Gut microbiota and precision drug therapy / 医学研究生学报

With the initiation and development of the Human Microbiome Project (HMP) and the Project on Metagenomics of the Human Intestinal Tract (MetaHIT), the studies of the gut microbiota (GMB) have entered a fast lane and proved that GMB is associated with several diseases. Recent studies have confirmed that GMB affects and modulates pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, making it one of the potential focuses of precision medicine. This article presents an overview of the potential mechanisms of GMB affecting drug treatment and advances in the relevant studies, hoping to shed some new light on the precision therapeutic strategy.

Ginkgo biloba extracts attenuate lipopolysaccharide-induced inflammatory responses in acute lung injury by inhibiting the COX-2 and NF-κB pathways / 中国天然药物

In the present study, we analyzed the role of Ginkgo biloba extract in lipopolysaccharide(LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS. G. biloba extract (12 and 24 mg·kg(-1)) and dexamethasone (2 mg·kg(-1)), as a positive control, were given by i.p. injection. The cells in the bronchoalveolar lavage fluid (BALF) were counted. The degree of animal lung edema was evaluated by measuring the wet/dry weight ratio. The superoxidase dismutase (SOD) and myeloperoxidase (MPO) activities were assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators, tumor necrosis factor-a, interleukin-1b, and interleukin-6, were assayed by enzyme-linked immunosorbent assay. Pathological changes of lung tissues were observed by H&E staining. The levels of NF-κB p65 and COX-2 expression were detected by Western blotting. Compared to the LPS group, the treatment with the G. biloba extract at 12 and 24 mg·kg(-1) markedly attenuated the inflammatory cell numbers in the BALF, decreased NF-κB p65 and COX-2 expression, and improved SOD activity, and inhibited MPO activity. The histological changes of the lungs were also significantly improved. The results indicated that G. biloba extract has a protective effect on LPS-induced acute lung injury in mice. The protective mechanism of G. biloba extract may be partly attributed to the inhibition of NF-κB p65 and COX-2 activation.

Population pharmacokinetics and pharmacodynamics of clopidogrel in patients with acute coronary syndrome / 药学学报

This study established a population pharmacokinetics-pharmacodynamics model of clopidogrel in patients with acute coronary syndrome. Fifty-nine patients were enrolled. The plasma concentration of clopidogrel active metabolite and vasodilator stimulated phosphoprotein platelet reactivity index (VASP-PRI) were selected as the pharmacokinetics index and the pharmacodynamics index, respectively. The covariates including demographic characteristics, laboratory indexes, combined medication, complications and genetic polymorphisms of related enzymes were screened for their influence on the pharmacokinetic and pharmacodynamics parameters. Population pharmacokinetic and pharmacodynamics data analysis was performed using NONMEM software. The general linear model and the indirectly effect model-turnover model for pharmacokinetic and pharmacodynamic analysis were selected as the basic model, respectively. The population typical values of K12, CL/F, V/F, EC50, K(in), and E(max) were 0.259 h(-1), 179 L x h(-1), 632 L, 1.57 ng x mL(-1), 4.29 and 0.664, respectively. CYP2C19 was the covariate in the final pharmacokinetic model, and the model was to design a prior dosage regimen.

Effect of Pingchuanguben Decoction on interleukin-17 of bronchial alveolar lavage fluid and airway inflammation in mice with asthma / 中华实用儿科临床杂志

Objective To study the effect of Pingchuanguben Decoction on IL-17 level of bronchial alveolar lavage fluid (BALF) and airway remolding in mice with asthma.Methods Forty healthy female Kunming mice were randomly divided into 4 groups (10 rats in each group):normal control group,asthma group,Pingchuanguben Decoction group and Budesonide group.The asthmatic models were established by ovalbumin (OVA) ; the normal control group was treated with phosphate buffer solution (PBS liquid) by celiac injection,during this period Pingchuanguben Decoction was administered to the mice in Pingchuanguben Decoction group each day.In stimulation stage,the normal control group was atomization inhalated PBS liquid,and the rest of the 3 groups were given aerosolized OVA instead.Budesonide atomization was administered to mice in Budesonide group before stimulation.The levels of IL-17 in BALF were measured with enzyme-linked immunosorbent assay (ELISA),and the levels of matrix metalloproteinase-9 (MMP-9)and the tissue inhibitor of metalloproteinase-1 (TIMP-1) in lung tissues were tested with immunohistochemical analysis.Results 1.The levels of IL-17 in BALF in Pingchuanguben Decoction group and Budesonide group were significantly lower than those in asthma group (all P ＜0.05),and the IL-17 in BALF was increased compared with the normal control group (P ＜0.01).2.The levels MMP-9,T IMP-1 and MMP-9/TIMP-1 were decreased in the Pingchuanguben Decoction group and Budesonide group compared with those of asthmatic group (all P ＜ 0.01),and the MMP-9 and MMP-9/TIMP-1 were increased compared with the normal control group(all P ＜0.01).There was no significant difference between Pingchuanguben Decoction group and Budesonide group (all P ＞ 0.05).Conclusions Pingchuanguben Decoction may restrain airway inflammation and remolding,which can replace Budesonide to a certain extent.

Population pharmacokinetic study of tacrolimus in patients with hematopoietic stem cell transplant / 药学学报

The present study is to establish the population pharmacokinetic (PPK) model of tacrolimus and to estimate PPK parameters of tacrolimus for the individualization of tacrolimus administration in patients with hematopoietic stem cell transplant. A total of 671 blood samples were collected from 68 hematopoietic stem cell transplant patients and clinical data were retrospectively collected from the medical records of these patients. Population pharmacokinetical analysis was performed using the nonlinear mixed-effect model (NONMEM) program. The Bootstrap and data splitting were used simultaneously to validate the final population pharmacokinetical models. The basic structural model was best described as one-compartment pharmacokinetical model with first-order absorption and elimination. A number of covariates including demographic characteristic, biochemical and hematological index, combined drugs, inter-occasion variability (IOV) and other variables, e.g. primary disease, post operation days (POD), the type of transplantation and the sources of donor, were screened for their influence on the pharmacokinetic parameters of tacrolimus. The population typical values of tacrolimus CL, V, F were 12.1 L x h(-1), 686 L, 42.2%; and the inter-individual variability of these parameters were 23.5%, 96.4%, 43.8%, respectively. The absorption rate constant was fixed 4.3 h(-1). The residual error between observed and model- predicted concentration was 3.03 ng x mL(-1). The CYP enzyme inhibitor (INHI), POD and age were identified to be the main covariates that influence tacrolimus CL, and hemoglobulin (HGB) was the main covariate that may explain the variability in tacrolimus V. The IOV of CL, V, F were 22.2%, 6.23%, 30.3%, respectively. The population pharmacokinetic data obtained in the present study have significant clinical value for the individualization of tacrolimus therapy in hematopoietic stem cell transplant patients.

Association between CYP2C9 and VKORC1 genetic polymorphism and warfarin dose requirements / 中华心血管病杂志

<p><b>OBJECTIVE</b>To assess the contribution of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotype, age, body size, height, and weight to warfarin dose requirement.</p><p><b>METHODS</b>Blood samples were collected from 191 patients receiving warfarin therapy. Patients's age, gender, height, and weight were registered. PCR-RFLP method was used for the detection of VKORC1-1639G > A and CYP2C9 genotype.</p><p><b>RESULTS</b>VKORC1-1639G > A genotyping showed that 159 patients were homozygous AA, 31 were heterozygous GA, and 1 was homozygous GG genotype. CYP2C9 genotyping showed that 176 patients were *1/*1, 15 patients were heterozygous *1/*3. Patients with VKORC1-1639 (G > A) GG + GA genotype required a significantly higher warfarin dose than those with AA genotype [(3.36 +/- 0.97) mg/d vs. (1.75 +/- 0.56) mg/d, P < 0.01], and patients with CYP2C9*1/*1 genotype also required a higher warfarin dose than those with CYP2C9*1/*3 genotype [(2.06 +/- 0.83) mg/d vs. (1.55 +/- 1.32) mg/d, P < 0.05]. The multiple linear regression model for warfarin dose indicated age, weight and VKORC1 genotype could explain the inter-individual variation in dose requirement of 9.3%, 7.4%, 51.9% patients, respectively; age, weight, CYP2C9 and VKORC1 genotype together could explain the inter-individual variation in dose requirement of 64.1% patients.</p><p><b>CONCLUSION</b>This study showed that age, weight and VKORC1 and CYP2C9 polymorphism had significant influences on warfarin dose requirements and should be considered on dosing regimens modification to improve the safety of warfarin therapy.</p>

Abnormal abundances of calcium cycling regulatory proteins in rabbit myocytes with heart failure / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the abnormal abundances of calcium regulatory proteins in rabbit myocytes with failing hearts.</p><p><b>METHODS</b>Sixteen rabbits were divided into two groups: 8 rabbits with heart failure induced by volume plus pressure overload and 8 sham-operated animals. The hemodynamic parameters and cardiac structure and function were detected via catheterization and echocardiography respectively. L-type calcium channel (LTCC), Ryanodine receptor 2 (RyR2), Sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), and Na(+)-Ca(2+) exchanger (NCX) protein abundances were determined by Western blot analysis.</p><p><b>RESULTS</b>The ratio of left ventricular mass to body weight, heart rate and left ventricular end diastolic pressure in heart failure rabbits were significantly increased compared with sham-operated rabbits (P < 0.01), but their left ventricular shorten fraction [(21.3 +/- 4.00)% vs. (36.5 +/- 1.36)%] and ejection fraction (0.45 +/- 0.07 vs. 0.70 +/- 0.02) were decreased (P < 0.01). In heart failure rabbits, the abundances of LTCC and RyR2 were significantly decreased (R(LTCC/actin): 0.287 +/- 0.029 vs. 0.624 +/- 0.009; R(RyR2/actin): 0.106 +/- 0.001 vs. 0.203 +/- 0.011; P < 0.01), whereas the expressions of SERCA2a and NCX were markedly increased (R(NCX/actin): 0.497 +/- 0.015 vs. 0.221 +/- 0.014; R(SERCA2a/actin): 0.611 +/- 0.036 vs. 0.433 +/- 0.008; P < 0.01).</p><p><b>CONCLUSIONS</b>Reductions of LTCC and RyR2 might contribute to risk factors of systolic dysfunction in failing hearts. In early stage of heart failure, upregulated SERCA2a and NCX protein levels may be helpful for maintaining cardiac performance.</p>