AKL4 [aka APPA]- Anti-Inflammatory.
 
After many years of research looking for new anti-inflammatory drugs, corticosteroids and NSAIDs (non steroidal anti-inflammatory drugs) are still the main agents used to control inflammation. Current clinical approaches to the treatment of inflammation mostly focus on the inhibition of pro-inflammatory mediator production and the suppression of the initiation of the inflammatory response, i.e. the suppression of positive signalling pathways of pro-inflammatory cytokines.
 
Most anti-inflammatory drugs inhibit the formation, or effects, of arachidonic acid metabolites, including prostaglandins, thromboxane and lipoxins, known collectively as eicosanoids. Corticosteroids induce many proteins, including the lipocortin and annexin families, whose anti-inflammatory activity can be explained, in part, by their ability to inhibit phospholipase A2. However before phospholipase A2 initiation corticosteroids can inhibit the upregulation of NFκB (nuclear factor kappa B) by stimulating the synthesis of its natural inhibitor IκB. This can also help explain why total turn-off of NFκB can be so immunosuppressive via this corticosteroid action in that conditionally essential pro-inflammatory cytokines are now turned off - thus no immunologic response is possible.
 
Although a majority of this research emphasizes the pharmaceutical applications of NSAIDs and selective COX-2 inhibitors, these agents fail to address alternate pathways available for the synthesis of pro-inflammatory eicosanoids.
 
However, the mechanisms by which the inflammatory response is resolved might provide new targets in the treatment of chronic inflammation.
 
The ALK IV clinical concept was to be able to provide a formulation that addressed the inflammatory cascade in a novel way that bypassed the historically typical 'aspirin like' anti-inflammatory pathways inhibitors of the cyclooxygenases (COX) enzymes I and II and Lipoxygenase (LOX) enzymes and their subsequent pathways.
 
This clinical concept could be subdivided into:
i) inhibition of the inflammatory response in the first instance (prevention)
ii) direct anti-inflammatory activity (response to insult)

 
In vitro laboratory findings were determined in assays using isolated human inflammatory cells. Significant activities found include 1) inhibition of inflammatory cell functioning, 2) scavenging of oxygen radicals (antioxidant activity), 3) modulation of mediators of inflammation, and 4) inhibition of enzymatic degradation of joint cartilage.
 
In vitro laboratory findings confirm the beneficial clinical effects observed in the treatment of osteoarthritis by stimulating production of the anti-inflammatory cytokine, IL-10 and downgrading other pro-inflammatory mediators. In vitro laboratory findings conclude that a number of significant activities have been found that underlie the clinical observations.
 
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