur.

Areas covered: This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide.

Expert opinion: Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

Background: Despite its advantages over other antipsychotics, for treatment-resistant schizophrenia, clinical use of Clozapine (CLZ) is challenging by its narrow therapeutic index and potentially life-threatening dose-related adverse effects.

Research design and methods: As the potential role in CLZ metabolism is assigned to CYP1A2 enzyme and consequently Cytochrome P450 oxidoreductase (POR) their genetic variations might help to determine CLZ levels in schizophrenia patients. For this purpose, 112 schizophrenia patients receiving CLZ were included in the current study. Plasma CLZ and N-desmethylclozapine (DCLZ) levels were analyzed by using HPLC and genetic variations were identified with the PCR-RFLP method.

Results: The patients' CYP1A2 and POR genotypes seemed to not affect plasma CLZ and DCLZ levels whereas in the subgroup analysis, POR *28 genotype significantly influenced simple and adjusted plasma CLZ and DLCZ levels concerning smoking habit and caffeine consumption.

Conclusions: The findings of the present study highlight the importance of both genetic and non-genetic factors (smoking and caffeine consumption) for the individualization of the CLZ treatment. In addition to that, it suggests that the added utility of not only the CLZ metabolizing enzymes but also POR, which is crucial for proper CYP activity, to guide CLZ dosing might be useful for clinical decision-making.

Introduction: The skin is an organ that has the largest surface area and provides a barrier against external environment. While providing protection, it also interacts with other organs in the body and has implications for various diseases. Development of physiologically realistic in vitro models of the skin in the context of the whole body is important for studying these diseases and will be a valuable tool for pharmaceutical, cosmetics, and food industry.

Area covered: This article provides an overview of the skin structure, physiology, as well as drug metabolism in the skin, and dermatological diseases. We summarize various in vitro skin models currently available, as well as novel in vitro models based on organ-on-a-chip technology. We also explain the concept of multi-organ-on-a-chip and describe recent developments in this field aimed at recapitulating the interaction of the skin with other organs in the body.

Expert opinion: Recent developments in the organ-on-a-chip field have enabled the development of in vitro model systems that resemble human skin more closely than conventional models. In the near future, we will be seeing various model systems that allow researchers to study complex diseases in a more mechanistic manner, which will help the development of new pharmaceuticals for such diseases.

Background: Acetylsalicylic acid (Aspirin), one of the oldest medicines, is widely used in various clinical fields. However, numerous adverse events (AEs) have been reported. In this study, we aimed to investigate adverse drug reactions (ADRs) of aspirin using real-worlddata from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: We assessed the disproportionality of aspirin-related AEs by calculating measures such as reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagationneural network (BCPNN), and Gamma-Poisson Shrinker (GPS).

Results: Out of 7,510,564 casereports in the FAERS database, 18644 reports of aspirin as the 'primary suspected (PS)' AEs were recorded. Disproportionality analyses identified 493 aspirin-related preferred terms (PTs) across 25 organ systems. Notably, unexpected significant AEs such as pallor (p=5.66E-33), dependence (p=6.45E-67), and compartment syndrome (p=1.95E-28) were observed, which were not mentioned in the drug's instructions.

Conclusion: Our findings align with clinical observations, highlighting potential new and unexpected ADR signals associated with aspirin. Further prospective clinical studies are necessary to confirm and elucidate the relationship between aspirin and these ADRs. This study offers a fresh and unique perspective for studying drug-AEs.

Introduction: Solid pharmacological rationale and clinical evidence support the use of a combination of an inhaled corticosteroid (ICS), a long-acting β₂-agonist, and a long-acting muscarinic antagonist in severe asthma, which clinically results in increased lung function, improved symptoms, and decreased exacerbation rates.

Areas covered: We examined the pharmacokinetic issues associated with triple therapy for uncontrolled asthma. We considered the pharmacokinetic characteristics of the three drug classes, the role of inhalers in influencing their pharmacokinetic behavior, and the impact of severe asthma on the pharmacokinetics of inhaled drugs.

Expert opinion: The pharmacokinetics of ICSs and bronchodilators are not affected to a great extent by severe asthma, according to a detailed review of the currently accessible literature. Compared to healthy people, patients with severe asthma show only minor variations in a few pharmacokinetic characteristics, which are unlikely to have therapeutic significance and do not require particular attention. However, the difficulty of obtaining pharmacokinetic profiles of the three drugs included in a triple therapy suggests that the clinical response should be followed over time, which can be considered a good surrogate indicator of whether the drugs have reached sufficient concentrations in the lung to exert a valid pharmacological action.

Introduction: The bronchodilator response (BDR) depends on many factors, including genetic ones. Numerous single nucleotide polymorphisms (SNPs) influencing BDR have been identified. However, despite several studies in this field, genetic variations are not currently being utilized to support the use of bronchodilators.

Areas covered: In this narrative review, the possible impact of genetic variants on BDR is discussed.

Expert opinion: Pharmacogenetic studies of β₂-agonists have mainly focused on ADRB2 gene. Three SNPs, A46G, C79G, and C491T, have functional significance. However, other uncommon variants may contribute to individual variability in salbutamol response. SNPs haplotypes in ADRB2 may have a role. Many variants in gene coding for muscarinic ACh receptor (mAChR) have been reported, particularly in the M₂ and, to a lesser degree, M₃ mAChRs, but no consistent evidence for a pharmacological relevance of these SNPs has been reported. Moreover, there is a link between SNPs and ethnic and/or age profiles regarding BDR. Nevertheless, replication of pharmacogenetic results is limited and often, BDR is dissociated from what is expected based on SNP identification. Pharmacogenetic studies on bronchodilators must continue. However, they must integrate data derived from a multi-omics approach with epigenetic factors that may modify BDR.