PDTC抑制阿霉素肾病大鼠转录因子NF-κB、AP-1活性

目的 探讨肾病综合征 (NS)大鼠肾组织转录因子核因子 -κB(NF -κB)、活化蛋白 - 1(AP - 1)DNA结合活性变化及二硫代氨基甲酸吡咯烷 (PDTC)对其活性的影响。方法 应用凝胶电泳迁移率法 (EMSA)和同位素放射自显影等方法检测 :①阿霉素肾病大鼠模型形成过程的不同时间点NF -κB、AP - 1的DNA结合活性、血液生化指标和尿蛋白排泄量 ;②PDTC治疗对上述指标的影响。结果 ①大鼠经尾静脉注射阿霉素后第 7天 2 4h尿蛋白排泄量 (UpV) (mg/ 2 4h)开始升高 ,第 2 1天出现大量蛋白尿、低蛋白血症、高脂血症 ;②注射阿霉素后第 7天肾皮质组织NF -κB活性开始升高 ,第 2 8天达高峰 ,其相对密度值 (RDU)明显高于正常对照组 (P <0 .0 1)。AP - 1活性升高迟于NF -κB ,于第 14天活性明显升高 ,第 2 8天活性最高 ,与正常对照组相比有明显差异 (P <0 .0 1)。③经用抗氧化剂PDTC后NF -κB结合活性明显下降 (P <0 .0 1) ,而AP - 1活性无变化 (P >0 .0 5 )。抗氧化剂治疗不能减少UpV(P >0 .0 5 )。结论 ①阿霉素肾病大鼠肾皮质中NF -κB、AP - 1DNA结合活性异常升高。②抗氧化剂PDTC能够抑制NF -κB活性但不能抑制AP - 1活性 ,亦不能减少尿蛋白排泄量。

Development of a New Azithromycin Glutamate for Parenteral Preparation, the Toxicity in Sprague-Dawley Rats and Pharmacokinetics in Human Healthy Volunteers

Aim In order to improve the solubility of azithromycin, the objectives of the present study were to screen an appropriate salt for azithromycin by comparing acute hepatic and renal toxicities in animals, and study the pharmacokinetics of final chosen azithromycin salt. Methods Various salts of azithromycin, such as glutamate, citrate, hydrochloride, sulphate, dihydrogen phosphate, lactobionate, tartrate, and aspartate were given intravenously to Sprague Dawley rats at a dose of 10 mg once daily for 14 consecutive days via tail vein. The acute hepatic and renal indicators were measured before and after administration. A pharmacokinetic study was performed on 12 healthy human volunteers. The subjects were equally divided into two groups by a randomized crossover design. Azithromycin glutamate injection was administered by intravenous infusion or intramuscular injection at a single dose of 500 mg, respectively. Azithromycin concentrations in plasma were determined by microbial inhibition zone assay, and the pharmacokinetic parameters were calculated using a practical pharmacokinetic software 3P87 program. Results Azithromycin glutamate was least toxic to the liver and kidney of the rats, thus being selected as a final salt for parenteral preparation of azithromycin. Pharmacokinetic results showed that the area under the plasma concentration-time curves （AUC0-120h） were 21.47 ± 1.57 h·μg·mL^-1 for intravenous infusion, and 19.36 ± 2.44 h·μg·mL^-1 for intramuscular injection. The absolute bioavailability of intramuscular injection was 92.59%. Conclusion Azithromycin glutamate is suitable for the future clinical application, and its pharmacokinetics is characterized in human volunteers in the present study.

Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis

OBJECTIVE: To make an open label prospective trial for comparing the therapeutic effects of mycophenolate mofetil (MMF) vs cyclophosphamide (CYC) pulse therapy on patients with diffuse proliferative lupus nephritis (DPLN). METHODS: Forty-six patients with biopsy proven active DPLN were enrolled in this study. Twenty-three patients were given MMF orally at a dosage of 1.0 - 1.5 g/d (MMF Group). Another 23 cases received conventional intermittent CYC pulse therapy (CYC Group). Supplemental steroid treatment was offered in the same manner to both groups. The age, sex distribution and severity of renal damage were matched in two groups. Therapeutic effects were evaluated at the end of six-month treatment. Fifteen patients in the MMF Group and 12 patients in the CYC Group had repeated renal biopsy at that time. RESULTS: MMF therapy was more effective in reducing proteinuria and hematuria. A 50% reduction of urinary protein and urinary red blood cell excretion from baseline value in 69.6% and 91.3% patients in the MMF Group, while only 47.8% and 65.2% in the CYC Group. MMF was more effective in inhibiting autoantibody production (especially anti-dsDNA antibody) and in decreasing serum cryoglobulin levels. Pathologically, the MMF group showed more markedly reduction in glomerular immune deposits with less glomerular necrosis, and less microthrombi, less crescent formation and vascular changes in the repeated renal biopsy as compared with the CYC group. Adverse reactions related to the treatment included gastrointestinal symptoms 26.1% and 43.5% in the MMF and CYC Groups respectively, infection 17.4% in the MMF group and 30.4% in the CYC group. CONCLUSION: MMF was more effective in controlling the clinical activity of DPLN and renal vascular lesions as compared with CYC pulse therapy in a 6 month follow-up study.

Mycophenolate mofetil plus prednisone for inducing remission of Henoch-Sch?nlein purpura nephritis: a retrospective study

Objective： The treatment of Henoch-Schonlein purpura （HSP） with moderate proteinuria remains con- troversial. We retrospectively analyzed the efficacy of immune suppressants, with a particular emphasis on myco- phenolate mofetil （MMF）. Methods： Ninety-five HSP patients with moderate proteinuria （1.0-3.5 g/24 h） after at least three months of therapy with angiotensin-converting enzyme inhibitor （ACEI） or angiotensin receptor blocker （ARB） were divided into three groups： an MMF group （n=33） that received MMF 1.0-1.5 g/d combined with prednisone （0.4-0.5 mg/（kg.d））, a corticosteroid （CS） group （n=31） that received full-dose prednisone （0.8-1.0 mg/（kg.d））, and a control group （n=31）. Patients in the MMF and CS groups continued to take ACEI or ARB at the original dose. The patients in the control group continued to take ACEI or ARB but the dose was increased by （1.73±0.58）-fold. The patients were followed up for 6-78 months （median 28 months）. Results： The baseline proteinuria was higher in the MMF group （（2.1±0.9） g/24 h） than in the control group （（1.6±0.8） g/24 h） （P=0.039）. The proteinuria decreased sig- nificantly in all groups during follow-up, but only in the MMF group did it decrease significantly after the first month. At the end of follow-up, the proteinuria was （0.4±0.7） g/24 h in the MMF group and （0.4±0.4） g/24 h in the CS group, significantly lower than that in the control group （（0.9±1.1） g/24 h）. The remission rates in the MMF group, CS group, and control group were respectively 72.7%, 71.0%, and 48.4% at six months and 72.7%, 64.5%, and 45.2% at the end of follow-up. The overall number of reported adverse events was 17 in the MMF group, 30 in the CS group, and 6 in the control group （P〈0.001）. Conclusions： MMF with low-dose prednisone may be as effective as full-dose prednisone and tend to have fewer adverse events. Therefore, it is probably superior to conservative treatments of adult HSP patients with moderate proteinuria.

Effect of Helichrysum plicatum DC. subsp. plicatum ethanol extract on gentamicin-induced nephrotoxicity in rats

The aim of this study was to evaluate the possible therapeutic or protective effects of Helichrysum plicatum DC.subsp.plicatum ethanol extract（HPE）against gentamicin-induced nephrotoxicity.Thirty-six Sprague Dawley male rats weighing between 200 and 250 g were used as live material.They were formed into six groups containing 6rats each and were allowed to adapt to laboratory conditions for 7 d.Group Ⅰ：control,5%DMSO intraperitoneal（i.p.）;Group Ⅱ：HPE 100 mg/（kg·d）i.p.;Group Ⅲ：HPE 200 mg/（kg·d）i.p.;Group Ⅳ：gentamicin as 80 mg/（kg·d）i.p.;Group Ⅴ：gentamicin as 80 mg/（kg·d）i.p.＋HPE 100 mg/（kg·d）i.p.;and Group Ⅵ：gentamicin as 80 mg/（kg·d）i.p.＋HPE 200 mg/（kg·d）i.p.for 8 d.Following treatment,serum,liver,and kidney tissues were used to assess blood urea nitrogen（BUN）,creatinine,enzymatic and non-enzymatic antioxidants,and lipid peroxidation.Gentamicin significantly increased serum BUN,creatinin,and liver and kidney levels of malondialdehyde（MDA）.It also decreased the activity of catalase（CAT）,glutathione peroxidase（GPx）,and superoxide dismutase（SOD）.Treatment with the HPE 100 mg/kg reversed gentamicin-induced alterations as evidenced by decreased serum BUN and creatinin,liver and kidney oxidant marker,and tubular necrosis as well as by an increase in antioxidant enzymes.It was found that HPE 200 mg/kg significantly increased liver and kidney tissue MDA levels in nephrotoxicity in rats.As a result,these findings support the proposition that HPE in 100 mg/kg dose demonstrates in the kidney and liver as free radicals and scavenger to prevent the toxic effects of gentamicin in both the biochemical and histopathology parameters.

A prospective cohort study on the relationship between vancomycin steady-state trough concentration and efficacy and safety in Chinese adults

Clinical guidelines recommend a steady-state vancomycin(VCM)trough concentration(SVTC)of 10–15 mg/L for regular infections and 15–20 mg/L for severe infections.However,clinical trials have shown that increasing SVTC is not beneficial for efficacy,and instead it leads to nephrotoxicity.To verify whether increasing the SVTC results in improved clinical outcomes with sustainable adverse effects,we prospectively determined its correlation with clinical efficacy and safety.The participants included patients hospitalized with Gram-positive bacterial infections from March 2017 through October 2018.The patients were classified into group I(SVTC<10 mg/L),II(10≤SVTC≤20 mg/L),or III(SVTC>20 mg/L).Clinical,microbiological,and laboratory data were collected.Clinical outcomes between group I and II were matched after propensity score matching(PSM).A total of 331 patients were included in this study.Clinical failure occurred in 59(29%)of 204 patients on day 14,with no significant difference between groups I and II(P=0.535).Infection recurred at 28 d in 62(30%)of 204 patients,and no significant difference in infection recurrence was observed between both the groups(log-rank,P=0.674).Except for a significant increase in the incidence of acute kidney injury in group II,no significant difference was observed between two groups for any clinical results.The incidence of adverse events in groups I and II was significantly lower than that in group III(P<0.001).SVTC had an applicable cut-off point at 14.55 mg/L.SVTC was not correlated with VCM clinical efficacy,while it was a good indicator of nephrotoxicity.