ABSTRACT
BACKGROUND: The clinical utility of genotype-guided warfarin dosing remains controversial. The objective of this trial was to evaluate the efficacy and safety of genotype-guided warfarin dosing in East Asians. METHODS: A double-blind, randomized control trial was performed to compare a genotype-guided dosing algorithm (CYP2C9, VKORC1, and CYP4F2) with a clinical-guided one in the initiation treatment for patients with mechanical heart valves. The primary outcomes included the time to reach a stable dose and the percentage of time in the therapeutic range (TTR). RESULTS: Two hundred one patients were randomly assigned to treatment, 101 to control and 100 to study. The major bleeding and thromboembolic event-free rate in the study group was 97.0% (95% confidence interval: 90.9% to 99.2%). Compared with the control group, the study group shortened the time to reach a stable dose (mean: 42.09 ± 23.655 days versus 33.52 ± 20.044 days, p = 0.009). The TTRs were 47.257% and 47.461% in the control and study group (p = 0.941), respectively. Patients with the CYP2C9 *1/*3 genotype had higher international normalized ratio (INR) variability than patients with the CYP2C9 *1/*1 genotype (p = 0.024). Compared with normal and sensitive responders, the highly sensitive responders were at increased risk of an INR of 4.0 or greater (p < 0.05). CONCLUSIONS: The genotype-guided warfarin dosing was safe and might be more efficient for the time to reach a stable dose. Pharmacogenomic testing might be beneficial to identify the patients with the CYP2C9 *1/*3 genotype and the highly sensitive responders, who were in the high-risk subgroup of patients with mechanical heart valves. An appropriately powered study is needed to further confirm these findings.
Subject(s)
Anticoagulants/administration & dosage , Heart Valve Prosthesis , Warfarin/administration & dosage , Asian People/genetics , Double-Blind Method , Female , Genotype , Heart Valve Diseases/genetics , Heart Valve Diseases/surgery , Humans , International Normalized Ratio , Male , Middle Aged , Prospective StudiesABSTRACT
The effects of ß adrenergic receptors (ß-ARs) and p38 mitogen-activated protein kinases (MAPK) pathways on cardiosphere-derived cells (CDCs) are largely unknown. This study aimed to investigate the roles of ß-ARs and p38MAPK pathways on the proliferation, apoptosis, and differentiation capacity of CDCs. The CDCs were treated with ß1-AR blocker (Met group), ß2-AR antagonist (ICI group), and p38MAPK inhibitor (SB group), non-selective ß-AR blocker (PRO group), and ß-AR agonist (ISO group). The viability, apoptotic rate and differentiation status of CDCs were determined by MST-1 assay, flow cytometery, and Western blot, respectively. The CDCs viability significantly reduced in ICI group (all P < 0.05), and SB group had a significant high viability after 48 h treatment (P < 0.05). Compared with control group, all treated groups had a low apoptotic rate. After treatment for 72 h, ISO treatment elevated the expression of Nkx2.5, and could partially or fully attenuate the inhibitory effects of ß-AR antagonists and/or p38MAPK inhibitor. A similar overall trend of protein expression levels among all groups could be observed between protein pairs of cTnT and ß1-AR as well as c-Kit and ß2-AR, respectively. These results suggested that ß-ARs and p38MAPK signaling pathways play crucial roles in the proliferation and differentiation of CDCs. Our findings should be helpful for better understanding the molecular mechanism underlying the physiological processes of CDCs.
Subject(s)
Myocytes, Cardiac/cytology , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Spheroids, Cellular/cytology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Apoptosis , Cell Culture Techniques , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Imidazoles/pharmacology , Isoproterenol/pharmacology , MAP Kinase Signaling System/drug effects , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Propanolamines/pharmacology , Propranolol/pharmacology , Pyridines/pharmacology , Rats , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolismABSTRACT
<p><b>OBJECTIVE</b>To study on the effect and mechanism of curcumin on inhibiting injury induced by free radical in pulmonary fibrosis.</p><p><b>METHOD</b>One hundred and forty-four male SD rats were randomly divided into 6 groups (24 rats in each group). Rats in the model control group, positive medicine group, and high, moderate and low curcumin groups were injected with a single dose of bleomycin by trachea, and rats in sham-model control group with same volume normal saline. One day after the injection, curcumin solution of different dosages (200,100,50 mg x kg(-1) x d(-1)) was respectively given to rats in the high, moderate and low curcumin group by daily gastrogavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone (0.56 mg x kg(-1) x d(-1)) was saline was given to those in positive medicine control group. On the 7, 14, 28 days, the contents of GSH-Px, SOD, MDA and iNOS in pulmonary tissues of different groups were measured.</p><p><b>RESULT</b>Curcumin can raise the content of SOD and GSH-Px and lessen the level of MDA and iNOS.</p><p><b>CONCLUSION</b>Curcumin can regulate the level of free radical in the body of rats with pulmonary fibrosis and lessen the oxidative injury of pulmonary tissues caused by free radical, in the body of rats with pulmonary fibrosis. The mechanisms of curcumin on idiopathic pulmonary fibrosis lie in adjusting the level of free radical and inhibiting the injury of lung tissue induced by free radical.</p>
Subject(s)
Animals , Male , Rats , Antioxidants , Pharmacology , Bleomycin , Curcuma , Chemistry , Curcumin , Pharmacology , Free Radicals , Metabolism , Glutathione Peroxidase , Metabolism , Lung , Metabolism , Pathology , Malondialdehyde , Metabolism , Nitric Oxide Synthase Type II , Metabolism , Plants, Medicinal , Chemistry , Pulmonary Fibrosis , Metabolism , Random Allocation , Rats, Sprague-Dawley , Superoxide Dismutase , MetabolismABSTRACT
Objective To observe the expression of bcl-2 gene in cell apoptosis of neonatal rats followed by hypoxic-ischemic brain damage(HIBD) and investigate the mechanism of neuronal apoptosis after HIBD.Methods Fifty-four neonatal SD rats were used in 1 sham-operated group and 8 trial groups. The models of HIBD were established in neonatal rats by inhaling the mixed gases of 92 % N 2 and 8 % O 2, the animals were sacrificed by dislocation their heads at different time points(0.5,1,3,6,12,24,48,72 h), the hippocampus were dissected for morphological analysis. The neuronal apoptosis and the expression of bcl-2 gene in hippocampus were detected by the methods of immunohistochemistry. Results The apoptotic cells appeared at the time point of 3 h, and reached the peak at 48 h, then decreased. The positive cell of bcl-2 protein increased from the time point of 30 min and reached the peak at 6 h and then decreased gradually following HIBD. Conclusion The expression of bcl-2 gene plays a role in the process of neuronal apoptosis following HIBD.
