Rheumatoid models

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

The best-known examples of this approach have been the diabetes/obesity, asthma, and rheumatoid arthritis models created by the firm Entelos. These... 

In addition to the NOD mouse, Entelos has models for several human metabolic diseases (diabetes, obesity, and metabolic syndrome), inflammatory diseases (rheumatoid arthritis), and respiratory diseases (asthma and COPD). 

Figure 1.7 Typical zero-order and corresponding second-derivative electronic absorption spectra of ethanol-reconstituted lipid/chloroform extracts of autoxidized model polyunsaturated fatty-acid compounds and inflammatory synovial fluid obtained after (1) reduction with NaBH4 and (2) dehydration with alcoholic H2S04- (a) Methyl linoleate subsequent to autoxidation in air at ambient temperature for a period of 72 h (—), or exposure to a Fenton reaction system containing EDTA (5.75 x 10 mol/dm ), H2O2 (1.14 X 10 mol/dm ) and Fe(ll) (5.75 x IO mol/dm ) as an aqueous suspension (—) (b) as (a) but with methyl linolenate (c) untreated rheumatoid knee-joint synovial fluid.

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

Key Words Chemokines chemokine receptors rheumatoid arthritis murine models. 

Anthony DD, Haqqi TM. Collagen-induced arthritis in mice an animal model to study the pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 1999 17(2) 240-244. 

Brahn E. Animal models of rheumatoid arthritis. Clues to etiology and treatment. Clin Orthop 1991(265) 42-53. 

Holmdahl R, Lorentzen JC, Lu S, et al. Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis. Immunol Rev 2001 184 184-202. 

Weekes J et al. Bovine dilated cardiomyopathy proteomic analysis of an animal model of human dilated cardiomyopathy Electrophoresis 1999 20 898-906. Doherty NS et al. Analysis of changes in acute phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two-dimensional gel electrophoresis. Electrophoresis 1998 19 355-363. 

For some autoimmune diseases, little is known about environmental factors involved in the initiation or progression of the disease. For other diseases, however, considerable research has been conducted on one or more types of exposures. Most epidemiologic studies of environmental influences have focused on multiple sclerosis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, and small vessel vasculitis, but experimental studies using murine models of these diseases is limited (Table 25.1). 

A glucocorticoid-resistance model has been proposed to provide an explanation for how stress might influence diseases in which excessive inflammation is observed (e.g., allergies, autoimmune diseases, rheumatoid arthritis, and cardiovascular disease). In these cases, chronic stress diminishes the immune system s sensitivity to glucocorticoids that normally terminate the inflammatory response. For example, in a study of a group of 50 parents caring for a child undergoing treatment for pediatric cancer, whole blood of parents of cancer patients exhibited a lesser dexamethasone-dependent suppression of IL-6 production in vitro compared to parents of medically healthy children.94... 

One of the first compounds reported to inhibit 5-LO was the NSAID benox-aprofen (167) (reviewed in [405]). This drug (marketed by Lilly as Oraflex ) was effective in rheumatoid arthritis, but was withdrawn because of phototoxicity, liver toxicity and reports of drug-related deaths [406]. The typical NSAID anti-inflammatory profile of this compound was remarkable for its very weak seminal vesicle CO activity [407]. Additional in vivo activities were found for benoxaprofen which were not shared by other NSAIDs, particularly inhibition of leukocyte influx in the carrageenan sponge, carrageenan pleurisy, and rat Arthus pleurisy models monocytes were affected more than neutrophils [408-411]. More recently, benoxaprofen was reported to inhibit the adhesion of monocytes to endothelium [412]. 

The idea of reduced adrenal capacity as a possible model for PTSD has also been recently raised by Heim et ah, who concluded that low cortisol may not be a unique feature of PTSD, but may represent a more universal phenomenon related to bodily disorders, having an etiology related to chronic stress (Heim et al. 2000). There are numerous stress-related disorders such as chronic fatigue syndrome, fibromyalgia, rheumatoid arthritis, chronic pain syndromes, and other disorders that are characterized by hypocortisolism. In one study, Heim et al. showed decreased cortisol responses to low-dose DEX, but failed to observe blunted ACTH responses to CRF in women with chronic pelvic pain, some of whom had PTSD, compared to women with infertility (Heim et al. 1998). Since the data were not analyzed on the basis of the subgroup with and without trauma and/or PTSD, it is not possible to directly compare results of that study to other reports examining PTSD directly. 

In previous decades, a pyramid model dominated the treatment of rheumatoid arthritis. Early in the course of the disease, sahcylates were used to control pain and stiffness. If sahcylates were poorly tolerated or began to lose efficacy, they were discontinued and a different NSAID was used. As the efficacy of NSAID therapy waned and joint deterioration progressed, treatment with a DMARD was added. DMARDs were employed... 

---