الفهرس 
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Abstract
Cyclosporine was the strongest immunosupressor to be discovered so far, it is also overcome many of the risk factor associated with Azathioprine and is relatively non-toxic to bone marrow. With the introduction of cyclosporine patient morbidity fell, it become possible to transplant organ with a one year success of 20% higher than previously which had only be done in experimentation.
This study madeto investigate the gross and histologic lesions associated with the oral administration of CsA at different doses in male albino rats with special focus on the role of apoptosis in CsAtoxicosis.
The present study was carried out 3 months old male albino rats of 100gm body weight. They were housed in four metal cages (10 rats each) .
Expermintaldesign :The pilot test was carried out on seven adult male albino rats. The main experiment was carried out on thirty, 3-month-old male albino rats of 100-120 gm body weight.
Cyclosporine A (trade name is Sandimmune®) oral solution 100 mg / ml was purchased from a local pharmacy. The drug is registered and manufactured by Novartis pharma. Olive oil was purchased from a local pharmacy.
The thirty used rats were randomly divided into three equal groups (10 rats of each) as follow :
Group 1: Rats were intubated with Cyclosporine A (CsA) using stomach tube at a dose of 50mg/kg B.wt. (double therapeutic dose) in olive oil (1:3 V/V) two consecutive days and escape one day for 21 days.
Group I2: In this group rats were intubated with Cyclosporine A using stomach tube at a dose of 75mg/kg B.wt. (triple therapeutic dose) in olive oil (1:3 V/V) two consecutive days and escape one day for 21 days.
Group 3: This group served as control in which rats receive only olive oil two consecutive days and escape one day for 21 days.
The body weight and clinical signs including mortalities were recorded throughout the experimental period.
Postmortem examination and histopathological studies
Half numbers of rats were euthanized after 10 days of the beginning of experiment by cervical dislocation . Dead rats were necropsied immediately and examined grossly. Remaining rats were euthanized at day 21 of the experiment. The postmortem examination was performed immediately to the euthanized as well as dead rats.
Specimens from liver, kidney, spleen, brain, spleen, bone marrow, testes, lung, femur, skull, and heart were rapidly fixed in 10% neutral buffered formalin for at least 24hrs then processed through the conventional paraffin embedding technique (dehydration through ascending grades of ethanol, clearing in xylene and embedding in paraffin wax at 60c).
Blood and Serum biochemical analysis :
Blood was collected from anaseathetic rats before euthanisia from the medial canthus of the eye after 10 and 21 days of experiment for monitoring ofserum urea, creatinine, Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT).
This study concluded that:
1- The most characteristic signs of the rats intoxicated with cyclosporine were: loss of appetite, weight loss, ruffled hair, and mild diarrhea. Rats of gp.2 experienced anorexia, lethargy, and mild diarrhea and increasing mortalities in treated groups. Inactivity with incoordination,
reluctance to move, and paleness of the conjunctival mucosa were particular observations directly before death.
2-The Cyclosporine causes decreasing of the body weight of treated rats.
3-The postmortem lesions can be summarized in Mild to moderate congestion was observed in parenchymatous organs, serosal membranes and cerebral blood vessels. Dead rats had mild hemothorax and enlarged diffusely congested spleen. Other than mild congestion of serosal covering membranes, no significant lesions were present in the heart, brain, intestines, stomach, and spleen allover the experiment. The livers of the euthanized rats at day 10 and 21 were diffusely pale, smaller in size, and had few multifocal pale necrotic areas that appeared slightly depressed from the liver surface. The hepatic lesions in dead rats were similar to those described in the euthanized ones. No significant lesions were present in the kidneys of euthanized rats. However, the kidneys of dead rats showed mild congestion with occasional mild renal cortical atrophy.
4. Histopathologic examination showed that:-
-In general, the pattern of lesions recorded in the dead animals was similar to those recorded in the euthanized animals but the lesions were more severe in the dead animals.
-The liver showed severe diffuse hepatocellular swelling with marked periacinar to midzonal hepatocellular coagulative necrosis characterized the examined sections from the dead and euthanized rats.
-The Kidneys showed prominent histopathologic findings included degeneration and necrosis of proximal tubular epithelium affecting 10-20% of available proximal convoluted tubules, sloughing of necrotic tubular epithelial cells.
-The spleen of dead rats had moderate to severe congestion of the medullatry and subcapsular sinuses with mild lymphoid follicular depletion.
-Heart showed significant lesions that, were present only in dead rats, wherein, the epicardium was mildly infiltrated with macrophages and fibroblasts.
-In testes there is a testicular lesions in the form of general mild and appeared in few rats in form of presence of few spermatogenic cells in the epididymal tubular lumen with accumulation of eosinophilic transudate inside the lumens of some seminiferous tubules.
-The brain, bone, bone marrow and lungs, appeared nearly within histological limits except for lungs which occasionally suffered mild degree of bronchopneumonia.
II-Biochemical analysis:-
The results of biochemical analysis showed that, the cyclosporine couses increasing the level of ALT, AST, urea and creatinine.