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BCH00022 - EFFECT OF ORAL ADMINISTRATION OF SEPTRIN AND PARACETAMOL IN LIVER, BRAIN AND SMALL INTESTINE OF FEMALE WISTAR RAT


ABSTRACT

            This work evaluated the effects of oral administration of septrin and paracetamol on the brain, liver and small intestine in female Wistar rates. Sixteen (16) healthy female Wistar rats were obtained locally in the animal holding facility in LAUTECH  and were picked into two groups, comprised of eight (8) rats  each. An oral dose of 105. 5mg/kg body weight of septrin and 101.3mg/kg body weight of paracetamol was administered to a group once daily for 21days, while the other group received distilled water. The activities Lactate dehydrogenase and Alkaline phosphatase were determined in the liver, brain, small intestine and plasma and subjected to statistical test at p <0.05. The administration of septrin and paracetamol did not affect the body weight of rats, the feed and water intake of the rats. Lactate dehydrogenase activity decreased (P < 0.05) in the liver of  rat administered paracetamol and septrin, no significant difference was obtained in brain but increase in the serum. In a similar pattern, the ALP activity decreased markedly (P>0.05) in the liver and small intestine with concomitant increase in the serum (P<0.05). There were no significant increase (P > 0.05) in the organ to body ratio of the control and the treated group of liver, brain and small intestine. Photomicrography of the liver indicated occlusion in the portal ventral vein with few fenestration in the hepatic parenchyma cell, while the brain showed neurodegeneration in the cerebral cortex with vacuolation and perinuclear spacing. However, small intestine reflected normal mucosa of epithelium and distortion in the histo-architecture of the circular muscle of muscularis external and the of brunner’s glands of the sub-mucosa also appears normal. These research work has shown that the misuse of septrin and paracetamol are very injurious and harmful to human health, especially the liver. However there should be a public health awareness to the misuse of drugs without doctor’s or physician’s prescription in order to eradicate the effect of these common drugs.

CHAPTER ONE

1.0       INTRODUCTION AND LITERATURE REVIEW

1.1       Introduction

            Self-medication is the use of non-prescribed drugs to treat self-diagnosed disorders or symptoms. This can include the use of over-the-counter (OTC) drugs available without a physician’s prescription through pharmacies (WHO, 2002; Jain, 2011) the irregular use of a prescribed drug, typically in chronic or intermittent diseases, or the use of leftover drugs from previous prescriptions. It also includes the use of a wide range of complementary and alternative medicine (CAM) such as herbal medicines (herbs or herbal preparations), nutritional supplements, traditional products, and home remedies (Pfaffenbach et al., 2010; WHO, 2015). People all over the world suffer common health problems (e.g. colds, headaches, digestive problems and muscle aches) in roughly the same frequency and respond in the same way to these problems. In 50% of the cases, they let the condition run its course or use at home remedy. In 25% of cases, they use non-prescription/OTC medications and the remaining 25% of cases visit a physician or use a prescription medicine previously obtained for the same condition. Surveys show that OTC medications are seen by many people as being as effective as prescription medications (France, 2015). The reasons for using self-medication are poorly understood. Most studies point to loose regulations about medication, and inadequate access to health care, as the main reasons (WHO, 2002). In many developing countries thousands of different prescription-only drugs are sold OTC. Many of these are drugs which potentially serious side-effects and need to be used with care (WHO, 2015). The potential risks of self-medication include using inappropriate drugs, or inaccurate dosages, which may result in adverse reactions. It may temporarily mask symptoms and delay patients from seeking medical advice, which could result in serious complications (WHO, 2002). Self-medication with antibiotics has the serious potential for development of drug-resistant microorganisms and hence future treatment failure (Gossesns et al., 2015).

Antibiotic is used to denote a chemical substance produced by one microorganism that kills or inhibits the growth of other microbes, the term now applies to both naturally produced substances and those synthesized in the laboratory (Russell, 2004). Most are produced by either fungi (e.g., penicillin, cephalosporins), Bacillus species (e.g., polymyxin, bacitracin), or Streptomyces species (streptomycin, tetracycline, erythromycin, kanamycin, neomycin, nystatin). Broad-spectrum antibiotics are those that act on both gram-positive and gram-negative bacteria (Brooks et al., 2004).

Medications that relieve pain without causing loss of consciousness are classified as analgesics. They are also commonly referred to as pain killer. There are various classes of analgesics, determined by their chemical structures and mechanisms of action. Analgesics drug are drugs that selectively inhibit the perception sensation of pain. Pain can be classified as acute or chronic (Carr, 1999). Acute pain is usually of short duration and the cause often identifiable (disease, trauma). Chronic pain persists after healing is expected to be complete, or is caused by a chronic disease. Those non-opioid analgesics which also have anti-inflammatory actions include salicylates and NSAIDs (nonsteroidal anti- inflammatory drugs); they can reduce both pain and inflammation of chronic inflammatory disorders such as rheumatoid arthritis, but they do not alter or modify the disease process itself (Zuckerman, 1994). The pain and inflammation of an acute attack of gout is treated with a NSAID; a xanthine-oxidase inhibitor is used for long-term control of gout (McCormack,1994).

Irrational use of analgesics and antibiotics may lead to adverse events including a variety of gastrointestinal complications, adverse effects on kidney function, risk of cardiovascular events and hepatic injury (Remington et al., 2006).

This research work was carriedout to investigate the effect of oral administration of septrin and paracetamol on lactate dehydrogenase and alkaline dehydrogenase activities in liver, brain and small intestine of the female Wiatar rats.

1.2       LITERATURE REVIEW

1.2.1    Antibiotics

            The term antibiotic was coined from the word „antibiosis‟ which literally means „against life‟. In the past, antibiotics were considered to be organic compounds produced by one microorganism which are toxic to other microorganisms (Russell, 2004). As a result of this notion, an antibiotic was originally, broadly defined as a substance, produced by one microorganism (Denyer et al., 2004), or of biological origin (Schlegel, 2003) which at low concentrations can inhibit the growth of, or are lethal to other microorganisms (Russell, 2004). However, this definition has been modified in modern times, to include antimicrobials that are also produced partly or wholly through synthetic means. While some antibiotics are able to completely kill other bacteria, some are only able to inhibit their growth. Those that kill bacteria are termed bactericidal while those that inhibit bacterial growth are termed bacteriostatic (Walsh, 2003). Although antibiotic generally refers to antibacterial, antibiotic compounds are differentiated as antibacterials, antifungals and antivirals to reflect the group of microorganisms they antagonize (Brooks et al., 2004; Russell, 2004). Penicillin was the first antibiotic discovered in September 1928 by an English Bacteriologist, late Sir Alexander Fleming who accidentally obtained the antibiotic from a soil inhabiting fungus Penicilliumnotatum but its discovery was first reported in 1929 (Aminov, 2010), and clinical trials first conducted on humans in 1940 (Russell, 2004; Schlegel, 2003). The discovery and development of the first significant antibiotic “penicillin” in 1920‟s, and subsequent introduction into man’s health care system in the 1940‟s has continued to transform the management and fight against bacterial infections (White and Cox, 2013). However, antibiotics are not totally selective in their antibacterial activity. While antagonizing disease causing bacteria, they also antagonize the normal and useful microbiotarial that we all have and need in our systems as those in the gastrointestinal tract (Walsh, 2003). Prescription and administration of any given antibiotics is therefore predicated on the overall intended benefit, taking into consideration the attendant side effects. For this reason, it is pertinent to understand the mechanism of action of every identified antibiotic before introduction into our health care delivery system, and recent molecular biological approaches have played very significant roles to elucidate our understanding in this regard. Hence this paper aimed to review the classification of antibiotics and their mode of action with emphasis on molecular perspectives.

1.2.2    Classes of antibiotics

There are several ways of classifying antibiotics but the most common classification schemes are based on their molecular structures, mode of action and spectrum of activity (Calderon and Sabundayo, 2007). Others include route of administration (injectable, oral and topical). Antibiotics within the same structural class will generally show similar pattern of effectiveness, toxicity and allergic-potential side effects. Some common classes of antibiotics based on chemical or molecular structures include Beta-lactams, Macrolides, Tetracyclines, Quinolones, Aminoglycosides, Sulphonamides, Glycopeptides and Oxazolidinones (van Hoek et al., 2011; Frank and Tacconelli, 2012; Adzitey, 2015).

  • Beta-lactams

            Members of this class of antibiotics contain a 3-carbon and 1-nitrogen ring that is highly reactive. They interfere with proteins essential for synthesis of bacterial cell wall, and in the process either kills or inhibits their growth. More succinctly, certain bacterial enzymes termed penicillin-binding protein (PBP) are responsible for cross linking peptide units during synthesis of peptidoglycan. Members of beta-lactam antibiotics are able to bind themselves to these PBP enzymes, and in the process, they interfere with the synthesis of peptidoglycan resulting to lysis and cell death (Heesemann, 1993). The most prominent representatives of the beta-lactam class include Penicillins, Cephalosporins, Monobactams and Carbapenems.

  • Tetracyclines

      Tetracycline was discovered in 1945 from a soil bacterium of the genus Streptomyces by Benjamin Duggar (Sanchez et al., 2004). The first member of this class was chlorotetracycline (Aureomycin). Members of this class have four (4) hydrocarbon rings   and they are known by name with the suffix „–cycline‟. Historically, members of this class of antibiotics are grouped into different generations based on the method of synthesis. Those obtained by biosynthesis are said to be First generation. Members include Tetracycline, Chlortetecycline, Oxytetracycline and Demeclocycline. Members such as Doxycycline, Lymecycline, Meclocycline, Methacycline, Minocycline, and Rolitetracycline are considered Second generation because they are derivatives of semi-synthesis. Those obtained from total synthesis such as tetracycline are considered to be Third generation (Fuoco, 2012). Their target of antimicrobial activity in bacteria is the ribosome. They disrupt the addition of amino acids to polypeptide chains during protein synthesis in this bacterial organelle (Medical News Today, 2015). Patients are advised to take tetracyclines at least two hours before or after meals for better absorption. All tetracyclines are recommended for patients above eight (8) years because the drugs have shown to cause teeth discoloration among patients below this age can be used in treating malaria, elephantiasis, amoebic parasites and rickettisia (Sanchez et al., 2004). In the past, antibiotics belonging to this class were very much the envy of numerous Clinicians owing to their wide antimicrobial spectrum but this is no longer the case because numerous bacteria are now able to resist them (Chopra and Roberts, 2001).

  • Aminoglycoside

            The first drug to be discovered among members of this class of antibiotics was streptomycin, first isolated in 1943 (Mahajan and Balachandran, 2012). Streptomycin has been greatly used against Mycobacterium tuberculosis, the causal agent of tuberculosis among humans. The aminoglycosides are compounds of usually 3-amino sugars connected by glycosidic bonds. They are obtained from soil Actimomycetes. Aminoglycoside have a broad spectrum of antibacterial activity. They are able to inhibit the protein synthesis in bacteria by binding to one of the ribosomal subunits (Peterson, 2008), and are effective against aerobic Gram-negative rods and certain Gram-positive bacteria. The oldest known aminoglycoside, as earlier inferred is Streptomycin which has been used severally in treating bubonic plague, tularemia and tuberculosis (Talaro and Chess, 2008). Notwithstanding its effectiveness against a wide array of infections, streptomycin was found to be highly toxic. This unfortunate feature of the drug necessitated the need to search for new members of aminoglycosides that would still be effective against bacteria but less toxic to humans. The search was fruitful with the discoveries of antibiotics such as Gentamicin, Neomycin, Tobramycin and Amikacin. Gentamicin is less toxic and is widely used for infections caused by Gram-negative rods (Escherichia, Pseudomonas, Shigella and Salmonella). Tobramycin, in particular, is used in treating Pseudomonas infections in cystic fibrosis patients (Gilbert, 2000).

  • Oxazolidinones

            Oxazolidinones are a group of synthetic antibiotics approved only recently for use.. Although the mechanism of action of oxazolidinone is not yet fully understood, they are reported to interfere with protein synthesis. Oxazolidinones inhibit protein synthesis by binding to the P site of the ribosomal 50S subunit (Shinabarger et al., 1997; Bozdogan and Appelbaum, 2004). They have a broad spectrum of activity against Gram-positive bacteria including methicillin and vancomycin-resistant staphylococci, vancomycin-resistant enterococci, penicillin- resistant pneumococci and anaerobes (Bozdogan and Appelbaum, 2004). Linezolid is used for treatment of respiratory tract and skin infections caused by Gram-positive bacterial pathogens (Moellering, 2003). Oxazolidinones constitute the choice drug in dealing with surgical infections because they easily penetrate and accumulate in the tissue including bone, lung, vegetations (plant-like growth in tissues), haematoma and cerebrospinal fluid (Bozdogan and Appelbaum, 2004). Although adhering to normal standard routines of linezolid administration are usually safe, side effects such as myelosuppression, resulting to anemia and thrombocytopenia are often encountered in cases when treatment is prolonged (Kuter and Tillotson, 2001).

  • Quinolones

            This class of antibiotics was first discovered as nalidixic acid by Scientists involved in search of antimalarial drugs. Nalidixic acid was discovered as an impurity during the development of quinine in the early sixties. They are able to interfere with DNA replication and transcription in bacteria. Two major groups of compounds have been developed from the basic   molecule: quinolones and naphthyridones which include cinoxacin, norfloxacin, ofloxacin, ciproxacin, temafloxacin sparfloxacin, nalidixic acid, enoxacin etc. (Domagala, 1994). Their structure generally consists of two rings but recent generations of quinolones possess an added ring structure which enables them to extend their spectrum of antimicrobial activity to some bacteria, particularly anaerobic bacteria that were hitherto resistant to quinolone. Since its discovery in the early 1960‟s, several modifications have been made to its parent structure and this has led to the development and synthesis of many derivatives with tested antibiotic potency. The nomenclature of members of this class of antibiotics is complex (Domagala, 1994) but members are often known by the suffix–oxacin, such as floxacin, ciprofloxacin and levofloxacin. Modifications in the basic structure of quinolones are reported to have improved their bioavailability and increased both their spectrum of activity and potency; enhancing their performance in the treatment of various forms of illnesses such as urinary, systemic and respiratory tract infections. Notwithstanding these notable feats, there still exist safety concerns with some members of this class of antibiotics which has led to the withdrawal of grepafloxacin, sparfloxacin, temafloxacin, trovafloxacin etc., all belonging to the class quinolones, from the market (Domagala, 1994). Although a good deal of progress is being made in terms of in vitro studies and pharmacodynamics, knowledge of the dynamics of toxicity amongst some of this class of antibiotics is yet inconclusive.           

1.2.1.1 Sulphonamides                     

            Sulphonamides are reportedly, the first group of antibiotics used in therapeutic medicine, and they still play very important role in medicine and veterinary practice (Eyssen et al., 1971). Sulphonamides inhibit both Gram-positive and Gram-negative bacteria such as Nocardia, E. coli, Klebsiella, Salmonella, Shigella and Enterobacter, Chlamydia trachomatis and some Protozoa, and are widely used in the treatment of various infections including tonsillitis, septicemia, meningococcal meningitis, bacillary dysentery and some urinary tract infections (Eyssen et al., 1971). Studies have shown that Sulphonamides are also able to impede cancerous cell agents (Stawinski et al., 2013; Xu et al., 2014). The original antibacterial sulphonamide (also spelt sulfonamide by some Workers), are synthetic antimicrobial agents that contain the sulphonamides bacteriostatic rather than bactericidal as in (Figure 1).  However, (Henry, 1943) in his thorough early work opined that sulphonamides may become bactericidal if their concentration is sufficiently high or if the presence of any sulfonamide concentration is accompanied by other environmental conditions unfavourable to bacteria. Such unfavourable conditions would include poor cultural conditions, adverse temperature, antibodies, toxic proteolytic product etc. Although sulphonamides are adjudged good and effective in treating various diseases and infections, they are recommended and administered with caution because of their toxicity and side effects, some of which include urinary tract disorders, haemolytic anaemia, porphyria, and hypersensitivity reactions (Slatore and Tilles, 2004; Choquet-Kastylevsky et al., 2002).Examples of Sulphonamides are; (Bactrim, Septra) and Erythromycin Sulfisoxazole (Eryzole, Pediazole).