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[Guest guest]

Hi ,

In today's (5-17-02) issue of the Wall Street Journal, there was an

article that reminded me of our earlier discussion....that of the

lack of clinical trials due to the lack of funds. I thought the

article was very interesting in and of itself, but if you substitute

antibiotics instead of the prednisone and substitute RP instead of

sepsis....you will see the similarities. It seems that this

situation happens over and over again.

Sending hugs,

Connie

here's the article:

Why Cheap Drugs That Appear

To Halt Fatal Sepsis Go Unused

By THOMAS M. BURTON

Staff Reporter of THE WALL STREET JOURNAL

It was strictly happenstance that sent the doctor off on his quest. A

young mother hovering near death in a Connecticut hospital was

misdiagnosed, and given a drug she wouldn't otherwise have gotten.

She recovered.

Then the doctor, G. Umberto Meduri, learned that what the woman

actually had was sepsis, a devastating condition that has long been

as baffling as it is deadly. Often beginning as a blood infection

after surgery, sepsis can quickly turn lethal. It kills an estimated

215,000 people in the U.S. annually -- more than the combined toll of

the worst cancers, of the lung and colon.

4th in a series: See previous articles in series

The puzzling thing was that the drug this woman got was a steroid,

supposedly worthless for sepsis. Research seeming to show this

futility was common at the time. " In the late 1980s, anyone in our

field would have said you're an idiot if you use steroids " for

sepsis, says Dr. Meduri, who is now at the University of Tennessee

Health Science Center in Memphis.

What followed was 15 years of tantalizing but tiny studies that

seemed to jibe with what happened in the Connecticut hospital. Now,

Dr. Meduri and colleagues in the U.S. and Europe have accumulated a

modest body of evidence that the deadliest forms of sepsis often

yield to cheap, common steroids such as cortisone. A researcher at

the University of Paris recently found that steroids led to nearly a

30% drop in deaths from septic shock, a severe form of sepsis in

which blood pressure plunges.

If the approach is indeed effective, it would be big economic news:

It typically costs less than $50. The only drug specifically approved

for severe sepsis is about $7,000 a dose.

That drug, Eli Lilly & Co.'s newly approved Xigris, was the fruit of

huge studies costing hundreds of millions of dollars, and Lilly is

spending lavishly to promote it. The Meduri approach languishes,

because no one has ever done the large-scale studies that most

doctors need to be convinced.

• See what happens when an infection invades the body and how it can

lead to sepsis, using the example of a respiratory infection.

The steroids saga illustrates one reason expensive brand-name drugs

don't face more competition from low-priced generics. There is little

incentive for big pharmaceutical companies -- the main financiers of

drug research -- to pay for studies of using steroids against sepsis,

because the steroids' patents have expired. The National Institutes

of Health also turned Dr. Meduri down. It primarily funds basic

scientific research, not human trials of drugs.

Dr. Meduri, who finally got modest funding from a church-affiliated

health-care foundation in Tennessee, has recently had to slash the

size of what he hoped would be a major study, as his funding runs

low. He has laid off some researchers and he lost one of his labs

when the University of Tennessee reassigned it. Sitting in freezers

are thousands of blood-plasma samples that might reveal which

patients' genetics make them likeliest to benefit -- samples there is

no money to analyze.

" Meduri has been a voice crying in the wilderness, " says J.

Marini, a University of Minnesota medical professor and specialist in

critical care. " His data are intriguing, and consistent with my

clinical experience. I have no doubt whatever that steroids have

saved patients of my own. "

It's a Catch-22: Because money is unavailable, only small studies are

possible. Because they are small, they are viewed as less than

convincing, allowing skepticism to persist -- and money to remain

unavailable. The drugs that draw the industry's heavy research and

promotional money are the branded ones, which are also far more

expensive.

By all accounts, the prime skeptic is Gordon R. Bernard, a prominent

Vanderbilt University critical-care specialist. He was the chief

investigator both on a 1987 study showing steroids ineffective, and

on the main large study of Lilly's Xigris. Dr. Bernard has been

sarcastic in his criticism of Dr. Meduri's work, attacking him in

unusually personal terms. In a medical-conference debate with Dr.

Meduri at Chicago's Drake Hotel in 1998, for instance, Dr. Bernard

seemed to question Dr. Meduri's IQ. At the same conference, in a

remark citing one of the steroids, Dr. Bernard said, " Elvis was

spotted again in Memphis ... only three hours after Dr. Meduri was

seen at the grave-site of Elvis at Graceland attaching

methylprednisolone to the grave. "

Dr. Bernard says he regrets his IQ remark. As for whether steroids

used the way Dr. Meduri proposes could help with sepsis, he says

it " is a fair hypothesis -- but give me some data. "

Sepsis -- which is often the culprit when a newspaper story says

someone died of " complications " from surgery or illness -- can savage

a young body as well as an old one. Shanna Carel, a member of the

pompom squad at the University of Memphis, went out for pizza one

night in 1998 and felt ill. Twenty-four hours later, she was

diagnosed with meningitis from airborne bacteria. It swiftly

progressed to septic shock and acute respiratory distress syndrome.

Within hours, Ms. Carel was on a ventilator, fighting for her life.

Given four weeks of low-dose, intravenous steroids in one of Dr.

Meduri's studies, she survived. She now is 24 and a nursing student.

Her story suggests why sepsis and the closely related acute

respiratory distress syndrome have escaped broad awareness. No one

suffers from them chronically. Patients usually either die -- as

about a third of those with severe sepsis do -- or return to general

health in a few months. This doesn't make for support groups or

publicity.

Out of Control

The body reacts to bacterial invaders such as Ms. Carel's with

inflammation, a response that is normally beneficial. But in severe

sepsis, the inflammation gets out of hand and turns into a raging

forest fire instead of a controlled blaze. It can cause the liver,

the lungs or other organs to simply shut down.

The body normally regulates its inflammatory response with steroids.

A signal sent from the pituitary gland in the brain to the adrenal

glands, sitting atop the kidneys, tells them to send out a steroid

called cortisol. The cortisol's role is to prevent overproduction of

inflammatory chemicals. However, in sepsis, cells become less

sensitive to the cortisol. It can't curb the inflammation.

Two decades ago, doctors tried common steroids for sepsis. They gave

them in megadoses, for 24 hours or so. By 1987, this approach had

been widely discredited by large-scale studies of human patients, the

most prominent of which was published by Vanderbilt's Dr. Bernard.

The approach of Dr. Meduri and others such as Djillali ne at the

University of Paris is quite different. Instead of megadoses, they

give steroids for days or weeks, intravenously, at doses of only 2%

or less of those used in the 1980s. They believe synthetic steroids

such as hydrocortisone and methylprednisolone can reactivate the

cells' sensitivity to cortisol, curtailing inflammation.

This may have been what helped Grady Marlow Jr., a retired accountant

and lawyer in Germantown, Tenn., who had a heart attack in late 1998.

During a cardiac procedure, he breathed in stomach contents he had

coughed up, developing sepsis and acute respiratory distress

syndrome. He lingered for seven days on a ventilator. Then, given a

low dose of methylprednisolone in a Meduri study, he improved enough

to have heart surgery. Now the 80-year-old widower is back home and

doing well. He says he has become a regular at a Baptist Church in

Memphis, where " there's a lot of widows. "

Most doctors facing a sepsis case don't try the treatment Mr. Marlow

got. There's little legal or economic reason not to, because the

steroids are approved drugs with long safety records. But some

doctors aren't interested unless they see results from a large trial,

and many others have never heard of the treatment. Many doctors get

most of their knowledge of new drug treatments from pharmaceutical

companies, which have no interest in dispatching emissaries to talk

about low-priced drugs with long-expired patents.

By contrast, Lilly promotes Xigris through a large sales force and

also pays 250 critical-care specialists to speak to colleagues about

the IV drug, for $1,000 to $1,500 per talk. Lilly also recently

treated critical-care doctors to a concert by jazz singer-guitarist

Benson during a conference in San Diego, and last year it gave

a dinner for other critical-care specialists during a Brussels

medical conference. It says it has decided to stop providing such

entertainment because of adverse public perceptions. Lilly has sold

$43 million of Xigris in the drug's first full quarter on the market.

The case that piqued Dr. Meduri's interest came in 1987. He was on

staff at Norwalk Hospital in Connecticut when Janet Machala, an

artist, was hospitalized for a severe respiratory infection. A

pathologist misread a biopsy slide and concluded she had a rare

pneumonia, which called for a low dose of steroids over many days.

Lingering near death on a mechanical respirator, Ms. Machala was

hooked up to a steroid IV drip for four weeks. After the first four

days, she was able to get off the respirator.

Then Dr. Meduri found out she had actually had sepsis and acute

respiratory distress syndrome. He continued to treat some sepsis

cases with steroids at a low dose, had success, and published his

results. A paper he wrote for Chest, a leading respiratory-disease

journal, carried the provocative title, " Is the Right Drug Used the

Wrong Way? "

What was needed was a large study matching the treatment against a

placebo. He sent out numerous grant requests to drug companies,

government agencies and foundations. They all said no, including

Upjohn Co., the maker of methylprednisolone. It had partly funded the

study that showed megadoses of the steroid ineffective. In addition,

the steroid's patent had expired.

A decade later, after Upjohn became part of Pharmacia Corp., Dr.

Meduri made a plea to Pharmacia's chief executive, Fred

Hassan. " Because of this drug developed by your company, we have seen

a precipitous drop in morbidity and mortality in patients with [acute

respiratory distress syndrome]. It is unfortunate and disappointing

that your company is unwilling to support this promising and life-

saving effort, " Dr. Meduri wrote. A Pharmacia spokeswoman says, " Drug

companies get loads of requests to do studies, but given this

background, we chose other priorities. "

Desperate for money, Dr. Meduri turned to an unlikely source and

finally struck paydirt. An official at Baptist Health Care Corp. in

Memphis, a foundation that operates 17 hospitals, had heard of his

work. It gave him funding for a clinical trial in patients with late-

stage acute respiratory distress syndrome.

This work resulted in a Journal of the American Medical Association

paper in 1998 concluding that " prolonged administration of

methylprednisolone " was associated with " improvement in lung injury "

and " reduced mortality " in respiratory distress, which often results

from sepsis. Specifically, none of 16 patients who got steroids from

the beginning died. Five of the eight who started out on a placebo

did.

Dr. Bernard criticizes both the study's size and its methodology. Its

24 patients contrast with the 1,690 in one study he supervised of

Lilly's Xigris. And the steroid researchers, though they didn't know

which patients were getting the drug and which a placebo, switched

the patients who weren't responding after 10 days to the other

treatment. That move made it harder to analyze the results.

" Gordon [bernard] is skeptical and Umberto [Meduri] is a big

advocate. The middle ground is probably correct, " says another

leading critical-care doctor, Philip Dellinger in Camden, N.J. He

says the Meduri research is " a very impressive study, and I found

encouraging the fact that there was a broad effect on inflammation.

But it was a small number of patients. "

Drop in Mortality

A study by Dr. ne in France linked low-dose steroids to a 29%

fall in deaths from septic shock. That appears to be a larger drop in

mortality than Xigris has shown in severe sepsis, and without the

bleeding risk the Lilly drug entails. Lilly officials say they

believe Xigris is superior. But " if steroid researchers are

successful, that's fantastic, " says Elaine Sorg, head of Lilly's

critical-care business. The French doctor's study, like Dr. Meduri's,

was far smaller than Lilly's.

Dr. Meduri had hoped to enroll 200 patients in a new sepsis study but

had to limit it to 80 for lack of funding. As a result, he worries

that this, too, " may not have the statistical power to show a

mortality benefit. "

But Dr. Meduri's fortunes may be changing. His group recently

published an analysis showing that steroids called glucocorticoids

lowered the levels of inflammatory chemicals in patients who survived

acute respiratory distress syndrome. One co-author was

Chrousos, an authority on that type of steroid, who is also the

National Institutes of Health's chief of pediatric and reproductive

endocrinology. Dr. Chrousos has become an influential believer in Dr.

Meduri's ideas.

He believes the NIH, which once declined to pay for Dr. Meduri's

research, will do so now. " This basically says that patients with

[acute respiratory distress syndrome] and early septic shock should

be on glucocorticoids, " Dr. Chrousos says.

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How Sepsis Can Occur

What happens when an infection invades the body and how it can lead

to sepsis, using the example of a respiratory infection.

1. Bacterial products or other inflammatory agents enter the lungs,

activating a protein called NFkB. NFkB stimulates the production

of " fighting " proteins called cytokines.

2. These cytokines are sent into the bloodstream to organs. The

resulting inflammation can kill bacteria, but if unabated,

inflammation can turn into sepsis and threaten vital organs.

3. When cytokines reach the brain's pituitary gland, it releases a

hormone called ACTH.

4. ACTH flows through the bloodstream and stimulates the adrenal

glands to produce a steroid called cortisol.

5. Cortisol attaches to cell proteins, called glucocorticoid

receptors, regulating the ability of NFkB to stimulate cytokine

production. When the regulation doesn't occur properly, inflammation

can spread, leading to sepsis. Dr. Meduri contends additional

cortisol-like steroids can restart the normal process.

Sources: WSJ Research; Merck Manual; University of Tennessee