艾拉莫德联合甲氨蝶呤治疗类风湿性关节炎的临床疗效及对患者骨代谢的影响

目的 探讨艾拉莫德联合甲氨蝶呤治疗类风湿性关节炎(RA)的临床效果及对患者骨代谢的影响。方法 将我院收治的86例RA患者随机分为两组各43例。对照组采用甲氨蝶呤治疗,观察组采用艾拉莫德联合甲氨蝶呤治疗。比较两组的临床疗效、骨代谢指标(β-CTX、 TPINP、 N-MID)及不良反应发生情况。结果 观察组治疗总有效率为95.35%,明显高于对照组的81.40%(P<0.05)。治疗后,两组的β-CTX水平降低, TPINP、 N-MID水平升高(P<0.05);观察组的β-CTX水平明显低于对照组, TPINP、 N-MID水平高于对照组(P<0.05)。两组的不良反应发生率(9.30%vs. 6.98%)比较差异无统计学意义(P>0.05)。结论 艾拉莫德联合甲氨蝶呤治疗RA效果显著,可有效改善患者的骨代谢,且安全性较高。     

Effect of iguratimod and other anti-rheumatic drugs on adenocarcinoma colon 26-induced cachexia in mice

Objective: To examine the effect of iguratimod (T-614) and other anti-rheumatic drugs on a mouse model of adenocarcinoma-induced cachexia. Methods: Cachexia was induced in BALB/c mice by s. c. inoculation of colon 26/clone 20 cells (day 0). The drugs were administered p. o. daily from day 0 for 15 days for prophylactic experiments and from day 7 for 8 days for therapeutic experiments. Serum biochemical parameters and wasting of adipose tissue and muscle were evaluated as the nutritional condition in tumor-bearing mice at day 14. Interleukin-6 (IL-6) levels in serum and tumor tissue of those mice were also quantified. Results: Administration of T-614 did not inhibit the tumor growth, but it resulted in attenuation of cachexia symptoms, such as the reduction in epididymal fat and gastrocnemius muscle, and the decrease of serum albumin. Furthermore, T-614 decreased the serum levels of IL-6, and reduced its gene expression in the tumor tissues. Exogenously administered IL-6 nullified the suppressive effect of T-614. Prednisolone prevented the weight loss and the wasting without inhibiting tumor growth. Methotrexate and indomethacin did not exert any preferable effects in a therapeutic dosing schedule. Conclusions: Our results demonstrate that T-614 exerts an anticachectic effect in tumor-bearing mice through the inhibition of IL-6 gene expression. Received 3 February 2006; returned for revision 9 April 2006; returned for final revision 5 June 2006; accepted by M. Katori 24 July 2006     

艾拉莫德(T-614)的临床前药代动力学研究

目的：研究 T-614 原料在动物体内的吸收、分布、代谢、排泄、蛋白结合及口服原料和片剂的相对生物利用度;研究 T-614 原料对5种人 P450 同工酶的体外抑制作用。方法：采用 HPLC 方法进行大鼠 ig T-614 原料 5、10和20 mg/kg 的药代动力学（吸收、分布、代谢、排泄、蛋白结合率）及 Beagle 犬po T-614 原料及片剂（5 mg/kg）的相对生物利用度研究;采用 LC/MS/MS 方法对大鼠 ig T-614 原料 50 mg/kg 后尿液中的主要代谢转化产物进行了分析;采用高通量 P450 酶抑制剂筛选试剂盒测定了 T-614 原料对人 P450 同工酶 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 的体外抑制活性。结果：大鼠 ig T-614 原料 5、10和20 mg/kg 后主要药动学参数t_1/2Ke 分别为（5.41 ± 1.28）、（4.31 ± 0.48）和（4.17 ± 1.04）h,t_1/2Ka 分别为（0.16 ± 0.06）、（0.30 ± 0.19）和（0.58± 0.37）h,t_max 分别为（0.81 ± 0.20）、（1.16 ± 0.60）和（1.78 ± 0.61）h,C_max 分别为（7.83 ± 1.85）、（15.46 ± 2.27）和（30.89 ± 6.54）μg/mL,AUC_0～t 分别为（72.08 ± 11.05）、（127.53 ± 17.68）和（296.24 ± 57.10）μg /mL · h;大鼠 ig T-614 原料 10 mg/kg 后在所有脏器组织中均能检测到原形物质,其中肝、肾、子宫的量最高,脑的量最低;大鼠 ig T-614 原料 10 mg/kg 72 h 后,粪中的排泄率达到 15.75 %,而尿与胆汁的排泄率分别为 0.836 %和 0.677 %;当质量浓度为 5、10和20 μg/mL 时,T-614 原料的蛋白结合率分别为（17.2 ± 5.1）%、（28.6± 7.1）%和（28.9 ± 10.2）%,平均蛋白结合率为（24.9 ± 9.2）%。Beagle 犬口服 T-614 原料和片剂 5 mg/kg,其主要药动学参数t_1/2Ke 分别为（11.10 ± 1.50）和（9.30 ± 3.29）h,t_1/2Ka 分别为（1.18 ± 0.22）和（1.53 ± 1.26）h,t_max 分别为（4.24 ± 0.48）和（4.23 ± 1.75）h,C_max 分别为（0.77 ± 0.13）和（1.01 ± 0.27）μg/mL,AUC_0～t 分别为（12.69 ± 2.77）和（16.81 ± 6.49）μg /mL·h;微粉化片剂相对于原料的相对生物利用度为 132.5 %。大鼠 ig 50 mg/kg T-614 后,尿液中检测到 T-614 的 5 种主要代谢物,包括 T-614 原结构的异构体、苯环羟基化、脱醛基后再羟基化、脱醛基后胺基乙酰化、脱醛基后的产物。体外CYP450酶活性抑制试验结果表明,T-614原料浓度为 20～0.009 1 μmol/L 时,对 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 活力抑制的 IC₅₀>20 μmol/L。结论：大鼠 ig T-614 原料 5、10 和 20 mg/kg 剂量的药代动力学特征符合一级吸收。在大鼠体内各组织中分布较广,蛋白结合率低于 30 %。粪、尿、胆汁中原形物质的总排泄量低于 20 %。Beagle 犬口服 T-614 片剂的相对生物利用度为 132.5 %。T-614 对人 P450 同工酶 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 活力无抑制作用。T-614 在肾脏中代谢转化的主要产物为原形物质的异构化、羟基化、脱醛基后再羟基化、脱醛基后胺基乙酰化、脱醛基等。     

The three-year efficacy of iguratimod in clinical daily practice in patients with rheumatoid arthritis

Abstract

Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients.

Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed.

Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years.

Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years.     

Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: An open-label extension of a randomized,double-blind,placebo-controlled trial

Abstract

Objective. To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with active rheumatoid arthritis (RA).

Methods. Following a 28-week, randomized, double-blind trial of adding iguratimod or placebo to stable MTX therapy, patients entered a 24-week extension. Patients randomized to the iguratimod + MTX group continued treatment. Patients treated with placebo + MTX switched to iguratimod + MTX [the (placebo/iguratimod) + MTX group].

Results. In the iguratimod + MTX group, the rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 52 (71.3%) was similar to that at week 24 (69.5%). ACR50, ACR70 and Health Assessment Questionnaire Disability Index at week 52 significantly improved compared with the values at week 24. In the (placebo/iguratimod + MTX) group, the switch to iguratimod treatment significantly improved ACR20 from 30.7% at week 24 to 72.1% at week 52. Frequent adverse events for 52 weeks in the iguratimod + MTX group were nasopharyngitis, upper respiratory tract inflammation, stomatitis, lymphocyte decrease, AST increase, ALT increase and blood iron decrease. These adverse events were predominantly mild or moderate in severity. No deaths occurred.

Conclusion. Efficacy and tolerance of iguratimod + MTX therapy was maintained to 52 weeks in patients with active RA with inadequate response to MTX.     

Efficacy of the clinical use of iguratimod therapy in patients with rheumatoid arthritis

Abstract

Objective. Iguratimod (IGU) is a new synthetic disease-modifying antirheumatic drug intended to treat patients with rheumatoid arthritis (RA). We conducted a 24-week study on the efficacy of IGU in RA patients with daily clinical use.

Methods. Forty-one patients were enrolled in this study, and the improvement in RA was evaluated every 4 weeks during the 24 weeks.

Results. The patient's global assessment of the disease activity with a scale (Pt VAS) was significantly decreased beginning at week 4. The disease activity score (DAS) 28-erythrocyte sedimentation rate, DAS28-C-reactive protein (CRP), simplified disease activity index and clinical disease activity index all significantly decreased at week 24. The matrix metalloproteinase-3 level was significantly decreased by the combination treatment with methotrexate at week 24. According to a logistic regression analysis, the factor which was most associated with the achievement of low disease activity (DAS28-CRP < 2.7) at week 24 was the DAS28-CRP at week 0.

Conclusions. IGU had significant clinical effects on the RA patients within 24 weeks. IGU might therefore represent a new practical choice to treat RA patients.     

Prolonged presence of SARS-CoV-2 in a COVID-19 case with rheumatoid arthritis taking iguratimod treated with ciclesonide

We report a coronavirus disease 2019 (COVID-19) case with rheumatoid arthritis taking iguratimod. The patient who continued iguratimod therapy without dose reduction was treated with ciclesonide had an uneventful clinical course, but prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was observed after resolution of symptoms. The effects of disease-modifying antirheumatic drugs (DMARDs) and ciclesonide on clinical course and viral shedding remain unknown and warrant further investigation.     

艾拉莫德治疗类风湿性关节炎临床疗效观察

目的：观察艾拉莫德治疗类风湿性关节炎的临床疗效。方法依治疗药物不同将60例确诊为类风湿性关节炎患者分为两组,对照组30例,给予甲氨蝶呤口服;治疗组30例,给予艾拉莫德口服,两组患者观察治疗12周。对比治疗前后两组患者的临床疗效,并分别评定关节疼痛指数、肿胀指数、晨僵及血沉、C-反应蛋白的变化情况。结果治疗组总有效率（93.33%）明显优于对照组总有效率（80.00%）,差异具有统计学意义（P〈0.05）;两组患者治疗后的主要症状、体征及血液学检查均有改善,与治疗前比较有显著性差异（P〈0.05）;治疗组治疗后的主要症状、体征及血液学检查与对照组治疗后比较,差异具有统计学意义（P〈0.05）。结论艾拉莫德治疗类风湿性关节炎有较好的临床疗效,且不良反应发生率低,值得在临床上推广。     

艾拉莫德联合重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗类风湿关节炎的临床研究

目的探讨艾拉莫德片联合注射用重组人Ⅱ型肿瘤坏死因子受体–抗体融合蛋白治疗类风湿关节炎的临床疗效。方法选取2015年4月—2016年4月在邢台市人民医院进行治疗的类风湿关节炎患者96例为研究对象,根据入院先后将患者分为对照组和治疗组,每组各48例。对照组皮下注射注射用重组人Ⅱ型肿瘤坏死因子受体–抗体融合蛋白,25 mg/次,2次/周。治疗组在对照组基础上口服艾拉莫德片,25 mg/次,2次/d。两组患者均连续治疗12周。观察两组的临床疗效,比较两组的关节症状、类风湿关节炎患者病情评价(DAS-28)评分、健康评估问卷(HAQ)评分和血清学指标。结果治疗后,对照组和治疗组的总有效率分别为79.17%、93.75%,两组比较差异有统计学意义(P0.05)。治疗后,两组关节疼痛数、关节压痛数、关节肿胀数和晨僵时间均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显低于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组DAS-28评分、HAQ评分均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-37(IL-37)、类风湿因子(RF)和血沉(ESR)水平均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。结论艾拉莫德片联合注射用重组人Ⅱ型肿瘤坏死因子受体–抗体融合蛋白治疗类风湿关节炎具有较好的临床疗效,可改善患者临床症状,降低机体炎症反应,改善患者生活质量,具有一定的临床推广应用价值。