Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr Gideon Koren

2nd Supervisor

Dr Michael Rieder

Joint Supervisor

Abstract

Adverse drug reactions (ADRs) are responsible for a high number of morbidities and mortalities worldwide and estimated to be the fourth most important cause of death in the US and Canada after heart diseases, cancer and stroke. ADRs are either type A (~80%) which are predictable, related to the drug pharmacology and dose-dependent or type B (~20%), which are unpredictable, unrelated to the drug pharmacology and have no clear dose-dependency. Drug hypersensitivity reactions (DHRs) represent the majority of type-B ADRs, which are rare but potentially fatal and unpredictable. The latter aspect makes DHRs very difficult to diagnose and necessitate the development of a reliable and safe in vitro diagnostic test to aid prediction and confirm diagnosis. The currently used tests are not well characterized and their predictive value is unknown. The aim of this work was to evaluate the clinical value of the currently used diagnostic tests for DHRs; to develop a simple, reliable and safe test; and to explore the pathophysiology of DHRs using different approaches for further understanding of the DHRs pathophysiology which will allow us to develop new means for prevention prediction and diagnosis.

Methodology used involved performing systematic literature reviews, population survey on previously tested patients, patient recruitment and laboratory techniques that include preparation and testing of liver microsomes from human and animal origin, using hematopoietic cell lines and primary cultures of different blood cell types as a surrogate model to explore DHRs pathphysiology and test patient susceptibility for DHRs.

Systematic review of available literature revealed that the currently used diagnostic tools for DHRs lack any characterization or standardization and much more work is needed to further characterize and improve these tools. We developed a novel laboratory approach for diagnosis of DHRs that proved to be less cumbersome and potentially more reliable than other currently used tests. Using different biochemical and genetic methods, we introduced novel concepts that explain some aspects of the pathophysiology of DHRs.

The main achievement in this research was the development of a novel diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA), which has a great potential as a clinical tool due to its simple procedure and good reproducibility. We hope that these features will allow its wider clinical use as oppose to other currently used tests. In addition, expanding our understanding of the molecular pathophysiology of DHRs using recent technical advances in genetic analysis and laboratory techniques will have a great impact on the management of these cases.

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