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Abstract
6. SUMMARY
The present study was carried out to elucidate the teratogenic effect, histopathological changes, blood level and tissue residues of some antibacterials in pregnant rats during organogenesis. Enrofloxacin and levofloxacin were chosen for this work.
Experiments were carried out on nine groups, each of 10 pregnant female rats. The first group was kept as control, the second, third, fourth and fifth group were given enrofloxacin orally in a therapeutic dose of (10 mg/kg b.wt.) for second and third group, while double therapeutic dose (20 mg/Kg b. wt) for fourth and fifth group were given respectively. The six, seventh, eighth and ninth groups were given levofloxacin intravenously in therapeutic dose (25 mg/kg b.wt.) for six and seventh group but double therapeutic dose (50 mg/kg b.wt.) for eighth and ninth groups respectively. The tested antibacterials were given once daily during period of organogenesis from 6th to 15th day of gestation period.
6.1. Enrofloxacin:
In doses of 10 and 20 mg/kg b.wt orally daily of enrofloxacin produced highly significant decrease in number of fetuses per mother, highly significant decrease in number of viable fetuses, highly significant increase in number of resorbed fetuses per mother and highly significant decrease in body weight and length of viable fetuses. Diverticulum dilatation in 20, 30%, thymus hypoplasia or thymus absence in 24.0, 35.0%, pulmonary hypoplasia in 52, 75%, cardiac hyperplasia in 44, 60%, hepatomegaly in 56%, 65%, kidney hypoplsia or atrophy with dilatation of renal pelvis either unilateral or bilateral in 76%, 85%, atrophy or small in size of suprarenal gland in 12, 20% of examined fetuses respectively were reported as visceral abnormalities. Skeletal examination revealed impaired ossification of skull in 18,75, 28.57%, absence of sternbrae in 62.6, 85.7%, absence of caudal vertebra in 56.25, 92.85% absence of digit’s bone of fore- and hind limb in 50.00, 64.28% and absence of metatarsal and metacarpal bones in 25.00, 71.4% and 31.25, 57.14% respectively.
Histopathological examination of internal organ of slaughtered rats at 20th day of pregnancy following administration of enrofloxacin either in therapeutic or double therapeutic dose revealed some changes in the lung as thickening in wall of blood vessels, alveolar emphysema with focal aggregation of mononuclear cell, spleen showed lymphoid depletion with excessive haemosiderosis, hyalinization of cardiac muscle, catarrhal enteritis, cloudy swelling of kidney, hydropic degeneration with necrosis of hepatocytes of liver with therapeutic dose, but increased incidence of pathological effects with double therapeutic dose. The placenta and uterus in rat given double therapeutic dose showed desquamation of endometrial gland and epithelium of the uterus and placenta showed precipitation of calcium salt (mineralization).
Serum and tissue concentrations of rats given therapeutic dose of enrofloxacin, (10 mg/kg b.wt) and slaughtered at 10th days of pregnancy, the liver and kidney contained the highest drug concentrations 0.48 ± 0.0085 and 0.33 ± 0.0167 g/gm respectively. While fetuses and brain contained lowest concentrations, (0.115 ± 0.0043, 0.088 ± 0.0018 g/gm) respectively. Rats slaughtered at 16th day of pregnancy, the liver, kidney, lung and skin contained the highest concentrations (0.79 ± 0.0191, 0.69 ± 0.0102, 0.53 ± 0.0116 and 0.44 ± 0.0058) g/gm respectively, on other hand the fetuses and brain contained the lowest concentrations of enrofloxacin (0.163 ± 0.0056 and 0.18 ± 0.0056 g/gm) respectively. The drug was disappeared from all tissues except liver and the kidney of rats slaughtered at 20th day of pregnancy, contained (0.047 ± 0.0093 and 0.035 ± 0.0017 g/gm respectively.
The serum and tissue concentration following administration of enrofloxacin in double therapeutic dose (20 mg/kg b.wt) orally, for rats slaughtered at 10th day of pregnancy, the highest concentration of drug were recorded in liver, kidney and lung (0.54 ± 0.0047, 0.449 ± 0.0052 and 0.35 ± 0.0091 g/gm respectively, while the fetuses, brain and spleen contained the lowest concentrations (0.169 ± 0.0048, 0.12 ± 0.0073 and 0.13 ± 0.0065 g/gm respectively. The liver, kidney, lung, skin, muscle (thigh and thoracic muscles) of rats slaughtered at 16th day of pregnancy contained the highest concentrations (1.21 ± 0.0032, 0.84 ± 0.0085, 0.628 ± 0.0061, 0.418 ± 0.0090, 0.44 ± 0.0063 and 0.39 ± 0.0070 g/gm respectively). Fetuses and brain contained the lowest concentrations (0.237 ± 0.0062, 0.28 ± 0.0074 g/gm respectively). The rats slaughtered at 20th day of pregnancy recorded that the drug was disappeared from all tissues except liver and kidney which contained low concentration as (0.056 ± 0.060 and 0.040 ±0.0073 g/gm respectively.
6.2. Levofloxacin :
Intravenous injection of (25 and 50 mg/kg) of levofloxacin induced significant decrease in the number of fetuses per mother, significant decrease in number of viable fetuses, significant increase in number of resorbed fetuses per mother either early or late uterine resorption and highly significant decrease in weight and length of fetuses. Visceral examination of living fetuses revealed diverticulum dilatation of brain in 25.92, 38.89%, thymus hypoplasia in 18.52, 27.67%, pulmonary hpoplasia in 59.25, 83.33%, cardiac enlargement in 48.14, 66.67% hepatomegaly in 40.74, 50.00%, kidney hypoplasia or atrophy with unilateral or bilateral dilatation of renal pelvis in 77.77, 94.44%, atrophy or small sized suprarenal gland in 29.62, 44.44%, respectively.
Skeletal examination revealed impaired ossification of skull in 31.58, 45.45% absence of strenebra or small sized in 52.63, 72.73%, absence of digit’s bone in fore and hind limb in 36.84, 63.64%, absence of some metatarsal bone in 21.05, 54.55%, absence of metacarpal bone in 26.32, 63.64%, absence of caudal vertebrae in 47.37, 81.82%, respectively.
Histopathological examination of internal organs of mother showed hydropic degeneration with lymphocytic infiltration of hepatocyte, kidney showed degeneration of renal tubule with lymphocytic aggregation but some cases showed necrosis and loss striation of cardiac muscle with lymphocytic aggregation. Focal proliferation of glial cell of brain with cerebral and cerebulum encephalomalasia. Lymphoid deplation with haemosiderosis of spleen. Histopathological changes of double therapeutic dose is the same as therapeutic dose but with increased incidence, also lesions of uterus and placenta recorded with double therapeutic dose. Uterus revealed congestion of blood vessels with lymphocytic infiltration but some cases showed necrosis. Placenta showed congestion of blood vessels in the surface with cellular desquamation in lining epithelium but some cases showed necrosis in the villous surface.
The serum and tissue concentration of levofloxacin following intravenous injection of therapeutic of (25 mg / Kg b. wt) once daily, in rats slaughtered at 10th day of pregnancy, showed that liver and kidney contained the highest drug concentration (0.41 ± 0.0043 and 0.45 ± 0.0061 g/gm) respectively. The fetuses and heart, brain and spleen contained the lowest concentrations (0.126 ± 0.0048, 0.12 ± 0.0029, 0.11 ± 0.0043, 0.10± 0.0037 g/gm respectively. The rats slaughtered at 16th day of pregnancy showed that liver, kidney, lung and skin contained the highest concentrations of drugs (0.80 ± 0.0087, 0.87 ± 0.0058, 0.63 ± 0.0049 and 0.46 ± 0.0049 g/gm respectively). On other hand, the whole fetus and spleen contained the lowest concentration of levofloxacin (0.202 ± 0.0047 and 0.22 ± 0.0108 g/gm respectively). The data for the rats slaughtered at 20th day of pregnancy indicated that the drug were disappeared from all tissues except liver and kidney which contained low concentrations (0.022 ± 0.0092 and 0.028 ± 0.092) g/gm respectively
The liver, kidney and lung in rats following administration of double therapeutic dose (50 mg/kg b.wt) contained the highest drug concentration for rats slaughtered at 10th day of pregnancy (0.55 ± 0.0053, 0.65 ± 0.0040 and 0.42 ± 0.0074 g/gm respectively), while fetus, heart and spleen contained the lowest drug concentrations (0.183 ± 0.0029, 0.178 ± 0.0036 and 0.14 ± 0.0034 g/gm respectively. In rats slaughtered at 16th day of pregnancy the liver, kidney, lung and skin contained the highest drug concentrations, (0.91 ± 0.0138, 1.38 ± 0.0270, 0.73 ± 0.0049, and 0.608 ± 0.0141 g/gm respectively. Fetuses, heart and spleen contained the lowest concentrations (0.247 ± 0.0060, 0.30 ± 0.0052 and 0.34 ± 0.0819 g/gm respectively. The rats slaughtered at 20th day of pregnancy indicated that the drug disappeared from all tissues except liver, kidney and lung (0.020 ± 0.0047, 0.036 ± 0.0071 and 0.046 ± 0.0060 g/gm respectively.
The obtained fetal abnormalities as decrease in number of fetuses per mother might be attributed to direct toxic 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 placenta because it have low molecular weight .The decrease in number of viable fetuses per mother might be attributed to incomplete formation of placenta with degeneration of trophoblast and decidual cell which play an important role in transmission of nutrient to the embryo. The increase in the number of resorbed fetuses might be attributed to the interference with placental transmission of essential element as magnesium and leucin produced high incidence of fetal resorption, or, discontinuation production of placental progestrones or due to the pathological changes appear in placenta and uterus by toxic effect of drug. Disturbance in metabolism and interferance of tested drugs to the placental transmission of some mineral as magnesium, zinc, potassium and ionized calcium with imbalance of intestinal flora of dams received these drugs 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. Abnormal morphogeneses 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 drugs mainly excreted via kidney as it reached to urine in high concentration with its poor water solubility at acidic pH have a result in formation of crystals in the urinary tract. These crystals are though to be responsible for observed renal lesion.
The recorded skeletal malformation might be attributed to formation of chelate complexes with divalent cations (magnesium) as this deficiency responsible for regular function of transmembrane proteins. Also, quinolone causes pathological alteration in tenocyte, decrease in total monosaccharides, change in number of N-linked oligosaccharides and faulty in calcification of cartilage due to decrease in ionized calcium and preciptation of calcium in placenta (mineralization).
This study concluded that, administration of enrofloxacin and levofloxacin was accompanied by adverse effect on different organs particularly with high dose. So precautions should be taken in consideration for uses of both tested drugs in human and animals especially pregnant female.