الفهرس 
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Abstract
Veterinary chemotherapeutic agents are widely used in animals
for prevention and treatment of infectious diseases and for growth
promotion. However, inappropriate use and abuse of these drugs may
bring about environmental pollution, drug resistance and even acute or
chronic toxic or allergic reactions by eating the editable tissues of poultry
or livestock. There are many concerns about safety of food contaminated
with antibacterial residues. Veterinary drug residues in aquatic products,
meats and milk products etc. are much more prevalent and risky
especially in developing countries. Chloramphenicol is a potent and
broad-spectrum antibiotics used in veterinary practice, including
treatment of aquaculture species and livestock husbandry.
Chloramphenicol is used extensively in nonindustrialized countries
for life-threatening infections because it is cheap and effective despite its
known haemotoxicity and linkage to fatal aplastic anemia in humans;
thus the need to design this experiment to explore the variable doseresponse
effect of chloramphenicol administration on several parameters
in either prophylactic or therapeutic dose for long term about 12 weeks on
hematological indices, liver and kidney enzymatic activities and
histopathological analysis.
Experimental Design
Total of 240 Male Albino Rats were divided into four groups, 60 each.
Prophylactic Group:
Chloramphenicol was administered in a dose of 25 mg/kg body weight
(half of therapeutic dose) for three months (12 weeks) dosing period.
English Summary 97
Control Group for the prophylactic dose: Rats in this group were given
distilled water in a volume of 10 ml per Kg body weight parallel to the
previous group.
Therapeutic Group: Chloramphenicol was administered in a dose of 50
mg/kg body weight (therapeutic dose) according to Chaplin, (1986), for
three months (12 weeks) dosing period.
Control Group for the therapeutic dose: Rats in this group were given
distilled water in a volume of 10 ml per Kg body weight parallel to the
previous group.
Drug administration
Solutions of chloramphenicol succinate diluted in distilled water, was
administered to rat by gavage at a constant dose volume of 10 ml/kg body
weight.
Collection of Samples
In all experimental groups, the rats were scarified under anesthesia after
2, 4, 6, 8, 10 and 12 weeks post dosing. Samples of blood with and
without anticoagulant were obtained for hematological and biochemical
determinations. Samples of liver and kidney were excised for
histopathological investigations.
Adopted Method
1-Heamatological picture
a) Red blood cell count b) Haemoglobin estimation
c) Packed cell volume, Mean corpuscular volume, and Mean corpuscular
haemoglobin concentration
d) White blood cells count e) Differential leucocytic counts
II-Biochemical parameters
Determination of AST, Gamma-GT, Alkaline phosphatase, Creatinine,
Uric Acid and LDH concentration.
III – Histopathology
Samples from Liver and Kidney were obtained from all experimental
groups and fixed in 10 % neutral buffered formalin or 5 % cold
glutradehyde for different histopathological procedures (Bancroft and
Stevens, 1982).
RBCs count, hemoglobin content (Hb) and packed cell volume
percentage (PCV) were significantly reduced at 10th and 12th week of
exposure in rats exposed to the prophylactic dose. As well as the results
of therapeutic dose of Chloramphenicol administration on these
parameters showed the same effect of reduction but the reduction
appeared earlier than the prophylactic dose at 8th week of post dosing.
The white blood cell count, lymphocytes, neutrophils, esinophils and
monocytes percentage were significantly reduced at 8th week post dosing
in prophylactic dose of Chloramphenicol - treated rat. In therapeutic
dose- treated rat, the total WBCs count showed a significant decrease at
8th week of exposure while individual leucocytes showed a significant
decrease at 6th week of post dosing at this group. The hematoxicity
induced by chloramphenicol may be attributed to inhibition of
mitochondrial ferrochelatase activity marrow cells, with a block in haem
synthesis and a depression of erythropoiesis. There was some evidence
for a possible effect by Chloramphenicols on haem synthesis. The
mechanism of these effects is related to the inhibition of protein synthesis
in mitochondria of bone marrow cells. The obtained results of liver
enzymatic activities including AP and -GT concentrations in serum
revealed a significant increase in their activities in both prophylactic and
therapeutic dose of chloramphinicol treated- rats compared to control.
The increased levels of these enzymes in the serum were resulted mostly
from the escape of these enzymes from injured liver cells or from the
damage of billiary epithelium or from bile duct obstruction. Further
findings in the study according to histopathology carried out indicated
that there were degenerative changes of hepatic parenchymal cells. This is
well corroborated by significant increase in serum activity in the animals
administered with chloramphenicol. The hepatotoxic effect of
chloramphenicol is attributed to inhibition of hepatic cytochrome P450;
the examined results of both Uric acid and creatinine levels in serum
showed a significant increase than the control in both prophylactic and
therapeutic dose of chloramphinicol treated- rats. This increase could be
attributed to renal damage, decrease in glomeruli infiltration. This
explanation was supported with the histopathological findings of kidney
tissues that showed degenerative and necrotic changes in the renal tubules
in acute hypercelluarity of glomerular tuft, congestion and atrophy of
renal tubules in long-term toxicity. Serum LDH concentrations showed a
significant increase after 4th week of exposure in prophylactic –treated
group and after 2nd week of exposure in therapeutic-treated group until
the end of experiment at 12th week. High rate of tissue turnover with
destroyed cells leading to an elevated LDH concentration in serum.
Therefore, increase the level of this enzyme in this study may be
attributed to cytotoxic effect induced by Chloramphenicol on multiple
cellular compartments including hemolysis of red blood cells or hepatic
tissue breakdown.
Histopathological studies in this research revealed observed
degenerative changes in the liver of rats. These lesions varied greatly in
its severity and distribution according to the duration of exposure and the
dose of Chloramphenicol. HyDROPic degeneration with hypertrophy of the
kupffer cells associated with the rough endoplasmic reticulum lost its
ribosomes, the mitochondria appeared slightly swollen, the bile canaliculi
dilated and some areas of necrosis was the most common
histopathological change. Dilatation of the bile canaliculi, swelling in
hepatic cells, and congestion of the hepatic vasculature, accumulation of
fat globules and presence of bundles of collagen fibers in between the
hepatic cells and in the Disse space represented chronic reaction to
Chloramphenicol toxicity or side effect. Such reaction could be
considered as secondary for hepatocellular degeneration and necrosis.
Histopathological investigation of the kidneys revealed detectable
lesions varied greatly in its severity and distribution according to the
length of the period of exposure and the dose of Chloramphenicol. A
prominent variable sized and shape of mesangial cells of the glomeruli
could be observed. Numerous variable sized and shaped electron dense
inclusions seems to be fragments of red blood cells engulfed by tubular
epithelium. In late stages changes were represented by necrosis of the
renal tubular epithelium with casts in its lumen, hypercelluarity of the
glomerular tuft with increase thickness of glomeruli matrix.
The obtained difference in our results between the prophylactic and
therapeutic dose of Chloramphenicol treated groups was time of
appearance of these changes. Toxic changes appeared earlier in
therapeutic dose treated rats than in prophylactic one.
Conclusion
It could be concluded that, the variable administered dose of
Chloramphenicol may play a significant role in its toxicity. This data
provoke that Chloramphenicol induced toxic effect in a manner of dose
and time related.