Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy.

The recently discovered neurological disorder NEDAMSS is caused by heterozygous truncations in the transcriptional regulator IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation. Moreover, patient astrocytes fail to support neuronal survival in coculture and exhibit aberrant mitochondria and respiratory dysfunction. Treatment with the small molecule copper ATSM (CuATSM) rescues neuronal survival and restores mitochondrial function. Importantly, the in vitro findings are recapitulated in vivo, where co-expression of full-length and truncated IRF2BPL in Drosophila results in cytoplasmic accumulation of full-length IRF2BPL. Moreover, flies harboring heterozygous truncations of the IRF2BPL ortholog (Pits) display progressive motor defects that are ameliorated by CuATSM treatment. Our findings provide insights into mechanisms involved in NEDAMSS and reveal a promising treatment for this severe disorder.

Role of Noncoding RNAs in Acetaminophen-Induced Liver Injury.

Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these noncoding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of 25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (2125 nucleotides) RNAs that are processed from precursor RNAs that have stemloop structure, whereas noncoding RNAs >200 nucleotides are termed long noncoding RNAs (lncRNAs). Circular RNAs (circRNAs) are newly identified lncRNA members that are generated by back-splicing of primary transcripts. The functions of ncRNAs in modulating liver toxicity of xenobiotics are emerging only recently. Acetaminophen (N-acetyl-para-aminophenol, paracetamol or APAP) is a safe analgesic and antipyretic drug at the therapeutic dose. However, it can cause severe liver toxicity that may lead to liver failure if overdosed or combined with alcohol, herbs, or other xenobiotics. This review discusses the role of ncRNAs in acetaminophen metabolism, toxicity, and liver regeneration after APAP-induced liver injury (AILI).

The pharmacovigilance of mirtazapine: results of a prescription event monitoring study on 13554 patients in England.

Mirtazpine is the first noradrenaline and serotonin specific antidepressant. We monitored the safety of mirtazapine as reported in primary practice in England. The exposure data were provided by monitoring the dispensed prescriptions issued between September 1997 and February 1999. Questionnaires sent to GPs provided outcome data. Drowsiness/sedation and malaise/lassitude were the most frequent ADRs (116, 71 respectively) and had the highest incidence density (per 1000 patient-months) in the first month of treatment (58.1, 27.8 respectively). Agitation (73), aggression (70), rash (20), hallucinations (13) and abnormal dreams (31 were unlabelled AES while abnormal liver function tests (12), syncope (8), abnormal behaviour (4) and visual disturbance (3) were labelled AES possibly due to mirtazapine use. Serious suspected ADRs reported were facial oedema (5), allergy (3), bone marrow toxicity (2) and myelodysplasia (1).

Pharmacovigilance in Asia.

An increase in drug safety concerns in recent years with some high profile drug withdrawals have led to raising the bar by various stakeholders more importantly by the regulatory authorities. The number of Adverse Drug Reactions (ADRs) reported have also resulted in an increase in the volume of data handled and to understand pharmacovigilance a high level of expertise is required to rapidly detect drug risks as well as to defend the product against an inappropriate removal. Proactive pharmacovigilance throughout the product life cycle is the way forward and the future direction for drug safety in Asia. It has been a constant challenge to standardize pharmacovigilance in Asia, in the context of clinical trials and post-marketing pharmacovigilance due to varied geaographical, cultural and medical practices in these regioon. While major advancements of the discipline of pharmacovigilance have taken place in the West, not much has been achieved in Asian countries, though several attempts have been taken. However, with more clinical trials and clinical research activity being conducted in the Asian continent, there is an immense need to understand and implement pharmacovigilance. For this to happen, the mind set of people working in regulatory agencies, the Pharmaceutical companies, prescribers and patients/consumers need to change.

Pharmacovigilance study of alendronate in England.

Alendronate sodium is an aminobiphosphonate, an analog of inorganic pyrophosphate, indicated for the treatment of osteoporosis in post-menopausal women. We analyzed events reported in patients prescribed alendronate by general practitioners (GPs) in England. A non-interventional observational cohort study was conducted using the technique of prescription event monitoring (PEM). Exposure data were obtained from dispensed prescriptions issued between October 1995 and January 1997. Outcome data were obtained by sending questionnaires to prescribing GPs. The cohort comprised 11,916 patients. Events most frequently reported as suspected adverse drug reactions and reason for stopping alendronate were recognized gastrointestinal events listed in the Summary of Product Characteristics. These included nausea/vomiting, abdominal pain, dyspepsia, esophagitis and esophageal reflux. Events with the highest incidence density (ID(1) per 1000 patient months treatment) were dyspeptic conditions (32.2), nausea/vomiting (20.8) and abdominal pain (13.8). The term dyspeptic conditions included dyspepsia, esophagitis, esophageal reflux, duodenitis, gastritis and heartburn. Serious suspected adverse reactions possibly related to alendronate were single reports of angioedema, erythema multiforme, hypercalcemia and hypocalcemia. There were 540 deaths in this elderly cohort. This study suggests that alendronate appears to be well tolerated, though there may be risk of developing gastrointestinal side effects including esophagitis and esophageal ulcers.