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The current investigation employed rosuvastatin for evaluation as an antiarthritic agent by in vitro and in vivo studies. In vitro studies comprised egg albumin and bovine serum albumin protein denaturation assays along with membrane stabilization assays, while in vivo studies comprised formaldehyde and complete Freund’s adjuvant (CFA)-provoked arthritis. The antioxidant potential was estimated via DPPH free radical scavenging and ferric reducing assays. Rosuvastatin significantly inhibited heat-provoked protein denaturation of egg albumin and bovine serum in a concentration-dependent way with the highest inhibition of 1225 ± 9.83 and 82.80 ± 4.03 at 6400 μg/mL. The percentage protection of the RBC membrane from hypotonicity-prompted lysis was found to be 80.67 ± 2.7. Rosuvastatin promisingly subdued formaldehyde-provoked arthritis, with maximum reduction (65.47%) of the paw volume being observed at a dose of 40 mg/kg. Rosuvastatin also significantly (p < 0.001) attenuated arthritis induced by CFA injection by reducing the paw volume and arthritic index. The reduction in the body weight due to CFA injection was also preserved by rosuvastatin treatment. Hematological and biochemical changes due to arthritis induction by CFA injection were also maintained near normal values by rosuvastatin. The histopathological and radiographic investigation also revealed the protective effect of rosuvastatin on preventing structural changes. Gene expression of IL-1β, TNF-α, and IL-6 was reduced, while IL-4 and IL-10 levels were elevated by rosuvastatin in comparison to those for the disease control group. Concentration-dependent antioxidant potential was shown by rosuvastatin. Thus, rosuvastatin possesses a notable antiarthritic potential as evidenced via in vitro and in vivo studies.

Pentosan polysulfate (PPS) is currently under investigation as a potential disease-modifying antiarthritic agent. In the present study the effects of PPS on arthritic profiles based on clinical score, ankle size, histological changes, and activity of inflammatory mediators using collagen-induced arthritic rat are reported. Model of arthritis was developed in Sprague Dawley rats by intradermal injection of bovine type II collagen emulsified with incomplete Freund's adjuvant. The rats were randomly divided into four groups: normal control, arthritic control, arthritic rats treated with PPS (at dose level 20 μg/g) and arthritic rats treated with meloxicam (2 μg/g). The treatment was continued daily until the day 30. Arthritic biomarkers (cartilage oligomeric matrix protein and tartrate-resistant acid phosphatase 5b) in synovial fluid, expression of inflammatory mediators (interleukin-1β, and tumor necrosis factor-α) and osteoclast marker genes (cathepsin K, tartrate-resistant acid phosphatase) in synovial membrane were measured. Daily administration of PPS to the arthritic rats significantly decreased the severity of arthritis by effectively suppressing the symptoms of arthritis and improving the functional recovery based on clinical score and histopathological evidence. Intriguingly, identical downregulation pattern of arthritis profiles, biological markers as well as relative mRNA levels of osteoclast markers and cytokines were monitored in arthritic rats treated with PPS. In conclusion, PPS exerted protective effects against collagen-induced arthritis in rats. The results suggest that PPS acts as an anti-inflammatory and anti-arthritic agent in decreasing the arthritic effects in collagen-induced arthritic rats.

Phytol is a diterpene constituent of chlorophyll and has been shown to have several pharmacological properties, particularly in relation to the management of painful inflammatory diseases. Arthritis is one of the most common of these inflammatory diseases, mainly affecting the synovial membrane, cartilage, and bone in joints. Proinflammatory cytokines, such as TNF-α and IL-6, and the NFκB signaling pathway play a pivotal role in arthritis. However, as the mechanisms of action of phytol and its ability to reduce the levels of these cytokines are poorly understood, we decided to investigate its pharmacological effects using a mouse model of complete Freund's adjuvant (CFA)-induced arthritis. Our results showed that phytol was able to inhibit joint swelling and hyperalgesia throughout the whole treatment period. Moreover, phytol reduced myeloperoxidase (MPO) activity and proinflammatory cytokine release in synovial fluid and decreased IL-6 production as well as the COX-2 immunocontent in the spinal cord. It also downregulated the p38MAPK and NFκB signaling pathways. Therefore, our findings demonstrated that phytol can be an innovative antiarthritic agent due to its capacity to attenuate inflammatory reactions in joints and the spinal cord, mainly through the modulation of mediators that are key to the establishment of arthritic pain.

Objectives Evodiamine (Evo) possesses strong anti-inflammatory activity. In this study, we determine the antiarthritic effect of Evo. Methods Evo was administered to rats with adjuvant-induced arthritis (AA). We evaluated arthritis symptoms & histopathological changes and measured inflammatory cell infiltration, pro-inflammatory cytokine production and Th17 & Treg percentages in arthritic rats. Key findings Evo significantly improved the clinical signs of AA in rats, including decreases in paw swelling, the polyarthritis index and the number of swollen paw joints. Based on the histopathological analysis, Evo improved synovial inflammation and bone injury by inhibiting inflammatory cell infiltration, synoviocyte proliferation, pannus formation and cartilage erosion. Furthermore, the numbers of synovial CD3+ or CD68+ inflammatory cells were reduced, and the elevated levels of tumour necrosis factor-α, interleukin-1β (IL-1β) and IL-6 were restored to control levels by the Evo treatment. In addition, Evo therapy regulated the abnormal differentiation of Treg and Th17 cells, decreasing IL-17 production and increasing IL-10 levels. Finally, Evo inhibited Stat3 phosphorylation and induced Stat5 phosphorylation in rats with AA. Conclusions Based on our results, Evo is a promising antiarthritic agent, potentially due to its inhibitory effect on synovial inflammation and regulatory effects on Treg and Th17 differentiation.

Background Ipomoea batatas L. Lam. is a functional food and belongs to family Convolvulaceae. It is used as an antiinflammatory, aphrodisiac, antiasthmatic, anticonvalescent, antitumor, antanemic and antidiabetic agent by local communities. This study has been planned to evaluate its antiinflammatory and antiarthritic potentials. Methods Dry powder of I. batatas tuber and roots were extracted with ethyl acetate (IPT-EA, IPR-EA) and methanol (IPT-M, IPR-M), respectively. These extracts were tested for total phenolic and flavonoid contents (TPC and TFC), HPLC finger printing, multidimensional in vitro and in vivo antioxidant potential and albumin denaturation inhibition. Carrageenan-induced paw edema, croton oil-induced ear and anal edema inhibition and Complete Freund’s Adjuvant (CFA)-induced antiarthritic assays were executed at a dose of 300 mg/kg body weight on Sprague-Dawley rats. Serum levels of interleukins IL-1β and IL-6 and nitric oxide (NO) were assessed to measure the inhibition of inflammation. Results Maximal TPC (319.81 ± 14.20 μg GAE/mg dry extract) and TFC (208.77 ± 9.09 μg QE/mg DE) were estimated in IPR-EA extract. IPT-EA and IPR-EA yielded the maximum amounts of rutin (7.3 ± 1.12 and 4.5 ± 0.55), caffeic acid (1.60 ± 0.25 and 2.17 ± 0.26) and myricetin (2.7 ± 0.14 and 1.01 ± 0.08 μg/mg DE), respectively in HPLC-DAD analysis. All extracts showed dose dependent response in in vitro antioxidant assays. Best inhibition (76.92 ± 3.07%) of albumin denaturation was shown by IPT-EA in comparison to ibuprofen (79.48 ± 4.71%). IPR-EA exhibited highest edema inhibition in models of carrageenan-induced paw edema (79.11 ± 5.47%) and croton oil-induced ear and anal edema (72.01 ± 7.80% and 70.80 ± 4.94%, respectively). Significant inhibition of CFA-induced arthritic edema and arthritic score were observed by IPR-EA as compared to ibuprofen. Suppression of pro-inflammatory cytokines (IL-1β, IL-6) and NO levels was shown by IPR-EA and IPT-EA, respectively. Conclusion These results depict that richness of polyphenols and phytoconstituents in I. batatas ameliorates oxidative stress and inflammation of acute and chronic nature. Dose dependent antioxidant potential and inhibition of inflammatory edema, pro-inflammatory cytokines and hematological, biochemical and histological changes prove I. batatas therapeutic potential as an antiinflammatory and antiarthritic agent. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s12906-018-2279-5) contains supplementary material, which is available to authorized users.

Rheumatoid arthritis (RA) is a systemic autoimmune disease, characterized by the irreversible joint destruction resulted from the attack of inflammatory cells to the joints. Recent studies demonstrated that crocin is able to alleviate arthritis and suppress inflammatory responses, implying crocin as a potential promising antiarthritic agent. In this study, we confirmed the effect of crocin on RA and revealed its underlying mechanism by measuring lipopolysaccharides (LPS)-stimulated cytokine production in presence or absence of crocin. The effect of crocin was also tested in vivo using a mouse model of collagen-induced arthritis (CIA). It was found that crocin significantly repressed the LPS-induced expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in human fibroblast-like synoviocytes (FLS). We tested the effect of crocin on nuclear factor-kappa B (NF-κB) signaling and observed that cells pre-treated with 500 μM of crocin exhibited lower levels of LPS-induced p-IκBα, p-IκB kinase (IKK) α/β, and p65 expression than those of untreated cells. In addition, we found when cells were stimulated with IKKβ, crocin pre-treatment showed significantly inhibitory effect on the luciferase activity of IL-1β. In vivo results also showed that crocin treatment dramatically reduced plasma levels of TNF-α, IL-1β, and IL-6 in CIA mice. Crocin is efficient to suppress the productions of TNF-α, IL-6, and IL-1β by blocking NF-κB signal activation through its interaction with IKK, suggesting that crocin could be an efficient treatment for RA.

Objective: The objective of this study was to evaluate the anti-inflammatory and antiarthritic potential of Parmelia perlata. Methods: The relative study is based on in vitro anti-inflammatory and antiarthritic activity using hydroalcoholic extract of P. perlata (HAEPP). The preliminary phytochemical tests showed the presence of various phytochemical compounds such as alkaloids, flavonoids, and glycosides since the lichen species of P. perlata has the folklore claim of anti-inflammatory activity, thus it was studied by human red blood cells membrane stabilization method, and arthritic activity was carried using protein denaturation method using diclofenac as a standard. Results: The results showed eminent anti-inflammatory and antiarthritic activity in a dose-dependent manner. The membrane stabilization showed the maximum effect at 78.54% at the concentration of 1000 μg/, and the protein denaturation was also found maximum at 1000 μg/ml concentration at 79.43%. Thus, our research states the potent anti-inflammatory activity and antiarthritic effect in P. perlata. Conclusion: The HEAPP has a potent anti-inflammatory activity and antiarthritic activity. A further study has to be conducted to establish the pharmacological evidence behind the compound and the mechanism of action of the HAEPP on the inhibition of the inflammation process.

The protective effect of latex of Calotropis procera in Freund's Complete Adjuvant (FCA) induced monoarticular arthritis was evaluated in rats. Arthritis was induced by a single intra-articular injection of 0.1 mL of 0.1% FCA in the right ankle joint. The effect of dried latex (DL, 200 and 400 mg/kg) and its methanol extract (MeDL, 50 and 500 mg/kg) following oral administration was evaluated on joint inflammation, hyperalgesia, locomotor function and histology at the time of peak inflammation. The effects of DL and MeDL were compared with antiinflammatory drugs phenylbutazone (100 mg/kg), prednisolone (20 mg/kg), rofecoxib (20 and 100 mg/kg) and immuno-suppressant methotrexate (0.3 mg/kg). Daily oral administration of DL and its methanol extract (MeDL) produced a significant reduction in joint inflammation (about 50% and 80% inhibition) and associated hyperalgesia. The antihyperalgesic effect of MeDL was comparable to that of rofecoxib. Both DL and MeDL produced a marked improvement in the motility and stair climbing ability of the rats. The histological analysis of the arthritic joint also revealed significant reduction in oedema and cellular infiltration by MeDL that was comparable to that of rofecoxib. Thus, our study suggests that the latex of C. procera has the potential to be used as an antiarthritic agent. Copyright © 2008 John Wiley & Sons, Ltd.

Zhaoling Zheng,1,* YanHua Sun,2,* Ziliang Liu,1 Mingqin Zhang,1 Chunqing Li,1 Hui Cai3 1Department of Traditional Chinese Medicine, Dongying People’s Hospital, Dongying, 2Shandong Provincial Key Laboratory of Microparticles Drug Delivery Technology, Jinan, 3Department of Integrated Traditional Chinese Medicine and Western Medicine, Nanjing Jinling Hospital, Nanjing, People’s Republic of China *These authors contributed equally tothis work Background: Rheumatoid arthritis (RA), induced by the prolonged inappropriate inflammatory responses, is one of the most prevalent of all chronic inflammatory joint diseases. Curcumin (CM), a yellow hydrophobic polyphenol derived from the herb turmeric, has various pharmacological activities against many chronic diseases and acts by inhibiting cell proliferation and metastasis and downregulating various factors, including nuclear factor kappa B, interleukin-1β and TNF-α. Given the pathogenesis of RA, we hypothesized that the drug also has antiarthritic effects. The aims of the present study included the following: 1) examining the therapeutic effect of CM administered via intravenous (iv) injection on RA and 2) formulating the drug into oil–water nanoemulsions (Ns) to overcome the low oral bioavailability of CM and achieve oral delivery of the drug.Methods: The effect of CM administered through iv injection on adjuvant-induced arthritis in rats was studied in terms of paw swelling, weight indices of the thymus and spleen, and pathological changes in nuclear factor kappa B expression and inflammatory cytokines. Methotrexate was used as a positive control. The CM-Ns were prepared using a high-pressure homogenizing method and characterized with respect to the particle size and morphology. The stability of the CM-Ns in simulated gastrointestinal (GI) fluids and in vitro release were also investigated. Apharmacokinetic study of the CM-Ns and suspensions in which the plasma levels were determined using an high performance liquid chromatography method and the pharmacokinetic parameters were calculated based on a statistical moment theory was also performed in rats.Results: CM administered via iv injection had a therapeutic effect on RA similar to methotrexate. CM-Ns with a diameter of approximately 150 nm were successfully prepared, and the drug was well encapsulated into the Ns without degradation in simulated GI conditions. The area under the curve (AUC) and Cmax for the CM-Ns were more than threefold greater than those for the suspensions; moreover, similar decreases in the levels of TNF-α and interleukin-1β in both synovial fluid and blood serum were obtained from oral administration of CM-Ns and iv injection.Conclusion: CM was an effective antiarthritic agent, and the present N formulation appeared to be a promising system that allowed RA therapy with CM to be converted from iv to oral administration. Keywords: curcumin, nanoemulsions, inflammatory cytokines, adjuvant-induced arthritis, drug release, oral bioavailability

Phyllanthus amarus Schum. & Thonn. (P. amarus) has been reported to exhibit anti-inflammation and antiarthritis properties leading to our interest to examine its beneficial effect in osteoarthritis. Thus, this study aimed to explore the chondroprotective potential of P. amarus extract (PAE) and its major compounds, phyllanthin and hypophyllanthin, in a cartilage explant model. Various concentrations of P. amarus extract, phyllanthin and hypophyllanthin, were treated on porcine articular cartilage explants induced with 25 ng/ml of interleukin-1 beta (IL-1β). After 4 days of incubation, the culture medium was measured for the release of sulfate glycosaminoglycans (s-GAGs) and matrix metalloproteinase-2 (MMP-2) activity by DMMB binding assay and zymography, respectively. The explant tissues were analyzed for the remaining of uronic acid content by colorimetric assay and stained with safranin-O for investigation of proteoglycan content. Cell viability of this model was evaluated by lactate dehydrogenase (LDH) assay. Chondroprotective potential of PAE and the major components against IL-1β-induced cartilage explant degradation were revealed by the decreased s-GAGs level and MMP-2 activity in culture medium consistent with an increase in uronic acid and proteoglycan contents in the explants when compared to the IL-1β treatment. These results agreed with those of diacerein and sesamin which used as positive controls. In addition, better chondroprotective activities of P. amarus crude extracts than those of the purified components were disclosed in this study. Hence, this is a pioneering study presenting the chondroprotective potential of PAE which may augment its application for therapeutic use as an antiarthritic agent.

Despite a multitude of reports on anti-inflammatory properties of ginseng extracts or individual ginsenosides, data on antiarthritic effect of ginseng saponin preparation with mixed ginsenosides is limited. On the other hand, a combined therapy of safe and inexpensive plant-derived natural products such as ginsenosides can be considered as an alternative to treat arthritis. Our previousin vitrodata displayed a strong anti-inflammatory action of red ginseng saponin fraction-A (RGSF-A). We, herein, report a marked antiarthritic property of RGSF-A rich in ginsenoside Rb1, Rc, and Rb2. Collagen-induced arthritic (CIA) mice were treated with RGSF-A or methotrexate (MTX) for 5 weeks. Joint pathology, serum antibody production and leukocye activation, cytokine production in the circulation, lymph nodes, and joints were examined. RGSF-A markedly reduced severity of arthritis, cellular infiltration, and cartilage damage. It suppressed CD3+/CD69+, CD4+/CD25+, CD8+T-cell, CD19+, B220/CD23+B-cell, MHCII+/CD11c+, and Gr-1+/CD11b+cell activations. It further suppressed anti-CII- or anti-RF-IgG/IgM, TNF-α, IL-1β, IL-17, and IL-6 secretions but stimulated IL-10 levels in the serum, joint, or splenocyte. RGSF-A attenuated arthritis severity, modified leukocyte activations, and restored cytokine imbalances, suggesting that it can be considered as an antiarthritic agent with the capacity to ameliorate the immune and inflammatory responses in CIA mice.

In the present study, the biopotential of capsaicin (an active principle of capsicum) as a topical antiarthritic agent was studied in arthritic rats. Transfersomal vesicular system was employed for the topical administration of capsaicin in experimental rats. The characterization of prepared capsaicin-loaded transfersomes reveals their nano size (94 nm) with negative surface charge (-14.5 mV) and sufficient structural flexibility, which resulted in 60.34% entrapment efficacy, penetration across the biomembrane (220 µm) and 76.76% of drug release from vesicular system in 24 h in their intact form as evident from confocal laser scanning micrographic study. Results of transfersomal nanoformulation (capsaicin loaded, test) were compared with that of conventional gel formulation available in the market (Thermagel, standard), with an aim to assess the antiarthritic efficacy of our prepared capsaicin-loaded transfersomal formulation. In vivo antiarthritic activity study shows that our formulation possesses superior inhibitory activity than the marketed Thermagel formulation at the same dosage level, which could probably be due to the lesser permeability of Thermagel across the dermal barriers compared to our specially designed transfersomal delivery system. Moreover, the better tolerance of prepared vesicular formulation in biological system further enlightens the suitability of the transfersomal vesicle to be used as a novel carrier system for the topical administration of such highly irritant substance.

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is expected to have minimal effects on platelet function. A double-blind, randomized, placebo-controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 [a thromboxane A2 receptor agonist]), bleeding time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs.

Phyllanthus amarus has been proven to exhibit chondroprotection. Regarding the morphological similarities among Phyllanthus species, we were attracted to evaluate the chondroprotective potential of Phyllanthus species including P. amarus obtained from Chiang Mai and Phuket, Phyllanthus urinaria L., Phyllanthus urinaria subsp. chamaepeuce, Phyllanthus debilis, and Phyllanthus airy-shawii using interleukin-1β-induced degradation of cartilage explants. The ethanolic extracts of the plants were evaluated for major lignans, phyllanthin, and hypophyllanthin by HPLC and further measurements of the total contents of flavonoids and phenolic compounds along with the assays for antioxidant and anti-collagenase activities. The interleukin-1β-induced cartilage explant degradation was performed with/without the extracts at concentrations of 50–250 µg/mL. After 4–14 days of incubation, the medium was assayed for the level of sulfated glycosaminoglycans while the explants were measured for the remaining content of uronic acid. Proteoglycan intensity in the explants was determined by safranin O staining. Diacerein, the antiarthritic agent, was used as the positive control. Although the two major lignans were found in P. amarus from Chiang Mai, P. amarus from Phuket, and P. urinaria L. extracts, similar chondroprotective activities were observed in all Phyllanthus extracts. Total phenolic content and total flavonoid content of the extracts showed a correlation with antioxidation, whereas the total phenolic content correlated with anti-collagenase activity. Among the six extracts, P. airy-shawii showed the greatest antioxidant and collagenase inhibitory activities. The results revealed that chondroprotective activities of all of the extracts of Phyllanthus species might result from an additive or synergistic influence of some constituents of these plants, which could be considered for antiarthritic purposes.

Hydroxychloroquine (HCQ) is a racemic antiarthritic agent that has a long half-life (t1/2) in plasma and accumulates in blood cells. To study the relationships between HCQ concentrations in plasma, serum, and whole blood and to determine the optimal blood fraction to use for therapeutic drug monitoring of the drug, we studied the relative distribution of the HCQ enantiomers in various fractions of human blood under in vivo and in vitro conditions. Substantially greater concentrations of both enantiomers were found in serum as compared with plasma because of release via platelet activation. After in vitro incubations of the separated blood cells with HCQ, high concentrations of both enantiomers were found in leukocytes, and low concentrations in erythrocytes and platelets; the R:S ratio in vitro was near unity in all of the cells examined. Unlike the in vitro cellular uptake, the concentrations of HCQ in vivo were significantly lower and stereoselective (R:S ratio = 2). There was almost no drug in the polymorphonuclear cells (PMN) in vivo, despite a substantial uptake in vitro after incubation of separated cells. The enantiomeric (R:S) ratio in the urinary excretion of the enantiomers was significantly correlated with that in plasma. The plasma-protein binding of the enantiomers was stereoselective and complimented the cellular uptake findings; the unbound fraction was dependent on the plasma concentrations of alpha 1-acid glycoprotein, but not albumin. Although concentrations in whole blood correlated well with those in lymphocytes and monocytes (the proposed site of HCQ action), stronger correlations were found between concentrations in serum and in the mononuclear cells.

A new calcium-chelated derivative of pentosan polysulfate (CaPPS) is currently under investigation as a potential disease-modifying antiarthritic agent. In the present study the effects of CaPPS on edema production, cellular infiltration, and activity of inflammatory mediators (prostaglandin E 2 [PGE 2 ], interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) using the rat subcutaneous air-pouch model of inflammation are reported. CaPPS or saline was injected subcutaneously daily for 7 days (study days 8 to 14) at concentrations of 0.5 to 10 mg/kg of body weight into the abdomen of rats with preformed noninflamed or peptone-inflamed dorsal pouches. The pouch fluid volume, white cell count, differential white cell count, PGE 2 , TNF-α, IL-6, and IL-1β levels were determined using standard methods after the rats were sacrificed on day 15. In saline-treated control animals, injection of peptone into rat air pouches provoked a large influx of fluid and white cells, with a concomitant increase in levels of PGE 2 , TNF-α, IL-6, and IL-1β. Although subcutaneously administered CaPPS had no effect on the accumulation of fluid, white cell numbers, or PGE 2 levels within the pouch, there was a 38% reduction in TNF-α activity in the presence of 2.5 to 10 mg/kg body weight of drug ( P P

Compound IX 207-887 is a novel antiarthritic agent which inhibits the release of interleukin-1 (IL-1) from human monocytes and mouse peritoneal macrophages in vitro at concentrations which are achieved therapeutically in human rheumatoid arthritis and in animal models of arthritis. In the present studies IL-1 activity in conditioned media, homogenates or lysates was monitored using four independent assay systems. Biologically active IL-1 was determined by, a) the induction of latent metalloproteinase-release from rabbit articular chondrocytes, which is relatively specific for IL-1 and b) by a sensitive thymocyte proliferation assay. Immunoreactive IL-1-beta was assayed by RIA and ELISA. In all test systems IX 207-887 significantly reduced both biologically active and immunoreactive IL-1 in culture media, whereas the levels of IL-1 in homogenates or lysates were either unaffected or only marginally reduced. The release of other monokines tested, such as interleukin-6 and tumour necrosis factor-alpha, and the secretion of lysozyme were only marginally influenced. IX 207-887 neither affected the adherence of human monocytes nor markedly inhibited IL-1 or IL-2-induced thymocyte proliferation. In the chondrocyte test no IL-1 antagonistic activity of IX 207-887 could be observed. All of these data indicate that IX 207-887 has the novel property of being an inhibitor of IL-1 release.

Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported as an inhibitor of group II phospholipase A2. In this study, ginkgetin was evaluated for in vivo antiarthritic and analgesic activities. Ginkgetin (10-20 mg/kg/day) strongly reduced arthritic inflammation in an animal model of rat adjuvant-induced arthritis (86% inhibition at 16 days at a dose of 20 mg/kg/day) via intraperitoneal injection, while prednisolone (5 mg/kg/day) showed 79% reduction. Histological examination of the knee joints confirmed our findings. When analgesic activity was measured, ginkgetin showed a dose-dependent inhibition in an animal model of acetic acid-induced writhing. ED50 values for ginkgetin and indomethacin were 8.9 and 3.8 mg/kg, respectively. All these results indicate that ginkgetin may be a potential antiarthritic agent having analgesic activity.

Objective: To evaluate the acute and chronic antiinflammatory properties of leaf extracts of Kalanchoe crenata in rats. Material and methods: The methylene chloride/methanol extract of K. crenata was extracted by using hexane, methylene chloride, ethyl acetate, and n-butanol. The antiinflammatory profile of these extracts was investigated on the basis of paw edema induced by carrageenan. The n-butanol fraction (most potent) was further assessed through acute inflammatory models induced by histamine, serotonin, and formalin. The chronic antiinflammatory and the ulcerogenic activities of the n-butanol fraction were also examined. Results: The oral administration of n-butanol fraction (600 mg/kg) caused a maximum inhibition of about 45% in paw edema induced by carrageenan. The n-butanol fraction also exhibited acute antiinflammatory activity on paw edema induced by histamine (47.51%), serotonin (54.71%), and formalin-(40.00%) . In the chronic inflammation model, this extract showed maximum inhibition of 61.26% on the ninth day of treatment. The ulcerogenic assessment showed that ulcer indices after oral treatment with n-butanol fraction were zero and 0.4±0.2, for the 300 and 600 mg/kg doses, respectively. Conclusion: On the basis of these findings, it may be inferred that K. crenata is an antiinflammatory and antiarthritic agent that blocks histamine and serotonin pathways. The results are in agreement with the traditional use of the plant in inflammatory conditions.

An in situ rat intestinal preparation was modified to include portal and jugular venous blood collection techniques as well as sampling from the intestinal lumen. Viability could be maintained for 3 h. The utility of the preparation was examined by studying the disposition of four model drugs, each with differing characteristics with respect to absorption and presystemic metabolism. Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1- butanone), a reference compound used for model development, disappeared from the intestinal lumen with a half-life of 14 +/- 3 min. When the antiarthritic agent, tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate), was studied in the preparation, it was rapidly absorbed (t1/2 for disappearance from the intestinal lumen = 8 min), achieved plasma concentrations comparable to in vivo data, and underwent little presystemic elimination. In contrast, fenoctimine sulfate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulfate), an antisecretory compound, disappeared more slowly from the intestinal lumen (t1/2 = 60 min), was present in portal plasma, but was not detected in systemic plasma. Extensive hepatic first-pass elimination of fenoctimine was evident. Tolmetin glycine amide (N-([1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl)glycine), a tolmetin prodrug, disappeared from the intestinal lumen very slowly (t1/2 approximately 3 h) compared with the other agents tested. It was determined that this drug was being hydrolyzed presystemically to tolmetin by the intestinal mucosa and the liver. These results establish the utility of this intestinal preparation for studying drug absorption and presystemic elimination.

Lobenzarit disodium (CCA) has been reported to have an inhibitory effect on the development of adjuvant arthritis (AA) in rats. Earlier studies have suggested that the therapeutic effect of CCA might be based on its immunoregulatory activity, although the precise mechanisms of action are unclear. In this paper, possible involvement of thymus-derived lymphocytes in the suppression of AA was studied. It was found that CCA failed to inhibit the development of AA in rats whose T lymphocytes were depleted by the injection of rabbit antithymocyte serum (ATS), whereas the same schedule of treatment with CCA significantly suppressed AA developed in control rats which were injected with normal rabbit serum. In addition, adult thymectomy abrogated the antiarthritic effect of CCA. These data suggest the possibility that the therapeutic effect of CCA in AA might be mediated by ATS-sensitive, short-lived, thymus-derived lymphocytes.

Auranofin, an oral chrysotherapeutic agent effective in the treatment of rheumatoid arthritis (RA), was found to be a potent, noncytotoxic inhibitor of IgG-RF immune complex-induced lysosomal enzyme release (LER) from human leukocytes. At a concentration of 1 microg Au/ml (5 microM), auranofin produced a marked reduction in beta-glucuronidase (100%), acid phosphatase (88%), and lysozyme (72%) release. In contrast, gold sodium thiosulfate (GST, an injectable gold compound) had no inhibitory activity on LER at equivalent gold concentrations (i.e., 1 microg Au/ml) and only modest activity (less than 36% inhibition) at concentrations as high as 40 microg Au/ml. The 50% inhibitory dose (LD50) of auranofin on LER was calculated to be 3-4 microM (0.6-0.8 microg Au/ml). Blood gold levels in auranofin-treated RA patients were found to be within the range required for in vitro inhibition of LER, and correlated with decreases in IgG, RF titers, and IgG-RF immune-complex formation in vitro. These results suggest that the therapeutic action of auranofin may be caused, at least in part, by inhibition of LER and/or decreases in immune-complex formation.

Auranofin (AF), an orally active, antiarthritic agent, modulates the functional activities of macrophages in vivo and in vitro . To better understand the molecular mechanism of action of auranofin with macrophages we have investigated its cellular association, intracellular distribution, and efflux with RAW 264.7 cells using auranofin radiolabeled within the triethylphosphine (Et 3 P)[ 3 H], the gold [ 195 Au] or the tetraacetylthioglucose (TATG)[ 14 C] moieties of the molecule. Evaluation of the effects of auranofin on RAW 264.7 cells demonstrates that (1) cellular association of this compound was concentration, time and temperature dependent; (2) cellular association of AF was inhibited by N -ethylmaleimide but not by 2,4-dinitrophenol and NaF; (3) cellular association and uptake of Au and Et 3 P into cells was reduced when the drug was preincubated with increasing concentrations of fetal calf serum and albumin; (4) no tetraacetylthioglucose from the auranofin molecule became cell associated whereas the Au and Et 3 P moieties were internalized and distributed between the nuclear, cytosolic and membrane fractions of cells; and (5) efflux of Au and Et 3 P from RAW 264.7 cells was time and temperature dependent. Based on these data we propose a model, a sequential ligand exchange process, that describes the molecular interactions of auranofin and possibly other gold compounds with these cells.

Auranofin (AF), at a concentration of 10 micrograms/ml, was found to be a potent inhibitor of ADP-, epinephrine-, or collagen-induced platelet aggregation utilizing platelet-rich plasma obtained from human blood. In contrast, aurothioglucose was less effective than AF in inhibiting epinephrine- or collagen- induced platelet aggregation. The inhibitory effect of AF was more evident on the second phase of aggregation. The inhibitory effect of AF was more evident on the second phase of aggregation and was a function of drug preincubation time. Compared to platelet-rich plasma, washed platelets were superior for detecting the inhibitory action of AF (greater than or equal to 0.1 microgram/ml) on ADP-induced platelet aggregation. This potent inhibitory action of AF on ADP-induced platelet aggregation was antagonized by dithioerythriol, a potent reducing agent. These results suggest that AF can inhibit both platelet release and aggregation mechanisms which may be relevant to its antiarthritic activity. Further studies are required to elucidate the cellular mechanism by which AF inhibits platelet aggregation.

A series of gold(I) coordination complexes including analogues of the antiarthritic agent auranofin 1 were evaluated for in vitro cytotoxic potency against both B16 melanoma cells and P388 leukemia cells and in vivo antitumor activity against P388 leukemia in mice. A number of the complexes showed potent cytotoxic activity in vitro and antitumor activity in vivo, with the phosphine-coordinated gold(I) thiosugar complexes demonstrating the greatest in vitro and in vivo activity. The data compiled for 63 complexes of the general structural formula LAuX provide the basis for the following observations: potent in vitro cytotoxic activity is observed for substituted (phosphine) gold complexes, lack of potency in vitro correlates well with lack of antitumor activity, potent cytotoxicity in vitro is not necessarily predictive of activity in vivo, in vivo antitumor activity is generally optimized by ligation of Au(I) with a substituted phosphine and a thiosugar.

The antirheumatic effect of cortisone administered parenterally or orally has been documented in numerous reports 1 during the past two years, but little has been written about cortisone administered locally into the arthritic joint. Apparently Thorn 2 was the first to instill an adrenal cortical hormone directly into a rheumatoid arthritic joint. Early in 1950 he injected 10 mg. of hydrocortisone (17-hydroxycorticosterone or compound F) into the inflamed knee of a patient with rheumatoid arthritis and noted a prompt local alleviating effect. Since this was coincident with a general improvement in the condition of the patient, it was felt that the action was systemic and no further experiments were conducted along this line. Cortisone has been used locally with encouraging results in various inflammatory diseases of the eye. 3 Some reports have claimed benefit from direct application of cortisone in certain skin diseases. 4 Since a locally used anti-inflammatory agent