الفهرس 
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Abstract
Summary
This experimental work aimed at evaluation of some of the possible hemorrhagic effects and blood coagulation disorders that may result from administration of large doses of commonly used antioxidants namely, d-α-tocopherol, retinol acetate and l-ascorbic acid.
This study was carried out in El-Minia University Hospital from 2002 – 2004. During the experimental period (7 days), all rats were examined daily and signs of hemorrhagic toxicity were recorded (Epistaxis, presence of blood in the cages, hemorrhages in the eyeballs, ……etc.).
This study was carried out on 120 albino rats divided into 4 groups. Each group consists of 30 rats as follows: Group I: Negative control group which was not subjected to treatment by any drug , Group II: d-α-tocopherol group which received d- α-tocopherol (vitamin E) in a daily dose of 24 mg/day which is equivalent to 1200 mg/day in human, Group III: retinol acetate group which received retinol acetate (vitamin A) in a daily dose of 1 mg/day which is equivalent to 60 mg/day in human, and Group IV: l-ascorbic acid group which animals received l-ascorbic acid (vitamin C) in a daily dose of 20 mg/day which is equivalent to 1000 mg/day in human .The drugs were given for 7 days orally by gavage after which the blood samples were withdrawn and the biochemical parameters were performed (PT-PTT-FactorX activity). After blood sampling, the liver, brain and kidneys were extracted carefully to undergo histopathological investigations.
The results of the current study revealed that there were hemorrhagic manifestaion such as epistaxis, presence of blood in the cages and conjunctival hemorrhage in the animal groups treated with a large dose of d-α-tocopherol (vitamin E) and retinol acetate (vitamin A). On the other hand l-ascorbic acid (vitamin C) administration in a large dose showed no hemorrhagic manifestation throughout the experimental study.
There were a very highly significant prolongation of prothrombin time and partial thromboplastin time in animals treated with a daily large dose of d-α-tocopherol for 7 days. In addition, PT and PTT indices were decreased in this group to about 29 and 30% respectively which is very highly significant. As regard activity of the blood coagulation factor X, there was a very highly significant reduction in factor X activity as shown by prolongation of the time needed for clotting.
Concerning retinol acetate (vitamin A) administration in a daily large dose for 7 days, has produced highly significant prolongation of PT and PTT as shown by the significant decrease in PT and PTT indices % to about 68 and 26% respectively. Also, a highly significant reduction in factor X activity as shown by prolongation of the time needed for clotting, was observed in this group.
As regard the administration of l-ascorbic acid (vitamin C) in a daily large dose for 7 days, has produced insignificant changes in PT, PTT and their indices % or factor X activity. It was apparent that there were unexpected shortening of PT and PTT and apparent increase of PT and PTT indices % to about 108 and 109% respectively in the treated group. In addition, there was minimal shortening of the time needed for clotting reflecting its effect on factor X activity.
Concerning the histopathological findings, the liver of rats which received d-α-tocopherol (group II) showed significant hemorrhage in most samples (27 samples) of various degrees (No affection: 3, mild hemorrhage: 5, moderate hemorrhage: 7, and severe hemorrhage:15). Also, liver of the animals treated with retinol acetate (vitamin A) (group III) showed significant hemorrhages in most samples (21 samples) of various degrees (No affection: 9, mild hemorrhage: 15, moderate hemorrhage: 5, and severe hemorrhage: 1 sample). But examination of the liver of rats of group IV (l-ascorbic acid group) revealed no hemorrhage in nearly all liver samples (28 samples), one sample showed mild hemorrhage and the other showed moderate hemorrhage.
The kidney of rats which received d-α-tocopherol (group II) showed significant hemorrhage in most samples (28 samples) of various degrees (No affection:2, mild hemorrhage: 6, moderate hemorrhage: 8, and severe hemorrhage:14). Also, kidney of the animals treated with retinol acetate (vitamin A) (group III) showed significant hemorrhages in most samples (22samples) of various degrees (No affection: 8, mild hemorrhage: 16, moderate hemorrhage:4, and severe hemorrhage: 2 samples). But examination of the kidney of rats of group IV (l-ascorbic acid group) revealed no hemorrhage in nearly all kidney samples (29samples), one sample showed mild hemorrhage.
As regard the brain of rats which received d-α-tocopherol (group II) showed significant hemorrhage in most samples (26 samples) of various degrees (No affection: 4, mild hemorrhage: 7, moderate hemorrhage: 8, and severe hemorrhage:11). Also, brain of the animals treated with retinol acetate (vitamin A) (group III) showed significant hemorrhages in most samples (19 samples) of various degrees (No affection: 11, mild hemorrhage:14, moderate hemorrhage: 5, and severe hemorrhage: no affection). But examination of the brain of rats of group IV (l-ascorbic acid group) revealed no hemorrhage in all samples (30 samples).
It is clear enough that the histopathological findings of the liver, kidney, and brain of each animal group were confirmatory to the reported biochemical coagulation disorders of the same group.
The results of this experimental work reported that administration of d-α-tocopherol (vitamin E) in large doses induces hemorrhagic toxicity and affects blood coagulation parameters namely, prolongs prothrombin time (PT) and partial thromboplastin time (PTT) as shown by the observed decrease in their indices %. In addition, d-α-tocopherol reduces the blood coagulation factor X activity as shown by prolongation of the time needed for clotting. α-tocopherol induces hemorrhage and increases tendency to bleed of liver, kidneys and brain of treated animals.
Also, retinol acetate (vitamin A) administration in large doses can induce hemorrhagic toxicity and affect blood coagulation parameters in the same manner as vitamin E (α-tocopherol) does.
Administration of l-ascorbic acid (vitamin C) in large doses in rats did not cause hemorrhages in internal organs nor affect blood coagulation parameters negatively but was in fact procoagulant as shown by the improvement observed in PT, PTT and factor X activity with large doses of vitamin C.