Stroke Study Reveals a Key Target For Improving Treatment

For over a decade, the drug called tPA has proven its worth as the most effective emergency
treatment for the most common kind of stroke. But its promise is blemished by two facts: tPA can cause dangerous bleeding in the brain, and its brain-saving power fades fast after the third hour of a stroke.

Now, a new paper published online in Nature Medicine reveals why tPA has these limitations. It also gives tantalizing evidence about how those problems might be overcome, if a stroke victim first takes a drug currently used to treat leukemia.

The researchers, from the University of Michigan and the Ludwig Institute for Cancer Research (LICR) Stockholm Branch at Karolinska Institutet in Stockholm, Sweden, emphasize that it's still too early to apply their findings -- made in mice -- to the treatment of stroke victims
everywhere.

But the LICR-Karolinska Institutet team will soon begin a clinical trial to test the theory in humans, using the leukemia drug known as imatinib (Gleevec). In mice, that drug greatly reduced bleeding, even if tPA wasn't given until five hours after a stroke began.

The new paper details a series of molecular and cellular experiments conducted by the two teams, which began collaborating after hearing of each other's work.

They report that tPA apparently causes its risk of bleeding, and leakage of fluid within the brain, by accident. The culprit: tPA's tendency to act upon a protein called PDGF-CC, and the PDGF-alpha receptor that it binds to. This interaction causes the usually impervious "blood-brain barrier" to become porous, leading to leakage. Gleevec inhibits the PDGF-alpha receptor, apparently counteracting tPA's effect.

This unwanted effect on the blood-brain barrier appears to be unrelated to tPA's main job, which is to break down clots that have lodged in the brain's blood vessels, cutting off blood supply to the area and starving brain tissue until it begins to die.

Such clots cause 80 percent of the 15 million strokes that occur each year worldwide. Five million people die, and 5 million more are permanently disabled, by strokes each year, according to the World Health Organization.

"Our findings may have immediate clinical relevance, and could be applied to find new treatments that will benefit stroke patients," says senior author Daniel Lawrence, professor of cardiovascular medicine in the U-M Medical School and member of the U-M Cardiovascular Center. "By better understanding how the brain regulates the permeability of the blood-brain barrier, and how tPA acts upon that system, we hope to reduce the risks and increase the time window for stroke treatment."

Ulf Eriksson, the leader of the team at the Ludwig Institute for Cancer Research Stockholm Branch at Karolinska Institutet, comments, "Our research group identified the growth factor PDGF-CC 10 years ago and we are now very excited having unraveled a mechanism in the brain involving this factor, which potentially will be a revolution in the treatment of stroke. Together with our clinical colleagues at the Karolinska University Hospital in Stockholm we are now rapidly continuing to explore this exciting possibility in clinical trials involving stroke patients."

If the clinical trial in human patients in Sweden bears out the findings seen in mice, perhaps Gleevec could be given immediately upon suspicion of stroke-like symptoms, before diagnostic scans and other tests can be made to determine if a patient could benefit from tPA.

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Results Promising for Computational Methods For Drug Development

New research, led by a Virginia Tech chemist, may someday help natural-products chemists decrease by years the amount of time it takes for the development of certain types of medicinal drugs. The research by T. Daniel Crawford, associate professor of chemistry, involves computations of optical rotation angles on chiral—non-superimposable—molecules. The research titled, "The Current State of ‘Ab Initio’ Calculations of Optical Rotation and Electronic Circular Dichcoism Spectra," appeared recently as the cover article in The Journal of Physical Chemistry A.

Many chiral molecules are important for medical treatment for illnesses ranging from acid-reflux to cancer. The term “chiral” means that two mirror images of a molecule cannot be superimposed onto each other. In other words, some are “left-handed” and some are “right-handed.”

“Most drugs have this handedness property,” Crawford says, “and for many of these drugs, even though both hands can cause a reaction, it is a situation where one hand does a good thing and one does a bad thing.” He used thalidomide as an example. A mixture of both hands of the drug was used in the late 1950s and early 1960s to treat morning sickness in pregnant women. Later studies revealed that, while one of the two hands acted as the desired sedative, the other hand was found to cause significant birth defects. Thalidomide was never approved by the FDA in the United States and was eventually taken off the market in Europe.

For chemists, therefore, it is often vital to determine which hand of a molecule they are using. In other words, when you have a sample of a chiral molecule, how do you distinguish between the left and right hand"

This is where a technique called polarimetry comes in to play. By shooting plane-polarized light through a sample of one hand, the chiral molecule in question will rotate to a characteristic angle either clockwise or counterclockwise, and the two hands of a chiral molecule produce opposite rotations.

“So if we figure out the direction and rotation of the light or each hand, we have a frame of reference for determining whether we have the left or right hand of a molecule,” Crawford says.

The problem with this method is that synthesizing the two hands of chiral molecules is often extremely time consuming. “It can take anywhere from weeks to years,” Crawford says.

Crawford’s research applies the theory of quantum mechanics to devise computational methods in order to eliminate having to create a synthetic molecule. “The hope is that this will allow us to calculate things like optical rotation very accurately,” he says. “So when an organic chemist has a molecule and doesn’t know if it is left- or right-handed, we can calculate that directly on the computer.”

Crawford says the ultimate goal in his research is to be able to provide organic chemists with computational tools to determine the handedness of a particular molecule they are working with. He said that such tools could speed up the drug development process by years.

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Researchers Find Deadly Prescription Drug Effects Six Years Before FDA

Northwestern University's Charles Bennett, M.D., is a super sleuth of potentially deadly prescription drug reactions. He leads a national SWAT team of doctors called RADAR (Research on Adverse Drug Events and Reports) based out of Northwestern's Feinberg School of Medicine.

They swoop in to investigate early signs of trouble years before the Food and Drug Administration (FDA) takes notice.

A new study by Bennett, the A.C. Buehler professor in Economics and Aging at Northwestern's Feinberg School of Medicine, and a hematologist and oncologist at Northwestern Memorial Hospital, found RADAR identified serious drug reactions six years earlier than the FDA and drug companies.

RADAR's proactive safety efforts and reports also were much more comprehensive than those from the FDA or drug companies, according to the study. RADAR's reports provided doctors with important medical insights as well as guidance for prevention, diagnosis and treatment.
The study will be published in Archives of Internal Medicine.

Since Bennett launched RADAR in 1998, his research has resulted in black box warnings on billion dollar drugs like Plavix that may have saved thousands of lives. He has also provided guidance to help physicians more safely administer drugs. More than 100,000 people die each year from reactions to medications. The FDA is under attack for its passive and inefficient methods of learning about these problems.

Why is RADAR so nimble" Bennett's network includes hematologists and oncologists around the country and the world. His phone rings weekly with calls from concerned doctors alerting him to possible new trouble. After such a call, Bennett probes for clues that led to a life-threatening reaction to a drug. ‘What's the age and weight of the patient, x-rays, details of the physical exam and blood tests"' he'll ask. He'll canvas doctors to see if they've seen similar cases. If a vital piece of evidence is missing, Bennett even will track down a doctor at home on a Sunday and ask her to drive back to her office to check a chart. Then Bennett and his team fit all the puzzle pieces together to figure out what happened and how to prevent it in the future.

The new study also shows, however, that the FDA and drug companies were faster than RADAR to spread the word about serious adverse drug reactions. RADAR relies on publishing its studies in peer-reviewed medical journals, a process that takes longer than the FDA's warning letters to doctors and the drug companies' package inserts.

Thus, it's time for a formal collaboration between RADAR and the FDA to wed their strengths, said Bennett, who also is co-director for cancer control of the Robert H. Lurie Comprehensive Cancer Center.

"We need to work together as partners," Bennett says of the FDA. "Pharmaceutical side effects are one of the top five causes of death in this country. We want to move it out of the top five. This is the way to start that process and save thousands of lives."

Bennett envisions a formal partnership with the FDA in which he would share RADAR's investigations on safety issues, arrive at a joint insight on drug problems and have the FDA distribute the information to doctors.


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Egyptians, Not Greeks Were True Fathers of Medicine

Scientists examining documents dating back 3,500 years say they have found proof that the origins of modern medicine lie in ancient Egypt and not with Hippocrates and the Greeks.
The research team from the KNH Centre for Biomedical Egyptology at The University of Manchester discovered the evidence in medical papyri written in 1,500BC – 1,000 years before Hippocrates was born.

"Classical scholars have always considered the ancient Greeks, particularly Hippocrates, as being the fathers of medicine but our findings suggest that the ancient Egyptians were practising a credible form of pharmacy and medicine much earlier," says Jackie Campbell.
"When we compared the ancient remedies against modern pharmaceutical protocols and standards, we found the prescriptions in the ancient documents not only compared with pharmaceutical preparations of today but that many of the remedies had therapeutic merit."

The medical documents, which were first discovered in the mid-19th century, showed that ancient Egyptian physicians treated wounds with honey, resins and metals known to be antimicrobial.

The team also discovered prescriptions for laxatives of castor oil and colocynth and bulk laxatives of figs and bran. Other references show that colic was treated with hyoscyamus, which is still used today, and that cumin and coriander were used as intestinal carminatives.
Further evidence showed that musculo-skeletal disorders were treated with rubefacients to stimulate blood flow and poultices to warm and soothe. They used celery and saffron for rheumatism, which are currently topics of pharmaceutical research, and pomegranate was used to eradicate tapeworms, a remedy that remained in clinical use until 50 years ago.

"Many of the ancient remedies we discovered survived into the 20th century and, indeed, some remain in use today, albeit that the active component is now produced synthetically," says Campbell. "Other ingredients endure and acacia is still used in cough remedies while aloes forms a basis to soothe and heal skin conditions."


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Pharmacists' Workload Contributes To Errors

High workloads for pharmacists increase the potential for medication errors, says a new study by University of Arizona College of Pharmacy researchers published in the May issue of the journal Medical Care.

The study was conducted by a team of researchers led by College of Pharmacy professor Daniel Malone, who is also a member of the Arizona Center for Education and Research on Therapeutics at the Critical Path Institute.

Researchers reviewed data submitted to insurance companies from 672 pharmacies in 18 metropolitan regions. The pharmacies filled an average of 18,000 prescriptions from January to March 2003, or 1,375 prescriptions per week. During that time, the average number of potentially harmful drug-drug interactions dispensed by each pharmacy was 32.1.

The pharmacies employed an average of 1.2 pharmacists for each hour the store was open, and each pharmacist filled an average of 14.1 prescriptions per hour. The risk of dispensing potentially harmful combinations of medications that could result in a drug interaction increased by 3 percent for each additional prescription filled per hour.

The study also found that computerized interaction alerts and telephone, Internet, and fax systems—which are intended to decrease pharmacist workload and increase the efficiency of prescription receipt and filling—also were associated with an increase in the number of prescriptions dispensed for medications that could interact.

“It appears that prescription volume is exceeding capacity and that automation and other pharmacy staffing may not sufficiently compensate for the increased pharmacist workload,” Malone says. “Additional research is needed to confirm and clarify this study, but our findings are consistent with other reports concerning workload and medication errors. We need to take a closer look at what we can do better in community pharmacies to reduce potentially dangerous interactions between dispensed medicines.”

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Space Technology Benefits Medical Community

A small group of Johns Hopkins Applied Physics Lab researchers, in collaboration with physicians from the Johns Hopkins Scleroderma Center in Baltimore, developed and recently completed initial trials for a miniature device to help physicians characterize Raynaud’s disease and measure treatment effectiveness.

“The Ambulatory Raynaud’s Monitor is a tiny, Band-Aid-like device that enables physicians to objectively characterize a patient’s condition, determine its severity and measure symptoms in real time,” says Frederick Wigley, director of the Hopkins Scleroderma Center and one of the country’s leading scleroderma experts, who asked the Johns Hopkins University Applied Physics Laboratory (APL), in Laurel, Md., to develop the device after reading about APL’s work developing miniature devices for spacecraft. “Until now, Raynaud’s research has been crippled without such a device.”

The small, low-cost monitor wraps around a patient’s finger and is secured with a bandage or medical tape. It contains two sensors that alternately record skin and ambient temperatures – indicators of surface blood flow – every 36 seconds. Interactive controls permit a patient to record the date and time of a suspected Raynaud’s attack. A week’s data is held by the monitor’s electronics and is retained even if the device’s power is unexpectedly interrupted.
Physicians can easily download data into a computer or PDA (personal digital assistant).

Software developed by APL enables physicians to quickly and easily display and plot data, which could be done during a patient’s appointment to provide real-time feedback. The monitoring system’s batteries store enough energy to operate for several months, and devices can be cleaned and reinitialized for use with multiple patients.

Triggered by cold temperatures or stress, Raynaud’s is characterized by numbness and coldness in the fingers, toes, ears and/or nose when blood vessels in those areas constrict during attacks. Insufficient blood flow near the skin’s surface also causes patients to experience skin color changes and varying levels of discomfort. Limited blood flow to the extremities can potentially lead to permanent loss of function. Raynaud’s can occur on its own, or be secondary to another condition, such as auto-immune disorders like scleroderma or lupus.

Field TrialsThe device recently underwent initial testing on patients with Raynaud’s being treated at the Johns Hopkins Medical Institutions. Patients wore a monitor for one week in their homes, pressing an “event button” on the device to indicate when a Raynaud’s event was occurring. The data – processed by APL engineers and evaluated by JHMI physicians – indicates Raynaud’s events can be successfully identified. Patients said the devices are comfortable and easy to use.

“The data from this preliminary study suggests that the monitor can help scientists and physicians learn more about Raynaud’s phenomenon and help investigators evaluate the effectiveness of drugs being developed to treat this disease,” says APL’s Binh Le, one of the inventors of the device.

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Webcast: Nanotech To Improve Developing Nations

What if doctors in Kenya could equip cells of the retina with photo switches that can be flipped on,essentially making blind nerve cells see and restoring light sensitivity in people with degenerative blindness? What if public health workers in Bangladesh could place contaminated water into transparent bottles, which when placed in direct sunlight could disinfect the water and help prevent water-borne diseases like cholera, dysentery or polio?

What if a medical technician in Vietnam could use a tiny "reporter"molecule that attaches itself to specific bacteria or viruses in a patient sample and read with an inexpensive laser device -- no bigger than a briefcase -- whether an infectious disease is present? What if a nurse in Brazil could dispense a gel that would stick to the AIDS virus surface like molecular Velcro and prevent it from attacking healthy cells in sexually active women?

These scenarios are not science fiction. They are just a few examples of the exciting potential of nanomedicine -- an offshoot of nanotechnology which researchers in both industrialized and developing countries hail as enabling the next big breakthroughs in medicine and which promises to change virtually every facet of health care, disease control and prevention.

Nanotechnology is the engineering of machines and materials at the atomic scale.

The Woodrow Wilson International Center for Scholars in Washington will hold a webcast on Tuesday, February 27 at 12 p.m. EST, with experts who will examine the role of nanotechnology to improve health in developing nations.

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