PROPUESTA DE MEJORA

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system and the kinnin system. Inflammatory mediators can be divided into exogenous and endogenous mediators. Bacterial products and toxins can act as exogenous mediators of inflammation and noteable among this is endotoxin. The immune system of higher organisms has probably evolved in a veritable sea of endotoxin, so it is perhaps not surprising that this substance evokes powerful response. For example, endotoxin can trigger complement activation resulting in the formation of anaphylatoxins (C3a and C5a) which cause vasodilation and increase vascular permeability. In addition, endotoxin elicit T cell proliferation and have been described as super antigen for T cells.

Endogenous mediators of inflammation are produced from within the innate and adaptive immune system itself as well as other systems. For example, they can be derived from molecules that are normally present in the plasma in an active form such as peptide, fragments of some components of complements, coagulation and kinnin systems. Mediators of inflammatory responses are also released at the site of injury by a number of cells types that either contain them as preformed molecules within storages granules e.g histamine which can rapidly switch on the machinery requires to synthesize the mediators when they are required for example, to produce metabolites of arachidonic acid.

Monocular phagocytes (monocytes and macrophages) are central to inflammation as they produce many components which participate in or regulate the different plasma enzymes systems and hence the mediators of inflammatory response. Early phase mediators are produced by mast cells and platelets. They are especially important in acute inflammation and include mainly histamine, serotonin and other vasoactive substances. To the early phase mediators also belong chemoatractants e.g (5a and cytokines such as IL-1, IL-6 and TNF.

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fever. They also protect the lining of the stomach and intestines from the damaging effects of acid and promote blood clotting by activating blood platelets. Prostaglandins also affect kidney function. The enzymes that produce prostaglandins are called cyclooxygenase (COX). There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation pain and fever, however only COX-1 produces prostanglandins that activate platelets and protect the stomach and intestinal lining, NSAIDs block COX enzymes and reduce production of prostaglandins. Therefore, inflammation, pain and fever are reduced.

Most prominent members of this groups of drugs are aspirin, ibruprofen and naproxes all of which are available over the counter in many areas (Stuart et al., 2010).

2.12.4.1 Mechanism of action of non steroidal anti-inflammatory drugs (NSAIDs)

Non sterioidal anti-inflammatory drugs (NSAIDs) act as non selective inhibitors of the enzyme cycoloxgenase (COX) which is known to have at least two distinct isoforms; COX-1 and the inducible isoform COX-2 . The NSAIDs inhibit both COX-1 and COX-2 isoenzymes.

Cycloxygenase (COX) catalyses the formation of prostaglandins and thomboxane from arachidonic acid. Prostaglandins act as messenger molecules in the process of inflammation.

COX-1 has clear physiological function. Its activation leads for instance to the production of prostaglandin which when released by the endothelium is antithrombogenic and when released by gastric mucosa is cytoprotecive. COX-2, discovered 6 years ago, is induced by inflammatory stimuli and cytokines in migratory and other cells. It is therefore attractive to suggest that the anti-inflammatory action of NSAIDs is due to inhibiton of COX-2, whereas the unwanted side effects such as irritation of the stomach lining are due to inhibition of COX-1. Drugs that have the highest COX-2 activity and a more favourable COX-2 : COX-1 activity ratio will have a more potent anti-inflammatory activity with fewer side effects than drugs with a less faovurably COX-2 : COX-1 activity ratio. The identification of selective inhibitors of COX-2 will, therefore, lead to an advance in therapy.

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Phospholipase A₂ Glucocorticoids Arachidonic

Acid

NSAID Cyclooxygenase Lipooxygenase COX -1, COX-2

Cyclic Endoperoxides Hydroperoxy Eicostatetranoic acid (HPETE)

Prostaglandins Thromboxane Hydroxyeicosa Leukotrienes PGD₂ PGE₂, PGF₂ TXA₂ tetranoic acid LTA4, LTB4, LTC4,

PGI2 (HETE) LTD4, LTE4

Three isoforms of cyclooxygenase have been identified, cyclooxygenase 1, cyclooxygenase 2 ( COX -1 and COX-2) and cyclooxygenase 3 ( or cyclooxygenase 1b). COX-1 is normally present in all tissues while COX-2 is induced by cytokines and certain serum factors.

Glucocorticoids inhibit phospholipase A2 and thus block the production of both prostaglandins and leukotrienes, exerting a potent anti-inflammatory effect. Glucocorticoids also block the action of cyclooxygenase -2.

Pain Pain

Inflammation, injury etc Cyclo – oxygenase/ Lower the threshold of Bradykinin, IL-1, IL-8 lipo- oxygenase pain receptors/C fibres

TNFa etc. Prostaglandins

Fever Fever

Infection, tissue damage, PGE 2 triggers the

Inflammation, graft hypothalamus to elevate

Rejection, etc. body temperature

IL-1,IL-6,TNFa

Inflammation (NSAIDs Block Here) Inflammation

Infectious agents, Vasodilation, increased

ischemia, antigen- capillary permeability;

antibody reactions, infiltration of leukocytes

thermal or physical injury and phagocytes; tissue

IL-1 and TNF- etc. degeneration, fibrosis etc.

Figure 6 : Cyclooxygenase and lipooxygenase pathway to produce prostaglandins and leukotrienes respectively (Nelson and Randy, 2005)

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Malaria is a mosquito borne infectious disease of humans and other animals caused by protozoans parasites of the genus Plasmodium. It is one of the most common infectious diseases and an enormous public health problem. It infects between 300-500 million people every year and causes between one and three million deaths annually mostly among young children in SubSaharan Africa (Miller et al., 1994; More, 2002; David et al., 2004; Martin et al., 2004;

Wright, 2005; WHO, 2005 ). It begins with a bite from an infected female mosquito which is introduced into the parasite via its saliva into the circulatory system and ultimately to the liver where they mature and reproduce. The disease causes symptoms that typically include fever and headache which in severe cases can progress to coma and death. Malaria is widespread in subtropical regions in a broad band around the equator, including much of SubSaharan Africa, Asia and the Americas. Five species of Plasmodium can infect and be transmitted by humans (Hardman et al., 2001). The vast majority of deaths are caused by Plasmodium falciparum while Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae cause a generally milder form of malaria that is rarely fatal. Plasmodium falciparum, the most important pathogenic representative of this species is responsible for the majority of cases (Tramputz et al., 2003; Batista et al., 2009; Kakkilaya, 2008) The zoonotic species Plasmodium knowlesi, prevalent in Southeast Asia causes malaria in macaques but can also cause severe infection in humans. Malaria is prevalent in the tropical region because significant amount of rainfall, warm temperature and stagnant waters provide habitats ideal for mosquito larvae. Disease transmission can be reduced by preventing mosquito bites; by distribution of mosquito nets and insect repellants, or with mosquito control measures such as spraying insecticides and draining standing water. Malaria is typically diagnosed by microscopic examination of blood using blood films with antigen based rapid diagnostic tests. Modern techniques that use the polymerase chain reaction to detect parasite DNA have also been developed but these are not widely used in malaria endemic areas due to their high cost and complexity.

The World Health Organization (WHO) has estimated that in the year 2010, there were 216 million documented cases of malaria. In that period, between 655,000 and 1.2 million people died from the disease (roughly 2,000-3,000 per day) (Hardman et al., 2001) many of whom

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were children in Africa. Malaria is commonly associated with poverty and is also a major hinderance to economic development. Despite a need, no effective vaccine currently exists;

although efforts to develop one are ongoing. Several medications are available to prevent malaria in travelers to malaria endemic countries (prophylaxis). A variety of antimalaria medications are available. Severe malaria is treated with intravenous or intramuscular quinine or since the mid-2000s, with the artermisinin derivative artesunate, which is superior to quinine, in both children and adults and is given in combination with a second antimalarial, such as mefloquine.