Coumarin and 7-Hydroxycoumarin Treatment of Canine Obstructive Lymphoedema

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Abstract
Canine obstructive lymphoedema was created in one hind leg of 30 dogs by irradiation of the groin and surgical removal of survivng lymph glands and lymphatics. The opposite leg served as a control. Once the oedema had stabilized, groups of 10 dogs were treated orally with 12.5 mg day-1 kg-1 for 8 months with either one of the benzopyrones coumarin (2H-1-benzopyran-2-one) and 7-hydroxycoumarin ()7-hydroxy-2H-1-benzo-pyran-2-one), or placebo. The two benzopyrones significantly (P < 0.01) but gradually reduced the oedema by 20-30% over 8 months, as judged by circumferential measurements of the oedematous and control limbs. There was no change with the placebo. In the oedematous fluids (lymph and interstitial fluid), benzopyrone treatment reduced the protein content and increased acid and neutral proteinase activity compared with the control limbs, while the levels of the proteinase with .alpha.2-macroglobulin remained unchanged. Furthermore, these active dogs reduced the excess water content, thickness and hydroxyproline content of skin biopsies from oedematous limbs compared with those from control limbs. No changes were observed for the placebo group. These biochemical changes suggest that benzopyrones can reduce the excess proteinaceous fluid in lymphoedema by increasing the levels of proteinase activity relative to the nunber of proteinase inhibitors. As a secondary even the amount of fibrosis in the skin is also reduced, presumably by an increase in collagenase activity from the mononuclear phagocytes. These results support the hypothesis that benzopyrones activate the production of proteinases by mononuclear phagocytes. The resultant small peptides can drain locally into the bloodstream, thus bypassing the blocked lymphatics and reducing the protein concentration and its associated oedema fluid.