Treatments and Medications

• Memory
• Alzheimer's Disease
  • AD Related Psychiatric Behavioral Symptoms
  • Currently Approved to Treat AD
• Frontotemporal Dementia / Pick's Disease
• Vascular Dementia
• Dementia with Lewy Bodies
• Resources
  

Memory
Introduction
Thomas Huxley, the 19th century physiologist and author noted, “The great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.” Unfortunately, this has been the story of a long line of failed drugs that were once touted as agents to enhance memory or reduce confusion in older adults suffering from what was once called organic brain syndrome or senile dementia and we know now as Alzheimer’s disease.

Now, more than 100 years since Alois Alzheimer described plaques and neurofibrillary tangles he found at autopsy in the brain of a middle-aged woman, the chaotic puzzle of Alzheimer’s disease (AD) is slowly being unraveled. While the 1990’s have been referred to as the “decade of the brain,” it probably should have been more correctly termed the “gateway to the brain.” As we move into the first decade of the 21 st century, the door is beginning to open on the path to treatments for AD and a variety of other dementias. Current medications will not cure or reverse the course of AD, but have the potential to improve the quality of life for patients and caregivers.

The term dementia defines a collection of symptoms and is not in itself a specific disease. Tacrine, donepezil, rivastigmine, galantamine and memantine are five FDA approved drugs for the treatment of AD. These drugs, with their limitations, are not perfect agents. Numerous therapeutic options are currently being investigated for treating AD and improving patient care.

Drug therapy is of great interest to patients, families, loved ones and clinicians. It should come as no great surprise that individuals diagnosed with probable AD as well as caregivers are very interested in both approved and unapproved drugs to treat AD. Many individuals use prescription, non-prescription and herbal/alternative remedies at the same time.

Alzheimer's Disease
Drug Therapy for AD
Over the years, numerous drugs and other agents have been used to treat “senile dementia”. Ergoloid mesylates (Hydergine®), clyclandelate (Cyclospasmol®), papaverine (Pavabid®), niacin, lecithin, choline hydrochloride, lecithin, all have been tried as agents to improve memory and reduce confusion. Although published research suggested many of these drugs should be effective in “dementia- patients,” this was not generally observed in actual patient care. Many of the early research trials used small numbers of patients, and frequently the study design was flawed. At this time, there appears to be little reason to prescribe any of these drugs for AD.

Neurotransmitters, such as acetylcholine (ACH), serotonin, norepinephrine and dopamine, are vital for communication between nerve cells. ACH has been noted to be especially reduced in AD and attempts have been made to increase the concentrations of ACH by either adding more ACH or preventing the normal metabolism of ACH. It is now recognized that other neurotransmitters also play a role in modulating the activity of ACH.

Currently there are five prescription medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease.

• Tacrine (Cognex®) - approved in 1993
• Donepezil (Aricept®) -approved in 1996
• Rivastigmine (Exelon®) - approved in 2000
• Galantamine (Razadyne®) - approved in 2001
• Memantine (Namenda®) in 2004

The first four medications are in a class of drugs known as cholinesterase inhibitors. Cholinesterase inhibitors are designed to enhance memory and other cognitive functions by influencing certain chemical activities in the brain.

Acetylcholine is a chemical messenger in the brain that scientists believe is important for the function of brain cells involved in memory, thought, and judgment. Acetylcholine is released by one brain cell to transmit a message to another. Once a message is received, various enzymes, including one called acetylcholinesterase, break down the chemical messenger for reuse.

In the Alzheimer-afflicted brain, the cells that use acetylcholine are damaged or destroyed, resulting in lower levels of the chemical messenger. A cholinesterase inhibitor is designed to stop the activity of acetylcholinesterase, thereby slowing the breakdown of acetylcholine. By maintaining levels of acetylcholine, the drug may help compensate for the loss of functioning brain cells.

Galantamine also appears to stimulate the release of acetylcholine and to strengthen the way that certain receptors on message-receiving nerve cells respond to it.

Cholinesterase Inhibitors
What effects did cholinesterase inhibitors have on the memories of persons who took it in clinical trials?
Donepezil and rivastigmine were associated with better performance in memory and thinking tests in patients who were on the active medication compared with patients taking a placebo (an inactive substance). It should be stressed that the degree of improvement was modest.

Galantamine also resulted in modest improvements in clinical trials. Additional research will help scientists determine which individuals are likely to benefit from the drug.

How are cholinesterase inhibitors used?
Donepezil (Aricept) is a tablet and can be administered once daily. Generally, the initial dose is 5 mg a day (given in the morning or evening). After four to six weeks, if it is well tolerated, the dose is often increased to the therapeutic goal of 10 mg a day.

Rivastigmine (Exelon) is available as a capsule or as a liquid. The dosage is gradually increased to minimize side effects. Usually the medication is started at 1.5 mg daily. After two weeks the dosage is increased to 1.5 mg twice a day. The therapeutic goal is to increase the dosage gradually every two weeks to reach 6 to 12 mg a day. There is a greater frequency of side effects at these higher doses; however, taking drugs with meals may be helpful in reducing the occurrence of side effects.

Galantamine (Razadyne) Is supplied in the form of tablets in strengths of 4, 8, and 12 milligrams. A once a day dosage form of Razadyne was recently approved. Galantamine appears to be as effective as the other medications in this class.

Tacrine was used since the 1940s for a variety of purposes including to reverse delirium caused by anticholinergic drugs. Cognitive function improved in about 30% of those patients taking tacrine in doses of at least 120 mg to 160 mg per day. Unfortunately, few people tolerated these doses. Given the frequent side effects, multiple dosing, and required tests to monitor liver function, tacrine has been replaced by newer, less problematic drugs. Tacrine did serve a useful purpose, however, by raising the healthcare providers’ and public’s level of awareness that AD could be treated.

What are the side effects of cholinesterase inhibitors?
Generally, cholinesterase inhibitors are well tolerated. Symptoms such as nausea, vomiting, loss of appetite, and increased frequency of bowel movements may occur with any cholinesterase inhibitor. It is strongly recommended that a physician who is comfortable and experienced in using these medications monitor patients treated with any of these compounds and that the recommended guidelines be strictly observed. There is no evidence or reason to believe that combining the drugs would be any more beneficial than taking either one alone, and it is likely that combining the drugs would result in greater side effects.

Recently there has been some concern that galantamine therapy, as demonstrated in three clinical trials, may be associated with a higher mortality rate when compared to a placebo. However, this remains to be proven.

Donepezil (Aricept®)
Donepezil (Aricept, E2020) though modestly efficacious, is a significant advance in AD treatment. Some—but not all—patients and caretakers will observe a noticeable improvement in mood or behavior, however slowing the progress of the disease should also be considered a benefit. As with tacrine and other available drugs to treat AD, donepezil's most prominent pharmacological action is to inhibit acetylcholinesterase. Since it is more active in the central nervous system and less in peripheral tissues, donepezil produces fewer side effects than tacrine. Donepezil has fewer drug interactions, when compared to tacrine, which is also true for rivastigmine and galantamine.

In some patients, there is good evidence the drug has a beneficial effect on cognition, and sometimes a positive impact on activities in daily living. Several studies suggest that the drug may delay the time to nursing home placement of patients with AD.

As with other drugs in this group, gastrointestinal side effects (nausea, diarrhea, decreased appetite) are the most common side effects associated with donepezil. These can be minimized or avoided by increasing the dose slowly. Insomnia, usually described by patients as “nightmares” that awaken the patient, can occur. Switching the dose to the morning hours usually corrects this problem.

Given its relatively benign side effect profile and the similar costs of the 5-mg and 10-mg tablet, donepezil should be titrated to the maximum suggested dose of 10 mg per day when possible.

The usual schedule is to start patients on 5 mg per day in the evening, allowing the patient/caregiver to change to a morning dose if insomnia occurs and then increase to 10 mg per day after 4–6 weeks. A few patients will not tolerate the 5 mg per day dose, usually because of gastrointestinal side effects, and they can be started at 2.5 mg per day, with the dose being escalated more slowly to the maximum dose tolerated. Dividing the dose into two daily dosages may enable patients who are encountering gastrointestinal side effects to reach a therapeutic dose.

Rivastigmine (Exelon®)
A minimum dose of 6 mg/day is necessary for substantial effects in AD. Some patients treated with doses of 6–12 mg/day experience substantial cognitive improvement.

Side effects with rivastigmine are also dose related, with more rapid titration being associated with more adverse effects. Gastrointestinal side effects occur most commonly, including nausea, vomiting, anorexia, and dyspepsia. Side effects are generally transient and mild-to-moderate in severity, unless the dose is increased too rapidly.

Weight loss has been reported with rivastigmine therapy, with 26% of women and 18% of men in the high-dose group of one clinical trial experiencing weight loss of 7% or more of their baseline body weight.

Rivastigmine is dosed twice daily, preferably with food. Few drug interactions would be expected since rivastigmine has minimal protein binding and is metabolized to only a small degree by the cytochrome P450 enzyme system (this is good because many/most drug interactions are a result of P450 issues). Rivastigmine doses should be reduced in patients with hepatic or renal impairment, which is also true for tacrine, donepezil and galantamine.

As with other acetylcholinesterase inhibitors, patients taking rivastigmine should be monitored when they have physical conditions that might be worsened by cholinergic drugs such as some heart conditions, and when they are taking other cholinergic drugs. In addition, medications with anticholinergic activity should be avoided where possible.

Galantamine (Razadyne®)
Galantamine (Razadyne), first isolated from the bulbs of the common snowdrop plant and several types of daffodils, is a acetylcholinesterase inhibitor as well as a modulator of nicotinic receptors. This “dual action” may enhance the impact of acetylcholine, however this remains to be proven. Recent clinical trials confirm the efficacy at doses of 16–24 mg/day, administered in divided doses, with apparent benefits in cognitive, functional, and behavioral symptoms. It appears that galantamine, if titrated slowly, has tolerable side effects. To date there are no “head to head” studies comparing the efficacy of drugs approved to treat AD.

Memantine (Namenda®) has been approved for the treatment of moderate-severe AD. In several clinical trials memantine reduced caregiver time and improved behavior in AD patients. As a NMDA antagonist memantine reduces the destruction of nerve cells by glutamate. Most patients will be prescribed a cholinesterase inhibitor and memantine together. Memantine appears to have few side effects and drug interactions. The current evidence suggests a role for memantine in the management of moderate to severe AD, with or without a cholinesterase inhibitor (most doctors will prescribe both). Memantine’s role in mild to moderate AD is uncertain, since some studies have yielded no benefit from memantine therapy. Memantine has been on the European market for many years, but was only approved two years ago in the US for the treatment of Alzheimer’s disease.

Memantine is useful for those individuals who can not tolerate a cholinesterase inhibitor or in those patients with heart disease that affects the timing mechanism of the heart. Side effects are uncommon, but increased confusion, falls, and headaches may occur. Nausea/vomiting should not be a problem, since memantine has some anti-nausea properties.

Non-Prescription and Alternative Treatments

Gingko biloba
Gingko biloba (GB) has been widely used in Asian and European medicine. GB can be used in AD, both as a prescribed therapy and a nonprescription dietary supplement.

GB may have a role in the treatment of AD and perhaps other conditions. Recent animal studies support a GB antioxidant effect. Egb 761, an extract of GB, is the predominant form of GB currently being investigated. While some studies have shown benefits from GB, they were not always apparent to clinicians. Currently, doses of 240 mg/day of GB are being studied in a multi-site trial. Previous studies generally used 120 mg total per day in divided doses.

GB has demonstrated a potent antioxidant effect and is known to possess antiplatelet activity. A possible interaction exists with other antiplatelet agents such as aspirin, clopidogrel, ticlopidine, or dipyridamole—and it may be prudent to avoid them or at least caution individuals taking these medications regarding a risk for bleeding or bruising. Opinion differs regarding whether patients taking anticoagulants (e.g., warfarin) should also be taking GB. Several case reports have associated GB with brain and eye hemorrhages; one of the individuals was taking aspirin. In one controlled trial, GB did not increase the anticoagulant effect in patients on warfarin. Patients taking both GB and warfarin should be closely monitored.

Vitamin E
How might Vitamin E supplements benefit a person with Alzheimer’s disease?

The normal cell function termed “oxidative metabolism” results in byproducts known as free radicals. Free radicals are highly reactive compounds that quickly “attack” other cell substances, causing damage to the cell wall, metabolic machinery, and genetic material (DNA). The cells have natural defenses against this damage, which include the antioxidants vitamins C and E, but with age some of these protective mechanisms decline. Brain cell damage caused by free radicals may play a role in Alzheimer’s disease.

What was the result of the multi-center national study of vitamin E and Alzheimer’s disease?
Research reported in the April 24, 1997, issue of the New England Journal of Medicine investigated the effectiveness of vitamin E and selegiline, a drug with antioxidant properties that is prescribed for treating Parkinson’s disease. The research was part of the Alzheimer’s Disease Cooperative Study, a consortium of academic Alzheimer research centers sponsored by the US National Institute on Aging. The study suggests that either selegiline or vitamin E delays the one or more of the following time points: death, institutionalization, progression from moderate to severe dementia, or loss of ability to perform two of three basic activities of daily living (eating, grooming, or toileting). When both agents were given together, there was also a delay in progression of Alzheimer’s disease as measured by these time points. However, both agents together did not help more than either drug alone. These agents did not improve memory and thinking test scores.

These results are encouraging but as yet have not been confirmed by other studies. We also do not know if these agents would be helpful in milder or severe stages of Alzheimer’s disease. There was no evidence that intellectual deterioration was slowed. Finally, any medication may have side effects or potential interactions with other drugs. For example, it is known that certain doses of selegiline (higher than those used in the study) can lead to serious interactions with some types of foods and certain medications.

Should vitamin E be prescribed?
Vitamin E worked at least as well as selegiline on Alzheimer’s progression in this study and had fewer side effects. Vitamin E also costs less. For these reasons it is preferred over selegiline in Alzheimer’s disease treatment. Vitamin E is considered to be a “benign” medication and most people can take it without side effects. However, any change in medications should first be discussed with your primary care physician because all medication can cause side effects or interactions with other medications. People taking “blood-thinners” like warfarin (Coumadin®) or ticlopidine (Ticlid®) may not be able to take Vitamin E or will need to be monitored closely by their physician if they take Vitamin E.

What is the best dose of vitamin E?
Exactly what dose of vitamin E is the “best” is not known. The doses of vitamin E in the study were 1,200 IU twice daily. Other doses need to be studied to answer this question confidently. Many doctors recommend 400 IU twice daily because they believe this dosage to be safe for most individuals and should have the antioxidant effect desired in the brain.

Failed Drug Trials
Estrogen therapy does not appear to be effective as a treatment for AD. NSAIDS have been suggested to reduce the risk of developing AD, but this remains to be proven. Any possible role for non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen and naproxen, remains to be determined. For now, the risks of NSAID-related side effects do not warrant recommending these drugs to reduce the risk of AD. Several clinical studies found NSAIDS are not effective to treat AD, while an older study suggested NSAIDS might be helpful. The older study used indomethacin and had many gastrointestinal side effects.

Behavior Problems Associated with AD
A significant number of patients diagnosed with AD will experience some behavioral problems. These include hallucinations (usually visual), delusions, paranoia, depression, aggressive behavior (both verbal and physical) inappropriate sexual behavior, restlessness/wandering, screaming to name a few. It is not uncommon for the term “agitation” to be used to describe an aberrant behavior, however it is important for the health care provider to know exactly what the behavior is, when it occurs, what may have provoked the behavior, and the environment of the behavior. Some problems like wandering, restlessness, poor grooming; aggressive behavior and often mild-to-moderate agitation are best managed by careful assessment and non-drug interventions. Non-drug interventions should generally be attempted prior to initiating drug treatment. Physical, psychological, pharmacological, and environmental factors should be assessed prior to selecting a drug therapy to treat the behavior. Drugs rarely should be the first choice for treatment. It should be noted that drugs rarely make the behavior disappear, and a 50% reduction in the behavior is a positive response. A variety of drugs are being prescribed, with variable success, for psychiatric behavioral problems associated with AD and other dementia. Hallucinations, paranoia, delusions, severe agitation with aggressive/combative features and depression are more apt to respond to psychotherapeutic agents. Keeping a detailed diary of “problem behaviors” can greatly assist the health care provider in evaluating these “behaviors” and selecting an appropriate medication, or as often happens recommending non-drug approaches to treating the behavior.

References
Vitamin E section: Prepared by John C. Morris, MD, Professor of Neurology at Washington University at St. Louis.

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Medications for AD Related Psychiatric Behavioral Symptoms

Conclusion
Alzheimer's disease is a progressive neurological disease that can burden both patients and family with emotional, financial, and social costs. Patients and families/caretakers have numerous questions regarding medications. Information regarding medications is of vital importance to these families. Recent advances in drug therapy and conflicting information in both the professional and consumer press make it difficult for these patients and caregivers to make informed decisions. The pharmacist is in an ideal professional position to act as a consultant to these patients and families.

Medications Currently Approved to Treat AD

Myths and Facts
Myth: Vitamin E improves memory.
Fact: High doses of Vitamin E may reduce the time to nursing home placement in AD, but do not appear to improve memory or cognition.

Myth: Currently available drugs to treat AD can cure the disease.
Fact: Unfortunately this is not true. Drugs are in clinical trials that appear to slow the progression of the disease. There is some evidence existing drugs may slow the progress of AD to some extent.

Additional Suggested References
International Psychogeriatric Association (IPA) has an excellent series of modules, downloadable in PDF, on Behavioral and Psychological Symptoms of Dementia (BPSD). Topics include Aspects of BPSD likely to vary across cultures, Clinical Issues, Non Drug Treatment, Drug Treatment and more.

Managing psychiatric behavioral problems with drugs has been a conundrum for many years. There is no specific drug for any given condition, such as hallucinations, paranoia, aggression, and lack of impulse control. Drug therapy may reduce the objectionable behavior. In most instances the behavior will not be eliminated. For conditions like wandering, screaming, asking repetitive questions etc. drug therapy is of little benefit and may not be appropriate. The following is a brief summary of drugs that are currently used in attempting to treat the patient with a dementia. The comments are intended to “point” the clinician in a specific direction and not to suggest that a specific drug will “cure” the behavior.

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Frontotemporal Dementia / Pick’s Disease
Perhaps the first step, before discussing drugs that might be useful in treating Pick’s disease/Frontotemporal dementia (Pick’s/FTD), is to note a few basic “rules of the road” in medication management that apply to anyone taking medications, but especially so to any person diagnosed with a dementia.

First — review all medications, including prescription drugs, non-prescription drugs (e.g., over the counter or OTC drugs), social drugs (caffeine, nicotine, alcohol) and/or alternative products (e.g., herbals, mega vitamin or minerals etc.) Note any that may not be necessary. Discuss discontinuing these medications with your family physician.

Second — review all medications that may cause or worsen confusion, be too stimulating, be depressants, or appear to be related to an unwanted behavior.

Third — current medications for behavior problems, hearing problems, vision problems, sleep problems, breathing problems, thyroid conditions, psychiatric conditions (e.g., depression, anxiety etc.) or for pain management should be evaluated for optimal or adequate response.

The following medications may be useful in managing some of the challenging psychiatric behavioral conditions associated with Pick’s/FTD:

Antidepressants
Antidepressants exist in numerous different chemical forms and are effective in treating depression. Certain antidepressants are also effective in treating anxiety disorders and obsessive compulsive behavior.

One group of antidepressants called selective serotonin reuptake inhibitors (SSRI’s) may be useful in reducing the aggressive impulses and lack of impulse control associated with early Pick’s/FTD. Thus far only small numbers of patients have bee studied with these drugs, so there is no good evidence to date as to how well these drugs might work.

In a 1997 study nine Picks/FTD patients were treated with fluoxetine, sertraline or paroxetine, with one-half of the patients experiencing a reduction in disinhibition, depressive symptoms, carbohydrate craving and compulsions. However, paroxetine in a recent study, with only ten patients, found no benefit for paroxetine over the placebo (e.g. sugar pill). A slightly different, but similar drug, trazodone was studied in Picks/FTD and showed some benefit, over the placebo, in reducing behavioral conditions. This study used doses up to 300 mg of trazodone per day, which is a fairly large dose and often associated with daytime sedation.

Examples of SSRI’s include: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro)

Other antidepressants that may be useful:

• Trazodone (Desyrel)
• Venlafaxine (Effexor)
• Duloxetine (Cymbalta)
• Bupropion (Wellbutrin)
• Mirtazepine (Remeron)

Antipsychotics, Antianxiety and Anti-Seizure Medications
Other classes of drugs that might be useful, but have not been studied in Picks/FTD are antipsychotics, antianxiety drugs and anti-seizure medications used as “mood stabilizers.”

Cholinesterase Inhibitors
To date the drugs typically prescribed for Alzheimer’s disease (cholinesterase inhibitors) such as donepezil (Aricept), rivastigmine (Exelon) and galantamine (Razadyne) have not been systematically studied in Picks/FTD. Some clinicians have reported a worsening of symptoms in these patients when prescribed drugs from this group.

Memantine (Namenda®)
Memantine (Namenda) may offer some benefit in treating Picks/FTD, but this is speculative at this point and remains to be proven.

The Memory and Aging Center will soon complete a research trial on Memantine.

Alternative/Herbal Treatments
Alternative/herbal treatments should be approached with caution and only after consulting with a knowledgeable health care provider. Alternative/herbal therapies also can have adverse effects and may have additional risks as well, such as drug-herbal interactions, contamination with heavy metals or pesticides and contain ingredients not noted on the label. This is not to say alternative or herbal treatments should never be considered, just that it is prudent to consider them, as “drug therapy” with the same caution of “first do no harm”.

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Vascular Dementia (Multi-Infarct dementia)
Vascular dementia, although not as common as once believed, remains a significant cause for cognitive impairment in older adults.

Treatment consists of primarily managing high blood pressure, cholesterol levels, elevated blood sugar levels and other risk factors for cardiovascular disease and stroke.

Once a vascular dementia or combined vascular-Alzheimer’s dementia is diagnosed prescribing the same cholinergic enhancing drugs (e.g. donepezil, rivastigmine, galantamine) used for Alzheimer’s disease may offer some benefit. As with other conditions a healthy diet and exercise are important factors for maintaining optimal health.

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Dementia with Lewy Bodies
Dementia with Lewy Bodies is especially responsive to cholinesterase inhibitors, with one medication not displaying an advantage over another.

In addition to cholinesterase inhibitors drugs frequently prescribed for Parkinson’s disease, such as Sinemet, Mirapex etc. may be useful in reducing body stiffness and improve the individuals walking performance. Anticholinergic drugs should generally be avoided if possible.

Patients with Dementia with Lewy Bodies are frequently very sensitive to drugs that affect the brain. It is prudent to start with a low dose and slowly increase the dose, over time.

As with all prescription medications it is not a good idea to suddenly stop a medication before discussing the medication issue with your physician or nurse practitioner.

Mild Cognitive Impairment (MCI)
Mild Cognitive Impairment (MCI), characterized by mild memory impairment that has not reached a level to affect daily activities, but is noticeable to the individual, is being studied to identify if people diagnosed with MCI eventually develop Alzheimer's disease (AD). Several clinical drug trials, some using combinations of donepezil and vitamin E, are examining a possible role for drug therapy in MCI. To date, none of these trials have demonstrated a clear role for drugs to improve MCI or reduce the risk of developing AD.

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Resources

Medications

Center for Drug Evaluation and Research
US Food and Drug Administration

Medline Plus
Service of the US National Library of Medicine and the National Institutes of Health

PubMED
PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.

Lexicomp

Epocrates
Guide to drugs.

Herbal

Natural Standard
Natural Standard was founded by clinicians and researchers to provide high quality, evidence-based information about complementary and alternative therapies. This international multidisciplinary collaboration now includes contributors from more than 100 eminent academic institutions.

Natural Medicines - Comprehensive Database

Geriatrics/Gerontology

The UCSF Academic Geriatric Resource Center Online Curriculum

Consumer Products

ConsumerLab.com
ConsumerLab.com is a provider of independent test results and information to help consumers and healthcare professionals evaluate health, wellness and nutrition products.

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