mbengineer- I was mostly just
strokin' with Gator.....
Seems he is infected with your eternal optimism.....lol....
And, although I do somewhat agree with your "Never Say Never" statement......
MY truth of the matter is.....I don't expect that ADVR will ever get a partner, (major Pharma or otherwise), and because of that.....I doubt that this drug will ever be approved under an NDA from the FDA of the USA......
Just as an observation.....the only real "miracle" that this drug has ever performed, has been it's ability to continue to carry this company thru the last 20 years, and on into the future......How it continues to garner just enough mystique to stay afloat without ever really moving forward in significant strides......
I was told some four years ago, and the notion is reinforced with each passing year that this drug & company continues to grasp the light of day......
"There is nothing here for media OR medicine"
Of course, that could all change tomorrow, right ???
Disclaimer: WTFDIK ??? DO NOT buy or SELL this stock based on MY observations......
On the Fringe of Big Pharma
This article has been reprinted from the amfAR Global Link
June 2004 — If last year was a monsoon, this year is a drought for new HIV drugs. No new drugs await FDA approval. Meanwhile, mounting reports of sluggish drug development and barren pipelines at the big pharmaceutical companies are alarming investors and consumers alike. To fill the gaps, many are buying late-stage products from smaller companies, a concept referred to as “in licensing.”
These smaller companies take a unique approach to finding drugs. Rather than invest the approximately $8 million required to discover a novel therapy, they begin by picking through what others have thrown away. Jumpstart companies, as they are known, find new drug candidates by rummaging through the trash bins—or, more likely, computer libraries—of other companies. They also explore using approved drugs for new diseases, what the industry calls “repurposing” old products.
“It’s a pragmatic approach that allows you to go to the clinic faster,” said Adeeb Mahmud, an associate in corporate development at CombinatoRx, a jumpstart company in Boston. “These compounds are already proven to be safe and are, most likely, easy to manufacture.”
Scavenger companies like CombinatoRx represent the latest trend in drug research. Consider them the thrift store shoppers of the pharmaceutical world. These small firms, frequently financed by venture capital, score by incurring minimal risk. Most, if not all, the compounds were already studied extensively and only need minor improvements to become viable drugs. Because large companies are unlikely to invest in such fine-tuning, jumpstart companies step in to alter the drugs, fund the initial testing, then often out-license the products to big pharma for large efficacy trials and eventual marketing approval.
“Nobody wanted to fund a company for the 6 or 7 years it took to get a compound from discovery to proof-of-concept. Companies needed to get drugs to proof-of-concept faster,” said Roger Longman, managing partner of Windhover Information, a Norwalk, Connecticut-based business and medicine communications company. “Jumpstarts are applying the discovery approach to old products. The idea isn’t new. What’s new is the number of businesses specifically following this approach,” he added.
This idea of recycling “dead” drugs has many forms. Some companies are seeking new uses for approved drugs; others look more closely at drugs that require personalized doses. The most radical approach abandons the mainstay of US drug development—profits—to bring discarded treatments to the developing world. All of these approaches are applicable to HIV drugs, though companies have yet to adopt antiretrovirals into their portfolios.
Trying the Shoe on the Other Foot
Burroughs Wellcome originally developed—and subsequently shelved—AZT (zidovudine or Retrovir) as a cancer treatment. When HIV emerged, the company went back and found a new use for this old compound. Similarly, when severe acute respiratory syndrome, or SARS, surfaced in humans last year, screening old drugs against the new virus led to its initial treatments.
While big pharma commonly searches through its archives when a new virus materializes, jumpstart companies focus their business plans solely on this process. Both Bionaut of Cambridge, Massachusetts and XenoPort of Santa Clara, California concentrate on old drugs. Bionaut is screening drugs that are already off patent or generically available to determine whether they can treat another condition, such as cancer or inflammation. XenoPort concentrates on making pro-drugs of existing medications. The improved versions are more easily absorbed by the body, making them more effective.
CombinatoRx puts a twist on repurposing old drugs. They pair drugs used to treat disparate diseases and analyze the combinations with a laboratory assay. [quote]Researchers can quickly see novel synergies of drugs and exploit them. The company uses two large libraries, or databases, of compounds—one library alone houses all approved drugs from the US, Japan, and Europe combined. Just by studying compounds within these libraries, “there are millions of binary combinations,” according to Daniel Grau, vice president of corporate development.
If it finds an effective combination, the company will simply invest in the proprietary formulation of the two compounds, and procure a new commercial product with patent protection. The new combination medicine could be marketed and priced competitively with other medicines in the field. CombinatoRx has a cancer drug in phase I/II development and two candidates for treating arthritis in phase I. These are the only therapeutic areas the company is currently exploring.
But according to Grau, CombinatoRx will branch into other areas soon. Such areas could include HIV, if additional funding becomes available. The company has raised $90 million in venture capital so far. “The biotech companies are trying to create first-in-class drugs. But more recently, investors have become increasingly risk averse. We combine innovation with a reduced risk,” said Grau, who is now seeking support outside of the industry. He predicts that CombinatoRx may begin working in HIV within the next few years. If the company can partner with a foundation, Grau emphasizes that they would avoid filing for a patent on the new product so the drug could quickly reach those in need.
Another jumpstart in Cambridge tweaks doses of forgotten drugs to improve effectiveness and lower side effects. Xanthus Life Sciences is a venture capital-funded company with a mere 30 employees. This group examines compounds rejected by other companies to determine if personalized doses can make the drugs successful.
The company’s lead compound is Xanafide, a potential treatment for breast and prostate cancer. Xanafide bounced around among Knoll Pharmaceuticals, the National Cancer Institute, and Abbott Laboratories, but was sidelined after some volunteers in phase I and II studies had toxic levels of the drug in their blood. “Once big pharma kills a product, it’s almost impossible for them to resurrect it,” said Richard Dean, chief executive officer of Xanthus.
Xanthus has renewed interest in the compound. Since the body uses the same pathway to metabolize both Xanafide and caffeine, trial participants drink a caffeinated soft drink and take a simple urine test to determine how they break down caffeine. This can inform how to adjust the dose to the individual’s metabolism and ultimately bring the compound from the shelf to the pharmacy. “This was the ideal candidate to revitalize,” Dean remarked.
Dean claimed that although the company does not plan to add new therapeutic targets any time soon, it has considered HIV drugs. “If there is a narrow window between severe side effects and a working drug, then it will benefit from this technology,” he stressed.
Sacrificing Profits for Products
Another sector of the jumpstart world focuses on compounds that big pharma rejected simply because they were not profitable. The paucity of medications for diseases that afflict poor countries gave birth to two nonprofit pharmaceutical companies, the Institute for OneWorld Health and the Drugs for Neglected Diseases Initiative.
OneWorld is the brainchild of Victoria Hale, a veteran of the pharma and biotech worlds. Hale spent a few years traveling the world in search of feasible compounds after conceiving of the first nonprofit drug company. She started her search at the World Health Organization (WHO), university laboratories, and pharmaceutical companies.
Just 3 years later, OneWorld is conducting a phase III trial of an anti-parasitic drug to treat visceral leishmaniasis. The drug, paromomycin, was approved in the 1960s as an antibiotic to treat intestinal infections. Twenty years later, an Italian company began testing the off-patent drug against parasitic infections, but funding dried up after phase II trials. After urgings from Indian scientists, Hale brought paromomycin to OneWorld.
People seeking treatment at the Bihar visceral leishmaniasis clinic in India.
The Bill and Melinda Gates Foundation rewarded the burgeoning nonprofit with a $4.7 million grant to inaugurate the organization and run clinical trials. Now the 25-person staff has received over 200 unsolicited proposals from companies offering sidelined compounds for development. “The pharmaceutical scientists are extremely excited about moving these things forward. The leads they generate may have applications in the developing world,” according to Michael MacHarg, senior associate for development and partnerships at OneWorld. There are also incentives for companies to donate compounds, including tax incentives and a positive public relations image.
Celera Genomics donated a compound to treat Chagas, a parasitic disease endemic to Latin America, and OneWorld now has it in preclinical development, with the NIH supporting animal studies. OneWorld is also considering diarrheal disease and will be launching a project on malaria this summer after more money arrives from the Gates Foundation.
Though OneWorld is not starting an HIV project, it remains a possibility. “Right now, we want to focus on some things that aren’t getting as much attention. But if we get large enough, then we could start looking at HIV/AIDS,” said MacHarg. OneWorld’s work may already impact India’s HIV epidemic (see next page). If approved, the leishmaniasis drug could prevent a major opportunistic infection from assailing HIV-positive people. A 21-day course of paromomycin provides lifetime immunity against the parasite. Since the treatment is not effective in immune-compromised individuals, MacHarg visualizes a 5-year window to cure leishmaniasis in India before the number of HIV infections soars.
OneWorld will seek approval for paromomycin in India and manufacture it there as well. The Indian government, along with nongovernmental organizations, will provide the drug to patients as cheaply as possible. “These are first-class drug leads,” said MacHarg. Confidence in the selectively chosen compound is necessary to the company’s mission. “We can’t take many risks with the funding we have,” he emphasized.
Although jumpstart companies must carefully calculate how to spend their cash, they are still required to invest hefty sums to ensure a drug’s ultimate safety and effectiveness. Drugs for Neglected Diseases Initiative plans to spend $250 million over the next 12 years to develop a handful of drugs to treat sleeping sickness, leishmaniasis, and Chagas disease in the developing world. Médecins Sans Frontiéres (Doctors Without Borders), the founding organization, will provide initial funding.
In its first year, Drugs for Neglected Diseases Initiative received 71 project suggestions, involving both existing compounds and new drug classes. The Geneva-based nonprofit will work closely with several international research institutes and the WHO to choose the strongest leads for development.
“Infectious diseases in the developing world were not being adequately addressed,” said Arthur Strosberg, senior program officer at OneWorld. “There is a dearth of drugs for diseases that are killing millions and millions of people and there isn’t a profit incentive large enough for mainline pharma to get involved.”
Strosberg predicts that more nonprofits will join the pharmaceutical industry in upcoming years. But as more and more companies look at old drugs, it may be only a matter of time before big pharma does the same.
Perils of a Parasite
A parasitic protozoa that lives in sandflies is responsible for transmitting a severe and increasingly prevalent disease called leishmaniasis. Endemic to tropical and temperate regions, leishmaniasis is present in 88 countries. The infection can develop into a grave health problem, especially in immunocompromised people. Leishmaniasis takes four forms, the most common being cutaneous and visceral. Cutaneous leishmaniasis causes disfiguring skin lesions that can result in permanent scarring. A more serious form, visceral leishmaniasis, attacks the internal organs and can be fatal if left untreated. An estimated 1.5 million new cases of cutaneous leishmaniasis and 500,000 new cases of visceral leishmaniasis occur worldwide every year.
Coinfection with HIV and visceral leishmaniasis is a growing concern in regions where leishmaniasis is common, particularly in parts of South America, Asia, and Africa where both diseases geographically overlap. The World Health Organiza-tion predicts that HIV/leishmaniasis coinfections will increase and move beyond endemic areas in the upcoming years.
— Olivia Weisser
DRUG TOXICITY AS A DRUG TARGET
Thalidomide entered the popular consciousness more than 40 years ago, when evidence of its horrific teratogenic prop-erties led to its withdrawal from the worldwide drug market. Originally marketed as a sedative, thalidomide was approved and became widely used in many countries (less so in the United States) to suppress nausea during pregnancy. More recently, although its general reputation is not yet rehabilitated, thalido-mide is back in the clinic, having won FDA approval 5 years ago as a treatment for leprosy.
Thalidomide is well-known as both an immunomodulator, with effects on tumor necrosis factor-α and other cytokines, and an anti-angiogenic agent. The latter effects, says Martin Hauer-Jensen (University of Arkansas Medical School), have in-spired a number of groups to test it against solid tumors. In the course of such a study, Hauer-Jensen’s colleague, oncologist Rangaswamy Govandarajan, observed that patients receiving thalidomide were markedly free of the severe diarrhea that often lands chemo patients in the emergency room. Hauer-Jensen and Govandarajan began collaborating to test thalidomide as an ad-junct treatment to increase patients’ tolerance for other drugs.
The Arkansas group showed several years ago that giving thalidomide to patients nearly eliminates the limiting toxicity of irinotecan, a second-line drug used in the treatment of colorec-tal cancer. According to Jerry Zeldis of Celgene (Warren, NJ), thalidomide and its less toxic derivative CC-5013 (Revimid®) are under active investigation as palliatives for conditions such as wasting and pain. These agents are also being studied to determine whether they improve the efficacy of other chemo agents, as well as to combat the gastrointestinal side effects of those drugs. Still, Zeldis stresses, thalidomide shows substan-tial effects even as a monotherapy against various tumor types, particularly multiple myeloma.
But as drugs to counter the side effects of other drugs, thalidomide and its derivatives are not alone. Indeed, “the con-cept [of targeting drug toxicity] is beginning to permeate the industry,” observes oncologist James D’Olimpio (NYU Medical School). D’Olimpio mentions the anti-emetic drug aprepitant (marketed by Merck as Emend®), an NK1 receptor antagonist that was approved last year for use with chemotherapeutics that are poorly tolerated because of their gastrointestinal effects.
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 unex-pected 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 har-ness it, D’Olimpio says.
Vol. 2, No. 2 March/April 2004 | Preclinica | 93
Source: LC Group via e-mail
"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
"Ahhhhhhhhhhh! Yessssserrrieeee! THAT's IT!!!
DRUG TOXICITY AS A DRUG
TARGETThalidomide entered the popular consciousness more than 40 years ago,
when evidence of its horrific teratogenic properties
led to its withdrawal from the worldwide drug market. Originally marketed as a sedative, thalidomide was approved and became widely used in many countries (less so in the United States) to suppress nausea during pregnancy. More recently, although its general reputation is not yet rehabilitated, thalidomide
is back in the clinic, having won FDA approval 5 years ago as a treatment for leprosy. Thalidomide is well-known as both an immunomodulator, with effects on tumor necrosis factor-α and other cytokines, and an anti-angiogenic agent. The latter effects, says Martin Hauer-Jensen (University of Arkansas Medical School), have inspired
a number of groups to test it against solid tumors. In the course of such a study, Hauer-Jensen’s colleague, oncologist Rangaswamy Govandarajan, observed that patients receiving thalidomide were markedly free of the severe diarrhea that often lands chemo patients in the emergency room. Hauer-Jensen and Govandarajan began collaborating to test thalidomide as an adjunct
treatment to increase patients’ tolerance for other drugs.Dose-Limiting ToxicityThe Arkansas group showed several years ago that giving thalidomide to patients nearly eliminates the limiting toxicity of irinotecan, a second-line drug used in the treatment of colorectal
cancer. According to Jerry Zeldis of Celgene (Warren, NJ), thalidomide and its less toxic derivative CC-5013 (Revimid®) are under active investigation as palliatives for conditions such as wasting and pain. These agents are also being studied to determine whether they improve the efficacy of other chemo agents, as well as to combat the gastrointestinal side effects of those drugs. Still, Zeldis stresses, thalidomide shows substantial
effects even as a monotherapy against various tumor types, particularly multiple myeloma.But as drugs to counter the side effects of other drugs, thalidomide and its derivatives are not alone. Indeed, “the concept
[of targeting drug toxicity] is beginning to permeate the industry,” observes oncologist James D’Olimpio (NYU Medical School). D’Olimpio mentions the anti-emetic drug aprepitant (marketed by Merck as Emend®), an NK1 receptor antagonist that was approved last year for use with chemotherapeutics that are poorly tolerated because of their gastrointestinal effects. Treating CachexiaD’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 thalidomide
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 immunomodulatory,”
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 company
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.—Carol Smith
- - - - -
HIV: Wasting syndrome overview
Updated: Aug 01, 2003
Involuntary weight loss, or wasting, is one of the most common symptoms of HIV infection. It can occur at any stage of infection and usually suggests that the HIV disease is progressing. Weight loss may be quite substantial and get progressively greater. In addition, chronic unintended weight loss is associated with malnutrition, which may contribute to increased immune suppression.
The technical term `wasting syndrome’ is usually used to describe a clinical syndrome in which an individual has lost more than 10% of his or her body weight in the absence of active infections or any other identifiable cause of weight loss.
Weight loss can result from malabsorption, diarrhoea, reduced food intake and altered metabolism. Wasting can occur in the absence of opportunistic infections or other identifiable causes of weight loss.
Malabsorption is impaired uptake of nutrients from the gut (known as the intestines). Nutrients are normally absorbed from food in the intestines by cells that make up finger-like protrusions called villi that line the intestinal wall. Certain disease processes including HIV infection can cause the villi to wither (atrophy) and shorten. This cell malfunction results in impaired absorption of nutrients. However, the association between HIV-associated wasting and malabsorption has been challenged by a recent study of over 100 people with wasting and diarrhoea which found that nutrient malabsorption was not associated with weight loss; rather, reduced calorie intake and frequency of diarrhoea were associated with wasting (Beaugerie; see Wasting syndrome - key research in the A to Z of illnesses for full details of this study and other references).
Many people with HIV or AIDS experience diarrhoea at some point. It can occur in people who are very healthy or very ill, and be short-lived and occasional or continuous. In Africa, diarrhoea is a major cause of death in HIV-infected children; Zairian infants have an eleven-fold increased risk of dying from diarrhoea compared with uninfected infants.
Malabsorption and diarrhoea can be caused by a number of opportunistic infections, including parasitic infections such as Cryptosporidium, Isospora belli, Microsporidium, Entamoeba histolytica and Giardia lamblia; viral infections such as CMV; and bacterial infections such as MAI, Salmonella, Campylobacter and Shigella. When people with HIV have diarrhoea, specific pathogens can often be identified in faecal samples. People with HIV may also experience diarrhoea for which no specific cause can be identified. This is often referred to as pathogen-negative diarrhoea.
A major cause of weight loss is reduced food intake. This may be a result of mouth ulcers and lesions due to candidiasis, herpes simplex, or other diseases may cause painful or difficult swallowing. Thrush, although not painful, may alter the sense of taste or cause nausea. Neuropsychological disorders associated with HIV infection can result in loss of appetite (anorexia). The depression and anxiety that may accompany a life-threatening illness often disrupt normal routines and also suppress the appetite. Psychosis and organic brain diseases such as HIV-associated dementia, toxoplasmosis, and cryptococcal meningitis can also inhibit a person's desire or ability to eat.
People with HIV may also experience changes in their metabolism which lead to weight loss. Depletion of lean body muscle mass has been observed in people at all stages of HIV infection. Kotler reports that wasting syndrome is distinguished from starvation in that the former results in body-fat content preservation while body cell mass is depleted. This progressive wasting may result solely from the underlying HIV infection.
The catabolic or destructive effects of any debilitating illness or opportunistic infection may result in weight loss and generalised wasting without evidence of anorexia or malabsorption.
Wasting syndrome in the era of HAART
Two studies presented at the Geneva World AIDS Conference in 1998 found that commencement of highly active antiretroviral therapy (HAART) may improve weight loss and malnutrition (Raghavan; Schwenk). However, HAART may not prevent loss of body cell mass (a component of lean body mass or muscle), and weight gain after starting treatment may be in the form of fat.
Despite the impact of HAART on illness and death rates amongst HIV-infected people over the past five years, wasting continues to be a problem for a significant minority of people. US researchers reported that around 20% of a group of 54 patients experienced reductions in body cell mass and body weight after commencing HAART (Berger).
Another study, which looked at 552 patients between 1995 and 2000, found that weight loss continued to predict an increased risk of death in people taking HAART. Weight loss of just 3% or more from baseline was found to predict a poorer prognosis, and the study did not distinguish between loss of fat-free mass, body cell mass or fat cell mass when measuring weight loss (Tang 2002).
Body fat and metabolic disorders associated with HAART differ from traditional HIV wasting. However, there is some overlap between traditonal HIV wasting and the new syndrome of body fat redistribution which may make diagnosis and treatment difficult. Lipoatrophy (wasting of the face, arms and legs) is a key feature of body fat changes that have been linked to the nucleoside analogue class of drugs. Some experts originally contended that HAART-related wasting was largely due to the effects of HIV itself but, more recently, most experts have acknowledged that anti-HIV therapy plays an important part in the recent manifestation of wasting and body fat changes among people on HAART.
Coping with cachexia
A weight loss condition occurring in people with advanced illness, cachexia poses challenges for both physicians and loved ones.
By Darrell E. Ward
The man is fighting to survive the ravages of lung cancer, but he looks more like a starved survivor of a concentration camp. His temples are hollowed, his eyes sunken, his shoulders bony, and his collarbones prominent. He is weak, pale, and can no longer cut grass, rake leaves, or trim his beloved roses. He's dropped from 210 pounds to 168. Unlike a concentration camp survivor, though, he has no desire to eat. In desperation, his wife brings him to the oncologist.
"If he would just eat, I know he'd get better," she tells the doctor.
The husband tells the doctor that sometimes, to ease his wife's distress, he forces himself to eat. "But after a bite or two, I'm full," he says.
The wife looks to the physician for help. "Isn't there something you can do, doctor? He's simply wasting away."
The distraught wife is literally right. The husband's dilemma is typical of a condition known as "cancer wasting" or the "cancer cachexia-anorexia syndrome."
The word cachexia comes from the Greek kakos for "bad" and hexis for "condition." Cachexia is one of the most distressing and devastating symptoms of cancer, robbing people of their energy, sense of well-being, and quality of life, and increasing their dependence on others. Cachexia often accompanies malignancies of the pancreas, stomach, esophagus, lung, and intestines, but cancer wasting is most common in people with advanced illness where it signals poor response to treatment and short survival time.
The foremost sign of cancer cachexia is weight loss, not only of fatty tissue but also of muscle tissue and even bone. This non-fatty tissue is also known as "lean body mass." In addition, there is loss of appetite (anorexia), weakness (asthenia), and a drop in hemoglobin level (anemia).
But coping with cachexia is not simply a matter of eating more. Even if the person wants to eat, even if he or she tries to eat, even if the person is given nutrients through a stomach tube or intravenously, the condition will not be reversed.
Recent research is revealing the fundamental causes of cachexia. The condition is now regarded as part of the body's reaction to the presence of cancer, a reaction that turns the body's normal metabolism topsy-turvy. Recent research also indicates that, in some cases, tumors themselves produce substances that induce cachexia.
New drugs and nutrient supplements are being developed and tested to block that reaction, including omega-3 fatty acids, antibody-based compounds, and thalidomide, a drug that became infamous in the 1960s as a cause of severe birth defects when it was taken by pregnant women.
Other research has focused on developing new strategies for improving a patient's sense of well-being and quality of life.
"Cachexia is an important problem for cancer patients," said Neil MacDonald, an authority on cachexia and director of the Center for Bioethics, Clinical Research Institute of Montreal. "But profound weight loss, weakness, and loss of function and dependence accompany most adult, ultimately fatal, chronic illnesses," including congestive heart failure, chronic obstructive pulmonary disease, AIDS, advanced kidney disease, severe infection, and autoimmune diseases such as rheumatoid arthritis and systemic lupus.
"A better understanding of cancer cachexia-anorexia may help cachectic patients with other disorders," said MacDonald.
Cachexia vs. Treatment-Related Malnutrition
Weight loss is a common feature of cancer and can even be the first sign of an undiagnosed tumor. At the same time, weight loss in cancer patients can have many causes, many of which are reversible and do not involve the central metabolic imbalance of true cachexia (the term "cachexia" is sometimes used loosely even by doctors when referring to severe weight loss in general).
For example, said Harrison Weed, associate professor of internal medicine at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, "a patient can become malnourished from not eating, and he or she may be not eating because of nausea, and the nausea could be caused by medication." In such cases, changing or terminating the medication might reverse the weight loss.
In some patients, the presence of the tumor itself can obstruct the throat or mouth, making eating or swallowing difficult or painful. A gastrointestinal tumor can prevent food from passing through the intestines. Removing the tumor can correct the problem.
Surgery, radiation therapy, and chemotherapy can also have side effects that cause temporary malnutrition and weight loss. The body needs a great deal of energy to heal and recover from surgery. Radiation therapy often damages healthy tissue in the area of the tumor and, depending on the tumor's location, can result in temporary nutritional difficulties. For example, treatment of the esophagus or nearby structures can lead to difficulties swallowing, while treatments in the abdomen can affect the intestines and result in diarrhea or poor absorption of nutrients.
Chemotherapy can have few or many side effects, depending on the regimen and the individual. Possible side effects include diarrhea, constipation, anorexia, nausea, and vomiting, all of which can affect a person's weight and nutritional status.
Such examples of tumor- or treatment-induced malnutrition really represent forms of starvation; there is no imbalance of metabolism, little loss of lean body mass, and weight gain occurs when the person resumes eating.
The Origin of Cachexia
At one time, some people believed that cancer cachexia occurred because the growing tumor soaked up nutrients to fuel its own growth, thereby starving the body. Others thought this unlikely because most tumors weigh 5 percent or less of a person's weight. In addition, cachexia occurs even in cancer patients receiving excess calories.
In the mid-1980s, scientists investigating cancer cachexia performed a revealing experiment. The scientists took a rat with a tumor and cachexia and joined its circulation to that of a healthy rat. This enabled blood from the cachectic rat to flow through the healthy animal. Soon, the healthy rat also became cachectic. When the rats were separated, cachexia in the healthy rat disappeared. Clearly, something circulating in the blood of the tumor-bearing rat produced wasting in the healthy rat.
If the rats were kept joined, and the tumor was surgically removed from the cancer-bearing rat, both animals regained weight and the cachexia disappeared.
Experiments such as these, together with other work done over the past decade, have shown certain substances produced by the body in response to the tumor play a key role in cancer cachexia. These substances-cytokines-are produced by cells, particularly immune system cells, to influence the behavior of other cells. The cytokines present during cachexia include tumor necrosis factor alpha, interferon gamma, interleukin 1, and interleukin 6. Several of these compounds produce cachexia-like symptoms when injected into animals.
Furthermore, these cytokines are also involved in inflammatory responses. Inflammation normally occurs during infection or following injury to a tissue and is part of the healing process.
Under some circumstances, though, the inflammatory response runs out of control or becomes excessive, and this can cause damage. Examples of an extreme inflammatory response occur in allergic reactions, asthma, and autoimmune diseases such as rheumatoid arthritis.
Many researchers now believe that cachexia may represent a kind of inflammatory reaction that occurs in response to the tumor.
Donna McCarthy, associate professor in the School of Nursing at the University of Wisconsin, has spent 12 years studying cachexia in animals. She believes the inflammatory response is triggered when a tumor has spread -- metastasized -- to other areas of the body. Metastatic tumors, she said, represent the growth of a tissue in an area of the body in which it is not supposed to be.
McCarthy induces cachexia in rats by taking a tumor out of one rat and transplanting a piece of the tumor into another rat. "We end up with this tissue where it normally wouldn't be found, which mimics a metastatic tumor." When the tumor grows, the rat becomes cachectic.
In humans, cachexia typically occurs only during advanced cancer, when metastatic tumors are present in the body. "Very rarely do weight loss and anorexia occur in people with early cancer," she said. "But once the tumor becomes invasive and metastatic, that's when we begin to see it, and that's when I think the inflammatory-immune process kicks in."
Research by McCarthy and others is showing that cachexia results from a complex interaction between the tumor and the body. "The body responds to certain cancers with an inflammatory response that flips a person's metabolism around," said Weed.
Those changes in metabolism include disruption of proper use and storage of fats, proteins, and carbohydrates. The body accelerates the breakdown of fatty tissue, which depletes fat stores. It also draws on its muscle tissue as a source of protein, producing the trademark loss of muscle mass. "Weight loss can happen at a rate of about two ounces per day, depending on the kind of illness," said Weed.
Often, the body's consumption of energy-calories-is also increased. That is, the body's metabolic rate, even when at rest, is increased, like a automobile idling on high. The loss of appetite, or anorexia, that accompanies cachexia is thought to result from cytokines acting either directly or indirectly on hunger centers in the brain.
How and why these metabolic changes occur is not understood, but overall they are responsible for a cancer patient's inability to gain weight even when receiving what are usually considered adequate calories. Nonetheless, people have tried to fight cachexia using appetite stimulants or nutritional supplements.
The results are often disappointing. The person may gain a few pounds, but the gain is usually temporary and in the form of fat and retained water; lean body mass does not recover.
McCarthy has tested the use of enriched diets to improve the nutritional state of cachectic animals. "When we then give them diets enriched in calories or protein, they respond by simply eating less than if they had received the normal preparation," she said. If, for example, the normal diet contained 20 percent protein, and she gave the animals 40 percent protein, they simply ate less food, taking in something between 20 and 40 percent.
In addition to calories, McCarthy monitored the animals' metabolism, muscle mass, and levels of appropriate hormones. In the end, she said, the dietary interventions produced no detectable improvements. "They looked just like rats that didn't receive the treatment. Feeding them enriched diets didn't improve the animals at all."
The Effect of Cachexia on Loved Ones
Cancer cachexia is also hard on a cancer patient's family who sees its loved one deteriorating almost before its very eyes. The family often responds to the problem by trying to coax or convince the patient to eat.
As a result, said Earl Metz, professor emeritus of hematology-oncology at The James Cancer Hospital, "cancer cachexia often becomes a source of conflict between patient, spouse, and family. There's a myth that eating will help fight cancer, and that has led some people with well-established cancer to take megavitamins and try macrobiotic diets."
There is little evidence, though, that nutrition will change the course of cancer. "We are under a constant barrage about how one kind of food or another might prevent cancer," he said, "and a healthy diet high in fruits and vegetables might help reduce the risk of cancer in people free of the disease. But the effect of diet on established cancer is unproven."
The spouse, however, may-out of love-try to tempt or even nag the patient to eat. But the best advice is to leave the patient alone. "A lack of appetite is not painful," said Metz, "but eating can be."
McCarthy had similar advice. "I've seen spouses say, 'I made this just for you; it's your favorite food.'
"I think the spouses feel helpless and making the person's favorite food, sitting with them, and encouraging them to eat is something they can do; it's something they feel they can influence."She advises spouses to listen to the patient. "If they (patients) feel like eating, feed them, but if they don't feel like eating, don't push them."
Help for the Cachexic Patient
"The ultimate treatment for cachexia is to eliminate the underlying disease that is causing it," said Weed. Abundant evidence from animal studies supports that maxim. "Take the tumor out and the animals bounce right back," said McCarthy.
Observations in humans show the same thing: successful cancer treatment eliminates cachexia. Ironically, successful treatment can sometimes lead to the opposite nutritional problem-overeating. Some cancer survivors come to equate wasting with the cancer itself and, upon recovery, overeat to gain weight as protection against their disease. "But we know that's not true," said Weed. "No matter how much fat you put on, it's the underlying disease that's responsible for the problem."
The spouse, however, may -- out of love -- try to tempt or even nag the patient to eat. But the best advice is to leave the patient alone.
"A lack of appetite is not painful," said Metz, "but eating can be."
While families have to be careful how they approach a loved one with cancer about eating, eating can improve the patient's sense of well-being. "People feel as though they're doing better if they're able to eat, and they feel that they're doing worse if they're not able to eat," said McCarthy.
There are simple things that can be done that sometimes help a person with cachexia to eat. For example, morning may be the best time for a person to attempt eating because people tend to eat more in the morning than they do in the evening.
"There are wonderful techniques for maintaining appetite and food intake that dietitians can recommend even for people with cachexia-anorexia," said MacDonald. "They involve simple methods for preparing food and recognizing which foods are likely to be most palatable."
Research is also continuing for food supplements that might help people with cachexia. One promising nutrient is fish oil, which contains long-chain omega-3 fatty acids. "Pilot studies have shown that fish-oil supplementation can stabilize weight loss or increase weight in people with cachexia due to pancreatic cancer," said Anne Coble Voss, a manager of outcomes research at Ross Products, a division of Abbott Laboratories.
The appetite stimulant, magestrol acetate (Megace(tm)), produces weight gain in some patients and is widely used to treat cachexia. Unfortunately, the weight patients tend to gain is temporary and comes mainly as fatty tissue; there is little improvement in protein balance. "But maintaining weight and appetite are still important," said MacDonald, "and there's evidence that it also improves a patient's sense of well-being and activity level, and those are very important."
The administration of corticosteroids can also lead to weight gain, but for only a very short time. After three or four weeks, corticosteroids begin to interfere with the synthesis of muscle protein, and their use becomes self-defeating, said MacDonald. "We're not sure why these agents work, but we presume that they interfere with cytokine production."
The drug thalidomide, responsible for causing birth defects in the late 1950s and early '60s when used by pregnant women, is now being cautiously used to help people with cachexia. The drug appears to work by interfering with certain cytokines.
The most drastic treatment for cachexia involves providing nutrients intravenously or through a tube in the intestines. Known as total parenteral nutrition, or TPN, this method is dangerous, expensive, and leads to increased risk of infection. It can improve a patient's protein balance over a period of one to two weeks. But there is presently no evidence that TPN improves patients' survival, "although that could change in the future as we learn more about cachexia," said MacDonald. (TPN can be very helpful, though, in patients who have lost weight due to reasons other than cachexia, such as when a tumor is obstructing the intestines or because the person cannot swallow.)
The knowledge that specific cytokines are involved in cachexia is leading to the development of drugs designed to block those cytokines and reverse the wasting syndrome. This strategy is in the early stages of development, and how successful it might be remains uncertain. "Blocking a single cytokine isn't going to work, but blocking several, well, maybe," said Weed.
Then again, cytokines have multiple roles in the body, and the thwarting of a cytokine to ease its role in cachexia may well cause problems elsewhere.
Time will tell. But it will only be through such research that physicians will gain a better understanding of this "bad condition" and develop ways to reverse it. Either that or find a cure for cancer.
Darrell Ward is a senior medical writer in the Office of University Communications.
Article from Frontiers
Ohio State University
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AVR118 and treating cachexia: