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Section 8. Medical science
However, the fetoplacental complex hemodynamics violations also have been noted in pregnant women with myocarditis on the background of normal FE values. Violation of blood flow in uterine arteries (FPI Ia) has been noted in 14 % of women, and violations of placental blood flow (FPI Ib) — in 10 % of cases. Violation of uteroplacental blood flow (FPI II) has been noted in 5 % of cases. In 67 % of cases the pregnancy proceeded on the background of antenatal hypoxia.
The obtained data once again confirm that the maternal hemodynamics violation, caused by myocarditis, plays a major role in the placental insufficiency development. However, the results obtained after 2nd stage of the study carrying out show that pregnant women with myocarditis can develop fetoplacental blood flow violation even on the background of normal ejection fraction value. This information once again emphasizes that there are unknown causes and pathogenetic mechanisms of violations in the system mother-placenta-fetus in case of myocarditis, which further study let scientists more deeply understand the pathogenesis of obstetric
complications on the background of this circulatory system disease in pregnant women.
Conclusions
Thus, the myocarditis that develops during pregnancy is a condition that threatens the mother and fetus life, and requires further study for pregnancy and childbirth management tactic development.
Central maternal hemodynamics in case of myocarditis development can be characterized by impaired LV contractile function, which underlies number of obstetric and perinatal complications development.
Consequently, the maternal hemodynamics dysfunction adversely affecting the fetoplacental complex, result in uterine arteries blood flow disorders development, which in turn leads to the placental vessels resistance index increasing.
However, role of immunological-inflammatory and autoimmune processes in the development of some obstetric and perinatal complications that require further study cannot be excluded.
References:
1. Koliushko G. I. Myocarditis among pregnant women. - Kharkov (Ukraine), 2011. - № 2. - (148). - Р. 35-38.
2. Struk R. I. Cardiac arrhythmias in pregnancy. Guidelines for physicians. - М.: Geotar-Media, 2007. - Р. 128.
3. Centers for diseases control and prevention. National center for chronic disease prevention and health promotion, pregnancy mortality surveillance system. - US, 2012. - Р. 114.
4. Gunderson E. P. et al. Gestation cardiomyophaty.//Obset Gynecol. - New York, 2011. - Vol. 118. - P. 583.
5. Stephan Hetmans. Myocarditis and heart failure: need for better diagnostic, predictive, and therapeutic tools.//Eur. Heart J. - 2007. - Vol. 28, № 11. - Р. 1279-1280.
Dmitrenko Diana Victorovna, Shnayder Nataliya Alekseevna, Govorina Yuliya Borisovna, Myravyova Anastasiya Vladimirovna, Krasnoyarsk State Medical University named after Prof. V. F. Voyno-Yaseneysky, the Department of Medical Genetics and Clinical Neurophysiology
E-mail: mart2802@yandex.ru
The effect of CYP2C9 gene polymorphism at the level of Valproic acid in serum in women of reproductive age with epilepsy
The study was sponsored by the Regional State Autonomous Institution “Krasnoyarsk regional fund to support scientific and technical activities” (a grant for the implementation of the initiative project “Investigation of mechanisms of genetically deterministic adverse drug effects while taking antiepileptic drugs” (Additional Agreement № 15/15 from 19.06.2015) under the Competition of scientific and technical of the Youth Creativity).
Abstract: The purpose of research — the study of the influence of single nucleotide polymorphisms (SNPs) of gene CYP2C9 on the concentration of valproic acid (VPA) in the blood. Higher levels of VPA was observed in patients with genotype CYP2C9*2/*3 (100 mkg/ml) and genotype CYP2C9*1/*2 (86 mkg/ml), compared with the genotype CYP2C9*1/*3 (72.5 mkg/ml) and genotype CYP2C9*1/*1 (66 mkg/ml).
Keywords: Epilepsy, Pharmacogenetics, Valproic acid, Therapeutic drug monitoring, CYP2C9.
Introduction. Epilepsy is a chronic brain disease charac- clinical and paraclinical manifestations, and requires long-term, terized by recurrent seizures that result from excessive electrical and in some cases — receiving life antiepileptic drugs (AEDs).
activity of neurons in the brain, accompanied by a variety of The purpose of AED-therapy, on the one hand, preventing
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The effect of CYP2C9 gene polymorphism at the level of Valproic acid in serum in women of reproductive age with epilepsy
epileptic seizure, and on the other hand, the absence of adverse drug events. The pharmacokinetic characteristics to a greater or lesser extent dependent on the genetic characteristics of a person (genetically determined reduction in the activity of an enzyme involved in the metabolism of the drug) [1; 2].
The purpose of research — the study of the influence of SNPs of gene CYP2C9 on the concentration ofVPA in serum of childbearing age women with epilepsy.
Materials and methods. The study included 148 Russian childbearing age women with epilepsy, living in the Krasnoyarsk region (RF). Age of the patients ranged from 15 to 58 years, mean age — 28.4 ± 8.2 years.
Methods: retrospective analysis of complaints and anamnesis (for outpatients); analysis of the daily doses of AEDs; laboratory methods, including therapeutic drug monitoring (TDM) and molecular genetic testing of SNPs of the gene CYP2C9.
TDM was conducted at a single point (2 hours after receiving valproate). Reference level of VPA in serum: 50-100 mcg/ml. Subtoxic levels of VPA is defined by 90 to 100 mcg/ml, toxic levels over 100 mcg/ml.
Molecular genetic study was conducted by PCR Real Time, using a fluorophore-labeled oligonucleotide samples agents (technology TaqMan, “Rotor-Gene 6000”, Corbet Life Science, Australia). A study of polymorphic allelic variants of the gene CYP2C9 (on chromosome 10q24.1-24.3) P450:
- allelic variant “wild” type CYP2C9*1 does not have a mutation in a single nucleotide substitution;
- polymorphic allelic variant CYP2C9*2 (R144C, c.430 C > T — single nucleotide substitution of cytosine to thymine at position 430);
- polymorphic allelic variant CYP2C9*3 (I359L, c.1075 A > C — single nucleotide substitution of adenine to cytosine at position 1075).
Descriptive statistics for the quality of accounting signs presented as absolute values, percentages and fractions errors. Data for variational series with non-parametric distribution described as medians and percentiles 25 and 75 — Me [P25; P75]. Total inter-group differences were assessed using H Kruskal-Wallis test. In case of differences of several samples was performed multiple comparisons using the nonparametric criteria options: Dunnett test (comparison of all samples with the control sample — without mutation) and Newman-Keuls test (for pair wise comparison of samples). To test the hypothesis of equality of shares used x2 test with Marasciulo procedure. To assess the risk of cumulation of VPA used the coefficient of relative risk. For all criteria critical level of significance was taken p < 0.05. Statistical analysis was performed using software packages STATISTICA v. 7.0, SPSS Statistics 20.0, Excel.
Results and discussion. The daily dose ofVPA ranged from 300 to 2000 mg/day, with a median of 1000 [600:1000] mg/day.
As a result of statistical processing of the data, we have shown that the prevalence of genotype CYP2C9*1/*1 was diagnosed in 100/148 (67.6 %) patients, genotype CYP2C9*1/*2 — in 18/148 (12.2 %) women, genotype CYP2C9*1/*3 —
in 28/148 (18.9 %), compound heterozygote (genotype CYP2C9*2/*3) — at 2/148 (1.4 %) women.
The frequency of CYP2C9*2 genotype correlates with the data obtained in Europe and the European part of Russia — 12.2 %. The frequency of the genotype CYP2C9*3-18.9 % higher than the incidence in Europe (10.8 %), but comparable to the frequency of occurrence in Turkey (17.23 %) [2] and Italy (14.5 %) [3] and exceed the frequency of occurrence in the European part of Russia. The incidence of compound heterozygotes CYP2C9*2/*3-1.4 % comparable with the frequency of occurrence in Turkey (1.1 %) [3] and Italy (2.0 %) [3].
The high frequency of genotype CYP2C9*3 in the studied sample can be explained by the influence of genetic drift smaller European population and the influence of genetic drift large Asian population in the central part of the population of Siberia. Asians genotype CYP2C9*3 is more common than genotype CYP2C9*2 [4; 5; 6].
The level ofVPA was 66 [53:86] mkg/ml in carriers of the genotype CYP2C9*1/*1, in carriers of the genotype CYP2C9*1/*2-86 [44:104] mkg/ml, CYP2C9*1/*3-72,5 [57.5:96] mkg/ml and in carriers of the genotype CYP2C9*2/*3-100 [100:100] mkg/ml. The daily dose of VPA in the groups had no significant differences.
Toxic, sub-toxic concentration of VPA in the blood at a greater frequency of cases found in carriers of genotype CYP2C9*1/*2 (38.5 %) and in the compound heterozygotes (100 %) and at least genotype CYP2C9*1/*3 (33.3 %) [8]. Which also significantly higher than the genotype CYP2C9*1/*1 (12.5 %).
The tendency to accumulation of VPA remained for heterozygous carriers of the mutant allele of a polymorphic variant CYP2C9*1/*2 even after dosing reduction on average of 16.7 % from baseline [7]. Two patients bearer compound heterozygous CYP2C9*2/*3 after correction dose of VPA (dose reduction the average of 15.5 % of the original) on the re-examination did not come. These findings are consistent with the data [8; 9; 10] of the higher risk of accumulation of VPA and other xenobiotics are metabolized in the liver in carriers of polymorphic allelic variants of the gene CYP2C9*1/*2.
According to the analysis of risk assessment, the risk of accumulation was 1.82, 2.1 and 5.46 times higher in genotype CYP2C9*1/*3, CYP2C9*1/*2 and CYP2C9*2/*3, respectively, than in genotype CYP2C9*1/*1.
Conclusions. According to our research, the accumulation of VPA in the blood at a greater frequency of cases detected in heterozygous carriers of the mutant allele of a polymorphic variant CYP2C9*1/*2 (38.5 %) and compound heterozygotes (100 %) and to a lesser extent in heterozygous carriers of the mutant polymorphic allelic variant CYP2C9*1/*3 (33.3 %) compared to homozygous carriers of advanced (“wild”) genotype CYP2C9*1/*1 (12.5 %). The obtained data are correlated with results of other authors, the higher the concentration of VPA in blood carriers allelic variants of polymorphic CYP2C9*2 and CYP2C9*3 in comparison with common carriers polymorphic allelic variant CYP2C9*1 [8; 10; 11; 12].
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Section 8. Medical science
However, accumulation of VPA in carriers of CYP2C9*3 poly- carriers of polymorphic allelic variants CYP2C9*3 compared
morphism can be traced not all authors [12]. On the other with carriers of “wild” polymorphic allelic variant is shown in a
hand, a higher concentration of VPA in the blood is shown in study conducted in Japan [9].
References:
1. Anderson G. D. Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs./ G. D. Aderson//Ther. Drug Monit. - 2008. - Vol. 30. - P. 173-180.
2. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin./A. S. Ayna-cioglu, J. Brockmoller, S. Bauer [et al.]//Br. J. Clin. Pharmacol. - 1999. - Vol. 483. - P. 409-415.
3. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population./M. G. Scordo, E. Aklillu, U. Yasar [et al.]//Br.J. Clin. Pharmacol. - 2001. - Vol. 52, № 4. - P. 447-450.
4. Takahashi H., Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications.//Clin Pharmacokinet. -2001. - 40: 587-603.
5. Allele and genotype frequencies of CYP2C9 in a Korean population./J.-W. Bae, H.-K. Kim, J.-H. Kim [et al.]//Br. J. Clin. Pharmacol. - 2005. - Vol. 60. - P. 418-422.
6. Frequency of cytochrome P450 2C9 (CYP2C9) alleles in three ethnic groups in Malaysia./K. C. Seng, G. G. Gin,J. V Sang-kar [et al.]//Asia Pacific J. Mol. Biol. Biotech. - 2003. - Vol. 1. - P. 83-91.
7. Pharmacogenetics of valproic acid as unmodified risk factor of adverse drug reactions./N. Shnayder, M. Pilugina, D. Dmi-trenko, [et al.]//Medical and Health Science Journal. - 2011. - Vol. 7. - P. 26-38.
8. Rosemary J. The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance./J. Rosemary, C. Adithan//Curr. Clin. Pharmacol. - 2007. - Vol. 2, № 1. - P. 93-109.
9. The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients./L. Tan, J. T. Yu, Y. P. Sun [et al.]//Clin. Neurol. Neurosurg. - 2010. - Vol. 112, № 4. - P. 320-323.
10. Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms./E. Garcia-Martin, C. Martinez, B. Tabares [et al.]//Clin. Pharmacol. Ther. - 2004. - Vol. 76. - P. 119-127.
11. Pharmacogenomic association study on the role of drug metabolizing, drug transporters and drug target gene polymorphisms in drug-resistant epilepsy in a north Indian population./R. Kumari, R. Lakhan, R. K. Garg [et al.]//Indian J. Human. Gen. - 2011. - Vol. 17, № 4. - P. 32-40.
12. Impact of CYP2C9 genetic polymorphisms on valproate dosage, plasma concentrations of valproate and clinical response to valproate./E. Brusturean-Bota, A. P. Trifa, C. A. Coada [et al.]//Hum. Veterinary Med. Int.J. Bioflux Soc. - 2013. - Vol. 5, № 3. - P. 94-98.
Dovlatov Zyaka Asaf ogly, City Clinical Botkin Hospital, Moscow, Russia, urologist, E-mail: dovlatov.zyaka@mail.ru Seregin Alexander Vasilyevich, chief of Urology Department E-mail: 41urology@41urology.ru Loran Oleg Borisovich,
Russian Medical Academy of Postgraduate Education, Moscow, Russia, chief of Urology and Chirurgical Andrology Department E-mail: oleg_loran@gmail.com
Late complications and quality of life of women after using mesh implants for the pelvic organ prolapsed
Abstract: Great experience clinical use mesh implants for pelvic organ prolapse treatment was the basis for achieving a low incidence of postoperative complications and high quality of life after surgery.
Keywords: pelvic organ prolapse, complications, quality of life.
Introduction 3 % and 94 %, depending on the approaches to the for-
The frequency of pelvic organ prolapse (POP) in the mation of a population sample and diagnosis of the dis-
female population according to various sources is between ease [1, 15-107]. Currently, synthetic mesh implants occupy
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