Dimebon News and Information

Tuesday, Pfizer Inc. and Medivation Inc. announced the initiation of Contact and Constellation, two Phase 3 trials of the investigational drug Dimebon in patients with moderate-to-severe Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative disorder that affects more than 5.3 million families in the United States each year. The disease carries an annual societal price tag of $148 billion, according to the Alzheimer’s Association. It destroys brain cells, which causes memory loss and problems with thinking, and the behavior of patients with the disease can deteriorate to the point that it affects work, lifelong hobbies and social function. Alzheimer’s gets progressively worse, and it is fatal.

The company noted that the Contact study will assess as primary endpoints the potential benefits of adding Dimebon to ongoing treatment with donepezil HCI tablets on neuropsychiatric symptoms and activities of daily living. The Constellation study will evaluate as primary endpoints the effects of adding Dimebon to memantine HCI, another standard of care, on cognition, memory and activities of daily living.

Pfizer said that in preclinical studies, Dimebon has been shown to protect brain cells from damage and enhance brain cell survival, potentially by stabilizing and improving mitochondrial function.

In preclinical studies, Dimebon has been shown to protect brain cells from damage and enhance brain cell survival, potentially by stabilizing and improving mitochondrial function. The Dimebon mechanism is distinct from currently available AD medications.

The company revealed that these studies are part of a comprehensive late stage clinical development program, currently consisting of seven trials, to assess the safety and efficacy of Dimebon across all stages of Alzheimer’s disease, as monotherapy and in combination with currently available Alzheimer’s treatments, and in Huntington disease.

Dimebolin hydrochloride, branded as Dimebon, is an antihistamine drug which has been used clinically in Russia since 1983. Medivation and Pfizer have a global collaboration to develop and commercialize Dimebon for the treatment of Alzheimer’s disease and Huntington disease. Under the terms of the agreement, the companies are working in partnership to advance the Phase 3 development program with the goal of submitting a new drug application to the FDA and bringing Dimebon to market in the United States.

Middle-aged adults whose parents have Alzheimer’s disease are at increased risk for high blood pressure, evidence of arterial disease and markers of inflammation — all of which may be associated with later development of Alzheimer’s disease.

That’s the finding of a study by researchers in the Netherlands who compared 206 adults in 92 families with a parental history of Alzheimer’s and 200 adults in 97 families with no parental history of the disease.

The team at the VU University Medical Center in Amsterdam measured the participants’ blood pressure, analyzed blood samples for genetic characteristics, cholesterol levels and levels of pro-inflammatory proteins called cytokines, and collected medical history and details about diet, exercise and stress levels.

The study found that 47 percent of adults with Alzheimer’s-afflicted parents carried the gene (APOE e4) known to be associated with the disease, compared with 21 percent of those with no family history of Alzheimer’s. Those with a family history had higher blood pressure readings, signs of arterial disease and higher levels of several different cytokines.

High blood cholesterol and glucose levels were not associated with parental Alzheimer’s disease, according to the study, which is published in the November issue of the journal Archives of General Psychiatry.

“Our study shows that high blood pressure and an innate pro-inflammatory cytokine response in middle age significantly contribute to Alzheimer’s disease,” wrote Dr. Eric van Exel and colleagues. “As these risk factors cluster in families, it is important to realize that early interventions could prevent late-onset Alzheimer’s disease. One could argue for a high-risk prevention strategy by identifying the offspring of patients with Alzheimer’s disease, screening them for hypertension and vascular factors and implementing various (non)pharmacological health measures.”

Source: ScienceDaily

There is no scientific proof that patients with moderate or severe Alzheimer’s disease benefit from drugs containing the agent memantine. This is the conclusion in the final report that the Institute for Quality and Efficiency in Health Care (IQWiG) published in September 2009.

The report is part of a broader commission awarded by the Federal Joint Committee (G-BA) to assess both drug and non-drug therapy options for Alzheimer’s disease. In addition to memantine, IQWiG has investigated cholinesterase inhibitors, Ginkgo biloba and non-drug therapy alternatives.

Memantine is intended to regulate excess glutamate

Memantine is approved for moderate to severe Alzheimer’s disease, but not for the mild stage of the disease. In Germany memantine is sold under the tradenames “Axura” (Merz) and “Ebixa” (Lundbeck).

Memantine is intended to prevent an excess of glutamate from damaging the brain. Glutamate is a neurotransmitter, in other words a substance that transmits neural signals. Animal experiments have shown that patients suffering from Alzheimer’s disease might have a permanent excess of glutamate, which leads to neural cells dying. Memantine is intended to prevent this without affecting the normal transmission of neural signals.

The substance was developed several decades ago and prescribed for other diseases such as Parkinson’s. Memantine has been used in the treatment of Alzheimer’s disease since 2002.

Studies with nearly 2000 participants included in the assessment

The scientists searched for studies which investigated outcomes that were relevant to patients and their families: this includes cognitive function (e.g. memory capacity) and activities of daily living (e.g. personal hygiene) as well as mental concomitant symptoms (e.g. depression, agitation), quality of life and avoiding being put in a nursing home.

IQWiG was able to include in its assessment 7 studies, in which a total of 1913 patients suffering from Alzheimer’s disease were treated with memantine over a period of 16 to 28 weeks. In 5 of these studies, the subjects received only memantine (monotherapy), in the remaining 2 the substance was administered as an add-on to an existing therapy with a cholinesterase inhibitor. Each study had a comparator control group, in which the patients took a placebo. Up till now, there have not been any usable studies comparing memantine with another dementia drug or with a non-drug therapy.

There are 2 other relevant manufacturer’s studies, but they could not be included in the assessment as not all the necessary data were made available.

Only minimal differences in cognition and activities of daily living

Point scales were used in order to measure activities of daily living and cognitive function. The values were determined on each scale, for example, by giving the patients observation tests or asking the patients and their families about changes in the disease symptoms and how they managed with activities of daily living. However, not every change on such a scale means that the patient’s disease stage actually improves or deteriorates. As the analysis of the study results shows, there are differences between the groups for these 2 outcomes, but these are minimal. Moreover, they are debatable due to the incompleteness of the data. It is therefore doubtful whether patients and their families can in fact see these differences as an advantage.

However, the manufacturer could also have provided evidence of benefit by means of a responder analysis. This investigates whether more patients in the memantine group notice a perceptible improvement in their symptoms than in the placebo group. However, the manufacturer did not provide a reliable responder analysis. Consequently, IQWiG did not find any overall proof of benefit from memantine in the activities of daily living and in cognitive function.

No reliable data on quality of life and necessity of inpatient care

The included studies did not provide reliable information on all outcomes. There are no data on the health-related quality of life of patients because they were not collected in the studies. However, there have been very few suitable instruments for displaying quality of life with this disease.

Although some studies did record whether patients had to be institutionalized, the results are not reliable. Consequently, it remains unclear whether memantine has an influence on how long persons with dementia can be cared for at home.

Data on concomitant symptoms do not reveal any differences

Information on concomitant psychopathological symptoms, such as depression, sleep disorders or severe agitation, was collected and reported. However, the studies do not document any difference between those patients treated with memantine and those given a placebo.

Nor did the scientists find a difference with regard to mortality. However, there is not much information on this as the studies were not designed to address this research question.

Memantine does not have any noticeable drug risks

Participants in the memantine group did not withdraw from the trial on account of adverse effects any more frequently than those in the placebo group. Nor was there any difference in the number of patients with (severe) adverse effects. Thus, there were no noticeable drug risks associated with memantine. However, the longest study only ran for 28 weeks, so it is not possible to draw conclusions on long-term effects. In addition, the number of subjects was altogether too low for potential rare side effects to be recorded.

Other family members do not appear to benefit either

IQWiG did not only consider the patients but also their families. However, the study results did not provide any proof that taking memantine reduces their burden, for instance, by lessening the amount of care required or the emotional burden. None of the included studies defined quality of life of the family caregivers as an outcome. The amount of care required was collected in most of the studies, but the majority of the data was not made available by the manufacturers. Consequently, the present results cannot be reliably interpreted.

Final report takes account of additional, previously unpublished data

IQWiG and its external experts had considerably more data available for the final report than for the preliminary report, in which only 4 studies with a total of 1263 patients could be included. In the course of the submission of comments procedure, the manufacturers submitted previously unpublished study analyses. For the final report, Merz provided subgroup analyses of participants with moderate and severe Alzheimer’s disease because in some studies memantine had also been given to patients with mild severity, which was not in compliance with approval when viewed from today’s perspective.

Nevertheless, the data pool for the final report is still incomplete. Relevant information is still lacking on 2 more clinical trials with a total of 580 participants. In contrast to the preliminary report, IQWiG has not placed a caveat on the final report because the small amount of information published on these 2 studies, including that disseminated at conferences, suggests that the minimal effects on cognition and activities of daily living would be even less if the missing data were included. There would be no change to the overall result — the lack of proof of benefit.

More research is needed

According to the scientists, the study pool for memantine is still insufficient overall. There is a lack of studies of longer duration that enable the long-term effects of therapy with memantine to be estimated. There is also a lack of research on patients living in nursing homes who suffer from the concomitant diseases typical in this age group. It cannot be excluded that memantine has a better effect in some patient groups.

“As long as it is not proven that therapies give patients or caregivers a perceptible advantage, it is very difficult to justify continuing to prescribe them when their costs are carried by the general public,” comments Peter Sawicki, Director of IQWiG. “The number of elderly people is growing and so are the medical and social problems associated with Alzheimer’s disease. I don’t think that we will find a simple solution to this problem in the near future. That’s why it is important at this stage to provide better social and medical care to patients and to relieve the burden for family caregivers. And it is surely better to ‘invest’ in this rather than in drugs, where we don’t know whether they actually provide a benefit.”

A devoted son puts his life on hold to care for his ailing mother, but it’s a decision that takes a toll on both hiscareer and his home life.

It’s three in the afternoon, and the bus is bringing Julia home from adult day care. Her son, Alvin Fouche, is there to meet her, but she has no idea who he is.

Since being diagnosed with advanced dementia, the only way Alvin could afford to care for his mom was to have her move in with him and his wife.

“It’s impacted just about every facet of my life from my relationship to my wife to financial to my health,” Fouche said.

Alvin helps her exercise, dress, eat and stay safe. It’s a difficult choice that many families are forced to make because they just can’t afford assisted living or hiring a professional caregiver.

“I think the economy, people are not wanting to take on… additional expenses, trying to stay home and keep expenses down,” said social worker Marsha Moran-Sackett.

This kind of caregiving is emotionally and physically exhausting and leaves Alvin with little time to work, even as a part-time handyman. “Right now, I can’t really work a regular job,” said Fouche.

With more people living longer, cases like Julia’s are on the rise, and in the next 20 years, dementia is expected to increase by 63-percent. Most experts agree America’s healthcare system isn’t ready for it.

“That is really putting a lot of pressure on the younger population, the younger generation, to provide care for their loved ones that are living longer,” said Sallie Justice with the Area Agency on Aging 1-B.

Alvin gets a brief break when Julia goes to Sheltering Arms adult daycare three days a week, but his real joy comes when, although his mom doesn’t know who he is, she recognizes what he does.

“She’ll look at me sometimes and just says, ‘I really appreciate what (you’re) doing. I love you dearly,’” Fouche said. “It’s those moments that… makes it all worth it.”

For people like Alvin, there is some help coming this weekend at the Caregiver Expo. You can go, bring a loved one and take classes on things like preventing falls and handling stress.

Recent studies show people who get less than the average amount of sleep may have a greater risk of getting Alzheimer’s disease.

When testing mice, researchers from Barnes-Jewish Hospital in St. Louis found that a lack of sleep increased the quantity of a harmful protein called beta amyloid in the brain. This same protein is found in the brains of many Alzheimer’s patients. As the mice slept, the researchers saw a decrease in beta amyloid but as the mice stayed awake, researchers found that the beta amyloid levels rose by 25 percent.

“Poor quality of sleep may speed up the onset of Alzheimer’s disease in humans and regularly getting a good night’s sleep could even slow its progression,” the researchers wrote in the journal Science.

“Most adults need between seven to nine hours of sleep per night. Teenagers need more, up to 10 hours nightly,” associate professor of medicine and medical director of the Drexel Sleep Center in Manayunk, Pa., Joanne Getsy said. “What most adults do is to cheat on their sleep during the week and then make up for it on the weekends. It’s better to try to get more sleep nightly, but if that’s not possible, at least recover whenever possible.”

With mid-terms around the corner, Drexel students are lucky to get sleep when they can.

“Before a test day I get around four hours of sleep,” Sahithi Gosala, pre-junior biology major ,said. “[The study] makes me think twice, but if I had an exam I [am] going to stay up, [not] think about Alzheimer’s.”

Anna Matthews, pre-junior biology major, said she’d rather think about Alzheimer’s later instead of changing her sleeping habits.

Alzheimer’s may only be associated with senior citizens, but a clinical diagnosis of Alzheimer’s can only be done post mortem.

“Currently, a diagnosis of Alzheimer’s really only can be guessed at based on behavioral changes,” associate professor Keith Vosseller said. “Only upon autopsy and detection of Abeta plaques and Tau tangles can Alzheimer’s be confirmed.”

Plaques and tangles are protein fragments and fibers that, if present in the body in inadequate amounts and forms, contribute to the degradation of neurons in the brain, according to the Alzheimer’s Disease Research Web site.

Though some find the St. Louis research compelling, many are still not sure if a lack of sleep is a contributing factor to Alzheimer’s.

“Nowadays, everyone says everything’s going to give you some disease,” Kelly Lavin, a pre-junior chemical engineering major, said.

Aleister J. Saunders, associate biology professor, is wary to believe the study, as well.

“So far the data [is] interesting but I don’t know if lack [of] sleep will be a risk factor for everyone or just a subset of seniors,” Saunders said.

In addition, a recent Spanish study contradicted the St. Louis study and found that people who sleep more than eight hours nightly were twice as likely to get dementia.

Though research is continued to be done on the effects of a lack of sleep, the contradicting data has made it hard to find any of the evidence truly conclusive.

Scientists studying Alzheimer’s disease (AD) in mice found that a high protein diet led them to develop smaller brains.

The research team from the US, Canada and the UK were focusing on triggers for brain plaque formation and monitored the effects of four different food regimes on rodents which were genetically modified to develop a severe form of early-onset Alzheimer’s.

Previous studies into AD pointed towards a low-calorie, low-fat diet rich in vegetables, fruit and fish, possibly delaying its onset or slowing its progression.

In the new study, the mice were fed either a regular diet; a high fat/low carbohydrate diet; a high protein/low carb version or a high carb/low fat option.

The researchers then looked at the brain and bodyweight of the mice, as well as plaque build up and differences in the structure of several brain regions that are involved in the memory defect underlying AD.

Unexpectedly, mice fed the high protein/low carb diet were found to have brains five per cent lighter than the others.

Regions of their hippocampus, a major component of the brain, were less developed than in their counterparts.

The researchers will investigate the tentative theory that a high protein diet may leave neurones more vulnerable to AD plaque.

The study will now be expanded to look at mice, which were not genetically altered, and investigate the implications for humans.

The study has been published in BioMed Central’s open access journal Molecular Neurodegeneration.

Source: Health Day News

A French study finding that people with Alzheimer’s disease and diabetes have less memory loss than those without diabetes should be regarded with caution, American experts say.

“It’s not clear from this study and others what the relationship is,” said William Thies, chief medical and scientific officer of the Alzheimer’s Association.

What is clear, Thies said, is that having diabetes increases the risk of developing Alzheimer’s disease — a relationship acknowledged in the first sentence of a report on the French study in the Oct. 27 issue of Neurology.

But there haven’t been too many studies looking at the effect of diabetes on the progression of Alzheimer’s, said the report by researchers at INSERM, the French National Institute for Health and Medical Research in Toulouse.

So, they followed 608 people with mild to moderate Alzheimer’s disease for four years, testing their memory and thinking skills twice a year.

The 63 participants with diabetes — 10.4 percent of the total — started with the same average score of 20 on the test of thinking ability. There was an average overall decline of 1.24 points on that test every six months. But the decline in thinking ability scores was 0.38 points greater every six months for those without diabetes.

Previous studies of the relationship between diabetes and loss of cognitive function have had mixed results, Thies said. “Some showed a faster decline, some showed a slower decline,” he said. “It is still a confused area.”

One factor that has a strong influence on the results is the stage of disease in the people being studied, Thies said. “You know that early on, the disease does not progress quickly,” he said. “So, if you study people in the early stage or the late stage, that can overwhelm the results.”

A close look showed that the diabetic participants in the French study had Alzheimer’s disease for a shorter period of time than the non-diabetics, said Dr. Robert Friedland, chair of neurology at the University of Louisville.

And the differences seen in the study “are very minimally significant, less than a point on a 30-point scale,” Friedland said. “The difference in many of the mental state examination scores was very small. It was statistically significant, but clinically meaningless.”

He ticked off several reasons why a difference was found. The medications taken for diabetes to help control blood sugar level could have a beneficial effect on the brain, Friedland said. “Also, patients with diabetes have more vascular disease in the heart as well as the retina, and some of their impairment might be due to that, so it was progressing more slowly,” he said.

There was also a possibility of misdiagnosis, since no autopsies were done in the study, Friedland said.

“The important message is that there are potentially modifiable risk factors for Alzheimer’s disease, some of which are also risk factors for diabetes — lack of physical activity, obesity,” he said.

For Thies, the lesson of the study is that “to understand relationships like this, you need more long-term cohort studies like this one. We need more studies, and the real barrier is money.”

Research suggests that a high protein diet could increase the risk of developing Alzheimer’s.

A diet high in protein could lead to a higher risk of developing Alzheimer’s disease, new research shows.

Researchers from the UK, US and Canada tested four menus on transgenic mouse model of Alzheimer’s, which express a mutant form of the human amyloid precursor protein (APP).

The mice fed a high protein/low carbohydrate diet had brains five per cent lighter than the others and regions of their hippocampus were less developed.

These findings led the authors to put forward a tentative theory that a high protein diet may leave neurones more vulnerable to Alzheimer’s disease plaque.

“Given the previously reported association of high protein diet with ageing-related neurotoxicity, one wonders whether particular diets, if ingested at particular ages, might increase susceptibility to incidence or progression of Alzheimer’s,” said lead author Sam Gandy.

He called for further trials to assess whether there is a real chance that Alzheimer’s disease could be slowed or avoided through healthy eating.

Only one who has “been there and done that” can even begin to appreciate all of the physical and mental problems involved with being a full time caregiver to an Alzheimer’s patient, especially for one that you love so deeply.

I think that most people have no idea when a loved one is originally afflicted with Alzheimer’s, I know that I didn’t. As a part of the disease, the patient is prone to keep the problem a secret. It was a year or more after my beloved wife died that I realized her Alzheimer’s started long before I had any inkling of the problem. After all, Alzheimer’s is something that other people get. No one in her family, or my family for that matter, ever had Alzheimer’s so why should I have suspected.

For many years my wife had made me promise that if anything happened to her I would not put her in a home, to which I had readily agreed. I take great pride in the fact that I was able to honor my pledge. We both had wills refusing resuscitation and were very strong in not wanting to live a life of dependency.

We didn’t have any family in the area that could help out so it was up to me to do everything. I started by reading everything I could get on the subject, books, the internet and the Alzheimer’s Association. The information was useful, but still didn’t prepare me for the difficult tasks involved.

It wasn’t until my wife started speaking more Japanese, her native language, than English that I realized that something was seriously wrong. Her primary care physician scheduled an MRI which indicated the strong possibility of Alzheimer’s. My reading had shown me that a positive diagnosis isn’t possible without a post mortem. At the physician’s suggestion we scheduled an appointment with a neurosurgeon. He, of course, couldn’t communicate with her so he diagnosed her with severe depression. A further appointment with a psychologist (one who spoke Japanese) confirmed that she was not depressed at all and most likely had Alzheimer’s.

I hadn’t realized that my wife was in a later stage of the disease until she started speaking all Japanese and no English. She had covered it up for a number of years, which I learned is a common thing for people with Alzheimer’s. For some reason there is a stigma attached to Alzheimer’s unlike other diseases causing people to hide it from everyone.

I learned very quickly how difficult things were to become. The lack of sleep for the caregiver due to the strange sleeping habits of the patient wound up being the most difficult part. She would wake at one thirty in the morning and want to eat breakfast. Other problems included the attempts at explaining things to a person using logic when the person isn’t able to think logically. How can you explain the reason for doing something if you can’t use logic? Trying to get the patient (loved one) to eat or take their medication when they continually refuse or spit it out. The refusal to bathe for no apparent reason. Washing and styling her hair, taking her to use the bathroom at home or outside of the home became major undertakings. The ability of the loved one to remember things from long ago yet unable to remember where you are going after being told over a dozen times. The loss of the loved one that you were married to, in my case for over 52 years, replaced by a totally different person who you just can’t get to know. The difficulty in dealing with the medical community, who are generally loving and caring, but for the most part don’t know how to deal with an Alzheimer’s patient, like the hospital laboratory technician who got mad when my wife screamed at her for no apparent reason.

The list of problems goes on and on. One of the greatest heartaches is knowing that things aren’t ever going to get better and that each day is going to be worse than the day before. Her physician prescribed the only medication that was available at the time for Alzheimer’s, but it gave her violent nightmares and had to be discontinued, it wasn’t any kind of a cure anyhow it just prolonged the disease for some people.

Help is available from numerous agencies for some people, but with my wife reverting back to her native language the inability to communicate was a major problem for everyone, including me. Of course there is nowhere in Maine where there is a day care program for Alzheimer’s patients where they speak Japanese. We have no local family and it is almost impossible to locate anyone to come in for a few hours that could handle the situation. Complicating the things was the intense jealousy my wife developed to any other female in the house. She was convinced that they were trying to steal me from her. Alzheimer’s causes changes to a person that defy explanation. I did finally get someone to come in a few hours a week posed as a nurse which allowed me to get away for short periods.

To maintain your sanity the caregiver must have some time to themselves.

There were other problems for my wife and I, like when in spite of my close monitoring she managed to get out of bed, fall and break her hip. The hospital stay, physical therapy and recovery of an Alzheimer’s afflicted 78-year-old woman with whom you couldn’t communicate was absolutely brutal. Again the medical people tried, but due to their lack of understanding of Alzheimer’s patients they sometimes caused more harm than good. Case in point; the nurse who scared her by hollering into my wife’s ear when she didn’t respond to a question in English and the physical therapist who insisted on procedures that caused my wife to have an extreme panic attack. They would try to reason with her, not realizing that late stage Alzheimer’s patients can no longer reason.

I could have put my wife in some sort of a home and if she had lived very much longer I might have had to do that. If they don’t have any money the government will pay for their care, if they do have money they can pay upwards of $100 a day for someone else to care for them until they their money is exhausted. One professional even suggested that I should get rid of any monetary assets my wife had so the state would pay for her care. I couldn’t do that as long as there was any way that I could care for my wife, it was the least that I could do for the woman I loved.

I have had people tell me “I know what you are going through. I used to see my grandmother about once a month when she had Alzheimer’s and it was hard”. I never said it, but I always thought “You don’t have a clue how hard it is unless you have been a 24 hour a day, 7 day a week caregiver for a loved one”.

Certainly I would do the same thing again. She died about three years ago from pneumonia brought about by Alzheimer. Not a day goes by that I don’t think about my departed wife, but I wouldn’t wish her to come back the way she was and I’m sure that she wouldn’t want to. As hard as it is to be a full time caregiver for an Alzheimer’s patient is it’s what you do for one you love. I’m glad that I had the chance.