LONG-TERM EFFECT OF ADMINISTRATION OF ACETAMINOPHEN AND EFFECTS OF AQUEOUS AND METHANOL EXTRACT OF ZINGIBER OFFICINALE ON LIVER ENZYMES OF HEALTHLY WISTAR RATS.

CHAPTER ONE INTRODUCTION 1.1 Background of study Acetaminophen (N-acetyl-p-aminophenol; APAP) is widely used as an analgesic and antipyretic drug worldwide. It produces alanine derivatives by hydrolysis, which are directly converted into hydroxylamine. N-Acetyl-p-benzoquinoneimine (NAPQI), is an intermediate product of acetaminophen produced in the presence of cytochrome-p450 that causes hepatic damage and tubular necrosis in the kidney in both humans and experimental animals. In this situation, a large amount of APAP is metabolized by the presence of P450s, which leads to reduced GSH levels by NAPQI conjugation and covalent binding of NAPQI. Acetaminophen’s clinical and biochemical side effects are well known and it is therefore used as a reference compound to assess the strengths and weaknesses of genomic and proteomic technologies as toxicological tools. The aim of the present study was to analyse the proteomic changes in male Wistar rat liver associated with toxicity induced by acetaminophen. Acetaminophen is one of the most commonly used analgesic agents for alleviating acute and chronic pain. Due to its safety, acetaminophen is prescribed for patients in whom non-steroidal, anti-inflammatory drugs (NSAIDs) are contraindicated, such as those with gastric ulcers and bronchial asthma, pregnant women, nursing mothers, and children (Leung, 2012; Roberts et al., 2016). It has also been placed on all three steps of pain treatment intensity of the WHO analgesic ladder for the treatment of cancer pain. However, its metabolism is complex, and its analgesic mechanisms have not been completely understood. Previously, it was thought that acetaminophen induces analgesia by inhibiting the enzyme cyclooxygenase (COX), but now it is believed that acetaminophen is metabolized to p-aminophenol, which crosses the blood-brain barrier and gets metabolized by fatty acid amide hydrolase to yield N-acylphenolamine (AM404) (Roberts et al., 2002; Jennings et al., 2003; Mallet et al., 2010). Therefore, acetaminophen induces analgesia via direct action on the brain (Bannwarthet al., 1992; Gelgor et al., 1992; de Lange et al., 1994; Hogestatt et al., 2005), and these receptor sites on the brain are the main mediators of acetaminophen-induced analgesia. Therefore, our results describing the new analgesic mechanism underlying the action of acetaminophen on the spinal dorsal horn, are reasonabr4le compared to previous reports (Ohashiet al., 2017). Acetaminophen does not possess any anti-inflammatory activity, because it is a very weak inhibitor of COX and does not inhibit neutrophil activation (Hanel and Lands, 1982). Therefore, even though it has always been discussed together with NSAIDs in terms of pharmacological mechanism, acetaminophen is not regarded as an NSAID and is no appropriate for treating inflammatory pain conditions. This review will allow clinicians to consider new pain management techniques using acetaminophen. It has been thought that acetaminophen induces analgesia by blocking prostaglandin synthesis from arachidonic acid by inhibiting the enzymes, COX-1 and -2. However, unlike NSAIDs, and Cannabinoid 1 Receptors Acetaminophen is first metabolized to p-aminophenol, which easily crosses the blood-brain barrier and is converted to AM404 by fatty acid amide hydrolase (Hogestatt et al., 2005). Acetaminophen is also metabolized to other compounds through another pathway, such as N-acetyl p-benzoquinoneimine (NAPQI), which also appears to produce analgesia by activating transient receptor potential ankyrin 1 receptors (Andersson et al., 2011; Gentry et al.,2015). They are also the reason why acetaminophen exhibits a “central” effect for long periods. Therefore, there is a possibility that, in addition to its actions in the brain, acetaminophen and its metabolite AM404 also induce analgesia via direct activation of TRPV1 and/or CB1 receptors in the spinal cord dorsal horn. Similar to the results in naïve rats, and we believe that our results will allow clinicians to consider new pain management techniques involving acetaminophen. When the appropriate dosage of acetaminophen is used, serious side effects occur. However, some case studies have reported liver toxicity caused by acetaminophen. Usually, acetaminophen is administered orally or intravenously. The maximum single-dose of acetaminophen for the treatment of pain or fever is 1,000 mg every 4 h as needed, up to a recommended maximum daily dose of 4g. Natural products of animals, plants and microbial sources have been used by man for thousands of years either in the pure forms or crude extracts to treat many diseases. Ginger root comes from the Zingiber officinale plant, and it has been used in Chinese and Indian medicine for thousands of years. Ginger originated in Maritime Southeast Asia and was likely domesticated first by the Austronesian peoples. It was transported with them throughout the Indo-Pacific during the Austronesian expansion (c. 5,000 BP), reaching as far as Hawaii. Ginger is one of the first spices to have been exported from Asia, arriving in Europe with the spice trade, and was used by ancient Greeks and Romans. The distantly related dicots in the genus Asarum are commonly called wild ginger because of their similar taste. The recent classification of ginger is Class Liliopsida, Sub-class Zingiberales, Family Zingiberaceae, Genus Zingiber, Species Zingiber officinale which is mainly based on the sequences of nuclear ribosomal DNA. Ginger is a flowering plant whose rhizome (ginger roots or ginger) is widely used as spice and folk medicine. It is a herbaceous perennial which grows annual pseudostems (false stem made up of the rolled bases of leaves). The inflorescences bear flowers having pale-yellow petals with purple edges and arise directly from the rhizome on separate shoots. Research shows that ginger may be helpful for mild nausea and vomiting associated with pregnancy, although its safety has not been demonstrated. It remains uncertain whether ginger is effective for treating any disease, and use of ginger as a drug has not been approved by FDA. 1.2 PROBLEM OF STUDY Prolonged and excessive use of acetaminophen can lead liver damage or failure. The liver metabolizes acetaminophen, and in high doses, it can overwhelm the livers ability to process it safely causing damage. Research shows that ginger may be helpful for mild nausea and vomiting associated with pregnancy, although its safety has not been demonstrated. It remains uncertain whether ginger is effective for treating any disease. Hence the need for this research. 1.3 AIM OF STUDY To determine the long-term effects of administration of acetaminophen and effect of aqueous and methanol extract of ginger on liver enzymes of healthy wistar rats. The aim of the present study was to analyse the proteomic changes in male Wistar rat liver associated with toxicity induced by acetaminophen. 1.4 OBJECTIVE OF STUDY  The effects of long-term administration of acetaminophen  The effect of aqueous and methanol extract of ginger on • Alanine Aminotransferase (ALT) • Aspartate Aminotransferase (AST) • Alkaline Phosphate (ALP) • Gamma-Glutamyl Transferase (GGT) • Bilirubin 1.5 SCOPE OF STUDY The scope of was limited the long-term effect of administration of acetaminophen and effect of aqueous and methanol extract of ginger on liver enzymes of healthy wistar rats. 1.6 JUSTIFICATION OF STUDY Acetaminophen is one of the most widely used over-the-counter pain relievers globally. Understanding its long-term effects helps ensure its safety for chronic use. Prolonged use or high doses of acetaminophen may cause adverse effects on the liver, kidneys and other organs investigating the risks is crucial for public health. Studying its long-term efficacy and safety aids in optimizing pain management strategies. Therefore the essence of this study is report is to determine the long-term effects of administration of acetaminophen and effect of aqueous and methanol extract of ginger. 1.7 SIGNIFICANCE OF STUDY The significance of this study lies in its far-reaching implications for healthcare, patient and wellbeing of public health. Findings from this research can influence the public health policies and guidelines related to the availability, labelling and usage recommendations for acetaminophen thereby reducing the risks of adverse outcomes. This study contributes to the understanding of drug safety and metabolism