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Sub-chronic Effect Of Co-administration Of Methformine And Amilodipine On Some Haematological Indices In Experimental Animal
[A CASE STUDY OF WISTAR RATS]
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CHAPTER TWO
2.0 LITERATURE REVIEW
2.1 Metformin
Metformin (1,1-dimethylbiguanide) is the most widely used drug to treat type 2 diabetes, and is one of only two oral anti-diabetic drugs on the World Health Organization (WHO) list of essential medicines (American Diabetes Association, 2009). Its history can be traced back to the use of Galega officinalis as a herbal medicine in medieval Europe. Its name derives from gale (milk) and ega (to bring on), as Galega has been used as a galactogogue in small domestic animals (hence the name “Goat’s rueâ€) (Patade and Marita, 2014). Studies in the late 1800s indicated that Galega officinalis was rich in guanidine and in 1918 guanidine was shown to possess hypoglycaemic activity in animals (Chen and Anderson, 1947). Jean Sterne was the first to investigate dimethylbiguanide (Metformin) for clinical development and proposed the name ‘Glucophage’ (glucose eater) and published his results in 1957 (Sterne, 1957). Metformin have therapeutic potential in other conditions in which insulin resistance constitutes part of the pathogenesis, including obesity, prediabetes, polycystic ovary disease, non-alcoholics fatty liver and premature pubarche (Viollet et al., 2012). Epidemiological studies have shown a decrease in cancer incidence in Metformin-treated patients, suggesting a potential application of the drug as an anti-cancer agent (Leone et al., 2014).
2.1.1 Mechanism of action of metformin
Although metformin is prescribed and used extensively since the end of the precise molecular (or biochemical) mechanism/s of action remain incompletely understood. It acts by countering insulin resistance, particularly in liver and skeletal muscle (Viollet et al., 2009). It suppresses hepatic gluconeogenesis, increases peripheral insulin sensitivity in insulin sensitive tissues such as muscle and adipose tissue, and enhances peripheral glucose utilization (Zhou et al., 2001). Metformin Decreases:
1. Hyperinsulinemia, Prediabetes ( IFG, IGT), T2DM
2. Decreased Glucose uptake, increased blood glucose, prediabetes, T2DM.
3. Increased gluconeogenesis, decreased glucose uptake increased blood glucose, increased lipogenesis, fatty liver.
4. Increased androgen secretion, hirsutism polycystic ovary disease. 5. Increased androgen secretion, premature pubarche. (Yamagduchi et al., 2005; Bogachus and Turcotte, 2010).
Metformin is the most widely prescribed drug to treat hyperglycemia in individuals with T2DM and is recommended, in conjunction with lifestyle modification (diet, weight control and physical activity), as a first line oral therapy in the recent guidelines of the American Diabetes Association and European Association of the Study of Diabetes (American Diabetes Association, 2009). It is effective anti-hyperglycaemic agent that inhibits hepatic glucose production and increases peripheral glucose uptake. Metformin also exerts beneficial effects on circulating lipids and exhibits cardio-protective features in obese patients (Saeedi et al., 2008). Clinical trials suggest that Metformin, that is effective in treating T2DM, may also However, have some main effect for example it appears to be decreasing hepatic glucose production through a mild inhibition of the mitochondrial respiratory-chain complex (American Diabetes Association, 2009).
This transient decrease in cellular energy status promotes activation of adenosine monophosphate-activated protein (AMPK), a well-known cellular energetic sensor. AMPK is a protein kinase ubiquitously expressed in mammalian tissues and it is involved in regulating energy balance (Stephenne et al., 2011). Activation of AMPK stimulates adenosine triphosphate (ATP)-producing catabolic pathways, while inhibiting ATP-consuming anabolic pathways, thereby, maintaining cellular energy stores (Owen et al., 2000; Stephenne et al., 2011). In skeletal muscle, activation of AMPK increases glucose uptake and lipid oxidation. In adipose tissue, activation of AMPK reduces both lipolysis and lipogenesis (Stephenne et al., 2011). Metformin regulates glucose transporter 4 (GLUT4) translocation through AMP-activated Protein Kinase (AMPK)-mediated Cbl/CAP Signaling. It enhances insulin signaling in insulin-dependent and -independent pathways (Collier et al., 2006). In the liver, activation of AMPK inhibits gluconeogenesis and lipid synthesis but increases lipid oxidation (Burcelin, 2014). The activated AMPK decreases flux of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity (reduces hepatic lipogenesis) and exert an indirect effect on hepatic insulin sensitivity to control hepatic glucose output (Miller et al., 2013). In the heart, Metformin increases fatty acids uptake and oxidation, and increases glucose uptake and glycolysis. Metformin can also antagonize the action of glucagon, thus reducing fasting glucose levels (Burcelin, 2014).
Additional action of Metformin action is through induction of a profound shift in the faecal microbial community profile in diabetic mice and it has also been proposed that this may contribute to its mode of action possibly through an effect on Glucagon-like peptide-1 (GLP-1) secretion (Boyle et al., 2010; Maida et al., 2011). Moreover, Metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells (Cho and Kieffer, 2011). These incretin-sensitising effects of Metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of Metformin action involving AMP-activated protein kinase (Cho and Kieffer, 2011).
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ABSRACT - [ Total Page(s): 1 ]ABSTRACTMetformin, which belongs to the biguanide class, is one of the most generally used oral hypoglycemic agents. It has been used for more than 50 years and was approved by the US Food and Drug Administration (FDA) in 1994 (American Diabetes Association, 2009) whereas Amlodipine is a long acting dihydropyridine calcium channel blocker, which is used in the treatment of angina to lower the BP (Blood pressure). the aim is to know the effect of co-administration of this two drugs in Wistar rats ... Continue reading---
APPENDIX A - [ Total Page(s): 1 ]APPENDIXAPPENDIX 1: MATERIAL USED1% Ammonium oxalate10% Formalin salineAbsorbent paperAutomatic pipetteBrilliant cresyl blueCounting chamber Cyanmethaemoglobin standardDrabkin’s ReagentEDTA sample containerHematoxylin and Eosin stainKhan tubes/rackLeisfhmann stainLight microscopeMicrohaematocrit centrifugeNormal salinePasteur pipettePipette tipsRotary microtomeSpectrophotometerTimer Turk’s solution Universal sample bottle ... Continue reading---
APPENDIX B - [ Total Page(s): 1 ]APPENDIX IITable 1: haematological parameters in control, Metformine treated and Amilodipine treated Rats (Values are expressed as mean ± Standard error of means) Group A(1): control (untreated), Group B(2): co-administration of Metformin 0.00264/ml/132g and Amlodipine 0.000849/ml/132g at a single dose for 30 daysPARAMETERS GROUP A GROUP BPacked cell volume (%) 44.16±2.83 38.47±3.53Red blood cell count (x1012/L) 7 ... Continue reading---
LIST OF TABLES - [ Total Page(s): 1 ]LIST OF TABLESTable 1: Haematological parameters in control, Co-administration of Metformin and Amlodipine treated ... Continue reading---
LIST OF FIGURES - [ Total Page(s): 1 ]LIST OF FIGURESFigure 1: Shows mechanism of action of metformin Figure 2: Shows Pie chat representation of Packed cell volume of control, Co-administration of metformin and amlodipine treated Wistar Rats Figure 3: Shows Histogram representation of Hemoglobin and red blood cell count of control, Co-administration of metformin and amlodipine treated Wistar Rats Figure 4: Shows Histogram representation of red cell indicies of control, Co-administration of metformin and amlodipine t ... Continue reading---
TABLE OF CONTENTS - [ Total Page(s): 1 ]TABLE OF CONTENTTitle page Declaration Certification Dedication Acknowledgement Table of content List of table List of figures Abstract CHAPTER ONE1.0 Introduction 1.1 Background of study 1.2 Statement of Problems 1.3 Justifications 1.4 Aims 1.5 Research Objectives 1.6 Research Hypothesis 1.7 Significance of research CHAPTER TWO2.0 Literature review 2.1 Metformin 2.1.1 ... Continue reading---
CHAPTER ONE - [ Total Page(s): 2 ]CHAPTER ONE1.0 INTRODUCTION1.1 Background of the studyMetformin, which belongs to the biguanide class, is one of the most generally used oral hypoglycemic agents. It has been used for more than 50 years and was approved by the US Food and Drug Administration (FDA) in 1994 (American Diabetes Association, 2009). Currently, many clinical practice guidelines for patients with type 2 diabetes, including the American Diabetes Association (ADA), the European Association for the Study of Diabetes ... Continue reading---
CHAPTER THREE - [ Total Page(s): 4 ]From the above table,Km of rats= 6 Km of human= 37For Amlodipine, Human dose= 10mg/70kg 1kg=10/70 =0.14mg/kgAED of Amilodipine= 0.14×(6/37) =0.02mg/kgAverage weight of experimental Animal is 132g(0.132kg)If 0.02mg of Amlodipine is administered per kg.bw,(0.02×0.132)mg of Amlodipine was administered to ... Continue reading---
CHAPTER FOUR - [ Total Page(s): 6 ]CHAPTER FOUR4.0 Results4.1 Hematological parameter in control and test groups As summarized in table 1, the mean RBC counts were 7.62 ± 2.83 x1012/L for the control and 6.53 ± 0.57 x1012/L for co-administration of metformin and amlodipine fed groups respectively. Although, decrease in RBC counts was observed in the treated (co-administration of metformin and amlodipine) dose group, these were statistically significant compared to control groups (student t test P0.05) higher in the tr ... Continue reading---
CHAPTER FIVE - [ Total Page(s): 2 ]CHAPTER FIVE5.0 DiscussionMetformin (1,1-dimethylbiguanide) is the most widely used drug to treat type 2 diabetes, and is one of only two oral anti-diabetic drugs on the World Health Organization (WHO) list of essential medicines (American Diabetes Association, 2009). Amlodipine is a long acting dihydropyridine calcium channel blocker, which is used in the treatment of angina to lower the BP. Co-administration of Metformin and Amlodipine have been discovered to lead to vitamin B12 deficiency. Al ... Continue reading---
REFRENCES - [ Total Page(s): 4 ]Senol, M.G., Sonmez, G., Ozdag, F. and Saracoglu, M. (2008). Reversible myelopathy with vitamin B12 deficiency. Singapore Medical Journal. 49(11): 330-332.Srinivasan, S., Ambler, G.R., Baur, L.A., Garnett, S.P. and Tepsa, M. (2006). Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. Journal of Clinical Endocrinology and Metabolism. 91: 2074-2080. Sterne, J. (1957). Du nouveau dans les anti ... Continue reading---
