Valproic acid (VPA), its unsaturated metabolites and pent-4-enoate (4-PA) were studied for potential hepatotoxicity in rats. 4-PA, 4-en-VPA and 2,4-dien-VPA were potent inducers of microvesicular steatosis in young rats. Microvesicular steatosis induced by the 4-en-VPA was accompanied by ultrastructural changes characterized by myeloid bodies, lipid vacuoles and mitochondrial abnormalities. Myeloid bodies and lipid vacuoles were seen to a lesser extent in 2,4-dien-VPA and 4-PA-treated rats. VPA failed to induce discernible liver lesions in young rats even at near lethal doses of 700 mg per kg per day. The drug did, however, induce hepatic lipid accumulation in mature rats and in young rats dosed concomitantly with phenobarbital. beta-oxidation inhibition and several other biochemical alterations were observed in rats dosed with VPA, its unsaturated metabolites and 4-PA. It was suggested that beta-oxidation inhibition observed in both VPA and en-metabolite-treated rats occurred by different mechanisms. VPA inhibits by a transient sequestering of CoA while the CoA esters of some en-VPA-metabolites, particularly 4-en-VPA, inhibit specific enzyme(s) in the beta-oxidation sequences.

Abstract. The histologic and histochemical features of quinolone-induced arthropathy were studied using 14 skeletally immature Beagle dogs (3 to 4 months old) dosed orally with difloxacin at 300 mg/kg body weight once daily for 1, 2, 5 , or 7 days. A placebo was given to eight other age-matched Beagle dogs that served as controls. A scoring technique that included lesion size and histologic features was used to determine the progression of lesions. Articular-epiphyseal cartilage complexes on the femoral and humeral heads and tibia1 tarsal bone were identified as predilection sites. Within predilection sites on femoral and humeral heads, lesions developed in specific areas. Lesions appeared within 2 days of the onset of treatment, and lesion scores increased with time. Grossly, the lesions were raised, fluid-filled vesicles on the articular surface. Histologic changes included vesicle formation with loss of proteoglycan, clumping of unmasked collagen, and degeneration and necrosis of chondrocytes. In lesions with higher scores, chondrocytes were often in clusters or they were undergoing metaplasia toward spindle-shaped cells. Although dissolution of matrix and necrosis of chondrocytes were typical of all lesions, smaller lesions had histologically normal chondrocytes adjacent to small vesicles. In sections stained with toluidine blue, proteoglycan was aggregated with collagen fibrils or was absent from the matrix adjacent to vesicles. Unique features, such as biomechanical forces, may predispose specific areas of articular cartilage to develop lesions.Key words: Arthropathy; articular cartilage; difloxacin; dog; fluoroquinolone.Despite the potential value of quinolone antibacterial compounds in treating infections caused by bacteria resistant to other antibacterial agents, the use of quinolones is restricted because of their toxic effects on articular-epiphyseal cartilage complexes. The use of quinolones in children and pregnant women (ie., the fetuses that they carry) is contraindicated, seemingly because of a report of arthralgia induced by nalidixic acid, a quinolone, in a 22-year-old woman. ' Additionally, laboratory evidence for quinolones causing lesions in articular cartilages of immature animals has prompted the need for caution in the use of these drugs in human beings with immature skeletons. Various reports have described the lesions produced in the articular cartilages of skeletally immature dogs and rats and other skeletally immature laboratory ani m a l~.~,~-~,~~-~~.~~ In general, gross lesions were fluid-filled vesicles that projected above the contour of the articular surface. Microscopically, lesions consisted of fissures within the intermediate zone of the articular cartilage. Along fissure margins, chondrocytes were necrotic in early lesions but formed clusters in chronic lesions undergoing repair. The matrix adjacent to fissures was disrupted, and collagen fibrils were clumped.In addition to lesions in articular cartilages, pipemidic acid and oxolinic acid caused synovitis in immature dogs.7...

The effect of a single oral dose (800 mg) of zileuton (A-64077), a specific 5-lipoxygenase inhibitor, on the early and late airway responses to inhaled allergen was studied in a randomised, double blind, placebo controlled, and crossover trial in nine subjects with atopic asthma. Leukotriene generation was also assessed in vivo by measuring urinary leukotriene (LT) E4 excretion, and ex vivo by measuring calcium ionophore stimulated whole blood LTB4 production. Zileuton almost completely inhibited ex vivo LTB4 production but reduced urinary excretion of LTE4 by only about half. There was a trend for the early asthmatic response to be less on the day of zileuton treatment, but this did not reach statistical significance (p = 0 08). The zileuton induced reduction in maximum fall in FEVy in the early asthmatic response was, however, significantly related to the reduction in urinary LTE4 excretion (r = 0 8), but not to the reduction in LTB4 generation ex vivo. There was no significant change in the allergen induced late asthmatic response, or in the increase in airway responsiveness to methacholine following antigen. The results provide some support for the hypothesis that the cysteinyl leukotrienes have a role in the allergen induced early asthmatic response. More complete in vivo inhibition of 5-lipoxygenase may be needed to produce a significant reduction in airway response to allergen challenge.

No abstract

The metabolic routes of valproic acid (VPA) were studied by i.p. administration of the mono-unsaturated and hydroxylated metabolites to rats. Conjugation with glucuronic acid was a major metabolic route for VPA and its metabolites. Conjugation with glycine was a minor route for VPA, but was of more importance with the unsaturated metabolites. The hydroxylated metabolites, which were further oxidized to oxo-derivatives and subsequently to the dicarboxylic acids, were not metabolically dehydrated to form unsaturated metabolites. Multiple metabolic pathways, including dehydrogenation, isomerization, hydration, hydroxylation, reduction and epoxidation were inferred from the metabolites obtained after dosage of the unsaturated metabolites. Six dien-VPA metabolites were detected in VPA-treated rats, four of which are present in patients. It was concluded that 3-en-VPA and 4-en-VPA pathways, originating through dehydrogenation, are distinct from the omega- and omega-1-hydroxylation pathways. Enzyme induction from co-administration of phenobarbital caused enhancement of the minor omega-1-oxidation pathway, yet the largest effect on clearance came from increases in glucuronidation. Mitochondrial processes were unaffected, resulting in decreased contribution to the total clearance.