الفهرس 
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Abstract
The main goal of this thesis is to evaluate the potential protective effect of rivaroxaban and dabigatran on metabolic syndrome (MetS)and diabetes mellitus in albino rats and the possible mechanism of action.
The present study was performed over a duration of 8 weeks. The experimental design consists of a pretreatment phase (0-5th weeks) and a treatment phase (6th-8th weeks). Forty Adult male albino rats weighing (160-180 gm) were used and randomly divided into four groups each contained 10 rats. group 1: (Normal Control group): rats were fed a standard chow diet and received vehicle (Normal saline, 1 ml) in the treatment phase.
During the pretreatment phase, the other 30 rats have been fed a high-fructose diet (HFD) and fructose drinking water for 5 weeks to induce metabolic syndrome.group 2: (MetS group): rats received vehicle (Normal saline, 1 ml). group 3: (MetS group treated with rivaroxaban): rats received oral rivaroxaban (3 mg/kg/day) for 21 days.group 4: (MetS group treated with dabigatran): rats received oral dabigatran (15mg/kg/day) for 21 days.
All drugs were given daily orally through a metallic tube dissolved in normal saline.Body weight and abdominal circumference of each rat were recorded at the start, after 5 weeks and in the 8th week. Electrocardiography (ECG) recordings, heart rate (HR) and Systolic blood pressure (SBP), were measured in the 8th week.Blood samples drawn for biochemical tests. Heart weight (absolute and relative) was recorded at the end of the 8th week.Heart and aorta of rats were removed for histopathological and immunohistochemical studies.
In the current study, HFD and fructose drinking water induced MetS in experimental rats. This was evident by a statistically significant increase in mean body weight and abdominal circumference, and a significant rise in HR and SBP. there was also, a statistically significant elevation in lipid profile including total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) with a significant decrease in high density lipoprotein (HDL) levels, a significant increase in fasting blood glucose, insulin and homeostatic model assessment for insulin resistance (HOMA-IR) index, a significant rise in creatine kinase myocardial band (CK-MB), troponin I and lactic acid dehydrogenase (LDH), a statistically significant increase inmalondialdehyde (MDA) and myeloperoxidase (MPO) levels and a decreased glutathione (GSH) level, a statistically significant reduction of prothrombin time (PT) and lowest level of activated partial thromboplastin time (APTT).
MetS groups treated with rivaroxaban or dabigatran showed a significant improvement in mean body weight and abdominal circumference, a statistically significant reduction in QRS and in QTc intervals, and a significant improvement in SBP,a significant decrease in TG, TC, and LDL and a significant increase in HDL levels, an appreciated alleviation in fasting blood glucose, insulin and HOMA-IR index, a significant improvement in CK-MB, Troponin I and LDH with a decrease in MDA and MPO levels and a significant increase in GSH when compared to MetS group.
MetS rats treated with dabigatran also showed a significant prolongation in RR interval and a decrease in HR as compared to MetSrats
In addition, MetS group treated with rivaroxaban showed a significant prolongation of PT when compared to MetS rats while MetS rats treated with dabigatran showed a remarkable prolongation of APTT when compared to normal control, MetS and rivaroxaban treated groups.
A marked improvement of histopathological and immunohistochemical findings was observed with both drugs. Sections of MetS rat heart treated with rivaroxaban or dabigatran revealed no hemorrhage or necrosis with decreased foamy and inflammatory cells as histiocytes and lymphocytes, and sections of rat aorta showed decreased perivascular and intimal infiltration by foamy and inflammatory cells. In addition, A positive reaction for TNF-α was detected in fewer cardiac cells as well as in the perivascular aortic tissue when compared toMetS group.
MetS groups treated with rivaroxaban or dabigatran did not show a significant reduction in heart weight when compared to the MetS group.
In conclusion, according to the findings of the current study, we can conclude that rivaroxaban and dabigatran have potent protective cardiovascular effects on metabolic syndrome and diabetes mellitus as both drugs showed a remarkable improvement in anthropometric, ECG parameters and SBP with a significant refinement of biochemical, histopathological and immunohistochemical studies’ findings, when compared to MetS group.