Cachexia clearly is recognized as a clinical problem in aa variety of diseases, especially in cancer in AIDS. Treatment with beta-anatgonists is well known. However, treatment with beta-agonists also seems possible. A nice kindoff paradox to be solved by pharmacologists... 

 Treatment of this syndrome is introduced in the clinical frame of thinking, for instance with hormones, ^[1][2], thalidomide ^[3], other compounds ^[4][5][6], Cannabis ^[7] and novel treatment approaches are under consideration. ^{[8][9][10][11]}

Mild obesity is currently not a risk factor in operations, and indeed recent data confirm that the overweight and the underweight patients have a higher risk of mortality and morbidity. ^{[12][13][14][15]} However, one of the factors for this outcome could be that younger patients are more obese than old patients, and that age is a confounding factor in some of these studies. ^[16]

The β-adrenoceptor agonists aproach for treating cachexia

The beta-2 agonist clenbuterol is very well known for its anti-waisting properties. ^[17] And this compound works in cachexia models, 20 years ago..^[18]  

β-adrenoceptor agonists (β-agonists) started their use in bronchodilation in the treatment of asthma, and soon after it became clear that in a high dose range, these agents promoted skeletal muscle growth. That finding resulted t has resulted in two decades of research to find ways to prevent or reverse the muscle wasting and cachexia associated with conditionas such as age-related muscle wasting, cancer cachexia, sepsis cachexia, denervation cachexia, AIDS and cachexia in chronic kidney disease, heart failure, chronic obstructive pulmonary disease and muscular dystrophies.

Within a clinical framework, β-agonists are used to treat cachexia, for instance in cardiac failure ^[19] Based on experimental work the hypertrophic response of muscle following treatment with high-dose β-agonist has been due to an increase in protein synthesis and a decrease in protein degradation. Apart from this classic finding it has becoming clear that β-agonists might be working via novel anabolic actions on the muscles. β-Agonist stimulate production of numerous growth factors, including insulin-like growth factors (IGF) and transforming growth factor βs, including effects on myoblast proliferation.

In a variety of animal studies, when the animals were treated chronically with high doses of β-agonists such as clenbuterol or fenoterol, a significant increase in muscle mass was demonstrated, as well an increase in function. 

In patients, β-agonists have also been used to increase the muscle tissue mass during cardiac surgery to increase the mass of a muscle of the back, latissimus dorsi , which is wrapped around the heart and helps the hart muscle to function in a better way. Other studies supported the therapeutic potential of β-agonists for muscle wasting disorders such as muscular dystrophies.

Newer generation beta-agonists (e.g. formoterol) are supporting anabolic responses in skeletal muscle even at low doses, with less effects on the heart and cardiovascular system compared with older generation beta-agonists, such as cimaterol, clenbuterol, fenoterol, formoterol, salbutamol and salmeterol. ^[20]

But...side effects and long term safety

Side effects associated with the chronic use of β-agonists such as nausea, headaches and insomnia have to be avoided. Overdose can lead to symptoms such as muscle tremor, palpitations, muscle cramps, headache, hypokalemia, hyperglycemia, hypophosphatemia, hyperlactatemia, and peripheral vasodilatation, all well known as side effects of clenbuterol. 

So it seems that this class of drugs has promises for treating cachexia, if the down-side of chronic use of these agents can be prevented. The beta-agonistic pathway is downregulation with chronic stimulation, and this may have clinical troublesome effects once the treatment will be stopped.

Furthermore, β-adrenoceptors are located in many other tissues. Any treatment involving the chronic administration of β-agonists has to be proven to be safe in the long run, especially for the functions of the heart.

Side effects associated with long-term therapeutic use of β-agonists are well known. Chronic use of β-agonists increases risk for ischemia, congestive heart failure, arrhythmias and sudden death. And a well documented side-effect of chronic β-agonist administration in animal models is cardiac hypertrophy.

This all means long clinical trials in order to generate enough safety-date to convince authorities about the safety of the beta-agonistic aproach.

Auteur: prof.dr. Jan M. Keppel Hesselink, MD, PhD ; update september 2009

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