Hypersensitivity reactions to low molecular weight heparins: different patterns of cross-reactivity in 3 patients.

Low molecular weight heparins (LMWHs) are used for a variety of indications. The most common type of hypersensitivity reactions to LMWHs are delayed-type hypersensitivity reactions (DHR). Immediate-type hypersensitivity reactions (IHR) occur only sporadically. Cross-reactivity of different LMWHs is a common and unpredictable problem. We present 2 cases of patients who developed DHR to nadroparin and enoxaparin, respectively. The third case presents a patient who developed IHR to nadroparin. Skin tests confirmed the hypersensitivity in all cases. In the cases of DHR, a skin test negative LMWH was identified and was tolerated in a challenge test. In the IHR case, cross-reactivity to all tested LMWHs was established. We hypothesize that the degree of cross-reactivity might depend on the type of hypersensitivity reaction with immediate reactions linked to more extensive cross-reactivity than delayed reactions. This is important to consider because, at least in some cases, a safe alternative LMWH can be identified.

Dapsone-induced agranulocytosis-possible involvement of low-activity N-acetyltransferase 2.

Dapsone-induced agranulocytosis is a rare but potentially fatal adverse drug reaction (ADR). A 45-year-old male Caucasian patient developed agranulocytosis caused by dapsone (diamino-diphenyl sulfone), which he was prescribed for leukocytoclastic vasculitis. Patient's treatment consisted of termination of dapsone, antibiotic therapy, and granulocyte colony-stimulating factor leading to prompt improvement of symptoms and normalization of laboratory blood values. Diagnostic evaluation revealed methemoglobinemia and excluded glucose-6-phosphate dehydrogenase deficiency. Pharmacogenetics testing showed that he was a carrier of NAT2 *5/*6 genotype, predisposing to low activity of the N-acetyltransferase 2 enzyme. This was the first and only ADR to dapsone reported in Croatia. In total, there have been 73 ADR to dapsone recorded worldwide, including only four cases of agranulocytosis.

CYP2D6 *6/*6 genotype and drug interactions as cause of haloperidol-induced extrapyramidal symptoms.

A 66-year-old male Caucasian, received 1 mg of haloperidol orally and rapidly developed severe iatrogenic extrapyramidal symptoms. Treatment was immediately discontinued, and the side effects resolved. Haloperidol is mainly metabolized by Phase I CYP2D6 and to the lesser extent by CYP3A4 and by Phase II UGT2B7 enzymes. Genotyping was performed revealing CYP2D6*6/*6, CYP3A4*1/*1, and UGT2B7 -161 C/T genotypes, implicating poor, extensive and intermediate metabolism, respectively. Of the CYPs, haloperidol is metabolized by CYP2D6 and CYP3A4 primarily. It was the introduction of ciprofloxacin which was a trigger for the development of adverse drug reaction due to inhibition of CYP3A4, which was in presented patient main metabolic pathway for haloperidol since he was CYP2D6 poor metabolizer. Presented case report highlights the importance of genotyping. Pharmacogenetics testing should be considered when drug toxicity is suspected, polymorphic metabolic pathways used and drugs concomitantly applied.