Non-Steroidal Anti-Inflammatory Drugs in the Therapy of Canine Osteoarthritis

Pearson, Timothy David (1989) Non-Steroidal Anti-Inflammatory Drugs in the Therapy of Canine Osteoarthritis. MVM(R) thesis, University of Glasgow.

Abstract

This thesis is in two parts. In the first three chapters the pathogenesis of osteoarthritis is discussed with particular reference to the mediators and enzymes involved. Current knowledge of medical treatment with analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying drugs is presented. Chapters 4 and 5 detail experimental work on the NSAID carprofen and the steroid-NSAID combination PLT Tablets. Canine osteoarthritis usually occurs secondary to primary joint incongruity or instabilty but it may occur as a primary entity in older animals. Over the last two decades some of the ultrastructural pathogenic mechanisms of osteoarthritis have become clearer. Whatever the initiating cause of articular cartilage degeneration, there appear to be common mediator and enzyme pathways which induce biochemical and gross changes in articular cartilage and synovium. The chondrocyte reacts to alterations in pressure and forces within articular cartilage. The synovium liberates a number of mediators which affect chondrocyte metabolism. Free proteoglycan fragments in the synovial fluid induce synovial production of the cytokine interleukin-1. An increasingly important role is being ascribed to interleukins, and a number of other cytokines, growth factors and chondrocyte stress proteins may also be involved. There is evidence of humoral immune response to 'hidden' autoantigen in articular cartilage which is liberated as the cartilage is damaged. The degradation of the matrix appears to be due to enzymatic destruction of proteoglycan by neutral metalloproteinases which are produced in increased quantities by chondrocytes in osteoarthritic cartilage. A reduction in specific tissue inhibitors of metalloproteinases (TIMP) may make available increased amounts of free active metalloproteinases. Proteoglycan loss exposes the collagen network to enzymatic damage and also reduces the elasticity and residence of articular cartilage such that mechanical damage of collagen is possible. Loss of matrix may reduce the barrier to mediators in the synovial fluid. The net result is cartilage fibrillation and erosion. The treatment of osteoarthritis involves the avoidance or elimination of factors which promote joint damage such as joint instability, obesity, or inappropriate exercise. Analgesics are used to control the symptoms of pain and stiffness. The opiates are not recommended for long term use because of their central depressent effects. NSAIDs, which have analgesic and anti-inflammatory activity, have demonstrated better efficacy in osteoarthritis than pure analgesics such as paracetamol. The activity of NSAIDs is primarily due to the inhibition of the synthesis of prostanoids, some of which are beleived to mediate or modulate synovial inflammation and pain. The inhibition of prostaglandin synthesis by NSAIDs can be potentially damaging since it is responsible for toxic effects, particularly in gastrointestinal and renal tissue. The NSAIDs have different pharmacokinetics in different species and dose rates cannot be extrapolated between species. A number of drugs have been used in the dog. Some of the drugs used in man are much more toxic in dogs and should not be used. The drugs presently available are discussed in Chapter 3. A clinical trial on the efficacy of carprofen in the therapy of osteoarthritis in dogs was carried out with the cooperation of practicing veterinarians. Although a blinded cross-over trial with radiological corroboration of the clinical diagnosis would have been the prefered experimental method, it was not considered practical since no funds were available for the remuneration of participating veterinarians. Instead, it was only possible to perform an unblinded trial using two groups of limited comparability, and using phenylbutazone treated dogs as positive controls. The experimental evidence suggested that carprofen was at least as efficacious as phenylbutazone in the therapy of osteoarthritis and may be a useful drug in the chronic therapy of osteoarthritis at 2-4 mg/kg/day as a single dose or divided into two doses. PLT Tablets are a development of Predno-Leucotropin Tablets which have been used in the therapy of musculoskeletal disorders for 22 years. PLT Tablets contain the NSAID cinchophen and a low dose of the steroid prednisolone but, unlike Predno-Leucotropin Tablets, they do not contain hexamine. The combination may have synergistic activity since the two drugs have anti-inflammatory activity at different levels of the arachidonic acid conversion pathway. The prednisolone dose rate is similar to that demonstrated to have chondroprotective properties in early experimental osteoarthritis. A clinical trial on the efficacy of PLT Tablets was carried out since there are no reports in the veterinary literature on the efficacy of cinchophen, or of cinchophen and prednisolone in combination. Trial design resembled that for the carprofen clinical efficacy trial and had the same drawbacks. PLT Tablets appeared to be at least as efficacious as phenylbutazone in the therapy of osteoarthritis in the dog and were efficacious at dose rates below the manufacturers recommendations.

• Item Type: Thesis (MVM(R))
• Qualification Level: Masters
• Keywords: Veterinary science
• Date of Award: 1989
• Depositing User: Enlighten Team
• Unique ID: glathesis:1989-77997
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2020 15:44
• Last Modified: 30 Jan 2020 15:44
• URI: https://theses.gla.ac.uk/id/eprint/77997