TABLE OF CONTENT
Title page
i
Declaration ii
Certification iii
Dedication iv
Acknowledgement v
Table of content vi
List of table vii
List of figures viii
Abstract ix
CHAPTER
ONE
1.0 Introduction 1
1.1 Background of study 1
1.2 Statement of Problems 2
1.3 Justifications 4
1.4 Aims 4
1.5 Research Objectives 5
1.6 Research Hypothesis 5
1.7 Significance of research 5
CHAPTER
TWO
2.0 Literature review 6
2.1 Metformin 6
2.1.1 Mechanism of metformin 7
2.1.2 Pharmacological properties of
metformin 10
2.1.3 Side effects and
contra-indications of metformin 11
2.1.4 Therapeutic application of
metformin 13
2.2 Vitamin B12: biochemistry,
deficiency and anaemia 15
2.3 Relationship between metformin
and vitamin B12 22
2.4 Metformin and haemolytic anaemia 24
2.5 Diagnosis of anaemia
25
2.6 Efficacy of Metformin 27
2.7 Amlodipine 31
2.7.1 Chemistry 31
2.7.2 Mechanism of action 31
2.7.3 Side effects 32
2.7.4 Pharmacokinetics 32
2.8 Angiotensin Converting Enzyme
Inhibitors 33
2.9 Reference range of haematological
parameters of rats 34
2.10 Comparative haematology of rat
and human 36
CHAPTER
THREE
3.1 Study Design 39
3.2 Preparation of animals 40
3.3 Sample size determination 40
3.4 Reagent Kits/Drug Preparation and Dosage 40
3.5 Dosage 41
3.6 Sample collection 43
3.7 Measurement of variables .
43
3.8 Ethical consideration 46
3.9 Statistical analysis 47
CHAPTER
FOUR
4.1 Result 48
42.Differential white blood cell counts in controls
and tests groups 49
CHAPTER
FIVE
5.0 Discussion 58
5.1 Conclusion 61
5.2 Recommendation 62
References 63
Appendix I 75
Appendix II 76
LIST OF TABLES
Table 1: Haematological
parameters in control, Co-administration of Metformin and Amlodipine treated 39
LIST OF FIGURES
Figure 1: Shows mechanism of action of metformin 10
Figure 2: Shows Pie chat representation of Packed cell
volume of control, Co-administration of metformin and amlodipine treated Wistar
Rats 54
Figure 3: Shows Histogram representation of Hemoglobin
and red blood cell count of control, Co-administration of metformin and
amlodipine treated Wistar Rats 55
Figure 4: Shows Histogram representation of red cell
indicies of control, Co-administration of metformin and amlodipine treated Wistar
Rats 56
Figure 5: Shows Histogram representation of platelet
and white blood cell count of control, Co-administration of metformin and
amlodipine treated Wistar Rats 57
ABSTRACT
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) 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. To assess the MCV,MCH,MCHC
level of experimental animal and that of control group after combined
administration with amilodipine and metformin.
Animals were randomly grouped into Two (A and B) groups, each groups
contains eight (8) animals. Group A was administered normal saline; Group
B was administered combined administration with amilodipine (0.00264mg/ml/132g)
and metformin (0.0438mg/ml/132g) once daily for 30days after 2 weeks of
acclamatization. Each group of rats was allowed to have free access to water ad libitum and standard rat chow (SRC)
throughout the experimental period. Blood
was collected from the Jugular vein at the end of the experiment to determine the full blood count of
each animal. There was a significant reduction (p≤0.05) in hemoglobin level,
RBC, PCV and increase in WBC and decrease in PLT count, and with increase in
MCV, MCH with no difference in MCHC after co-administration of Metformin and
Amlodipine in Wistar Rat as compared to control. These findings suggests that
Co-administration of Metformin and Amlodipine causes decrease in red cell
dependent parameters gradually leading to anaemia with long term usage thus
regarded as a hematotoxicity agent to the blood profile.
Key
words: Metformin, Amlodipine, haematological parameters, Wistar
Rats.
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.
1.3
Justification
There are no local
studies on the hematotoxicity of potential drug-drug interactions among
patients receiving both hypoglycemic and antihypertensives drug and thus the
need to carry out the study. Many hypothesis and theory have been postulated by
researchers that long term usage of metformin have the ability to induce
Vitamin B12 deficiency as well as some institutions having the complain that
metformin drug despite it’s world-wide acceptability as anti-diabetic drug
causes haemolytic anaemia. This led to the need to bridge the knowledge gap by
carry out the study. Also, hypothesis have been postulated that long term usage
of anti-hypertensive drugs causes a decrease in haemoglobin in which the
mechanism is not known yet. This led to the need to bridge the knowledge gap by
carry out the study. The findings of this study will create
awareness to the clinicians and pharmacists on the need for a better dosage or
a better drug so as to prevent hematotoxicity effect of drug-drug interactions
in the case of diabetics with concomitant hypertension.
1.4
Aim
This study aims at investigating the combine
effect of Metformin and Amilodipine on haematological experimental animal
(Wistar Rats)
1.5
Research objectives
1.
To assess the MCV level of experimental
animal and that of control group after combined administration with amilodipine
and metformin.
2. To
investigate the MCH level of experimental animal and that of control group
after combined administration with amilodipine and metformin.
3.
To determine the MCHC level of
experimental animal and that of control group after combined administration
with amilodipine and metformin.
1.6 Research hypothesis (Null)
(a)
There is no
significant difference in the level of MCV level after co-administration of amilodipine
and metformin.
(b)
There is no
significant difference in the level of MCH level after co-administration of amilodipine
and metformin.
(c)
There is no
significant difference in the level of MCHC level after co-administration of amilodipine
and metformin.
1.7
Significance of research
Findings from this study will help
policy makers to determine if long term exposure to Amilodipine and Metformin
causes anaemia thus thus creating awareness of the drug usage to prevent
hematoxicity (another form of complication to diabetic-hypertensive situation).
Also
the findings from the effect of Metformin
and Amilodipine on experimental animal (Wistar Rat) will further
generate need to examine the other complications that arise from the combined
drug usage.
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