الفهرس 
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Abstract
Twenty–four apparently healthy male New Zeeland rabbits were divided into 4 equal groups (n= 6) namely group (A), (B), (C) and (D). Group (A) was served as a control. Group (B) rabbits were intubated with a daily oral dose of 25mg ciprofloxacin /Kg B.W. equivalent to single therapeutic dose. Groups (C) and (D) animals were intubated with 50 and 100 mg ciprofloxacin, respectively representing double and quadrable therapeutic doses of ciprofloxacin using insulin syringe after dissolving of the drug powder in water. Half of the animals in each group was sacrificed after 30 days and the remaining were sacrificed after 60 days from the beginning of the experiment.
Following necropsy, tissue specimens were collected from liver, kidneys, spleen, brain, heart, lungs and bone marrow. They were rapidly fixed in 10% neutral buffered formalin solution. Blood samples were collected during euthanization of animals in a clean, dry dipotassium EDTA containing vials for estimation of complete blood picture using the automatic cell counter. The estimated parameters were: RBCs count, PCV, Hb, MCV, MCH, MCHC, TLC, lymphocytic count, granulocytic count, monocytic count and blood platelets count. Similar blood samples were collected to estimate total proteins, albumin AST, ALT, alkaline phosphatase, bilirubin, glucose, triglycerides, total cholesterol, calcium, inorganic phosphorus, BUN, creatinine, sodium and potassium levels.
Clinically, no mortalities were recorded at any dose group except for 66.6% (2 out of 3 animals) deaths only in the highest dose group during the 58th day. Only, at 60 days post- treatment, the highest dose group animals exhibited mild anorexia toward the end of the experiment. Moreover, all treated group animals showed a significant decrease in feed consumption in a dose-dependant fashion, in addition to turbidity of the urine and fur loss. In addition, pale kidneys and mild renal cortical atrophy as well as grossly enhanced lobular pattern were evident only in the highest dose group sacrificed on 60 days. Furthermore, the collected blood from these animals coagulated rapidly. Regarding body weight only administration of ciprofloxacin for 60 days showed a significant decrease of the body weight in a dose dependant manner.
Hematological and biochemical findings:
All treated groups did not show a significant effect on RBCs count, PCV, Hb, MCV, MCH and MCHC as compared to control group. The quadrable dose group up to 60 days showed a significant increase in TLC lymphocytic, granulocytic count and platelets. Moreover, All treated groups showed a non significant change in monocytic count at any time point of ciprofloxacin administration. Only the quadrable sixty days dosed group showed a significant decrease in serum total proteins, serum albumin and serum globulins. The drug at any dose level during any experimental period dose not change serum total, indirect and direct bilirubin. The double and quadrable dose treated groups animals for 60 days showed a significant increase in alkaline phosphatase as compared to control group. Only, daily administration of ciprofloxacin to rabbits for 60 days induced a significant increase of both of urea ALT and AST enzymes activity (in a dose- dependant manner) and creatinine (no differences among treated groups). Also, only the double and quadrable sixty days dosed group showed a significant decrease in serum sodium and phosphorus and a significant increase in serum potassium levels as compared to control group. There was no significant change in serum calcium level of any treated group at any time point as compared to control group. The quadrable sixty days dosed group showed a significant increase in blood sugar level. There was no significant change in cholesterol level in any group at any time as compared to control group. However, there was a significant decrease in triglyceride level only in the quadrable sixty days dosed group.
Histopathological findings:
Lesions of the liver were in the form of mild periductal fibrosis of some bile ducts and congestion of the portal blood vessels. Also, lymphocytic infiltrates within the portal tracts besides multifocal hyDROPic degeneration of the hepatocytes, few minute necrotic foci and hyperactivation of Kupffer cells. brooding of the portal areas with obvious connective tissue proliferation with the formation of newly formed bile ducts.
Lesions of the kidneys were in the form of subacute multifocal interstitial nephritis characterized by interstitial lymphocytic infiltrates. Some medullary tubules showed cystic dilatation and their lining epithelial cells appeared flattened. Some tubules contained eosinophilic albuminous cast.
Lesions of the spleen were in the form of lymphoid cell necrosis and depletion in splenic corpuscles.
Lesions of the heart were in the form of congestion of the myocardial blood vessels associated with focal mild sarcoplasmic vacuolation.
Lesions of the brain were in the form of mild perivascular lymphocytic cuffs of very few blood vessels in the neo cortex. neuronal degeneration and pyknosis was evident accompanied by satellitosis
Lesions of the lungs were the presence of numerous alveolar macrophages were seen besides few fibrin threads inside some alveoli and the peribronchial lymphoid follicles appeared hypertrophied. Sixty days postintubation of ciprofloxacin
Lesions of the bone marrow were marked activation of all hemopiotic elements, particularly megakaryocytes and lymphoblasts.
Finally, it could concluded that:.
- The most of the encountered lesions were time - and dose -
dependant.
- The single therapeutic dose treatment induced relatively mild
lesions followed by the double; however, the severest lesions
were noticed in the quadruple dose treatment, particularly up
to 60 days.
- Liver and kidneys were plausible target organs in chronic
ciprofloxacin toxicity.
- Further studies are needed to know the reversibility of such
effect through withdrawal assay study and also the possible
prophylactic potential of antioxidants.