Adjuvant arthrits

Weithmann KU, Schlotte V, Jeske V et al. (1997) Effects of tiaprofenic acid on urinary pyridinium crosslinks in adjuvant arthritic rats Comparison with doxycycline. Inflamm Res 46 246-252... 

Mercaptopyrldoxine (62) was reported to enhance the intensity of the secondary reaction in adjuvant arthritic rats and to augment pertussis vaccine edema. Also, it stimulated lymphocyte responses to Concanavalin A.203 Another sulfhydryl compound, a-mercaptoproplonylglyclne (64), enhanced antibody formation to SRBC in mice when given for five days before immunization. T- and B-cell mitogen reactivity of lymphoid cells from EL4 leukemia-bearing mice was restored and production of cytotoxic antibody to EL4 increased by the administration of 64.204... 

Anti-arthritic medicinal substances obtained from plants and hydrocortisone were studied with regard to their effect on essential metalloelement metabolism in the adjuvant-arthritic rat following oral treatment for 15 days. Medicinal substances derived from Withania somntfera and Clerodendron inerme decreased copper levels on day 3 compared with nontreated control levels, while hydrocortisone (15 mg/kg) had no effect. However, hydrocortisone treatment lowered serum copper values on days 15 and 49 after induction of inflammation, while the plant-derived drugs did not lower serum copper values [130]. 

These observations add emphasis to the caution that lipid peroxidation measurements be made on fresh tissue samples [700]. While no phenanthro-line-detectable copper, no loss of ceruloplasmin activity, and very little lipid peroxidation were found for samples stored for 4 weeks in the cold, there was a marked increase in phenanthroline-detectable copper, a loss in ceruloplasmin activity, and an increase in lipid peroxidation in these samples after 4 weeks of storage at 40 °C. Storage of these samples at - 20 °C or - 70 °C slowed but did not prevent these artifactual deteriorations in tissue samples. This may also provide some mechanistic insight into the observation that Cu-Zn-SOD-treated adjuvant arthritic rats experienced less paw swelling and tissue lipid peroxidations (/ < 0.001) [701]. 

The Cu chelate of niflumic acid was also found to be active in all three models. Comparison here is somewhat lacking, since one cannot directly compare activities of two compounds given by different routes of administration. However, the following comparison is viewed as helpful with regard to disclosure of potentially useful information. The parent compound was active at 40 and 25 mg kg" orally in the CPE and CWG models respectively, while the chelate was active at 8 and 10 mg kg" s.c. in these 2 models. The lowest active dose in the AA model was 6 mg kg" orally for niflumic acid and 1.2 mg kg" s.c. for Cu(II)n(niflumate)2n- When both Cu(II) (niflumate)2n and niflumic acid were tested intravenously in the adjuvant arthritic rat, the lowest active dose of niflumic acid was only 30 mg kg" while its Cu complex was active at 6 mg kg" . 

Figure 9 (A) MR images from longitudinal assessment of degeneration of the posterior tibio-tarsal joint of a rat, rendered arthritic by intra-venous injection of a Mycobacterium butyricum suspension at Day 1 (200 MHz, TE/TR = 9/2500 ms, 100 x 100 pm in plane resolution, 1 mm trans-plane resolution). (B) 400 MHz images of excised tibio-tarsal joints from control and adjuvant-arthritic rats, acquired using autosampler technology (TE/TR = 8/1000 ms, 70 x 70 x 250 pm resolution). Reproduced by permission of Dr. Rasesh Kapadia, SB Pharmaceuticals, Upper Merion, PA.

Several other modifications have been explored for the targeted delivery of SOD. Chemical modification with hydrophilic monomethoxypolyethyleneglycol polymers (MPEG) resulted in a derivative with an increased molecular weight of 130 kDa, and hence a reduced renal elimination rate. The MPEG-SOD preparations reduced arthritic lesions in a complete adjuvant arthritis model in the rat, while native SOD did not show an anti-inflammatory effect [55]. 

Anti-arthritic effect. Oral administration of AJA, a cannabinoid acid devoid of psychoactivity, reduced joint tissue damage in rats with adjuvant arthritis. Peripheral blood monocytes (PBM) and synovial fluid monocytes (SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AJA (0-30 mM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for messenger RNA (mRNA), and supernatants were collected for cytokine assay. Addition of AJA to PBM and SFM in vitro reduced both steady-state levels of interleukin-ly (IL-ly) mRNA and secretion of IL-ly in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 mM AJA (p < 0.05 vs untreated controls, n = 7). AJA did not influence tumor necrosis factor-a (TNF-a) gene expression in or secretion from PBM . 

Monoarticular arthritis was produced in the left knee joints of rabbits by using ovalbumin and Freund s complete adjuvant as antigen and adjuvant. Naproxen sodium nanoparticles that were smooth and spherical in shape with a particle size of approximately 5-9 pm were injected into the knee joints. A decrease in the arthritic to normal joints ratios was observed over time. The naproxen sodium nanoparticles were more efficacious than the free drug. 

D.S. Karabelas, Copper Metabolism in the Adjuvant Induced Arthritic Rat, (University Microfilms Limited, Ann Arbor, MI, 1972). 

On the other hand, rat adjuvant-induced arthritis is a model of chronic inflammation frequently reported in screening for anti-arthritic agents. Adult rats are the animals of choice because the disease does not occur in hamsters, mice or guinea pigs. The clinical and pathological changes in adjuvant disease are comparable to those of rheumatic arthritis [56]. 

Apart from the acute anti-inflammatory activity described in the preceding section, taraxasterol acetate was also tested for chronic activity in the model of Freund s adjuvant-induced rat arthritis. When 80 mg/kg of this compound were administered i.p., a 57% decrease with respect to the control value for the injected limb was observed at 18 h. After 21 days, the secondary reaction, which is measured on the non-injected limb, was reduced by 78%. Given the fact that in this condition the injected limb suffered a comparable reduction of 67%, it seems that taraxasterol acetate did not act by modifying immune mechanisms [64]. Duwiejua et al. [66] also reported appreciable anti-arthritic activity for glutin-3-one 44% and 74% reductions in the ipsilateral and contralateral paw swelling, respectively, after 10 days. 

Collagenase production and release are partly responsible for the joint destruction that characterises human rheumatoid arthritis. Triterpenes from the lupane and a-amyrin groups have been studied in vitro to examine their effects on the release of the arthritic joint degradative enzyme collagenase using the rat osteosarcoma. This test and the rat synovial granuloma of adjuvant arthritis are similar both models are based on connective tissue tumours with bone-invasive properties. The pentacyclic triterpenes assayed have been shown to possess general antiproteolytic effects that can explain the anti-arthritic effects in adjuvant arthritis in rats [71,103]. 

The search for new and effective treatment modalities requires the availability of adequate screening tests. Although no model adequately reflects the events that occur in human arthritic conditions, several in vivo and in vitro assays are used. The most common in vivo animal assays measure the ability of anti-inflammatory drugs to inhibit edema induced in the rat paw by carrageenan (a mucopolysaccharide derived from a sea moss of the Chondrus species), to inhibit adjuvant arthritis in rats induced by Mycobacterium butyricum or M. tuberculosis, to inhibit granuloma formation usually induced by the implantation of a cotton pellet beneath the abdominal skin of rats, or to inhibit erythema of guinea pig skin as a result of exposure to ultraviolet radiation. In vitro techniques include the ability of NSAIDs to stabilize erythrocyte membranes or, more commonly, to inhibit the biosynthesis of prostaglandins, particularly in cultured human synoviocytes and chondrocytes, and monocyte culture fluid stimulated bovine synoviocytes and chondrocytes. 

Mycoplasmal injections Into swine and mice produce syndromes which approximate the symptoms seen in arthritic patients. These models are based on the theory of microbial infection as a trigger mechanism. The non-pathogen Corynebacterium rubrum can induce adjuvant arthritis in rata. ... 

Figure 6. Comparison of GTase activities of peripheral and paired splenic lymphocytes and the effect of adjuvant treatment on enzyme activity, a) Peripheral lymphocytes The marked reduction in pooled P.GTase activity is only evident in the Coll induced arthritic and not the age-matched CFA treated group [p < 0.03). b) Splenic lymphocytes GTase activity is markedly lower in the splenic compared with the paired peripheral lymphocytes, and is unaffected by CFA treatment or Coll immunization.

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