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Adverse reactions and the proliferation of risk
Published in Kevin Dew, Public Health, Personal Health and Pills, 2018
Clinical trials do not only pose a risk for those who base drug consumption decisions on trial findings. In the first instance, they pose a risk for those who participate in the trials. Risks for trial participants are arguably justifiable if the likelihood of determining clinical benefit is high, but this is perhaps rarely the case as most drugs that are tested are likely to have only marginal benefit if they get to the market (Yusuf et al. 2008). In some cases there have been suggestions of moral irresponsibility on the part of drug companies. For example, in January 2016 a phase 1 trial of a drug, BIA-10–2474, was conducted in France. A phase 1 trial is when a drug is tested for the first time in healthy humans. BIA-10–2474 had no clear potential to provide therapeutic value, and the trial led to the death of one healthy volunteer and serious neurological damage for three others. The trial used ascending doses of the drug, but the increases were steep and high doses were given. Nicholas Moore (2016) suggests that one possible reason for the high dose is that the drug company was on a fishing expedition to try to find some kind of activity that might have therapeutic value. But this came at a high cost for volunteers. Another widely publicised example of harm caused to volunteers in trials occurred in Northwick Park Hospital in 2006 when six men suffered multiple organ failure (Brown and Calnan 2010).
Errors in Toxicology
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
Two cases where early studies failed to predict adverse effects are reviewed in Focus Box 20.1; that of TGN1412, in which single administration to human volunteers was associated with life-threatening effects, and of BIA-102474-101, in which single doses were shown to be safe but repeated administration was associated with severe effects and death.
Off-target identification by chemical proteomics for the understanding of drug side effects
Published in Expert Review of Proteomics, 2020
During the past decades, ABPP has been successfully employed to identify the off-targets of many drugs. A recent example is BIA 10–2474, an inhibitor of fatty acid amide hydrolase (FAAH). BIA 10–2474 was a potential drug for the treatment of anxiety and pain but failed in phase I clinical trial due to unknown severe neurotoxicity. To uncover the mechanism of this side effect, competitive ABPP was performed to profile the serine hydrolase interactome of BIA 10–2474. As a result, BIA 10–2474 was found to interact with several other lipases and cause lipid network alterations in human cortical neurons, which may contribute to its neurotoxicity [8]. In another study, quantitative acid-cleavable ABPP (QA-ABPP) was developed to map the acetylated target proteins of aspirin. In total, 523 acetylated proteins were identified as potential targets of aspirin, which may explain its multiple drug actions or side effects [9]. However, due to the specific characteristics of different probes, ABPP is only available to investigate defined enzymes families, which represent a small portion of the whole proteome.
Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?
Published in Expert Opinion on Drug Discovery, 2020
Domenico Fazio, Emanuele Criscuolo, Alessandra Piccoli, Barbara Barboni, Filomena Fezza, Mauro Maccarrone
In this context, it has to be recalled the tragic use of BIA 10–2474, a purported FAAH inhibitor, in phase I clinical trials. In 2016 one volunteer died and four others were hospitalized because of serious adverse neurological events [77]. Although the exact mechanism of action leading to the severe adverse events of BIA 10–2474 remains unknown, subsequent research highlighted the existence of many off-targets for this molecule [78,79]. Indeed, ABPP analysis demonstrated that this molecule inhibited not only FAAH, but also many other serine hydrolases (ABHD6, FAAH2, CES1, CES2, CES3, ABHD11, LIPE, and PNPLA6), clearly pointing out that it was not particularly selective for the intended target [78]. Moreover, FAAH inhibition occurred at a much higher concentration in vitro (IC50 > 1 μM) than those needed with many other FAAH inhibitors. Overall, many off-targets of BIA10-2474 are lipolytic enzymes, raising the possibility that disruption of broad cellular lipid networks may have contributed to the neurotoxicity of the compound, without any direct role of FAAH [78]. This BIA 10–2474 disaster clearly reminds us that accurate preclinical characterization of the biochemical profile of any new chemical entity must be performed, before claiming that a new FAAH inhibitor has been discovered, and especially before allowing its use in clinical trials.
18th world congress of basic and clinical pharmacology: thought-provoking lectures on drug safety issues
Published in Expert Opinion on Drug Safety, 2019
Icilio Cavero, Henry H Holzgrefe
The implementation of sentinel dosing during FIH investigations, as recommended by the EMA guideline [15,16], will add a further safety level to classic FIH studies, but may still be insufficient to prevent certain serious adverse effects. For instance, if this precaution were applied to the BIA-102474-101 MAD, it still would not have averted the disaster, as this occurred beyond a common and reasonable observation period. The best way to prevent irreversible adverse drug reactions during FIH studies is to proactively apply the approaches of prevention, which directs that all available data on a drug candidate be carefully scrutinized by competent, bioethics-observant investigators and, in the presence of even a slight doubt that the investigational product can produce a serious adverse efferct during FIH studies, the golden precaution principle 'primum non nocere' ('First, to do no harm') attributed to Hippocrate, the father of medicine, should be applied without hesitation.