1. Collin Belk, Kirsten Carstarphen, Jace Engstler, Kelly Ferris
A Comparative Analysis of PrevagenⓇ Supplementation and Current Nootropic Agents
Collin Belk, Kirsten Carstarphen, Jace Engstler, Kelly Ferris

2. Prevagen Story – Background/Purpose
“Prevagen is a dietary supplement that has been clinically shown to help with mild memory problems associated with aging. Prevagen contains apoaequorin, which is safe and uniquely supports brain function”
Manufactured and marketed by Quincy Bioscience starting in 2007
Improves memory and supports:
Healthy brain function
Sharper mind
Clearer thinking
Available as oral capsules and chewables
Regular strength - 10 mg
Extra strength - 20 mg
Prevagen Story – Background/Purpose

3. Study Objectives Methods
Evaluate the claims made about Prevagen by Quincy Bioscience, and determine through research and literature evaluations if these claims are scientifically supported.
Compare FDA approved drug targets for nootropic agents and how they relate to the mechanism proposed by the makers of Prevagen.
Methods
A literature review and critiques of Prevagen
A comparison of nootropic agents, their mechanism of action, pharmacological basis and how it relates to Prevagen’s proposed mechanism and biochemical properties.

4. Results (keep as a title slide?)

5. What would make a good nootropic agent?
Molecular weight < 500 Da
Neutral or basic molecule with pKa between
LogP < 5
Polar surface area < Å2  
Number of hydrogen bonds in molecule: < 8
The sum of nitrogen and oxygen atoms in molecule: ≤ 5
What would make a good nootropic agent?

6. Apoaequorin History and Rationale
Natural, bio-luminescent calcium-binding protein found in jellyfish
Historically has been used as a calcium-sensor for research
History
Secondary messenger with many important physiological functions
Ex: Synaptic and neuronal plasticity, enzyme activation, regulation of gene expression
Endogenous calcium-binding proteins help regulated Ca2+ levels
As we age, Ca2+ homeostasis is not maintained as effectively
Elevated intracellular levels
Decreased levels of calcium-binding proteins
Calcium
Apoaequorin History and Rationale
-apoaequorin acts as a calcium-binding apoprotein that is conjugated with the prosthetic group, coelenterazine, which acts as a luciferin.  This conjugated photoprotein is known as aequorin. In the presence of aequorin, free calcium has been shown to bind the apoaequorin subunit, causing coelenterazine to be oxidized and emit a blue light.

7. Apoaequorin – Biological Plausibility
Digestion
Orally ingested proteins are highly digestible
No evidence to support apoaequorin surviving digestion
Simulated gastric environment - 90% digested in 30 seconds
Bioavailability
Sharp decrease as molecular weights eclipse Da
Apoaequorin = 22.3 kDa with 196 amino acid residues
No evidence to support absorption
Blood-Brain Barrier
No evidence of transporters or receptors
Cut-off for transmembrane diffusion is often propos

8. Apoaequorin – EffICACY – MADISON MEMORY STUDY
Study Design
Randomized, double-blind, placebo controlled
Population
N: 218, aged years old
Cognitive function: AD8 screening test
Normal: 0-2
Impaired: 2-5
Intervention
90 days
1 oral capsule of 10 mg apoaequorin daily
Computerized testing sessions at baseline, day 8, day 30, day 60 and day 90
International Shopping List (ISL)
International Shopping List - Delayed Recall (ISL-DR)
Comparison
1 size and color matched placebo capsule daily
Same computerized testing sessions
Outcome
Change in performance on tasks from baseline to day 90 on:
ISL
ISL-DR

9. Apoaequorin - Madison Memory Study Continued
ISL - AD8 0-2
Apoaequorin: 10.86% increase, t56=4.40, p<.001
Control: 3.79% increase, t32=1.059, p=.298
ISL-DR - AD8 0-2
Apoaequorin: 15.82% increase, t56=3.010, p=.004
Control: 7.41% increase, t32=1.202, p=.238
ISL-DR - AD8 2-5
Apoaequorin: 13.74% increase, t42=4.913, p<.001
Control: 8.14% increase, t36=1.423, p=.163
AD8 0-2
AD8 2-5
Apoaequorin 59 68
Control 38 56

10. Apoaequorin - Madison Memory Study Continued
Limitations
Subjective bias and conflict of interest
All authors are Quincy Bioscience employees
No mention of independent party assistance with randomization, blinding or statistics
Paid advertisement in journal
Did not directly compare apoaequorin to placebo to show it worked better
Only provided paired t test results
Paired t test degrees of freedom different that what would be expected
Data from 51 subjects is missing
Did not provide evidence or rationale for apoaequorin’s mechanism in reaching therapeutic target

11. Amphetamine Salts - Methylphenidate
MOA: Block the reuptake of norepinephrine and dopamine into the presynaptic neuron, and increase their release into extraneuronal space
Place in therapy: Both agents FDA approved for the treatment of ADHD
Known as “smart pills” that are believed to enhance cognitive ability
New York Times, Wall Street Journal, Vogue, & CNN all have reported a trend toward growing use of stimulants by healthy people for the purpose of enhancing school or work performance

12. Reviewed data on prescription stimulants as neuroenhancers from over forty laboratory Studies of subjects who were considered healthy, non-elderly adults
Studies varied in many ways
Type of tasks used
Specific drug used
Dosage determination (weight dependant or dose dependant)
Sample size
Subject characteristics
Studies

13. Amphetamine Salts - Methylphenidate Studies
3 Types of Cognition
Learning
Ex: memorizing a list of words for a designated amount of time
Results: Some enhancement
Working Memory
Considered a temporary store of information that has a role in executive function
i) Ex: series of items is presented to the subject for repetition, transcription, or recognition
ii) Results: Some enhancement for lower performers
Cognitive control
Refers to the guidance of cognitive processes. Attention and working memory are thought to rely on cognitive control
i) Ex: go/no-go task, the stop-signal task, and the Flanker test
ii) Results: Some benefit but limited support for general population

14. Memantine MOA: Place in therapy: Impact on Cognitive Function:
Studies to support

15. Donepezil Drug Class: Acetylcholinesterase inhibitor (AChEI)
MOA: Inhibits the key enzyme, AChE, responsible for the breakdown of acetylcholine.
Physiological basis for acetylcholine :
Plays many roles as an inhibitory or excitatory neurotransmitter depending on the receptor it binds to (e.g., muscarinic, nicotinic)
Acetylcholine plays an important role in the enhancement of alertness, sustaining attention and in learning/memory processes in the CNS.
A lack of ACh in the basal forebrain is associated with cognitive dysfunction
In the PNS: activates muscle contractions (when ACh binds to receptors on skeletal muscle, it opens ligand-gated sodium channels. Influx of sodium into the cell initiates a cascade of events resulting in muscle contraction).
It can be inhibitory in when it binds to muscarinic effectors - resulting in decreased heart rate, slowed GI motility, etc.

16. Donepezil Continued Place in therapy: Nootropic Properties:
Approved by FDA in 1996 for the treatment of Alzheimer Disease (mild, moderate or severe)
Nootropic Properties:
Good bioavailability with decent BBB penetration
Small molecule ( kDA)
LogP < 5 (3.6)

17. Donepezil - Rogers et. al 1998
Population
Age: 73 years (range 50-94)
Cognitive Function:
ADAS-cog score ≥ 10 and ≤ 26
Clinical Dementia Rating of 1 or 2
Intervention
30-week double-blinded, randomized
24 treatment period
5 mg/day
10 mg/day (with an initial 7 day titration from 5 to 10 mg/day)
6 week washout period
Comparison
Placebo
24 weeks
6 week “washout”
Outcomes
5 mg/day treatment arm: -0.67point decrease in ADAS-cog
10 mg/day treatment arm: point decrease in ADAS-cog
Statistically significant compared to placebo (-2.49 and -2.88, respectively, p﹤0.001)
ADAS = Alzheimer Disease Assessment Scale

19. Donepezil in Healthy Adults
Population
N= 24 young, healthy males, aged years, BMI between 20-25, graduate/post-graduate students
Intervention
Comparison
Outcomes
They met the usual exclusion criteria (e.g., allergy or intolerance to thedrug under investigation, chronic clinical, neurologic, or psychiatric disorders), had no history of learning disorders, attention deficits, drug abuse, or heavy drinking, did not smoke or regularly use drugs of abuse, were on no medication at the time of the study, and had normal trait anxiety (x.35.2; SD.8.3) and depression scores (x.3.6; SD.2.7)

20. Modafinil Drug Class: Central Nervous System Stimulant
MOA: Exact mechanism unknown. Binds to the dopamine transporter, thereby inhibiting dopamine reuptake
Place in therapy: FDA approved for the treatment of narcolepsy, obstructive sleep apnea, and shift work sleep disorder
Nootropic Properties:
Molecular Weight: 273 kDa
LogP: 0.6
Modafinil

21. Modafinil Studies
Systematic review of cognitive neuroenhancement in healthy non-sleep-deprived subjects
Characteristics of included studies
24 placebo-controlled studies
Study Design: parallel and cross-over
Sample sizes ranged from 10 to 64 participants
Modafinil dose ranged from 100 mg to 400 mg (over half of studies used 200 mg)

22. Modafinil Studies Continued
Cognitive domains assessed 
Attention
Ex: Participants must detect letters/numbers and then determine whether they are immediately followed by another, related, letter or number.
Results: The majority of studies showed no improvement in selective, sustained, or divided attention
Executive function
Ex: Participants must respond rapidly to visually-presented “go” signals with a key stroke, and inhibit any response when a “stop” signal is suddenly presented
Results: Some benefits in simple assessments, but significant effects in higher executive functions such as planning, decision making, and fluid intelligence
Learning and memory
Ex: Participants are required to immediately repeat a list of digits in reverse order, presented visually or verbally
Results: Some benefits were observed for short-term memory tasks, although an equal number of studies failed to observe any effect
Selective attention: ability to detect specific stimuli within an environment containing distractors
Sustained: maintenance of a consistent behavioral response during continuous or repetitive activity
Divided: ability to allocate cognitive resources to two or more stimuli or separate tasks

23. Discussion
Can we answer the question? - Does Prevagen compare to current nootropic agents?
Limitations
Prevagen is a supplement not regulated by the FDA for efficacy…
Not all studies can be directly compared
Otherwise healthy individuals vs. those with cognitive dysfunction
Many ways to measure cognitive function - not all are standardized, not all are comparable to each other (i.e., measure different aspects of cognitive function)

24. Exploration of other natural products used to enhance memory/cognition
Effects of commonly used cognitive enhancers such as caffeine and drugs of abuse.
Community pharmacists’ input on Prevagen
What are the current recommendations in the community?
How do pharmacists in this practice setting handle this question?
What pharmacies endorse the sale of Prevagen or other “memory enhancing” supplements
Future Directions