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Point of View : Nov 15, 2008 (Vol. 28, No. 20)

New Treatment Strategies for Inflammation Gain Ground

PLA2 Modulation Is Being Explored as a Potential Steroid Alternative
  • Yuval Cohen

Inflammation is a natural and necessary function forming part of the body’s defense mechanism from infection. In its beneficial capacity, it is a temporary reaction, passing as soon as the infectious threat has been eliminated. There are many cases in which inflammation does not switch itself off, or is triggered by benign events. These conditions can be acute or chronic, triggered by allergy, hereditary disease, chemical intolerance, or an overreaction to pathogens.

When inflammation goes awry it can produce discomfort, pain, loss of organ function, disability, and even death. Inflammation can affect any organ of the body and there are hundreds, possibly thousands, of inflammatory diseases. Examples include psoriasis and dermatitis (skin), hay fever and asthma (airways), conjunctivitis (eye), ulcerative colitis and Crohn’s disease (the gut), multiple sclerosis (CNS), and rheumatoid arthritis (joints).

Some are allergy based (e.g., hay fever), some are clearly hereditary (e.g., cystic fibrosis), and some have no known cause (e.g., psoriasis). Some can affect the patient for decades (e.g., rheumatoid arthritis and asthma) while some can kill or maim in a matter of days (e.g., sepsis).

Some inflammatory diseases affect hundreds of millions of people (e.g., arthritis, hay-fever, and COPD) while others are ultraorphan diseases that affect only a few thousand (e.g., cystic fibrosis).

Inflammatory diseases affect different organs and thus exhibit different symptoms, however, they all share the same fundamental biochemical processes regarding the inflammatory reaction itself. These involve a well-characterized inflammatory cytokine cascade that may be triggered by various events but always progresses through common actors.

Anti-Inflammatory Drugs

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.

How Corticosteroids Work

What’s the alternative, if any? The answer lies in understanding how corticosteroids work and why they work so well. Corticosteroids affect more inflammatory actors than any of the alternative therapies and they can be administered in almost every imaginable way—as a pill, an inhaler, a nasal spray, cream or injection. Furthermore, they are inexpensive to manufacture because they are synthetic. Therefore, what the market needs is something that works as well as steroids, can be administered as diversely, does not cost tens of thousands of dollars a year, and offers a better safety profile.

Cascade Reaction

One solution that may prove promising is to remember that inflammation is indeed a cascade reaction. It starts with a trigger (and there are many triggers out there); then the first light bulb is lit, which lights the next one, and the next one, etc. In other words, the tree does not switch itself on at once but gradually. By focusing on one of the earliest light bulbs, a family of enzymes known as PLA2, one can dim the tree, affecting dozens of measurable inflammatory mediators but without switching them off completely and hence, avoiding the toxicity associated with steroids. A synthetic, easy-to-formulate class of drug targeting, the PLA2 family is currently in clinical studies in man.

It’s still early to speculate, but if upcoming results in patients are indeed promising, it is very likely that by focusing on this unique and logical approach a real alternative to steroids may have been discovered. Walk into your local pharmacy and see for yourself how many drugs contain steroids. If PLA2 modulation is indeed a viable steroid alternative then the future looks very bright indeed.