ABSTRACT
This work aimed at evaluating the chronic effect of therapeutic dose of acetaminophen and ameliorative effects of antioxidant vitamins in wistar albino rats. A total of 56 male Wistar rats with body weights range 70 – 100 g used in this study were fed Vital growers mash and water ad libitum, and grouped into 7 (n=8). Group 1 was fed Vital growers mash and water ad libitum while groups 2 and 3 received only acetaminophen at 1500 mg and 1000 mg per 70 kg body weight, respectively. Groups 4 and 5 were administered acetaminophen at 1500 mg and 1000 mg per 70 kg body weight with concomitant administration of vitamin C at a dose of 100 mg/kg body weight, while groups 6 and 7 were administered acetaminophen at 1500 mg and 1000 mg per 70 kg body weight respectively, together with vitamin E 1000 iµ/70 kg body weight. These administrations were done for weeks 1, 3, 5 and 7 while nothing was administered on the 2nd, 4th and 6th week during which the animals were fed only feed and water ad libitum. At the end of each administration week, two animals selected randomly from each group were anaesthetized using chloroform and blood samples collected via cardiac puncture. The blood samples for biochemical assays were respectively collected in anticoagulant-free tubes and allowed to clot before centrifugation. The sera were separated thereafter and used for the assays, while the blood samples for haematological parameters were collected in EDTA-containing sample bottles and used for the tests. These assays and tests were carried out using standard methods. Results show that in the 7th week, the groups administered 1500 and 1000 mg/70 kg BW paracetamol, had a significant (p<0.05) increase in activity of the determined liver marker enzymes: aspartate aminotransferase, alanine amino transferase and alkaline phosphatase. The exposure also caused a significant (p<0.05) increase in concentration of the determined kidney function parameter (urea) as well as total protein. A significant (p<0.05) increase was also observed in activities of the determined serum antioxidants (superoxide dismutase, catalase), as well as in the concentration of malondialdehyde. The haematological parameters of the untreated animals showed significant (p<0.05) decrease in results of all parameters at the 5th and 7th week. The altered results showed a significant (p<0.05) increase in the treated groups when compared with the control. These significant (p<0.05) decreases were observed when groups 4, 5, 6 and 7 (administered with varying doses of paracetamol and antioxidant vitamins C and E) were compared with group 1 as well as groups 2 and 3. Serum urea concentration was also significantly (p<0.05) decreased in the groups administered acetaminophen only at the varying doses; these alterations were also significantly (p<0.05) corrected in the groups co-administered antioxidant vitamins. Histopathological examinations seemingly corroborated the serum chemistry. Thus, the therapeutic dose of acetaminophen when taken over time can lead to depletion of serum antioxidants, increase in generation of toxic compounds and finally, damage to some vital biological organs. Hence, co-administration of antioxidant vitamins will ameliorate the observed effects of long term consumption of acetaminophen.
TABLE
OF CONTENTS
Title
page ii
Declaration iii
Certification iv
Dedication v
Acknowledgement vi
Table
of contents vii
List
of tables viii
List
of figures ix
List
of plates x
Abstract
xvi
CHAPTER
1: INTRODUCTION
1.1 Background
of the study 1
1.2 Free radicals and oxidative stress 1
1.2.1 Mechanism of reaction of free
radicals and oxidative stress 2
1.3 Vitamins 3
1.4 Statement of the problem and
justification 4
1.5 Aim
of the study 5
1.6 Objectives
of the study 5
CHAPTER
2: LITERATURE REVIEW
2.1 Introduction 7
2.2 Physical and chemical properties 8
2.3 Metabolism of acetaminophen 9
2.4 Drug-drug interactions of acetaminophen 11
2.5 Pharmacodynamics of acetaminophen 13
2.6 Classification of vitamins 14
2.6.1 Fat soluble vitamins 14
2.6.1.1 Vitamin A 14
2.6.1.2 Vitamin D 15
2.6.1.3 Vitamin
E 16
2.6.1.3.1 Biochemistry of vitamin E 16
2.6.1.3.2
Biological activities of vitamin
E 18
2.6.1.4 Vitamin K 20
2.6.2 Water soluble vitamins 21
2.6.2.1 Vitamin-B1 (thiamin) 21
2.6.2.2 Vitamin-B2 (riboflavin) 22
2.6.2.3 Vitamin-B3 (niacin) 23
2.6.2.5 Vitamin-B5 (pantothenic
acid) 24
2.6.2.6 Vitamin-B6 (pyridoxine) 25
2.6.2.7 Vitamin B9 (folate) 26
2.6.2.8 Vitamin B12 (cobalamin) 28
2.6.2.9 Biotin
(coenzyme R, vitamin H, and vitamin B7) 30
2.6.2.10 Vitamin
C (ascorbic acid) 31
2.6.2.10.1 Absorption of vitamin C 33
2.6.2.10.2 Biological functions of Vitamin C 35
CHAPTER 3: MATERIALS AND METHODS
3.1 Materials 37
3.1.1 Acetaminophen 37
3.1.2 List of chemicals/reagents used 37
3.2 Method 37
3.2.1 Animals 37
3.2.2 Experimental design 37
3.2.3 Serum
preparation 38
3.2.4 Biochemical analysis 38
3.2.4.1 Assay of serum alanine
aminotransferase (ALT) activity 39
3.2.4.2 Assay of serum aspartate
aminotransferase (AST) activity 39
3.2.4.3 Assay
of serum alkaline phosphatase (ALP) activity 40
3.2.4.4 Determination of serum total protein concentration 41
3.2.4.5 Determination of urea concentration 42
3.2.4.6 Assay
of superoxide dismutase activity 43
3.2.4.7 Assay of catalase activity 44
3.2.4.8 Estimation
of glutathione peroxidase activity 44
3.2.4.9 Reduced glutathione estimation 45
3.2.4.10 Estimation of extent of lipid
peroxidation 46
3.2.4.11 Determination of
erythrocyte count by haemocytometry 47
3.2.4.12 Packed cell volume
(PCV) estimation 48
3.2.4.13 Determination of
haemoglobin concentration 49
3.2.4.14 Determination of
platelet count 51
3.2.4.15 Determination of total white blood cell count by haemocytometry 52
3.2.5 Histopathological examination 53
3.2.5.1 Tissue
preparation 53
3.2.5.2 Slide examination 54
3.2.6 Statistical analysis 54
CHAPTER
4: RESULTS AND DISCUSSIONS
4.1 Results 55
4.1.1 Effect
of acetaminophen on aspartate transaminase activity in
wistar
rats 55
4.1.2 Effect
of acetaminophen on alanine amino transferase activity in
wistar
rats 56
4.1.3 Effect
of acetaminophen on alkaline phosphatase activity in
wistar
rats 57
4.1.4 Effect
of acetaminophen on serum urea concentration in
wistar
rats 58
4.1.5 Effect
of acetaminophen on serum total protein concentration in
wistar
rats 59
4.1.6 Effect
of acetaminophen on serum malondialdehyde concentration in
wistar
rats 60
4.1.7 Effect
of acetaminophen on serum superoxidedismutase activity in
wistar
rats 61
4.1.8 Effect
of acetaminophen on serum catalase activity in wistar rats 62
4.1.9 Effect
of acetaminophen on serum glutathione peroxidase activity in
wistar
rats 63
4.1.10 Effect
of acetaminophen on serum glutathione activity in wistar rats 64
4.1.11 Histopathology 67
4.1.11.1 The Liver at 5th week of administration 67
4.1.11.2 The Kidney at 5th week of administration 75
4.1.11.3 The Liver at 7th week of administration 82
4.1.11.4 The Kidney at 7th week of administration 88
4.2 Discussion 94
CHAPTER
5: CONCLUSION AND RECOMMENDATIONS
5.1 Conclusion 100
5.2 Recommendations 100
References
Appendix
LIST
OF TABLES
1: List of
chemicals and reagents and their manufacturers. 37
2: List of equipment
and their manufacturers. 38
3: Effect of acetaminophen on
haematological parameters of wistar rats at
weeks 1, 3 and 5 66
4: Effect of
acetaminophen on haematological parameters of wistar rats at week 7 67
LIST
OF FIGURES
2.1: Acetaminophen metabolism 9
2.2: Metabolism of acetaminophen at
supratherapeutic dose 11
2.3: Structure
of vitamin E 16
2.4: Structure
of vitamin C 33
4.1: Activity
of aspartate transaminase in different animal groups 56
4.2: Activity
of alkaline amino transferase in different animal groups 57
4.3: Activity
of alkaline phosphatase in different animal groups 58
4.4: Serum
urea concentration in wistar rats of different groups 59
4.5: Serum total protein concentration in wistar
rats of different groups 60
4.6: Serum
total malondialdehyde concentration in wistar rats of different groups 61
4.7: Serum
superoxidedismutase activity in wistar rats of different groups 62
4.8: Serum
catalase activity in wistar albino rats of different groups 63
4.9 Serum glutathione peroxidase activity in wistar
rats of different groups 64
4.10: Serum
glutathione activity in wistar rats of different groups 65
LIST OF PLATES
|
Plate 1A
|
Sections
of the liver collected from the
control group showed the normal
features of the hepatic histomorphology/histo-architecture for laboratory
rodents. Normal hepatic lobules, with normal hepatocytes arranged in
interconnecting cords around the central veins (V) were observed. The hepatic
cords are separated from each other by the hepatic sinusoids as they radiate
towards the periphery of the hepatic lobules where they meet with the
components of the portal areas (P)/portal triad (Hepatic artery, Hepatic vein
and Bile duct) suspended in loose connective tissue matrix. H&E x400.
|
68
|
|
Plate 2A
|
Photomicrograph
of liver of 1500 mg/70 kg group showing mild widespread hepatocellular
swelling with partial occlusion of adjacent sinusoids whereby affected cells
appear swollen and contain numerous minute intracytoplasmic clear vacuoles
(arrow). Multifocal areas of leucocytic aggregations were also observed with
random distribution in relation to the hepatic sinusoids. M x400. H and E
|
69
|
|
Plate 3A
|
Sections
of the liver collected from the
animals in the group administered 1000 mg/70 kg acetaminophen showed the
normal hepatic histo-architecture for laboratory rodents. Central vein (V);
Sinusoid (arrow). H&Ex400.
|
70
|
|
Plate 4A
|
Sections
of the liver collected from the
animals administered 1500 mg/70 kg acetaminophen + vitamin C showed the
normal hepatic histo-architecture for laboratory rodents. Central vein (V);
Portal area (P). H&E x160.
|
71
|
|
Plate 5A
|
Sections
of the liver collected from the
animals administered 1000 mg/70 kg acetaminophen + vitamin C showed the
normal hepatic histo-architecture for laboratory rodents. Central vein (V);
Portal area (P). H&E x160.
|
72
|
|
Plate 6A
|
Sections
of the liver collected from the
animals administered 1500 mg/70 kg acetaminophen + vitamin E showed the
normal hepatic histo-architecture for laboratory rodents. Central vein (V).
H&E x400.
|
73
|
|
Plate 7A
|
Sections
of the liver collected from the
animals administered 1000 mg/70 kg acetaminophen + vitamin E showed the
normal hepatic histo-architecture for laboratory rodents. Central vein (V).
H&E x400.
|
74
|
|
Plate 1B
|
Sections
of the kidney collected from the animals in the control group showed the
normal features of the renal histomorphology/histo-architecture for
laboratory rodents. The sections showed normal Glomeruli (G) in their thin
Bowman’s capsules (arrow) surrounded by a sea of renal tubules (RT) (proximal
convoluted tubules, pars recta, distal convoluted tubules and collecting
ducts) in the cortex and outer medulla. The inner medulla also showed normal
renal tubules. The sections also showed normal renal interstitium composed of
loose connective tissue with rich capillary network. H&E x160; x400.
|
75
|
|
Plate 2B
|
Sections
of the kidney collected from the animals administered 1500mg/70kg Acetaminophen
showed the normal renal histo-architecture (see control group for detailed
histological description). Glomeruli (G); Bowman’s capsule (Arrow); Renal
tubules (RT); Blood vessel (BV). H&E x400.
|
76
|
|
Plate 3B
|
Sections
of the kidney collected from the animals administered 1000mg/70 kg Acetaminophen
showed the normal renal histo-architecture (see control group for detailed
histological description). Glomeruli (G); Bowman’s capsule (Arrow); Renal
tubules (RT); Blood vessel (BV). H&E x400.
|
77
|
|
Plate 4B
|
Sections
of the kidney collected from the animals administered 1500mg/70 kg Acetaminophen
+ vitamin C showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT). H&E x400.
|
78
|
|
Plate 5B
|
Sections
of the kidney collected from the animals administered 1000mg/70 kg Acetaminophen
+ vitamin C showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT). H&E x400.
|
79
|
|
Plate 6B
|
Sections
of the kidney collected from the animals administered 1500mg/70 kg Acetaminophen
+ vitamin E showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT). H&E x400.
|
80
|
|
Plate 7B
|
Sections
of the kidney collected from the animals administered 1000mg/70 kg Acetaminophen
+ vitamin E showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT). H&E x400.
|
81
|
|
Plate 1C
|
Sections
of the liver collected from the animals administered 1500mg/70kg Acetaminophen
only showed a mild widespread hepatocellular swelling with partial occlusion
of adjacent sinusoids. The affected cells appear swollen and contain numerous
minute intracytoplasmic clear vacuoles (arrow). Central vein (V). H&E
x400.
|
82
|
|
Plate 2C
|
Sections
of the liver collected from the
animals administered 1000mg/70kg
acetaminophen
showed the normal hepatic histo-architecture for laboratory rodents. Central
vein (V). H&E x400.
|
83
|
|
Plate 3C
|
Sections
of the liver collected from the animals administered 1500mg/70kg Acetaminophen
+ Vitamin C showed a very mild widespread hepatocellular swelling with
partial occlusion of adjacent sinusoids. The affected cells appear swollen
and contain numerous minute intracytoplasmic clear vacuoles (arrow). Central
vein (V). H&E x400.
|
84
|
|
Plate 4C
|
Sections
of the liver collected from the
animals administered 1000mg/70kg Acetaminophen + Vitamin C showed the normal
hepatic histo-architecture for laboratory rodents (See control group for
detailed histopathological descriptions). Central vein (V). H&E x400.
|
85
|
|
Plate 5C
|
Sections
of the liver collected from the animals administered 1500mg/70kg Acetaminophen
+ Vitamin E showed a mild widespread, centrilobular hepatocellular swelling
with partial occlusion of adjacent sinusoids. The affected cells appear
swollen and contain numerous minute intracytoplasmic clear vacuoles (arrow).
Central vein (V). H&E x400.
|
86
|
|
Plate 6C
|
Sections
of the liver collected from the
animals administered 1000mg/kg Acetaminophen + Vitamin E showed a mild
periportal infiltration of inflammatory cells. The inflammatory cells
composed primarily of mononuclear leucocytes aggregate around the components
of the portal triads. A few random aggregates in the hepatic lobules were
also observed. Hepatic artery (HA); Bile duct (BD). H&Ex400.
|
87
|
|
Plate 1D
|
Sections
of the kidney collected from the animals administered 1500mg/70kg Acetaminophen
showed the normal renal histo-architecture (see control group for detailed
histological description). Glomeruli (G); Bowman’s capsule (Arrow); Renal
tubules (RT); Blood vessel (BV). H&E x400.
|
88
|
|
Plate 2D
|
Sections
of the kidney collected from the animals in this group showed the normal
renal histo-architecture (see control group for detailed histological
description). Glomeruli (G); Bowman’s capsule (Arrow); Renal tubules (RT).
H&E x400.
|
89
|
|
Plate 3D
|
Sections
of the kidney collected from the animals administered 1500mg/70kg Acetaminophen
+ Vitamin C showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT); Blood vessel (BV). H&E x400.
|
90
|
|
Plate 4D
|
Sections
of the kidney collected from the animals administered 1000mg/kg Acetaminophen
+ Vitamin C showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT). H&E x400.
|
91
|
|
Plate 5D
|
Sections
of the kidney collected from the animals administered 1500mg/70kg Acetaminophen
+ Vitamin E showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT)Blood vessel (BV). H&E x400.
|
92
|
|
Plate 6D
|
Sections
of the kidney collected from the animals administered 1000mg/kg Acetaminophen
+ Vitamin E showed the normal renal histo-architecture (see control group for
detailed histological description). Glomeruli (G); Bowman’s capsule (Arrow);
Renal tubules (RT). H&E x400.
|
93
|
CHAPTER 1
INTRODUCTION
1.1
BACKGROUND OF STUDY
Acetaminophen (also known as paracetamol)
is the most frequently consumed anti-pyretic and non-opioid analgesic for
management of pains and fever; and belongs to the non-steroidal
anti-inflammatory drug (NSAID) class of drugs (Mazer and Perrone, 2008). It is
arguably the most commonly used medications worldwide and as such, has a very
high rate of abuse which leads to toxicity with well over 165, 000 reported
exposures in the United States (Mazer and Perrone, 2008). Acetaminophen
is a powerful inducer of cytochrome-P450 whose activity leads to generation of
highly reactive quinoneimine that combines with the sulfhydryl group of
proteins. The toxicity occurs because of its reactive metabolite N-acetyl-p-benzoquinone
imine (NAPQI) which exerts its toxicity primarily via its oxidative effect on
cellular proteins (Attia, 2010). This toxic effect in animals and man produces
hepatic necrosis and depletion of both mitochondrial and cytosolic pools of
reduced glutathione (Sandhu et al., 2010;
Dasgupta et al. 2012). Kidney is the second target organ
of acetaminophen toxicity, although nephrotoxicity may exists in the absence of
hepatotoxicity following an overdose of acetaminophen (Gulnaz et al., 2010), even though it (kidney)
has been badly ignored in studies aimed at treatment of Acetaminophen toxicity
with herbal preparations (Sharma et al., 2008).
1.2 FREE RADICALS AND OXIDATIVE STRESS
Biochemical
reactions that take place in the cells and organelles of our bodies are the
driving force that sustains life. The laws of nature dictate that one goes from
childhood, to adulthood and finally enters a frail condition that leads to
death. Due to the low number of births and increasing life expectancy, in the
near future, worldwide population will be composed in a considerable number of
elderly. This stage in life is characterized by many cardiovascular, brain and
immune system diseases that will translate into high social costs (Rahman,
2007). It is therefore important to control the proliferation of these chronic
diseases in order to reduce the suffering of the elderly and to contain these
social costs. Free radicals, antioxidants and co-factors are the three main
areas that supposedly can contribute to the delay of the aging process (Rahman,
2007). The understanding of these events in the human body can help prevent or
reduce the incidence of these and other diseases, thus contributing to a better
quality of life.
1.2.1 Mechanism of reaction of free radicals and
oxidative stress
Free
radicals are atoms, molecules or ions with unpaired electrons that are highly
unstable and active towards chemical reactions with other molecules. They
derive from three elements: oxygen, nitrogen and sulfur, thus creating reactive
oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulfur
species (RSS). Reactive oxygen species (ROS) include free radicals like the
superoxide anion (O2-・),
hydroperoxyl radical (HO2・),
hydroxyl radical (・OH),
nitric oxide (NO), and other species like hydrogen peroxide (H2O2),
singlet oxygen (1O2), hypochlorous acid (HOCl) and peroxynitrite (ONOO-).
Reactive nitrogen species (RNS) derive from NO by reacting with O2-・, and forming ONOO-.
Reactive sulphur species (RSS) are easily formed by the reaction of ROS with
thiols (Lü et al., 2010). The
hydroperoxyl radical (HO2・)
disassociates at pH 7 to form the superoxide anion (O2 -・) which is extremely
reactive and can interact with a number of molecules to generate ROS either
directly or through enzyme or metal-catalyzed processes. Superoxide ion can
also be detoxified to hydrogen peroxide through a dismutation reaction with the
enzyme superoxide dismutase (SOD) (through the Haber-Weiss reaction) and
finally to water by the enzyme catalase (CAT). If hydrogen peroxide reacts with
an iron catalyst like Fe2+, the Fenton reaction can take place (Fe2+
+ H2O2 → Fe3+ + OH. + OH-)
forming the hydroxyl radical HO・
(Flora, 2009). With regard to RNS, the mechanism forming ONOO- is:
NO. + O2-. (Squadrito and Pryor, 1998). Finally, RSS
derive, under oxidative conditions, from thiols to form a disulfide that with
further oxidation can result in either disulfide-S-monoxide or
disulfide-S-dioxide as an intermediate molecule. Finally, a reaction with a
reduced thiol may result in the formation of sulfenic or sulfinic acid (Giles et al., 2001).
1.3 VITAMINS
Vitamins are groups of highly
complex compounds, organic in nature, present in foodstuffs in traces,
essential for normal metabolism and absence of these nutrients cause disorders
whereas, resupply of these nutrients can cure the deficiency symptoms
(Marshall, 1986). Vitamins are diverse in nature relative to fats, carbohydrates and proteins and differentiated from other groups
by their organic nature whereby their classification depends on
chemical nature and function. Vitamins are classified into two main categories
i.e. water soluble and fat soluble vitamins. Vitamins of B complex and C are
water soluble whereas, vitamin A, D, E, and K are fat soluble. Fat soluble
vitamins have association with fats and absorb with
dietary fats making them to follow
the same mechanics as for absorption of fats while water soluble vitamins
are not associated with fats and thus, rendered unaffected by
alterations in fat absorption (McDowell, 2000; Wardlaw et al., 2004).
The
human body is unable to synthesize the vitamins so, their intake through diet
is necessarily vital. Vitamins are chemically complex compounds and have
significant role in growth and development of the human body. There are
numerous vitamins like; vitamin A, vitamin C (ascorbic acid), vitamin D,
vitamin E, vitamin B12 (cobalamin), vitamin B6, vitamin B5
(Pantothenic acid), vitamin B1 (thiamin), vitamin B3
(niacin), vitamin B2 (riboflavin) and vitamin B9 (folate,
folic acid, or folacin), flavonoids (vitamin P). Severe or even fatal diseases
are caused by deficiency of vitamins. Vitamin deficiencies are associated with
specific disease like, vitamin A associated with Blindness, vitamin B1 with
beriberi, vitamin B3 with pellagra, vitamin B6 with anaemia, vitamin C with
scurvy and vitamin D with rickets (Asensi-Fabado and Munne´-Bosch, 2010).
In earlier days of vitamin
discovery, chemical composition of vitamins was unknown and these factors were
designated with alphabet letters. Alphabetizing became complicated due to
different forms of vitamins (vitamin B complex), differences in chemical
structure within groups and determination of chemical functions. Vitamins were
also named based on their function and sources. Vitamin H was named to the
factor which protects the haut, a German word meaning skin. Vitamin K is
derivative from Danish word koagulation meaning coagulation. Pantothenic
acid derived from Greek word pantos, means found
everywhere (Cnain,
1981).
1.4 STATEMENT OF THE PROBLEM AND
JUSTIFICATION
Acetaminophen
is used frequently as an over-the-counter analgesic for minor aches, pains and
fevers. Potentially acetaminophen in overdose, have a variety of effects on the
liver and kidney. Severe adverse renal effects may partly be due to
vasoconstriction consequent upon inhibition of renal prostaglandin-mediated
vasodilatation, decreasing renal blood flow, and resulting in a reduction in
glomerular filtration rate (Bower et al., 2007).
Acetaminophen induced hepatic and renal failure depends on the drug, dose,
duration of pharmacologic effect, and the health of the patient. Therefore, it
is imperative to study the chronic dose dependant toxicity of acetaminophen and
check whether vitamin E and vitamin C will ameliorate such toxic effect.
In our day to day life we are using so many drugs as
medicines. We consume such medicines not knowing their toxicity, etc. One of
such is acetaminophen which is often used to get relief from fever, headache
and certain pains such as muscle aches, arthritis, backache, toothache and
cold; though, research have shown that high doses of acetaminophen consumption
can lead to liver failure. This has led many individuals to consume the
approved therapeutic dose and in some instances, over a long period of time.
Thus, this study is aimed at investigating the effect of chronic consumption of
acetaminophen and if co-administration with antioxidant enzymes have potential
relevance in ameliorating such effects.
1.5 AIM
OF THE STUDY
This
study is aimed at determining the chronic effect of therapeutic doses of
acetaminophen and possible ameliorative potentials of antioxidant vitamins C
and E on Wistar albino rats.
1.6 OBJECTIVES
OF THE STUDY
a.
To investigate the chronic
effect of therapeutic doses of acetaminophen and possible ameliorative
potentials of antioxidant vitamins C and E on endogenous antioxidant enzymes
(superoxide dismutase, catalase, glutathione peroxidase and glutathione) in
Wistar albino rats.
b.
To investigate the
chronic effect of therapeutic doses of acetaminophen and possible ameliorative
potentials of antioxidant vitamins C and E on activities of some liver function
markers (aspartate transaminase, alanine amino transferase, alkaline
phosphatase and total protein) in Wistar rats.
c.
To investigate the
chronic effect of therapeutic doses of acetaminophen and possible ameliorative
potentials of antioxidant vitamins C and E on renal function marker (urea) in
Wistar albino rats.
d.
To investigate the chronic
effect of therapeutic doses of acetaminophen and possible ameliorative
potentials of antioxidant vitamins C and E on lipid peroxidation marker
(malondialdehyde) in Wistar albino rats.
e.
To investigate the
hepatic histopathological effect of therapeutic doses of acetaminophen and
possible ameliorative potentials of antioxidant vitamins C and E in wistar
albino rats.
f.
To investigate the renal
histopathological effect of therapeutic doses of acetaminophen and possible
ameliorative potentials of antioxidant vitamins C and E in wistar albino rats.
g.
To investigate the
chronic effect of therapeutic doses of acetaminophen and possible ameliorative
potentials of antioxidant vitamins C and E on haematological parameters (packed
cell volume, red blood cells, total white blood cell count, platelets count and
haemoglobin) in wistar albino rats.
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