Molecular Therapeutics Studies - Report Example

Therapeutic Value Of Cyclo-Oxygenase 2 Inhibitors And The Role Of Structural Studies In The Development Of These Drugs. 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. Hamberg and Samuelson were eventually able to clearly elucidate the mechanism of prostaglandin biosynthesis in 1967 (Lawrence, et. al.1999). It became clear, afterwards, that prostaglandins were formed from polyunsaturated fatty acids by a complex reaction involving oxygenation, cyclization and the generation of five chiral centres from an achiral substrate (Lawrence et al 1999). 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 to limelight and became a pharmacologic target when it was discovered by Vane in 1971 that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin formation. 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 anti-inflammatory effects of classical NSAIDs was due, in large part, to the inhibition of cyclooxygenase 2, while the gastrointestinal and ulcerogenic adverse effects was as a result of COX-1 inhibition (Serbert et al 1994). Also, the serious gastrointestinal toxicity cause by therapeutic doses of NSAIDs was demonstrated to be due to their non-selective inhibition of COX-1 and COX-2 (Remmel et al 2003). With the discovery of COX-2 early in the 1990s and the discovery that the coding gene for it has a different protein distribution and profile compared to COX1, there were hopes of the possibility of separating the beneficial therapeutic effect of NSAIDs from most, if not all, of the known adverse effects, by the development of isoform selective inhibitors (Remmel et al 2003, Lawrence et al 1999). The hypothesis that selective COX-2 inhibitors will rid NSAIDs of the several adverse effects was validated when it was demonstrated that COX-2 inhibitors are anti-inflammatory and analgesic therapeutically, but lack the gastric toxicity, bleeding and other adverse effects associated with conventional NSAIDs. This was demonstrated in several research studies with animal models of inflammation and human clinical trials using COX-2 selective inhibitors like Celecoxib, Rofecoxib and Valdecoxib (Remmel et al 2003; Lawrence et al 1999). Assessing the therapeutic value of these COX-2 inhibitors, one is faced with products like Celecoxib, Valdecoxib and Rofecoxib (with brand names - Celebrex, Bextra and Vioxx), which came into existence after several researches aimed at developing portent and highly selective COX-2 inhibitors. The outcome has definitely being worthwhile. Bextra and Vioxx are reported to be about 300times more portent at inhibiting COX-2 than COX-1. This brings the possibility of complete relief from pain and inflammation without suffering gastrointestinal irritation and other NSAIDs adverse effects (COX-2 Inhibitors,2005). The therapeutic advantages of COX-2 inhibitors became widely acknowledged when in 1999, rofecoxib and celecoxib were introduced into the market. Within the span of 1-2yrs they became the most frequently prescribed new drugs in the United States and a couple of other countries (Hunsche, 2001). The widespread acceptance of these drugs will be seen to be based on the relief it promises from pain and inflammation without the attendant gastrointestinal toxicity, ulcer and gastric bleeding that comes with the conventional NSAIDs. This therapeutic utility and safety of the COX-2 inhibitor drugs was established in several clinical and research studies (Lawrence et al 1999; COX-2 Inhibitors, 2005). In two separate studies, the Celecoxib Long-term Arthritis Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR), COX-2 specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. The CLASS clinical trial compared Celecoxib (Celebrex) 800mg/day to Ibuprofen 2400mg/day and diclofenac 150mg/day as treatment for osteoarthritis or rheumatoid arthritis for a period of six months. Celebrex was shown, at the end of the trial, to be associated with a significantly reduced occurrence of gastrointestinal complication and with no significant difference in the incidence of cardiovascular events in patients not talking aspirin for cardiovascular prophylaxis. While in the VIGOR study, Vioxx (rofecoxib) 50mg/day was compared with naproxen as treatment for rheumatoid arthritis for the same length of time. Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events like perforation, obstruction and bleeding by 54% (from 3% to 1.4%), reduced the risk of complicated upper gastrointestinal events by 57% and reduced the risk of bleeding from anywhere in the gastrointestinal tract by 62% (COX-2 Inhibitors). These studies successfully established the therapeutic relevance of COX-2 inhibitors in treating pain without the fear of gastrointestinal complications (COX-2 Inhibitors, 2005). Besides arthritic pain, COX-2 inhibitors have also been demonstrated to be important in the platelet COX-1 inactivation caused by aspirin in a study by Ouellet and his colleagues (2001) to examine the effect of COX-2 inhibitor in the cardioprotective function of the non-selective NSAIDs, aspirin. Aspirin is currently indicated for cardiovascular prophylaxis. The cardio protective function of aspirin is understood to be achieved by the irreversible inactivation of platelet COX-1 resulting in a reduced production of pro-aggregatory Thromboxane A2 and thereby inhibiting the platelet functionality for the rest of its lifespan. Though, the COX-2 inhibitors show no effect on platelet aggregation, it was established in this study that co-administration with aspirin tends to re-inforce the cardiovascular function of aspirin showing that COX-2 inhibitors could be relevant in treating coronary events, especially as it concerns inflammatory responses (Ouellet et al 2001). In another study, Harris and others (2000) investigated the chemopreventive potentials of Celecoxib, a COX-2 inhibitor, against breast cancer using female Sprague Dawley rats. At the end of the study, the researchers concluded that the administration of celecoxib, suppressed the incidence, multiplicity and size of malignant breast tumour induced by DBA in the female rats. They also noted that in comparison with conventional NSAIDs (Ibuprofen as case study) and other chemopreventive agents evaluated during the course of the study, the degree of inhibition recorded with celecoxib was far more pronounced. This study result again, suggest that celecoxib, a COX-2 inhibitor may be effective for the treatment and chemo prevention human breast cancer (Harris et al 2000). Researching the therapeutic approach to athero-inflammatory induced coronary diseases, Altman (2003) demonstrated the relevance of COX-2 inhibitors in anti-thrombotic and anti inflammatory therapy which happen to have become the cornerstone in the treatment of acute coronary syndromes. He explained that since COX-2 is inducible, for example, by pro inflammatory cytokines and growth factor, it implies that COX-2 plays a role in both inflammation and the control of cell growth. He further explained that COX-2 inhibitors exhibit their anti-thrombotic effect by blocking prostacyclin formation in endothelial cells, with celecoxib demonstrated to significantly improve endothelium dependent vasodilatation. Summarising his findings, Altman concluded that COX-2 inhibitors decrease endothelial inflammation, reduce monocyte infiltration, improve vascular cell function and plaque stability and perhaps, also decrease coronary atherothrombotic events. Therefore, re-inforcing the body of evidence that supports the relevance of COX-2 inhibitor drugs in anti-inflammatory therapy for preventing atherosclerosis and inflammation (Altman, 2003). The development of COX-2 inhibitor drugs came to fruition due to the discovery that there were two genes coding for the cyclooxygenase isozmyes and the difference in protein pattern and distribution in these genes. Discussing the relevance of structurally studies in the development of these COX-2 inhibitor drugs, Lawrence et al explained that the belief that a selective COX-2 inhibitor will bring relief from the adverse effects suffered by those who require NSAIDs for therapy triggered a world class race to develop relevant drugs. After several structural studies, several classes of COX-2 inhibitors were discovered. The most extensively studied of these inhibitors was diarylheterocycles, while other classes include acidic sulfonamides, indomethacin analogs, zomepirac analogs, and di-t-butylphenols, it was also discovered that the COX-2 inhibitors are able to selectively inhibit COX-2 by binding to regions accessible in COX-2 but not in COX-1. Establishing the molecular basis for cyclooxygenase selective inhibition has been very crucial in the development of the two major COX-2 inhibitor drugs currently in the market. It is believed that if these drugs are as safe in the general population as we have seen in the several clinical and research studies reviewed, they will represent a major public health advancement by reducing mortality from gastrointestinal complications, while also effectively reducing pain and inflammation in the general population. 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