scholarly journals Therapeutic Effects of Bruton’s Tyrosine Kinase Inhibitor HM71224 as Monotherapy and in Combination with Methotrexate on Collagen-Induced Arthritis in Rats

2020 ◽  
Author(s):  
InHwan Bae ◽  
Yu-Yon Kim ◽  
SunYoung Jang ◽  
Joo-Yun Byun ◽  
TaeHun Song ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Liver Enzymes ◽  
Bone Erosion ◽  
Cartilage Degradation ◽  
Therapeutic Effects ◽  
Arthritis Score ◽  
Collagen Induced Arthritis ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
And Cartilage

Abstract Background: The purpose of this study was to determine the potential effects of HM71224, a Bruton’s tyrosine kinase (BTK) inhibitor, as a monotherapy and in combination with methotrexate (MTX) in rats with collagen-induced arthritis (CIA) and to evaluate the effects of drug-drug interactions in combination therapy.Methods: The therapeutic effect of HM71224 and the combination effects with MTX were evaluated in CIA rats. Arthritis was induced through immunization by type II collagen in Lewis rats. The therapeutic effects were evaluated by arthritis score, paw volume, body weight changes, and histopathological examination. The effective dose levels (ED) were determined from arthritis score. Bone erosion, synovial inflammation, and cartilage degradation were assessed by staining with hematoxylin and eosin (H&E) and safranin-O in ankle joints. The drug-drug interaction between HM71224 and MTX was investigated by the comparison of plasma levels and monitoring of liver enzymes, creatinine and blood cell counts in CIA rats. Results: HM71224 dose dependently ameliorated the clinical signs, paw volume and body weight loss on the development of arthritis in CIA rats, and ED50 and ED90 values were 1.0 and 2.5 mg/kg, respectively. The combination of HM71224 with MTX decreased the arthritis score, bone erosion, synovitis and cartilage degradation compared with HM71224 and MTX alone; however, no drug-drug interactions in the plasma and no abnormalities in the liver enzymes, creatinine or blood cell counts were observed. Conclusion: BTK inhibition by HM71224 prevented the development of arthritis and the combination therapy with MTX produced additive therapeutic effects with no drug-drug interactions in CIA rats. Therefore, we suggest that HM71224 may be useful as a monotherapy and in combination with MTX for the treatment of patients with rheumatoid arthritis.

Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice

2009 ◽  
Vol 613 (1-3) ◽  
pp. 155-162 ◽  
Author(s):  
Lena Svelander ◽  
Helena Erlandsson-Harris ◽  
Leif Astner ◽  
Urszula Grabowska ◽  
Lars Klareskog ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Cathepsin K ◽  
Cartilage Degradation ◽  
Collagen Induced Arthritis

scholarly journals Aqueous extract of Kan-Lu-Hsiao-Tu-Tan ameliorates collagen-induced arthritis in mice by regulating immune and inflammatory responses

2020 ◽  
Author(s):  
Chih-Chao Chiang ◽  
Yi‐Rong Li ◽  
Kuei-Hung Lai ◽  
Wei-Jen Cheng ◽  
Shih-Chao Lin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Peroxide ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Bone Erosion ◽  
Cartilage Damage ◽  
Radical Scavenging ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Anti Inflammatory

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease featured by joint inflammation and systemic comorbidities. Kan-Lu-Hsiao-Tu-Tan (KLHTT), a Chinese medicine formulation, has free radical scavenging capacity and anti-inflammatory activity in vitro. However, its anti-arthritic effect remains unknown. Herein, we aimed to explore the anti-arthritic effects of KLHTT on collagen-induced arthritis (CIA) in mice and investigate the underlying mechanisms. Methods KLHTT was extracted using boiling water. KLHTT (50 and 100 mg/kg) was fed orally for 21 days once a day on CIA in DBA/1J mice. The severity of CIA was evaluated by histological assessments. Levels of inflammatory cytokines, malondialdehyde (MDA), and hydrogen peroxide (H2O2) were measured using ELISA, thiobarbituric acid reactive substances, and hydrogen peroxide assay kits, respectively. Anti-collagen type II (CII) antibody was assayed by ELISA. Proliferation of splenocytes was tested using radioactive thymidine incorporation assay. Levels of Th1 and Th17 cells were obtained using flow cytometry. Results KLHTT significantly ameliorated paw edema and restored body weight in CIA mice. The synovitis, cartilage damage, and bone erosion were reduced by KLHTT. KLHTT exhibited anti-inflammatory effects by decreasing the levels of interleukin (IL)-1β, IL-6, IL-17A, and tumour necrosis factor-α in the paw homogenates and serum. KLHTT also showed antioxidant activity by reducing the concentrations of MDA and H2O2 in paw tissues. Moreover, KLHTT reduced anti-CII antibody formation, suppressed splenocyte proliferation, and mitigated the levels of splenic Th1 and Th17 cells in CIA mice. Conclusion The therapeutic effects of KLHTT in CIA mice were through regulating immune and inflammatory responses. Our results suggest that KLHTT has potential to treat rheumatoid arthritis.

An Alternative Elastase-mediated Degradation of Fibrinogen and Fibrin Observed in a Patient with Herpes Simplex Encephalitis and Pneumonia

1996 ◽  
Vol 76 (02) ◽  
pp. 184-186 ◽  
Author(s):  
Kenji lijima ◽  
Fumiyo Murakami ◽  
Yasushi Horie ◽  
Katsumi Nakamura ◽  
Shiro Ikawa ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Blood Cell ◽  
White Blood Cell ◽  
Herpes Simplex Encephalitis ◽  
Pmn Elastase ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Sds Page ◽  
White Blood Cell Counts ◽  
Pmn Élastase

SummaryA 74-year-old female developed pneumonia following herpes simplex encephalitis. Her white blood cell counts reached 28,400/μl, about 90% of which consisted of granulocytes. The polymorphonuclear (PMN) elastase/α1-arantitrypsin complex levels increased and reached the maximum of 5,019 ng/ml, indicating the release of a large amount of elastase derived from the granulocytes. The mechanism of PMN elastase release was most likely to be granulocyte destruction associated with phagocytosis. The cleavage of fibrinogen and fibrin by PMN elastase, independent of plasmin, was indicated by the presence of the fragments in immunoprecipitated plasma from the patient corresponding to elastase-induced FDP D and DD fragments and the absence of fragments corresponding to plasmin-induced FDP D and DD fragments on SDS-PAGE. These findings suggested that the large amount of PMN elastase released from the excessive numbers of granulocytes in this patient with herpes simplex encephalitis and pneumonia, induced the cleavage of fibrinogen and fibrin without the participation of plasmin.

Sign in / Sign up

Export Citation Format

Share Document