Association between CYP2C19*2 variant and clinical outcome in Clopidogrel treated patients from Republic of Macedonia

Clopidogrel is the thienopyridine of choice for prevention of ischemic events and stent thrombosis in patients with atherotrombotic disease. Recent studies suggest that certain genetic variants involving CYP450 system are responsible for wide interindividual variability in treatment response profiles among clopidogrel treated individuals. The aim of this study was to define the prevalence of most common CYP2C19*2: 681G>A (rs4244285) allelic variant in Macedonian population and determine the risk association with major cardiovascular adverse events in clopidogrel treated patients with atherotrombotic cardiovascular disease. CYP2C19 *2 genotype was assessed in 198 subjects from R.Macedonia. The association between the reduced function CYP2C19 *2 A allele and clinical outcome was evaluated in 67 clopidogrel treated patients within a follow up period of at least 6 months (from 6 to 60 months) after initializing clopidogrel therapy. The population frequency of polymorphic A allele responsible for impaired clopidogrel metabolism in Macedonian population was 0.18. CYP2C19*2 variant was significantly associated with increased rate of adverse cardiovascular events in the allelic (OR= 3.188; 95% CI= 1.437-7.058), dominant (OR=3.477; 95% CI= 1.256-9.630) and co-dominant model ( OR=6.750, 95% CI: 1.186-38.410) of statistical analysis (adjusted OR= 2.619; Ptrend=0.0088). The influence of CYP2C19*2 was most strongly correlated with worse event free survival in patients carrying AA genotype (log rank P = 0.0024) and patients carrying at least one CYP2C19*2 reduced function allele (log rank P=0.0058). CYP2C19*2 genetic variant in the population from Republic of Macedonia has similar distribution as determined in other European populations. Carriage of reduced function CYP2C19 *2 allele is associated with worse event free survival in clopidogrel treated patients with atherotrombotic disorders

Frequency of the most common CYP3A5 polymorphisms in the healthy population of the Republic of Macedonia

The genetic polymorphism affecting the CYP3A5 enzyme is responsible for inter-individual and interethnic variability in the metabolism of CYP3A5 substrates. The aim of this study was to analyze the distribution of the most common CYP3A5*3 allelic variants in the healthy population of R. Macedonia and to investigate if the allelic frequency falls within the assumed range for European Caucasians. The total of 174 healthy volunteers from the general population were included. The genotyping of the CYP3A5*3 variant alleles, *3A (rs15524) and *3E (rs28365095), was performed with Real-Time PCR based on the allelic discrimination method using a TaqMan SNP genotyping assay according to the manufacturer’s instructions. The CYP3A5*3 allele is abundantly present displaying an allelic frequency of 0.922. We estimate that 0.82 of the Macedonian population are homozygotes for the variant and do not have a CYP3A5 enzymatic activity. Our study demonstrated a high prevalence of CYP3A5*3 allele in the Macedonian population. The distribution of CYP3A5 alleles was similar to that found in other European Caucasians. As the goals of personalized medicine are beginning to be realized, this provides basic information on the CYP3A5 allele frequency for the future pharmacogenetic research in R. Macedonia

Assessment of Patient Satisfaction with Pharmaceutical Community Services in R. Macedonia

Measuring and analyzing patients’ satisfaction with pharmacist’s consultation is a relatively new development which is enforced by the new demands of society. High number of variables, such as their state of health, socio-demographic variables (age, sex, and cultural level), characteristics of their healthcare provider (affective care, quantity of information, technical expertise, etc), or waiting time are related to patients’ satisfaction. At present, in R.Macedonia, there are 834 community pharmacies, which accounts for pharmacy vs. population ratio of 1:2500. The pharmacies are situated in 8 different regions (the Vardar region, Pelagonia, North-East, South-West, Polog, East and South East). The present cross-sectional descriptive study based on interview data was carried out in order to ascertain patients’ satisfaction from their experience with the cumulative quality of pharmaceutical services. A total of 651 patients of both sexes (59,3% male and 39,1% female) were included in the study. The results from our analysis showed the influence of different factors in the process of choosing pharmacy: distance, medicines price, well-stocked with medicines, professional advice by the employees in the pharmacy, hygiene in pharmacies, the privacy they offer, waiting time, possibility for private conversation with professionals

AKR1D1*36 C>T (rs1872930) allelic variant is associated with variability of the CYP2C9 genotype predicted pharmacokinetics of ibuprofen enantiomers – a pilot study in healthy volunteers

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(–)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0–∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified

AKR1D1*36 C>T (rs1872930) allelic variant is associated with variability of the CYP2C9 genotype predicted pharmacokinetics of ibuprofen enantiomers – a pilot study in healthy volunteers

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(–)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0–∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified

AKR1D1*36 C>T (rs1872930) allelic variant is associated with variability of the CYP2C9 genotype predicted pharmacokinetics of ibuprofen enantiomers – a pilot study in healthy volunteers

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(−)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0–∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified