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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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2.1.2 Pharmacological properties of metformin
Metformin has a half-life of around five hours and undergoes renal excretion with 90% being eliminated within 24 hours. It can be prescribed as 500 mg or 850 mg tablets. In adults, it can be started at the 500 mg dose and increased in weekly increments until the maximum tolerated dose is achieved, normally 2 g/day (Gong et al., 2012). The intestinal absorption of Metformin may be primarily mediated by plasma membrane monoamine transporter, which is expressed on the luminal side of the enterocytes (Salpeter et al., 2006). Metformin has an oral bioavailability of 50-60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (Cmax) are reached within one to three hours of taking immediate-release Metformin and four to eight hours with extended-release formulations (Nathan et al., 2009). Steady state is usually reached in one or two days. Food decreases the extent of and slightly delays the absorption of Metformin, as shown by approximately a 40% lower mean peak plasma concentration. The plasma protein binding of Metformin is negligible. It should be taken with food to reduce the potential for gastrointestinal side effects. Metformin is undetectable in blood plasma within 24 hours of a single oral dose (Salpeter et al., 2006). After administration of a single oral Metformin HCl 500 mg tablet with food, geometric mean Metformin Cmax and AUC did not differ between adolescents with T2DM (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age) (Gong et al., 2012).
2.1.3 Side-effects and contra-indications of metformin
Gastrointestinal upsets are the main complain associated with Metformin use (Burcelin, 2014). However the main side effect of alarm is its association with lactic acidosis particularly in the setting of renal and cardiac impairment (Salpeter et al., 2006). Saeedi et al. (2008) discovered that lactic acidosis is associated with Metformin and it is known to be a rare condition. A systematic review of the risk of lactic acidosis was carried out by Saeedi et al. (2008) with Metformin and found no cases of fatal or non-fatal lactic acidosis in 274 comparative trials and cohort studies, and estimated that the upper limit of the true incidence of lactic acidosis per 100,000 patient years was 5.1 with Metformin and 5.8 without. Most cases of Metformin-associated lactic acidosis documented in the literature happen during periods of tissue hypoxia (myocardial infarction, acute left ventricular failure or septicaemia). The most common symptoms following overdose appear to include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and, rarely, hypoglycemia (Stephenne et al., 2011). This gut irritating effect is believed to be mediated through inhibition of serotonin reuptake transporter (SERT) -mediated intestinal reuptake of serotonin resulting in increased intestinal motility and water retention (Yamagduchi et al., 2005).
Although 90% is renally excreted, accumulation is rare in the Metformin enhances insulin signaling in insulin-dependent and - independent pathways. Metformin Stimulates AMPK Activation which activates Insulin Signalling, Inhibits lipogenic enzymes Activates GLUT-4, Decreases Lipogenesis, Increases Fatty acid oxidation, Increases basal glucose uptake, Increases insulin-dependent glucose uptake, Decreased Insulin Resistance absence of moderate-to-severe renal impairment (Leone et al., 2014). Members of the American Diabetes Association and European Association for the Study of Diabetes, report that Metformin seems safe unless eGFR falls to <30 mL/min per 1.73 m2. The National Institute for Health and Clinical Excellence specifies that Metformin be stopped if serum creatinine exceeds 150 μmol/L (1.7 mg/dL) or eGFR is below 30 mL/min per 1.73 m2. In contrast, the Canadian Diabetes Association practice guidelines recommend caution with eGFR <60 mL/min per 1.73 m2 and contraindicating its use with eGFR <30 mL/min per 1.73 m2 (Zhou et al., 2001; Bogachus and Turcotte, 2010). Therefore, Metformin should not be given to patients with severe renal impairment, hepatic disease, cardiac or respiratory insufficiency, or who are receiving radiographic contrast materials. Metformin should be temporarily discontinued during a gastrointestinal illness. Hypoglycemia is very uncommon with Metformin monotherapy but has been reported in combination regimens, likely due to Metformin potentiating other therapeutic agents (Viollet et al., 2012).
Long-term use of metformin has been associated with increased homocysteine levels and malabsorption of vitamin B12. Malabsorption of vitamin B12 occurs with metformin in 30% of diabetic subjects (Rojas and Gomes, 2013). The earliest manifestations are numbness and paresthesias in the feet, which, unless the vitamin B12 deficiency is corrected, can be followed by weakness, ataxia, sphincter disturbance, and changes in mental status (Rojas and Gomes, 2013). B12 deficiency –associated macrocytic anemia, is often preceded by the development of neuropathy. While the anemia of vitamin B12 deficiency is reversible, the progress of the neuropathy is only arrested and not reversed with initiation of vitamin B12 therapy (Viollet et al., 2012).
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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---
