Clinical efficacy of recombinant canine interferon-gamma therapy in dogs with cutaneous epitheliotropic T-cell lymphoma.

BACKGROUND: The antitumour effects of interferon-gamma (IFN-γ) in humans with cutaneous epitheliotropic T-cell lymphoma (CETCL) have been described; however, the efficacy of IFN-γ in dogs has not been investigated. HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate the efficacy of recombinant canine IFN-γ (rCaIFN-γ) therapy in dogs with CETCL. ANIMALS: Twenty dogs with CETCL recruited from seven veterinary clinics were enrolled in the study. MATERIALS AND METHODS: Fifteen dogs were treated with rCaIFN-γ, and five control dogs were treated with prednisolone. We evaluated survival time, skin lesions (erythema, nodules, ulcers and bleeding), pruritus and general condition (sleep, appetite and body weight). In the rCaIFN-γ group, a questionnaire regarding the therapy was administered to owners after the dogs died. RESULTS: No significant differences existed in the median survival time between the rCaIFN-γ and control groups (log-rank test: p = 0.2761, Wilcoxon's rank sum test: p = 0.4444). However, there were significant differences in ulcer, bleeding, pruritus, sleep, appetite and body weight between the groups (Wilcoxon-Mann-Whitney U-test: p = 0.0023, p = 0.0058, p = 0.0005, p = 0.0191, p = 0.0306 and p = 0.0306, respectively). Two (40%) of five dogs were euthanised in the control group, compared with none in the rCaIFN-γ group. Fourteen questionnaires were collected, and owners reported that they were satisfied with the rCaIFN-γ treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Although the median survival time was not prolonged, rCaIFN-γ could be helpful in maintaining good quality of life for dogs with CETCL.

Cytochrome P450 CYP307A1/Spook: a regulator for ecdysone synthesis in insects.

The prothoracic gland (PG) has essential roles in synthesizing and secreting a steroid hormone called ecdysone that is critical for molting and metamorphosis of insects. However, little is known about the genes controlling ecdysteroidogenesis in the PG. To identify genes functioning in the PG of the silkworm, Bombyx mori, we used differential display PCR and focused on a cytochrome P450 gene designated Cyp307a1. Its expression level positively correlates with a change in the hemolymph ecdysteroid titer. In addition, Drosophila Cyp307a1 is encoded in the spook locus, one of the Halloween mutant family members showing a low ecdysone titer in vivo, suggesting that Cyp307a1 is involved in ecdysone synthesis. While Drosophila Cyp307a1 is expressed in the early embryos and adult ovaries, the expression is not observed in the PGs of embryos or third instar larvae. These results suggest a difference in the ecdysone synthesis pathways during larval development in these insects.

Effects of angiotensin-II receptor blocker candesartan cilexetil in rats with dilated cardiomyopathy.

We examined effects of an angiotensin-II receptor blockers, candesartan cilexetil, in rats with dilated cardiomyopathy after autoimmune myocarditis. Candesartan cilexetil showed angiotensin-II blocking action in a dose-dependent manner in rats with dilated cardiomyopathy. Twenty-eight days after immunization, surviving Lewis rats were divided into four groups and given candesartan cilexetil at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg per day (Group-C0.05, n = 15, Group-C0.5, n = 15 and Group-C5, n = 15, respectively) or vehicle alone (Group-V, n = 15). After oral administration for 1 month, the left ventricular end-diastolic pressure and heart weight/body weight ratio were lower in Group-C0.05 (13.3+/-1.1 mmHg and 3.7+/-0.2 g/kg, respectively), in Group-C0.5 (8.0+/-0.9 mmHg and 3.3+/-0.1 g/kg, respectively) and in Group-C5 (5.5+/-1 mmHg and 3.1+/-0.1 g/kg, respectively) than in Group-V (13.5+/-1.0 mmHg and 3.8+/-0.2 g/kg, respectively). The area of myocardial fibrosis was also lower in Group-C0.05 (25+/-3%), in Group-C0.5 (20+/-3%), and in Group-C5 (12+/-1%) than in Group-V (32+/-4%). Furthermore, expressions of transforming growth factor-beta1 and collagen-III mRNA were suppressed in Group-C0.05 (349+/-23% and 395+/-22%, respectively), Group-C0.5 (292+/-81% and 364+/-42%, respectively) and in Group-C5 (204+/-63% and 259+/-33%, respectively) compared with those in Group-V (367+/-26% and 437+/-18%, respectively). These results suggest that candesartan cilexetil can improve the function of inefficient heart.

Contribution of sympathetic nervous system activity during administration of carvedilol in rats with dilated cardiomyopathy.

We investigated the contribution of the sympathetic nervous system (SNS) in maintaining blood pressure during administration of carvedilol in rats with dilated cardiomyopathy, and examined whether SNS hyperactivity induced by high-dose carvedilol is related to severity of heart failure. The hypotensive effect of carvedilol in rats with heart failure (Group F) was not significantly different to that in rats without (Group N). However, enhancement of the plasma norepinephrine concentration during carvedilol administration in Group F was higher than in Group N. The constitutive plasma NE concentration in Group F (562 +/- 146 pg/ml) was significantly higher than in Group N (203 +/- 55 pg/ml) and there was a significant positive correlation between the heart weight to body weight ratio and the plasma norepinephrine concentration. Values for the maximal effect of the norepinephrine hypertensive effect during norepinephrine intravenous infusion (Emax) decreased, and plasma norepinephrine concentrations at half-maximal effect of the norepinephrine hypertensive effect (EC50) increased in Group F compared with Group N (20.8 +/- 6.1 and 28.6 +/- 2.2 mmHg, and 4.5 +/- 1.9 and 1.5 +/- 0.2 ng/ml, respectively). These results suggested that the number of receptors (Emax) and sensitivity (EC50) to the norepinephrine hypertensive effect decreased in Group F. Changes in these parameters in Group F corresponded with the results of a beta-adrenergic receptor binding assay using I-125 iodocyanopindolol (Bmax = 32 +/- 4 in Group F and 53 +/- 2 fmol/mg protein in Group N). These results showed that the SNS (presynaptic) activity increased and the SNS receptor sensitivity in the blood pressure regulation system decreased in heart failure. Therefore, high-dose carvedilol treatment should be used with caution to avoid worsening heart failure.

Comparative effects of perindopril with enalapril in rats with dilated cardiomyopathy.

Angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type-1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type-1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin-converting enzyme inhibitors improved ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and area of myocardial fibrosis were lower, and +/- dP/dt was higher in Group P2 (4.9 +/- 0.6 mmHg, 7.5 +/- 1.4% and +2651 +/- 254/-2622 +/- 189 mmHg/s, respectively) than in Group V (16.7 +/- 1.3, 36 +/- 2.6 and +2659 +/- 176/-2516 +/- 205, respectively) and Group E20 (7.5 +/- 2.5, 15.6 +/- 2.0 and +2018 +/- 110/-2097 +/- 102, respectively). Although the expression levels of transforming growth factor-beta1 and collagen-III mRNA in Group V (36.3 +/- 5.7 and 157.6 +/- 12.7%) were significantly higher than those in Group N (19.6 +/- 3.0 and 65.2 +/- 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 +/- 5.9 and 75.2 +/- 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type-1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin-angiotensin system in heart failure.