D’Olimpio serves as an advisor to the Yonkers (NY)-based firm Advanced Viral Research, which has developed another agent that may have value as an adjunct therapy to be used along with drugs with dose-limiting toxicities. That agent, AVR118, is an immunomodulator (unrelated chemically to tha-lidomide or aprepitant) with unusual properties. A covalent complex of two peptides linked by a short stretch of nucleic acid, AVR118 is described by its manufacturer as a "switch-type immunomodulator"—a reference to its apparent ability to induce inflammatory antiviral responses under some conditions while suppressing autoimmunity in rheumatoid arthritis and multiple sclerosis. "The mechanisms are anti-inflammatory and immu-nomodulatory," says D’Olimpio, noting that they are not yet well understood.
AVR118 has several in vitro activities that are potentially valuable against AIDS, including suppression of HIV replication, induction of inflammatory cytokines, and down-regulation of the HIV co-receptor proteins CCR5 and CRXC4. But anecdotal reports arising from early clinical work also suggested an unexpected benefit: suppression of the cachexia (muscle wasting) that occurs in advanced AIDS.
Cachexia is among the most difficult problems in treating AIDS and some types of cancer, D’Olimpio notes, but patients taking AVR118 along with various drugs used to treat AIDS, leukemia, or solid tumors have reported improved quality of life, including weight gain and increased energy. The company’s web site cites clinical evidence that AVR118 can mitigate the pro-cachexic effects of other AIDS drugs and of certain cancer chemotherapeutics. "Immunomodulator-type drugs," the com-pany suggests, could be used "to decrease the toxicity of drugs employed in the therapy of a variety of diseases."
Advanced Viral has begun a phase I/II study of AVR118 in Israel to try to understand the mechanism and how best to harness it, D’Olimpio says.
Immunomodulator-type drugs could be used to decrease the toxicity of drugs employed in the therapy of a variety of diseases.
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Catabolic wasting or cachexia is a clinical wasting syndrome that is characterized by unintended and progressive weight loss, weakness, and low body fat and muscle. At least 5% of body weight is lost. Cachexia is not caused by poor appetite and nutritional intake, but rather by a metabolic state in which a "breaking down" rather than a "building up" occurs in bodily tissues no matter how much nutritional intake occurs. Additionally, whether a patient receives nutrition orally or intravenously makes no difference. The patient simply cannot gain weight, so eating more is not an answer.
It is estimated that half of all cancer patients experience catabolic wasting, with a higher occurrence seen in cases of malignancies of the lung, pancreas, and gastrointestinal tract. The syndrome is equally common in AIDS patients and can also be present in bacterial and parasitic diseases, rheumatoid arthritis, and chronic diseases of the bowel, liver, lungs, and heart. It is usually associated with anorexia and can manifest as a condition in aging or as a result of physical trauma. Catabolic wasting is a symptom that diminishes the quality of life, worsens the underlying condition, and is a major cause of death.
Cachexia and Cancer
Researchers previously believed that cancer increased metabolic demand (stolen protein), produced toxins, and suppressed appetite, resulting in malnutrition. New research, however, shows that although cancer may raise resting metabolic rate, improved nutrition does not alleviate the symptoms of anorexia, chronic nausea, early satiety, and changes in taste that make even favorite foods unpalatable to some cancer patients. The view of clinicians is that bodily wasting is the result of a combined action of tumor products and host immune factors--in particular, cytokines--that lead to poor appetite, muscle wasting, and an altered metabolism. The cytokines interleukin-1 (IL-1), IL-6, interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and brain-derived neurotrophic factor appear to increase and play a role in the progression of cachexia in cancer, as well as in other diseases associated with bodily wasting.
Other metabolic alterations associated with the syndrome are hyperglyceridemia, lipolysis, and accelerated protein turnover, all leading to a loss of fat mass and body protein. The dysregulation of metabolic processes produces a negative energy balance.
Clinicians are currently treating cancer-related catabolic wasting with a variety of interventions, including nutritional supplementation, administration of cytokine inhibitors, steroids, hormones, cannabinoids, and thalidomide. Gemcitabine, a chemotherapeutic drug, has shown clinical benefits in treating cachexia. Newer nutritional intervention with megestrol acetate derivatives, gamma-receptor agonists, amino acid manipulations, myostatin inhibitors, and uncoupling protein modifiers is currently being explored. Further research must be done to investigate gender differences in relation to pathophysiology and therapy.
There is some evidence that the drug hydrazine sulfate may help cancer patients gain weight and improve the cachectic state. The drug is by prescription and should be given by a complementary physician familiar with its use, as it can be toxic. The dose is usually 60 mg a day. Narcotic painkillers or benzodiazepine anxiety-reducing agents cannot be given concomitantly.
Cachexia and HIV
Bodily wasting is a common manifestation of HIV, occurring at any state of infection and indicative of disease progression. Malnutrition, a result of appetite loss, is commonly due to nausea and vomiting. Weakness and diarrhea are often present as well. Persons with HIV may also experience malabsorption of nutrients due to enteric infections associated with the disease, even if they consume sufficient calories.
The effects of malnutrition are thought to contribute to increased immune suppression including a reduction in T-lymphocyte helper and suppressor cells, altered phagocytic functions, and decreased killer-cell activity, leading to opportunistic infections and cancers. Proinflammatory cytokines IL-1, IL-6, and TNF have been cited in many studies as potential causes of wasting. Most people with advanced HIV and AIDS have some degree of wasting.
To reverse weight loss, appetite stimulants, anabolic agents (such as growth hormone or testosterone), cytokine inhibitors, and hormones are often prescribed. Megestrol acetate and dronabinol (which contains the active ingredient in marijuana) are approved for the treatment of wasting. Thalidomide, which aids in the healing of aphthous ulcers of the mouth and esophagus, is now available.
Unfortunately, the cachectic state is all too apparent to any observer. In severe chronic disease with the development of multiple organ failure, some degree of malabsorption of nutrients probably contributes to the cachectic state. The entire picture is reflected in a continuing decline of the serum albumin as the illness progresses. Conversely, an increase in serum albumin suggests an improvement in the nutritional state. As long as a patient is maintained on nutrition by the normal route (by mouth), optimizing the state of digestive secretions is probably advisable, although there may not be clinical studies demonstrating this. The Heidelburg test reflects this environment and can be used to ascertain the need for either hydrochloric acid or pancreatic enzyme supplementation.