The paper reported an investigation of the pharmacokinetics of SN-38 (7-ethyl-10-hydroxy-camptothecin) in rats and the tissue distribution in mice after injection of irinotecan hydrochloride nanoparticles (CPT-11) via tail veins. An LC-MS/MS method was established to determine the concentrations of SN-38 in whole blood of rats and in different tissues of mice. The pharmacokinetics and tissue distribution of SN-38 were compared after the intravenous injection of CPT-11 NPs and CPT-11 solution. Compared with irinotecan solution, the elimination half-life of SN-38 was prolonged from 2.17 h to 2.67 h after the intravenous injection of CPT-11 NPs, but its AUC had little change. After the injection of CPT-11 NPs in mice, over time, the concentrations of CPT-11-metabolized SN-38 in CPT-11 NPs were significantly higher in the whole blood, colon and lungs than those in CPT-11 solution, followed by in the spleen and liver, but those in the heart and brain had no change. However, the amount of SN-38 in the kidneys was reduced with time. CPT-11 NPs could prolong SN-38's (one of its metabolites) blood circulation time in rats and significantly increased the concentration of CPT-11-metabolized SN-38 in the whole blood, colon and lungs of mice. CPT-11 NPs made SN-38 efficiently target-bind to the colon and lungs of mice.
Animals ; Antineoplastic Agents, Phytogenic ; pharmacokinetics ; Camptothecin ; analogs & derivatives ; pharmacokinetics ; Chromatography, Liquid ; Colon ; metabolism ; Half-Life ; Injections, Intravenous ; Lung ; metabolism ; Mice ; Nanoparticles ; administration & dosage ; Rats ; Tandem Mass Spectrometry ; Tissue Distribution

The object of this study is to investigate the pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in healthy adult Beagle dogs following single and multiple oral dose administration. A randomized, cross-over study was conducted with nine healthy adult Beagle dogs assigned to three groups. Each group was arranged to take atorvastatin calcium (A), pioglitazone hydrochloride (B), atorvastatin calcium and pioglitazone hydrochloride (C) orally in the first period, to take B, C, A in the second period, and to take C, A, B in the third period for 6 days respectively. The blood samples were collected at the first and the sixth day after the administration, plasma drug concentrations were determined by LC-MS/MS, a one-week wash-out period was needed between each period. The pharmacokinetic parameters of drug combination group and the drug alone group were calculated by statistical moment method, calculation of C(max) and AUC(0-t) was done by using 90% confidence interval method of the bioequivalence and bioavailability degree module DAS 3.2.1 software statistics. Compared with the separate administration, the main pharmacokinetic parameters (C(max) and AUC(0-t)) of joint use of pioglitazone hydrochloride and atorvastatin calcium within 90% confidence intervals for bioequivalence statistics were unqualified, the mean t(max) with standard deviation used paired Wilcoxon test resulted P > 0.05. There was no significant difference within t1/2, CL(int), MRT, V/F. Pioglitazone hydrochloride and atorvastatin calcium had pharmacokinetic interaction in healthy adult Beagle dogs.
Administration, Oral ; Animals ; Anticholesteremic Agents ; administration & dosage ; blood ; pharmacokinetics ; Area Under Curve ; Atorvastatin Calcium ; administration & dosage ; blood ; pharmacokinetics ; Biological Availability ; Cross-Over Studies ; Dogs ; Drug Interactions ; Female ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; administration & dosage ; blood ; pharmacokinetics ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Random Allocation ; Thiazolidinediones ; administration & dosage ; blood ; pharmacokinetics

To investigate the pharmacokinetics of irinotecan hydrochloride (CPT-11) in rats and the tissue distribution of CPT-11 in mice after injection of irinotecan hydrochloride nanoparticles (CPT-11 NPs) via tail veins, separately, a LC-MS/MS method was established to determine the concentration of CPT-11 in whole blood of rats and in different tissues of mice. The pharmacokinetics and tissue distribution of CPT-11 were compared after the intravenous injection of CPT-11 NPs and CPT-11 solution. Compared with CPT-11 solution, the elimination half-life of CPT-11 was prolonged from 2.28 h to 3.95 h after the intravenous injection of CPT-11 NPs, and its AUC was 1.47 times than that of CPT-11 solution. After the injection of CPT-11 NPs in mice, the concentrations of CPT-11 loaded in CPT-11 NPs were significantly higher in the whole blood, colon and lungs than those in CPT-11 solution, but lower in the spleen, liver, kidney and heart, but the least in brain. CPT-11 NPs could improve CPT-11 's AUC, and help CPT-11 to reach long circulation activity.
Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; blood ; pharmacokinetics ; Area Under Curve ; Camptothecin ; administration & dosage ; analogs & derivatives ; blood ; pharmacokinetics ; Chromatography, High Pressure Liquid ; Female ; Injections, Intravenous ; Male ; Mice ; Nanoparticles ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization ; Tissue Distribution

Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-kappaB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR-98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop.
Animals ; Cell Line, Tumor ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Interleukin-6/*genetics ; Male ; Melanoma/epidemiology/*genetics/*pathology ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*genetics ; Neoplasm Metastasis/genetics/pathology ; Signal Transduction ; Survival Analysis

OBJECTIVETo study the effect of mining operations on the mental health of residents living in a mining area in Hubei province.

METHODSVillagers (n = 93) living in the mining area were compared with a control group of residents (n = 101) in mental health status, and knowledge of environment and health. The mental health status of villagers was assessed using the Symptom Checklist 90 (SCL-90), State-Trait Anxiety Inventory (STAI); The knowledge of environment and health was evaluated using a self-designed questionnaire. The urine and hair samples were collected from some subjects. The lead, cadmium, arsenic, copper and zinc contents were detected as well as the total protein, NAG, d-ALA in the urine.

RESULTSThe occurrence rate of lead, cadmium, arsenic exposure symptoms was significantly higher in the exposed group than in the control group. The urine cadmium, the hair cadmium, the hair arsenic and hair lead were significantly higher in the exposed group than in the control group (P < 0.05). The positive symptom detection rate of SCL-90 in the exposed group was 8.60% compared with 0.99% of the control group. For the SCL-90, the total scale, somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, paranoid ideation, psychoticism, other symptom in the exposed groups were significantly higher than those in the control group (P < 0.05), indicating the status of the psychological hygiene of the exposed group was worse than the control group. The total S-AI (anxiety) score and the sex-specific value in the exposed group were higher than the control group (P < 0.05, P < 0.01), which showed that the anxiety of the exposed group was more evident. The total T-AI score and the sex-specific value in women of the exposed group were significantly higher than the control group (P < 0.01), showing that the anxiety were more significant in the exposed group, especially the women of the exposed group.

CONCLUSIONThe mental health status of the residents who living in a mining area is affected and they have a higher S-AI and T-AI scale than those living a non-mining area.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anxiety ; epidemiology ; China ; epidemiology ; Environment ; Environmental Exposure ; adverse effects ; Female ; Health Knowledge, Attitudes, Practice ; Health Status ; Humans ; Male ; Mental Health ; Metals, Heavy ; adverse effects ; Middle Aged ; Mining ; Sex Factors ; Surveys and Questionnaires ; Young Adult

Objectives:To systemically review the safety and efficacy of bioresorbable vascular scaffold (BVS) versus everolimus eluting stent (EES) for percutaneous coronary intervention (PCI). Methods:The database searched includes PubMed, Medline, MEDILINE, EMBASE, Cochrane library, CNKI and Wanfang. Database retrieval time was between database establishment time to October 2017. During the same time, authors accessed the conference summary and related websites to collect published randomized controlled trials of published data. To evaluate the quality of the literature according to the modified Jadad scale and extracted the data. Meta-analysis was performed using Review Manager 5.3 software. Results:Nine trials were included; 6 721 patients were randomized to receive BVS (n=3 670) or EES (n=3 051). Time of follow-up was ranged from 6 to 36 months. Compared with metallic EES, risk of target lesion failure (RR=1.31, 95%CI:1.08-1.58; P=0.005) and in-stent thrombosis (RR=2.89, 95%CI:1.85-4.53; P＜0.0001), ischemia-driven target lesion revascularization (RR=1.44,95%CI:1.12-1.86, P=0.005)、target-vessel myocardial infarction (RR=1.74, 95%CI:1.33-2.27, P＜0.0001) and all myocardial infarction (RR=1.49, 95%CI:1.16-1.91, P=0.002) were all significantly higher in BVS group than in EES group. There were no significant differences in all-cause death (RR=0.87, 95 % CI:0.57-1.33, P=0.520), cardiovascular mortality (RR=0.78, 95%CI:0.54-1.11, P=0.160) and composite endpoints (RR=1.10, 95%CI:0.95-1.27, P=0.210) between the two groups. Conclusions:Compared with metallic EES, the BVS appears to be associated with both lower efficacy and higher thrombotic risk during the observation period.

OBJECTIVETo investigate the therapeutic effects of Enalaprilat on the myocardial kinetics in rats at early stage of severe scald.

METHODSEighty-four SD rats were inflicted with 30% TBSA full-thickness scald, and randomly divided into scald (S, with intraperitoneal injection of isotonic saline according to Parkland formula, n=30), L (n=30), M (n=12) and H (n=12) groups. The rats in L,M,H groups were intraperitoneally injected with 1,2,4 mg/kg Enalaprilat. Other 6 healthy rats were enrolled into study as control (C group). The myocardial kinetic parameters including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), +/- dp/dt max and the levels of A II in myocardium were observed at 1,3,6,12 and 24 post scald hour (PBH) in L and S groups,and at 6,12 PBH in M and H groups. The above indices in C group were also examined.

RESULTSThe levels of LVSP, LVEDP, +/- dp/dt max in C group were higher than those in other groups during 3-24 PBH (P < 0.05 or P < 0.01), while those in L,M,H groups were obviously higher than those in S group (P < 0.05 or P < 0.01). The level of +/- dp/dt max in H group at 6,12 PBH were obviously lower than those in L and M groups. The level of A II in S group at 1 PBH was (53.0 +/- 2.6) pg/200 mg, which was significantly higher than thatin C group [(14.8 +/- 0.7) pg/200 mg, P < 0.05 or P < 0.01]; it peaked at6 PBH and lowered afterwards, and they were significantly higher than that in C group at 24 PBH (P < 0.01). The levels of A II in L group during 3-24 PBH were obviously higher than those in C group (P < 0.01), which were also lower than those in S group. The level of A II in S group was significantly higher than in L,M,H groups at 6 PBH [(145.2 +/- 14.5) pg/200 mg. vs. (65.1 +/- 0.9) pg/200 mg, (53.6 +/- 1.1) pg/200 mg, (34.2 +/- 0.9) pg/200 mg, respectively, P < 0.01].

CONCLUSIONMyocardium can be obviously damaged at early stage after severe scald,cardiac function is impaired. Enalaprilat injection (especially at low dose) can significantly ameliorate the myocardial kinetics indices, and it seems to exert a protective effect on cardiac function.

Animals ; Burns ; drug therapy ; physiopathology ; Dose-Response Relationship, Drug ; Enalaprilat ; pharmacology ; therapeutic use ; Myocardium ; pathology ; Rats ; Rats, Sprague-Dawley ; Ventricular Remodeling

OBJECTIVETo investigate the preventive and therapeutic effects of enalapril maleate (Enalaprilat) (E) on myocardial damage in early stage after burns.

METHODSA total of 60 SD rats were subjected to 30% TBSA III degree scald injury, and randomly divided into scald group (with conventional fluid transfusion after scald) and ENA group (with intraperitoneal injection of 1 mg/kg Enalaprilat after scald). Normal control consisted of 6 rats. Plasma levels of cTnI and CK-MB were determined in all the groups at 1, 3, 6, 12, 24 post-scald hours (PSH) by enzyme linked immunosorbent assay. The pathological changes in myocardium were observed at the same time-points.

RESULTS(1) The serum level of cTnI and CK-MB in scald group were significantly higher than that of normal controls at each time-point (P < 0.01). The serum level of cTnI and CK-MB in ENA group were (1.32 +/- 0.12 microg/L to 2.47 +/- 0.22 microg/L) and (438 +/- 68 U/L to 5569 +/- 322 U/L), respectively, which were obviously lower than those in B group (6.42 +/- 0.96 microg/L to 15.10 +/- 3.69 microg/L) and (2556 +/- 74 U/L to 8047 +/- 574 U/L, P < 0.05 or P < 0.01) at different time-points. (2) Compared with normal controls, cloudy swelling, stromal blood vessel dilatation and congestion inflammatory cell infiltration were observed in scald group, but these pathological changes were less marked in ENA group.

CONCLUSIONSevere myocardial damage in rat occurred early after burns. Enalaprilat injection can markedly alleviate myocardial damage.

Animals ; Burns ; blood ; drug therapy ; pathology ; Creatine Kinase, MB Form ; blood ; Enalapril ; therapeutic use ; Myocytes, Cardiac ; metabolism ; pathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Troponin I ; blood

OBJECTIVETo investigate the influence of microtubule depolymerization of myocardial cells on distribution and activity of mitochondria, and energy metabolism of cells in adult rats.

METHODSMyocardial cells of SD adult rats and SD suckling rats were isolated and cultured. They were divided into adult and suckling rats control groups (AC and SC, normally cultured without any stimulating factor), adult and suckling rats microtubule depolymerization agent groups (AMDA and SMDA, cultured with 8 micromol/L colchicine containing nutrient solution for 30 minutes) according to the random number table. (1) The expression of polymerized beta tubulin in myocardial cells of adult and suckling rats was detected with Western blot. (2) Myocardial cells of rats in AC and AMDA groups were collected. The expression of cytochrome c was detected with Western blot. Distribution of voltage-dependent anion channels (VDAC) and polymerized beta tubulin in myocardial cells were observed with immunofluorescent staining. Mitochondrial inner membrane potential was determined with immunocytochemical method. Activity of myocardial cells was detected with MTT method. Contents of ATP, adenosine diphosphate (ADP), and adenosine monophosphate (AMP) and energy charge of cells were determined with high performance liquid chromatography.

RESULTS(1) The expression of polymerized beta tubulin:in AMDA group it was 0.52 + or - 0.07, which was obviously lower than that (1.25 + or - 0.12) in AC group (F = 31.002, P = 0.000); in SMDA group it was 0.76 + or - 0.12, which was significantly lower than that (1.11 + or - 0.24) in SC group (F = 31.002, P = 0.000), but was obviously higher than that in AMDA group (F = 31.002, P = 0.009). (2) The expression of cytochrome c in AC group was 0.26 + or - 0.03, which was obviously lower than that (1.55 + or - 0.13) in AMDA group (t = -24.056, P = 0.000). (3) Immunofluorescent staining result: in AC group, microtubules of myocardial cells were in linear tubiform, distributed in parallel with myocardial fiber; VDAC staining result showed that mitochondria were in granular form, distributed in the same direction as microtubules. In AMDA group, the normal distribution regularity of microtubules was destroyed, with weakened immune fluorescence intensity, microtubules structure indistinct, continuity lost, rough in appearance, and the distribution of mitochondria became disrupted. (4) Mitochondrial inner membrane potential in AC group fluorescent intensity was 1288 + or - 84, which was obviously higher than that (331 + or - 27) in AMDA group (t = 26.508, P = 0.000). (5) Cellular activity: in AC group absorbance value was 1.75 + or - 0.11, which was obviously lower than that (0.81 + or - 0.07) in AMDA group (t = 17.348, P = 0.000). (6) Energy metabolism: compared with those in AC group, content of ATP decreased, contents of ADP and AMP increased, and ATP/ADP value and energy charge decreased in AMDA group.

CONCLUSIONSMicrotubules and mitochondria distribute in the same direction in normal myocardial cells in adult rats. After microtubule depolymerization, mitochondria are arranged in disorder fashion; cytochrome c leaks from mitochondria; mitochondrial membrane potential, energy supply, and cellular activity decrease in the myocardial cells.

Animals ; Cells, Cultured ; Energy Metabolism ; Male ; Membrane Potential, Mitochondrial ; Microtubules ; metabolism ; Mitochondria, Heart ; metabolism ; Myocytes, Cardiac ; metabolism ; Rats ; Rats, Sprague-Dawley ; Tubulin ; metabolism

ObjectiveTo investigate the clinical features of systemic lupus erythematosus (SLE) patients with fever and find out the related factors.MethodsData was collected by the same methods in the past ten years in fifteen hospitals in Jiangsu province and then the data wereretrospectively analyzed.The potentially possible risk factors of fever in SLE were selected and then analyzed by chi-square test,Wilcoxon rank sum test and Logistic regression analysis.ResultsAll 1762 patients were investigated.Seven hundred and twenty-nine had active fever.Age at hospitalization,initially treated patients,photosensitivity,serositis,nervous system involvement,generalized lymphadenopathy/hepatosplenomegaly,white blood cell count (WBC),haemoglobin (HB),erythrocyte sedimentation rate (ESR),C-reaction protein (CRP),alanine aminotransferase(ALT),albumin(ALB),serum creatinine (Scr),complement C3,anti-dsDNA antibodies positive rate,anti-Sm antibodies positive rate,SLEDAI score and past therapies were factors associatedwith SLE fever.Logistic regression analysis showed that abnormal WBC count (OR=1.396,95％CI 1.114-1.711,P=0.004),CRP(OR=1.005,95％CI 1.002-1.009,P=0.002),ALT(OR=1.003,95％CI 1.001-1.005,P=0.005),Scr (OR=0.997,95％CI0.995-0.999,P=0.007),HB (OR=0.986,95％CI 0.981-0.992,P=0.000),age (OR =0.984,95％ CI 0.974-0.993,P=0.001 ) and past usage of cyclophosphamide (CTX) (OR =0.557,95％CI 0.382-0.813,P=0.002) were correlated with SLE fever.ConclusionFever is one of the most common clinical manifestations of SLE patients.Leucopenia,elevated CRP levels,liver function abnormalities,anemia,younger age are risk factors for SLE fever,while renal impairment and past usage of CTX are protective factors.