Better drugs for Alzheimer's

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nepezil (Aricept)

MEDICATION: THE WORLD'S MOST POPULAR DEMENTIA-DRUG IS DONEPEZIL. Donepezil (Brand-name: Aricept®) boosts memory & thinking in Alzheimer's. More donepezil means more boost - along with intensified side-effects. Learn how it can be safely boosted when combined with solifenacin.

---

IRVINE, California -- Donepezil helps Alzheimer's and other types of dementia. Doctors often minimize its use because it can have a variety of side-effects. Progressive research shows that by adding solifenacin to each pill of donepezil, a patient could potentially boost the dosage by as much as 400% without added side-effects.

How It Works

Here's a simplified explanation of how it works.

Early-to-Midstage Alzheimer's
Brand Name	Generic Name
Aricept®	donepezil
Exelon®	rivastigmine
Remynil or Razadyne®	galantamine
Drugs for Moderate-to-Severe Stage
Namenda® or Ebixa®	memantine

1. Acetylecholine is used by the brain to send messages from cell to cell.
2. If there is not enough acetylecholine in the brain, memory and thinking start to fail.
3. Alzheimer's often experiences dangerous drops in acetylcholine.
4. Donepezil helps boost the level of acetylcholine throughout the body.
5. This can help an Alzheimer's brain get back to normal. However, it can also overload other systems in the body, causing nausea, weight-loss and other side-effects.
6. The brain is separated from the rest of the body by the "blood-brain barrier".
7. A pill of donepezil travels from the stomach to the entire body. It passes through the blood-brain barrier, boosting acetylcholine in the brain.
8. Solifenacin is another drug that blocks donepezil. However, it CANNOT pass through the blood-brain barrier.
9. Therefore, it seems that solifenacin cannot get to the brain and as a result, cannot block donepezil in the brain.
10. At the same time, solifenacin can block donepezil everywhere else in the body, stopping side-effects like nausea in the stomach.
11. The result is no nausea or other side-effects in the body. The patient just gets the good effect in the brain.

New Combination

For now, researchers call this combination of donepezil-plus-solifenacin by the name CPC-201. The new combination will mean that the brain can get the benefits of a lot more donepezil with fewer side-effects.

Chase Pharmaceuticals Corporation (Chase) announced its results from a Phase 2 study of CPC-201.

400%

What Do Aricept, Exelon & Razadyne Do?

Teepa Snow
MEDICATION VIDEO
See Teepa Snow talk about the top medications for Alzheimer's & dementia. In plain English, she explores what they do and how they work. Get clarity on Aricept, Exelon and Razadyne (generic donepezil, rivastigmine and galantamine).

The CPC-201 Phase 2 results, presented by Thomas Chase, MD, chief scientific officer and co-founder of Chase, and the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke, confirmed that solifenacin attenuated donepezil adverse events, enabling the tolerable administration of doses of donepezil to as much as 400 percent of the current standard treatment of donepezil. Secondary endpoints provided signals of enhanced efficacy, as would be predicted from increased tolerable dosing of donepezil. The data were presented during an oral session at the 2016 Alzheimer’s Association Conference (AAIC) in Toronto, Canada (Abstract a12446).

The primary endpoint of this Phase 2 single-blind, crossover trial was to safely increase the tolerated dose of donepezil from 10 mg/day up to as much as 40 mg/day. This trial consisted of 41 moderate (MMSE 10-20) Alzheimer’s type subjects who were being successfully treated with 10 mg/day of donepezil. The anticholinergic solifenacin was first titrated to 15 mg/day and then donepezil escalated to each subject’s maximum tolerated dose or to the protocol limit of 40 mg/day. Subjects then continued for a three-month maintenance period. All subjects were able to tolerably maintain above the currently approved doses of donepezil and 85 percent of subjects reached and tolerated the maximum allowable donepezil dose of 40 mg/day. Moreover, in the maintenance phase of the trial, subjects experienced significantly less dose-limiting side effects than those that would be predicted for 10 mg/day of donepezil.

A Real Difference

Although this Phase 2 study was not designed nor powered to provide meaningful estimates of anti-dementia efficacy, both the ADAS-Cog and the CGI-I scales in the study yielded positive signals of enhanced efficacy.

During the dose maintenance phase, at a median donepezil dose of 40 mg/day, total gastrointestinal adverse events were greatly attenuated and about 80 percent below those predicted from trials of previously approved doses of 10 mg/day of donepezil. As would be expected with a cholinergic blocker that does not cross the blood-brain barrier, solifenacin had no effect on cognitive function and there were no drug-related serious adverse events (SAE) or clinically significant cardiovascular or laboratory abnormalities. There were no drug related drop­outs and no new AEs or evidence of solifenacin toxicity.

“Pre-clinical studies have repeatedly shown that there is a strong dose/efficacy relationship associated with AChEIs. Further, PET scan studies in humans show that at the typical dose of 10 mg/day of donepezil, the central enzymatic inhibition is no greater than about 30 percent, substantially lower than that which would be expected from optimal dosing. Yet, historically, it has not been possible to tolerably increase the dose of donepezil to meaningfully higher levels,” said Douglas Ingram, chief executive officer of Chase. “We believe we have the means to finally unlock the true potential of optimally dosed AChEIs. Moreover, we are employing an efficient development and regulatory pathway and plan to commence a superiority trial versus the current gold-standard treatment for Alzheimer’s, 10 mg/day of donepezil. If successful in Phase 3, CPC-201 could be the new standard for the symptomatic treatment of Alzheimer's disease and benefit millions of suffering patients.”

Technical Talk

“We believe that adverse events have long limited AChEI dosing to suboptimal levels, in turn limiting the efficacy of donepezil and other AChEIs,” said Thomas Chase, M.D. “Our Phase 2 findings, together with those from our earlier Phase 1 studies, robustly support our hypothesis that the co-formulation of a peripheral anticholinergic with donepezil enables the safe and tolerable administration of multiples of the current standard of care doses of AChEI such as donepezil.”

The mean change in ADAS-Cog over the course of the study showed improvement versus subject baseline and, adjusted for underlying disease progression using a multi-study meta-analysis, subjects showed a mean (± SEM) benefit of 2.45 points over 10 mg/day donepezil or 5.4 ± .84 points compared to predicted untreated disease progression. Combined Clinical Global Impression (CGI-I) scores from investigators and caregivers at 26 weeks averaged 3.1 ± .20 points, thus improving by .94 ± .20 points (p < .001; n = 16). The responder rate (as measured by those who either did not worsen or improved over the course of the study) was over 90 percent.

MORE INFORMATION:

About CPC-201
Chase’s lead candidate, CPC-201, is a patent-protected combination of donepezil (an AChEI), one of the few pharmaceuticals proven to improve cognition in Alzheimer’s patients, and solifenacin, a peripherally acting cholinergic blocker.

SOURCE:

About Chase
Chase Pharmaceuticals Corporation is a clinical-stage biopharmaceutical company focused on the development and commercialization of improved treatments for neurodegenerative disorders. Chase’s development program, if successful, will profoundly improve the symptomatic treatment of Alzheimer's disease. The company was co-founded by Thomas Chase, MD, the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke and Kathleen Clarence-Smith, MD, PhD, the former head of CNS development at each of Sanofi, Hoffmann-La Roche and Otsuka. Chase is led by its chief executive officer and president, Douglas Ingram, formerly the president of Allergan, Inc.

Chase has closed over $24 million in funding to date, with approximately $22 million through a Series B financing led by New Rhein Healthcare Investors, LLC and including, among others, Edmond de Rothschild Investment Partners, Cipla Ventures and Brain Trust Accelerator Fund.

EDITED BY:
Peter Berger

Why curry for Alzheimer's

Caregivers, and healthcare professionals,here is some great information

Here is a great dementia resource for caregivers and healthcare professionals,

Follow alzheimersideas on twitter
The Dementia Caregiver's Little Book of Hope [Kindle Edition]

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Salk researchers

J147 is a derivative of curry's turmeric spice. It beat the Alzheimer's drug Aricept (generic: donepezil) on several memory tests. The Salk Institute says it may benefit Parkinson's, Huntington's & vascular dementia. Find out how J147 prevented memory loss & slowed Alzheimer's. 

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LA JOLLA, CA—A drug developed by scientists at the Salk Institute for Biological Studies, known as J147, reverses memory deficits and slows Alzheimer's disease in aged mice following short-term treatment. 

J147 was developed at Salk in the laboratory of David Schubert, a professor in the Cellular Neurobiology Laboratory.

India has Less Alzheimer's than the USA

Dr. Schubert said,

"It's been known for a long time that people in India don't get very much Alzheimer's relative to what happens in the United States and the rest of the world.

"One of the curiousities about the diet in India is that they eat a lot of curry. A major spice in curry is turmeric. A major component of turmeric is curcumin.

"Curcumin has been around for a while. It is an FDA-Approved drug for cancer. A friend of mine in Los Angeles, Greg Cole, found that if you give curcumin to very similar mice to what this study's author has been using, they get a little better, the (Alzheimer's) plaques go away.

"The problem with curcumin is that it is not a great drug, in the sense that it gets degraded very rapidly. It's availability is quite low in the bloodstream and the brain.

"We decided to make a better version of this.We did a lot of medicinal chemistry. We came up with J147."

"Strong Potential to Slow Alzheimer's"

Lead study author Marguerite Prior, a research associate in Salk's Cellular Neurobiology Laboratory, added,

"J147 is an exciting new compound because it really has strong potential to be an Alzheimer's disease therapeutic by slowing disease progression and reversing memory deficits following short-term treatment."

Because of its broad ability to protect nerve cells, the researchers believe that J147 may also be effective for treating other neurological disorders, such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS), as well as vascular dementia from stroke, although their study did not directly explore the drug's efficacy as a therapy for those diseases. 
The findings, published in the journal Alzheimer's Research and Therapy, may pave the way to a new treatment for Alzheimer's disease in humans. 

Despite years of research, scientists are still seeking the first disease-modifying drugs for Alzheimer's. Current FDA-approved medications include

1. Aricept^® (generic donepezil)
2. Razadyne^® (generic galantamine)
3. Exelon^® (generic rivastigmine, sometimes branded as Ebixa^® in Europe)

These offer only fleeting short-term benefits for Alzheimer's patients, but they do nothing to slow the steady, irreversible decline of brain function that erases a person's memory and ability to think clearly.

Protecting Brain Cells

Professor Schubert and his colleagues bucked the trend within the pharmaceutical industry, which has focused on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. Instead, the Salk team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against several pathologies associated with brain aging. 

From the test results of each chemical iteration of the lead compound, they were able to alter their chemical structures to make them much more potent. Although J147 appears to be safe in mice, the next step will require clinical trials to determine whether the compound will prove safe and effective in humans. Professor Schubert said,

"Alzheimer's disease research has traditionally focused on a single target, the amyloid pathway, but unfortunately drugs that have been developed through this pathway have not been successful in clinical trials. Our approach is based on the pathologies associated with old age - the greatest risk factor for Alzheimer's and other neurodegenerative diseases - rather than only the specificities of the disease."

Salk scientists developed J147, a synthetic drug shown to improve memory and prevent brain damage in mice with Alzheimer's disease.

Images: Courtesy of the Salk Institute for Biological Studies

To test the efficacy of J147 in a much more rigorous preclinical Alzheimer's model, the Salk team treated mice using a therapeutic strategy that they say more accurately reflects the human symptomatic stage of Alzheimer's. Administered in the food of 20-month-old genetically engineered mice, at a stage when Alzheimer's pathology is advanced, J147 rescued severe memory loss, reduced soluble levels of amyloid, and increased neurotrophic factors essential for memory, after only three months of treatment. 

In a different experiment, the scientists tested J147 directly against Aricept (generic donepezil), the most widely prescribed Alzheimer's drug, and found that it performed as well or better in several memory tests. 

"In addition to yielding an exceptionally promising therapeutic, both the strategy of using mice with existing disease and the drug discovery process based upon aging are what make the study interesting and exciting," says Schubert, "because it more closely resembles what happens in humans, who have advanced pathology when diagnosis occurs and treatment begins." Most studies test drugs before pathology is present, which is preventive rather than therapeutic and may be the reason drugs don't transfer from animal studies to humans.

Helps New Neurons Grow & Connect

Prior and her colleagues say that several cellular processes known to be associated with Alzheimer's pathology are affected by J147, including an increase in a protein called brain-derived neurotrophic factor (BDNF), which protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation. Postmortem studies show lower than normal levels of BDNF in the brains of people with Alzheimer's. 

The Salk researchers say that J147, with its memory enhancing and neuroprotective properties, along with its safety and availability as an oral medication, would make an "ideal candidate" for Alzheimer's disease clinical trials. They are currently seeking funding for such a trial. 

MORE INFORMATION:
Other researchers on the study were Richard Dargusch, Jennifer L. Ehren and Chandra Chiruta, of the Salk Institute.

The work was supported by the Alzheimer's Drug Discovery Foundation, the Bundy Foundation, the Fritz Burns Foundation, the George E. Hewitt Foundation, the Alzheimer's Association, and the National Institutes of Health.

About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark

Best Alzheimer's drugs

Caregivers, and healthcare professionals,here is some great information

Here is a great dementia resource for caregivers and healthcare professionals,

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Follow alzheimersideas on twitter
The Dementia Caregiver's Little Book of Hope [Kindle Edition]

St. Michael's Hospital: 

A new study ranks the safety and effectiveness of four Alzheimer's drugs. Ranked on concentration, memory, alertness and mood, learn what the researchers found. 

---

A new study ranking the safety and effectiveness of four drugs taken to enhance concentration, memory, alertness and moods, found that donepezil was most likely to effectively improve cognition in patients with Alzheimer's dementia. 

However, patients who took donepezil were more likely to experience side effects including nausea, vomiting and diarrhea than those who received a placebo, according to the study, published online in the Journal of the American Geriatrics Society.

Improving Cognition in Alzheimer's

Drugs for Early to Midstage
Brand Name	Generic Name
Aricept®	donepezil
Exelon®	rivastigmine
Remynil or Razadyne®	galantamine
Drugs for Moderate to Severe Stage
Namenda® or Ebixa®	memantine

In 2015, 46 million people worldwide had Alzheimer's disease, according to the study. In 2013, 146,593 people aged 65 and older in Ontario alone used cognitive enhancers, according to a 2016 Ontario Drug Policy Research report. 

"Alzheimer's dementia is the most common form of dementia in North America, and most people who have moderate to severe Alzheimer's will be on these medications," said Dr. Andrea Tricco, a scientist in the Li Ka Shing Knowledge Institute of St. Michael's Hospital and lead author of the study. "This analysis will give both patients and clinicians a full picture of how each of these drugs will likely affect their cognition, as well as their overall he alth."

Safety & Effectiveness

Although there have been previous reviews of the safety and effectiveness of cognitive enhancers in treating Alzheimer's dementia, the authors said this was the first to rank their comparative safety and effectiveness. 

The study used network meta-analysis, an advanced statistical analysis technique, to systematically review existing evidence from 142 clinical trials of four common cognitive enhancers administered alone or in combination published between 1996 and 2015. The number of patients in each study ranged from 13 to 2,045, and the review evaluated a total of 33,889 patients.

The researchers compared the safety and effectiveness of any combination of donepezil, rivastigmine, galantamine or memantine in treating moderate to severe Alzheimer's dementia based on the results of the clinical trials that examined a number of patient outcomes, including cognition, function behaviour, global status, mortality, serious adverse events, falls, bradycardia, headache, diarrhea, vomiting and nausea. Donepezil was likely the most effective medication for Alzheimer's dementia across all effectiveness outcomes, including cognition, behavior and overall health, according to the study.

Best Course of Alzheimer's Treatment

Donepezil was also the only cognitive enhancer that reached the minimal clinically important threshold -- meaning effects on outcomes were observed clinically, as well as statistically -- on the Alzheimer's Disease Assessment cognition scale, making it the likely first choice for those patients and clinicians considering these medications, the authors said.

Although no significant risk of serious harm, falls or reduced heart rate was associated with any of the medications in the study, the data was limited on these specific outcomes.

Previous research by the authors found that cognitive enhancers do not improve cognition or function in people with mild cognitive impairment, and these patients experience significantly more nausea, diarrhea, vomiting and headaches.

The findings of the current study will help guide patients and clinicians who are making decisions about the best course of treatment for Alzheimer's dementia, said Dr. Tricco.

"The more information we are able to gather about how each of these medications can affect a patient's cognition and health, the more likely we are to be able to improve their health outcomes," she said.

REFERENCE:

• Andrea C. Tricco, Huda M. Ashoor, Charlene Soobiah, Patricia Rios, Areti Angeliki Veroniki, Jemila S. Hamid, John D. Ivory, Paul A. Khan, Fatemeh Yazdi, Marco Ghassemi, Erik Blondal, Joanne M. Ho, Carmen H. Ng, Brenda Hemmelgarn, Sumit R. Majumdar, Laure Perrier and Sharon E. Straus. Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis. Journal of the American Geriatrics Society, September 2017 DOI: 10.1111/jgs.15069

SOURCE:

• St. Michael's Hospital:
  St. Michael’s Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in more than 29 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, care of the homeless and global health are among the Hospital’s recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Centre, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael’s Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto.

Does a drug for dementia increase bone density?

Caregivers, and healthcare professionals,here is some great information

Here is a great dementia resource for caregivers and healthcare professionals,

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

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Follow alzheimersideas on twitter
The Dementia Caregiver's Little Book of Hope [Kindle Edition]

Elsevier

The most common drug for Alzheimer's also increases bone mass in mice. Find out what this means for people with dementia in fear of bone fractures, as well as conditions like osteoporosis or periodontitis. 

---

The most common drug used to treat Alzheimer's disease increases bone mass in mice, according to a groundbreaking research article published in the open access journal Heliyon. The authors of the study, from Saitama Medical University in Japan, say this means the drug could also be used to treat bone loss diseases like osteoporosis and periodontitis, following further clinical research.

Alzheimer's disease is the most common form of dementia and the incidence is increasing in our aging population. In the early stages of Alzheimer's disease, bone density decreases, putting patients at a higher risk of bone fractures.

Donepezil (Brand name : Aricept^®)

The new Heliyon study suggests that treating Alzheimer's disease with a drug called donepezil (Brand name : Aricept^®) not only improves cognitive function but also increases bone density, reducing the risk of fractures.

"We think that donepezil can improve cognitive function and increase bone mass, making it a very useful drug for patients with dementia and osteoporosis," said lead author Dr. Tsuyoshi Sato, Associate Professor in the Department of Oral and Maxillofacial Surgery, Saitama Medical University. "From the viewpoint of medical economics, this dual purpose could reduce the cost of treating these diseases."

Bone Mass & Density

Two different kinds of cell control the bone mass and density in our bodies: osteoblasts make bone and osteoclasts absorb it. A molecule called acetylcholine causes osteoclasts to die in vitro. Although an enzyme called acetylcholinesterase breaks this molecule down, the effect of this enzyme on osteoclasts remains unclear.

The most common drug used to treat Alzheimer's disease, donepezil, stops acetylcholinesterase from working, leading to an increase in the amount of acetylcholine in the brain. Recent retrospective clinical studies have suggested that patients being treated with donepezil for Alzheimer's disease have a lower risk of hip fracture, and that risk was dependent on the dose they were taking.

The researchers wanted to understand how donepezil prevents bone degradation. They looked at the drug's activity in vitro using mouse bone marrow cells, and found that more acetylcholinesterase is produced when osteoclasts are being made, which leads to even more osteoclasts being made. Donepezil stops acetylcholinesterase from working, therefore preventing osteoclasts from being made.

Surprising Point

The team also looked at the effect of the drug in a mouse model with bone loss. They found that donepezil increases bone mass in mice by preventing the production of osteoclasts.

"We were surprised to see that donepezil directly inhibits the production of osteoclasts and subsequently increases bone mass in vivo," said Dr. Sato. "This is very surprising point - donepezil directly controls the molecule that is responsible for macrophages becoming osteoclasts."

Previous research has shown that acetylcholinesterase activity increases continuously with age, and may accelerate the risk of bone loss in elderly people. The researchers noted that the concentration of acetylcholinesterase in macrophages was higher when the tissue was inflamed. This suggests that inflammation causes bone to be degraded in part due to acetylcholinesterase production.

"Our findings are very promising and suggest that there is a role for donepezil in increasing bone mass in elderly patients with inflammation and dementia," said Dr. Sato. "There is still work to be done and we look forward to observing the effect of this drug in patients."

The team now plans to work with the Department of Neurology at Saitama Medical University on clinical research. They plan to study whether taking donepezil reduces patients' risk of bone fracture by looking at its effect in a group of patients compared to a control group.

MORE INFORMATION:
"Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase" by Sato et al. (doi: 10.1016/j.heliyon.2015.e00013). The article appears in Heliyon (September 2015), published by Elsevier.

SOURCE:
Elsevier

Safely increase Aricept dosage

Caregivers, and healthcare professionals,here is some great information

Here is a great dementia resource for caregivers and healthcare professionals,

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Follow alzheimersideas on twitter
The Dementia Caregiver's Little Book of Hope [Kindle Edition]

Chase

DEMENTIA DRUGS: Donepezil (Aricept) boosts memory & thinking in Alzheimer's. More donepezil means more boost - along with intensified side-effects. A key trial shows how donepezil can be safely boosted when combined with solifenacin. Find out more.

---

IRVINE, California -- Donepezil helps Alzheimer's and other types of dementia. Doctors often minimize its use because it can have a variety of side-effects. Progressive research shows that by adding solifenacin to each pill of donepezil, a patient could potentially boost the dosage by as much as 400% without added side-effects.

Here's a simplified explanation of how it works.

Early-to-Midstage Alzheimer's
Brand Name	Generic Name
Aricept®	donepezil
Exelon®	rivastigmine
Remynil or Razadyne®	galantamine
Drugs for Moderate-to-Severe Stage
Namenda® or Ebixa®	memantine

1. Acetylecholine is used by the brain to send messages from cell to cell.
2. If there is not enough acetylecholine in the brain, memory and thinking start to fail.
3. Alzheimer's often experiences dangerous drops in acetylcholine.
4. Donepezil helps boost the level of acetylcholine throughout the body.
5. This can help an Alzheimer's brain get back to normal. However, it can also overload other systems in the body, causing nausea, weight-loss and other side-effects.
6. The brain is separated from the rest of the body by the "blood-brain barrier".
7. A pill of donepezil travels from the stomach to the entire body. It passes through the blood-brain barrier, boosting acetylcholine in the brain.
8. Solifenacin is another drug that blocks donepezil. However, it CANNOT pass through the blood-brain barrier.
9. Therefore, it seems that solifenacin cannot get to the brain and as a result, cannot block donepezil in the brain.
10. At the same time, solifenacin can block donepezil everywhere else in the body, stopping side-effects like nausea in the stomach.
11. The result is no nausea or other side-effects in the body. The patient just gets the good effect in the brain.

For now, researchers call this combination of donepezil-plus-solifenacin by the name CPC-201. The new combination will mean that the brain can get the benefits of a lot more donepezil with fewer side-effects.

Chase Pharmaceuticals Corporation (Chase) announced its results from a Phase 2 study of CPC-201.

400%

The CPC-201 Phase 2 results, presented by Thomas Chase, MD, chief scientific officer and co-founder of Chase, and the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke, confirmed that solifenacin attenuated donepezil adverse events, enabling the tolerable administration of doses of donepezil to as much as 400 percent of the current standard treatment of donepezil. Secondary endpoints provided signals of enhanced efficacy, as would be predicted from increased tolerable dosing of donepezil. The data were presented during an oral session at the 2016 Alzheimer’s Association Conference (AAIC) in Toronto, Canada (Abstract a12446).

The primary endpoint of this Phase 2 single-blind, crossover trial was to safely increase the tolerated dose of donepezil from 10 mg/day up to as much as 40 mg/day. This trial consisted of 41 moderate (MMSE 10-20) Alzheimer’s type subjects who were being successfully treated with 10 mg/day of donepezil. The anticholinergic solifenacin was first titrated to 15 mg/day and then donepezil escalated to each subject’s maximum tolerated dose or to the protocol limit of 40 mg/day. Subjects then continued for a three-month maintenance period. All subjects were able to tolerably maintain above the currently approved doses of donepezil and 85 percent of subjects reached and tolerated the maximum allowable donepezil dose of 40 mg/day. Moreover, in the maintenance phase of the trial, subjects experienced significantly less dose-limiting side effects than those that would be predicted for 10 mg/day of donepezil. 

A Real Difference

Although this Phase 2 study was not designed nor powered to provide meaningful estimates of anti-dementia efficacy, both the ADAS-Cog and the CGI-I scales in the study yielded positive signals of enhanced efficacy. 

During the dose maintenance phase, at a median donepezil dose of 40 mg/day, total gastrointestinal adverse events were greatly attenuated and about 80 percent below those predicted from trials of previously approved doses of 10 mg/day of donepezil. As would be expected with a cholinergic blocker that does not cross the blood-brain barrier, solifenacin had no effect on cognitive function and there were no drug-related serious adverse events (SAE) or clinically significant cardiovascular or laboratory abnormalities. There were no drug related drop­outs and no new AEs or evidence of solifenacin toxicity.

“Pre-clinical studies have repeatedly shown that there is a strong dose/efficacy relationship associated with AChEIs. Further, PET scan studies in humans show that at the typical dose of 10 mg/day of donepezil, the central enzymatic inhibition is no greater than about 30 percent, substantially lower than that which would be expected from optimal dosing. Yet, historically, it has not been possible to tolerably increase the dose of donepezil to meaningfully higher levels,” said Douglas Ingram, chief executive officer of Chase. “We believe we have the means to finally unlock the true potential of optimally dosed AChEIs. Moreover, we are employing an efficient development and regulatory pathway and plan to commence a superiority trial versus the current gold-standard treatment for Alzheimer’s, 10 mg/day of donepezil. If successful in Phase 3, CPC-201 could be the new standard for the symptomatic treatment of Alzheimer's disease and benefit millions of suffering patients.”

What Do Aricept, Exelon & Razadyne Do?

Teepa Snow
MEDICATION VIDEO
See Teepa Snow talk about the top medications for Alzheimer's & dementia. In plain English, she explores what they do and how they work. Get clarity on Aricept, Exelon and Razadyne (generic donepezil, rivastigmine and galantamine).

Technical Talk

“We believe that adverse events have long limited AChEI dosing to suboptimal levels, in turn limiting the efficacy of donepezil and other AChEIs,” said Thomas Chase, M.D. “Our Phase 2 findings, together with those from our earlier Phase 1 studies, robustly support our hypothesis that the co-formulation of a peripheral anticholinergic with donepezil enables the safe and tolerable administration of multiples of the current standard of care doses of AChEI such as donepezil.”

The mean change in ADAS-Cog over the course of the study showed improvement versus subject baseline and, adjusted for underlying disease progression using a multi-study meta-analysis, subjects showed a mean (± SEM) benefit of 2.45 points over 10 mg/day donepezil or 5.4 ± .84 points compared to predicted untreated disease progression. Combined Clinical Global Impression (CGI-I) scores from investigators and caregivers at 26 weeks averaged 3.1 ± .20 points, thus improving by .94 ± .20 points (p < .001; n = 16). The responder rate (as measured by those who either did not worsen or improved over the course of the study) was over 90 percent.

MORE INFORMATION:

About CPC-201
Chase’s lead candidate, CPC-201, is a patent-protected combination of donepezil (an AChEI), one of the few pharmaceuticals proven to improve cognition in Alzheimer’s patients, and solifenacin, a peripherally acting cholinergic blocker.

Drug for dementia and osteoporosis

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The most common drug for Alzheimer's also increases bone mass in mice. Find out what this means for people with dementia in fear of bone fractures, as well as conditions like osteoporosis or periodontitis. 

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The most common drug used to treat Alzheimer's disease increases bone mass in mice, according to a groundbreaking research article published in the open access journal Heliyon. The authors of the study, from Saitama Medical University in Japan, say this means the drug could also be used to treat bone loss diseases like osteoporosis and periodontitis, following further clinical research.

Alzheimer's disease is the most common form of dementia and the incidence is increasing in our aging population. In the early stages of Alzheimer's disease, bone density decreases, putting patients at a higher risk of bone fractures.

Donepezil (Brand name : Aricept^®)

The new Heliyon study suggests that treating Alzheimer's disease with a drug called donepezil (Brand name : Aricept^®) not only improves cognitive function but also increases bone density, reducing the risk of fractures.

"We think that donepezil can improve cognitive function and increase bone mass, making it a very useful drug for patients with dementia and osteoporosis," said lead author Dr. Tsuyoshi Sato, Associate Professor in the Department of Oral and Maxillofacial Surgery, Saitama Medical University. "From the viewpoint of medical economics, this dual purpose could reduce the cost of treating these diseases."

Bone Mass & Density

Two different kinds of cell control the bone mass and density in our bodies: osteoblasts make bone and osteoclasts absorb it. A molecule called acetylcholine causes osteoclasts to die in vitro. Although an enzyme called acetylcholinesterase breaks this molecule down, the effect of this enzyme on osteoclasts remains unclear.

The most common drug used to treat Alzheimer's disease, donepezil, stops acetylcholinesterase from working, leading to an increase in the amount of acetylcholine in the brain. Recent retrospective clinical studies have suggested that patients being treated with donepezil for Alzheimer's disease have a lower risk of hip fracture, and that risk was dependent on the dose they were taking.

The researchers wanted to understand how donepezil prevents bone degradation. They looked at the drug's activity in vitro using mouse bone marrow cells, and found that more acetylcholinesterase is produced when osteoclasts are being made, which leads to even more osteoclasts being made. Donepezil stops acetylcholinesterase from working, therefore preventing osteoclasts from being made.

Surprising Point

The team also looked at the effect of the drug in a mouse model with bone loss. They found that donepezil increases bone mass in mice by preventing the production of osteoclasts.

"We were surprised to see that donepezil directly inhibits the production of osteoclasts and subsequently increases bone mass in vivo," said Dr. Sato. "This is very surprising point - donepezil directly controls the molecule that is responsible for macrophages becoming osteoclasts."

Previous research has shown that acetylcholinesterase activity increases continuously with age, and may accelerate the risk of bone loss in elderly people. The researchers noted that the concentration of acetylcholinesterase in macrophages was higher when the tissue was inflamed. This suggests that inflammation causes bone to be degraded in part due to acetylcholinesterase production.

"Our findings are very promising and suggest that there is a role for donepezil in increasing bone mass in elderly patients with inflammation and dementia," said Dr. Sato. "There is still work to be done and we look forward to observing the effect of this drug in patients."

The team now plans to work with the Department of Neurology at Saitama Medical University on clinical research. They plan to study whether taking donepezil reduces patients' risk of bone fracture by looking at its effect in a group of patients compared to a control group.

MORE INFORMATION:
"Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase" by Sato et al. (doi: 10.1016/j.heliyon.2015.e00013). The article appears in Heliyon (September 2015), published by Elsevier.