21^st Century Therapies for COPD
Richard Casaburi, Ph.D.,M.D. 
President, PERF

V. Anabolic Drugs

    Until we can find ways to repair the damage to lungs damaged by cigarette smoking, we need to focus on other ways to improve functionality and quality of life of patients with COPD.  Pulmonary rehabilitation has shown us that programs of exercise training can improve exercise tolerance.  Since exercise intolerance is often the chief complaint of patients with COPD, this is an important benefit.  Research in the past 10 years has shown that exercise training can improve the efficiency of the leg muscles.  More efficient muscles allow a given amount of work to be done with a lower level of breathing.  Therefore exercise training takes stress off overworked lungs – and, therefore, dyspnea is improved. 

      The problems with exercise training are twofold.  First, many patients with COPD are so debilitated that they can do only a little exercise – not enough, at least initially, to do much good to the exercising muscle.  The second problem is that exercise training is hard work.  To get much benefit, the program has to be quite vigorous – several times a week, 30-60 minutes a session and at fairly high exercise intensity.  It must be continued indefinitely, since the benefits recede once training stops.  It would be a great to find a medicine that confers the benefits of a training program.

      Sounds simple, but it’s not.  Clearly, there must be a message that exercise training sends to the muscle that tells it to grow and become more efficient.  Unfortunately, we have only the sketchiest idea of how this works.  Even worse, we would have to decide what kind of exercise training benefits we would want to reproduce.  Endurance training (like walking, cycling or swimming) makes the muscle grow new blood vessels and increases the cellular machinery that allows oxygen to be used efficiently.  Strength training (like weight lifting or push-ups) makes the muscle get bigger and increases the amount of force that can be generated.  So we must suppose that something about riding a bicycle releases chemicals in the muscles that, for example, cause blood vessels to grow.  Lifting weights must release chemicals that tell the muscles to increase their volume.  Logic tells us that these chemicals must be released locally, and not into the circulation, since training of a given muscle group (for example, the legs) does not make other muscle groups (for example, the arms) work better. 

      There are efforts underway to define the pathways by which exercise training works its magic.  Unfortunately, this generally requires a piece of the muscle to be obtained, so it can be sent to a laboratory to have its properties assessed.  Muscle biopsy sounds a bit scary, but isn’t really so bad (I have done over 700 muscle biopsies!).  What we have learned is that there are growth factors that influence how the muscle changes.  I think that pretty soon we may have the ability to predict how the specific changes seen with training are produced and soon after that drugs will be introduced that stimulate these pathways. 

      In the meantime, we can try out drugs that we know make muscles grow.  There are two classes of drugs that we know are anabolic (increases metabolic capabilities) for muscles.  The first is growth hormone.  This is produced by the pituitary (an organ in the base of the brain) and directly and indirectly yields muscle growth.  So far, it looks like the changes growth hormone produces are more similar to strength than endurance training.  However, clinical trails of growth hormone in COPD and in other subject groups have been rather disappointing.  Though increases in muscle mass have been observed, the muscles haven’t been shown to get much stronger.  Worse, growth hormone is very expensive and has to be given by injection several times a week.

      Anabolic steroids are the second class of drugs that are anabolic to the muscles.  Testosterone is the most important naturally occurring anabolic steroid.  In men testosterone is produced by the testes in response to hormones released by the pituitary.  In women, the circulating level of testosterone is about tenfold lower than in men; much of it is produced in the ovaries.  Testosterone has been used for more than 50 years by athletes (mostly men) to improve muscle strength.  Recently, however, well designed studies have started to show the relation between the dose of testosterone and the structural changes that are seen in the muscles.  Only a couple of fairly simple studies of testosterone in men with COPD have been performed.  A more comprehensive study is now in progress in our laboratory.  An interesting new concept is that women may benefit from testosterone, as well.  Although high doses of testosterone makes women grow beards (!), low doses seem capable of causing the muscles to grow without adverse effects.

      This discussion would not be complete without mentioning nutritional therapies.  Patients with COPD sometimes have weight loss that impairs function.  The weight loss usually decreases both muscle mass and fat mass.  The cause of the weight loss usually not simply unwillingness to eat; it is suspected (but not yet proven) that there are chemical imbalances underlying involuntary weight loss.  One approach now being tried is to administer an appetite stimulating drug.  A large multicenter trial of such a drug is now underway.

      I think it is likely that anabolic drugs will find their way into clinical practice.  However, to be used as chronic therapies, drugs with better side effect profiles will have to be devised.  For now, we would be satisfied with drugs that could be used in conjunction with pulmonary rehabilitation, to help the patient more comfortably accommodate the increased exercise levels that have been found to be beneficial.

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