Vitamin E, Aricept Cocktail, Model of Alzheimer's Enzyme, Reminyl Requires Less Caregiver Time

Oct. 28, 2003 - A vitamin cocktail containing Vitamin E and the prescription drug Aricept is showing promise as a therapy to help slow the progression of Alzheimer's disease.

A three-year study shows that combining the prescription drug Aricept with vitamin E can help slow the progression of the disease, according to Alzheimer's researcher Dr. David Beversdorf.

"What we found was that the decline at years 1, 2 and 3 compared to the baseline was significantly less for our group," said Beversdorf.

Patients treated with the prescription combination scored better on mental exams, showing less mental decline than the group that did not get the cocktail, according to the study. Patients were given a minimum of 670 mg of vitamin E combined with a normal dosage of Aricept. Although the study was promising, researchers still have many questions to answer before they know if the combination will benefit every patient.

The research appears in the journal Alzheimer Disease and Associated Disorders. The research was funded by an unrestricted educational grant from Pfizer/Eisai, manufacturers of Aricept, and the National Institutes of Health.

In the United States, about 4.5 million Americans have Alzheimer's disease, according to the Alzheimer's Association. As the baby boom generation ages, the estimated Alzheimer prevalence is 11.3 million to 16 million by the year 2050.

Patients Treated With Alzheimer's Drug Reminyl(R) Require Less Caregiver Time

Oct. 28, 2003 - Caregivers of patients with mild to moderate Alzheimer's disease being treated with the drug Reminyl® (galantamine HBr) spend less time providing care each day than do those caring for a patient taking a placebo, according to a newly published study. Patients treated with Reminyl may also be unsupervised for more time per day compared to those taking placebo. The study appears in this month's issue of the peer-reviewed International Journal of Geriatric Psychiatry.

"Galantamine has been shown to have positive effects on cognition, function, global response and behavior in patients with mild-to-moderate Alzheimer's disease," according to Mary Sano, PhD, director of the Alzheimer's Disease Research Center, Mt. Sinai School of Medicine in New York City, and one of the study's authors. "The results of this study show that the drug is also associated with benefits to the caregiver."

More than four million Americans are estimated to have Alzheimer's disease. According to the Alzheimer's Association, more than 70 percent live at home, with 75 percent of their daily care being handled by family members.

Early in the disease, caregivers provide assistance with complex tasks, such as managing personal finances and legal matters. As the disease progresses, caregivers provide assistance in cooking, bathing, dressing and toileting. Because of the risk of wandering, falls and other accidents, caregivers also spend considerable time supervising the person with Alzheimer's disease, which detracts from their ability to participate in social events and employment. In fact, at the beginning of the study, many caregivers estimated that the person they cared for could be unsupervised for four or fewer hours per day.

This study analyzed data pooled from two large, placebo-controlled, randomized, six-month trials involving 825 patients with mild to moderate Alzheimer's disease. At various points throughout the trial, caregivers recorded the amount of time they spent assisting with activities of daily living and time patients could be left unsupervised each day.

Caregivers of patients in the Reminyl-treated group spent an average of 32 minutes (p=0.011) less per day assisting with activities of daily living. The effect was more pronounced among caregivers of patients with moderate- stage disease being treated with Reminyl, who spent nearly an hour (53 minutes; p=0.021) less each day.

Researchers also found that patients in the Reminyl treatment group could spend more time unsupervised than those in the group taking placebo. Overall, Reminyl patients could be unsupervised for 27 minutes more per day than those taking a placebo. This translates to slightly more than three hours per week.

Analyses also showed that caregivers of patients treated with Reminyl were almost twice as likely to report an increase in the amount of time that patients could be left unsupervised compared with caregivers of patients taking placebo (p=0.015).

"Caregiver burden is one of the main considerations when deciding whether or not to move a family member with Alzheimer's disease into a nursing home," said Dr. Sano. "Results of this study show that treatment with galantamine may help reduce that burden."

Reminyl is used to treat patients with mild to moderate Alzheimer's disease. The most frequent adverse events are nausea, vomiting, diarrhea, anorexia and weight loss. They are usually mild and temporary.

Reminyl was developed by J&JPRD under a co-development and licensing agreement with UK-based Shire Pharmaceuticals Group plc. Reminyl is marketed by Janssen Pharmaceutica Products, L.P. in the United States, Janssen-Ortho in Canada, and Janssen-Cilag elsewhere - with the exception of the United Kingdom and Ireland, where it is registered and marketed by Shire under co-promotion agreement with Janssen-Cilag. The product is approved for the treatment of mild to moderate Alzheimer's disease in more than 30 countries.

For more information, refer to the full prescribing information for Reminyl or visit www.reminyl.com. Janssen Pharmaceutica Products, L.P., also supports a web site dedicated to caregivers, www.SharingCare.com.

New Model of Alzheimer's Enzyme May Help Refine Future Treatments

Oct. 28, 2003 - The enzyme largely responsible for the development of Alzheimer's disease may work in a different way than previously thought, according to a report compiled by an international team of scientists led by researchers at Washington University School of Medicine in St. Louis

"We're very excited to provide more insight into how this bizarre process takes place," says principal investigator Raphael Kopan, Ph.D., professor of medicine and of molecular biology and pharmacology. "The more we understand the way this enzyme works, the easier it will be to design better and more intelligent approaches to tweaking the enzyme to do what we want."

The results are published online in the early edition of the Proceedings of the National Academy of Sciences and will appear today in the print edition. The study was an international collaboration between researchers at the School of Medicine, Merck and Co. Inc., University of Tokyo, Harvard Medical School, University of Tennessee at Memphis, and the K.U. Leuven and Flanders Interuniversity Institute for Biotechnology in Belgium.

The results focus on gamma-secretase, an enzyme that clips a long protein called amyloid precursor protein (APP), which results in fragments that accumulate as brain plaques. The plaques are a hallmark of Alzheimer's disease, making inhibition of gamma-secretase activity a main objective for new Alzheimer's drugs.

Kopan and colleagues previously found the enzyme also is required for another protein called Notch to function. Notch helps produce many cell types and, using a thymus organ culture model system, Kopan's team found gamma-secretase inhibitors had the potential to interfere with production of key immune cells.

"Ideally, the next generation of drugs will be able to prevent gamma-secretase from triggering production of plaques without interfering with the enzyme's role in Notch signaling," Kopan says. "That goal is made easier with every additional glimpse into how the enzyme works."

The team's latest findings, which suggest that gamma-secretase may contain multiples of one subunit, are a step in that direction.

To confirm the enzyme cleaves both APP and Notch, Kopan's team first examined whether the two compete with each other for the enzyme's attention in culture cells. They did indeed find evidence of competition: Notch cleavage was significantly stunted after the addition of C99, the piece of APP upon which gamma-secretase acts. The opposite also was true: In the presence of Notch fragments, there was significantly less production of ABeta40, one product of APP cleavage.

The team also ranked each of seven different gamma-secretase inhibitors in order of its ability to interfere with cleavage of Notch or APP. The rankings were the same for both proteins. Six of the inhibitors also had an identical effect on Notch and APP.

Together, these findings suggest gamma-secretase cleaves both APP and Notch and treats them interchangeably — rather than distinguishing between the two, it simply clips whichever it runs into first. The presence of either protein can therefore influence gamma-secretase's effect on the other.

Next, the team examined how the same enzyme is responsible for clipping each molecule at two separate sites. A breakthrough came from observing the activity of a particular mutation in Notch that is protected from gamma secretase cleavage. As expected, Kopan's team found that this fragment does not compete with C99. Surprisingly, though, it did bind to the enzyme.

According to Kopan, enzymes can either have one site where they interact with molecules or have separate cutting and binding sites. This study suggests that gamma-secretase belongs to a class of enzymes where, in addition to the active site (which is in limited supply and therefore leads to competition between APP and Notch), there also are "binding" sites, where molecules can latch onto the enzyme without competing with each other and without becoming subject to cleavage.

"The active site is like a mouth — it chews whatever it touches but can only chew one thing at a time," Kopan explains. "The other site is like a hand — it's used for holding, and doesn't interfere with the ability of the mouth to chew another object. Maybe one molecule acts as the "hand" serving a meal to the "mouth," which is located on another molecule."

The researchers tested this theory in several ways. Gamma-secretase is a large, complex enzyme composed of four proteins. At its core is a molecule called presenilin. Kopan's team found that antibodies designed to find a tag on one presenilin molecule also could latch onto a different presenilin molecule with a different tag. This implies the two molecules are located close to each other.

Kopan's team confirmed the molecules' close proximity to each other by creating an irreversible chemical bond between the two molecules using a small inhibitor molecule designed by Merck and Co. in England.

"The data generated by our colleagues at Merck shows conclusively that there are two presenilin molecules in very tight proximity to each other," Kopan says. "But we still can't differentiate how the catalytic core of gamma-secretase, the "mouth" of the enzyme, is organized and whether it functions as a single entity or at the interface between two molecules."

To further investigate the complex organization and function of the enzyme, the researchers examined the effects of presenilin mutations found in people who develop the early, genetically linked form of Alzheimer's disease. They reintroduced mutated presenilin proteins from Alzheimer's disease patients to cultured cells missing both presenilin molecules. The mutant proteins failed to completely restore gamma-secretase activity, but the cells still produced ABeta42, the product of APP cleavage that accumulates to form brain plaques. In fact, some even resulted in production of more ABeta42 than when only normal presenilin molecules were present.

Kopan's team hypothesized that perhaps the mutated presenilin molecules influence production of ABeta42 by gamma-secretase activity by interacting with each other differently than do normal molecules, even though they themselves cannot efficiently clip APP or Notch. If a mutated presenilin molecule could be developed that is completely incapable of performing the active functions of gamma-secretase on its own and yet still is capable of increasing production of ABeta42, it would confirm that the enzyme has a functional unit at the interface between two presenilin proteins and suggest that familial forms of Alzheimer's disease are caused by inter-molecular interactions between mutant and normal proteins.

The team was able to observe that exact phenomenon; however, the finding was fleeting and, thus far, has not been reproducible.

"There are many reasons why this experiment shouldn't work, and yet for a short while it did," Kopan says. "Perhaps some component in the experimental conditions that allowed this to happen has changed; however, we don't fully understand what those key variables are and therefore have lost the ability to replicate the result. Our hope is that by publishing this study and proposing this experimental approach we will inspire other scientists to try different pairs of mutations or to develop better experiments while we continue to work on ours."

Published by NewTechMedia.com - NewTechMedia.com

E-mail - editor@SeniorJournal.com