Apr 10, 2012Science and Technology
New research on old drugs: Molecular understanding of pharmaceuticals teases apart curative and negative effects

Better understanding of the molecular mechanism of rapamycin, shown here, may lead to treatment without serious side effects.If you are one of the 48 percent of Americans that took a prescription drug in the past month, you probably read through a litany of potential side effects attributed to that pharmaceutical. Even if you didn’t take a prescription drug, perhaps you had a headache and reached for a Tylenol. A quick glance at the back of the bottle shows even this over the counter pain reliever could potentially cause serious adverse effects.

In a perfect world pharmaceutical drugs would provide curative properties without nasty side effects. Of course, our world is far from perfect and our pharmaceutical drugs come with a slew of harmful effects. While drug discovery requires treatment effectiveness, side effects that are too harmful can limit or nullify a drug's use. This means that understanding the mechanism of negative side effects could be as important as understanding a drug's curative properties. New research focused on molecular mechanisms aims to tease apart the curative and toxic pathways of drugs, including of those currently on the market. Ideally, this research could lead to pharmaceuticals that treat without the harm.

Rapamycin is used to avoid rejection after organ transplant and in cancer treatment. Beyond these specific diseases, evidence also suggests that it might play an important role in increasing the longevity of disease-free life.  Rapamycin, however, has a dark side -- diabetes.  Around 15 percent of individuals taking it develop diabetic-like symptoms including glucose intolerance and insulin resistance. This dichotomy of life saving, perhaps even life extending, and disease-causing effects has lead to the investigation of the mechanism of prodiabetic action of rapamycin.

The lab of Pere Puigserver at the Dana Farber Institute elucidated a downstream pro-diabetic effect of rapamycin. This lab found that rapamycin blocked the phosphorylation of the transcription factor yin yang 1 (YY1) leading to the recruitment of the polycomb repressor complex, which suppresses the transcription of insulin. Further addressing this issue, the lab of David Sabatine at Whitehead Institute for Biomedical Research assessed whether the prodiabetic effects and life extending effects of rapamycin could be dissociated. They found that the inhibition of the protein mTORC1 provided longevity effects, but the disruption of the protein mTORC2 resulted in diabetic symptoms. This means that specific inhibition of mTORC1 targets could potentially provide longevity without the diabetic side effects.

Over the counter medications may also be improved by molecular research.Pain relief is another line of research that may benefit from molecular evaluation of mechanisms of action, with studies shedding light on the mechanisms of side effects in non-steroidal anti-inflammatory drugs (NSAIDs) and morphine.

NSAIDs are widely used for over the counter relief from pain. Prolonged use of these drugs, however, can cause gastrointestinal and cardiac problems. Studies investigating the stereochemistry of these types of drugs suggest that the pain relieving effects could occur in the absence of these side effects. The action of these drugs is attributed to inhibition of the enzymes COX 1 and COX2. Lawrence Marnett at Vanderbilt showed that a version of these drugs inhibited the metabolism of">endocannabinoids, increasing its levels and resulting in analgesia. These results suggest that isospecific development of these compounds could result in the beneficial effects of these drugs without the negative consequences.

Morphine is a common treatment for more serious pain. However, its use is limited by side effects including addiction, development of tolerance and increased sensitivity to pain. Collaboration between researchers at the University of Colorado and the University of Adelaide showed that inflammation in the brain during morphine use is due to activation of an immune receptor in the brain and blocking this receptor resulted in the loss of the inflammatory response. Since the pain relieving effects of morphine are attributed to its effects on the opioid receptors, rather than the immune receptors, this means that the positive effects of morphine could potentially be dissociated from the negative effects.

Studies investigating specific mechanisms of drug action are providing clues for drug targets that maintain the curative effects while minimizing or avoiding the side effects. This ability would be a great medical advancement, but would also have economic implications for the pharmaceutical industry. Annual revenues for the pharmaceutical industry total around $234.1 billion but major challenges may be ahead. From 2010 to 2014 major money making drugs including Lipitor, Plavix and Zyprexa come off patent and face generic competition. The impending loss of patents is estimated to result in $113 billion in lost revenue and the current business model for R&D does not appear to be able to recoup these lost costs.

The average cost to bring a new drug to market is around $1.8 billion. Changes in the pharmaceutical business model could lead to improvements in R&D productivity, i.e. the relationship between the value of a drug and its costs to develop. Currently, R&D focuses funding at the later stages of development (Phase II and III clinical trials), but attrition at these stages is the most costly. Emphasizing early development could mean safer more effective drugs and less attrition at later stages. The aforementioned research focused on mechanistic effects, both curative and negative, could provide solutions. These studies provide specific targets for drug development that maximize curative and minimize negative effects and could greatly improve the pharmaceutical business model by improving the likelihood of drugs having positive benefit to risk ratios, which could improve the success of these drugs during clinical trials and R&D productivity. This model shows that good medicine can also equal good business.

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