Anti-inflammatory therapy for preventing stroke and other vascular events after ischaemic stroke or transient ischaemic attack

It is just a review of research so nothing useful will come of this for a protocol.

Anti-inflammatory therapy for preventing stroke and other vascular events after ischaemic stroke or transient ischaemic attack

Many pages prior to what I copied here;

Description of the intervention

Anti-inflammatory medications are a widely heterogeneous group of drugs that are used to suppress the innate inflammatory pathway and thus prevent persistent or recurrent inflammation. Broadly, they consist of steroids (e.g. glucocorticoids), non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, colchicine, antimetabolite drugs such as methotrexate and azathioprine, and anticytokine agents including TNF-alpha-binding proteins (e.g. infliximab). Mycophenolate is another immune-modulating drug. Each of these types of drug have different pharmacokinetics and pharmacodynamics.

Glucocorticoids

Glucocorticoids are potent anti-inflammatory agents targeting both the early and late phases of inflammation. Glucocorticoids target inflammation through multiple pathways including the decreased activation of neutrophils, macrophages and T-helper cells. They also downregulate the production of multiple cytokines, including IL-1, IL-2, IL-6 and TNF-alpha, through the inhibition of gene transcription. In addition, glucocorticoids inhibit the production of prostanoids through decreased expression of COX-2, and are partly responsible for the upregulation of anti-inflammatory factors, including IL-10 and annexin 1.

Non-steroidal anti-inflammatory drugs

NSAIDs are very commonly used anti-inflammatory medications. They are weak organic acids that are highly metabolised to form an active agent. Their anti-inflammatory activity is primarily as a result of the biosynthesis of prostaglandins; however, they also inhibit chemotaxis, IL-1 production and free-radical formation. NSAIDs also decrease the sensitivity of blood vessels to bradykinin and histamine, as well as decreasing the production of lymphokines from T lymphocytes.

Cyclooxygenase-2 inhibitors

The COX-2 isoenzyme is induced by proinflammatory cytokines (e.g. IL-1ß, TNF-alpha) and endotoxins in response to inflammation, and is responsible for the increased level of prostaglandins during inflammation. By inhibiting this isoenzyme the inflammatory process is downregulated as the production of regulatory cytokines is not inhibited, and B- and T-cell proliferation is reduced.

Colchicine

The anti-inflammatory effect of colchicine is mediated primarily through the inhibition of microtubule assembly. This inhibits inflammasome activation, cell chemotaxis, and the production of leukotrienes and cytokines thus inhibiting inflammation. By inhibiting the inflammasome, colchicine inhibits IL-1ß activation from its precursor, proIL-1ß, thus limiting the inflammatory response. Colchicine is also responsible for inhibiting the expression of IL-1ß, IL-6 and TNF-alpha through the reduced activation of macrophages.

Antimetabolites (e.g. methotrexate, azathioprine)

Different antimetabolite drugs have different mechanisms of action. Methotrexate, an antifolate drug that interferes with DNA replication, exerts its anti-inflammatory action through the inhibition of cytokines. The exact mechanism via which this inhibition occurs remains unknown. Methotrexate is also believed to inhibit lymphocyte proliferation through the inhibition of purine synthesis. Azathioprine, a purine analogue that also inhibits DNA synthesis, inhibits T-cell proliferation through complex genetic interactions leading to a depressed immune response.

Anticytokine drugs

This is a class of recombinant engineered antibodies that interact with the immune system. Within this broad class of immunomodulating agents, different agents target different cytokines involved in the inflammatory pathway. The main targets are TNF-alpha (infliximab, adalimumab), IL-1 antagonism (canakinumab, anakinra) and IL-2 antagonism (daclizumab).

How the intervention might work

Anti-inflammatory agents have the potential to stabilise atherosclerotic plaques by impeding the inflammatory pathway. By targeting specific cytokines the inflammatory pathway may be interrupted at various stages. Non-specific agents, including NSAIDs, COX-2 inhibitors and colchicine, inhibit inflammation through downregulation of prostaglandin synthesis and chemokine modulation. Inflammatory cells, such as neutrophils and mast cells, as well as endothelial cell adhesion molecules, are inhibited, thus impeding the initiation and intensification of inflammation. Using medications such as infliximab, etanercept and adalimumab, which target TNF-alpha (a multifunctional proinflammatory cytokine that may be involved in the development of atherosclerosis), the production of more downstream inflammatory cytokines such as IL-6, as well as the proliferation of leucocytes, may be impeded. TNF-alpha antagonism may also inhibit the earliest stages of atherosclerosis development as this may downregulate smooth muscle proliferation as well as inhibiting the expression of VCAM-1, thus decreasing the adherence of leucocytes to endothelial cells. By targeting IL-6 with agents such as tocilizumab, both membrane-bound and circulating IL-6 receptors may be blocked. This may help minimise endothelial dysfunction and reduce arterial stiffness in addition to minimising the proinflammatory effect of IL-6. IL-1ß is also a promising target. IL-1ß receptor inhibition may reduce leucocyte adhesion in vascular endothelial cells, which leads to procoagulant activity, and serves as a trigger for human vascular smooth muscle cell proliferation. Such agents include canakinumab and anakira. Certain harms may, however, be associated with the use of anti-inflammatory agents. By impeding anti-inflammatory pathways, many anti-inflammatory medications will also affect the overall immune system, leaving recipients of these drugs vulnerable to infection, in particular opportunistic infections, such as systemic fungal infections, and those caused by mycobacteria and other atypical organisms. These infections can be potentially life threatening. Some anti-inflammatory drugs, such as methotrexate and cyclophosphamide, can lead to myelosuppression, causing a decrease in the white cell count and suppression of the immune system. NSAIDs, COX-2 inhibitors and steroids have also been shown to increase the risk of gastrointestinal mucosal injury through the inhibition of prostaglandins. 
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