Inflammation research
An inflammation is the body’s response to an external irritation stimulus. Infections are the most common reason for an inflammation, but all injurious effects on the body, such as trauma, heat, cold, chemical substances, allergens (e.g. pollen) or smoke can cause an inflammation. The irritation leads to the release of signal substances for example histamine, prostaglandins and leukotrienes in the tissue, which in turn give rise to the classic inflammation symptoms, swelling, redness, fever and, perhaps, reduced bodily functions.
In normal circumstances, the acute inflammatory response functions as a protection of the body and promotes healing. In other cases, the inflammatory response is inappropriate for the purpose as in the case of certain excessive reactions such as hay fever, in which the provocative allergen (pollen) does not normally release an inflammatory reaction. Another example is chronic inflammation that arises in the lungs during smoking and can lead to the emergence of COPD (chronic obstructive pulmonary disease), also referred to as smoker’s disease. Generally, there is an inflammatory component in almost all illnesses, including autoimmune illnesses (such as rheumatoid arthritis, multiple sclerosis, ulcerous colic and Crohn’s disease) and many types of cancers and even atherosclerosis. The pain experience after, an operation, for example, or a torn muscle or in rheumatoid arthritis depends also on the inflammatory reaction that occurs in the tissue.
The role of the arachidonic acid cascade in the inflammatory process
One of the key elements in inflammatory processes is the arachidonic acid cascade, which is the general term for the biological reactions that occur when arachidonic acid, a natural fatty acid in the body, is converted into various necessary – but occasionally injurious – biological mediators.
In the inflammatory reaction, certain cells in the body are activated to release arachidonic acid and, using enzymes, convert it in several steps into biologically active substances, called mediators, including prostaglandins and leukotrienes. Prostaglandins play an important role in the regulation of blood pressure and blood coagulation, but some of them, especially the prostaglandin E2 (PGE2), can also cause inflammation, pain and fever. Leukotrienes cause asthmatic symptoms such as broncho constrictions, swelling and mucus production, which in turn can result in respiratory difficulties.
Many of the most common drugs used to treat inflammatory diseases belong to the group referred to as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), such as Voltaren and Naproxen. They function by blocking cyclooxygenase (COX) the initial step in the formation of PGE2 and are thus referred to as COX inhibitors. Since they inhibit the formation of prostaglandins high up in the chain, they not only inhibit the formation of PGE2 but also other significant prostaglandins, which leads to gastrointestinal and cardiovascular side effects. The later developed and more selective COX-2 inhibitors were developed to reduce mainly the gastrointestinal side effects. Unfortunately these drugs had a higher frequency of cardiovascular side effects, which led to the withdrawal of a number of them from the market.
Orexo’s OX-MPI project is aimed at developing a drug that inhibits further down in the arachidonic acid cascade (the mPGES enzyme), which accounts for the second step in the formation of PGE2 from arachidonic acid. This could prove to be the key to a more selective anti-inflammatory and pain-relieving treatment that is equally effective but has fewer side effects.
In addition to prostaglandins and leukotrienes, Orexo’s proprietary research has identified a whole new group of inflammatory mediators: eoxins, a discovery that contributes to an understanding of the mechanism underlying inflammation in the respiratory tracts. Eoxins are formed from arachidonic acid via the enzyme 15-lipoxygenase (15-LO), especially by cells in the airways. Other known inflammatory mediators that are released during asthma and allergies also give rise to higher eoxin production. Eoxins have proven to have a powerful pro-inflammatory effect and the release of eoxins in the lung can therefore make a key contribution to the inflammation seen in asthma and COPD.
Orexo’s unique expertise in the arachidonic acid area has opened new opportunities in the search for effective treatments of widespread illnesses such as asthma, COPD, rhinitis, inflammatory and arthritic pain. OX-MPI and OX-AAF are based on mechanisms related to the arachidonic acid cascade.
Projects
The development projects OX-MPI and OX-AAF are based on Orexo's knowledge in the Arachidonic acid cascade. OX-MPI early inhibits the transformation of mediators within the same family as the prostaglandins.