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2.
Transl Psychiatry ; 11(1): 467, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497262

RESUMO

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.


Assuntos
Encéfalo/anatomia & histologia , Citocromo P-450 CYP2C19 , Hipocampo , Polimorfismo Genético , Adulto , Encéfalo/diagnóstico por imagem , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Hipocampo/anatomia & histologia , Humanos
3.
Int J Cardiol ; 343: 15-20, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34506827

RESUMO

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) patients are treated with dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor. Clopidogrel is widely used in these patients in several areas worldwide, such as Middle East, but is associated to sub-optimal platelet inhibition in up to 1/3 of treated patients. We investigated a CYP2C19 genotype-guided strategy to select the optimal P2Y12 inhibitor. METHODS: This prospective randomized clinical trial included STEMI patients. The standard-treatment group received clopidogrel, while the genotype-guided group were genotyped for CYP2C19 loss-of-function alleles and carriers were prescribed ticagrelor and noncarriers were prescribed clopidogrel. Primary outcome was a combined ischemic and bleeding outcome, comprising myocardial infarction, non-fatal stroke, cardiovascular death, or Platelet Inhibition and Patient Outcomes major bleeding one year after STEMI. RESULTS: STEMI patients (755) were randomized into a genotype-guided- (383) and standard-treatment group (372). In the genotype-guided group, 31 patients carrying a loss-of-function allele were treated with ticagrelor, while all other patients in both groups were treated with clopidogrel. Patients in the genotype-guided group had a significantly lower risk of primary outcome (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.20-0.59,), recurrent myocardial infarction (OR 0.25, 95%CI 0.11-0.53), cardiovascular death (OR 0.16, 95%CI0.06-0.42) and major bleeding (OR 0.49, 95%CI 0.32-0.74). There was no significant difference in the rate of stent thrombosis (OR 0.85, 95%CI 0.43-1.71). CONCLUSION: A genotype-guided escalation of P2Y12 inhibitor strategy is feasible in STEMI patients treated with clopidogrel and undergoing PCI and is associated with a reduction of primary outcomes compared to conventional antiplatelet therapy.


Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Clopidogrel , Citocromo P-450 CYP2C19/genética , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Inibidores da Agregação Plaquetária , Testes Imediatos , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Resultado do Tratamento
4.
Xenobiotica ; 51(10): 1199-1206, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34402388

RESUMO

Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity. The aims of this study are to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with haematological malignancies.A total of 89 patients received an initial dose of 6 mg/kg followed by 4 mg/kg every 12 h were included in the study. Blood samples were collected before and 2 h after administration for subsequent testing and for the extraction of DNA samples. Voriconazole and voriconazole N-oxide in the plasma were detected by LC-MS/MS. The effect of voriconazole on CYP3A activity was evaluated by the ratio of the endogenous biomarkers 6ß-hydroxycortisol and cortisol.During the study period, the overall incidence of adverse reactions was 33.6% (with no deaths). The metabolite type of CYP2C19 and combined use of CYP2C19 enzyme inhibitors both had a significant impact on voriconazole exposure. Voriconazole has a long-lasting and potent inhibitory effect on CYP3A activity. The exposure of CYP3A substrate in combination with metabolic enzyme inhibitors voriconazole could increase. Therefore, the combination uses with voriconazole need to be considered carefully and assessed adequately.


Assuntos
Citocromo P-450 CYP3A , Neoplasias Hematológicas , Antifúngicos , Cromatografia Líquida , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Genótipo , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Humanos , Espectrometria de Massas em Tandem , Voriconazol
7.
Antimicrob Agents Chemother ; 65(9): e0020721, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34152823

RESUMO

Voriconazole (VRC), a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by human cytochrome P450 (CYP) 2C19. In this study, a retrospective analysis was performed to investigate the key factors that influence the plasma trough concentration (Cmin) of VRC, and an appropriate dosing regimen for pediatric patients was drafted subsequently. Overall, factors such as age, CYP2C19 phenotype, and combination medication with proton pump inhibitors accounted for 23.4% of variability in dose-normalized Cmin values of VRC by a multiple linear regression analysis. Dose-normalized Cmin values in the poor metabolizers (PMs) and intermediate metabolizers (IMs) were significantly higher than those in extensive metabolizers (EMs) (P < 0.001). To achieve therapeutic Cmin for CYP2C19 ultrarapid metabolizers (UMs) or EMs, patients aged no more than 12 and more than 12 years required doses of 6.53 ± 2.08 and 3.95 ± 0.85 mg/kg of body weight twice daily (P = 0.007). For CYP2C19 PMs or IMs, patients aged under 12 and over 12 years required doses of 5.75 ± 1.73 and 4.23 ± 0.76 mg/kg twice daily, respectively (P = 0.019). Furthermore, coadministration of rifamycin sodium or omeprazole exhibited significant effects on VRC Cmin. Taken together, it is necessary to pay attention to the impact of CYP2C19 phenotype and drug-drug interactions to achieve optimal therapy.


Assuntos
Antifúngicos , Preparações Farmacêuticas , Idoso , Antifúngicos/uso terapêutico , Criança , Citocromo P-450 CYP2C19/genética , Interações Medicamentosas , Genótipo , Humanos , Fenótipo , Estudos Retrospectivos , Voriconazol
8.
Antimicrob Agents Chemother ; 65(9): e0062321, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34097481

RESUMO

Prophylactic voriconazole use is recommended for children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential, due to the narrow therapeutic window of voriconazole. Known covariates do not sufficiently explain the large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. We investigated genetic and clinical covariate associations with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. This study was conducted as part of a single-institution, phase I study of intravenous voriconazole therapy for children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. We analyzed plasma voriconazole and N-oxide metabolite concentrations from 58 children <21 years of age (including 12 children <2 years of age). A two-compartment parent mixed linear/nonlinear model best described our data. The CYP2C19 phenotype and body weight were significant covariates (P < 0.05 for both). Our model performance for age <2 years was comparable to that for other age groups. Simulation of the final model suggested the following doses to attain target steady-state trough concentrations of 1.5 to 5.0 mg/liter for the CYP2C19 normal phenotype: 16 mg/kg (weight of <15 kg), 12 mg/kg (weight of 15 to 30 kg), or 10 mg/kg (weight of >30 kg); doses were 33 to 50% lower for CYP2C19 poor/intermediate phenotypes and 25 to 50% higher for CYP2C19 rapid/ultrarapid phenotypes. We propose a new starting-dose regimen, combined with therapeutic drug monitoring, for intravenous voriconazole therapy in children of all ages. Future studies should validate this dosing regimen.


Assuntos
Antifúngicos , Transplante de Células-Tronco Hematopoéticas , Antifúngicos/uso terapêutico , Peso Corporal , Criança , Pré-Escolar , Citocromo P-450 CYP2C19/genética , Genótipo , Humanos , Lactente , Fenótipo , Voriconazol
9.
Int J Lab Hematol ; 43(4): 786-794, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34129280

RESUMO

INTRODUCTION: Light transmission aggregometry (LTA), used to detect clopidogrel resistance in patients under antiplatelet therapy, is prone to multiple variables potentially influencing results and interpretation. Currently, no attention is given to type of aggregometer or reagent used. The aim of this study was to evaluate the interassay variability between two aggregometers (Chronolog700 and TA-8V), using two different ADP reagents (Chrono-Par® and Agro-Bio ADP) in patients under clopidogrel therapy. Additionally, LTA results were correlated to CYP2C19-polymorphism. METHODS: Light transmission aggregometry was performed in 20 healthy individuals and 30 patients using both aggregometers, and applying two different reagents (2.5 and 5 µmol/L). The maximum platelet aggregation (ADPmax ), the platelet aggregation at 6 minutes (ADP6min ), and the percentage of disaggregation at 6 min (ADP%disaggr ) were compared between four applied combinations. Additionally, 23 clopidogrel-resistant patients according to Chronolog700-Chrono-par® ADP reagent analysis were tested for CYP2C19*2 polymorphism. RESULTS: Comparison of the LTA of healthy individuals revealed a significant lower ADPmax , lower ADP6min , and higher ADP%disaggr with the TA-8V aggregometer compared to Chronolog700, regardless of the reagent. In contrast, LTA results in patients are depending on the reagent, with significant higher ADPmax and ADP6min and lower ADP%disaggr using Chrono-Par® compared to Agro-Bio ADP reagent. All intermediate clopidogrel metabolizers (CYP2C19*2 carriers) were correctly classified as clopidogrel resistant using Chrono-Par® , in contrast to the Agro-Bio ADP reagent. CONCLUSION: Light transmission aggregometry in clopidogrel-treated patients is mainly depending on the type of ADP reagent. Comparison of LTA with genotype reveals that the choice of instrument seems less influencing. In contrast, in the healthy individuals, differences could be attributed to the instrument.


Assuntos
Clopidogrel/uso terapêutico , Monitoramento de Medicamentos/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Clopidogrel/farmacologia , Citocromo P-450 CYP2C19/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacologia , Polimorfismo Genético , Adulto Jovem
10.
Eur J Intern Med ; 90: 49-65, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34092486

RESUMO

BACKGROUND: Antiplatelet agent clopidogrel has been widely used for stroke management for many years, although resistance to clopidogrel may increase the chance of stroke recurrence. CYP2C19 loss-of-function (LoF) polymorphism is assumed to be responsible for the poor metabolism of clopidogrel that ultimately turns to resistance. Previous publications could not provide firm evidence due to highly conflicting and heterogeneous outcomes. AIM: To get clear evidence from an updated meta-analysis on CYP2C19 LoF polymorphism association with stroke risk in clopidogrel treated patients, this study has been performed. METHODS: We conducted a meta-analysis with 72 selected studies from authentic databases, including 40,035 coronary artery disease patients treated with clopidogrel. RESULTS: This analysis showed that the worldwide carrier of one or more CYP2C19 LoF alleles had a significantly higher risk of stroke and composite events than the non-LoF carriers (RR=1.78, 95% CI=1.52-2.07, p<0.00001 and RR=1.39, 95% CI=1.26-1.54, p<0.00001, respectively). Besides, subgroup analysis showed that Asian CYP2C19 LoF carriers had a significantly increased risk of stroke (RR=1.91, 95% CI=1.60-2.28, p<0.00001) while the risk of composite events was significantly higher in all ethnic populations (Asian: RR=1.58, 95% CI=1.32-1.89, p<0.00001; Caucasian: RR=1.27, 95% CI=1.08-1.50, p=0.003; Hispanic and others: RR=1.21, 95% CI=1.09-1.34, p=0.0003). CONCLUSION: Our meta-analysis confirmed that the presence of CYP2C19 LoF alleles increases the risk of stroke and composite events recurrence in the worldwide population, especially in Asians undergoing clopidogrel treatment. Alternative antiplatelet therapy should be investigated thoroughly for the intermediate and poor metabolizers.


Assuntos
Doença da Artéria Coronariana , Acidente Vascular Cerebral , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Citocromo P-450 CYP2C19/genética , Grupos Étnicos , Genótipo , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Resultado do Tratamento
11.
Arh Hig Rada Toksikol ; 72(3): 129-134, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34187105

RESUMO

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants - 16.2 and 20.4 %, respectively - nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.


Assuntos
Hidrocarboneto de Aril Hidroxilases , Alelos , Hidrocarboneto de Aril Hidroxilases/genética , Bósnia e Herzegóvina , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Humanos , Polimorfismo Genético , Prevalência
12.
Chem Biol Interact ; 345: 109552, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34147487

RESUMO

Ethofumesate is a chiral herbicide that may display enantioselective behavior in humans. For this reason, the enantioselective potential of ethofumesate and its main metabolite ethofumesate-2-hydroxy to cause pesticide-drug interactions on cytochrome P450 forms (CYPs) has been evaluated by using human liver microsomes. Among the evaluated CYPs, CYP2C19 had its activity decreased by the ethofumesate racemic mixture (rac-ETO), (+)-ethofumesate ((+)-ETO), and (-)-ethofumesate ((-)-ETO). CYP2C19 inhibition was not time-dependent, but a strong inhibition potential was observed for rac-ETO (IC50 = 5 ± 1 µmol L-1), (+)-ETO (IC50 = 1.6 ± 0.4 µmol L-1), and (-)-ETO (IC50 = 1.8 ± 0.4 µmol L-1). The reversible inhibition mechanism was competitive, and the inhibition constant (Ki) values for rac-ETO (2.6 ± 0.4 µmol L-1), (+)-ETO (1.5 ± 0.2 µmol L-1), and (-)-ETO (0.7 ± 0.1 µmol L-1) were comparable to the Ki values of strong CYP2C19 inhibitors. Inhibition of CYP2C19 by ethofumesate was enantioselective, being almost twice higher for (-)-ETO than for (+)-ETO, which indicates that this enantiomer may be a more potent inhibitor of this CYP form. For an in vitro-in vivo correlation, the Food and Drug Administration's (FDA) guideline on the assessment of drug-drug interactions used in the early stages of drug development was used. The FDA's R1 values were estimated on the basis of the obtained ethofumesate Ki and distribution volume, metabolism, unbound plasma fraction, gastrointestinal and dermal absorption data available in the literature. The correlation revealed that ethofumesate probably inhibits CYP2C19 in vivo for both chronic (oral) and occupational (dermal) exposure scenarios.


Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Inibidores do Citocromo P-450 CYP2C19/química , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Citocromo P-450 CYP2C19/metabolismo , Mesilatos/química , Mesilatos/farmacologia , Praguicidas/química , Praguicidas/farmacologia , Citocromo P-450 CYP2C19/química , Inibidores do Citocromo P-450 CYP2C19/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Estereoisomerismo
13.
Indian Heart J ; 73(3): 281-288, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34154743

RESUMO

OBJECTIVE: To study the use of CYP2C19 genotyping to guide P2Y12 inhibitor selection to maximize efficacy, and attenuate risk in appropriate patients who underwent PCI for CAD. METHODS: We performed a retrospective analysis of 868 patients with CAD who received CYP2C19 genotyping after PCI and changed P2Y12 inhibitor based on the results. Patients were divided into two groups based on clopidogrel metabolizer status. Group I: Intermediate (IM) and poor metabolizers (PM). Group II: Ultra-rapid (UM), rapid (RM) and normal metabolizers (NM). Each group was then categorized to one of two treatment arms guided by CYP2C19 genotype. Category 1: IM/PM started on clopidogrel, switched to ticagrelor or prasugrel; 2:IM/PM started on ticagrelor/prasugrel, continued these medications; 3: UM/RM/NM started on ticagrelor/prasugrel, switched to clopidogrel; 4: UM/RM/NM started on clopidogrel, continued clopidogrel. Death due to cardiac causes, bleeding events, non-fatal MI, target vessel revascularization (TVR), and MACE in all four categories were considered at 1, 6 and 12 months. RESULTS: We did not observe significant difference between phenotypes for MACE at 1 (p = 0.274), 6 (p = 0.387), and 12 months (p = 0.083). Death due to cardiac causes, MI, and bleeding events were not significant at 1, 6, and 12 months. There was no significant difference in TVR at 6 (p = 0.491), and 12 months (p = 0.423) except at 1 month (p = 0.012). CONCLUSION: CYP2C19 genotype-based intervention can be implemented effectively and reliably to guide selection of P2Y12 inhibitor to optimize patient quality and safety when appropriate in post PCI patients.


Assuntos
Intervenção Coronária Percutânea , Síndrome Coronariana Aguda , Citocromo P-450 CYP2C19/genética , Genótipo , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y , Estudos Retrospectivos
14.
Sci Rep ; 11(1): 12343, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117307

RESUMO

Prior knowledge of allele frequencies of cytochrome P450 polymorphisms in a population is crucial for the revision and optimization of existing medication choices and doses. In the current study, the frequency of the CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*6, CYP2C19*17, and CYP3A4 (rs4646437) alleles in a Thai population across different regions of Thailand was examined. Tests for polymorphisms of CYP2C9 and CYP3A4 were performed using TaqMan SNP genotyping assay and CYP2C19 was performed using two different methods; TaqMan SNP genotyping assay and Luminex x Tag V3. The blood samples were collected from 1205 unrelated healthy individuals across different regions within Thailand. Polymorphisms of CYP2C9 and CYP2C19 were transformed into phenotypes, which included normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and rapid metabolizers (RM). The CYP2C9 allele frequencies among the Thai population were 0.08% and 5.27% for the CYP2C9*2 and CYP2C9*3 alleles, respectively. The CYP2C19 allele frequencies among the Thai population were 25.60%, 2.50%, 0.10%, and 1.80% for the CYP2C19*2, CYP2C19*3, CYP2C19*6, and CYP2C19*17 alleles, respectively. The allele frequency of the CYP3A4 (rs4646437) variant allele was 28.50% in the Thai population. The frequency of the CYP2C9*3 allele was significantly lower among the Northern Thai population (P < 0.001). The frequency of the CYP2C19*17 allele was significantly higher in the Southern Thai population (P < 0.001). Our results may provide an understanding of the ethnic differences in drug responses and support for the utilization of pharmacogenomics testing in clinical practice.


Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Frequência do Gene , Polimorfismo de Nucleotídeo Único , Fenótipo , Tailândia
15.
Cancer Chemother Pharmacol ; 88(3): 533-542, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34114066

RESUMO

PURPOSE: Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients. METHODS: CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug. RESULTS: We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing. CONCLUSION: Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Citocromo P-450 CYP2C19/genética , Farmacogenética , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacologia , Neoplasias da Mama/genética , Ciclofosfamida/análogos & derivados , Ciclofosfamida/metabolismo , Ciclofosfamida/farmacocinética , Ciclofosfamida/farmacologia , Citocromo P-450 CYP2B6/genética , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Biomed Res Int ; 2021: 6150628, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937401

RESUMO

Background: Helicobacter pylori eradication with therapies employing a proton pump inhibitor (PPI) and antimicrobial agents is mainly achieved via bacterial susceptibility to antimicrobial agents and the magnitude of acid secretion inhibition. However, annual eradication rates have greatly declined in Mainland China, and therefore, tailored H. pylori eradication regimens that inhibit acid secretion and employ optimal antimicrobial agents determined based on gene clip testing may improve eradication rates. This study was aimed at evaluating the efficacy of tailored H. pylori eradication therapy guided by visual gene clip testing for antibiotic resistance and PPI metabolism genotypes. Methods: This prospective study included 244 patients (141 men and 103 women aged 20-79 years) receiving initial treatment for H. pylori infection. Visual gene clip testing using gastric mucosal specimens was performed to detect antibiotic resistance to clarithromycin conferred by the A2142G and A2143G point mutations of the H. pylori 23S rRNA gene and to levofloxacin conferred by the Asn87 and Asp91 point mutations of the H. pylori gyrA gene. Patients received a 14-day bismuth quadruple therapy regimen guided by testing for antibiotic resistance and CYP2C19 polymorphisms, and primary H. pylori eradication was assessed at least 4 weeks after therapy. Results: H. pylori strains were successfully isolated from the gastric mucosa tissues of 244 patients. Antibiotic resistant isolates were identified in 63 patients, with clarithromycin resistance observed in 50 patients, levofloxacin resistance in 7 patients, and dual resistance in 6 patients. The PPI metabolic genotype of CYP2C19 was detected in 242 of 244 cases, and 97 cases were categorized as extensive metabolizers, 141 as intermediate metabolizers, and 4 as poor metabolizers. Among the 242 patients who received tailored therapy, the H. pylori eradication rate was 90.9% (95% confidence interval 87.3%~94.6%) in the intention-to-treat analysis and 96.9% (95% confidence interval 94.7%~99.2%) in the per protocol analysis. Conclusions: Tailored therapy for H. pylori infection guided by determination of antibiotic resistance and CYP2C19 polymorphism using visual gene chip technology may provide high clinical effectiveness as initial H. pylori eradication therapy.


Assuntos
Erradicação de Doenças , Infecções por Helicobacter/genética , Infecções por Helicobacter/terapia , Helicobacter pylori/fisiologia , Adulto , Idoso , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Citocromo P-450 CYP2C19/genética , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Resistência Microbiana a Medicamentos/genética , Feminino , Genótipo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Adulto Jovem
17.
Georgian Med News ; (312): 52-56, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33964826

RESUMO

The new cardiovascular events development remains the main factors limiting its long-term effectiveness despite technological progress and the widespread use of percutaneous coronary intervention (PCI). Objective - to assess the effect of clinical and genetic factors on the development of complication after percutaneous coronary intervention with double antiplatelet therapy (DAT). Case-control. The main group included 34 (46.57%) patients with ischemic heart disease after the procedure of percutaneous coronary intervention with bleeding, the control group included 39 (53.43%) patients with verified ischemic heart disease after the procedure of percutaneous coronary intervention without bleeding signs. The average age of the patients in the main group was 63.25±8.7, this group included 65% men and 35% women. The average age of the patients in the control group was 63.82±8.9, this group included 87% men and 13% women, respectively. It was found on the base of the clinical and laboratory characteristics of the bleeding risk in patients after percutaneous coronary intervention that the bleeding predictors after PCI against a background of DAT were: female gender (OR=3.405, p=0.027), the presence of diabetes mellitus (OR=2.399, p=0.046), body mass index (BMI) (OR=1.200, p=0.038), coronary artery stenting (OR=1.045, p=0.030), erythrocytes level (OR=2.292, p=0.049), platelet count (OR=3.964, p=0.048), hemoglobin (Hb) (OR=1.333, p=0.042), erythrocyte sedimentation rate (ESR) (OR=1.008, p=0.009), ejection fraction (OR=1.248, p=0.043), glomerular filtration rate (OR=1.227, p=0.002). According to a genetic study, CYP2C19*17 C/T gene polymorphism was detected in 9% of patients with double antiplatelet therapy. There was no statistically significant difference in genotypes of the 17th allele CYP2C19 in accordance with the results of the analysis of genotypes in the first and second groups. The Odds Ratio values (OR=0.658), 95% confidence interval [0.145-2.984] were obtained for all the studied polymorphisms, which indicates the absence of polymorphism association of СYP2C19*17 gene with a risk of bleeding.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Doenças Cardiovasculares/genética , Citocromo P-450 CYP2C19/genética , Feminino , Hemorragia , Humanos , Masculino , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo Genético , Fatores de Risco , Resultado do Tratamento
18.
Biol Pharm Bull ; 44(5): 737-741, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952830

RESUMO

For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CLtot/F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CLtot/F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.


Assuntos
Antifúngicos/farmacocinética , Candidíase Invasiva/tratamento farmacológico , Nutrição Enteral/métodos , Voriconazol/farmacocinética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Voriconazol/administração & dosagem
19.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799598

RESUMO

We sought to develop a cell-based cytotoxicity assay using human hepatocytes, which reflect the effects of drug-metabolizing enzymes on cytotoxicity. In this study, we generated luminescent human hepatoblastoma HepG2 cells using the mouse artificial chromosome vector, in which click beetle luciferase alone or luciferase and major drug-metabolizing enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are expressed, and monitored the time-dependent changes of CYP-mediated cytotoxicity expression by bioluminescence measurement. Real-time bioluminescence measurement revealed that compared with CYP-non-expressing cells, the luminescence intensity of CYP-expressing cells rapidly decreased when the cells were treated with low concentrations of aflatoxin B1 or primaquine, which exhibits cytotoxicity in the presence of CYP3A4 or CYP2D6, respectively. Using kinetics data obtained by the real-time bioluminescence measurement, we estimated the time-dependent changes of 50% inhibitory concentration (IC50) values in the aflatoxin B1- and primaquine-treated cell lines. The first IC50 value was detected much earlier and at a lower concentration in primaquine-treated CYP-expressing HepG2 cells than in primaquine-treated CYP-non-expressing cells, and the decrease of IC50 values was much faster in the former than the latter. Thus, we successfully monitored time- and concentration-dependent dynamic changes of CYP-mediated cytotoxicity expression in CYP-expressing luminescent HepG2 cells by means of real-time bioluminescence measurement.


Assuntos
Aflatoxina B1/toxicidade , Efeito Fundador , Medições Luminescentes/métodos , Primaquina/toxicidade , Imagem com Lapso de Tempo/métodos , Xenobióticos/toxicidade , Animais , Linhagem Celular Tumoral , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células Hep G2 , Humanos , Concentração Inibidora 50 , Luciferases/genética , Luciferases/metabolismo , Luminescência , Camundongos
20.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915807

RESUMO

Clopidogrel is a widely-used antiplatelet drug. It is important for the treatment and prevention of coronary heart disease. Clopidogrel can effectively reduce platelet activity and therefore reduce stent thrombosis. However, some patients still have ischemic events despite taking the clopidogrel due to the alteration in clopidogrel metabolism attributable to various genetic and non-genetic factors. This review aims to summarise the mechanisms and causes of clopidogrel resistance (CR) and potential strategies to overcome it. This review summarised the possible effects of genetic polymorphism on CR among the Asian population, especially CYP2C19 *2 / *3 / *17, where the prevalence rate among Asians was 23.00%, 4.61%, 15.18%, respectively. The review also studied the effects of other factors and appropriate strategies used to overcome CR. Generally, CR among the Asian population was estimated at 17.2-81.6%. Therefore, our overview provides valuable insight into the causes of RC. In conclusion, understanding the prevalence of drug metabolism-related genetic polymorphism, especially CYP2C19 alleles, will enhance clinical understanding of racial differences in drug reactions, contributing to the development of personalised medicine in Asia.


Assuntos
Clopidogrel/farmacologia , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Resistência a Medicamentos/genética , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/farmacologia , Polimorfismo de Nucleotídeo Único , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Alelos , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Clopidogrel/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Gerenciamento Clínico , Interações Medicamentosas , Feminino , Humanos , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Vigilância da População , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Medição de Risco , Fatores de Risco
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