Abstract

Chemotherapy is a term use in the 21st century to describe the treatment or the inhibition of abnormal cells or the growth of an infectious agent in the system of an organism. These infectious agent might be benign or malignant tumors or a microbe like a bacteria or virus.  To investigate the effects of these cyclophosphamide and imidacloprid when combined on blood glucose level of an organism precisely male albino rats is the aim and the base line of this study or research program.

The animals where kept for two weeks for acclamatisation, base  line information collected like weight ranging from 150g to 200g. these animals were divided into four groups  treated as follows, group one (Distilled water10mg/kg/bwt), group two (CP 5mg/kg/bwt), group three (CP5mg/kg/bwt)+ iron 70(16.1mg/kg/dl), group four iron70(16.1mg/kg/bwt) , each group containing four animal.

Treatment was done for 21days, after which their oral blood glucose were measured at 0, 30, 60, 90,120 and 240 minutes. It was found that a part of group one all other groups had a rise in glucose level, this rise is as a results of the treatment that each group had received which has actually affected that their glucose regulatory mechanism. As a result these combined or individual chemicals should be apply with appropriate prescription by a qualify medical personnel and a continuous follow up.

CHAPTER ONE

INTRODUCTION AND LITERATURE REVIEW.

1.1 Introduction

There is a serious and dilapidating consequences of chemotherapeutic agents such as cyclophosphamide, this agents was discovered since early 1950s by two scientist from the United States of America precisely Godman and Gulman during the Second World War. This chemical was discovered to treat cancerous cells such as leukemic cells (Yasuda H et al 2021) lymphomas and others (P Nygreen et al 2001).

But the central dogma is that each drug has site effects which can be handle (sub clinical manifestation express by a patients as a result of administration of a drug). In this case cyclophosphamide is not excluded as far as pharmacology is concern, affecting brush intestinal enzymes such as carboxyl peptidase and other different enzyme of the body, it can also induce autoimmune diabetes response by the suppressor of T-cells and increase pro -inflammatory T helper type 1 in animal models (LH Frasier et al 1991) .In humans this association is not clear due to the presence of the risk factors for hyperglycemia , but it could be the precipitant for acute complications

IN the other hand, pesticides are chemicals that are widely used in agricultural fields and at home in the complete eradication of unwanted pest around the farms and house respectively, (Akash Sabarwal et al 2018). As such too much application of these chemicals in the environment leads to the generation of toxic effects (Mortafalou S et al 2023), loss of appetite and genetic diseases such as Parkinson’s disease and many others. (Kwok et al 2000)

Imidacloprid is not excluded in this domain of classes of pesticides, precisely an insecticide which affects both rodents and insects, in rodents it affects catecholamine and the beta cells of the pancreas (Samah et al 2017).

1.2 Literature Review

Looking into the insight of this work chemotherapeutic agents are; are chemicals or drugs that are used to treat cancerous cells of the body, as a result of this they are classified into different types, which include the following; antimetabolite which are drugs that interferes with a cell’s RNA and DNA, anti-metabolites (Mu D et al 1996) works when cells are dividing example include fluorouracil, methotrexate and fludarabin (Erbitus el al 2006),

Ant-alkaloids; these are drugs that are made up of natural products, this group of chemotherapeutic drugs can (Wani MC et al 1969) blocks the cells ability to divides and becomes two cells, Anti example include ,vincristine, paclitaxel and topotecan                                                                                                            antitumor atibiotics ,these are drugs that are made up from micro-organisms, these antibodies do not attack like the normal antibodies use to treat infections (Billing et al 1992) they may work in all phase of the cell cycle they either break down DNA strands or slows down or stop DNA synthesis (Zamble et al 1999) that cells need to grow, for example we have bleomycin doxorubicin and motixantrone. Hormonal agent these are two types of hormonal agents use in the treatment of cancer that is corticosteroids hormones and the sex hormones.

Corticosteroids are to treat some cancers (leukemia, multiple myeloma and lymphoma),(Linda C et al 2006) steroids are also use in reducing tumors around the brain and spinal cord steroids are also use in combination with other chemotherapy drugs in combination chemotherapy example include; prednison and dexamethasone.

Sex hormones change how female and male made and act, they can be used to control the growth of breast uterine and prostrated cancer, this drug do not kill cells as typical chemotherapeutic agents rather they cut off the food supply to destroy the cancer cells example include; tamoxifen , leuprolide. Biological response modifiers, these are drugs that strengthen the body’s immune system to fight the growth of cancer cells. Other agents may stop or slow cancer (Shalini Gupta et al 2006) growth by disruption process that are needed to grow or spread, this growing group of anti- cancer medicine is always separated from normal chemotherapy (Erbitus  el al 2006), example of drugs include ;Herceptin and  avastin                                                                                                                      topoisomerase, these are drugs which interferes with topoisomerase enzyme in DNA replication (from the Scotland care foundation, fourth mentoring program 2001 to 2022). Drugs inhibiting topoisomerase I are irotecan (Tasso. SW et al 2013) Topoisomerase II are; amsacrin, etoposide, and Nitrosourase, these are group of alkylating agents that has special action that other group of alkylating agent do not have, that is the ability of crossing the area of the brain (Zustorich.F et al 2013) called the blood –brain barrier (a special area that keeps the drug out from the brain) this action makes the drug more important in the treatment of brain cancer or tumors, example (Ferrp.A.et al 2013) include streptozocin (also a drug that can inhibit the secretion of insulin), ( American cancer society. 2019).

Targeted therapies works by finding specific substances called protein or receptors (Britten. CD et al 2009) these receptors or proteins are targeted by the drug, normal cells are not destroy by this drug, this different from how chemotherapy drugs works, the targeted drugs may be used for the main treatment of cancer or may be use after the treatment to keep the cancer under control or keep it from coming back.

Preventing the strand of the double helix from linking as it should, this would cause a breakage of the strand.  Speaking more on cyclophosphamide and imidacloprid which is my point of focus, is an alkylating agent (substances that add alkyl group to the guanine base of the DNA (Shields HM et al), preventing the cancer cell to multiply while imidacloprid a pesticide to rodents to unwanted pests.

Pesticides

Pesticides is define as a chemical that is use to control or destroy pests (Rasndy. Horsak et al 1964. The root word is a latin word ‘cida’ which means kill. Pesticides is a generic term which can be applied to a wide range of chemicals including herbicides, fungicides, insecticides, insecticides and even biocides. At such pesticides can be important an non-important, the important ones are transported and exported to other countries for diverse usage.(Linde et al 2016). But in this case organic chemicals are frequently used in the control of pest. At such all pesticides have or exert harmful effects to the natural environment and humans, since most are not rapidly decomposed as expected (Rajadesing et al)

Since it may run into streams and even other water bodies and consumption by humans and animals may leads to undesired medical conditions like affecting the blood glucose level, assessing the effects of this chemicals on blood glucose level of individuals expose to it is call for concern.

Imidacloprid

Insecticides are a specific group of pesticides that are widely use against harmful insects in agriculture and greenhouse (Ball et al 2012), Pesticides (insecticides) poisoning can occur when the chemicals intended to control a pest affects non- target forms of having organism including humans (ozdemir et al 2014) here this study is subjected to investigate the effects of pesticides (imdacloprid) on the blood glucose level.

Imidacloprid was first important group of systematic insecticides group worldwide accounting for more than 25% of the market insecticides. Imidacloprid is a neonicotinoid which is a class of neuro active modelled after nicotin, is a potent chemical which act on the central nervous system, which binds to acetylcholine receptors (Suchail et al 2001), also is an alkaloid found in the leaves of natural plant such as tobacco. This chemical has a chemical name of 1-(6-chloro-3 pyridymethl) N-Nitromidazolidin -2-ylideneamine). To rodents; imidacloprid will cause insulin (Montgomery M. et al 2003) resistance of the cells that is making the cell to be resistance in the absorption of insulin leading to high glucose level in blood than normal. Giving rise to a medical condition called hyperglycemia. This situation refers to that (Son H-K; KIM et al 2010) is general called diabetes type two. Hence it is interesting to carry out an investigation on how it affect the blood glucose level in mammals

Glucose homeostasis

The balance of insulin and glucagon to maintain blood glucose. The endocrine cells secrete their respective hormones in the regulation of blood glucose. In response high glucose in blood stimulated the beta cells  to release insulin, the uptake of glucose in the cells, its undergoes glycolysis thereby generating adenosine triosphosphate.ATP) resulting to an increase ratio of ATP/ADP ratio, this lead to the closure of the potassium positive channel to close.

Upon non stimulation these channels are open to ensure resting potential by transporting positively charged potassium iron down the concentration gradient out of the cell, upon closure it will cause calcium ion channels to open causing insulin containing granules to fuse and thereby releasing insulin, hence glucose is regulated. (Brown et al). In the other hand were glucose is limited in amount in blood glucagon will be released by alpha cells, this will stimulated glycogenolysis where, phosphorylase kinase cleaves glucose-1-phosphate (G-1-P) from glycogen by activating glycogen phosphorylase A converting it to glucose -6-phosphate , eventually  releasing free glucose into circulation.(Binbing et al 2015)

Disorders associated to the combination of cyclophosphamide and Iron 70

Cyclophosphamide is a cytotoxic chemotherapeutic agents used in the treatment of hematological disease, also imidacloprid is a pesticide use in the control of pest, the combined chemicals can leads to an auto immune disorder called diabetes, Which is diabetes type and type two. The type one diabetes is a situation where by the beta cells of the pancreas are not secreting the required amount of insulin needed in the regulation of blood glucose level. This situation is mostly common in young people of about 20 years to 35 years. While in the other hand, diabetes type two is a situation where the body cells are resistance to insulin secreted by the beta cells of the pancreas. It is common with people of 40years and above. (Manuel et al 2018). Hence leading to hyperglycemia.

Diagnosis

These are the scientific methods which are used to detect the onset of diabetes in an individual. These methods are given below.

Oral Glucose Tolerance Test (OGTT)

Oral glucose tolerant test was discovered ABOUT 100 years ago and found to be the best of test in measuring the blood glucose level. Which is the accurate quantification of glycaemia with reliable and feasible test for screening and early detection of pre-diabetes (Linn JJ et al 2021) the glucose tolerance test is a scientific method use to judge how well the body metabolized glucose.

Here, glucose is the type of sugar one’s body needs to supply energy to its cell. The body breaks down food into glucose by using proteolytic enzymes and release glucose into the blood streams (Laffel et al 2020). The hormone called insulin release by the pancreas facilitate to bring the glucose in blood streams to cells of the body in order for the cells to carry out it functions.

The function of the digestive system in regulation of blood glucose

The digestive system is a system that is made up of different organs that are capable of metabolizing ingested food material in the body and get rid of undigested food particles and unique in carrying out it functions (Miller et al 2019) it can also be define as the organ that takes in food and liquid and break them down into substance that the body can use for energy, growth and tissues repairs and waste products that the body can’t use are release through bowels (Dong-Hua Liao et al 2007)

The digestive system is made up of the gastro internal tract also called the GIT, the liver pancreas and gall bladder, the GIT is a series of which function in the release of insulin and glucagon to enable bring to normality of the blood glucose level.(Yang W et al 2007).The liver, pancreas and gall bladder are the solid parts of the digestive system.

The liver is the largest intestinal organ of the body and ranges from 1.2kg to 1.6kg (Ogiu N et al 1997) it is soft and pink- brown in color, located in the right quadrant below the diaphragm and protected by the ribs. It is divided into unequal two lobes with the right lobe six time the left lobe these (Fan ST et al 200) (lobes are further divided into lobules which are functional units of the kidney .

The liver is a high vascularized organ which received blood from two sources; 25% of oxygenated blood from through the hepatic artery and 75% deoxygenated blood from the portal vein (Arjun Karla et al 2022). It is also made up of cells like kupffer cells which help in the detoxification and metabolisation of drugs as well as biotransformation of drug and slow release of end products to prevent the hyper state (Graffian et al 2003)

The pancreatic function in blood glucose homeostasis.

The pancreas has key roles in the regulation of macronutrient digestion and hence metabolism/energy homeostasis by releasing various digestive enzymes and pancreatic hormones. It is located behind the stomach within the left upper abdominal Cavity and is partitioned into head, body and tail (Chandra R et al, 2009) The majority of this secretory organ consists of acinar—or exocrine—cells that secrete the pancreatic juice containing digestive enzymes, such as amylase, pancreatic lipase and trypsinogen, into the ducts, that is, the main pancreatic and the accessory pancreatic duct. In contrast, pancreatic hormones are released in an endocrine manner, that is, direct secretion into the blood stream (Suzanne F et al 2017).

The endocrine cells are clustered together, thereby forming the so-called islets of Langerhans, which are small, island-like structures within the exocrine pancreatic tissue that account for only 1–2% of the entire organ There are five different cell types releasing various hormones from the endocrine system: glucagon-producing α-cells, which represent 15–20% of the total islet cells; amylin-,C-peptide and insulin producing β-cells, which account for 65–80% of the total cells; pancreatic polypeptide (PP)-producing γ-cells, which comprise 3–5% of the total islet cells;  somatostatin producing δ-cells, which constitute 3–10% of the total cells; and ghrelin-producing ε-cells,4 which comprise o1%  of total islet cells, ghrelin can inhibit the effect of insulinotropic GLP-1 (Damdindorj et al 2012) Each of the hormones has distinct functions. Glucagon increases blood glucose levels, whereas insulin decreases them (Osundiji et al 2012) Somatostatin inhibits both, glucagon and insulin release, whereas PP regulates the exocrine and endocrine secretion activity of the pancreas.

Altogether, these hormones regulate glucose homeostasis in vertebrates, as described in more detail below. Although the islets have a similar cellular composition among different species, that is, human, rat and mouse, their cytoarchitecture differs greatly. Although islets in rodents are primarily composed of β-cells located in the center with other cell types in the periphery human islets exhibit interconnected α- and β-cells. Through its various hormones, particularly glucagon and insulin, the pancreas maintains blood glucose levels within a very narrow range of 4–6mM. This preservation is accomplished by the opposing and balanced actions of glucagon and insulin, referred to as glucose homeostasis (Wachters et al 2004). During sleep or in between meals, when blood glucose levels are low, glucagon is released from α-cells to promote hepatic glycogenolysis. In addition, glucagon drives hepatic and renal gluconeogenesis to increase endogenous blood glucose levels during prolonged fasting (Mathieu G et al 2009)

In contrast, insulin secretion from β-cells is stimulated by elevated exogenous glucose levels, such as those occurring after a meal. After docking to its receptor on muscle and adipose tissue, insulin enables the insulin-dependent uptake of glucose into these tissues and hence lowers blood stream glucose (Berglund ED et al 2012)  further more  insulin promote glycogenesis, lipogenesis and the incorporation of amino acids into protein, thus is an anabolic hormone as compare to it catabolic activity of glucagon.

1.3 Rationale

Auto-medication of cancers patients as well as other forms of medication also is a big problem, as an attempted solution to this problem, health talks will be discussed to the entire population on the dangers involved in auto-medication of cancerous drugs, as opposed to pesticides exposure to these chemicals may leads to an effects on the blood glucose level of this individuals, therefore assessing the glucose level of these individuals after the exposure of those two classes of chemical when combined is important.

1.4 Research Hypothesis.

The combination of cyclophosphamide and iron-70 has an effect on the oral blood glucose tolerant test.

1.5 Main Objectives.

To determine the effect of the combination of cyclophosphamide and Iiron-70 on oral blood glucose tolerance test in male albino rats.

1.6 Specific Objectives.

To assess oral glucose tolerance test from the combination of iron-70 and cyclophosphamide

To assess the effect of cyclophosphamide on oral glucose tolerance test

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