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ObjectiveTo investigate the clinical efficacy and safety of iguratimod combined with the Chinese medicine Runzaoling in the treatment of primary Sjögren's syndrome （pSS）. MethodSeventy-two patients treated in the Department of Rheumatology and Immunology of the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine（TCM） from January 2021 to June 2022 who met the Western medical diagnosis of pSS and had the TCM syndrome of Yin deficiency and heat toxin syndrome were randomly assigned into an observation group and a control group， with 36 patients in each group. The observation group was treated with iguratimod combined with Runzaoling， and the control group was treated with iguratimod. The treatment in both groups lasted for 12 weeks. The clinical symptoms， EULAR Sjogren's syndrome patient reported index （ESSPRI）， EULAR Sjögren's syndrome disease activity index （ESSDAI）， erythrocyte sedimentation Rate （ESR）， C-reactive protein （CRP）， immunoglobulin （IgG）， Schirmer score， and saliva flow of the two groups were determined before and after treatment. Furthermore， the incidence of adverse reactions was compared between the two groups. ResultThe total response rate in the observation group was 75.0% （27 patients with response and 9 patients with no response）， which was higher than that （61.11%， 22 patients with response and 14 patients without response） in the control group （P<0.05）. After treatment， the ESSPRI， ESSDAI， and TCM syndrome scores in both groups decreased and the decreases were more obvious in the observation group than in the control group （P<0.05）. The treatment in both groups recovered the ESR， CRP， IgG， Schirmer score， and saliva flow （P<0.05）. Moreover， the observation outperformed the control group in terms of the ESR， CRP， IgG， and saliva flow （P<0.05） and had no significant difference in the Schirmer score compared with the control group. During the treatment period， 2 patients in the observation group had nausea， and 1 patient had an abnormal liver function， which were relieved after symptomatic treatment and did not affect the treatment. In the control group， 1 patient withdrew from the study due to rashes and showed no special discomfort in the follow-up 4 weeks， and 1 patient had nausea， which was relieved after symptomatic treatment. ConclusionIguratimod combined with Runzaoling has good clinical efficacy and safety in the treatment of pSS.
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Objective:To investigate the effect of iguratimod (IGU) on transforming growth factor-β 1 (TGF-β 1)-induced primary human lung fibroblasts (pHLFs) activation and collagen secretion. Methods:Mice pulmonary fibrosis (PF) models were established in vivo and were divided into three groups: the control group (CTR group), the Bleomycin (BLM) group and the BLM+IGU group, hematoxylin-eosin (HE) staining was used to observe lung morphology, and Masson staining was used to observe the degree of collagen accumulation in lung. Fibronectin and smooth muscle 22 (SM22) were detected by immunofluorescence, and the content of hydroxyproline in lung tissue was detected by chloramine-T method. In vitro, pHLFs were used to assess the effect of IGU on TGF-β 1 stimulation in four groups: CTR group, IGU group, TGF-β 1 group and TGF-β 1+IGU group, the apoptosis of cells was detected by flow cytometry, and the mRNA expression of collagen type Ⅰ (COL-Ⅰ) and collagen type Ⅲ (COL-Ⅲ) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of α-smooth muscle actin (α-SMA), fibronectin, p-Smad2, p-Smad3 and transcription coactivator p300 were detected by Western blot and immunofluorescence. One-way ANOVA was used for all data, and LSD- t test or Kruskal-Wallis test was used for pair comparison. Results:The content of hydroxyproline in CTR group, the BLM group and the BLM+IGU group was (0.552±0.075) μg/mg, (1.293±0.081) μg/mg and (0.833±0.053) μg/mg ( F=169.672, P<0.01) respectively. IGU reduced the content of hydroxyproline in the lung tissue of mice, reduced the accumulation of collagen in the lung, and thus reduced the degree of BLM-induced pulmonary fibrosis, and improved the pathological changes in the lung of mice. In cell experiments, IGU had no significant effect on apoptosis ( F=0.83, P=0.54). The relative expression levels of COL-Ⅰ mRNA in the CTR group, TGF-β 1 group and TGF-β 1+IGU group were (100.4±1.2), (299.0± 13.0) and (202.5±7.0) respectively ( F=468.7, P<0.01). The relative expression levels of COL-Ⅲ mRNA in the CTR group, TGF-β 1 group and TGF-β 1+IGU group were (99.8±1.9), (350.6±8.0) and (220.3±9.9) respectively ( F=468.7, P<0.01). The relative expression levels of α-SMA protein were (0.193±0.038) in CTR group, (0.530±0.061) in TGF-β 1 group, and (0.410±0.065) in TGF-β 1+IGU group ( F=35.620, P<0.01); The relative expression levels of fibronectin in CTR group, TGF-β 1 group, and TGF-β 1+IGU group were (0.200±0.020), (0.700±0.020) and (0.410±0.066) respectively ( F=123.326, P<0.01). The relative expression levels of p-Smad3 protein in CTR group, TGF-β 1 group, and TGF-β 1+IGU group were (0.120±0.020), (0.573±0.586) and (0.327±0.252) respectively( F=92.987, P<0.01); The relative expression levels of p300 in CTR group, TGF-β 1 group and TGF-β 1+IGU group were (0.180±0.055), (0.923±0.025) and (0.650±0.050) respectively ( F=207.676, P<0.01). IGU significantly decreased the mRNA expression levels of COL-Ⅰ and COL-Ⅲ induced by TGF-β 1, inhibited the protein expression levels of α-SMA, fibronectin, p300, and phosphorylation of Smad2/3. Conclusion:Our results revealed the beneficial effect of IGU on the inhibition of TGF-β 1-mediated pHLFs activation and collagen secretion via the Smad3/p300 pathway, thus suggest that it might act as an effective anti-fibrotic agent in preventing the progression of PF.
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Iguratimod (IGU, also known as T-614), a novel disease modifying antirheumatic drug intended to cure patients with rheumatoid arthritis (RA). The purpose of this study is to evaluate the effect of IGU on the pharmacokinetics of CYP2C9 probe drug diclofenac and its metabolite 4′-hydroxy diclofenac in vivo and in vitro. In in vivo experiments, 24 rats were randomly assigned to three groups consisting of the control group (Normal saline), low dose IGU group (10 mg/kg) and high dose IGU group (30 mg/kg). Blood samples were collected from orbital sinuses vein before 1 hour and serial times of giving diclofenac (15 mg/kg) to all the rats. Plasma concentration of diclofenac and its metabolite 4´-hydroxy diclofenac were assayed by high performance liquid chromatography. Pharmacokinetic parameters were assessed by Winnonlin 6.4 pharmacokinetic software. Moreover, in vitro studies were performed in recombinant human CYP2C9 yeast cell system. IGU at low dose showed no significant differences in the pharmacokinetic parameters of diclofenac and 4-hydroxy diclofenac in vivo when compared with control group (p>0.005). However, at the high dose of IGU, the pharmacokinetic parameters of 4´-hydroxy metabolite of diclofenac increase in half-life (T1/2) and mean area under the curve (AUC0→24), while a decrease in mean clearance (CL, mL/h/kg) and volume of distribution Vz (mL/kg). In addition, in in vitro study, high doses of IGU reduces the metabolism rate of diclofenac. IGU at high dose significantly increase the pharmacokinetics parameters of 4´-hydroxy diclofenac in rats. Additionally, it also showed the potent inhibitory effect on diclofenac metabolism in recombinant human CYP2C9 yeast cells.
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Animals , Male , Female , Rats , Diclofenac/adverse effects , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP2C9/pharmacokinetics , Anti-Inflammatory Agents/adverse effects , Arthritis, Rheumatoid/classification , In Vitro TechniquesABSTRACT
Objective Overexpressed inflammatory factors play an important role in the process of intervertebral disc degeneration. This study aimed to investigate the effect of iguratimod on the expression of inflammatory factors in degenerative intervertebral disc cells. Methods Sixty 8-12 weeks old SD rats were equally randomized into a compression (the tail compressed by external fixation) and a non-compression control group. The nucleus pulposus cells (NPC) of the degenerated intervertebral disc were isolated and treated with iguratimod at the concentrations of 0, 0.3, 3, 10, 20, and 30 μg/mL, followed by measurement of the contents of inflammatory factors and matrix metalloproteinases (MMP) secreted from the NPCs and determination of the effects of different concentrations of iguratimod on the expressions of inflammation-related genes in the NPCs by RT-PCR. Results After treatment with iguratimod at 3, 10, 20, and 30 μg/mL, the expression levels of IL-6 in the NPCs were (204.18 ± 6.96), (122.73 ± 9.38), (97.87 ± 7.81), and (86.31 ± 8.57) pg/mL, respectively, and those of TNF-α were (202.46 ± 7.84), (132.52 ± 11.4), (101.26 ± 10.38), and (96.89 ± 9.60) pg/mL, respectively, all decreased significantly in a concentration-dependent manner (P < 0.05). Meanwhile, the contents of MMP-2, MMP-3 and MMP-9 in the iguratimod-treated NPCs also showed remarkable concentration-dependent decreases (P < 0.05). Conclusion Iguratimod can effectively inhibit the expression of inflammatory factors in nucleus pulposus cells and block the progression of inflammatory response, which has provided a new idea for the treatment of degenerative intervertebral disc disease.
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Objective To investigate the protective effects of iguratimod on systemic lupus erythematosus model mice. Methods A total of 30 female BALB/c mice were randomly divided into blank control group,model control group and igurati-mod drug intervention group,with 10 mice in each group.The blank control group was given saline by intraperitoneal injection in-tervention group.The model control group and iguratimod intervention group were given 0.5 mL of pristane, Then the drug inter-vention group began to be fed with iguratimod 6.5 mg·kg-1·d-1from the next day.After 7 months of feeding,the serum autoanti-body(anti nuclear antibody,anti ds-DNA antibody,anti RNP/sm antibody),the level of urine protein,serum urea nitrogen and serum creatinine,as well as the renal pathological changes of the three groups were detected and compared. Results Serum an-ti nuclear antibody,anti ds-DNA antibody and anti RNP/sm antibody levels of the drug intervention group were significantly lower than those of the model control group (P<0.05);Positive rate of urine protein,serum urea nitrogen,serum creatinine of the drug intervention group were significantly lower than those of the model control group(P<0.05).while the renal pathological change of this group is not obvious. Conclusion Iguratimod can inhibit the occurrence of serum antibody in a certain extent,improve the urine protein,serum urea and serum creatinine level of mouse model with systemic lupus erythematosus,which has protective effects on systemic lupus erythematosus.
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Objective To explore the effect of different concentrations of iguratimod (IGU) on mouse model of bleomycin-induced pulmonary fibrosis.Methods A total of 108 female C57BL/6 mice were randomly divided into the control group,the model group,the low dose IGU group,the moderate dose IGU group,high dose with group and the methylprednisolone (MP) group (n=18 in each group).The mice in the control group were injected with 0.2 ml normal saline endotracheally,and others were injected with 0.2 ml bleomycin (5 mg/kg) from endotracheally to induce pulmonary fibrosis model.The next day,the mice in both control group and the model group were fed with 0.2 ml normal saline every day;The mice in the IGU groups and methylprednisolone group were fed with 0.2 ml iguratimod liquid the IGU (10,30,90 mg/kg) and 0.2 ml methylprednisolone (10 mg/kg) every dayrespectively.Finally the mice were sacrificed at day 7,day 14,day 28 respectively,and the lung tissue was examined by HE staining and Masson staining to evaluate the degree of alveolitis and fibrosis.Repeated measurement of variance analysis was used to compare the differences for time and group,and multi-factor analysis of variance LSD test was used for the comparison between groups.Results ① The body mass of mice in bleomycin-induced groups were decreased compared to the control group.② The pathological alveolitis scores in the high dose IGU group and methylprednisolone group were significantly decreased compared to those of the model IGU group at day 7 and day 14 (P＜0.05),and the pathological fibrosis scores were decreased dramatically compared with the model group at day 14 and day 28 (P＜0.05).Conclusion High concentration of IGU and methylprednisolone can reduce and inhibit lung inflammation and fibrosis of bleomycin-induced pulmonary fibrosis in mice.
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OBJECTIVE:To observe clinical efficacy and safety of iguratimod combined with methotrexate in the treatment of rheumatoid arthritis.METHODS:A total of 82 patients with rheumatoid arthritis selected from our hospital from Feb.2015 to Feb.2016 were randomly divided into observation group and control group,with 41 cases in each group.Control group was given Methotrexate tablets 10 mg orally,once a week,increasing to 15 mg 2 weeks later,once a week.Observation group was addtionally given Iguratimod tablets 25 mg orally after meal,bid,on the basis of control group.Treatment course of 2 groups lasted for 6 months.Clinical efficacies and the occurrence of ADR were observed in 2 groups.The joint tenderness count,joint swelling count and morning stiffness time were also observed before and after treatment.The erythrocyte sedimentation rate,CRP,platelet count,serum immunoglobulin (IgG,IgA and IgM) and T lymphocyte subsets (CD3+,CD4+ and CD8+) levels were detected in 2 groups before and after treatment.RESULTS:The total response rate of observation group was 90.24％,which was significantly higher than 78.05％ of control group,with statistical significance (P＜0.05).Before treatment,there was no statistical significance in above indexes between 2 groups (P＞0.05).After treatment,the number of joint tenderness and joint swelling in 2 groups were significantly lower than before treatment,and the time of moming stiffness was significantly shorter than before treatment.The erythrocyte sedimentation rate,CRP,platelet count,serum immunoglobulin and T lymphocyte subsets were significantly lower than before treatment.The observation group was significantly lower than the control group,with statistical significance (P＜0.05).No obvious ADR was found in 2 groups.There was no statistical significance in the incidence of ADR between 2 groups (P＞0.05).CONCLUSIONS:Compared with methotrexate alone,iguratimod with methotrexate can improve therapeutic efficacy,relieve clinical symptom and inhibit immune function so as to control the progression of rheumatoid arthritis with good safety.
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OBJECTIVE:To compare the effects of iguratimod combined with methotrexate and diacerein respectively on relat-ed indexes of refractory rheumatoid arthritis (RRA). METHODS:98 RRA patients were randomly divided into control group (48 cases)and observation group(50 cases). Control group received Iguratimod tablet 25 mg,twice a day+Methotrexate tablet with ini-tial dose of 10 mg,once a week,increased to 12.5 mg after 2 weeks,increased to 15 mg in the second courses,once a week. Ob-servation group received Iguratimod tablet(the same dosage and usage with control group)+Diacerein granule 50 mg,twice a day. 4-week was a course,they were treated for 6 courses. Morning stiffness time,the numbers of 28 joints tenderness and swelling,28 joint disease activity score (DAS28),erythrocyte sedimentation rate (ESR),rheumatoid factor (RF),IL-1,vascular endothelial growth factor (VEGF),tumor necrosis factor (TNF)-α,C-reaction protein (CRP),malondialdehyde (MDA),superoxide dis-mutase(SOD),total antioxidant capacity(TAOC),early peak flow(peak E),left ventricular late flow peak flow(peak A),E/A and left ventricular ejection fraction(LVEF)before and after treatment,and the incidence of adverse reactions in 2 groups were ob-served. RESULTS:Before treatment,morning stiffness time,the numbers of 28 joints tenderness and swelling,DAS28 score, ESR,RF,IL-1,TNF-α,CRP,VEGF,MDA,TAOC and peak A in 2 groups were significantly lower than before treatment,and observation group was significantly lower than control group;SOD,peak E,E/A and LVEF in 2 groups were significantly higher than before treatment,and observation group was significantly higher than control group,with statistical significances (P0.05). CONCLUSIONS:Iguratimod combined with diacerein is superior to iguratimod combined with methotrexate in improving cardiac function,oxidation-antioxidant imbalance play and reducing inflammatory reactions in the treatment of RRA,with similar safety.
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Objective Rheumatoid arthritis (RA) is a systemic autoimmune disease, which mainly involves joints across the body, resulting in joint stiffness and loss of daily activity. Recent evidence suggests that numerous self-reacting T cells, including Th1 and Th17, infiltrate the synovium in RA patients, accompanied by functionally-compromised Treg. Iguratimod, a new small molecule with anti-inflammatory and immunomodulatory effects, has shown curative effects in animal models of arthritis. In this study, we aimed to test the clinical effects of Iguratimodˊs on RA patients and its role in immunoregulation. Methods We examined the clinical effects of iguratimod on RA patients in a random controlled clinical trials and analyzed its effects on Th1, Th17 and Treg as well as their associated cytokines and transcription factors by flow cytometry and real-time polymerase chain reaction (PCR). Then t-test, chi-square test and rank sum test were used to conduct statistical analysis. Results Our results revealed that iguratimod therapy provided significantly greater clinical benefit [ACR20, ACR50, ACR70 reached 50%, 20%, 15% respectively in iguratimod treatment group, Z=-2.216,P=0.027] than placebo group with the reduction of Th1 and Th17 but increment of Treg after iguratimod treatment [Th1: week 0 (26.5 ±8.0)%, week 24 (14.2 ±7.3)%, P<0.01; Th17:week 0 (1.7±0.7)%, week 24 (1.3±0.4)%, P<0.05;Treg:week 0 (6.8±1.6)%, week 24 (8.9±2.9)%, P<0.05], which was statistically significant. Conclusion Our results provide theoretical and clinical based evidence for the impact of iguratimod on immunomodulation of RA.
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Cytokines are believed to be involved in a "vicious circle" of progressive interactions in bone metastasis. Iguratimod is a novel anti-rheumatic drug which is reported to have the capability of anti-cytokines. In this study, a rat model was constructed to investigate the effect of iguratimod on bone metastasis and it was found that iguratimod alleviated cancer-induced bone destruction. To further explore whether an anti-tumor activity of iguratimod contributes to the effect of bone resorption suppression, two human breast cancer cell lines MDA-MB-231 and MCF-7 were studied. The effect of iguratimod on tumor proliferation was detected by CCK-8 assay and flow cytometry. The effects of iguratimod on migration and invasion of cancer cells were determined by wound-healing and Transwell assays. Results showed that high dose (30 μg/mL) iguratimod slightly suppressed the proliferation of cancer cells but failed to inhibit their migration and invasion capacity. Interestingly, iguratimod decreased the transcription level of IL-6 in MDA-MB-231 cells in a concentration-dependent manner. Moreover, iguratimod partially impaired NF-κB signaling by suppressing the phosphorylation of NF-κB p65 subunit. Our findings indicated that iguratimod may alleviate bone destruction by partially decreasing the expression of IL-6 in an NF-κB-dependent manner, while it has little effect on the tumor proliferation and invasion.
Subject(s)
Animals , Female , Humans , Rats , Apoptosis , Bone Neoplasms , Drug Therapy , Pathology , Bone Resorption , Drug Therapy , Pathology , Breast Neoplasms , Drug Therapy , Genetics , Pathology , Carcinogenesis , Cell Movement , Cell Proliferation , Chromones , Interleukin-6 , Genetics , MCF-7 Cells , Neoplasm Invasiveness , Genetics , Pathology , Sulfonamides , Transcription Factor RelA , GeneticsABSTRACT
Objective To study the clinical efficacy and safety of iguratimod in the treatment of active rheumatoid arthritis. Methods Ninety patients with rheumatoid arthritis were randomly divided into three groups, with 30 cases in each group. Group A: oral administration of iguratimod, 25 mg two times a day, and oral administration of methotrexate, 10 mg once a week. Group B:oral administration of iguratimod, 25 mg two times a ady. Group C: oral administration of methotrexate, 15 mg once a week. According to the American College of Rheumatology criteria for judging 20%, 50%and 70%(ACR20, ACR 50 and ACR 70) improvement of swollen and tender joint was judged according to the American College Of Rheumatology criteria, and the adverse reactions were observed. Results After the treatment in group A and group B ACR20, ACR50 and ACR70 were higher than those in group C [76.67%(23/30) and 60.00% (18/30) than 40.00% (12/30), 50.00% (15/30) and 33.33% (10/30) than 20.00% (6/30), 23.33%(7/30) and 13.33%(4/30) than 6.67%(2/30)], and in group A was higher than that in group B. The differences were statistically significant (P0.05). Conclusions Monotherapy with iguratimod in the treatment of active rheumatoid arthritis is superior to methotrexate, and has fewer side effects. The combined application of the two drugs is more effective, and can reduce the dose of methotrexate and reduce the incidence of side effects, which is worthy of clinical application.
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Objective To observe the effects of iguratimod ( IT) combined with methotrexate ( MTX) in patients with refractory rheumatoid arthritis ( rRA) . Methods Sixty patients with rRA were randomly divided into 2 groups ( n=30 each group) . The cases in treatment group received 50 mg.d-1 of iguratimod and 10 mg of MTX for 16 weeks. The cases in control group were treated by 10-15 mg of MTX. DAS28 was analyzed. Levels of VEGF and endostatin ( ES) were quantified. Results In the treatment group,after 16-week treatment,DAS28,levels of VEGF and ES were (3.0±1.2),(818.9±178.8) pg.mL-1, (337.8±132.6) ng.mL-1,and those in the control group were (5.7±1.9),(1000.2±245.9) pg.mL-1,(253.8±77.8) ng.mL-1,respectively. In the treatment group,DAS28 and VEGF after the treatment were significantly decreased as compared with those before the treatment ( P<0.01) . The decrement was more significant in the treatment group than in the control group ( P<0.01) . At the 16th week of treatment,ES was significantly increased as compared with that before the treatment ( P<0.01) , and there was a significant difference between the treatment group and the control group (P<0.01). Conclusion Iguratimod combined with MTX have a prominent effect on rRA with high safety. The efficacy of IT on RA might be related with decreasing VEGF release,increasing ES production and alleviating synovium angiogenesis.
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Objective To observe the possible anti-inflammatory and anti-angiogenesis effects of iguratimodon human synovial fibroblast cell line MH7A derived from patients with rheumatoid arthritis (RA).Methods MH7A cells were stimulated with interleukin (IL)-1β and treated simult aneously or sequenti-ally with different concentrations of iguratimod and methotrexate (MTX).Release of vascular endothelial growth factor (VEGF), endostatin (ES) and tumour necrosis factor-α (TNF-α) was quantified by enzyme linked immunosorbent assay (ELISA).The statistics software SPSS 13.0 was used for statistical analyses.The experimental data were analyzed in terms of variance analysis and LSD test.In all cases, a P value lower than 0.05 was considered significant.Results The concentrations of VEGF, ES and TNF-α of the control group were (57±98) pg/ml, (924±39) pg/ml, (16.40±6.08) pg/ml respectively, while those of the experimental group were (1 155±177) pg/ml, (295±35) pg/ml and (36.90±3.54) pg/ml respectively.The differences of VEGF (t=9.092, P＜0.01) and ES (t=19.685, P＜0.01) between the control group and the experimental group was statistically significant.There was significant difference in the levels of TNF-α between the two groups (t=2.495, P＜0.05).VEGF of the iguratimod groups was (640±127) pg/ml in the iguratimod group (100 μmol/L), (787±172) pg/ml in the iguratimod group (25 μmol/L), and (776±99) pg/ml in the iguratimod group (6.25 μmol/L).VEGF of the MTX groups was (1 322±264) pg/ml in the MTX group (100 μmol/L), (1 071±63) pg/ml in the MTX group (25 μmol/L), and (863±70) pg/ml in the MTX group (6.25 μmol/L).All concentration of the iguratimod groups could effectively reduce the expression of VEGF in MH7A cells.Compared with the experimental group, the difference was statistically significant (100 μmol/L group: t=4.264, P＜0.01;25 μmol/L group: t=3.045, P＜0.01;6.25 μmol/L group: t =3.132, P ＜0.01).MTX (6.25 μ mol/L) could reduce the expression of VEGF in MH7A cells.Compared with the experimental group, the difference was statistically significant (t=2.415,P＜0.05).ES of the iguratimod groups was (979±30) pg/ml in the iguratimod group (100 μmol/L), (842±14)pg/ml in the iguratimod group (25 μmol/L), and (485 ±72) pg/ml in the iguratimod group (6.25 μmol/L).ES of the MTX group was (934±23) pg/ml in the MTX (100 μmol/L) group, (825±28) pg/ml in the MTX group (25 μmol/L), and (772 ±44) pg/ml in the MTX group (6.25 μmol/L).Both iguratimod and MTX groups effectively increased the expression of ES in MH7A cells.Compared with the experimental group, the difference was statistically significant (100 μmol/L group: t=21.387, P＜0.01;25 μmol/L group: t=17.122,P＜0.01;6.25 μmol/L group: t=5.929, P＜0.01).The expression of ES of the iguratimod group (100 μmol/L)and iguratimod group(25 μmol/L) was higher than that of the iguratimod group (6.25 μmol/L).The difference was statistical significant(100 μmol/L group: 6.25 μmol/L group was t=15.458,P＜0.01;100 μmol/L group: 6.25 μ mol/L group was t=11.193, P＜0.01).The expression of ES of the iguratimod group(6.25 μmol/L) was lower than that of the MTX group (6.25 μmol/L).The difference was statistically significant (t=9.001, P＜0.01).TNF-α was (4.73 ±1.15) pg/ml in the iguratimod group (100 μmol/L), (4.40±2.65) pg/ml in the iguratimod group (25 μmol/L), and (4.40±0.10) pg/ml in the iguratimod group (6.25 μmol/L).TNF-α of the MTX groups were (4.40±3.61) pg/ml in the MTX group (100 μ mol/L), (13.40±16.46) pg/ml in the MTX group (25 μmol/L),and (21.73±16.50) pg/ml of the MTX group (6.25 μmol/L).Both the iguratimod groups and the MTX group (100 μmol/L) effectively reduced the expression of TNF-α in MH7A cells.Compared with the experimental group, the difference was statistically significant(100 μmol/L group: t=3.914, P＜0.01;25 μ mol/Lgroup: t=3.955,P＜0.01;6.25 μ mol/L group: t=3.955, P＜0.01).Theexpression of TNF-α of the MTX groups (100 μ mol/L and 25 μmol/L) reduced significantly.Compared with the experimental group, the difference was statistically significant (100 μmol/L group: t=3.955, P＜0.01;25 μmol/L group: t=2.859, P＜0.05).The expression of TNF-αof the iguratimod group (6.25 μmol/L) was lower than that of the MTX group (6.25 μmol/L).The difference was statistical significant (t=2.359, P＜0.05).Conclusion Iguratimod presents strong anti-inflammatory and antiangiogenesis properties.This study provides insight into the possible molecular mechanisms of iguratimod and suggests that it can be a medication for the treatment of chronic inflammatory diseases like RA.
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OBJECTIVE: To identify a suitable polymer system for iguratimod (T-614), a poorly water-soluble compound with high melting point, and prepare a chemically stable single phase solid dispersion (SD) of T-614 by hot-melt extrusion (HME) technique to enhance its dissolution rate. METHODS: Melting method and adsorption based screening techniques were utilized to screen hydrophilic polymers suitable for immediate release formulations. T-614 SDs were prepared with polymer carriers such as PVP/VA 64, Soluplus, HPMC AS-LF and HPC-SL via HME below the drug melting point, and suitable temperature and plasticizer for HME were chosen. The dissolution behaviors of SD powder and SD tablets were compared with those of T-614 powder and commercial T-614 tablets, respectively. State of T-614 in HME SDs was characterized by X-ray powder diffraction. The homogenous SD tablets were analyzed further for physical stability in an influencing factors test. The bioavailability of SD tablets was assessed in rats. RESULTS: Results of the screening studies demonstrated that PVP/VA 64, Soluplus, HPMC AS-LF and HPC-SL provided higher degree of miscibility and dissolution enhancement. The HWE SD tablets showed significantly enhanced dissolution. The supersaturation state of HME SD powder in water was maintained for at least 120 min, suggesting that PVP/VA 64 had an inhibitory effect on recrystallization of T-614 from a supersaturated solution. Samples prepared via HME at 160°C were substantially amorphous, which were unchanged in the influencing factors test at high temperature and strong light, but recrystallization occurred at high humidity. PEG1500 appeared to be a promising plasticizer. Same bioavailability was achieved when compared with commercial T-614 tablets. CONCLUSION: The polymersas carriers for T-614 SD have significant impact on the dissolution behavior and state of T-614. Using PVP/VA 64 as the carrier, hot-melt extrusion is an effective technology for improving the in vitro dissolution of T-614.
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BACKGROUND: Iguratimod is a new type of disease modifying anti-rheumatic drug, which reduced the production of inflammatory cytokines. The purpose of this study was to evaluate pharmacokinetic characteristics and safety profiles of iguratimod after a single oral administration in healthy Korean volunteers. METHODS: A randomized, double-blind, placebo-controlled, parallel group, single oral dose study was conducted in 24 healthy male volunteers. Three groups of eight subjects each received 25 mg, 50 mg, or 100 mg dosage, respectively. Two subjects in each dose group were administered matching placebo. Plasma concentrations of iguratimod were measured till 72 hours after drug administration. Tolerability was evaluated by monitoring adverse events, clinical laboratory tests, and 12-lead electrocardiograms. RESULTS: The mean area under the concentration-time curve from 0 to 72 hours (AUClast) were 11.9, 25.2, and 51.8 mg x h/L and the maximum plasma concentration (Cmax) were 1.15, 2.33, and 4.78 mg/L in 25, 50 and 100 mg dose groups, respectively. All doses of iguratimod were well tolerated without serious adverse events or clinically meaningful changes. CONCLUSION: Cmax and AUClast values of iguratimod proportionally increased with incremental dose. Iguratimod was generally safe and well tolerated.
Subject(s)
Humans , Male , Administration, Oral , Cytokines , Electrocardiography , Pharmacokinetics , PlasmaABSTRACT
ObjectiveTo study the pharmacokinetics of iguratimod in rats. MethodsThe concentration ofiguratirnod in the samples was determined by HPLC method. The pharmacokineties parameters were calculated withDAS softwrare. ResultsThe mainpharmacokineties parameters of normal group(6mg/kg) were as follows:t1/2Ke:3.56h, tpeak: 4.00h, Cmax : 8.87μg/ml, AUC0.24 : 74.76μg· ml-1·h-1. The main pharmacokineties parameters of threemodel groups(3,6,12mg/kg) were as follows: t1/2Ke: 4.54,3.20,3.17h, tpcak:3.83,3.83,4.67h,Cmax:3.84, 8.31,12.69μg/ml, AUC0.24 :40.21,76. 72,117.06μg·ml-1·h-1. Except Cmax and AUC, no significant differenceswere found between the three model groups. And the differences between normal group and model group were notsignificant. ConclusionThe pharmacokinetics of rats ks fit to one-compartment model.