ENHANCEMENT OF ANTIMALARIAL EFFECTS OF CHLOROQUINE WITH CHLORPHENIRAMINE IN PLASMODIUM BERGHEI INFECTED MICE

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ABSTRACT

The emergence and spread of Plasmodium spp with resistance to chloroquine CQ, the cheapest antimalarial drug coupled with the high cost of artermisinin combination therapies has necessitated the need to combine chloroquine with drugs that improve its effectiveness The present study determines the ability of chlorpheniramine CP to enhance the therapeutic efficacy of chloroquine against Plasmodium berghei malaria in mice P berghei was used to develop respective experimental rodent malaria models based on intraperitoneal injection of 106 parasitize erythrocyte suspension in PBS pH, 72 and subsequent development of parasitaemia Effect of 0057 and 0029 mg/kg of CP on the therapeutic efficacy of CQ at 14 mg/kg for 2 days and 7 mg/kg on day 3 was evaluated using these experimental models The level of parasitaemia in the different groups was monitored throughout the period of the study using microscopic method Haematological parameters: RBC, Hb, PCV and WBC were determined using standard methods The acute toxicity of the CQchlorpheniramine combinations was determined enzymatically by the methods of Reitman and Frankel Also, histopathology study of the liver was carried out to determine the histopathological changes in the liver using Bancroft and Steven method The results from this study demonstrate that at day 3, CQ in combination with normal dose CP had significantly higher reduction 939 in percentage parasitaemia compared to CQ alone 561 It was also noted that CP demonstrated antiplasmodial activity in Pberghei infected mice at Day 1, 2 and 3 with percentage reduction of 192, 402 and 694 respectively The untreated group of mice infected with P berghei recorded 582 , 555 and 523 reduction in RBC, PCV and Hb respectively compared with the uninfected group The result of the liver enzyme assay shows that CQ and CP combination showed ameliorative effect of the liver damages caused by malaria parasitaemia However, CP indeed enhanced the therapeautic efficacy of CQ with minimal deleterious effect in Pberghei infected mice Chlorpheniramine is a safe therapeutic drug; therefore, the clinical use of chlorpheniramine as a cheap and highly effective combination with chloroquine holds great promise against malaria treatment

 

TABLE OF CONTENTS

Title Page i

Certification Page ii

Dedication iii

Acknowledgement iv

Table of Contents v

List of Abbreviations x

List of Figures xii

Abstract xiii

 

CHAPTER ONE: INTRODUCTION

11 Background of the Study 1

12 Malaria 2

121 Definition of Malaria 2

122 Incidence/Prevalence of Malaria 2

123 Epidemiology 4

124 Life Cycle of Plasmodium Parasite 5

125 The Clinical Manifestation of Malaria 9

1251 Prognosis of Malaria 11

126 Diagnosis of Malaria 11

1261 Clinical Diagnosis 12

1262 Parasitology Diagnosis 13

1263 Molecular Diagnosis 15

127 Establishing of Malaria Parasite Counts 15

1271 Method One: Parasites Per Micro Litre of Blood 15

1272 Method Two: The Plus System 16

128 The Past and Present Anti Malaria Drug Discovery 17

129 Resistance 19

1210 Impact of Resistance 20

1211 Factors Contributing to the Spread of Resistance 21

12111 Biological Influence on Resistance 21

12112 The Programmatic Influence on Resistance 26

1212 Detection of Resistance 27

12121 In Vivo Test 28

12122 In Vitro Test 30

12123 Animal Model Studies 31

12124 Molecular Techniques 31

12125 Case Report and Passive Detection of Treatment Failure 32

13 Chloroquine 33

131 Definition 33

132 Absorption, Metabolism and Execration of CHQ 34

133 Mechanism of Action 37

134 Mechanism of Chloroquine Resistance 38

14 Chlorphenramine 39

141 Definition 39

142 Combination Medications 40

143 Synthesis 41

15 White Blood Cells 42

151 Granulocytes 42

1511 Neutrophils 43

1512 Eosinophils 43

1513 Basophils 43

152 Agranulocytes 44

1521 Lymphocytes 44

1522 Monocytes 44

153 White Blood Cell Production 45

17 Red Blood Cell 45

171Morphology of Human Erytrocytes 46

172 Life Cycle 47

173 Packed Cell Volume PCV 48

1731 Measurement Method 48

18 Haemoglobin 49

181 Genetics 50

182 Synthesis 52

19 The Aminotransferases 52

191 Aspartate Aminotransferase 53

1911 Function 53

1912 Mechanism 54

1913 Clinical Significance 55

192 Alanine Transaminase 56

1921 Function 56

1922 Clinical Significance 56

110 Liver 56

1101 Anatomy of the Liver 57

1102 Histology 58

111 Statement of Problem 58

112 Purpose of the Study 58

113 Significance of the Study 59

 

CHAPTER TWO: MATERIALS AND METHODS

21 Materials 60

211 Drugs 60

212 Animals 60

213 Parasites 60

214 Equipments and Reagents 61

22 Methods 62

221 Parasite Density Determination and Inoculums Preparation 62

222 Parasitaemia Determination 62

223 Curative Treatment 62

224 Haematological Parameters 64

2241 Determination of Packed Cell Volume 64

2242 Haemoglobin 64

2243 Determination of Total Leukocyte White Blood Cell Count 64

2244 Determinaton of Total Erythrocyte Red Blood Cell Count 65

225 Biochemical Parameters 65

2251 Determination of Aspartate Aminotransferase AST Activity 65

2252 Determination of Alanine Aminotransferase ALT Activity 66

226 Histopathology 66

227 Statistical Analysis 67

 

CHAPTER THREE: RESULTS AND DISCUSSION

32 Results 68

321 Results of Antiplasmodial Testing 68

312 Haematology 72

313 Biochemistry 81

314 Histopathology 85

 

CHAPTER FOUR: SUMMARY, CONCLUSION AND RECOMMENDATION

41 Summary 89

42 Conclusion 90

43 Recommendations 90

References 92

Appendix 103

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ENHANCEMENT OF ANTIMALARIAL EFFECTS OF CHLOROQUINE WITH CHLORPHENIRAMINE IN PLASMODIUM BERGHEI INFECTED MICE

3,000.003,200.00 (-6%)

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