Inosine induces acute hyperuricaemia in rhesus monkey (Macaca mulatta) as a potential disease animal model

ContextThe uric acid metabolism pathway is more similar in primates and humans than in rodents. However, there are no reports of using primates to establish animal models of hyperuricaemia (HUA).ObjectivesTo establish an animal model highly related to HUA in humans.Materials and methodsInosine (75, 100 and 200 mg/kg) was intraperitoneally administered to adult male rhesus monkeys (n = 5/group). Blood samples were collected over 8 h, and serum uric acid (SUA) level was determined using commercial assay kits. XO and PNP expression in the liver and URAT1, OAT4 and ABCG2 expression in the kidneys were examined by qPCR and Western blotting to assess the effects of inosine on purine and uric acid metabolism. The validity of the acute HUA model was assessed using ulodesine, allopurinol and febuxostat.ResultsInosine (200 mg/kg) effectively increased the SUA level in rhesus monkeys from 51.77 ± 14.48 at 0 h to 178.32 ± 14.47 μmol/L within 30 min and to peak levels (201.41 ± 42.73 μmol/L) at 1 h. PNP mRNA level was increased, whereas XO mRNA and protein levels in the liver were decreased by the inosine group compared with those in the control group. No changes in mRNA and protein levels of the renal uric acid transporter were observed. Ulodesine, allopurinol and febuxostat eliminated the inosine-induced elevation in SUA in tested monkeys.ConclusionsAn acute HUA animal model with high reproducibility was induced; it can be applied to evaluate new anti-HUA drugs in vivo and explore the disease pathogenesis.     

Role of genetic polymorphisms in hepatitis C virus chronic infection

AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C(CHC).METHODS: We conducted an electronic search on the Pub Med and MEDLINE(2000-2014) databases and Cochrane library(2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.RESULTS: Several studies associated polymorphisms in the interleukin 28 B gene on chromosome 19(19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon(PegIFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation. CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.     

HPLC法测定不同产地地龙中尿嘧啶、次黄嘌呤、尿苷、肌苷的含量

目的:测定不同产地、品种的地龙药材中尿嘧啶、次黄嘌呤、尿苷、肌苷的含量,建立地龙质量控制的客观指标。方法:用0.9%生理盐水超声提取地龙药材,采用反相高效液相色谱法,Waters Symmetry C₁₈色谱柱（150mm×4.6mm,5μm）,以0.01mol·L^-1磷酸二氢钾溶液和50%甲醇为流动相,流速为0.8ml·min^-1,梯度洗脱,检测波长254nm,柱温27℃,同时测定尿嘧啶、次黄嘌呤、尿苷、肌苷等4种成分的含量。结果:尿嘧啶的线性范围为0.75～24.00μg·ml^-1（r=0.9993）,平均回收率99.82%,RSD=2.34%（n=6）;次黄嘌呤的线性范围2.50～80.00μg·ml^-1（r=0.9992）,平均回收率101.93%,RSD=1.45%（n=6）;尿苷的线性范围1.25～40.00μg·ml^-1（r=0.9992）,平均回收率97.53%,RSD=1.73%（n=6）;肌苷的线性范围5.00～160.00μg·ml^-1（r=0.9991）,平均回收率102.06%,RSD=2.44%（n=6）。结论:该方法重复性,回收率好,可用于地龙药材中尿嘧啶等4种成分的含量测定。     

Differential reactivity of isolated mast cells from the rat and guinea pig

The effects of various chemical histamine liberators on isolated rat peritoneal, rat mesenteric and guinea-pig mesenteric mast cells were examined. All three cell types responded, but to different degrees, to calcium ionophores and surface active agents. The rat mesenteric cells also reponded, but less effectively than the peritoneal cells, to compound 48/80, peptide 401 from bee venom and ATP. Rat mesenteric cells were essentially refractory to the action of dextran and guinea-pig cells were almost totally unresponsive to the named secretagogues. These results show that there are marked functional differences between the mast cells examined and suggest that isolated tissue cells may usefuly complement rat peritoneal cells in the study of anaphylactic and anaphylactoid reactions.     

Anticonvulsant doses of inosine result in brain levels sufficient to inhibit [3H] diazepam binding

Several purines have been shown to be competitive inhibitors of [³H] diazepam binding. Inosine has also been shown to have benzodiazepine-like neurophysiologic, pharmacologic and behavioral effects, and to partially inhibit caffeine-induced seizures in mice. Using presumptive therapeutic doses of inosine, levels were determined in mouse brain at various times following injection. Inosine and hypoxanthine concentrations in brain increased several fold following inosine administration, indicating that inosine permeated the blood-brain barrier. The levels of inosine and hypoxanthine attained in brain were sufficient to inhibit by more than 50% the GABA-stimulated [³H] diazepam binding. These data suggest that that the anticonvulsant properties of inosine are related to its interaction with the benzodiazepine receptor.     

Pre-treatment role of inosine triphosphate pyrophosphatase polymorphism for predicting anemia in Egyptian hepatitis C virus patients

AIM: To investigate and clarify, for the first time, the role of inosine triphosphate pyrophosphatase (ITPA ) polymorphism in Egyptian chronic hepatitis C virus (HCV) patients.METHODS:The human genomic DNA of all patients was extracted from peripheral blood cells in order to determine the single nucleotide polymorphism (SNP) of ITPA (rs1127354). SNP genotyping was performed by real time polymerase chain reaction (PCR, ABI TaqMan allelic discrimination kit) for 102 treatment-naive Egyptian patients with chronic HCV. All patients had no evidence of cardiovascular or renal diseases. They received a combination treatment of pegylated interferon α (PEG-IFNα) as a weekly subcutaneous dose plus an oral weight-adjusted dose of ribavirin (RBV). The majority received PEG-IFNα2a (70.6%) while 29.4% received PEG-IFNα2b. The planned duration of treatment was 24-48 wk according to the viral kinetics throughout the course of treatment. Pre-treatment liver biopsy was done for each patient for evaluation of fibrosis stage and liver disease activity. The basal viral load level was detected quantitatively by real time PCR while viral load throughout the treatment course was performed qualitatively by COBAS TaqMan assay. RESULTS: Ninety-three patients (91.2%) had ITPA SNP CC genotype and 9 (8.8%) had non-CC genotype (CA and AA). The percentage of hemoglobin (Hb) decline was higher for CC patients than for non-CC patients, particularly at weeks 4 and 8 (P=0.047 and 0.034, respectively). During the first 12 wk of treatment, CC patients had significantly more Hb decline > 3 g/dL than non-CC patients: 64.5% vs 22.2% at weeks 8 and 12, respectively, (P=0.024 and 0.038). Reduction of the amount of the planned RBV dose was significantly higher for CC patients than non-CC patients during the first 12 wk (18% ± 12.1% vs 8.5% ± 10.2%, P=0.021). The percentage of CC patients with RBV dose reduction was significantly greater than that of non-CC patients (77.4% vs 44.4%, P=0.044). Multivariate analysis identified only the percentage of     

高碘酸滴定法测定肌苷的含量

目的建立高碘酸滴定法测定肌苷的含量。方法用高碘酸滴定法测定肌苷的含量并与紫外分光光度法作对比。结果高碘酸滴定法作肌苷含量测定,方法简便快捷,终点变色灵敏,测定结果准确可靠。结论分析结果准确,重现性好,更有效地测定肌苷的含量,不受仪器设备条件限制。使肌苷的含量测定在容量分析中占有一位置。     

肾综合征出血热患者血清Cys-C测定临床意义

目的:研究胱抑素C(Cys-C)在肾综合征出血热(HFRS)患者各病期的变化及其临床意义。方法:测定23例HFRS患者各病期血清肌酐(Cr)、尿素(Urea)、胱抑素C(Cys-C)的含量,采用47例发热患者(排除肾脏疾病)及30例健康体检者为对照组,使用SPSS10.0统计学软件进行分析。结果:Urea、Cr在HFRS患者各病期均显著增高,以低血压休克期、少尿期、多尿期增高最为明显,但三期间互无显著性差异。Cys-C在HFRS患者各病期均显著增高,以低血压休克期最为明显,发热期与恢复期之间、少尿期与多尿期之间无显著差异。在恢复期,Urea仍有43.5%的患者高于正常对照组,Cr为69.5%,而Cys-C为82.6%。结论:与传统肾功能指标血清肌酐(Cr)、尿素(Urea)相比,血清胱抑素C(Cys-C)测定在肾综合征出血热各病期的变化更明显,恢复期下降的最慢,是肾综合征出血热患者肾功能变化更敏感的标志物。     

Clinical Phenotype in a Swedish Family with a Mutation in the IMPDH1 Gene

Purpose: Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) have recently been discovered to cause a form of autosomal dominant retinitis pigmentosa (adRP). Such mutations are estimated to account for approximately 2–5% of the adRP cases among Americans of European origin and Europeans. Aiming towards an understanding of the molecular background of retinitis pigmentosa, this paper describes the phenotype of a Swedish family with a mutation in IMPDH1. Methods: Venous blood samples were obtained from 12 family members and screened for mutations in IMPDH1. Six individuals with the mutation were examined clinically and with full-field electroretinography (ERG), dark adaptometry, multifocal electroretinography (mfERG), and optical coherence tomography (OCT). Also reviewed were the clinical findings and ERGs obtained 14 years earlier. Results: The proband and eight other relatives from three generations were found to harbor the Asp226Asn mutation in IMPDH1. These individuals, from three generations, showed clinical and electrophysiological signs of retinitis pigmentosa. The cone responses to the full-field, 30-Hz flicker ERG demonstrated an unusual pattern, with implicit times within normal limits or only slightly prolonged. Rod ERG responses, however, were undetectable. OCT showed intraretinal fluid and swelling, changes that were more pronounced in younger individuals. mfERG showed residual preserved central function. The older the individual, the smaller the area of preserved central function. Conclusion: In this family with a mutation in IMPDH1, we found a specific phenotype with rod function affected more than cone function, foveal edema, and central retinal function preserved for a long period of time. Foveal edema could be a pathogenic feature in this form of retinal degeneration.     

反相高效液相色谱法测定肌苷氯化钠注射液中的有关物质含量

目的建立肌苷氯化钠注射液有关物质的检测方法。方法反相高效淳相色谱法,HypersiL C18柱（4．6×250mm,10μm）,流动相：甲醇-水（10：90）,检测波长：248nm。结果肌苷及共有关物质得到基线分离（R〉1．5）,最低检测量为0．5ng,控制总杂质量不得过1．0％。结论本法简便、快速、准确,适用于肌苷及其制剂的质量控制。