This article first appeared in the St. Louis Beacon: August 14, 2008 - When Dr. Elbert P. Trulock started practicing 25 years ago, a diagnosis of pulmonary arterial hypertension was basically a death sentence.
Physicians had little knowledge about the disease, which causes runaway high-blood pressure in arteries of the lungs, labored breathing, lung damage and reduced blood-pumping ability of the heart.
The disease attacks in three ways. It narrows arteries, causes scars that stiffen and thicken blood vessels, and it causes blood clots. The net result: a steadily weakening heart and eventual heart failure.
Doctors often failed to make a quick diagnosis of pulmonary arterial hypertension (PAH) because symptoms can be mistaken for asthma, bronchitis or other respiratory ailments.
"Recognition has certainly improved, but it's still possible for the disease to be missed in its early stages," says Dr. Trulock, medical director of the Barnes-Jewish Hospital-Washington University lung transplant program.
Twenty-five years ago, even an accurate diagnosis wasn't helped much by medicine. Drug companies hadn't developed specific compounds for PAH. The best they could offer was general blood-pressure medications, diuretics and anticoagulants that aided a few patients but provided only palliative care for most.
Today, doctors know a lot more about PAH, which the Food and Drug Administration says affects only 100,000 Americans; and drug companies have produced six drugs. More are in development.
Researchers can pinpoint the sources of some PAH cases even though the disease remains relentless. The American Lung Association says approximately half the people diagnosed with PAH die within five years. The average survival is about three years without treatment.
However, the association uses data from 2004. The FDA has approved three PAH drugs since late 2004 while three others were approved between 1995 and 2002. All seek to help patients improve their ability to exercise and to slow PAH's progression.
"They are not cures," says Dr. Trulock, who also is professor of medicine at the Washington University School of Medicine. He was a clinical investigator for Flolan, the first PAH drug. "They clearly improve the symptoms and performance status of patients."
Since Trulock started practicing, St. Louis has become an important center for treating and researching PAH. A website tracking experimental-drug testing shows that in recent years, St. Louis has been the site for 14 PAH clinical trials that have been completed, are in progress or are recruiting patients.
Barnes-Jewish Hospital has emerged as a leader in lung transplants for PAH and other dangerous diseases. Transplants aren't cures for PAH; but for patients who no longer respond to even the most powerful drugs, transplants are the last-gasp chance for extra years of life.
From January 1988 through May 2008, Barnes-Jewish Hospital has performed more adult lung transplants than all but one U.S. medical center, says the Organ Procurement and Transplantation Network. If you add the lung transplants performed at St. Louis Children's Hospital since 1988, institutions affiliated with Washington University lead the U.S. in lung transplants.
Despite the advances in treating PAH, there's still a knowledge gap for physicians.
When Racheal Locklear, 36, lived in Tennessee, it took her nine years and four doctors to get an accurate diagnosis. "I was told I had exercise-induced asthma," says Locklear, who moved to Granite City, Ill., in May to be closer to family members.
Symptoms include shortness of breath, fatigue, light-headedness, fainting and chest pain, many of which occur during some physical activity.
Locklear learned about PAH the hard way. While touring India with a church group in May 2007, she collapsed. Indian doctors gave her a battery of tests, including an echocardiogram. She brought the data back home and met with a specialist who diagnosed PAH.
Locklear, who previously worked as an executive assistant at an information technology company, hasn't been able to work for the last three years. She wasn't always so winded; she served in the Army.
Locklear is one of those PAH patients for whom a cause remains a mystery. When doctors don't know the source of a disease, they call it idiopathic.
"Many idiopathic patients are young and healthy-appearing, " Dr. Trulock says. "If someone is overweight, shortness of breath can be written off."
Over the years, researchers have linked some PAH cases to certain drugs, such as the now-withdrawn diet pills known as the fen-phen cocktail. Cocaine, amphetamines and methamphetamines can cause PAH.
PAH also is linked to HIV, liver disease and autoimmune diseases such as lupus and scleroderma. Lupus is an inflammatory disease that can affect the skin, joints, heart, lungs, blood, kidneys and brain. Scleroderma causes a thickening of the skin and blood vessels as well as damage to internal organs.
PAH can be caused by congenital heart and lung defects at birth, and researchers believe there may be a genetic link to some PAH cases.
Florine Tripp, now 60, of Jefferson City, Mo., is one of those mystery PAH patients. She began feeling shortness of breath in February 2002 while walking up stairs.
At the time, she was living in Colorado Springs, Colo. After a few months, her family doctor conducted tests and detected an enlarged heart. She was referred to a cardiologist who suspected PAH and referred her to a specialist in Denver. After more detailed tests, she was diagnosed with PAH in December 2002.
Living in a high-altitude city exacerbates the effects of PAH, so Tripp moved to Jefferson City -- that's where her husband was born -- in March 2006.
In Colorado, before she became ill, she worked full-time as a paralegal. Now, she is able to work part-time as an executive assistant at an association of school counselors.
When she lived in Colorado, she recalls meeting people in a PAH support group who recounted stories of inaccurate diagnoses. "If I meet someone today who's been told she has asthma or COPD [chronic obstructive pulmonary disease], I tell them to ask their doctor its pulmonary [arterial] hypertension," she says. "Make sure the doctor checks everything."
In this case, "everything" could include several tests, says the American Lung Association. "There is no one way to diagnose PAH." Tests may include a chest X-ray, electrocardiogram (to measure heart-beat regularity), and an echocardiogram (an ultrasound measurement of heart function).
Another test is cardiac catheterization which measures how well the heart is pumping and how much oxygen is in the blood. Doctors insert a thin tube into a vein in the leg or arm and move it into heart's chambers.
Other tests include assessing lung-function, conducting a six-minute walking test and preparing a lung scan, which involves injecting radioactive dye to determine how well blood is flowing through the lungs' arteries.
Drug companies continue to conduct PAH research looking for compounds that are more convenient for patients to take or more effective than existing drugs. Researchers also are working on drugs that have fewer side effects than today's products or fewer interactions with other drugs.
Flolan, approved by the FDA in 1995, remains the most effective for most patients with severe PAH. "When I was first diagnosed, the doctor said you have a year to live, or you can go on Flolan now," says Locklear.
Like all powerful drugs, Flolan, which is now subject to generic competition, has powerful side effects. It is administered intravenously, which means a patient must have a catheter implanted in her chest. Catheters can produce infections, causing patients to switch temporarily to other drugs until the infection has been treated.
For all PAH drugs, however, "the benefits outweigh the side effects," says Dr. Murali Chakinala, associate professor of medicine at the Washington University School of Medicine. "After Flolan came out, people who previously had been given a death sentence were able to prolong their lives."
All PAH drugs take different approaches to a common theme: They aid blood flow in arteries of the lungs, reducing blood-pumping the strain on the heart and improving breathing.
"Since Flolan, there have been tremendous scientific discoveries in the field," says. Chakinala, who also is director of the university's pulmonary hypertension center and who has received research funds from five companies that market or are testing PAH drugs. "There is still a lot of room for improvement."
Today's medications range from tablets and pills to drugs that are injected under the skin or administered intravenously for the most debilitating types of PAH.
Some pills are given to patients with milder forms of the disease, but some are given to those with more severe forms. An inhaled drug, Ventavis, must be taken six to nine time per day; various pills must be taken from one to three times daily.
It's rare for many drug companies to compete for treating a disease that affects relatively few patients because there usually isn't enough profit -- even for drugs that patients must take for life. In addition to some 100,000 U.S. patients, drug companies say there's probably another 100,000 PAH patients worldwide.
Drug development is time-consuming and expensive. The trade group Pharmaceutical Research and Manufacturers of America says only five of every 5,000 experimental compounds make it to a clinical trial.
The Tufts Center for Drug Development says only one of those five becomes a commercial product. Using data from 2000, the center says it cost $802 million for the average drug to go from laboratory to marketplace, a period that takes 10 to 15 years.
Despite the research expense and presence of many drugs on the market, companies have five drugs in late-stage clinical testing for PAH, says Sagient Research Systems, an independent research firm that analyzes drug development. Seven other compounds are in early- to mid-stage clinical trials.
There are financial incentives for pursuing PAH drugs.
Drugs designed specifically for PAH have received "orphan" status, a reward conferred by the FDA under federal law that encourages development of drugs affecting fewer than 200,000 people. Companies get tax incentives for research as well as seven years of marketing exclusivity after the agency approves an orphan product.
And because side effects can cause patients to discontinue certain products, there's always an opportunity for alternatives. Some patients take more than one drug.
For a company like United Therapeutics, even comparatively small sales can be a big deal. Its $125 million in sales of Remodulin during the first half of 2008 accounted for most of its revenue.
For Switzerland's Actelion, the twice-a-day pill Tracleer produced $557 million in first-half revenue, or 89 percent of corporate sales. Ventavis contributed $35 million.
Although most PAH drugs are designed specifically for this disease, Pfizer secured FDA approval in 2005 for a PAH treatment called Revatio containing the same ingredient as Viagra. Pfizer conducted extra clinical tests for Revatio; and Eli Lilly is testing its impotence drug Cialis as a PAH treatment.
Some experimental drugs are based on the science of existing drugs; the Lilly and Pfizer drugs inhibit an enzyme that constricts arterial blood flow.
Other experimental compounds are trying to improve on upon marketed drugs that block endothelin, a natural chemical which causes blood vessels to constrict.
And some experimental drugs are building upon current products that provide a synthetic form of prostacyclin, which opens blood vessels. PAH patients lack adequate natural prostacyclin.
However, some experimental drugs feature a different strategy. For example, Novartis is testing Gleevec, now approved for types of leukemia and stomach cancer, as a PAH treatment.
"We need new approaches to therapies," says Chakinala. "We need new classes of drugs. There's still a major clinical need."
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Robert W. Steyer, a freelance journalist in New York, was a business writer for the St. Louis Post-Dispatch.