AIMTo study the pharmacokinetics and bioequivalence of acipimox sustained-release tablets (SRT) after a single and multiple oral dose in healthy dogs.

METHODSThe plasma concentrations of of SRT and reference capsules with a single and multiple oral doses.

RESULTSThe drug concentration-time profiles fitted to a noncompartment model. After a single dose administration of sustained-release tablets and capsules, the pharmacokinetic parameters were as follows: AUC were (158 +/- 30) and (147 +/- 37) microg x h x mL(-1); Tmax were (4.3 +/- 0.8) and (2.6 +/- 1.3) h; Cmax were (29 +/- 6) and (42 +/- 10) microg x mL(-1); T(1/2) were (2.3 +/- 0.7) and (1.60 +/- 0.10) h; MRT were (6.0 +/- 0.8) and (3.9 +/- 0.7) h, respectively. The relative bioavailability of the sustained-release tablet was (108 +/- 16) %. After a multiple oral administration of sustained-release tablets and capsules, the pharmacokinetic parameters were as follows: AUC were (209 +/- 23) and (195 +/- 26) microg x h x mL(-1); Tmax were (6.3 +/- 0.8) and (3.4 +/- 1.5) h; Cmax were (27 +/- 4) and (36 +/- 5) microg x mL(-1); Cmmin were (2.2 +/- 1.0) and (0.20 +/- 0.20) microg x mL(-1); Cav were (8.7 +/- 1.0) and (8.1 +/- 1.1) micro x mL(-1); FI were (293 +/- 73) % and (448 +/- 91) % , respectively. The relative bioavailability of the sustained-release tablet was (114 +/- 19) %.

CONCLUSIONThe results of two one-side test from single dose administration shown that two preparations were bioequivalent. The Cmax of sustained-release tablet was lower than that of capsules, while the Tmax and MRT of sustained-release tablet were higher than that of capsule, which indicating a good retarding effect. The results from multiple dose administration also shown that two preparations were bioequivalent and the DF of sustained-release tablet was significant lower than that of capsule.

Administration, Oral ; Animals ; Area Under Curve ; Biological Availability ; Capsules ; Delayed-Action Preparations ; Dogs ; Dose-Response Relationship, Drug ; Hypolipidemic Agents ; administration & dosage ; pharmacokinetics ; Pyrazines ; administration & dosage ; pharmacokinetics ; Random Allocation ; Tablets ; Therapeutic Equivalency

OBJECTIVETo investigate the effect of docosahexaenoic acid (DHA) on invasiveness of aflatoxin B1 (AFB1)-induced hepatocellular carcinoma cells in vitro.

METHODSHepG2.2.15 cells were exposed to different concentrations of AFB1 and DHA plus AFB1. The cell migration and invasion were assessed using wound-healing and Transwell assay, and flow cytometry was used to analyze the cell cycle changes. The ultrastructural changes of the cells were observed by transmission electron microscopy.

RESULTSCompared with the control group, the cells exposed to2 µmol/L AFB1 showed obviously enhanced migration and invasion with decreased cell ratio in G1/G1 phase and increased cell ratio in G2/M phase but no changes in S phase cells; transmission electron microscopy revealed the presence of multiple nucleoli and significantly increased mitochondria and Golgi apparatus in the exposed cells. Compared with AFB1-exposed cells, the cells treated with DHA and AFB1 showed decreased migration and invasion abilities, and the G1/G1 phase cells increased and G2/M phase cells decreased significantly; ultrastructurally, the cells contained single nucleoli with decreased mitochondria and vacuolization occurred in the cytoplasm.

CONCLUSIONDHA can significantly inhibit AFB1-induced enhancement of cell migration and invasion in hepatocellular carcinoma cells in vitro.

Aflatoxin B1 ; pharmacology ; Carcinoma, Hepatocellular ; pathology ; Cell Cycle ; Cell Movement ; drug effects ; Docosahexaenoic Acids ; pharmacology ; Golgi Apparatus ; Hep G2 Cells ; Humans ; Liver Neoplasms ; pathology ; Mitochondria ; Neoplasm Invasiveness

OBJECTIVETo extract the active component from the root of Actinidia valvata Dunn and to investigate the effects on hepatocellular carcinoma (HCC) cells in vitro.

METHODSTotal saponin was extracted from the root of A. valvata (TSAVD). HCC cells, such as BEL-7402, HepG2, PLC, SMMC-7721, MHCC-97-H, and MHCC-97-L, were treated with TSAVD in 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT) assay. BEL-7402 and MHCC-97-H cells were also treated respectively with TSAVD at different concentrations for 24 h in wound healing and adhesion assays, and the effects of TSAVD on BEL-7402 and MHCC-97-H cells mobility and adhesion abilities were observed. Meanwhile, the effects of TSAVD on invasion and migration of BEL-7402 and MHCC-97-H cells were also investigated by transwell chamber in invasion and migration assays.

RESULTSTSAVD at 1.5 mg/mL inhibited BEL-7402 cell proliferation with inhibition ratios (IRs) of 61.08%, 74.12%, 84.55% at 24, 48, and 72 h, respectively. Meanwhile, TSAVD inhibited MHCC-97-H proliferation in a concentration-dependent manner from 1.5 to 0.5 mg/mL, with the IR of 36% at 1.5 mg/mL at 24 h. For SMMC-7721, PLC, and HepG2, the IR was lower than 30% at 1.5 mg/mL at 24 h. In the wound healing assay, mobility abilities of BEL-7402 and MHCC-97-H cells in TSAVD treated groups were significantly weaker than those of the control group. After pretreatment for 24 h with TSAVD, adhesion abilities were reduced in both MHCC-97-H and BEL-7402 cells, with IRs of 48.50%±4.86% and 49.85%±5.25% at 200 μg/mL. The IRs of MHCC-97-H and BEL-7402 cells in the migration assay were 49.13%±2.91% and 79.37%±0.09% at 200 μg/mL. In the invasion assay, IRs were 69.78%±4.88% and 82.48%±0.25% at 200 μg/mL.

CONCLUSIONSOf all HCC cells, the highest inhibition by TSAVD was seen for BEL-7402 proliferation. TSAVD could restrain adhesion, invasion, mobility, and migration abilities of BEL-7402 and MHCC-97-H cells in vitro.

Actinidia ; chemistry ; Carcinoma, Hepatocellular ; drug therapy ; pathology ; Cell Adhesion ; drug effects ; Cell Line, Tumor ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Drug Screening Assays, Antitumor ; Humans ; Liver Neoplasms ; drug therapy ; pathology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; drug therapy ; prevention & control ; Plant Roots ; chemistry ; Saponins ; pharmacology ; therapeutic use ; Wound Healing ; drug effects

OBJECTIVETo observe the impacts of acupuncture on intelligent structure, social adaptability and fMRI brain function in children mental retardation (MR).

METHODSSixty cases of MR in compliance with the diagnostic standard were randomized into an acupuncture group and a medication group, 30 cases in each one. In the acupuncture group, Sishenzhen [four points, 1.5 cun anterior, posterior and bilateral to Baihui (GV 20)], Zhisanzhen [Shenting (GV 24), bilateral Benshen (GB 13)], Niesanzhen (the point 2 cun directly above the ear a-pex, the two points 1 cun bilateral the first point) and Naosanzhan [Naohu (GV 17) and bilateral Naohu (GB 19)] were selected as the main points. In the medication group, piracetam tablets were prescribed for oral administration. One course of treatment was 4 months in the two groups. The comprehensive efficacy was compared between the two groups at the end of treatment course. China-Wechsler Intelligence Scale for Children (C-WISC) was used to assess the intelligent improvements. Infant-Junior School Student Social Life Ability Scale was adopted to assess the improvements of social adaptability. Five cases were selected from the acupuncture group and fMRI was adopted to compare the brain function imaging changes before and after acupuncture treatment.

METHODSIn the acupuncture group, the final intelligence quotient (FIQ) and social adaptability score after treatment were higher than those before treatment (P<0.05), of which, the performance intelligence quotient (PIQ) was improved significantly, indicating the statistically significant difference (P<0.05). But the verbal intelligence quotient (VIQ) did not change apparently (P>0.05). In the medication group, the changes in all the indices were not apparent before and after treatment (P>0.05). In comparison of the changes after treatment between the two groups, FIQ, PIQ and social adaptability score in the acupuncture group were improved more significantly as compared with the medication group (P<0.05). The fMRI brain function images did not change apparently before and after treatment in those 5 cases of the acupuncture group.

CONCLUSIONAcupuncture promotes the intelligent recovery of MR children and improves their social adaptability. It indicates the satisfactory clinical efficacy. But, the fMRI brain function images do not change apparently before and after treatment.

Acupuncture Points ; Acupuncture Therapy ; Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Intellectual Disability ; psychology ; therapy ; Intelligence Tests ; Male ; Social Adjustment ; Treatment Outcome

OBJECTIVE: To study the predictive value of Pediatric Age-adapted Sequential Organ Failure Assessment Score (pSOFA), Pediatric Risk of Mortality Score III (PRISM III), and Pediatric Critical Illness Score (PCIS) in children with severe sepsis. METHODS: A retrospective analysis was performed for the clinical data of 193 hospitalized children with severe sepsis. According to the final outcome, these children were divided into a survival group with 151 children and a death group with 42 children. The scores of pSOFA, PRISM III, and PCIS were determined according to the worst values of each index within 24 hours after admission. The receiver operating characteristic (ROC) curve was used to analyze the efficiency of each scoring system in predicting the risk of death due to sepsis. Smooth curve fitting was used to analyze the correlation between the three scoring systems and the threshold effect of each scoring system. Decision curve analysis (DCA) was used to evaluate the application value of each scoring system. RESULTS: The ROC analysis showed that PCIS and pSOFA had a similar predictive value (P=0.182) and that PRISM III and pSOFA had a similar predictive value (P=0.210), while PRISM III had a better predictive value than PCIS (P=0.045). PRISM III had the highest degree of fitting with prognosis, followed by pSOFA and PCIS. The DCA analysis showed that when the risk of death was 0.4 and 0.6 in children with severe sepsis and the three scoring systems were used as the basis for emergency intervention decision-making, pSOFA achieved the highest standardized net benefit, followed by PRISM III and PCIS. CONCLUSIONS All three scoring systems have a certain value in predicting the prognosis of children with severe sepsis, and pSOFA has a better value than PRISM III and PCIS.
Child ; Critical Illness ; Humans ; Organ Dysfunction Scores ; Prognosis ; ROC Curve ; Retrospective Studies ; Sepsis

Objective To investigate the mechanism of Chonghe soft extract on ulcer wound healing in diabetic rats through protein kinase B(Akt)/mammalian Sirolimus target protein(mTOR)-mediated nucleotides binding oligomeric acid domain-like receptor protein 3(NLRP3)inflammasome inactivation.Methods Thirty six SD rats with diabetic ulcer,which were established by feeding with high glucose and high fat diet and injecting intraperitoneally with streptozocin(STZ)combined with skin defect,were randomly divided into model group,Chonghe soft extract group and growth factor group,with twelve rats in each group.Another twelve SD rats were injected an equal dose of citric acid-sodium citrate buffer solution and used as blank group.The blank group and the model group were not received drug intervention,but the Chonghe soft extract group and the growth factor group were externally applied Chonghe soft extract and growth factor gel,respectively.The wound healing of each group was observed and recorded.After 7 days and 14 days of treatment,the histopathology of wound were observed by HE staining and the number of fibroblasts were counted.The levels of IL-1β,IL-18 and TNF-α in serum were detected by ELISA.The expression of autophagy-related protein Beclin-1 and LC3Ⅱ in granulation tissue was detected by immunohistochemistry.The expression of NLRP3,apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),Caspase1,Pro-Caspase1 and Akt/mTOR autophagy pathway-related proteins Akt,p-Akt,mTOR and p-mTOR were detected by Western Blot.Results Compared with the blank control group,the pathological wound repair of the model group was delayed on the 7th day and 14th day,the number of fibroblasts per unit area was decreased(P<0.01).The levels of IL-1β,IL-18 and TNF-α were increased(P<0.01).The expression levels of ASC,Pro-Caspase1,Caspase1,and NLRP3 were increased in the wound tissues(P<0.01),while the expression levels of Beclin-1,LC3-Ⅱ,mTOR,p-mTOR,Akt and p-Akt were decreased in the wound tissues(P<0.01).Compared with the model group,the pathological injury in Chonghe soft extract group and growth factor group was significantly improved on the 7th day and 14th day.The number of fibroblasts per unit area was significantly increased(P<0.01).The levels of IL-1β,IL-18 and TNF-α were significantly decreased(P<0.01).The expression levels of ASC,Pro-Caspase1,Caspase1,and NLRP3 in the wound tissues were decreased(P<0.01),while the expression levels of Beclin-1,LC3-Ⅱ,mTOR,p-mTOR,Akt and p-Akt were increased(P<0.01,P<0.05).Conclusion Chonghe soft extract can reduce inflammatory reaction,promote the generation of fibro,regulate the Akt/mTOR-mediated NLRP3 inflammasome inactivation,improve the level of autophagy in wound,and promote ulcer wound healing in diabetic rats.

OBJECTIVETo study the distribution of genomovars and microevolution of Yersinia pestis in the Qinghai-Tibet Plateau.

METHODSPrimer pairs targeting the twenty-two different regions(DFRs) were designed for detecting the presence or deletion of each DFR in 297 strains isolated from the Qinghai-Tibet Plateau.

RESULTS9 genomovars, i. e. Genomovar 1, 5, 6, 7, 8, 10, 11, new type and Ype-ancestor were identified in the Marmota himalayana plague focus of the Qinghai-Tibet Plateau. Among these genomovars, genomovar 5,8 and 10 were dominant types. The total rate of the three genomovars was 80.6% (204/253) and the genomovars in different regions were different. All of 44 strains of Y. pestis in the Microtus fuscus plague focus of the Qinghai-Tibet Plateau belonged to genomovar 14.

CONCLUSIONThe distribution of genomovars of Y. pestis in the Qinghai-Tibet plateau had remarkable characteristics geographically. Based on the distribution of genomovars of Y. pestis, the routes of transmission and microevolution of Y. pestis were proposed.

Biological Evolution ; China ; Geography ; Humans ; Plague ; transmission ; Yersinia pestis ; genetics

OBJECTIVESIsovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. IVA is considered to be a severe, potentially life-threatening disorder that manifests with acute neonatal encephalopathy in approximately half of affected individuals, and recurrent episodes of vomiting, lethargy, coma and varying degrees of developmental delay in the other half of patients. This study was conducted to investigate the clinical features and IVD gene mutations of a Chinese patient with IVA.

METHODSThe clinical features, routine laboratory data, blood amino acid and acylcarnitine profiles and urinary organic acid profiles of a patient with IVA were reviewed. Whole coding exons of IVD gene were PCR-amplified for DNA sequencing. The novel mutation c.466G > C (G127A) was confirmed by RFLP with restriction endonuclease Hph I.

RESULTSThe patient was a 2 year and 7 month-old boy. At 3 days of age, he began to show severe vomiting and acidosis. He was treated with pyloromyotomy at 10 days of age. His recurrent vomiting was not ameliorated until beginning transition to a diet that included more carbohydrate from 4 months. He had 3 recurrent severe vomiting and acidosis later and showed obvious psychomotor retardation. Blood spot acylcarnitine profiles by MS-MS demonstrated an elevation of C5-carnitine with a peak concentration of 12.89 micromol/L (< 0.5 micromol/L). Organic acid analysis of urine by GC-MS revealed a relatively high level of isovaleric glycine. Mutational analysis of the patient's IVD gene revealed heteroallelic mutations of c.149G > A (R21H) and c.466G > C (G127A) which is a novel missense mutation. G127A mutation was not detected in any of 50 normal controls.

CONCLUSIONSFrom the clinical course, obvious elevation of blood C5-carnitine and urine isovaleric glycine, this patient's disorder should be classified as "metabolically severe" type of IVA which suggest that c.466G > C (G127A) mutation could severely damage the function of the IVD protein. To our knowledge, this is the first characterization of IVD gene mutations in the mainland of China.

Amino Acid Metabolism, Inborn Errors ; enzymology ; genetics ; Child, Preschool ; DNA Mutational Analysis ; Exons ; Gas Chromatography-Mass Spectrometry ; Humans ; Isovaleryl-CoA Dehydrogenase ; genetics ; Male ; Mutation ; Tandem Mass Spectrometry

Aim To investigate the mechanism by which formononetin (FN) inhibits mitochondrial dynamic-related protein 1 (DRP1) -NLRP3 axis via intervening the generation of ROS to reduce allergic airway inflammation. Methods In order to establish allergic asthma mouse model, 50 BALB/c mice aged 8 weeks were divided into the control group, model group, FN treatment group and dexamethasone group after ovalbumin (OVA) induction. Airway inflammation and collagen deposition were detected by HampE and Masson staining. Th2 cytokines and superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and IgE levels in bronchoalveolar lavage fluid (BALF) were measured by ELISA, ROS in BEAS-2B cells was assessed by DCFH-DA staining, DRP1 expression in lung tissue and BEAS-2B cells was detected by immunohistochemistry and immunofluorescence, and the DRP1-NLRP3 pathway was analyzed by immunoblotting. Results FN treatment could effectively ameliorate the symptoms of asthmatic mouse model, including reducing eosinophil accumulation, airway collagen deposition, decreasing Th2 cytokine and IgE levels, reducing ROS and MDA production, increasing SOD and CAT activities, and regulating DRP1-NLRP3 pathway-related protein expression, thereby relieving inflammation. Conclusion FN ameliorates airway inflammation in asthma by regulating DRP1-NLRP3 pathway.