The association of C3435T single-nucleotide polymorphism, Pgp-glycoprotein gene expression levels and carbamazepine maintenance dose in patients with epilepsy

The ABCB1 gene encodes the P-glycoprotein (Pgp) protein, which is thought to transport various antiepileptic drugs. The single nucleotide polymorphism (SNP) (C3435T) in exon 26 of this gene correlates with the altered expression levels of P-glycoprotein, range of drug response and clinical conditions. In order to investigate the influence of this polymorphism on the susceptibility to and efficacy of carbamazepine therapy, we evaluated the allelic frequency and genotype distribution of this variant in 162 epilepsy patients from the Republic of Macedonia. Statistically significant differences were detected neither in the allelic frequency and genotype distribution between carbamazepine-resistant and carbamazepine-responsive epilepsy patients nor between the subgroups of carbamazepine (CBZ)-responsive patients treated with different CBZ doses. However, the T-allele was enriched in CBZ-responsive patients who required higher maintenance CBZ doses, This observation was substantiated by the findings that the median total plasma levels were the lowest in patients with CC (20 μmol/L) followed by CT (23 μmol/L) and TT (29 μmol/L) genotypes. Patients with a CC genotype also had a higher likelihood of response compared to patients with CT or TT genotypes over a wide range (400–1000 mg/day) of initial doses of CBZ. The T allele showed a reduced expression of ~5% compared to the C allele in peripheral blood mononuclear cells in heterozygotes for the variant. This difference might be translated into ~10% difference in homozygotes for the variant, which would explain the trend towards a dose-dependent efficacy of the CBZ treatment in patients with different genotypes. A larger prospective study is warranted to clarify the clinical utility of a genotypespecific individualized CBZ therapy

Patents and licensing in pharmaceutical industry

Intellectual property rights (IPR) have been defined as ideas, inventions, and creative expressions based on which there is a public willingness to bestow the status of property. IPR provide certain exclusive rights to the inventors or creators of that property, in order to enable them to reap commercial benefits from their creative efforts or reputation. There are several types of intellectual property protection like patent, copyright, trademark, etc. Patent is recognition for an invention, which satisfies the criteria of global novelty, non-obviousness, and industrial application. IPR is prerequisite for better identification, planning, commercialization, rendering, and thereby protection of invention or creativity. Each industry should evolve its own IPR policies, management style, strategies, and so on depending on its area of specialty. Pharmaceutical industry currently has an evolving IPR strategy requiring a better focus and approach in the coming era. The protection of inventions with patents in the pharmaceutical industry have a specific role in the development of society and represent one of the drivers of economic development. The license agreements are considered as one of the most common types of transfer of industrial property rights. The right holders often transfer their rights to patents by concluding licensing agreement. While the patent license may give the license a right to use the technology many license agreements have provisions for the transfer of know-how in addition to the patent

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

Optimization and validation of bioanalytical SPE – HPLC method for the simultaneous determination of carbamazepine and its main metabolite, carbamazepine-10, 11-epoxide, in plasma

Carbamazepine is widely used as an antiepileptic drug in the treatment of partial and generalized tonic-clonic seizures. Carbamazepine 10,11-epoxide is the most important metabolite of carbamazepine, because it is a pharmacologically active compound with anticonvulsant properties. According to that, the routine analysis of carbamazepine 10,11-epoxide along with carbamazepine may provide optimal therapeutic monitoring of carbamazepine treatment. The aim of this study was to optimize and validate a simple and reliable solid - phase extraction method followed by RP-HPLC for the simultaneous determination of plasma levels of carbamazepine and carbamazepine-10,11-epoxide, in order to assure the implementation of the method for therapeutic monitoring. The extraction of the analytes from the plasma samples was performed by means of a solid-phase extraction procedure. The separation was carried out on a reversed-phase column using isocratic elution with acetonitrile and water (35:65, v/v) as a mobile phase. The temperature was 30°C and UV detection was set at 220 nm. The extraction yield values were more than 98% for all analytes, measured at four concentration levels of the linear concentration range. The method displayed excellent selectivity, sensitivity, linearity, precision and accuracy. Stability studies indicate that stock solutions and plasma samples were stabile under different storage conditions at least during the observed period. The method was successfully applied to determine the carbamazepine and carbamazepine-10,11-epoxide in plasma of epileptic patients treated with carbamazepine as monotherapy and in polytherapy. In conclusion, the proposed method is suitable for application in therapeutic drug monitoring of epileptic patients undergoing treatment with carbamazepine

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

Razvoj i validacija bioanalitičke LC-UV metode s ekstrakcijom na čvrstoj fazi za određivanje valproične kiseline u slini

A bioanalytical HPLC method with UV detection for the determination of the antiepileptic drug valproic acid in human saliva has been developed and validated. Saliva represents an alternative matrix for monitoring of antiepileptic drugs due to the increasing interest in free drug concentration. The proposed method involved solid-phase extraction for sample preparation and yielded very good mean recoveries of 99.4 % and 97.9 % for valproic acid and IS, respectively. The calibration function for valproic acid was linear over the concentration range of 1.0–50.0 µg mL1 (R2 = 0.9989). Within-run and between-run precision and accuracy were studied at four concentrations and RSDs were less than 7.3 and 2.2 %, while accuracy values were higher than 96.8 and 97.5 %, respectively. The described method provides sensitivity, linearity, precision, accuracy and is suitable for analyses of valproic acid in saliva samples.U radu je opisana i validirana bioanalitička HPLC metoda s UV detekcijom za određivanje antiepileptika valproične kiseline u slini čovjeka. Zbog sve većeg interesa za praćenje koncentracije slobodnog lijeka slina predstavlja alternativni matriks za praćenje antiepileptika. Predložena metoda u pripremi uzorka uključuje ekstrakciju na čvrstoj fazi. Dobiven je vrlo dobar srednji analitički povrat od 99,4 % i 97,9 % za valproičnu kiselinu, odnosno IS. Kalibracijska funkcija za valproičnu kiselinu bila je linearna u koncentracijskom području od 1,0–50,0 µg mL1 (R2 = 0,9989). Preciznost i točnost procijenjene unutar jednog i više mjernih dana dale su RSD niže od 7,3 i 2,2 %, te vrijednosti za točnost iznad 96,8, odnosno 97,5 %. Opisana metoda je dovoljno osjetljiva, precizna i točna, osigurava linearni odgovor te je pogodna za analizu valproične kiseline u slini