Repeated intravenous doses of all-trans-retinoyl beta-D-glucuronide is not effective in the treatment of bacterial bronchopneumonia in lambs but is devoid of gross and acute toxicity.
BACKGROUND
All-trans-retinoyl beta-D-glucuronide, a water-soluble glucuronic acid conjugate of all-trans-retinoic acid, has demonstrated high biological activity and low toxicity in most in vitro and in vivo models. Since the reparative effects of retinoids on epithelium are well-known, our aim was to study the effect(s) of intravenously-administered all-trans-retinoyl beta-D-glucuronide in lambs with chronic bacterial bronchopneumonia.


METHODS
Two groups of lambs were inoculated intrabronchially with either pyrogen-free saline or Mannheimia haemolytica. Thirty-three days later, lambs were injected four times at five-day intervals with 2 mL of 116 mM all-trans-retinoyl beta-D-glucuronide (6.0-9.3 mmol/kg or 2.86-4.42 mg/kg animal body weight) in dimethyl sulfoxide, or dimethyl sulfoxide alone. Animal behavior and signs of clinical illness were logged daily. Lung and liver samples were assessed for histopathology, while serum and liver samples were extracted for retinoids and analyzed by reversed-phase gradient high-performance liquid chromatography.


RESULTS
Repeated injections of highly concentrated all-trans-retinoyl beta-D-glucuronide did not cause changes in appetite, activity or other behaviors nor did it cause histologic lesions in liver and lung. However, it had no effect on resolution of lung lesions resultant of chronic Mannheimia haemolytica bronchopneumonia.


CONCLUSIONS
Repeated intravenous administration of high amounts of all-trans-retinoyl beta-D-glucuronide to lambs did not elicit signs of gross or microscopic toxicity. However, administering all-trans-retinoyl beta-D-glucuronide too late in the progression of bacterial pneumonia is thought to be the main reason for its lack of effect in this model. A retinoid lactone derivative was detected in sheep serum and liver several days after treatment.
Gallup
Jack M
JM
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames 50011-1250, USA. eag@iastate.edu
Grubor
Branka
B
Barua
Arun B
AB
Mohammadi
Gholamreza
G
Brogden
Kim A
KA
Olson
James A
JA
Ackermann
Mark R
MR
D000818:Animals; D001519:Behavior / Q000187:drug effects; D001769:Blood / Q000382:microbiology; D001980:Bronchi / Q000382:microbiology; D001996:Bronchopneumonia / Q000188:drug therapy* / Q000382:microbiology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007262:Infusions, Intravenous; D008099:Liver / Q000473:pathology; D008297:Male; D016978:Mannheimia haemolytica / Q000378:metabolism; D012176:Retinoids / Q000097:blood / Q000378:metabolism; D012756:Sheep; D014212:Tretinoin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity*
D012176:Retinoids; C026787:retinoyl glucuronide; D014212:Tretinoin