Bad medicine

Bad medicine

Preventing adverse drug reactions
September 1, 2002

When Sheba the Samoyed and Edward Wen developed serious liver problems shortly after taking antibiotics, both the dog's veterinarian and Wen's dermatologist knew something was wrong. In searching for answers to their separate dilemmas, both specialists ended up seeking out the same researcher for help: Alastair Cribb at the University of Prince Edward Island.

Lucky for both man and beast, Cribb was quickly able to analyze samples—sent in to his UPEI laboratory—for clues. As it turns out, four-year-old Sheba and 19-year-old Wen were both suffering from adverse drug reactions to antibiotics they had been given. Sheba was being treated for damage to an eye caused when she caught it on a stick. Wen had been given antibiotics to treat a potential infection after his family doctor had found blood in his urine. Although the two problems were different, both experienced a rare adverse drug reaction to the same class of antibiotics. And that's the connection that brought them to Cribb.

Cribb's expertise is so sought-after that his publications drew the attention of Dr. Stacy Smith, the California dermatologist who was frantically searching for someone to help Wen. The teenager had developed a severe and painful skin rash as well as the liver damage. Cribb's research prompted Smith to contact him, and to send him a sample that enabled the P.E.I. researcher to make the diagnosis.

Though Sheba's veterinarian was a local Island doctor, he too knew of Cribb's reputation in the field of adverse drug reactions. He turned to Cribb for help.

"The wrong diagnosis in either situation could have worsened the conditions," says Cribb. "This is the challenge that you face. A lot of these reactions are caused by the immune system, but they can look like viral infections. If the reaction is related to the drug, you can treat it with high doses of steroids. If the diagnosis is wrong and it's a viral infection, (the steroids) make them far more susceptible to the viral infection."

Cribb should know. At the University's new Drug and Chemical Safety Research Laboratory, he's studying unusual adverse reactions to certain classes of drugs, including a type of antibiotics known as "sulphonamides." He's also studying anticonvulsants and non-steroidal anti-inflammatory drugs.

Cribb is looking for the link between humans and animals, trying to discover why only some people and some animals react negatively to the same drugs that heal others. With infrastructure support from the Canada Foundation for Innovation, he now has a state-of-the-art lab and the critical equipment he needs to help him in his task.

The ultimate goal of Cribb's research is to develop safer drugs or to be able to predict which people and animals will have a negative reaction, so they are never again prescribed the drugs that can do more harm than good. As part of his work, Cribb is trying to isolate the genetic factors that may influence these adverse reactions—factors that animals and humans may share. Along the way, because Cribb's work involves the study of the human metabolism and the way it absorbs drugs, he has also become involved in a study about breast cancer. Cribb is investigating the way different women metabolize estrogen, and whether that contributes to the reason some of them develop breast cancer while others do not.

"What we're trying to do is come up with information or knowledge that will help us develop safer drugs," says Cribb. "The critical aspect of this research is its potential to expand both human and veterinary medicine. By bringing these two fields together, we feel that it gives us a unique perspective on the problem."

Benefits

Cribb's research has several goals. First, by using animal models as well as humans, he hopes to pinpoint the factors that lead to adverse drug reactions in both people and animals. He then hopes to be able to identify people—as well as animals—who might have adverse drug reactions so doctors won't prescribe potentially risky drugs to them. Second, Cribb hopes to be able to develop better ways to diagnose and treat patients who are experiencing reactions to drugs.

In the United States, studies have identified adverse drug reactions as a leading cause of death. Based on these U.S. studies and other factors, Cribb believes adverse drug reactions are likely responsible for a similar number of deaths here in Canada. But it's difficult to pinpoint the statistics, in part because the reporting of adverse drug reactions depends on the ability of family physicians to identify the problem. After they've identified it, those same over-worked physicians then have to report the reaction to drug companies and to Health Canada. "There are lots of places where the system can fall down," says Cribb. "It's not necessarily a criticism. We just don't have a better system yet."

Adverse drug reactions bring with them steep economic costs. A recent Canadian study indicates the cost of treating a patient suffering from an idiosyncratic drug reaction to anti-convulsants is, on average, more than $3,000. Idiosyncratic, or adverse, drug reactions are also a major reason some drugs are pulled off the market. That means the pharmaceutical company that developed the medication can lose millions of dollars. That drug is then also lost to the patients it does help—those who don't suffer adverse reactions when they take it.

Within 10 years, Cribb believes the growing field of pharmacogenomics will revolutionize drug therapy. Already, researchers can predict the increased likelihood of adverse reactions in certain people. In the not-too-distant future, Cribb believes genotyping profiles of every individual could allow doctors to prescribe drugs more safely and effectively. But compiling that information also comes at a cost. Individual genotype profiling raises ethical issues involving privacy. It also carries with it repercussions for insurance and, potentially, even employment. "We could improve our therapy—the studies are out there to show you could do this—but then you have to know everybody's genotype in advance. What kind of ethical issues does that raise?" Cribb asks.

It's a discussion that is sure to absorb Canadians in the coming years.

Partners

At the University of P.E.I.'s Drug and Chemical Safety Research Laboratory, Alastair Cribb is engrossed in a productive partnership with the Canadian Breast Cancer Research Initiative. The project involves studying 1,200 P.E.I. women to try to determine the links between estrogen and breast cancer.

Cribb's research is focused on the enzymes responsible for metabolizing estrogen in the body. He's investigating whether genetic variations in that metabolizing process are the reason some women get breast cancer while others don't. Like his other work involving adverse drug reactions, the link is Cribb's interest in genetic factors that may influence the process.

"It's very important research," says Dr. Dagny Dryer, director of medical oncology for the P.E.I. Cancer Treatment Centre. "Genes that have been identified as having an increased risk of breast cancer have only been identified with about five percent of all women that get breast cancer. There is some reason to think perhaps 30 percent of breast cancer may have a genetic basis, but this is hypothetical," she explains.

For about 70 percent of the women who develop breast cancer, that means the diagnosis comes out of the blue. "Dr. Cribb's research may identify alternate metabolic pathways for estrogen that put women at risk for breast cancer," says Dryer. "It may be that those are the kinds of women that should be on some kind of preventative treatment."

Dryer is working with Cribb and the Drug and Chemical Safety Research Laboratory by identifying and approaching patients in the hospital clinic. Those patients participate in the study by having a swab taken from inside their cheek. Cribb and his team then compare the results from 300 women with breast cancer to those of about 1,200 women without breast cancer.

"We don't envision this being an example of where you would do genetic testing to identify women at risk, but where you would identify pathways you could modify with lifestyle changes," says Cribb. For example, his research might suggest foods that women could eat to change the way they metabolize estrogen, to protect them from breast cancer.

Dr. Marilyn Schneider, executive director of the Canadian Breast Cancer Initiative, believes Cribb is among the leading researchers in the world to conduct this type of study. "It's a novel approach," says Schneider, whose organization has provided Cribb with funding beginning in July 2000. "He's saying, 'What are the internal events that are involved with how that woman's body responds to the estrogen?'"

"The bottom line is that the incidence rate of breast cancer is rising. People have all kinds of fears about what might be the cause. What is it that makes some women get it and others not get it? It would be an important thing to know," says Schneider.

Schneider says she is convinced that partnerships like this one work. "If your goal is to beat a disease, to achieve a specific result, fragmentation does not work. Coming together as partners is effective. It works, and we're simply achieving more than we could possibly achieve separately."