Clinical Prospects

Clinical Prospects

Authors

Mohammad yusuf and Bahar AhmedDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110062, Email: [email protected]

Maria KhanDepartment of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110062. Email: [email protected]

Vaibhav Dubey Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Christian School of Pharmacy, Allahabad Agriculture Institute, Allahabad Uttar Pradesh-211007. Email: [email protected]

Alzheimer’s disease (AD) is one of the most common causes of dementia in the elderly, affecting at least thirty five million people

world wide. It is now the fifth leading killer, which rose by 47% from 2000 to 2006. AD is defined as memory loss with at least one other area of cognitive impairment (e.g., language, attention, orientation, self-monitoring, judgment, motor skill, inability to perform daily activities). Generally loss of memory begins at about age of 65 and slowly progresses to severe impairment over 8 to 10 years, but it may occur sooner and advance at a different rate. Some prominent symptoms are language deficits, includ-ing word finding (especially nouns), comprehension, repetition, and fluency. Social graces, surprisingly, remain intact for a year, which eventually deterio-rates to a loss of inhibition with periods of aggres-

Treatment of Alzheimer disease and its

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Cite this Article:Yusuf M, Khan M, Dubey V. Treatment of Alzheimer disease and its Clinical Prospects. The Clinical Research Plus. 2010;2:51-61.

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The Clinical Research Plus52 June - 2010 The Clinical Research Plus 53June - 2010

• Thyroid disease

• Hydrocephalus

• Parkinson’s disease

• Lewy body dementia

• Sleep disorders

Diagnosis• AD is diagnosed on clinical grounds and by

ruling out all other possible causes. A thoroughevaluation includes neuropsychologic testing,EEG, chest radiograph, and a CBC.

• Electroencephalogram and lumbar puncture—especially for rapid onset with delirium to ruleout other causes

• Sleep study—to rule out sleep disorders

• Mini Mental State Examination—measure ofcognitive function

Laboratory Test

Tests such as complete blood count (e.g., for vitamin B12 or folate deficiency), chemistry battery (e.g., for chronic renal or liver failure), thyroid function tests, and others are done to rule out differential diagnoses. Testing of beta amyloid precursor protein levels in blood is still investigational but appears promising

Pathophysiology

• Diffuse atrophy of the cerebral cortex; second-ary enlargement of the ventricular system

• Neurofibrillary tangles (first noted by Alzheim-er) in neuronal cytoplasm

• Neuritic plaques—containing A beta amyloid

and Apo E; which accumulates in the cerebral blood vessel walls; testing of Apo E is contro-versial, however Apo E epsilon 4/4 homozy-gotes diagnose AD at about 97% accuracy

• Levels of acetylcholine and A beta amyloid de-crease and tau protein increases in CSF.

• Cholinergic transmitter deficiency and continualloss of cholinergic cells occur.

• Amyloid angiopathy is common

Imaging• Imaging is used to exclude other diagnoses such

as neoplasms, hematomas, or infarcts.

• MRI or CT—detect diffuse cortical atrophy,including the hippocampus seen particularly asdisease progresses; enlargement of sulci.

• EEG—normal or nonspecific slowing.

• Positron emission tomography (PET)—showsearly metabolic changes in parietal cortex.

sion or withdrawal. Personality and behavioral changes as well as problems in judgment occur with increasing severity as aging proceeds. Death usually occurs from malnutrition, heart disease, or infection. Clinical diagnosis cannot be definitively confirmed without autopsy.

Etiology

The etiology of AD is unknown. Speculative causes include viruses, autoimmune disorders, accelerated aging process, and environmental contaminates, no-tably aluminum and aluminum-containing products.

Risk factors• Family history- especially of epsilon 4 apolipo-

protein (Apo) E gene on chromosome 19

• Advanced age (20% to 40% of those with fullydeveloped symptoms of Alzheimer’s disease areover age 85)

• Female > male

• Possibly head trauma, low education level, andenvironmental factors.

• Down syndrome

• Oxidative stress > antioxidant reserve

• Glutamate excess

• Aluminum and mercury toxicity may contrib-ute

• Physical inactivity

Sign and symptoms• Temporal and spatial disorientation

• Cortical blindness

• Extrapyramidal dysfunction

• Memory loss-eventually includes loss of per-sonal information and inability to recognizefamily

• Inability to perform daily activities

• Aphasia-language deficits including fluency,comprehension, word naming/finding

• Accusatory behaviors

• Problems with sequential motor tasks

• Denial of symptoms

• Hallucinations, delusions, psychosis

• Aggression, agitation, anxiety, restlessness

• Withdrawal, apathy

• Insomnia or disturbances in sleep/wake pat-terns

• Muscle rigidity

• Weight loss

• Incontinence

• Seizures

• Depression

Differential Diagnosis• Depressive disorders

• Delirium through other causes

• Multi-infarct dementia

• Vitamin deficiency

• Brain tumor

• Drug intoxication, alcoholism

• Huntington’s disease

• Pick’s disease

• Stroke

• Creutzfeldt-Jakob disease

• Advanced syphilis

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Acetylcholinesterase Inhibitors

Those suffering from Alzheimer’s disease have low levels of acetylcholine, an important brain chemical involved in nerve cell communication. There are four drugs, called cholinesterase inhibitors, approved by the Food and Drug Administration (FDA) that are designed to regulate AD’s symptoms and delay its course. Cholinesterase inhibitors slow down the met-abolic breakdown of acetylcholine, and make more of this chemical available for communication between cells. Although, there is no cure for Alzheimer’s disease, however, these drugs helps in slowing the progression of cognitive impairment and can be ef-

fective for some patients in the early to middle stages.

The four FDA-approved cholinesterase inhibitors are:

Razadyne® Generic name: galantamine Year approved by the FDA: 2001 Indications: Early to moderate Alzheimer’s disease Mechanism of Action: Razadyne® prevents the breakdown of acetyl-choline and stimulates nicotinic receptors to release more acetyl-choline in the brain. Side Effects: Nausea, vomiting, diarrhea, weight loss Miscellaneous: This medication was formerly known as Reminyl®.

Exelon® Generic name: rivastigmine Year approved by the FDA: 2000 Indications: Early to moderate Alzheimer’s disease Mechanism of Action: Exelon® prevents the breakdown of ace-tylcholine and butyrylcholine (a chemical similar to acetylcholine) in the brain.

Side Effects: Nausea, vomiting, weight loss, upset stomach, weakness.

In 2007, FDA approved the Exelon®Patch (rivastig-mine transdermal system) to deliver this medica-tion through a skin patch as an option to the oral capsule.

Aricept® Generic name: donepezil Year approved by the FDA: 1996 Indications: Early, moderate and severe Alzheim-er’s disease Mechanism of Action: Aricept® prevents the

Treatment and therapy of Alzheimer disease

There is no proven treatment to stop AD. For people with mild or moderate AD, donepezil (Aricept®), rivastigmine (Exelon®), or galantamine (Raza-dyne®) may help to maintain cognitive abilities and help to control certain behavioral symptoms for a

few months to a few years. Donepezil can be used for severe AD, too.

Another drug, memantine (Namenda®), is used to treat moderate to severe AD. However, these drugs don’t stop or reverse AD and appear to help patients only for months to a few years by maintaining memory, thinking, and speaking abilities and may help with certain behavioral problems.

These drugs work by regulating neurotransmit-ters. Other medicines may ease the behavioral symptoms of AD-sleeplessness, agitation, wan-dering, anxiety, anger, and depression. Treating these symptoms is comforting for the patients.

No published study directly compares the four ap-proved AD drugs. Because they work in a similar way, it is not expected that switching from one of these drugs to another will produce significantly dif-ferent results. However, an AD patient may respond better to one drug than to the other.

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when about six percent of participants developed a potentially serious side effect, acute encephalitis (in-flammation in the brain). Several participants later died from other causes. Autopsies revealed that a large amount of beta amyloid had been cleared from their brains, their brain volume was lower, and lower levels of tau, another protein related to Alzheimer’s disease, were found in their spinal fluid. Further, for the living trial participants who developed antibod-ies, there was evidence of better memory, attention and concentration.

In 2007, further human trials testing the efficacy and safety (Phase II) of passive immunotherapy were initiated. In passive immunotherapy, antibodies to a protein rather than the protein itself are given to the recipients. By using this form, researchers believe they can avoid the side effects that resulted from ear-lier trials of the active vaccination. Phase III clini-cal trials that will involve more participants are also planned.

Active immunotherapy

The most advanced such active vaccine, called aac-001, is a modified version of AN-1792, and is intend-ed to trigger the natural antibodies for beta-Amyloid. One A-α vaccine was found to be effective against inclusion body myositis in mouse models.

Passive immunotherapy

Also derived from the AN-1792 immunotherapy pro-gram. The most advanced such candidate is known as bapineuzumab or aab-001, and this antibody is designed as essentially identical to the natural anti-body triggered by the earlier AN-1792 vaccine. The aab-001 antibody is in Phase 3 clinical trials for both Apolipoprotein E4 gene carriers, and Apolipoprotein E4 gene non-carriers.

Statins

Several clinical trials are underway to test whether various types of statins (cholesterol-lowering drugs) can help slow the progression of Alzheimer’s dis-ease. Past studies have produced conflicting results,

Claim Evidence Comments

Improves cognition All 24-to 26-week clinical trials showed statistically significant benefit in the ADAS-cog and MMSE. About 30 to 60 percent of treated patients had a 4-point ADAS-cog improve-ment compared with those who received placebo; average improvement in MMSE was 1 point. Cognitive benefits were sustained over 1 to 2 years.

Study populations were highly selected; patients with signifi-cant comorbid condi-tions were excluded.

Improves global impressions

In the 24- to 26-week trials, 20 to 40 percent of patients were thought to have improved.

Stabilization or less-than-expected deterioration would not be evident to a physician.

Improves functional ability

Results in the 24- to 26-week trials were contradic-tory. A subsequent, industry-sponsored trial showed sustained benefit of donepezil (Aricept) therapy given for 1 year.

Because functional ability is likely to be related to physical ability and psycholog-ical health and cogni-tion, the exclusion of frail and ill patients from the trials may give a greater impres-sion of benefit.

Delays nursing home placement

One trial of tacrine (Cognex) showed a reduced risk of nurs-ing home placement. Statistical extrapola-tions from completed trials of donepezil showed a 12- to 21-month delay.

The tacrine trial had strict inclusion criteria; the donepezil trials also involved a highly selected population.

Improves disturbed behaviors

A galantamine (Remi-nyl) trial reported sta-tistically significant improvement in NPI. A subsequent trial of donepezil suggested benefit.

Excluding patients with severe behavior disorders or minimiz-ing the number of such patients in a trial may result in overstatement of the benefits of drug therapy.

Claims Made for Acetylcholinesterase Inhibitor Therapy in Alzheimer’s disease

Rivastig-mine (Exelon)

Acetylcho-linesterase inhibitor Butyryl-cholin-esterase inhibitor

Start at 1.5 mg twice daily, taken with food; at 2-week inter-vals, increase each dose by 1.5 mg, up to a dosage of 6 mg twice daily.

6 mg twice daily

3 mg twice daily

Galan-tamine (Remi-nyl)

Acetylcho-linesterase inhibitor Nicotinic receptor actions

Start at 4 mg twice daily with food; at 4-week intervals, in-crease each dose by 4 mg, up to a dosage of 12 mg twice daily.

12 mg twice daily

8 mg twice daily.

breakdown of acetylcholine in the brain. Side Effects: Nausea, diarrhea, vomiting

Aricept may also have a limited slowing effect on the progression from mild cognitive impairment (MCI) to AD. Study results published in April 2005 by the New England Journal of Medicine indicated that over the first year of a three-year trial, those with MCI treated with Aricept had a reduced risk of progressing to AD compared to participants who took vitamin E or a placebo (an inactive pill). How-ever, by the end of the study, there was no differ-ence among the three groups except for those with the ApoE4 gene. Aricept’s effect lasted up to two to three years in those participants. Previous studies have indicated those with the ApoE4 gene have a higher chance of developing AD than the general population.

Cognex® Generic name: tacrine Year Approved by the FDA: 1993 (Cognex is still available but no longer actively marketed by the manufacturer, due to the severe side effects.) Indications: Early to moderate Alzheimer’s disease Mechanism of Action: Cognex prevents the break-down of acetylcholine in the brain. Side Effects: Nausea, diarrhea, possible liver dam-age

Selegiline

A number of studies have examined evidence for the use of Selegiline (Eldepryl), a selective monoamine oxidase inhibitor, in the treatment of Alzheimer’s disease. Most of these studies have shown some improvement in cognition, behavior, and mood, but little evidence of a global benefit in cognition, func-tional ability, and behavior. In 2000, the authors of a meta-analysis of 15 clinical trials concluded that there was not enough evidence to recommend selegi-line as a treatment for Alzheimer’s disease.

Because of the risk of stupor, rigidity, severe agi-tation, and elevated temperature, selegiline therapy is contraindicated in patients who are taking mep-

eridine (Demerol), and this precaution often is ex-tended to other opioids. Concurrent use of selegiline with tricyclic antidepressants and selective serotonin reuptake inhibitors also should be avoided. These re-strictions may limit the use of Selegiline in patients with Alzheimer’s disease.

Anti-Inflammatory Drugs

Inflammation surrounding α-amyloid plaques which results in destruction of neurons is thought to be a key factor in the pathogenesis of Alzheimer’s dis-ease. Observational studies have found that persons who regularly use nonsteroidal anti-inflammatory drugs (NSAIDs) have a decreased incidence of Al-zheimer’s disease. Thus, NSAIDs likely have some neuroprotective effect.

Alzheimer’s Vaccine

Scientists have succeeded in eradicating many dead-ly diseases through vaccination, and same approach might prevent or cure Alzheimer’s disease.

A build up of beta amyloid protein in the brain plays an important role in Alzheimer’s disease. Thus, pre-vention or clearing of the protein accumulation could be an effective treatment. In 1999, studies revealed that injection of the beta amyloid itself, called ac-tive immunization, caused laboratory mice to pro-duce antibodies against the protein and reduced its accumulation. Spurred on by the potential of immu-notherapy, some pharmaceutical companies started clinical trials. In 2001, Elan and Wyeth began ac-tively immunizing over 300 Alzheimer’s patients with beta amyloid. The trials were halted in 2002

Drug Pharma-cologic actions

Dosage Target dosage

Minimum therapeutic dosage

Done-pezil (Aricept)

Acetylcho-linesterase inhibitor

Start at 5 mg once daily, taken at bedtime; after 6 weeks, increase to 10 mg once daily.

10 mg once daily

5 mg daily

Acetylcholinesterase Inhibitors used in the Treat-ment of Alzheimer’s disease

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selective amyloid beta 42 lowering agent. It reduces the production of the toxic amyloid beta in favor of shorter forms of the peptide. Negative results were announced regarding tarenflurbil in July 2008 and further development was canceled.

Metal-protein interaction attenuation

PBT2 is an 8-hydroxy quinoline that removes cop-per and zinc from cerebrospinal fluid, which are ap-prehended to be necessary catalysts for amyloid beta aggregation. This drug has been in a Phase II trial for early Alzheimer’s and which has been reported preliminarily promising.

Methylthioninium chloride

In July 2008, researchers announced positive re-sults from methylthioninium chloride (MTC), (trade name: rember) a drug that dissolved Tau polymers. Phase II results indicated that, it is the first therapy that succeeded in modifying the course of disease in mild to moderate AD.

Dimebon

In July 2008 antihistamine that was formerly avail-able in Russia, Dimebon was given to a group of AD patients. The group receiving Dimebon improved somewhat over the 6 months of the study (and this continued for the next six months), whereas those on placebo deteriorated. Unfortunately the consecutive phase-III trial failed to show significant positive ef-fects in the primary and secondary endpoints. The sponsors acknowledged in March 2010 that initial results of the phase III trial showed that while the drug had been well tolerated, its outcomes did not significantly differ from the placebo control.

Antibiotic therapy

Only one clinical trial is being done (at McMaster University) to investigate the efficacy of antibiotic therapy. The authors of the study indicated that it was effective in delaying the progress of the disease: “In conclusion, a 3-month course of doxycycline and rifampin reduced cognitive worsening at 6 months of

follow-up in patients with mild to moderate AD.” A re-examination of the same data using: “AUC analy-sis of the pooled index showed significant treatment effect over the 12-month period”.

Several studies using minocycline and doxycycline, in an animal model of Alzheimer’s disease, have indicated that minocycline and doxycycline exerts a protective effect in preventing neuron death and slowing the onset of the disease.

Antiviral therapy

The possibility that AD could be treated with anti-viral medication is suggested by a study showing collocation of herpes simplex virus with amyloid plaques.

Angiotensin receptor blockers

A retrospective analysis of five million patients re-corded by the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35-40% less likely to develop AD than those using other anti-hypertensives.

Cannabinoids

Treatments that target the endocannabinoid system may have a place in the treatment of AD, although research is still incipient.

Allopregnanolone

Allopregnanolone has been identified as a potential drug agent. Levels of neurosteroids such as allopreg-nanolone decline in the brain in old age and in AD. Allopregnanolone has been shown to aid the neuro-genesis that reversed cognitive deficits in a mouse model of AD.

Insulin sensitizers

Recent studies suggests that an association between insulin resistance and AD (sensitivity to insulin can decline with aging): In a clinical trial, certain insulin

and further clinical trials will be necessary before any statin therapy is recommended. In 2007, researchers at the Boston University School of Medicine ex-amined data from the U.S. Veterans Affairs Medi-cal System, and found that a statin called Zocor® (simvastatin) appeared to reduce the incidence of Al-zheimer’s. However, in January 2008, data obtained from Catholic clergyman by scientists at the Rush University Medical Center showed no relationship between statins and cognitive decline. In April 2008, Pfizer, a pharmaceutical company that manufactures Lipitor® (atorvastatin calcium), reported no signifi-cant difference between clinical trial participants given Lipitor and Aricept®, and those given Aricept and a placebo.

Estrogen

Research suggests that estrogen taken to manage the symptoms of menopause may also protect the brain. Therefore, scientists have been interested in know-ing whether estrogen could reduce the risk or slow the advance of Alzheimer’s. However, clinical trials of those already diagnosed with the disease, showed that estrogen had no impact on its progression. Other studies indicate that women who begin using estro-gen after age 60 to 65 are at an increased risk of de-veloping dementia, as well as heart attack and stroke. Estrogen is now only recommended for short term use to treat menopausal symptoms.

Recent research has helped to clarify the neuropro-tective role of estrogen which is taken by younger

women before menopause. According to a study published in August 2007, scientists from the Mayo Clinic found that women who had one or both ova-ries removed prior to menopause had an increased long-term risk of dementia or cognitive impairment. However, those who underwent ovary removal, but also had estrogen treatment until at least age 50 did not experience this higher risk. These findings sug-gest that if taken before menopause, the neuropro-tective benefits of estrogen may outweigh the risks of side effects, such as heart problems, stroke and cognitive impairment.

Omega-3 Fatty Acids

Omega-3 fatty acids are found mainly in “oily” fish such as salmon and albacore tuna, but are also pres-ent in certain nuts and oils. Scientists believe they may have a protective effect on the brain. Clinical trials are underway to test whether these fatty acids can slow both the cognitive and functional decline in those with mild to moderate Alzheimer’s.

Gamma secretase inhibition

Gamma secretase is a protein complex thought to be a fundamental building block in the development of the amyloid beta peptide. A gamma secretase inhibi-tor known as LY451039 is in Phase 3 trials.

Gamma secretase modulation

Tarenflurbil (MPC-7869, formerly R-flubiprofen) is a gamma secretase modulator sometimes called as

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with Alzheimer’s disease:

• Drugs that block the enzymes that split off the toxic A-beta from APP (secretases inhibitors).

• Drugs that prevent the threatening clumping to-gether of newly formed A-beta molecules.

• Drugs (like Neprilysin) that help clear away the accumulating A-beta molecules before they be-gin clumping together.

• “Neuroprotective” drugs (like the growth fac-tors) that increase the ability of threatened nerve cells to stay alive.

• Drugs that will prevent the chemical modifica-tion of tau protein, and so prevent tangles.

• New vaccines that will eliminate both the pro-duction and the accumulation of amyloid (A-be-ta) but not have the dangerous side effects of the first vaccines.

• New vaccines that will eliminate tangles.

• Improved techniques to implant genetically en-gineered living cells into the brain for delivery of growth factors and other drugs to counteract the development of plaques and tangles.

• New anti-diabetic drugs that will correct glu-cose metabolism in the brains of people with Al-zheimer’s disease.

• New drug delivery techniques which will ensure that drugs get to the regions of the brain where they are needed.

• Drugs that block the enzymes that split off the toxic A-beta from APP (secretases inhibitors).

• Drugs that prevent the threatening clumping to-gether of newly formed A-beta molecules.

• Drugs (like Neprilysin) that help clear away the accumulating A-beta molecules before they be-gin clumping together.

• “Neuroprotective” drugs (like the growth fac-tors) that increase the ability of threatened nerve cells to stay alive.

• Drugs that will prevent the chemical modifica-tion of tau protein, and so prevent tangles.

• New vaccines that will eliminate both the pro-

duction and the accumulation of amyloid (A-be-ta) but not have the dangerous side effects of the first vaccines.

• Improved availability of non-invasive imaging techniques that will reveal plaques and tangles even before dementia develops. Special chemi-cals are injected into the blood that reach the brain and attach to plaques. These are visualized by imaging, so facilitating early diagnosis and revealing whether treatment strategies are reduc-ing the brain abnormalities.

• New biological markers for Alzheimer’s disease that can be measured in the blood, in the CSF, in urine, and in the skin, to help in early diagnosis, and in evaluation of treatment therapies.

• Early diagnosis based on the pattern of brain waves (EEG).

• New cognitive training regimens will help slow down the decline in brain functioning without the use of drugs.

• Delivery of therapeutic agents via the nose, in some instances associated with harmless viruses called “phages”. <

(References on demand)

Mohammad yusuf and Bahar AhmedDepartment of Pharmaceutical Chemistry, Fac-ulty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110062, Email: [email protected]

Maria KhanDepartment of Pharmacognosy and Phy-tochemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110062. Email: [email protected]

Vaibhav Dubey Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Christian School of Pharmacy, Allahabad Agriculture Institute, Allahabad Uttar Pradesh-211007. Email: [email protected]

Authors

sensitizer called “Rosiglitazone” improved cognition in a subset of AD patients; it vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated.

Essential Nutrients• Vitamin E (400 to 800 IU/day), vitamin C (1,000

mg tid), and coenzyme Q10 (50 mg tid) protects against oxidative stress.

• Acetyl-L-carnitine (1,000 to 1,500 mg/day) im-proves energy metabolism of brain tissue and neurotransmitter activity.

• Phosphatidyl serine (100 mg bid to tid) facili-tates membrane receptor activities and improves cognition and mood.

• NADH (10 mg/day) stimulates biosynthesis of dopamine and noradrenaline.

• Vitamin B12 (1,000 mcg/day) and folic acid (800 to 1,000 mcg/day) may improve cognitive function even in the absence of abnormal serum values. Vitamin B1 (300 to 2,000 mg daily) and zinc (45 mg daily) are also beneficial.

• Melatonin—investigational for insomnia; 1 to 2 mg before bed, or 3 to 10 mg daily.

• Antioxidants—vitamin E (1,000 IU bid) and selegiline (not FDA approved for Alzheimer’s) may slow progression of AD.

Herbal therapyHerbs may be used as dried extracts (pills, capsules,

or tablets), teas, or tinctures (alcohol extraction, unless otherwise noted). Dose is 1 heaped tsp. herb/cup water steeped for 10 minutes (roots need 20 minutes).

• Ginkgo biloba (120 mg bid, standardized to 24% ginkgo flavone glycosides and 6% terpene) in-creases cerebral circulation and regulates plate-lets. Monitor carefully with concurrent use of anticoagulants.

• Combine the following in equal parts to enhance peripheral circulation and improve mood: gotu kola (Centella asiatica), rosemary (Rosemarinus officinalis), hawthorn (Crataegus monogyna), prickly ash bark (Xanthoxylum clava-herculis),

passionflower (Passiflora incarnata), and laven-der (Lavendula angustifolia). For anxiety, sub-stitute kava (Piper methysticum) for lavender. For depression, substitute St. John’s wort (Hy-pericum perforatum) for lavender. Take 30 to 60 drops tincture bid to tid, or drink one cup of tea tid.

Homeopathy Acute dose is three to five pellets of 12X to 30C ev-ery one to four hours, until symptoms resolve. Rem-edies to consider include the following:

• Alumina for mental dullness with slowed speech and loss of identity

• Argentum nitricum for poor memory with im-pulsivity, anxiety, depression, and compulsive thoughts or behavior.

• Cocculus for slowed mentation with grief and vertigo

• Conium for progressive mental deterioration with emotional flatness

• Helleborus for stupefaction with indifference to the outside world alternating with anguish and incomprehension

• Zincum for confusion with slowed speech, use of incorrect words, and suicidal thoughts

• Anacardium for cruel behavior, cursing, memory loss

Prevention• NSAIDs—very preliminary studies indicate that

they may lower risk; potentially serious side ef-fects at necessary doses and duration

• Estrogen use for women—trials indicate it may lower risk of getting AD; potentially serious side effects

• Reducing aluminum and mercury exposure may be helpful. Chelation for aluminum with desfer-rioxamine slows progression compared to con-trols.

• Clinical trials (many already begun and some well advanced) will test the following, and hope-fully within the next five to seven years the most promising of them will be approved for people

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