Pharmacy Blog

Right after Lori Spickard's heart attack, St. Luke's Hospital doctors prescribed her the standard drug therapy. She just hopes it works.

Researchers at the hospital have discovered that some heart attack patients taking these drugs, called beta blockers, had a risk of death five times higher than patients who had the best response to the drugs.

The reason for this startling difference appears to be in the patients' genes.

Scientists are finding that genetics plays a major role in why some people benefit a lot from the drugs they take while others get little or no help.

This field of study, called pharmacogenomics, is becoming a major focus of research that promises to change the way doctors prescribe.

Researchers predict that physicians will be able to order up genetic profiles of their patients so they can select the medications that are most likely to be effective.

With that knowledge in hand, doctors can avoid the costly and frustrating hit-or-miss experimentation it often takes to get the right fit of patient and drug. And they can avert potentially deadly drug reactions.

"I think in five to 10 years you'll see a whole lot of therapy driven by our understanding of genetic mechanisms," said Robert Piepho, dean of the pharmacy school at the University of Missouri-Kansas City.

Roche Diagnostics has just started marketing a $500 genetic test that can measure a patient's response to a wide spectrum of pain relievers, psychiatric drugs and heart medications.

And earlier this year NitroMed Inc. launched a medication for heart failure called BiDil that is aimed at African-Americans.

According to the Human Genome Project, putting pharmacogenomics into practice could reduce adverse drug reactions that cause about 100,000 deaths and 2 million hospitalizations a year.

Nearly 3 million people in the United States are at risk of an overdose from the standard dose of warfarin, a drug frequently used to prevent blood clots.

About 10 percent of patients taking high dosages of the high-blood-pressure drug hydralazine develop severe lupuslike symptoms such as joint pain, fever and anemia.

And in rare cases, the usually safe dose of mercaptopurine, a drug used to treat leukemia, can cause the death of a child who has an unusual change in a single gene.

"One size doesn't fit all," Piepho said. "You can't always have a drug that works for everybody."

Beta blockers have been a medical success story, helping to control abnormal heart rhythms and lower the blood pressure of heart patients. But doctors have found that the drugs work better in some patients than in others.

St. Luke's Hospital and Washington University researchers looked at nearly 600 patients who were hospitalized for heart attacks or chest pains at St. Luke's in Kansas City, Mo., or Truman Medical Center in the Kansas City area, and then discharged on beta blocker therapy.

The researchers found that patients who had certain variations in a gene that affected the body's response to beta blockers had the highest risk of death over three years.

"What we're showing is that in a proportion of patients, beta blockers are not enough to assure survival," said St. Luke's cardiologist John Spertus, whose study was published in the Journal of the American Medical Association.

Although the study's genetic tests are feasible for general use, more research is needed before doctors know how to apply them as a part of routine care, Spertus said.

"We are really at the dawn of the era when people will incorporate genetic information into their treatment recommendations," he said.

Spickard wasn't in the study and doesn't know what genetic category she's in. But she's going to follow the doctor's orders and keep taking her beta blockers.

"I'm hoping I'm in the lucky group," said the 80-year-old woman from Trenton, Mo.

Steven Leeder, a clinical pharmacologist at Children's Mercy Hospital in the Kansas City area, is studying how genetics affect the likelihood that the medications a woman takes during pregnancy could cause birth defects in her child.

Many expectant mothers fret over whether they should continue taking drugs for depression, asthma, epilepsy or other conditions.

"Not every mom that took thalidomide had a malformed infant," Leeder said. "The logical question is what makes individuals who are susceptible different from those who aren't? Right now, nobody has a good answer."

Leeder and his colleagues are working with Boston University researchers who are gathering data on births at dozens of hospitals. The Boston team sends Children's Mercy DNA samples from the children and their parents.

Leeder now is looking at why a small number of infants born to mothers who took the pain reliever acetaminophen during pregnancy have defects in their intestinal wall.

"The last thing we want is mass hysteria that (acetaminophen) in pregnancy causes birth defects. But lots of women take it and may take it when they are unaware they are pregnant," Leeder said. "There is a small risk of a relatively rare event, and we'd like to understand its genetic basis."

At the University of Illinois at Chicago, researchers have found that children with a variant form of a gene associated with ADHD respond poorly to one of the most common stimulant medications.

About half the children who take the drug, Concerta, see a dramatic reduction in their symptoms. But about 20 percent or more don't respond to the drug at all.

"If we can identify them early, that could make a huge difference," said Illinois researcher Mark Stein. "We could put them on a different medication right away rather than have trial and error in each case."

At the University of Minnesota, Timothy Tracy is beginning a study on how genetics affect the way the body handles combinations of drugs. His test tube experiments already have shown that a change in a single gene can multiply by 10 times the interaction of two drugs.

That can make a critical difference, for example, when a patient is taking amiodarone to regulate heart rhythms, along with warfarin.

"To me, they're even more vulnerable (than other patients), so we need to make the right decision on dosage," said Tracy, a clinical pharmacologist.

One of pharmacogenomics' best-studied areas involves the genes that regulate the liver's production of cytochrome P450 enzymes.

These enzymes evolved to neutralize harmful chemicals in the plants people eat, but they also metabolize and eliminate many drugs from the body.

The activity of these genes varies from person to person, so some will metabolize drugs much faster or more poorly than average. That can have critical effects on their reactions to drugs.

Take, for example, the pain reliever codeine, which has to be metabolized into morphine to be effective. Someone whose genes give a limited response may not receive pain relief. Someone who metabolizes codeine very quickly may experience symptoms of an overdose such as slow and labored breathing.

This year, Roche Diagnostics received Food and Drug Administration approval for its AmpliChip, a device for conducting blood tests for variations in two cytochrome P450 genes. A patient's DNA is applied to the chip and then scanned by a laser. A computer prints out a report on how active the genes are.

The AmpliChip's results cover about 25 percent of the most widely prescribed drugs, said Roche Diagnostics spokeswoman Lori LeRoy.

Getting doctors to use the test and insurance companies to pay for it are the next hurdles.

One national laboratory recently started offering AmpliChip tests and a second one is about to start. The cost to the labs of each one-use chip is about $500.

"We're working closely with some of the payors (insurance companies)," LeRoy said. "We're hoping that the payors will adopt it."

Piepho, the University of Missouri-Kansas City dean, thinks the AmpliChip will find a market in cases where adjusting drug dosages are critical or where there's a risk of harmful drug side effects.

"Will it be a mass screening tool? At $500 a pop, I doubt it," Piepho said. "But when you think of (preventing) adverse drug reactions, that's a lot of money saved."

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