The role of in vitro testing in pharmacovigilance for ß-lactam-induced serum sickness-like reaction: A pilot study.

Background: Current pharmacovigilance (PV) methods for detection of adverse drug reactions (ADRs) fail to capture rare immune-mediated drug hypersensitivity reactions (DHRs) due to their scarcity and the lack of clear diagnostic criteria. Drug-induced serum sickness-like reactions (SSLRs) are rare type of DHRs that occur in susceptible patients 1-3 weeks after exposure to the culprit drug with ß-lactam antibiotics being the most associated drugs. The diagnosis of drug induced SSLR is difficult due to the lack of safe and reliable diagnostic tests for identifying the culprit drug. The lymphocyte toxicity assay (LTA) is an in vitro test used as a diagnostic tool for drug hypersensitivity reactions (DHRs). Objective: To evaluate the role of the LTA test for diagnosing and capturing SSLR due to ß-lactam antibiotics in a cohort of patients. Methods: Patients were recruited from patients referred to the Drug Hypersensitivity Clinic at Clinic at London Health Science Centre with suspicion of drug allergy. Twenty patients (10 males and 10 females) were selected to be tested to confirm diagnosis. Demographic data was collected form the patents and blood samples were withdrawn from all patients and from 20 healthy controls. The LTA test was performed on all subjects and data is expressed as percentage increase in cell death compared to control (vehicle without the drug). Results: In the result of LTA tests performed on samples from the selected 20 patients. There was a significant (p < 0.05) concentration-dependent increase in cell death in cells isolated from patients as compared to cells from healthy controls when incubated with the drug in the presence of phenobarbitone-induced rat liver microsomes. Conclusion: Giving its safety and good predictive value the LTA test has very strong potential to be a useful diagnostic tool for ß-lactam-induced SSLR. The test procedure is relatively simple and not overly costly. Further studies including other drug classes are needed to evaluate the utility of the LTA test for SSLR due to other drugs.

Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides.

Antimicrobial sulfonamides are important medications. However, their use is associated with major immune-mediated drug hypersensitivity reactions with a rate that ranges from 3% to 4% in the general population. The pathophysiology of sulfa-induced drug hypersensitivity reactions is not well understood, but accumulation of reactive metabolites (sulfamethoxazole [SMX] hydroxylamine [SMX-HA] and SMX N-nitrosamine [SMX-NO]) is thought to be a major factor. These reactive metabolites contribute to the formation of reactive oxygen species (ROS) known to cause cellular damage and induce cell death through apoptosis and necroptosis. ROS can also serve as "danger signals," priming immune cells to mount an immunological reaction. We recruited 26 sulfa-hypersensitive (HS) patients, 19 healthy control subjects, and 6 sulfa-tolerant patients to this study. Peripheral blood monocytes and platelets were isolated from blood samples and analyzed for in vitro cytotoxicity, ROS and carbonyl protein formation, lipid peroxidation, and GSH (glutathione) content after challenge with SMX-HA. When challenged with SMX-HA, cells isolated from sulfa-HS patients exhibited significantly (P ≤ .05) higher cell death, ROS and carbonyl protein formation, and lipid peroxidation. In addition, there was a high correlation between cell death in PBMCs and ROS levels. There was also depletion of GSH and lower GSH/GSSG ratios in peripheral blood mononuclear cells from sulfa-HS patients. The amount of ROS formed was negatively correlated with intracellular GSH content. The data demonstrate a major role for oxidative stress in in vitro cytotoxicity of SMX reactive metabolites and indicate increased vulnerability of cells from sulfa-HS patients to the in vitro challenge.

Orthopedic Injuries in Pediatric Trauma.

BACKGROUND: Trauma remains the leading cause of death in children, of which the majority of patients have orthopedic injuries. The range of injured bones is various, each requiring knowledge and expertise to appropriately manage in a timely fashion. OBJECTIVES: The importance of a systematic approach to the pediatric polytrauma patient is paramount. This chapter will highlight orthopedic issues important to the pediatric polytrauma patient including the unique anatomy and properties of pediatric bone. A systematic approach to the pediatric polytrauma patient will also be discussed. METHODS: A review of the literature was undertaken to identify current practices in pediatric orthopedic trauma care. RESULT AND CONCLUSION: Orthopedic injuries in polytrauma are a common and important entity in children. Special attention to the unique anatomy and injury patterns in children should be undertaken as they are important for their management.

Predictable and Preventable: Historical and Current Efforts to Improve Child Injury Prevention.

BACKGROUND: Childhood injuries are a global epidemic. Accidents resulting in childhood injury and death were first identified as a concern over a century ago. However, "accidents" leading to injury were not recognized as being predictable and preventable until more recently. OBJECTIVES: To describe the worldwide epidemic of childhood injuries, and look at international successes in the field of injury prevention. METHODS: Literature pertaining to injury prevention was reviewed to describe the history of childhood injury prevention, guiding principles of injury prevention, successful strategies for prevention, and future directions. RESULT AND CONCLUSION: Through surveillance, evidence-based injury prevention initiatives, and multi-disciplinary collaboration, we anticipate further reduction in childhood injuries.