Adverse Drug Reactions

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By Manuela Neuman, PhD

The Spectrum of Adverse Drug Reaction
The use of chemotherapies can sometimes produce unwanted side-effects known as adverse drug reactions (ADRs). A large number of ADRs occur when therapies are used, and although many are called allergies, these reactions are often not immune-mediated. A hypersensitivity reaction (HSR) is a type of ADR restricted to a small subset of the general population and may be either immune- or non-immune-mediated.
This article focuses on immune-mediated drug reactions and defines HSRs as ADRs that are attributable to a drug-specific immunologic response that results in pathology to the host. The immune response generated may recognize the drug or its metabolite, which acts as a hapten to modify self-proteins. HSRs are adverse events that are not qualitatively derived from the known toxicologic properties of the drug. Nevertheless, such reactions — and the fear they may constitute serious and potentially life-threatening consequences of therapy — have a vital impact on clinical practice, drug development and public health.

Clinical Practice Concerns
The toxic effects of certain medications and drug-related problems can have profound medical and safety consequences. This is especially prevalent in older adults who take one to six medications daily, and may have an economic effect on the health-care system. Individual patients with prior drug reactions (or even a history of HSRs to other non-cross-reacting drugs) are at greater risk for HSRs. Increasing age is also a risk factor — though children can also present HSRs — and it is uncertain that the effect of age is independent of cumulative drug exposure.1 According to our studies,2 there are also gender differences in HSR prevalence. In complicated clinical scenarios that include multiple drug exposures, an exact medication history, including a timeline, must be developed for drug-exposure analysis. The timeline should encompass all drugs prescribed to the patient, including over-the-counter and complementary/alternative medications and prescriptions.3 Once identified, patient-related risk factors could be used to target and choose diagnostic methods for high-risk groups, thus facilitating surveillance and providing early treatment. Availability of a diagnostic test for HSR is critical for safe procedure. This includes establishing the type of reaction, determining patient management, identifying which drug is responsible for the reaction, and tracking the incidence of HSR to that specific drug.

Public Health Concerns
The costs associated with ADRs that occur in hospitalized patients are likely to be in the range of $2,013 to $2,595 per patient for excess costs from an extended stay of 1.7–2.2 days.4,5 HSRs accounted for 137,000 to 230,000 hospital admissions in the United States in 1998, with estimated attendant costs of $275 to $600 million annually.6 HSRs are estimated to account for six to 10 per cent of all ADRs,6 most of which occur in non-hospitalized patients with unknown direct costs for the health-care delivery system. Concerns surrounding HSRs, which are currently unpredictable, and the compromises in optimal medical care undertaken in an effort to avoid recurrence of such reactions in patients with prior histories, are substantial impediments to delivering the best available medical care. For example, many of the estimated 25 million North Americans who have had some adverse experience with beta-lactam antibiotics received alternative antibiotics, which were sometimes less effective, often more toxic, and usually more expensive. Several research groups7,8,9 have performed systemic evaluations of penicillin allergies. Using a diagnostic test to screen patients that are inclined to HSRs from minocyclines and other useful antibiotics will permit cost savings in the health-care system.

Drug-development Concerns
The minimal progress in basic HSR research has also had a significant impact on drug-development costs. This is a result of the lack of mechanism-based preclinical methods using animal testing or screen-out drugs that may potentially produce HSR. Thus, potentially beneficial drugs may be unnecessarily eliminated from development on the basis of preclinical findings (such as reactive metabolite generation, covalent binding to tissues, or hypersensitivity reactions in animals). Conversely, drugs may progress through standard preclinical toxicity testing without being detected. When this occurs, there would be increases in both the risk to subjects enrolled in clinical drug trials and the cost to industry when compounds are discontinued late in the development process as a result of HSRs.10, 11 Screening a drug with a good diagnostic tool in vitro in human cells may identify a beneficial molecule in early stages of development or survey a drug that is producing post-market problems.

Mechanisms of HSR and Lymphocyte Toxicity Assay
Increasing public awareness of ADRs is helping to create a climate that encourages the development of new and improved surveillance systems. The purpose of our initiative was to personalize the medication, and avoid potentially inappropriate medication use as a general standard for a disease in children and adults, regardless of their genetic background. The medication should be tailored without posing unnecessary risks and a safer alternative should be offered if it is available. Our group2 developed an in vitro lymphocyte toxicity assay (LTA) that compares peripheral blood lymphocytes of patients with history of HSR to control individuals that took the same medicine without developing a reaction.
There are identifiable host-risk factors (metabolism, infection, radiation, genetic background, immunodeficiency) and drug characteristics (metabolites, reactive groups) in hypersensitivity reactions.12, 13, 14 In addition, in a previous study, we demonstrated the fact that in immune-compromised patients, HSRs to drugs are more intense than in immune-competent patients, demonstrating the imminent need to monitor these patients.15 In order to achieve better diagnostic methods to discriminate between immune and non-immune reactions, and to identify culprit drugs producing a reaction, we developed mechanism-based in vitro screening methods.
Increasing the knowledge of the role of reactive drug metabolites in the initiation and propagation of ADRs and HSRs will lead to the development and validation of assays to diagnose and predict the risk of HSRs for each population. Assessing ADR/HSR risk is important for patients if the drugs involved may be needed for future treatment. The analysis is specific for each drug and takes into consideration the pharmacological mechanisms by which the drug is metabolized. An example is the antibiotic based upon sulpha (SMX) moiety. The mitochondrion is critically damaged when it is exposed to sulpha that will produce reactive oxygen species (ROS) while the levels of mitochondrial glutathione (GSH) are low. When SMX is metabolized via the cytochrome P450 pathway, the production of ROS is maintained by detoxifying agents such as superoxide dismutase and glutathione S transferase (GST). While ROS are being generated, the redox cycling of SMX-NOH and nitroso-SMX deplete the levels of cytosolic GSH. This would lead to a drop in the mitochondrion’s detoxifying capability and damage from ROS. If apoptosis ensues, then the recruitment of chemokines would also follow. This effect adds to the inflammatory process and accelerates the cellular necrosis, leading to an HSR.
In Vitro Drug Safety and Biotechnology employs new technologies such as pharmaco-genomics, pharmaco/proteomics and immunopathology. The imaging will provide more insight into the pathogenesis of disease and the activities of therapeutics. In Vitro Drug Safety Testing and Biotechnology combines both patients’ sera and cells. The cells are typically isolated from donors’ native tissue and normal human cells are utilized. This is a tool for identifying potentially inappropriate medication use in a specific individual. We developed a LTA for antibiotics, painkillers, anti-convulsants, anti-psychotics, statins, non-steroidal anti-inflammatory drugs, and anti-retrovirals.16,17,18 We validated the testing, based on clinical data, of several positive and negative controls of different chemical classes and we determined the sensitivity and specificity for the targeted population.
Molecular biology provides methods to study events during acute reactions. Differing cytokines profiles, such as those seen in T helper cell (Th1 and Th2) responses, may determine to what degree humoral or cellular adaptive systems are involved.14, 19, 20, 21 The tumour necrosis factor (TNF) a promoter region gene polymorphisms was identified in carbamazepine severe HSR together with it HLA DR3 and DQ2 phenotypes. Special tests identifying the cytokine and chemokine profile of patients have been established and are used in our laboratory to identify such reactions. In severe reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis elevated levels of TNFa and interferon (IFN) g and Fas ligand are potentially synergistic causing widespread keratinocyte apoptosis, partially via de CD95 death receptor.18, 22, 23 These molecular biological changes carry implications for diagnosis and treatment. Therefore, tests were established to help the clinician in identifying and monitoring these diseases.
Accumulating evidence indicates that some HSRs may aggregate within families, suggesting genetic predispositions.2 Pharmacogenetics is not a new concept. Recent progress in molecular genetics put pharmacogenetics in drug development on the path to contribution, but this still has to be realized. Pharmacogenetics provides the tools for understanding variability in drug response. 24 There are examples of risk factors that are due to polymorphisms in drug metabolism and possibly to differences in the genetic control of the immune recognition of foreign chemicals (drugs). Using recent advances in the genomics of drug metabolism, and immune regulation, specific tests were created that allow our team to analyze a possible family-linked HSR. This is an unprecedented opportunity for profiling individual risk factors for a wide variety of HSRs. This information, coupled with the dramatically increasing knowledge base in immunology and drug metabolism, could result in significant strides in basic HSR research, and could also save individuals prone to such a reaction undue sufferance. The analysis will continue to enable patients, physicians and health-care providers to plan interventions for decreasing both drug-related costs and overall costs, thus minimizing drug-related problems. Understanding the great need for better pre-clinical and clinical biomarkers and models for earlier assessments is crucial.

References
1.     Kamada MM, Twarog F, Leung DY. “Multiple antibiotic sensitivity in a pediatric population.” Allergy Proc 12 (1991): 347-50.
2.     Neuman MG, Malkiewicz IM, Shear NH. “A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes.” Clin Biochem 33(7) (2000):517-24.
3.     Neuman M. :Metabolic effects and drug interactions provoked by certain vegetables: grapefruit, St. John's wort and garlic.” Presse Med 21;31(30) (2002): 1416-22.
4.     Bates DW, Spell N, Cullen N, et al. “The costs of adverse drug events in hospitalized patients.” JAMA 29(4) (1997): 307-11.
5.     Lazarou J, Pomeranz BH, Corey PN. “Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies.” JAMA 279 (1998):1200-05.
6.     Svensson CK, Cowen EW, Gaspari AA. “Cutaneous drug reactions.” Pharmacol Rev 53 (2000): 357-79.
7.     Romano A, Quaratino D, Di Fonso M, et al. “A diagnostic protocol for evaluating nonimmediate reactions to aminopenicilin.” J Allergy Clin Immunol 103 (1999): 1186-90.
8.     Schnyder B, Pichler WJ. “Skin and laboratory test in amoxicillin- and penicillin-induced morbiliform eruption.” Clin Exp Allergy 30 (2000):590-95.
9.     Smith JW, Johnson JE, Cluff LE. “Studies on the epidemiology of adverse drug reactions. II. An evaluation of penicillin allergy.” N Engl J Med 274 (1996): 998-1002.
10.     Boston Collaborative Drug Surveillance Program. “Drug-induced anaphylaxis: a cooperative study.” JAMA 224 (1973): 613-15
11.     Brewer T, Colditz GA. “Postmarketing surveillance and adverse drug reactions. Current perspective and future needs.” JAMA 281(1999): 824-29.
12.     Bayard PJ, Berger TG, Jacobson MA. “Drug hypersensitivity reactions and human immunodeficiency virus disease.” J Acquir Immune Defic Syndr 5 (1992): 1237-57.
13.     Jacobson-Brown P, Neuman MG. “Immunopathogenesis of hepatitis C viral Infection: Th1/Th2 responses and the role of cytokines.” Clin Biochem 34(3) (2001): 167-171.
14.     Weaver JL, de Saint-Denis A, Swann J, et al. “Analysis of immune-related adverse events associated with therapeutic use of drugs.” The Toxicologist 49 (2000): 120.
15.     Neuman MG, Malkiewicz IM, Phillips EJ, Rachlis A, Ong D, Yeung E, Shear NH. “Monitoring adverse drug reactions to sulphonamide antibiotics in human immunodeficiency virus infected individuals.” Therapeutic Drug Monitoring 24(6) (2002): 728-736.
16.     Krivoy N, Struminger L, Bendersky R, Aviv I, Neuman MG, Pollack S. “Rifampin-induced thrombocytopenia and hemolysis: diagnosis by a novel in-vitro lymphocyte toxicity assay.” The Israel Med Association J 3 (2001): 536-37.
17.     Shapiro LE, Knowles SR, Weber E, Neuman MG, Shear NH. “Safety of celecoxib in individuals allergic to sulfonamide: a pilot study.” Drug Safety, 26(3) (2003): 187-195.
18.     Neuman MG, Shapiro L, Malkiewicz I, Taeri M, Cohen L, Gomez M, Fish J, Shear N. “Signaling for hypersensitivity syndrome.” Dig Disease & Sc 50, 10, 1991-1992, 2005.
19.     Mauri-Hellweg D, Betten F, Mauri D, et al. “Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine.” J Immunol 155 (1995): 462-472.
20.     Tsutsui H, Terano Y, Sakagami C, et al. “Drug-specific T cells derived from patients with drug-induced allergic hepatitis.” J Immunol 149 (1992): 706-716.
21.     Zanni MP, Mauri-Hellweg D, Brander C, et al. “Characterization of lidocain-specific T cells.” J Immunol 158 (1997): 1139-48.
22.     Rougeau JC, Huynh TN, Bracq C, Guillaume JC, Revuz J and Rouraine R. “Genetic susceptibility to toxic epidermal necrolysis.” Arch Dermatol 123 (1987):1171-73.
23.     Viard I, Wehrli P, Bullani R, et al. « Inhibitios of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobuline.” Science 282 (1998): 490-3.
24.     Ozdemir V, Shear NH, Kalow W. “What will be to role of pharmacogenetic evaluating drug safety and minimizing adverse effects?” Drug Safety 24 2001: 75-85.

Manuela G. Neuman, PhD is an assistant professor of pharmacology at the University of Toronto (U of T) (Toronto, ON), and director of In Vitro Drug Safety & Biotechnology,, located at the MaRS Centre (Toronto, ON).
Manuela.Neuman@utoronto.ca.