Repeated intravenius doses of all-trans-retinoyl B-D-glucuronide is not effectiv in the treatment of

Abstract

All-trans-retinoyl β-D-glucuronide, a water-soluble glucuronic acid conjugate of all-transretinoic<br><br>acid, has demonstrated high biological activity and low toxicity in most in vitro and in<br><br>vivo models. Since the reparative effects of retinoids on epithelium are well-known, our aim<br><br>was to study the effect(s) of intravenously-administered all-trans-retinoyl β-D-glucuronide in<br><br>lambs with chronic bacterial bronchopneumonia.<br><br>Material/Methods: Two groups of lambs were inoculated intrabronchially with either pyrogen-free saline or<br><br>Mannheimia haemolytica. Thirty-three days later, lambs were injected four times at five-day<br><br>intervals with 2 mL of 116 mM all-trans-retinoyl β-D-glucuronide (6.0–9.3 μmol/kg or<br><br>2.86–4.42 mg/kg animal body weight) in dimethyl sulfoxide, or dimethyl sulfoxide alone.<br><br>Animal behavior and signs of clinical illness were logged daily. Lung and liver samples were<br><br>assessed for histopathology, while serum and liver samples were extracted for retinoids and<br><br>analyzed by reversed-phase gradient high-performance liquid chromatography.<br><br>Results: Repeated injections of highly concentrated all-trans-retinoyl β-D-glucuronide did not cause<br><br>changes in appetite, activity or other behaviors nor did it cause histologic lesions in liver and<br><br>lung. However, it had no effect on resolution of lung lesions resultant of chronic Mannheimia<br><br>haemolytica bronchopneumonia.<br><br>Conclusion: Repeated intravenous administration of high amounts of all-trans-retinoyl β-D-glucuronide to<br><br>lambs did not elicit signs of gross or microscopic toxicity. However, administering all-transretinoyl<br><br>β-D-glucuronide too late in the progression of bacterial pneumonia is thought to be<br><br>the main reason for its lack of effect in this model. A retinoid lactone derivative was detected<br><br>in sheep serum and liver several days after treatment.