Cachexia

Potential Clinical Uses of SARMs 8.4.3.1 Cancer Cachexia 

The potential role of SARMs in the treatment of cancer cachexia and weight loss focuses again on the building of muscle mass. This therapeutic indication stands as 

Patients with advanced cancer, human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) and a number of other chronic diseases are frequently undernourished. Physically they show all the signs of marasmus, but there is considerably more loss of body protein than occurs in starvation. The condition is called cachexia, from the Greek Ka% io for in a poor condition ). A number of factors contribute to the problem  

The patients are extremely sick, and because of this their wish to eat may be impaired. 

Many of the drugs used in chemotherapy can cause nausea, loss of appetite and alteration of the senses of taste and smell (section 1.3.3.1), so that foods that were appetizing are now either unappetizing or even aversive. 

A number of factors account for the increase in metabolic rate in cachexia  

Both decreased synthesis and accelerated catabolism contribute to the loss of tissue protein. 

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Human growth hormone, used as a human pharmaceutical, is approved for only one indication in the United States, treatment of growth failure owing to hGH deficiency, a condition known as pituitary dwarfism. However, clinical trials are under way to test its efficacy in Turner s syndrome, bums, wound healing, cachexia, osteoporosis, constitutional growth delay, aging, malnutrition, and obesity. 

Meg estrolAceta.te. This compound is used outside the United States as an oral contraceptive. In the United States, it is used for the paUiative treatment of breast cancer and endometrial cancer, or as an adjunct to other therapies. Its use has been associated with an increased appetite and food intake and has been evaluated in the treatment of anorexia and cachexia (107). 

Hydrazine sulfate [10034-93-2] N2H4 H2SO4, originally advanced by the Syracuse Cancer Research Institute for treatment of cancerous cachexia and tumor inhibition (221), now has Investigational New Dmg (IND) status in the United States. Clinical evaluations are under way at various institutions such as Harbor-UCLA Medical Center (222) and the Mayo Clinic. After extensive trials, hydrazine sulfate has been approved as an anticancer dmg in Russia (223). Chemical stmctures for estabUshed dmgs in the United States may be found in Reference 224. 

AIDS (acquired immunodeficiency syndrome) is the final stage of disease caused by infection with HIV. In this stage, the vims infection has severely affected the immune system, causing a depletion of CD4+ T-helper cells. AIDS is characterized by the manifestation of typical diseases caused by opportunistic infections (Pneumocystis carinii pneumonia, CMV retinitis, candidiasis of the esophagus, cerebral toxoplasmosis), neurological manifestations, cachexia, or certain tumors (Kaposi sarcoma of the skin, B-cell lymphoma). 

Cachexia refers to a physical wasting due to loss of muscle and fat. Cachexia is often found in end-stage cancer patients but is also caused by autoimmune disorders or by infectious diseases such as AIDS and tuberculosis. 

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

Under normal feeding patterns the rate of tissue protein catabolism is more or less constant throughout the day it is only in cachexia that there is an increased rate of protein catabolism. There is net protein catabolism in the postabsorptive phase of the feeding cycle and net protein synthesis in the absorptive phase, when the rate of synthesis increases by about 20-25%. The increased rate of protein synthesis is, again, a response to insulin action. Protein synthesis is an energy-expensive process, accounting for up to almost 20% of energy expenditure in the fed state, when there is an ample supply of amino acids from the diet, but under 9% in the starved state. 

Pathogen-suppressing oligosaccharides in human milk were quantitated using capillary Electrophoresis by MEKC with detection by absorption at 205 nm.90 A 24 kDa glycoprotein associated with muscle-wasting cachexia... 

Choudhary, G., Chakel, J., Hancock, W., Torres-Duarte, A., McMahon, G., and Wainer, I., Investigation of the potential of capillary electrophoresis with offline matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for clinical analysis examination of a glycoprotein factor associated with cancer cachexia, Anal. Chem. 71, 855, 1999. 

Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-a [TNF-a], interleukin-1, interleukin-6, and interferon-y) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about TNF-a, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples 3-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied. 

Hypoperfusion of skeletal muscles leads to fatigue, weakness, and exercise intolerance. Decreased perfusion of the central nervous system (CNS) is related to confusion, hallucinations, insomnia, and lethargy. Peripheral vasoconstriction due to SNS activity causes pallor, cool extremities, and cyanosis of the digits. Tachycardia is also common in these patients and may reflect increased SNS activity. Patients will often exhibit polyuria and nocturia. Polyuria is a result of increased release of natriuretic peptides caused by volume overload. Nocturia occurs due to increased renal perfusion as a consequence of reduced SNS renal vasoconstrictive effects at night. In chronic severe HF, unintentional weight loss can occur which leads to a syndrome of cardiac cachexia. This results from several factors, including loss of appetite, malabsorption due to gastrointestinal edema, elevated metabolic rate, and elevated levels of proinflammatory cytokines. 

A similar classification scheme is used to gauge the severity of active CD.2 Patients with mild to moderate CD are typically ambulatory and have no evidence of dehydration, systemic toxicity, loss of body weight, or abdominal tenderness, mass, or obstruction. Moderate to severe disease is considered in patients who fail to respond to treatment for mild to moderate disease, or those with fever, weight loss, abdominal pain or tenderness, vomiting, intestinal obstruction, or significant anemia. Severe to fulminant CD is classified as the presence of persistent symptoms or evidence of systemic toxicity despite outpatient corticosteroid treatment, or presence of cachexia, rebound tenderness, intestinal obstruction, or abscess. 

Cachexia is a severe wasting syndrome that is seen in many cancer patients. Although it is more common in advanced disease, it... 

Cachexia is more difficult to treat, although it may resolve following treatment of the underlying malignancy. Nutritional consultation may be of aid, although cachexia is thought to be more attributable to internal pathophysiologic processes than malnutrition. 

Cachexia Weight loss, wasting of muscle, loss of appetite, and general debility. 

Cardiac cachexia Physical wasting with loss of weight and muscle mass caused by cardiac disease a wasting syndrome that causes weakness and a loss of weight, fat, and muscle. 

Rabbit (New Zealand) 90 d 10.3 101 (cachexia, head droop, anorexia, and lethargy) MacEwen and Vemot 1983 Durad MP280... 

Aerosols of Cellulube 220 produced deaths associated with severe dyspnea and mild diarrhea in one of two rabbits exposed to 2,000 mg/m3 for <4 hours/day, 5 days/week for 11 or 22 days (Carpenter et al. 1959). Continuous exposure for 30-160 days to aerosols of a triaryl phosphate U.S. military hydraulic fluid (see Table 3-2), at concentrations <110 mg/m3, produced no deaths in dogs or rats, but deaths associated with severe neurotoxic symptoms occurred in chickens exposed to concentrations >23 mg/m3 and in rabbits exposed to 102 mg/m3 (Siegel et al. 1965). Aerosols of Durad MP280 or Fyrquel 220 (continuous exposure for 90 days) produced no deaths in rats or hamsters exposed to 100 mg/m3. Deaths associated with lethargy, cachexia, and head droop occurred in rabbits exposed to 101 mg/m3 Durad MP280, but not in rabbits exposed to 100 mg/m3 Fyrquel 220 (MacEwen and Vemot 1983). Some of the Durad MP280-exposed rabbits were also infected with Pasteurella, which may have contributed to neurological symptoms. No deaths occurred in rats exposed to cyclotriphosphazene at 990 mg/m3, 6 hours/day,... 

MP280 (continuous exposure for 90 days) produced kyphosis (a deformity of the spine characterized by extensive flexion) and a decrease in the tail tip curl reflex in rats and anorexia, lethargy, cachexia, and head droop in rabbits after exposure to 101 mg/m3 exposure to 10.3 mg/m3 produced no signs of neurotoxicity in these species (MacEwen and Vemot 1983). Hamsters similarly exposed to 101 mg/m3 Durad MP280 showed no evidence of neurotoxicity in this study. Aerosols of Fyrquel 220 (continuous exposure for 90 days) likewise produced kyphosis in rats at 100 mg/m3, but no clinical signs of neurotoxicity in rabbits or hamsters at 100 mg/m3 (MacEwen and Vemot 1983). Because of the uncertainty that the kyphosis observed in rats is a neurological or muscular effect, this effect has been discussed in both sections. 

Following a 90-day continuous exposure to 101 mg/m3 of Durad MP280, leukocytosis, kyphosis, and testicular atrophy were observed in rats and 100% mortality, cachexia, head droop, anorexia, and lethargy were observed in rabbits. No effects were observed in either species at 10.3 mg/m3 Durad MP280 (MacEwen and Vemot 1983). Continuous exposure to 100 mg/m3 of Fyrquel 220 for 90 days resulted in kyphosis in rats (MacEwen and Vemot 1983) the NOAEL for this effect was 10.1 mg/m3. No adverse effects were observed in rabbits exposed to 100 mg/m3 Fyrquel 220 continuously for 90 days (MacEwen and Vemot 1983). At the lowest tested concentration of Cellulube 220 (2,000 mg/m3, 4 hours/day,... 

Neuropeptides play key roles in appetite regulation and obesity. Many genes for neuropeptides and neuropeptide receptors have been implicated in obesity and cachexia, anorexia and bulimia [34]. For example,NPY administration into the CNS causes overeating and obesity. A second peptide involved in obesity is leptin, a product of adipocytes and the stomach. The leptin gene is defective in the ob/ob mouse but in normal mice leptin binds to its receptor in the hypothalamus, causing a decrease in the synthesis and release of hypothalamic NPY. 

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