Iveta Šimić

ABCG2 gene polymorphisms as risk factors for atorvastatin adverse reactions: a case–control study

AIM To explore the association between dose-related adverse drug reactions (ADRs) of atorvastatin and polymorphisms of ABCG2, taking into account the influence of CYP3A4 and SLCO1B1 genes. MATERIALS & METHODS Sixty patients who experienced atorvastatin dose-related ADRs and 90 matched patients without ADRs were enrolled in the study. Genotyping for ABCG2 421C > A, CYP3A4*22, SLCO1B1 388A > G, SLCO1B1 521T > C variants was performed by real-time PCR. RESULTS Patients with ABCG2 421CA or AA genotypes had 2.9 times greater odds of developing atorvastatin dose-dependent ADRs (OR: 2.91; 95% CI: 1.22-6.95; p = 0.016) than those with ABCG2 421CC genotype. After adjustments for clinical and genetic risk factors, ABCG2 remained a statistically significant predictor of adverse drug reactions (OR: 2.75; 95% CI: 1.1-6.87; p = 0.03;). Also, carriers of SLCO1B1 521 TC or CC genotypes had 2.3 greater odds (OR: 1.03-4.98; 95% CI: 1.03-4.98; p = 0.043) of experiencing ADRs caused by atorvastatin in comparison with carriers of SLCO1B1 521 TT genotype. CONCLUSION Our study demonstrated an association between atorvastatin-induced ADRs and genetic variants in the ABCG2 gene.

Interaction of genetic risk factors confers increased risk for metabolic syndrome: the role of peroxisome proliferator-activated receptor γ.

AIM The aim of the study was to estimate the influence of interactions between peroxisome proliferator-activated receptor γ (PPARγ) and target genes lipoprotein lipase (LPL), interleukin 6 (IL6), angiotensin converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) on metabolic syndrome (MetSy) and its traits. METHODS The study included 527 participants (263 with MetSy and 264 controls). Genotyping of PPARγ Pro12Ala, LPL PvuII (-/+), IL6 -174G>C, ACE I/D and AT1R 1166A>C was performed using polymerase chain reaction-restriction fragment length polymorphism-based methods. RESULTS Interaction between PPARγ Pro12Ala and LPL Pvu(-/+) improved prediction of MetSy over and above prediction based on a model containing no interactions (χ(2)=7.22; df=1; p=0.007). In the group of participants with PPARγ Pro12Ala or Ala12Ala genotypes, those with the LPL Pvu (-/+) or (+/+) genotype had greater odds for MetSy (odds ratio OR=5.98; 95% confidence interval CI: 1.46-24.47, p=0.013). Interaction between PPARγ Pro12Ala and IL6 -174G>C improved prediction of high fasting blood glucose (χ(2)=13.99; df=1; p<0.001). PPARγ Ala12 variant was found protective in patients with IL6 -174GG genotype (OR=0.10; 95% CI: 0.02-0.57, p=0.01), while in the case of IL6 -174C allele carriers, for PPARγ Ala12 carriers, larger odds for high glucose levels compared with Pro12 variant were observed (OR=2.39; 95% CI: 1.11-5.17, p=0.026). Interactions of PPARγ and ACE were significant for BMI. In the group with ACE DD genotype, those with PPARγ Pro12Ala or Ala12Ala genotype have greater odds for obesity (OR=9.98; 95% CI: 1.18-84.14, p=0.034). CONCLUSIONS PPARγ gene variants can, in interaction with some of its target genes, modulate physiological processes leading to the development of MetSy.

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.

Pharmacoeconomic Analysis of Antithrombotic Treatment In Coronary Artery Disease (Cad) Patients With Clopidogrel Hypersensitivity After Percutaneous Coronary Intervention (Pci)

PharmaCoeCoNomiC aNalySiS of aNTiThromboTiC TreaTmeNT iN CoroNary arTery DiSeaSe (CaD) PaTieNTS WiTh CloPiDogrel hyPerSeNSiTiViTy afTer PerCuTaNeouS CoroNary iNTerVeNTioN (PCi) I. Cegec; I. Simic; V. Erdeljic Turk; K. Makar Ausperger; M. Aumiler Radacic; I. Kraljickovic; D. Juricic Nahal; and R. Likic University Hospital Centre Zagreb, Zagreb, Croatia; and University of Zagreb School of Medicine, Zagreb, Croatia Antithrombotic treatment for CAD patients undergoing PCI includes dual antiplatelet therapy with a 300 mg oral loading dose of acetylsalicylic acid followed by 100 mg orally daily plus a clopidogrel 600 mg loading dose followed by 75 mg daily. Hypersensitivity reactions to clopidogrel are reported in up to 6 percent of patients. Most commonly, they present as generalized, pruritic, erythematous rash (93%) and urticaria. Approximately 6529 patients undergo PCI procedures in Croatia per year, and we estimate that up to 4% of them require revision of dual antiplatelet therapy of some kind. In our abstract, we try to provide the pharmacoeconomic analysis for overall cost of yearly therapy for one patient behind each of the three possible approaches:

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.Complete List of Authors: Juricic Nahal, Danica; University Hospital Centre Zagreb, Division of Clinical Pharmacology; Agency for Medicinal Products and Medical Devices of Croatia Cegec, Ivana; University Hospital Centre Zagreb, Division of Clinical Pharmacology Erdeljic Turk, Viktorija; University Hospital Centre Zagreb, Division of Clinical Pharmacology Makar Ausperger, Ksenija; University Hospital Centre Zagreb, Division of Clinical Pharmacology Kraljickovic, Iva; University Hospital Centre Zagreb, Division of Clinical Pharmacology Simic, Iveta; University Hospital Centre Zagreb, Division of Clinical Pharmacology; University of Zagreb School of Medicine

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. Patients 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.

Testing for Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) At the University Hospital Zagreb

Anti-TB drugs 3 ABCB1,CYP2E1, NAT2,CYP2E1 Azathioprine 1a TPMT Flucloxacillin 3 HLA-B*57:01:01 Flupirtine 3 HLA-DRB1*16:01-HLADQB1-*05:02 Gemtuzumab-ozogamicin 3 SLCO1B1 Isoniazid 2a/3 NAT2, TNF, GSTM1, GSTT1 Lapatinib 2b HLA-DQA1 Methotrexate 3 TYMS Nevirapine 2a/4 ABCB1, CYP2B6, HLA-B*35:01, HLADRB1*01:01:01 Pyrazinamide 2a/3 NAT2, TNF, GSTT1, STAT3 Rifampicin 2a/3 NAT2, TNF, NOS2, GSTM1, GSTT1, STAT3 Tacrolimus 3 CYP3A5 Ticlopidine 3 HLA-B*44:03

No Adverse Effects After Radioiodine Treatment at 3 Weeks of Pregnancy.

Radioactive iodine is used for the treatment of hyperthyroidism. Because it accumulates in the fetal thyroid, its administration during pregnancy may cause severe and potentially irreversible hypothyroidism in neonates, with consequent mental retardation, and it is contraindicated during the whole pregnancy. We present a case of a pregnant woman inadvertently treated with 1 mCi (37 MBq) of I in the earliest period of pregnancy and subsequently gave birth to a male infant without signs or symptoms of hypothyroidism or any other damage. This case illustrates that when radioactive iodine administration happens around the third week of gestation pregnancy outcome can be normal.