PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
June 25, 2004

In this month's edition:

1. Minimally Invasive Vascular Surgery was Last, Best Hope for Life-Threatening Thoracic Aortic Aneurysm
2. MossRehab Joins Multi-National Clinical Study of Medication to Treat Severe Traumatic Brain Injury
3. Adrenaline Packs a Powerful Punch in the Use of Antidepressants, According to an Animal-Model Study at Penn


Editors note: Research by Philadelphia International Medicine physicians may lead to new ways to treat some of our most challenging diseases. Below are just three examples from our hospitals.


Minimally Invasive Vascular Surgery was Last, Best Hope for Life-Threatening Thoracic Aortic Aneurysm

Philadelphia - At age 82, Louis Hankins was not in any shape for major surgery. He had a long history of health problems including undergoing a triple bypass for his heart, renal disease, emphysema, diabetes and dialysis three times a week. But, he had just learned that he had a life-threatening descending thoracic aortic aneurysm (TAA) which would require him to have vascular surgery. He and his family knew he could not handle the physical trauma of an open surgical procedure.

Thoracic aortic aneurysms, which are diagnosed in more than 20,000 U.S. patients annually, occur when a section of the aorta, the body's main circulatory vessel, weakens and bulges outward like a balloon in the section of the artery that runs through the chest. Should the aneurysm grow to the point where it ruptures, the patient would be at high risk for rapid death due to internal bleeding.

But surgeons at Thomas Jefferson University Hospital in Philadelphia were able to offer Mr. Hankins an alternative that successfully repaired the damage without putting him at such a major risk.

Mr. Hankins was recently part of a multi-center clinical trial, in which surgeons at Jefferson were the first to use a newly designed endovascular stent graft for patients with TAA. The surgical team led by Joseph Lombardi, MD, chief of Vascular Surgery, Methodist Hospital Division of Thomas Jefferson University Hospital, has performed the procedure twice since March 30 without the need for the trauma of open surgical repair.

Patients diagnosed with TAA traditionally have had to undergo a highly invasive open surgical procedure where a surgeon opens the chest cavity, clamps off the aorta and sews a surgical graft in place to prevent the aneurysm from rupturing. Such open surgical procedures carry high health risks for many older patients, who may also suffer from other significant medical conditions such as diabetes or hypertension.

But using the investigational graft, which was designed by Cook Incorporated, Jefferson surgeons needed to make only one incision in Mr. Hankins' groin to allow the insertion of the graft's advanced delivery system into the femoral artery. Once the catheter was guided into position through the patient's arteries under fluoroscopy, a two-piece, fabric-covered, self-expanding stent graft was secured inside the weakened section of the thoracic aorta to relieve pressure on the aneurysm, greatly reducing the risk of rupture.

"The procedure was very straightforward and Mr. Hankins was virtually pain-free," said Dr. Lombardi, assistant professor of Surgery, Jefferson Medical College of Thomas Jefferson University. "This research may demonstrate that there are significant benefits with the minimally invasive approach."


MossRehab Joins Multi-National Clinical Study of Medication to Treat Severe Traumatic Brain Injury

Patients at MossRehab with severe traumatic brain injuries may be eligible to participate in an international clinical study funded by a five-year, $3-million grant from the National Institute on Disability and Rehabilitation Research. The study is designed to test the effectiveness of a drug called amantadine hydrochloride for treating patients with prolonged impairments of consciousness.

"Many drugs are used to try to speed the recovery of consciousness in individuals with severe brain injuries, but there is very little research available to help physicians select a drug that is effective in treating patients in vegetative and minimally conscious states," said John Whyte, MD, PhD, Director, Moss Rehabilitation Research Institute.

According to Dr. Whyte, amantadine hydrochloride, introduced in the 1960s as an antiviral agent, has been shown to enhance the transmission of nerve impulses in the brain. The encouraging results of earlier pilot studies using this drug in patients recovering from disturbances in consciousness paved the way for this major study in which as many as 180 patients are expected to be enrolled at multiple sites.

Between 15,000 and 45,000 Americans survive severe traumatic brain injury each year. Survival rates have improved considerably during the last 25 years as the result of better emergency room care and surgical procedures. Yet the average lifetime per-patient cost for care after a severe traumatic brain injury remains very high at about $2 million, according to a 1999 National Institutes of Health survey. In addition, the family disruption caused by involuntary role changes is often overwhelming.

Those with the most severe injuries may survive in the vegetative state (commonly but inaccurately referred to as a long-term "coma") or the minimally conscious state (in which there are inconsistent but definite signs of consciousness) for prolonged periods and sometimes permanently, noted Dr. Whyte.

In the first phase of the earlier pilot study -- funded in 1997 through the Irving I. and Felicia F. Rubin Family Brain Injury Research Grant -- the Consciousness Consortium assessed the rate of spontaneous recovery of 149 patients who were in either vegetative or minimally conscious states of awareness. All patients were enrolled in the study between 4 and 16 weeks after brain injury and assessed using the Disability Rating Scale (DRS). The pilot study showed that scores during their first two weeks in the study were highly significant predictors of how well the patients would recover four months after injury.

During the second phase of the pilot study, focus shifted from spontaneous recovery rates to the impact of several rehabilitation treatments on recovery. Researchers noted that of all the medications patients received in the first month of treatment, only amantadine hydrochloride had a significantly positive relationship to outcome at four months post-injury.

These and other promising findings from similar studies of the drug led to this successful proposal for a larger, double-blind clinical study designed to rule out the possibility that physicians in the earlier studies were more inclined to give the drug to patients already showing signs of improvement.

Among patients with prolonged disorders of consciousness, regions of the brain important in the transmission of a chemical called dopamine are prominently involved, Dr. Whyte explained. Dopamine plays a critical role in the central nervous system by influencing arousal, movement, perception and behavior. Amantadine hydrochloride may help patients in vegetative and minimally conscious states by stimulating dopamine transmission.

To be eligible to enroll in the study, a patient must be between the ages of 16 and 65, must be admitted to one of the eight participating clinical facilities for brain injury care and rehabilitation, and be between 4 to 16 weeks post-injury with no or inconsistent ability to follow commands or communicate. Each patient will receive either amantadine hydrochloride or placebo, determined at random, for four weeks in a double-blind study, which means that neither the patient nor attending physician will know the group to which the patient has been assigned.

Results will be measured after the fourth and sixth weeks of the study using two well-established behavioral rating scales to gauge recovery and measure whether improvements persist after the drug is stopped. All patients will have CT scans before entering the study to help determine whether the location and extent of brain injury influence response to amantadine hydrochloride.

Facts About Amantadine Hydrochloride (AH)

AH is generally well-tolerated and adverse reactions are generally mild and reversible. Side effects include insomnia, poor concentration, depression, swollen ankles and gastrointestinal effects such as upset stomach.


Adrenaline Packs a Powerful Punch in the Use of Antidepressants, According to an Animal-Model Study at Penn

Researchers from the University of Pennsylvania Medical Center found that norepinephrine (adrenaline) plays an important role in animals in determining behavioral effects in some of the most commonly prescribed antidepressants, regardless of which biochemical pathway the drug uses to alleviate symptoms of depression. This finding -- published in the May 2004 Proceedings of the National Academy of Sciences -- should help scientists design more effective drugs for patients.

Using genetically-altered mice unable to produce norepinephrine, they tested behavioral changes brought on by two different antidepressant classes. With the exception of one drug, they found that those lacking norepinephrine did not respond to the drugs. "Millions of Americans suffer from major depressive disorders and this study helps us understand how antidepressant drugs are processed to produce clinical therapeutic effects. It helps us understand how to redesign better drugs and which treatments will work better for which patients," says the study's lead author, Irwin Lucki, PhD, Professor of Psychiatry and Pharmacology and Director of the Behavioral Psychopharmacology Laboratory at Penn.

There are currently two major classes of antidepressants used to treat depression: norepinephrine reuptake inhibitors (which work by increasing the synaptic activty of adrenaline in the brain); and selective serotonin reuptake inhibitors (which elicit their effects by increasing the activity of serotonin in the brain). Previously, it was believed that SSRIs - whose over-the-counter names include Prozac, Zoloft, Paxil, and Celexia - produced effects on the serotonergic system only; but the Penn researchers' findings showed that the effects of most SSRIs can also depend on responses from the noradrenergic system. "This study is the first to use this unique animal model to test whether the drugs are still effective in animals that lack norepinephrine, a key neurotransmitter in the brain," Lucki adds.

The researchers tested eight commonly prescribed antidepressant drugs, including four SSRIs. The SSRI medications tested were fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil) and citalopram (Celexia). In animal models, those able to produce norepinephrine experienced behavioral changes when given the antidepressants. But all of the antidepressants, except citalopram, failed to work in the models lacking norepinephrine. These results provide striking evidence that norepinephrine plays a critical role for the creation of desired behavioral effects of most classes of antidepressant compounds including the SSRIs.

Penn researchers also contributing to this study include: John F. Cryan, Olivia F. O'Leary, Sung-Ha Jin, Julie C. Friedland, Ming Ouyang, Bradford R. Hirsch, Michelle E. Page, Ashutosh Dalvi, and Steven A. Thomas.

The study was funded by grants from the United States Public Health Service, The National Institute of Mental Health, The National Institute of Neurological Disorders and Stroke, and a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.


Philadelphia International Medicine is an organization that provides medical and patient support services to international patients. It also provides continuing medical education and health care training and education to international physicians, administrators and other practitioners. As the international department of several Philadelphia-area hospitals, international patients gain access to physicians and hospitals rated among the best in the world through one telephone call to PIM. You can reach PIM by calling 1-215-735-3575; fax, 1-215-790-1267; or e-mail, physicians@philadelphiamedicine.com . You can find out more about PIM through its Website at www.philadelphiamedicine.com .