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1.
J Hum Genet ; 62(12): 1009-1014, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28878340

ABSTRACT

Valproic acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. Adverse effects of valproic acid are rare, but hepatotoxicity is severe in particular in those younger than 2 years old and polytherapy. During valproic acid treatment, it is difficult for prescribers to predict its individual response. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect valproic acid efficacy and safety. In this review, a large number of candidate genes that influence valproic acid pharmacokinetics and pharmacodynamics are discussed, including metabolic enzymes, drug transporters, neurotransmitters and drug targets. Furthermore, pharmacogenomics is an important tool not only in further understanding of interindividual variability but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.


Subject(s)
Anticonvulsants/pharmacology , Bipolar Disorder/drug therapy , Epilepsy/drug therapy , Pharmacogenetics , Valproic Acid/pharmacology , Anticonvulsants/adverse effects , Anticonvulsants/metabolism , Cytochrome P-450 Enzyme System/genetics , Drug Delivery Systems , Genetic Variation , Humans , Neurotransmitter Agents/genetics , Pharmacokinetics , Precision Medicine , Valproic Acid/adverse effects , Valproic Acid/metabolism
2.
Clin Exp Hypertens ; 39(8): 726-731, 2017.
Article in English | MEDLINE | ID: mdl-28640647

ABSTRACT

This study aimed to evaluate the effect of PRKCH rs2230500 genetic polymorphism on efficacy of amlodipine and telmisartan for patients with hypertension. A total of 136 essential hypertension (EH) patients were treated with amlodipine (70 patients) or telmisartan (66 patients), respectively. Genetic polymorphism was genotyped by Sanger sequencing. Both baseline and post-treatment blood pressure (BP) and heart rate were measured to evaluate the influence of genetic polymorphism on the antihypertensive response. No significant difference in the absolute decrease in diastolic blood pressure (DBP),systolic blood pressure (SBP), and mean arterial pressure (MAP) was observed among PRKCH rs2230500 genotypes after 4-week amlodipine or telmisartan therapy (p > 0.05). However, when compared with carriers or GG genotype, the antihypertensive effect of PRKCH rs2230500 GA/AA carriers was superior in telmisartan treatment group. PRKCH rs2230500 gene polymorphism is significantly related to the efficiency in telmisartan therapy (p = 0.02). The PRKCH rs2230500 may influence the antihypertensive efficacy of telmisartan in Chinese EH patients, and further studies are needed to confirm these findings.


Subject(s)
Amlodipine/therapeutic use , Antihypertensive Agents/therapeutic use , Benzimidazoles/therapeutic use , Benzoates/therapeutic use , Essential Hypertension/drug therapy , Essential Hypertension/genetics , Protein Kinase C/genetics , Adult , Aged , Arterial Pressure/drug effects , Arterial Pressure/genetics , Asian People , Female , Heart Rate/drug effects , Heart Rate/genetics , Heterozygote , Homozygote , Humans , Male , Middle Aged , Polymorphism, Genetic , Telmisartan
3.
Blood Coagul Fibrinolysis ; 26(8): 874-81, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26083990

ABSTRACT

Activation of platelet implicated a series of signal conduction including outside-in and inside-out related receptor-mediated signaling pathways. Ticagrelor is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect. Given that platelet aggregation varies among individuals, genetic polymorphisms in P2Y12 and subsequent signal molecular such as the G-protein beta 3 subunit (GNB3) are supposed to influence the antiplatelet effect of ticagrelor. The aim of this study was to determine whether genetic polymorphisms in P2Y12 and GNB3 genes influence ex-vivo antiplatelet activity of ticagrelor in healthy Chinese subjects. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined by using light transmittance aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 µmol/l ticagrelor, respectively. Nine single-nucleotide polymorphisms (SNPs) in P2Y12 and the GNB3 rs5443 polymorphism were genotyped by PCR-direct sequencing. P2Y12 haplotypes were inferred. Baseline platelet aggregation was increased in carriers of the common alleles of P2Y12 SNPs (rs1907637, rs2046934, and rs6809699) and rs6787801 TC heterozygotes (P < 0.05 for all). Results of the haplotype analyses were consistent with those of the single SNPs. Ticagrelor at both concentrations of 15 and 50 µmol/l decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). Neither single SNPs nor haplotypes of P2Y12 affected ticagrelor-induced ex-vivo inhibition of platelet aggregation. P2Y12 and GNB3 polymorphisms have no effect on the ex-vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects.


Subject(s)
Adenosine/analogs & derivatives , Blood Platelets/drug effects , Heterotrimeric GTP-Binding Proteins/genetics , Polymorphism, Single Nucleotide , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y12/genetics , Adenosine/pharmacology , Adenosine Diphosphate/pharmacology , Adolescent , Adult , Alleles , Asian People , Blood Platelets/cytology , Blood Platelets/metabolism , Drug Antagonism , Genotype , Healthy Volunteers , Humans , Male , Platelet Activation/drug effects , Platelet Activation/genetics , Platelet Aggregation/drug effects , Platelet Aggregation/genetics , Platelet-Rich Plasma/chemistry , Primary Cell Culture , Sequence Analysis, DNA , Ticagrelor
4.
Int J Hematol ; 99(3): 263-71, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24474638

ABSTRACT

Ticagrelor (TIC) is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect by indirect inhibition of the GPIIb/IIIa complex. Polymorphisms in genes coding GPIIb/IIIa, namely ITGA2B and ITGB3, are associated with aspirin resistance and risk for thrombotic diseases. We assessed whether ITGA2B and ITGB3 polymorphisms can influence the ex vivo antiplatelet activity of ticagrelor in Chinese population. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined using optical aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 µM ticagrelor, respectively. Single nucleotide polymorphisms in ITGA2B (rs5911 G>T) and ITGB3 (rs4642 A>G and rs4634 G>A) were genotyped by sequencing. TIC at both concentrations of 15 and 50 µM decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). As compared to ITGA2B rs5911 GG homozygotes, individuals with the rs5911 TG genotype showed significantly increased inhibition of platelet aggregation (IPA) by both 15 and 50 µM ticagrelor incubation (P < 0.05, respectively). Neither rs4642 nor rs4634 polymorphism affected ticagrelor-induced IPA. We suggest that the ITGA2B rs5911 GG genotype is associated with decreased ex vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects.


Subject(s)
Adenosine/analogs & derivatives , Integrin alpha2/genetics , Integrin beta3/genetics , Platelet Aggregation/drug effects , Platelet Aggregation/genetics , Polymorphism, Single Nucleotide , Purinergic P2 Receptor Antagonists/pharmacology , Adenosine/pharmacology , Adenosine Diphosphate/pharmacology , Adult , Asian People/genetics , Cohort Studies , Dose-Response Relationship, Drug , Humans , Male , Ticagrelor , Young Adult
5.
Zhongguo Zhong Yao Za Zhi ; 38(17): 2859-62, 2013 Sep.
Article in Chinese | MEDLINE | ID: mdl-24380311

ABSTRACT

OBJECTIVE: To evaluate the effect of Notoginseng Radix on hepatic expression of transforming growth factor beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in rats with alcoholic liver disease (ALD), in order to discuss its protective effect on alcoholic cirrhosis. METHOD: Fifty SD male rats were divided into the normal control group, the model group, the high-dose and low-dose Notoginseng Radix groups (3.0, 12.0 g x kg(-1)) and the magnesium isoglycyrrhizinate group (24 mg x kg(-1)), with 10 rats in each group. Apart from the control group, other groups were administered with ethanol-cornoil-pyrazole for 14 weeks to establish the alcoholic liver disease model. During the establishment of the model, the high-dose and low-dose Notoginseng Radix groups were administered with 12 g x kg(-1) x d(-1) Notoginseng Radix for 14 weeks, once everyday. Efforts were made to detect liver function, pathology with Masson staining, and the expressions of TGF-beta1, Smad3, Smad7 and CTGF mRNA. RESULT: Compared with the rats in model group, rats in Notoginseng Radix groups showed significant reduction in liver ALT, AST, collagen fiber deposition, and TGF-beta1, Smad3 and CTGF mRNA expressions in liver tissues, with the increase in the expression quantity of Smad7 mRNA. There were differences between the Notoginseng Radix groups. No significant difference was observed between the high-dose Notoginseng Radix group and the magnesium isoglycyrrhizinate group. CONCLUSION: Notoginseng Radix can affect TGF-beta1/Smads signaling pathway and reduce the expression of CTGF.


Subject(s)
Connective Tissue Growth Factor/genetics , Drugs, Chinese Herbal/administration & dosage , Liver Diseases, Alcoholic/drug therapy , Liver Diseases, Alcoholic/genetics , Panax notoginseng/chemistry , Smad3 Protein/genetics , Smad7 Protein/genetics , Transforming Growth Factor beta1/genetics , Animals , Connective Tissue Growth Factor/metabolism , Gene Expression/drug effects , Humans , Liver Diseases, Alcoholic/metabolism , Male , Rats , Rats, Sprague-Dawley , Smad3 Protein/metabolism , Smad7 Protein/metabolism , Transforming Growth Factor beta1/metabolism
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