With so many diseases at stake, affecting so many people, it is no surprise that developing anti-inflammatory drugs is a top priority for the pharmaceutical industry. What is surprising is how few drugs reach their therapeutic end points.
Walk into a pharmaceutical industry conference dealing with anti-inflammatory drugs and you will be bombarded with a multitude of new and dazzling approaches from monoclonal antibodies, peptides, DNA or RNA therapy, kinase inhibitors, and even antioxidant molecules. Some, like the anti-TNF alpha antibodies, are already on the market while some, like some COX2 inhibitors, have even been withdrawn due to possible side effects. Many others are in the pipelines. Judging from this picture, one would conclude that the future is bright for the anti-inflammatory drug industry. The landscape, however, is much more complicated.
Visit your doctor or pharmacist and ask them how they treat inflammatory diseases (acute or chronic) and a very different picture emerges: by far the most common drugs given, regardless of the pathology, remain the corticosteroids (steroids). These drugs, discovered over 50 years ago, are often generic and are available in hundreds of different brands and formulations. In fact, steroids are second only to antibiotics in their ubiquitous worldwide usage. What is even more remarkable is that steroids are so popular despite their well-documented and frequent side effects. These include changes in weight, bone density, skin fragility, and the risk of cataracts. So why are steroids so popular? Simply put: they work. And here lies the crux of the problem.
If steroids did not suffer from such serious and common side effects there would be little need for an alternative treatment. While their full mechanism of action remains unknown, we do know that they suppress the inflammatory cascade by shutting down the production of a multitude of its actors.
If you imagine the inflammatory cascade as a Christmas tree in which each light bulb signifies a different inflammatory actor, steroids don’t bother unscrewing one light bulb at a time. They just yank the electrical cord from its socket. The result: a very efficient and broad anti-inflammatory activity but at a terrible cost, since many of these light bulbs not only contribute to the inflammatory pathology but also play a role in other, necessary, cellular functions. In fact, steroids not only shut down your Christmas tree, they tend to shut down the fridge, TV, and microwave as well.
So ideally, if one were looking for an alternative to steroids, one would want a drug that rather than switching the whole tree off, would only dim it down. Steroids are not a dimmer. And neither are their current alternatives.
Newer drugs, like biologics (e.g., TNF alpha inhibitors) and COX-2 inhibitors (e.g., NSAIDs such as Vioxx®) try to unscrew just a single lightbulb, leaving hundreds of other inflammatory actors untouched. The results are drugs that are often not efficient (NSAIDs) or are efficient in only a limited number of cases (biologics). Furthermore, turning off a light bulb completely not only suppresses its role in inflammation, but can also eliminate its role in homeostasis since so many of these cytokines have a housekeeping role in their basal expression levels. The other current approaches seem to suffer from similar defaults.