**5. Treatment of cachexia**

#### **5.1 Resistance exercise training**

Weight training or more commonly known as resistance exercise training in which an individual contracts his muscles against the force of a weight stack, free weights, or sometimes resistance bands is a way in which to increase muscle protein synthesis [20]. This bodes well for the cancer patient if they have the functional ability to undergo these types of workouts. It is well known that this increase in protein synthesis chronically will result in an increase in muscle mass. An additional benefit of exercise and likely a precursor to muscle growth is a decrease in intramuscular proinflammatory cytokine mRNAs and an increase in mechano-growth factor mRNA which is a slice variant of IGF-1.

## **5.2 Creatine monohydrate**

An adjunct nutritional supplement to resistance training is creatine (monohydrate). Creatine when ingested in sufficient quantities, for example, 20 g/day for 5 days will elevate the intramuscular stores of creatine. This elevation of intramuscular creatine can increase the rate of phosphocreatine resynthesis in man [21]. This is by way of the reaction ATP + creatine yields PCr + ADP. Where ATP is adenosine triphosphate, PCr is phosphocreatine, and ADP is adenosine triphosphate. Creatine ingestion in the manner described above improves not only PCr resynthesis but also exercise capacity [22].

### **5.3 Ibuprofen and acetaminophen**

It is well known that a bout of resistance training will increase muscle protein synthesis in the hours after exercise [20]. Resistance exercise also increases the muscle protein degradative cytokines IL-6 and murf-1 mRNA [23]. Resistance exercise with ibuprofen or acetaminophen ingestion blunts the IL-6 and murf-1 response to resistance exercise [23]. Cancer cachexia increases IL-6 and murf-1 leading to more protein degradation [10]. Therefore resistance exercise with acetaminophen or ibuprofen is beneficial for increasing muscle protein synthesis and decreasing muscle protein breakdown to achieve a more favorable response (increasing synthesis and decreasing breakdown = more + net protein balance; Trappe et al. [23]). This would improve the ability to accrete more muscle mass in the face of cancer cachexia. It is suggested that future clinical trials combine resistance training with acetaminophen or ibuprofen at the maximal daily dosage in cachectic cancer patients. For detailed schematic on how these analgesic agents affect protein metabolism see Trappe et al. [23].

### **5.4 Albuterol**

In humans, Uc et al. [24] found that administration of the beta-2 agonist albuterol increased thigh cross-sectional area by 5.3% and whole-body fat free mass by 9.5% in Parkinson's patients over 14 weeks (16 mg/day). Unpublished data suggests that muscle protein synthesis is elevated by ~90% in elderly individuals with 16 mg/day over 10 days of albuterol administration (Lambert et al. unpublished observations). Albuterol would appear to be an anabolic agent that should be administered off label in cancer cachexia in clinical trials.

#### **5.5 Anamorelin and ibutamorelin**

Anamorelin is active orally, centrally penetrant, and selective agonist of the ghrelin/growth hormone secretagogue receptor-1a and was under development for the treatment of cancer cachexia and anorexia [25] (Drug Bank). It increases growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein (IGFBP-3) and apparently has no side effects as testosterone administration does. It also stimulates appetite [9]. It has been shown in Phase III Clinical Trials to increase appetite, body weight, lean body mass, but not muscle strength as measured by hand grip strength [9]. The natural agonist for ghrelin/growth hormone secretagogue receptor-1a,

#### *Attenuating Cancer Cachexia-Prolonging Life DOI: http://dx.doi.org/10.5772/intechopen.101250*

ghrelin has a short half-life, however; anamorelin has better pharmacokinetic properties as evidenced by a more sustained delivery [26]. It is a dipepetide of molecular weight 546.716 (Drug Bank). Apparently, this drug failed in Phase III Clinical Trials due to lack of an effect on grip strength although it increased lean body mass [9]. The only side effect noted with anamorelin was a small risk of headache [26]. Anamorelin is approved for clinical use in Japan but not the US or Europe.

Ibutamorelin, like anamorelin, is another ghrelin analogue that stimulates growth hormone secretion from the pituitary and IGF-1 secretion from the liver. Svenson et al. reported that 2 months of treatment of individuals 18–50 years old with 25 mg of ibutamorelin resulted in and increase in growth hormone and IGF-1 and a significant increase in fat free mass when measured by DEXA or by a four compartment model. Basal metabolic rate was elevated at 2 weeks but not at 8 weeks. Nass et al. [27] reported that in individuals 60–81 years of age, 25 mg of ibutamorelin administered over 2 years resulted in a loss of 0.5 kg of fat free mass in placebo group but a gain of 1.1 kg in the ibutamorelin group. This was accompanied by an increase in growth hormone and IGF-1 and a reduction in LDL cholesterol of 0.14 mmol/L. Murphy et al. (1998) reported that in individuals 24–39 years of age, ibutamorelin (25 mg/day) accompanied by a 18 kcal/kg/ day energy intake for 2, 14 day periods resulted in a + 2.69 nitrogen balance for the ibutamorelin group but a −8.97 for the placebo group during the last 7 days of the second 14 days, which suggests that this anabolic agent would be preventative of muscle loss with a very low energy intake. Unfortunately, ibutamorelin did not show efficacy in functional tests which are the criteria the FDA uses for cancer cachexia drugs [1] and in other conditions which induce muscle loss such as hip fracture [28]. Both anamorelin and ibutamorelin did not show functional efficacy in clinical trials. Why functional capacity improvement would be the ultimate criteria for cancer cachexia would be beyond me. Since the problem in cancer cachexia would be considered muscle wasting and not a functional problem [1]. Maybe it is time for the FDA to change their criteria for approval of safe and effective drugs which cause anabolism and prevent catabolism during cancer cachexia. Because of the FDAs short sightedness, both of these drugs (anamorelin and ibutamorelin) have been rendered the status of nutritional supplements.
