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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 ONE
1.0 INTRODUCTION
1.1 Background of the study
Metformin, 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 (EASD), and the Korean Diabetes Association (KDA), recommend that metformin treatment should begin at the time of diagnosis of diabetes with lifestyle modification in the absence of contraindications. Metformin is now the most widely used anti-diabetic drug, with almost all guidelines throughout the world recommending metformin as first-line treatment for patients with type 2 diabetes mellitus (T2DM). Metformin may also be used to treat other conditions involving insulin resistance, such as polycystic ovary syndrome (PCOS) (Boyle et al., 2010). Metformin has beneficial effects on carbohydrate metabolism, weight loss, and vascular protection but also has important side effects. For example, patients on long-term metformin therapy were found to be at risk of anaemia (Maida et al., 2011). This may be due to a metformin related vitamin B12 reduction. It is reported that, 30% of patients receiving long-term metformin treatment experienced malabsorption of vitamin B12, with a decrease in serum vitamin B12 concentration of 14% to 30% (Burcelin, 2014).
Vitamin B12 is a vital nutrient for health. It plays an important role in the functioning of the brain and nervous system, and in the formation of red blood cells. In addition to anemia, vitamin B12 deficiency may increase the severity of peripheral neuropathy in patients with T2DM (Owen et al., 2000; Stephenne et al., 2011). Furthermore, because vitamin B12 participates in the most important pathway of homocysteine (Hcy) metabolism, a reduction in vitamin B12 would increase plasma concentrations of Hcy, which is strongly linked to cardiovascular disease in patients with T2DM and PCOS (Saeedi et al., 2008). Although some clinical studies have reported that metformin lowered vitamin B12 level, other studies have reported that it did not. To date, no consensus has been reached on whether metformin induces vitamin B12 reduction. It is therefore imperative to know the effect of metformin on the hematological parameters of experimental animal (Wistar Rats) so as to arrive at a conclusion if the vitamin B12 deficiency is as a result of Diabetes mellitus or due to metformin (anti-diabetic drug) (Leone et al., 2014).
On the other hand, co-administration of metformin and amilodipine have been used in patients with type 2 diabetes with concomitant hypertension (type 2 diabetes-induced hypertension) (Wang et al., 2009). Amlodipine (as besylate, mesylate or maleate) is a long acting calcium channel blocker (dihydropyridine class) used as an anti-hypertensive and in the treatment of angina (Viollet et al., 2012). Like other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing peripheral resistance and hence reducing blood pressure; in angina it increases blood flow to the heart muscle (Patade and Marita, 2014).
Amilodipine (an antihypertensive medication) have been found to be associated with a reduction in hemoglobin concentration with a long term exposure (Yamagduchi et al., 2005). The magnitude of such a change is generally small, but in certain instances it can be extreme enough to produce a clinically significant degree of anemia (Zankat et al., 2015). The mechanistic basis for antihypertensive medication-related changes in hemoglobin concentration include hemodilution, hemolytic anemia, and suppression of red blood cell production, as this occurs most commonly with angiotensin- converting enzyme inhibitors and angiotensin receptor blockers (Lakshmi et al., 2015). Researchers are suspecting that reduction in hemoglobin concentration in a patient who is receiving treatment for hypertension and does not have an obvious source of blood loss should account for potential antihypertensive therapy involvement (Bogachus and Turcotte, 2010). To find solution to the un-going suspicions and hypothesis.
It was therefore imperative to investigate the effect of co-administration of metformin and amilodipine on some hematological parameters in experimental animal (Wistar Rats).
1.2 Statement of problem
Drug-drug interactions are a major problem in health facilities the world over. The prevalence of interactions is estimated to be between 1- 22% (Lakshmi et al., 2015). Underlying risk factors for drug-drug interactions include polypharmacy and co-morbid conditions. High blood pressure in patients with diabetes presents a major health problem because of increased risk of polypharmacy. Polypharmacy leads to prescribing drugs that may have drug interactions. The interactions can lead to life threatening situations, hospitalization, increased burden to patients, hematotocixitiy (anaemia either haemolytic or vitamin B12 deficiency) as well as suppression of bone marrow activity from calcium blocker mechanism of antihypertensive drugs and adjusted quality of life. A considerable number of the drug-drug interactions can be avoided if health workers involved in patient care have the right information. Various hospitals and clinics serves patients from various regions that visit the facility for various ailments including diabetes and hypertension which are among the conditions on the rise, thus availability of data for the study is essential.
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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 TWO - [ Total Page(s): 12 ]The current use of serum Vitamin B12 level relies on several different range points for Vitamin B12 status. Serum Vitamin B12 level under 148 pmol/L are said to be deficient, low/borderline levels are interpreted from levels between 148-220 pmol/L (Mazokopakis and Starakis, 2012). Normal ranges of Vitamin B12 serum range from 220- 800 pmol/L, levels that exceed this are rarely suspicious in cause, although excessive B12 serum may be a marker of myloproliferative disorders (Pernicova and Korbonit ... 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---
