الفهرس 
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Abstract
The present study was carried out to elucidate the neonatal teratogenicity effects and the histopathological changes of diclofenac in pregnant rats during the pre-implantation stage and the organogenesis period by using two different doses, the first dose was therapeutic dose (6.75 mg/kg b.wt.) and the second dose was the double-therapeutic dose ( 13.50 mg/kg b.wt.).Experiments were carried out on five groups; each group consisted of ten pregnant rats. The first group was served as control and receiving normal saline orally by oro-gastric tube, the second and third groups were given diclofenac potassium orally once daily at a dose of 6.75 mg/kg b.wt. and 13.50 mg/kg b.wt. respectively during the period of pre-implantation (from 1st to 4th day of pregnancy) while the fourth and fifth groups were given diclofenac potassium orally once daily at a dose of 6.75 mg/kg b.wt. and 13.50 mg/kg b.wt. respectively during the period of organogenesis (from 6th to 15th day of pregnancy). On the 20th day of pregnancy, the animals were sacrificed for morphological examinations of uteri and feti. The number and position of the implantations, early or late resorptions, live and dead feti, were counted. The two-third of the obtained feti was randomly selected for visceral examination while the remained one- third of the available feti was used in the skeletal examination. Also collection specimens from different organs of treated pregnant rats in the whole groups for histopathological examination. During both the pre-implantation period and the organogenesis period of pregnancy, diclofenac potassium induced marked decrease in the number of viable feti per rat at a dose of 6.75 mg/kg b.wt. But at a dose of 13.50 mg/kg b.wt., it was noticed that highly significant decrease in the number of viable feti per female rat. The resorption rates were significantly higher in the double therapeutic dose than the therapeutic dose. There were incomplete dead feti obtained from a group of pregnant female rat administered diclofenac potassium at a dose of 6.75 mg/kg b.wt. of the pre-implantation period of pregnancy. During administration the therapeutic dose of diclofenac potassium to pregnant female rats, it was noticed that decreased in the fetal body length and weight in compare to those of the feti of control group but there were highly significance decreased in the length and body weight of feti of pregnant female rats administered the double therapeutic dose of diclofenac potassium. The obtained fetal abnormalities as decrease in number of feti per mother might be attributed to direct effect of the drug on early developed fertilized ovum or to the lack of oval production or of the basic cell constituent by the mother as the drug easily pass through the placenta because it had low molecular weight. The decreased in number of viable feti per mother might be attributed to incomplete formation of placenta with degeneration of trophoblast and decidual cell which played an important role in the transmission of nutrients to the embryo. The increase in the number of resorbed feti might be attributed to the interference with placental transmission of essential elements as magnesium and leucin produced high incidence of fetal resorption or discontinuation production of placental progesterone or due to the pathological changes appeared in placenta and uterus by toxic effect of drug. Diclofenac potassium at both therapeutic and double therapeutic doses revealed visceral abnormalities in the feti during the pre-implantation period and the organogenesis period as diverticulum dilatation of the brain in 50 %, 57.1% and 46.8%, 50%. Thymus atrophy or thymus hypoplasia in 59%, 71.4% and 53.1%, 62.5%. Cardiac enlargement in 77.2%, 85.7% and 62.5%, 68.75%. Pulmonary hypoplasia in 63.6% ,71.4% and 56. 25%, 62.5%. Hepatomegaly in 54.5%, 57.1% and 59.3%, 68.75%. kidney enlargement in 31.8 %, 42.8% and 37.5%, 43.75% respectively were observed while suprarenal glands were normal at both doses 6.75 and 13.50 mg/kg b.wt. of examined feti. Abnormal morphogenesis of lung, heart and kidney induced by tested drugs might be attributed to block of cardiac potassium channel, effect of drug in cell proliferation, also the drug mainly excreted by kidney as it reached to urine in high concentration with its poor water solubility at acidic pH had a result in formation of crystals in the urinary tract. These crystals were thought to be responsible for observed renal lesion. Disturbance in metabolism and interference of the tested drugs to the placental transmission of some mineral as magnesium, zinc, potassium and ionized calcium with imbalance of intestinal flora of dams received that drug is the main causes of retardation in fetal growth. Inhibition of cell differentiation of mide brain of rat embryo with combination of gamma aminobutyric acid caused brain abnormalities as diverticulum dilatation. Skeletal examinations revealed impaired ossification of skull in 33.3%, 75% and 27.7%, 36.3%. Absence of sternbrae or reduction of size of sternebrae’s bones in 50%, 50% and 33.3%, 45.5%. Absence of metacarpal bones in 58.3%, 75% and 16.6%, 63.6%. Absence of metatarsal bones in 41.6%, 50% and 50%, 36.3%. Also absence of digit’s bones of fore and hind limb in 66.6%, 75% and 50%, 63.6%. Absence of coccygeal vertebrae in 66.6%, 75% and 66.6%, 72.7% of examined feti respectively while ribs were normal in number and shape at both doses 6.75 and 13.50 mg/kg b.wt. during the period of pre-implantation and organogenesis.