Photoacoustic imaging and photoacoustic spectrum analysis in mouse models of cutaneous squamous cell carcinoma / 中华皮肤科杂志

Objective To establish a photoacoustic detection system and data processing methods for skin tumors,and to explore photoacoustic imaging and photoacoustic spectrum in mouse models of cutaneous squamous cell carcinoma (CSCC).Methods A total of 60 healthy specific pathogen-free (SPF) female BALB/C nude mice aged 6-8 weeks were randomly and equally divided into 2 groups to be inoculated with a murine CSCC cell line XL50 and a human CSCC cell line A431 respectively on the right back near the upper limbs,and mouse models of murine CSCC (n =20) and human CSCC (n =20) were successfully established.The 850-nm photoacoustic detection system was applied in the above 2 kinds of mouse models,and photoacoustic imaging and photoacoustic spectrum data were collected.The fitted slope of acoustic power spectrum curves was compared between squamous cell carcinoma tissues and normal skin on the left back of the mouse model.After the photoacoustic detection,tumor tissues and normal skin at the opposite side were excised from the 2 kinds of mouse models,and subjected to histopathological examination.The fitted slope of different tissues was compared by using t test.Results Photoacoustic imaging showed higher photoacoustic signals of hemoglobin in squamous cell carcinoma tissues compared with the normal skin tissues.In the model of murine CSCC,the fitted slope of acoustic power spectrum curve was significantly lower in the tumor tissues (-1.827 ± 0.153 1) than in the normal skin tissues (-1.059 ± 0.117 8,t =3.973,P ＜ 0.001).In the model of human CSCC,the fitted slope of acoustic power spectrum curve was also significantly lower in the tumor tissues (-1.537 ± 0.125 5) than in the normal skin tissues (-0.960 ± 0.259 7,t =2.166,P =0.043).Histopathological examination showed that the number of vessels increased in the tumor tissues compared with the normal skin tissues.Conclusion CSCC tissues are different from normal skin tissues in photoacoustic imaging signals and the fitted slope of acoustic power spectrum,which may lay a foundation for non-invasive photoacoustic diagnosis of CSCC.

Quantitative Estimation of Blood Concentration of Lamotrigine in Chinese Han Pediatric Patients with Epi-lepsy Based on UGT1A4142T>G Polymorphism and Blood Concentration of Valproic Acid / 中国药房

OBJECTIVE:To investigate the effects of UGT1A4142T>G polymorphism and blood concentration of valproic ac-id(VPA)on blood concentration of lamotrigine(LTG)in southern Chinese Han children with epilepsy,and to establish the predic-tion equation for quantitatively estimating blood concentration of LTG. METHODS:A total of 72 southern Chinese Han children with epilepsy selected from Guangzhou Women and Children's Medical Center during Jan. 2010-Sept. 2016 were given LTG+VPA. LC-MS/MS and enzyme amplified immunoassay were adopted to determine the blood concentration of LTG and VPA. RFLP-PCR was adopted to determine UGT1A4142T>G polymorphism. The relationships of age, gender, blood concentration of VPA, UGT1A4142T>G polymorphism and LTG concentration-to-dose-ratio (CDR) were also investigate. The prediction equation for blood concentration of LTG was established by multiple linear regression analysis. RESULTS:Age and blood concentration of VPA were positively related to CDR of LTG(r=0.225,0.300,P0.05). UGT1A4 TT,TG and GG genotypes were detected in 39,29,and 4 cases respectively;the frequencies of each genotype were in line with the Har-dy-Weinberg balance(P>0.05). CDR of LTG of TT genotype was significantly lower than those of TG and GG genotype,with sta-tistical significance(PG polymorphism(x4)were all related to blood concentration of LTG(PG polymorphism may associated with blood concentration of LTG. Established prediction equation can provide reference for precise medication in south-ern Chinese Han children with epilepsy.

Relationship between the genetic factors and lamotrigine efficacy in epileptic children received valproic ac-id therapy in south China / 实用医学杂志

Objective To investigate the effect of age,gender,weight and UGT1A4142T>G gene poly-morphism on the efficacy of LTG in epileptic children treated with valproic acid ,and to determine the effective se-rum concentration of LTG in children with epilepsy in south China. Methods A total of 72 pediatric patients with epilepsy received LTG and VPA treatments were enrolled in this study. Patients were treated from January 2010 to September 2016 in Guangzhou women and childrens′medical center. Serum concentration of LTG was measured by using the liquid chromatography-tandem mass spectrometry. UGT1A4142T > G was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. The correlations between the efficacy of LTG and age,gender,weight were analyzed by chi-square test,non-parametric test and logistic regression analysis,respec-tively. Results The curative effect of patients who were younger and with lighter weight were relatively poor ,and men were better than women in the curative effect. UGT1A4142T > G was not related with LTG efficacy. When combined with VPA,the effective serum concentration of LTG in children with epilepsy was more than 2 g/mL. Conclusion There is a good correlation between age and LTG curative effect. The effective serum concentration of LTG in children with epilepsy,who were co-treated with VPA,was more than 2 g/mL. This study provides a refer-ence for the individual administration of children with epilepsy in south China.

Relationship between the genetic factors and lamotrigine efficacy in epileptic children received valproic ac-id therapy in south China / 实用医学杂志

Objective To investigate the effect of age,gender,weight and UGT1A4142T>G gene poly-morphism on the efficacy of LTG in epileptic children treated with valproic acid ,and to determine the effective se-rum concentration of LTG in children with epilepsy in south China. Methods A total of 72 pediatric patients with epilepsy received LTG and VPA treatments were enrolled in this study. Patients were treated from January 2010 to September 2016 in Guangzhou women and childrens′medical center. Serum concentration of LTG was measured by using the liquid chromatography-tandem mass spectrometry. UGT1A4142T > G was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. The correlations between the efficacy of LTG and age,gender,weight were analyzed by chi-square test,non-parametric test and logistic regression analysis,respec-tively. Results The curative effect of patients who were younger and with lighter weight were relatively poor ,and men were better than women in the curative effect. UGT1A4142T > G was not related with LTG efficacy. When combined with VPA,the effective serum concentration of LTG in children with epilepsy was more than 2 g/mL. Conclusion There is a good correlation between age and LTG curative effect. The effective serum concentration of LTG in children with epilepsy,who were co-treated with VPA,was more than 2 g/mL. This study provides a refer-ence for the individual administration of children with epilepsy in south China.

Association between genetic polymorphisms and variation of imatinib pharmacokinetics in gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients.</p><p><b>METHODS</b>Clinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate(IM) and its main metabolic N-demethyl imatinib (NDI) were determined by LC-MS/MS. CYP3A4 rs2242480, CYP1A2 rs762551, CYP2C19 rs28399505 and NR1I2 rs3814057 were genotyped by MassArray system. Association between drug concentration and polymorphism was examined by Whitney U test. P≤0.05 indicated close association and 0.05<P<0.10 indicated marginal association.</p><p><b>RESULTS</b>Among 118 GIST patients, 63 were male and 55 were female with a median age of 55 (44 to 63) years. Primary lesion location was the stomach in 87 cases, intestine in 13 cases and other sites in 18 cases. All the patients received standard 400 mg/d IM. Concentration of IM (C) was (1 501.1±646.8) μg/L and concentration of NDI (C) was (221.7±92.5) μg/L. Association analysis showed that CYP2C19 rs28399505 was closely associated with concentration of IM and NDI(P=0.002 and 0.028). The concentration of IM and NDI in patients with TC heterozygote was significantly lower than those with wildtype TT [C: (695.4±202.9) μg/L vs. (1 518.9±716.8) μg/L, P=0.002; C:(133.3±59.8) μg/L vs. (244.5±99.1) μg/L, P=0.028]. NR1I2 rs3814057 was marginally associated with concentration of IM and NDI(C:P=0.079; C:P=0.082), while CYP3A4 rs2242480 and CYP1A2 rs762551 were not associated with concentration of IM or NDI(all P>0.10).</p><p><b>CONCLUSIONS</b>CYP2C19 may play an important role in IM metabolism. Detection of CYP2C19 polymorphism may be beneficial to clinical monitoring of IM and decision making of individualized treatment.</p>

Prospective Evaluation of Pharmacogenomics and Metabolite Measurements upon Azathioprine Therapy in Inflammatory Bowel Disease: An Observational Study.

Up to approximately 40% to 50% of patients discontinue thiopurine therapy during the course of inflammatory bowel disease (IBD). We investigated the role of the metabolite thiopurine in IBD treatment. This was a prospective study. IBD patients receiving azathioprine (AZA) were prospectively included. Thiopurine methyltransferase (TPMT) genotypes were examined before therapy, and thiopurine metabolite levels were examined at weeks 2, 4, 8, 12, 24, and 48. In total, 132 patients were included. The frequency of leucopenia increased at 6-thioguanine nucleotide (6-TGN) levels ≥420  pmol/8 × 10(8) RBC (odds ratio [OR] = 7.9; 95% confidence interval (95%CI): 3.5-18.0; P < 0.001) and increased more during the initial 12 weeks of thiopurine therapy (OR = 16.0; 95%CI: 5.7-44.9; P < 0.001). The patients with 6-TGN levels ≥420 pmol/8 × 10 RBC at weeks 4, 8, and 12 had an increased likelihood of leucopenia. Clinical response increased at 6-TGN levels ≥225 pmol/8 × 10(8) RBC (OR = 13.5; 95% CI: 3.7-48.9; P < 0.001) in Crohn disease (CD) patients. The CD patients with 6-TGN levels ≥225 pmol/8 × 10(8) RBC at weeks 8, 12, and 24 had an increased likelihood of successful clinical response. TPMT*3C had a specificity of 100%, but a sensitivity of 8% for predicting leucopenia.A 6-TGN level between 225 and 420 pmol/8 × 10(8) RBC could be a therapeutic window in patients receiving AZA therapy, and it could likely predict leucopenia in the initial 12 weeks of AZA therapy and a reasonable chance of successful clinical response in CD patients. The value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia.

Synthesis and Quantitative Structure-activity Relationships Study for Arylpropenamide Derivatives as Inhibitors of Hepatitis B Virus Replication.

A series of new arylpropenamide derivatives containing different aryl groups were synthesized, characterized, and evaluated for their anti-hepatitis B virus (HBV) activities. A new high accuracy QSAR model of arylpropenamide was constructed based on a more completely activities data and calculation parameter. The 2D-QSAR equations, by using DFT and multiple linear regression analysis methods, revealed that higher value of thermal energy (TE) and lower entropy (S(Ó©) ) increase the anti-HBV activities of the arylpropenamide molecules. Predictive 3D-QSAR models were established by SYBYL multifit molecular alignment rule. The optimum models were all statistically significant with cross-validated and conventional coefficients, indicating that they were reliable enough for activity prediction.

Progress in Genetic Polymorphism of Related Metabolic Enzymes Influencing Individualized Thiopurine Therapy / 中国药师

Thiopurines, one kind of immunosuppressants, represent an effective and widely prescribed therapy in clinic. Howev-er, the narrow therapeutic window and pharmacokinetic individual differences are always the problems in the clinical application of these drugs. Many factors can affect the metabolism and pharmacological effects of thiopurines, and the genetic polymorphisms of relat-ed metabolic enzymes involved in the metabolic process are considered to be the main factors. Recently, there is growing attention to the influence of the pharmacogenetics of related metabolic enzymes on the pharmacokinetics and pharmacodynamics of thiopurines. Therefore, based on the literature data, this review summarizes the correlation between the genetic polymorphisms of related metabolic enzymes ( TPMT, ITPA, GST, HPRT, XO, IMPDH and GMPS) and efficacy and side effects of thiopurines in order to provide guid-ance for the individualized thiopurine treatment in the clinical practice.

Distribution of 5-FU in rat hepatoma, liver tissue and plasma after locoregional infusion / 中国癌症杂志

Background and purpose: Locoregional infusion chemotherapy such as hepatic artery, or hepaticportal vein infusion is one of the most important treatments for hepatocelluar carcinoma. This study was aimed to investigate the distribution of fluorouracil(5-FU) in rat hepatoma, liver tissue and plasma after administrated by caudal vein or locoregional routes of hepatic artery, hepaticportal vein, and hepaticportal vein with ligated hepatic artery. Methods:Twenty-four tumor-bearing rats were divided into 4 groups randomly, and they were infused with 5-FU through peripheral vein(caudal vein), hepatic artery, hepaticportal vein or hepaticportal vein with ligated hepatic artery, which dose was 20 mg/kg. High performance liquid chromatography was adopted to measure the content of 5-FU in hepatoma, liver tissue and plasma, and the drug penetration rate among them were calculated. Results:The group of hepaticportal vein with ligated hepatic artery reached the highest concentrations of 5-FU in live tissue and hepatoma, which concentrations were (22.1±9.5)μg/g and (16.4±7.2)μg/g. Then was the hepatic artery group, and the concentration of the hepaticportal vein group in the hepatoma focus was much smaller than the former 2 groups, which was (8.9±3.7)μg/g. The peripheral vein group got the lowest concentrations both in the liver tissue and hepatoma, which were (9.4±3.7) and (4.3±2.2)μg/g. The concentrations of 5-FU in the plasma in the peripheral vein group, the hepatic artery group, the group of hepaticportal vein with ligated hepatic artery and the hepaticportal vein group were (26.8±12.5), (16.4±9.7), (15.9±10.1) and (14.9±8.5)μg/mL, which indicated that the drug concentrations of the latter 3 groups were much lower than the former group. The hepatoma/plasma penetration rate of 5-FU in the group of hepaticportal vein with ligated hepatic artery, the hepatic artery group, the hepaticportal vein group and the peripheral vein group were 103.47%, 92.94%, 59.58% and 16.08%. Conclusion: Compared to the peripheral venous bolus injection, locoregional infusion could significantly increase the concentrations of chemotherapy agent in hepatoma focus and liver tissue, and decrease the drug distributions in peripheral blood. And the infusion through hepaticportal vein with ligated hepatic artery and through hepatic artery reaches higher concentrations in the hepatoma focuses, which indicate that they are 2 practical and promising routes for the locoregional chemotherapy of hepatoma.

Advances in the research of pharmacogenomics of cyclophosphamide / 药学学报

Cyclophosphamide (CPA) is the most common alkylating antineoplastic agent, as well as a strong immunosuppressant that is frequently applied to autoimmune diseases and organ transplantation. It is metabolized by cytochrome P450 oxidases (CYPs) to its active metabolite which played a critical role in therapy. CPA has serious and even fatal side effects, and its efficacy and adverse reactions are significantly varied among individuals. In this review, the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the disposition of CPA with the efficacy and adverse effects of CPA were summarized, thereby providing fundamental reference for further pharmacogenomic study of CPA.

Effects of carbamazepine on plasma concentrations of valproic acid and its toxic metabolite in epileptic patients / 药学学报

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.

Associations of POR polymorphisms and warfarin stable maintenance dose in Han Chinese patients / 中国药理学通报

Aim To explore the effect of genetic poly-morphisms of POR on the stable warfarin maintenance doses in Han Chinese patients receiving mechanical heart valve replacement. Methods The association between POR gene polymorphisms and warfarin doses of 185 Han Chinese patients were investigated through ANOVA or t test. SNPs of POR and VKORC1 were de-tected by Sequenom? DNA MassArray genotyping method. CYP2C9*3 was genotyped by polymerase chain reaction-restriction fragment length polymorphism method ( PCR-RFLP ) . Patients ’ clinical characteris-tics, INR value and daily dose were obtained from their medical records. Statistical analysis was performed by SPSS 21. 0 software. Results No mutant carriers of POR rs17148944 , POR rs56256515 and rs72553971 were found in this study. The genotype frequencies of other SNPs were in accordance with Hardy-Weinberg e-quilibrium. In the group of patients with CYP2C9*1*1 , the mutant type carriers ( T carriers ) of POR rs17685 had a significantly higher dose than CC carri-ers(3. 50 ± 1. 07) mg·d-1 vs (3. 14 ± 0. 94) mg· d-1,P =0. 03. Also, in the group of patients with CYP2 C9*1*1 and VKORC1 rs9934438 G allele carri-ers, the mutant type carriers ( T carriers ) of POR rs17685 had a significantly higher dose than CC carri-ers(4. 76 ± 0. 90) mg·d-1 vs (4. 08 ± 1. 03) mg· d-1 ,P=0. 04. No significant difference was found in different genotypes of POR rs2868177 . Conclusion These results illustrate that POR rs17685 T carrier is closely associated with a higher warfarin maintenance dose, suggesting that this SNP is useful for clinical guidance of warfarin.

Small interfering RNA mediated silencing of cytochrome P450 3A4 gene / 中国基层医药

Objective To investigate the inhibitory effect of the cytochrome P450 3A4(CYP3A4) gene expression and function in CHL-3A4 cells lines by vector-ecpressed small hairpin interfering RNA(shRNA).Methods The shRNA expression vectors targeting CYP 3A4 gene(CYP3A4Ⅰ,CYP3A4Ⅱ,CYP3A4Ⅲ) were designed and constructed.The inhibitory effect of shRNA was detected by Western blot and RT-PCR analysis.The inhibitory effect of cytotoxic of cyclophosphamide using shRNA was measured by MTT assay.Results CYP3A4Ⅲ shRNA expressing vector significantly reduced the CYP3A4 mRNA(70%) and protein expression levels(75%) of the CYP3A4 gene in CHL3A4 cells suppression of CYP3A4 gene expression by CYP3A4Ⅲ largely reversed cyclophosphamide cytotoxicity(75%) in CHL-3A4 cells.Conclusion Vector-based RNAi could suppress CYP3A4 gene expression and function,and the use of RNAi to inhibit CYP3A4 gene expression in mammalian cells was a promising new tool for the study of cytochrome P450 gene function.

Study on Pharmacokinetics and Bioavailability of Ranitidine Hydrochloride Capsule in Human Body / 中国药房

OBJECTIVE:To study the pharmacokinetics and bioequivalence of both domestic ranitidine hydrochloride capsules and imported ranitidine hydrochloride tablets.METHODS:20healthy volunteers were randomized into groups,whose plasma concentrations of ranitidine were determined at different time after single oral dose of300mg ranitidine hydrochloride capsule or ranitidine hydrochloride tablets300mg by own control by a RP-HPLC method,the pharmacokinetic parameters were computed and which were experienced variance analysis and two-way t-tests and one-way t-tests.RESULTS:The respective pharmacokinetic parameters of ranitidine hydrochloride tablets and ranitidine hydrochloride capsuless were as fol?lows,the C max were(1247.1?547.5)?g/L and(1294.8?613.2)?g/L;t max were(2.98?0.73)h and(2.73?0.80)h;t 1/2 were(3.17?0.36)h and(3.33?0.42)h;AUC 0～t were(5805.9?1403.5)(?g?h)/L and(5941.2?1526.3)(?g?h)/L;AUC 0～∞ were(6163.8?1456.4)(?g?h)/L and(6351.8?1652.7)(?g?h)/L;The relative bioavailability of the ranitidine hydrochloride capsules to ranitidine hydrochloride tablets was(104.3?24.3)%.CONCLUSION:Ranitidine hydrochloride capsules and the ranitidine hydrochloride tablets were bioequivalent.