Determining the optimal PD-1/PD-L1 inhibitors for the first-line treatment of non-small-cell lung cancer with high-level PD-L1 expression in China.

BACKGROUND AND OBJECTIVE: The programmed death 1 and ligand (PD-1/PD-L1) inhibitors have significantly altered therapeutic perspectives on non-small-cell lung cancer (NSCLC). However, their efficacy and safety are unknown since direct clinical trials have not yet been performed on them. It is also necessary to determine the economics of PD-1/PD-L1 inhibitors due to their high cost. The aim was to evaluate the efficacy, safety, and cost-effectiveness of PD-1/PD-L1 inhibitor monotherapy for advanced NSCLC patients in China with high PD-L1 expression as first-line treatment. METHODS: From the PubMed, Cochrane, and Web of Science databases, we retrieved survival, progression, and safety data on PD-1/PD-L1 inhibitor monotherapy for advanced NSCLC patients. A network meta-analysis (NMA) was performed to consider PD-1/PD-L1 inhibitors in efficacy and safety. A Markov model with a full-lifetime horizon was adopted. Clinical and utility data were collected through the trial. The cost per quality-adjusted life year (QALY) was as incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. RESULTS: This study included five phase III clinical trials using four drugs: nivolumab, pembrolizumab, atezolizumab, and durvalumab. The NMA demonstrated that the four drugs had similar efficacy and safety, while pembrolizumab and atezolizumab were better for than for nivolumab (hazard ratio (HR) = 0.66, 95% confidence intervals (CIs): 0.46-0.95 and HR = 0.59, 95%CI: 0.37-0.94) in progression-free survival (PFS), and the risk of a severe adverse event was higher for atezolizumab than for nivolumab and pembrolizumab. Compared with nivolumab, durvalumab, pembrolizumab, and atezolizumab had QALY of 0.19, 0.38, and 0.53, respectively, which induced ICERs of $ 197,028.8/QALY, $ 111,859.0/QALY, and $ 76,182.3/QALY, respectively. CONCLUSION: The efficacy and safety are similar among types of PD-1/PD-L1-inhibitor monotherapy. The cost-effectiveness of nivolumab appears optimal, but the other PD-1/PD-L1 inhibitors are not as cost-effective for the first-line treatment of advanced NSCLC in China.

Concordance of Treatment Recommendations for Metastatic Non-Small-Cell Lung Cancer Between Watson for Oncology System and Medical Team.

OBJECTIVE: The disease complexity of metastatic non-small-cell lung cancer (mNSCLC) makes it difficult for physicians to make clinical decisions efficiently and accurately. The Watson for Oncology (WFO) system of artificial intelligence might help physicians by providing fast and precise treatment regimens. This study measured the concordance of the medical treatment regimens of the WFO system and actual clinical regimens, with the aim of determining the suitability of WFO recommendations for Chinese patients with mNSCLC. METHODS: Retrospective data of mNSCLC patients were input to the WFO, which generated a treatment regimen (WFO regimen). The actual regimen was made by physicians in a medical team for patients (medical-team regimen). The factors influencing the consistency of the two treatment options were analyzed by univariate and multivariate analyses. RESULTS: The concordance rate was 85.16% between the WFO and medical-team regimens for mNSCLC patients. Logistic regression showed that the concordance differed significantly for various pathological types and gene mutations in two treatment regimens. Patients with adenocarcinoma had a lower rate of "recommended" regimen than those with squamous cell carcinoma. There was a statistically significant difference in EGFR-mutant patients for "not recommended" regimens with inconsistency rate of 18.75%. In conclusion, the WFO regimen has 85.16% consistency rate with medical-team regimen in our treatment center. The different pathological type and different gene mutation markedly influenced the agreement rate of the two treatment regimens. CONCLUSION: WFO recommendations have high applicability to mNSCLC patients in our hospital. This study demonstrates that the valuable WFO system may assist the doctors better to determine the accurate and effective treatment regimens for mNSCLC patients in the Chinese medical setting.

Paediatric acute kidney injury induced by vancomycin monotherapy versus combined vancomycin and meropenem.

WHAT IS KNOWN AND OBJECTIVE: Increasing reports of the combined use of vancomycin (VAN) and piperacillin/tazobactam leading to higher nephrotoxicity have led to carbapenems being recommended as an alternative option to combine with VAN when nephrotoxicity is a major concern. However, whether carbapenems also increase the nephrotoxicity of VAN is unclear. This study aimed to determine whether meropenem is a suitable drug to combine with VAN based on whether meropenem enhances the nephrotoxicity of VAN. METHODS: This retrospective cohort study enrolled hospitalized children ranging in age from 1 month to 18 years at two tertiary hospitals from 1 February 2017 to 1 February 2018. Patients treated with either VAN or combined VAN and meropenem (VM) for more than 48 hours were eligible for inclusion. Those with underlying kidney diseases or abnormal age-adjusted baseline serum creatinine (SCr) at admission were excluded. Propensity score matching (PSM) was applied to the patients to balance factors associated with acute kidney injury (AKI). In addition, VAN trough concentrations were also compared. AKI was defined as an increase in SCr by ≥50% from baseline or by ≥0.3 mg/dL sustained over at least two consecutive measurements ranging from the time of initiation until 72 hours after the completion of VAN therapy. RESULTS AND DISCUSSION: The eligibility criteria were met by 183 of 243 identified patients: 101 patients received VAN alone and 82 received VM. PSM resulted in 154 hospitalized children being included (77 patients in each group). The incidence of AKI was 10.7% (8/77) in both of the compared groups, while the VAN trough concentration was significantly higher in the VM group (9.0 mg/L) than in the VAN group (6.6 mg/L, P = 0.007) after controlling for confounders. WHAT IS NEW AND CONCLUSION: Despite the elevated VAN trough concentration, meropenem did not increase the nephrotoxicity of VAN and might therefore be an acceptable antibiotic to combine with VAN when necessary.

The Polymorphism in ADORA3 Decreases Transcriptional Activity and Influences the Chronic Heart Failure Risk in the Chinese.

AIM: To investigate the genetic contribution of adenosine A3 receptor (ADORA3) gene polymorphisms in the pathogenesis of chronic heart failure (CHF). METHODS: Firstly, a case-control study was performed to investigate the association of ADORA3 polymorphisms with CHF risk. Three hundred northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls were included. Four polymorphisms were genotyped. This case-control study was also replicated in 304 CHF patients and 402 controls from southern China. Finally, the functional variability of positive polymorphism was analyzed using luciferase reporter assay and real-time PCR. RESULTS: Overall, the rs1544223 was significantly associated with CHF risk under the dominant model (P = 0.046, OR = 1.662, 95% CI = 1.009-2.738). But it did not affect disease severity. These results were also consistent in replicated population. In addition, the transcriptional activity for promoter with the A allele was lower than that with the G allele (n = 3, 4.501 ± 0.308 versus 0.571 ± 0.114, P < 0.01) and ADORA3 mRNA levels were significantly higher in GG homozygotes than subjects carrying GA (n = 6, 0.058 ± 0.01 versus 0.143 ± 0.068, P = 0.004) or AA genotypes (n = 6, 0.065 ± 0.01 versus 0.143 ± 0.068, P = 0.008). CONCLUSIONS: Should the findings be validated by further studies with larger patient samples and in different ethnicities, they may provide novel insight into the pathogenesis of CHF.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.

Histone deacetylase inhibitor reverses multidrug resistance by attenuating the nucleophosmin level through PI3K/Akt pathway in breast cancer.

The development of multidrug resistance (MDR) is the major obstacle in the chemotherapy of breast cancer, and it restricts the application of antitumor drugs in the clinic. Therefore it is urgent to search for ways to reverse MDR and restore sensitivity to chemotherapeutics in breast carcinoma. Currently, histone deacetylase inhibitors (HDACIs) offer a promising strategy for tumor therapy as the effective anticancer drugs. Based on the potential resistant target of nucleophosmin (NPM), the purpose of this study was to explore the reversal effect of a new synthetic histone deacetylase inhibitor, FA17, on MDR in methotrexate-resistant breast cancer cells (MCF-7/MTX) and xenograft tumors. It was shown that the abnormal expression of NPM induced MDR and inhibited downstream mitochondrial apoptotic pathway by activating PI3K/Akt signaling pathway in MCF-7/MTX cells. The reversal effect and molecular mechanism of FA17 were investigated both in vitro and in vivo. We found that FA17 could significantly reverse resistance and sensitize MCF-7/MTX cells to methotrexate. FA17 obviously enhanced resistant cell apoptosis, inhibited expressions of NPM and efflux transporters. Additionally, FA17 could reverse MDR via inactivating PI3K/Akt pathway and accelerating mitochondrial apoptotic pathway both in MCF-7/MTX cells and in xenograft tumors. Taken together, the novel histone deacetylase inhibitor could effectively reverse drug resistance due to suppressing the activity of NPM and drug efflux pumps by PI3K/Akt and mitochondrial apoptotic pathway. The above not only indicated the potential applied value of FA17 in reversing MDR and enhancing the sensitivity of chemotherapy, but also confirmed the role of NPM in the development of MDR in breast cancer.

The association of ADORA2A and ADORA2B polymorphisms with the risk and severity of chronic heart failure: a case-control study of a northern Chinese population.

The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of ADORA2A (rs2236625, rs2236624, rs4822489, and rs5751876) and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors (p = 0.040, OR = 1.912, 95% CI = 1.029-3.550). However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required.

The adenosine deaminase gene polymorphism is associated with chronic heart failure risk in Chinese.

Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10-2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.

Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses.

OBJECTIVE: A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase µ, π and θ (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship. METHODS: A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2. RESULTS: Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05-1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29-1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians. CONCLUSIONS: This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia.

Glutathione S-transferase gene polymorphisms and susceptibility to chronic myeloid leukemia.

Glutathione S-transferase (GST), a phase II metabolizing enzyme, plays an important role in the cellar defense system, and its activity may modulate leukemia risk. A large body of evidence has shown the possible relevance of functional polymorphisms of the genes that encode GSTs µ, π, and θ (GSTM1, GSTP1, and GST1, respectively) to the genetic susceptibility of chronic myeloid leukemia (CML). Because of the lack of available conclusive data, we performed a meta-analysis of all relevant available studies to derive a more precise estimation of the relationship. A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until December 20, 2013, and the extracted data were statistically analyzed using Review Manager version 5.2. Finally, 16 eligible studies were identified in the literature. The GSTT1 null genotype was associated with an increased risk of CML, as were the double null GSTT1 and GSTM1 genotypes. These findings suggest that heritable GST status influences the risk of developing CML and that more attention should be paid to carriers of these susceptibility genes.

Association between reduced folate carrier G80A polymorphism and methotrexate toxicity in childhood acute lymphoblastic leukemia: a meta-analysis.

Abstract Methotrexate (MTX) is a key component of chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL), and enters the cell via active transport mediated by the reduced folate carrier (RFC1). A major single-nucleotide polymorphism of the RFC1 gene, G80A, which affects the activity of RFC1, may influence MTX toxicity in pediatric ALL. We collected all studies that investigated the association of RFC1 G80A polymorphism and MTX toxicity in pediatric ALL, and found inconsistency among their results. The aim of this meta-analysis was to summarize all of these studies in order to clarify the correlation between the RFC1 G80A polymorphism and MTX toxicity in pediatric ALL. A recessive model demonstrated no influence of the RFC1 G80A genotype on MTX toxicity. In conclusion, the RFC1 G80A polymorphism does not seem to be a good marker of MTX-related toxicity in pediatric ALL.

Influence of the gastrointestinal microflora and efflux transporters on the absorption of scutellarin and scutellarein.

Scutellarin (SG) and its aglycone, Scutellarein (S), are flavonoids of therapeutic cardiocerebrovascular disease. SG was hydrolyzed by bacterial enzyme into S which was absorbed in the intestine. The aim of this study was to determine the effects of the microflora in the intestinal lumen and the efflux transporter of intestinal epithelial cells on the absorption process of SG and S. After oral administration of antibiotics in Sprague-Dawley rats, the reduced bacterial enzyme formation significantly hinders the absorption of SG, whereas scarcely that of S. The absorption study in situ single-pass intestinal perfusion revealed that S could be absorbed throughout the intestine of rats. The effective intestinal permeability of S in the jejunum was much lower than in the other sections of the GI tract. The efflux transporter promoted SG secretion into lumen from enterocytes, which hindered the absorption of both SG and S into the bloodstream. The efflux transporter protein inhibitor (verapamil, probenecid and reserpine) remarkably enhanced the absorption of S and the bioconversion of S into SG in both the rat intestine and Caco-2-monolayer models.

Establishment of paclitaxel-resistant breast cancer cell line and nude mice models, and underlying multidrug resistance mechanisms in vitro and in vivo.

BACKGROUND: Breast cancer is a common malignant tumor which affects health of women and multidrug resistance (MDR) is one of the main factors leading to failure of chemotherapy. This study was conducted to establish paclitaxel-resistant breast cancer cell line and nude mice models to explore underlying mechanisms of MDR. METHODS: The breast cancer drug-sensitive cell line MCF-7 (MCF-7/S) was exposed in stepwise escalating paclitaxel (TAX) to induce a resistant cell line MCF-7/TAX. Cell sensitivity to drugs and growth curves were measured by MTT assay. Changes of cell morphology and ultrastructure were examined by optical and electron microscopy. The cell cycle distribution was determined by flow cytometry. Furthermore, expression of proteins related to breast cancer occurrence and MDR was tested by immunocytochemistry. In Vivo, nude mice were injected with MCF-7/S and MCF-7/TAX cells and weights and tumor sizes were observed after paclitaxel treatment. In addition, proteins involved breast cancer and MDR were detected by immunohistochemistry. RESULTS: Compared to MCF-7/S, MCF-7/TAX cells had a higher resistance to paclitaxel, cross-resistance and prolonged doubling time. Moreover, MCF-7/TAX showed obvious alterations of ultrastructure. Estrogen receptor (ER) expression was low in drug resistant cells and tumors while expression of human epidermal growth factor receptor 2 (HER2) and Ki-67 was up-regulated. P-glycoprotein (P-gp), lung resistance-related protein (LRP) and glutathione-S-transferase-π (GST-π) involved in the MDR phenotype of resistant cells and tumors were all overexpressed. CONCLUSION: The underlying MDR mechanism of breast cancer may involve increased expression of P-gp, LRP and GST-π.

Protective effects of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis induced by trinitrobenzenesulfonic acid in rats.

BACKGROUND: 3,4-Oxo-isopropylidene-shikimic acid (ISA) is a derivative of shikimic acid (SA). SA is extracted from Illicium verum Hook.fil., which has been used in traditional Chinese medicine and used for treating vomiting, stomach aches, insomnia, skin inflammation, and rheumatic pain. AIMS: To investigate the effects and the protective mechanism of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. METHODS: Colitis in rats was induced by colonic administration with TNBS. ISA (50, 100, and 200 mg/kg) was administered for 12 days to experimental colitis rats. The inflammatory degree was assessed by macroscopic damage score, colon weight/length ratios (mg/cm), and myeloperoxidase (MPO) activity. Malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) activities were measured with biochemical methods. RESULTS: ISA significantly ameliorated macroscopic damage, reduced colon weight/length ratios and the activity of MPO, depressed MDA and NO levels and iNOS activity, and enhanced GSH level, and GSH-Px and SOD activities in the colon tissues of experimental colitis in a dose-dependent manner. Moreover, the effect of ISA (200 mg/kg) was as effective as sulfasalazine (500 mg/kg). CONCLUSIONS: The findings of this study demonstrate the protective effect of ISA on experimental colitis, probably due to an antioxidant action.

Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces.

AIM: To study the metabolic and pharmacokinetic profile of scutellarin, an active component from the medical plant Erigeron breviscapus (Vant) Hand-Mazz, and to investigate the mechanisms underlying the low bioavailability of scutellarin though oral or intravenous administration in rats. METHODS: HPLC method was developed for simultaneous detection of scutellarin and scutellarein (the aglycone of scutellarin) in rat plasma, urine and feces. The in vitro metabolic stability study was carried out in rat liver microsomes from different genders. RESULTS: After a single oral dose of scutellarin (400 mg/kg), the plasma concentrations of scutellarin and scutellarein in female rats were significantly higher than in male ones. Between the female and male rats, significant differences in AUC, t(max2) and C(max2) for scutellarin were found. The pharmacokinetic parameters of scutellarin in the urine also showed significant gender differences. After a single oral dose of scutellarin (400 mg/kg), the total percentage excretion of scutellarein in male and female rats was 16.5% and 8.61%, respectively. The total percentage excretion of scutellarin and scutellarein in the feces was higher with oral administration than with intravenous administration. The in vitro t(1/2) and CL(int) value for scutellarin in male rats was significantly higher than that in female rats. CONCLUSION: The results suggest that a large amount of ingested scutellarin was metabolized into scutellarein in the gastrointestinal tract and then excreted with the feces, leading to the extremely low oral bioavailability of scutellarin. The gender differences of pharmacokinetic parameters of scutellarin and scutellarein are due to the higher CL(int) and lower absorption in male rats.

[Absorption and transportation characteristics of scutellarin and scutellarein across Caco-2 monolayer model].

OBJECTIVE: To investigate the absorption and transepithelial transport characteristics of scutellarin and scutellarein in the human colonic adenocarcinoma cell (Caco-2) monolayer model. The influence factors on these two compounds' absorption were investigated, such as buffer solution, duration of culture, and inhibitors of multidrug resistance-associated protein 2 (MRP(2)), breast cancer drug resistance protein (BCRP) and P-glycoprotein (P-gp). METHODS: By using Caco-2 monolayer as an intestinal epithelial cell model, the transport process was studied from apical (AP) side to basolateral (BL) side or from BL to AP. The two compounds were determined by high-performance liquid chromatography coupled with diode-array-detector detection. Transport parameters and apparent permeability coeffients (P(app)) were calculated. RESULTS: The P(app) values of scutellarin and scutellarein were different in two buffer solutions, respectively. In phosphate buffered saline, scutellarin had no absorption from AP to BL, while its P(app) value was 0.74×10(-6) to 1.58×10(-6) cm/s from BL to AP. The P(app) values of scutellarein were 4.33×10(-6) to 6.79×10(-6) cm/s and 1.32×10(-6) to 2.56×10(-6) cm/s from AP to BL and from BL to AP, respectively. The P(app) value gradually decreased with time. The absorption of scutellarein was better than that of scutellarin. The scutellarin absorption was improved by verapamil, MK-571 and reserpine. The scutellarein absorption was improved by verapamil whereas its excretion was improved by MK-571. CONCLUSION: Absorption of scutellarin is difficult in Caco-2 monolayer cells, which contributes to its low bioavailability. Scutellarein absorption is better than scutellarin absorption. Scutellarein transepithelial transport is passive diffusion. The inhibitor of P-gp can improve scutellarin and scutellarein transportation. The inhibitors of MRP(2) and BCRP can promote transportation of scutellarin. The inhibitor of MRP(2) can promote efflux of scutellarein. The multidrug resistance-associated protein may be the second reason for low bioavailability of scutellarin.

[The comparison about inhibition of five Chinese herbal medicines to two different resources alpha-glycosidase].

OBJECTIVE: To compare alpha-glycosidase inhibitor microamount screening models which are established by two different resources alpha-glycosidase to screen the Chinese herbal medicines which have great alpha-glycosidase inhibition. METHODS: Comparing the activities of two different resources alpha-glycosidase with glucose oxidase method, then establishing optimal reaction conditions. Extracting the water soluble compositions of Chinese gallnut, paeoniae radix, Glycyrrhiza, rhubarb, fructus by boiling ,then using the alpha-glycosidase inhibition model to check and compare their alpha-glycosidase inhibitions. RESULTS: Five Chinese herbal medicines all had alpha-glycosidase inhibition, and the greatest was Chinese gallnut. CONCLUSION: The activities of two resources alpha-glycosidase are certainly different, but they do not have significant influence on findings of screening alpha-glycosidase inhibitors in vitro. Water soluble compositions of five Chinese herbal medicines have alpha-glycosidase inhibition.

[Pharmacokinetic and tissue distribution study of scutellarin in rats].

OBJECTIVE: To investigate the pharmacokinetic and distribution character of scutellarin in plasma and tissues in rats, in order to provide some references for rational drug use in the clinic. METHOD: The solution of scutellarin was administered to rats (80 mg x kg(-1)) by oral gavage. A high performance liquid chromatography method determinated the scutellarin concentration in rat plasma and tissue. The plasma samples were performed by solid phase extraction method. The other biological samples were extracted by ethyl acetate. RESULT: The range of scutellarin in plasma and tissue in rats were 10-1280 ng x mL(-1) (R2 > 0.99), 40-1280 ng x g(-1) (R2 > 0.99), respectively. The lowest detection of scutellarin were 10 ng x mL(-1) and 40 ng x g(-1), the precision were less than 8%. The main pharmacokinetic parameters of scutellarin were as follows: tmax, Cmax, AUC and MRT being (7.7 +/- 0.9) h, (288.0 +/- 75.2) microg x L(-1), (5.6 +/- 1.6) microg x mL(-1) x h(-1), (17.5 +/- 1.4) h(-1), respectively. CONCLUSION: These methods applied the study of pharmacokinetics of scutellarin. After oral the scutellarin in rats, the concentration-time course doesn't obey any compartment model. The concentration-time curve is the double peaks.

[Effect of taspine hydrochloride on skin wound healing in rats and its mechanism].

OBJECTIVE: To study the effect of taspine hydrochloride (TA/HCl) on skin wound healing in rats and its mechanism. METHODS: Bilateral round wounds were made on the backs of SD rats. The effect of TA/HCl on the skin wound was evaluated through determining closure time and contracting ability of the skin wound, observing histopathological characteristics and measuring contents of hydroxyproline (Hyp) and protein in the wound tissue. RESULTS: The closure time of the skin wounds was significantly shorter in the TA/HCl-treated groups than that in the model group. The percentages of wound contraction were higher in the TA/HCl-treated groups than that in the dimethyl sulfoxide (DMSO) control group of the same group (P<0.05 or P<0.01) on the 3rd to 14th days after wounding. The content of the protein in the wound tissue in the TA/HCl-treated group (2 mg/ml) was higher than that in the model group (P<0.05) on the 3rd to 7th days after wounding, and it arrived at the peak on the 7th day and gradually decreased to the normal level in skin tissue on the 14th to 21st days after wounding. The contents of Hyp in the wound tissues in the TA/HCl-treated groups were higher than that in the model group (P<0.05 or P<0.015) on the 3rd to 21st days after wounding, and they arrived at the peak on the 14th day and at the normal level in skin tissue on the 21st day. Histopathological test results showed that TA/HCl could promote the formation of newly born capillaries in the early period of the wound healing. CONCLUSION: TA/HCl has the ability of promoting skin wound healing in rats, and it can also accelerate the growth of newly born capillaries and raise the production of protein and collagen in wound tissue.