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Molecular Therapeutics - Essay Example

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The scientific journey of cyclooxygenase began as early as the 1930s when prostaglandins were first discovered in human semen (Bindra, 1977). Albeit, due to the relative instability and low concentration of prostaglandin found in the semen, it was difficult to clearly identify them for almost thirty years afterwards…
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Molecular Therapeutics
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"Molecular Therapeutics"

Download file to see previous pages Later in 1970, the mechanism of prostaglandin biosynthesis was demonstrated to involve the formation of bicyclic peroxides or endoperoxides as the initial product of polyunsaturated fatty acid oxygenation. Prostaglandin endoperoxides were successfully isolated and the name 'cyclooxygenase' came into existence as a term that describes the enzyme that is responsible for this complex biochemical transformation (Lawrence et al 1999; Hamberg and Samuelson 1973).
According to Lawrence and his colleagues (1999), the chemical process catalysed by cyclooxygenase; the conversion of arachidonic acid, (which is known to be the precursor to prostaglandins), to Prostaglandin G2 (PGG2) involves the enzymatic removal of the 13-pro-S-hydrogen, giving rise to a Pentadienyl radical with maximal electron density at C-11 and C-15. Trapping of the carbon radical at C-11 with Oxygen produces a peroxyl radical, which when added to C-9 generates a cyclic peroxide and a carbon-centred radical at C-8. The double bond at C-12 become re-inforced by the C-8 radical, generating the bicyclic peroxide and an allylic radical with maximal electron density at C-13 and C-15. The carbon radical at C-15 is trapped with oxygen to form a peroxyl radical, which is reduced to prostaglandin G2.
Cyclooxygenase came t...
Prostaglandins were shown to be involved in a wide array of physiological and pathophysiological responses such as pain, inflammation, homeostasis, regulation of renal function and maintenance of the mucosal integrity of the stomach wall (Remmel et al 2003), their inhibition therefore spells the anti-inflammatory and analgesic utility of NSAIDs and also their adverse effects, such as gastrointestinal toxicity and bleeding.
However, Non-steroidal anti-inflammatory drugs happen to be the most widely used drugs in the treatment of pain and inflammation, their therapeutic effects was seen to stem from their ability to inhibit cyclooxygenase induced prostaglandin synthesis, which was also their major source of adverse side effects. The dilemma that ensued was how to separate the pharmacologic value of these drugs from the adverse effects.
In the course of the search for a specific inhibitor of the negative effects of prostaglandins, which could spare the positive effects while reducing the adverse effects, it was discovered that depending on the structure of the cyclooxygenase enzyme involved in their synthesis, prostaglandins could be separated into two groups (Green 2001). This led to the discovery of two different cyclooxygenase isozymens encoded by two genes with different protein pattern and distribution (Remmel, 2003; Lawrence et a 1999; Ouellet, 2001) with Cyclooxygenase 1 (COX-1) constitutively expressed in most cell types, including platelets while COX-2, though not found in healthy tissues of the body, was induced in response to proinflammatory and proliferative stimuli (Ouellet et al 2001) essentially in response to cytokines, endotoxins, mitogens and at times growth factor (Herschman, 1996) . Available body of evidence, therefore showed that the ...Download file to see next pagesRead More
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