Educational case series: Mechanisms of drug allergy

Once administered, a drug can activate the immune system by various mechanisms and lead to a large range of clinical manifestations closely related to the type of immune reaction elicited. Administration of the drug can classically result in an immunoglobulin E (IgE)-type sensitization, but can also result in more complex activation of the immune system potentially resulting in severe syndromes, such as the drug-induced hypersensitivity syndrome (DIHS). Although there has been a major increase in our knowledge over the last years, the exact mechanisms of drug allergy are not well understood for most clinical manifestations. A complex interaction between individual characteristics, environmental factors, and the drug itself is usually responsible for adverse reactions to drugs. In this educational review series, we described three cases of drug allergy: first, a child with a typical IgE-mediated drug allergy, second, a child with a non-immediate reaction to penicillin, and in the third patient, we will discuss the drug-induced hypersensitivity syndrome, which is rare but potentially fatal. These cases are correlated to the immune mechanism potentially involved.

Hepatocellular toxicity of clopidogrel: Mechanisms and risk factors

Clopidogrel is a prodrug used widely as a platelet aggregation inhibitor. After intestinal absorption, approximately 90% is converted to inactive clopidogrel carboxylate and 10% via a two-step procedure to the active metabolite containing a mercapto group. Hepatotoxicity is a rare but potentially serious adverse reaction associated with clopidogrel. The aim of this study was to find out the mechanisms and susceptibility factors for clopidogrel-associated hepatotoxicity. In primary human hepatocytes, clopidogrel (10 and 100μM) was cytotoxic only after cytochrome P450 (CYP) induction by rifampicin. Clopidogrel (10 and 100μM) was also toxic for HepG2 cells expressing human CYP3A4 (HepG2/CYP3A4) and HepG2 cells co-incubated with CYP3A4 supersomes (HepG2/CYP3A4 supersome), but not for wild-type HepG2 cells (HepG2/wt). Clopidogrel (100μM) decreased the cellular glutathione content in HepG2/CYP3A4 supersome and triggered an oxidative stress reaction (10 and 100µM) in HepG2/CYP3A4, but not in HepG2/wt. Glutathione depletion significantly increased the cytotoxicity of clopidogrel (10 and 100µM) in HepG2/CYP3A4 supersome. Co-incubation with 1μM ketoconazole or 10mM glutathione almost completely prevented the cytotoxic effect of clopidogrel in HepG2/CYP3A4 and HepG2/CYP3A4 supersome. HepG2/CYP3A4 incubated with 100μM clopidogrel showed mitochondrial damage and cytochrome c release, eventually promoting apoptosis and/or necrosis. In contrast to clopidogrel, clopidogrel carboxylate was not toxic for HepG2/wt or HepG2/CYP3A4 up to 100µM. In conclusion, clopidogrel incubated with CYP3A4 is associated with the formation of metabolites that are toxic for hepatocytes and can be trapped by glutathione. High CYP3A4 activity and low cellular glutathione stores may be risk factors for clopidogrel-associated hepatocellular toxicity.

Mechanisms of drug-induced allergy

We identified English-language publications on hypersensitivity reactions to xenobiotics through the PubMed database, using the search terms drug and/or xenobiotic, hypersensitivity reaction, mechanism, and immune mediated. We analyzed articles pertaining to the mechanism and the role of T cells. Immune hypersensitivity reactions to drugs are mediated predominantly by IgE antibodies or T cells. The mechanism of IgE-mediated reactions is well investigated, but the mechanisms of T-cell-mediated drug hypersensitivity are not well understood. The literature describes 2 concepts: the hapten/prohapten concept and the concept of pharmacological interactions of drugs with immune receptors. In T-cell-mediated allergic drug reactions, the specificity of the T-cell receptor that is stimulated by the drug may often be directed to a cross-reactive major histocompatibility complex-peptide compound. Thus, previous contact with the causative drug is not obligatory, and an immune mechanism should be considered as the cause of hypersensitivity, even in reactions that occur on primary exposure. Indeed, immune-mediated reactions to xenobiotics in patients without prior exposure to the agent have been described recently for radiocontrast media and neuromuscular blocking agents. Thus, the "allergenic" potential of a drug under development should be evaluated not only by screening its haptenlike characteristics but also by assessing its direct immunostimulatory potential.

Modeling of ore-forming and geoenvironmental systems: Roles of fluid flow and chemical reaction processes

Ore-forming and geoenviromental systems commonly involve coupled fluid flowand chemical reaction processes. The advanced numerical methods and computational modeling have become indispensable tools for simulating such processes in recent years. This enables many hitherto unsolvable geoscience problems to be addressed using numerical methods and computational modeling approaches. For example, computational modeling has been successfully used to solve ore-forming and mine site contamination/remediation problems, in which fluid flow and geochemical processes play important roles in the controlling dynamic mechanisms. The main purpose of this paper is to present a generalized overview of: (1) the various classes and models associated with fluid flow/chemically reacting systems in order to highlight possible opportunities and developments for the future; (2) some more general issues that need attention in the development of computational models and codes for simulating ore-forming and geoenviromental systems; (3) the related progresses achieved on the geochemical modeling over the past 50 years or so; (4) the general methodology for modeling of oreforming and geoenvironmental systems; and (5) the future development directions associated with modeling of ore-forming and geoenviromental systems.