Effects of triptolide on the pharmacokinetics of cyclophosphamide in rats: a possible role of cytochrome P3A4 inhibition / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of a 10-day course of triptolide (TP) on rat cytochrome (CY) P3A4 activity, and on the pharmacokinetics of cyclophosphamide (CPA).</p><p><b>METHODS</b>In the pharmacokinetics experiment, rats were orally given 0.9% NaCl solution (n=5) and TP [1.2 (mg/kg·d)] for 10 days and a single dose of CPA was administered intravenously (100 mg/kg) to rats on day 11. Blood samples were collected up to 4 h at predetermined time intervals, the plasma concentration of CPA was determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were determined. In the in vitro CYP3A4 activity inhibition research, rat blank liver microsomes were divided into 3 groups: a control group, a TS (5 μL, 200 μmol/L) with TP (5 μL, 12.5 μmol/L) group, a TS with ketoconazole (5 μL, 1 μmol/L) group. Concentration of 6β-hydroxylated testosterone (6β-OHT) in liver microsomes was measured by HPLC and the activity of CYP 3A4 was calculated through the following formula: Einhibitor/Econtrol × 100%=Cinhibitor/Ccontrol × 100%.</p><p><b>RESULTS</b>Compared with the control group, the area under the plasma concentration-time curve (AUC0-∞) of CPA was significantly increased by 229.05% pretreated with TP (P<0.01). Peak plasma concentrations (Cmax) of CPA was significantly increased and plasma half-life was correspondingly extended. The CYP3A4 activity was significantly inhibited by ketoconazole 93.5%±0.2% and TP 84.6%±0.3% compared with the control group (P<0.01 and P<0.05, respectively).</p><p><b>CONCLUSION</b>Our results strongly suggested that long-term oral intake of TP can distinctly inhibit the CYP3A4 activity and this inhibition evidently decrease the formation of toxic metabolites of CPA.</p>

Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Acute gout is an intensely painful, inflammatory arthritis. Although the non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for this condition, the efficacy is based on only a few studies, particularly in China. We tried to assess the safety and efficacy of etoricoxib in the treatment of acute gouty arthritis in China.</p><p><b>METHODS</b>A randomized, double-blind, active comparator study was conducted at 10 sites in China. Patients (n = 178; ≥ 18 years of age) with acute gouty attack (< 48 hours) were treated for 5 days with etoricoxib (120 mg/d; n = 89) or indometacin (75 mg twice daily; n = 89). The primary efficacy end point was self-assessed pain in the affected joint (0-4 point Likert scale) from days 2 - 5. Secondary end points included investigator assessments of tenderness and swelling, patient/ investigator global assessments of response to therapy, and patients discontinuing treatment. Safety was assessed by adverse events (AEs).</p><p><b>RESULTS</b>Etoricoxib and indometacin had comparable primary and secondary end points. Mean change difference from baseline from days 2 - 5 was 0.03 (95% confidence interval (CI) -0.19 to 0.25; P = 0.6364), which fell within the prespecified comparative bounds of -0.5 to 0.5. No severe AEs were associated with etoricoxib use. Non-severe AEs were mainly digestive and general, and most (73.7%) were mild, although they caused withdrawal of two subjects in the etoricoxib group, due to bilateral renal calculi and uronephrosis of the left kidney (unrelated to etoricoxib) and fever and chills (potentially etoricoxib-related). Overall, AEs were similar, although the absolute number of AEs in the etoricoxib group (n = 31) was less than the indometacin group (n = 34).</p><p><b>CONCLUSIONS</b>Etoricoxib (120 mg once daily) is effective in treating acute gout, is generally safe and well-tolerated, and is comparable in efficacy to indometacin (75 mg twice daily).</p>

Safety and efficacy of T-614 in the treatment of patients with active rheumatoid arthritis: a double blind, randomized, placebo-controlled and multicenter trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>A novel anti-rheumatic drug, T-614, has been shown to have an anti-inflammatory effect and to improve abnormal immunological findings in rheumatoid arthritis (RA). To assess the safety and efficacy of T-614 versus placebo in patients with active RA we conducted a 24-week clinical study in 280 Chinese patients.</p><p><b>METHODS</b>In a multicenter, randomized, double blind, placebo controlled study, 280 patients were randomly assigned to receive placebo (n = 95) or T-614 at 50 mg (n = 93) or 25 mg (n = 92) daily. Active disease was defined by 4 of the following 5 criteria: >or= 5 tender joints, >or= 3 swollen joints, morning stiffness lasting for >or= 60 minutes, and Westergren erythrocyte sedimentation rate (ESR) >or= 28 mm/h, the assessment of pain at the rest by patient as moderate or severe. Clinical and laboratory parameters were analyzed at baseline, 2, 4, 6, 12, 18 and 24 weeks. The primary efficacy variable at week 24 was the American College of Rheumatology (ACR) response rate using the intent-to-treat population.</p><p><b>RESULTS</b>The ACR response rate was significantly higher in the T-614 treatment group compared with the placebo group within 8 weeks after the initiation of treatment. After 24 weeks, the 25 mg/d and 50 mg/d dosage groups and the placebo group showed 39.13%, 61.29% and 24.21% in ACR20 and 23.91%, 31.18% and 7.37% in ACR50, respectively. A time-response in ACR response was observed, with clear superiority for the 25 mg/d and 50 mg/d dosage groups compared to placebo (P < 0.0001), and the 50 mg/d dose compared to the 25 mg/d dose (P < 0.05) when using the ACR response analyses after 24 weeks. ESR and c-reactive protein (CRP) were significantly different in the treatment groups after 24 weeks. The incidence of adverse events (AEs) was not significantly higher with T-614 than with placebo, but upper abdominal discomfort, leucopenia, elevated serum alanine aminotransferase (sALT), skin rash and/or pruritus were more common in the 50 mg and 25 mg dosage groups.</p><p><b>CONCLUSION</b>T-614, a new slow-acting drug, is effective in treatment of rheumatoid arthritis and is well tolerated.</p>

Effect of T-614 on proliferation characteristics of fibroblast like synovial cells in osteoarthritis / 中华风湿病学杂志

Objective To investigate the proliferation characteristics of fibroblast like synovial cells (FLS)in osteoarthritis in vitro and the mechanism of the immnnosuppressive effect of T-614 [N-(3-formy- lamino-4-oxo-6-phenoxy-4H-chromen-7-yl)methanesulfonamide ] on them.Methods FLS of OA and non- inflamed synovium(NS)were cultured and identified in vitro in the presence or absence of T-614.After incu- bation,the survival fraction(SF)of FLS was evaluated by MTT,cell cycle was observed using fluorescence - activated cell sorting(FCS)method and the expression of c-fos and COX-2 mRNA was examined by RT- PCR in FLS of OA patients.Results No statistically significant difference was noted between the OA and NS FLS in proliferation ability and cell cycle.High dose T-614 suppressed FLS SF obviously in OA and NS sta- tistically(P＜0.05),whereas the inhibition degree was not different between the two kinds of FLS.The agent induced cell apoptosis and reduced the accumulation of c-fos mRNA in OA-FLS at dose 1000 ml/L,prolonged G_1 term and shortened S term at dose 200 ml/L.The expression of COX-2 mRNA in OA FLS was suppressed obviously by T-614 at dose 1000 ml/L.Conclusion OA FLS do not display a distinct activated unlimited viability compared with NS cells,without stimulated by proinflammatory cytokine in vitro.High dose T-614 moderately inhibits the proliferation and differentiation of FLS,directly affects gene of the c-fos and COX-2 expression in OA,which may contribute to its immunosuppressive effect on OA'synovitis.

Effect of total glucosides of paeony on the proliferation of fibroblast-like synovial cells in osteoarthritis / 中华风湿病学杂志

Objective To investigate the proliferative characteristics of fibroblast-like synovial cells (FLS)in osteoarthritis in vitro and the mechanism of the immunosuppressive effect of total glucusides of paeony(TGP).Methods FLS of OA and non-inflamed synovium(NS)were cultured and identified in vitro in the presence or absence of TGP.After incubation,the survival fraction(SF)of FLS was evaluated by MTI' and the TNF-?,IFN-?and bFGF level in cultured FLS supernatant was measured by ELISA.The expression of FLS c-los mRNA and cell cycle of OA-FLS was observed by RT-PCR and flow eytometry respectively at the same time.Results No statistical significant differences were noted between the OA and NS FLS in pro- liferating double time.High doses of TGP suppressed FLS-SF more evidently in OA patients than in NS(P0.05).Conclusion High dose TGP can inhibit OA-FLS proliferation,modulate cy- tokine secretion and c-fos expression in OA.This suggests that TGP has immunosuppressive effect on OA syn- ovitis,probably by preventing the synovial hypertrophy in OA.

Treatment of rheumatoid arthritis with T-614:a multicenter,randomized,double blind,placebo-controlled trial / 中华风湿病学杂志

Objective To study the efficacy and safety of T-614 in treating rheumatoid arthritis(RA). Methods Two hundred and eighty patients with active RA were randomly allocated to 3 groups:T-614 50 mg each day,25 mg each day or placebo.Clinical and laboratory parameters were analyzed at baseline,2,4,6,12, 18 and 24 weeks.Results The ACR response rate was significantly higher in the T-614 treatment group com- pared with the placebo group during the first 6 weeks.After 24 weeks,25 mg/d,50 mg/d dosage group and the placebo group showed 39.1%,61.3% and 24.2% in ACR20,23.9%,31.2% and 7.4% in ACR50 respectively.A time-response in ACR response after 24 weeks was observed,with clear superiority of the 25 mg/d and 50 mg/d dosage groups compared to the placebo,and 50 mg/d dosage group compared to 25 mg/d dosage group(P

Clinical analysis of 12 patients with Kimura's disease / 中华风湿病学杂志

Objective In order to improve the understanding of Kimura's disease,the clinical features and the pathological changes of 12 patients were analyzed.Methods Twelve cases with Kimura's disease ad- mitted to Qilu Hospital of Shandong University were retrospectively reviewed.Results All 12 patients were in relatively good condition and presented as subcutaneous nodules or swelling lymph nodes.Peripheral blood eosinophilia did not occur in 5 cases,4 out of 6 patients had high-level serum IgE.Biopsies were taken in all cases and the characteristic histological presentations were discovered.Only one patient developed pulmonary inflammation and acute myocardial infarction which were rare in Kimura's disease.Conclusions Definite di- agnosis of Kimura's disease mainly relies on biopsy.A patient with Kimura's disease can suffer from severe pulmonary and cardiac diseases,but the relationship between them should be studied further.

Identification of serum biomarkers for rheumatoid arthritis using protein fingerprint / 中华风湿病学杂志

Objective To identify serum biomarkers for rheumatoid arthritis(RA)by protein finger- print pattern. Methods One hundred and forty-one serum samples of 90 RA patients, 20 systemic lupus ery- thematosus(SLE)patients, and 31 healthy individuals were randomly divided into training set(n=93, 60 RA patients, 13 SLE patients and 20 healthy individuals)and test set(n=48, 30 RA patients, 7 SLE patients and 11 healthy individuals). They were detected by surface enhanced laser desorption/ionization-time of flight- mass spectrometry(SELDI-TOF-MS). The protein fingerprint pattern obtained from SELDI-TOF was trained by a multi-layer artificial neural network(ANN)to establish a diagnostic model. Results The detective mod- el obtained by ANN was used to detect the 48 unknown serum samples. The sensitivity and specificity for RA detection was 90% and 90.9% respectively. Conclusion In comparison with traditional methods, SELDI- TOF-MS could identify new serum biomarkers in RA. Combined with ANN, it provides high sensitivity and specificity for RA diagnosis.

In vitro proliferation and differentiation characteristics of fibroblast like synovial cells in patients with rheumatoid arthritis / 中华风湿病学杂志

Objective To investigate the proliferation and differentiation characteristics of fibroblast like synovial cells(FLS)in rheumatoid arthritis(RA)in vitro and the mechanism of the immunosuppressive effect of differentiation inducers, such as all trans retinoid acid(ATRA), ealcitriol [1,25(OH)_2D_3] and dexamethasone(DEX). Methods FLS of knee synovial tissues from RA patients were cultured and identified in vitro in the presence or absence of ATRA, 1,25(OH)_2D_3 and DEX respectively. Synoviocyte proliferation in RA were measured by MTT colorimetrie assay and the survival fraction(SF)of FLS was evaluated. Cell cycle of FLS was observed using fluorescence-activated cell sorting(FCS)method in RA patients. Results The identified synovial cells in patients with RA were FLS(Vimentin and Fibronectin expression was positive), and hadn't been transformed or differentiated to adipocytes and osteoblasts with the three inducers. The SF of all RA-FLS interfered by ATRA, 1,25(OH)_2D_3 and DEX was much lower than that without drugs vehicle group in RA-FLS(P