Pamantasan ng Lungsod ng Maynila

College of Medicine

CLINICAL THERAPEUTIC CONFERENCE

ALZHEIMER’S DISEASE

Submitted in Partial Fulfillment

of the Requirements in Medical Therapeutics

Section 3B Group 1

Submitted by:
Baetiong, Camille
Francisco, Andrea Louise
Oliveros, Alona
Ruiz, Christian Frnco
Tawingan, Denielle James
Tolentino, Joyce

March 12, 2018

CLINICAL THERAPEUTIC CASE

A 72 year old female presented with history of “forgetfulness” started 2 years

ago. Eventually progressed to having difficulty in recalling names and problems with
immediate memory. Caregiver noted difficulty remembering dates and navigating self at
home. Signs and symptoms interfere with her activities of daily living because she easily
gets lost and confused which requires daily supervision.
She has not manifested “sundowning” effect or “phantom guest” syndrome.
MMSE score = 25

CT Scan show neurofibrillary degeneration, consisting of neurofibrillary tangles

and neutrophil threads affecting medial temporal lobes.

What is your management/RDU for this case?

SALIENT FEATURES

PERTINENT POSITIVES PERTINENT NEGATIVES

• 72 year old female • (-) “sundowning” effect

• history of “forgetfulness” started 2 • (-)“phantom guest” syndrome
years ago
• difficulty in recalling names
• problems with immediate memory
• difficulty remembering dates and
navigating self at home
• neurofibrillary degeneration on CT
scan
o neurofibrillary tangles and
neutrophil threads affecting
medial temporal lobes
• MMSE score=25- mild cognitive
impairment

DIAGNOSIS

The diagnostic criteria for mild neurocognitive impairment are the following:
A. Evidence of modest cognitive decline from a previous level of performance in one
or more cognitive domains (complex attention, executive function, learning and
memory, language, perceptual motor, or social cognition) based on:
1. Concern of the individual, a knowledgeable informant, or the clinician that
there has been a mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented
by standardized neuropsychological testing or, in its absence, another
quantified clinical assessment.
B. The cognitive deficits do not interfere with capacity for independence in everyday
activities (i.e., complex instrumental activities of daily living such as paying bills
or managing medications are preserved, but greater effort, compensatory
strategies, or accommodation may be required).
 C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not better explained by another mental disorder (e.g.,
major depressive disorder, schizophrenia).

The patient satisfied the criterion A for mild neurocognitive disorder evidenced by the
concern of both the patient herself and her caregiver that she has difficulty recalling
names, problems with immediate memory, difficulty remembering dates and navigating
self at home and an MMSE score of 25 indicating mild cognitive impairment. Although,
the patient has difficulty navigating herself at home, and she easily gets lost and
confused, requiring supervision, patient still satisfied criterion B because she could still
perform complex instrumental activities. Criteria C and D were also satisfied as there
was no mention in the history of any signs and symptoms of delirium or another mental
disorder.

The diagnostic criteria for mild neurocognitive disorder due to Alzheimer’s disease are:

A. The criteria are met for mild neurocognitive disorder.

B. There is insidious onset and gradual progression of impairment in one or more
cognitive domains (for major neurocognitive disorder, at least two domains must
be impaired).
C. Criteria are met for either probable or possible Alzheimer’s disease as follows:
For mild neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if there is evidence of a causative
Alzheimer’s disease genetic mutation from either genetic testing or family history.
Possible Alzheimer’s disease is diagnosed if there is no evidence of a
causative Alzheimer’s disease genetic mutation from either genetic testing or
family history, and all three of the following are present:
1. Clear evidence of decline in memory and learning.
2. Steadily progressive, gradual decline in cognition, without extended
plateaus.
3. No evidence of mixed etiology (i.e., absence of other neurodegenerative
or cerebrovascular disease, or another neurological or systemic disease
or condition likely contributing to cognitive decline).
D. The disturbance is not better explained by cerebrovascular disease, another
neurodegenerative disease, the effects of a substance, or another mental,
neurological, or systemic disorder.

The patient satisfied criteria A and B for mild neurocognitive disorder due to
Alzheimer’s disease evidenced by the patient’s history. Possible Alzheimer’s disease is
diagnosed because of the clear evidence of decline in memory and learning (difficulty
recalling names, remembering dates, and problems with immediate memory). There was
also steady progressive, gradual decline in cognition starting from 2 years ago. Lastly,
the patient did not present with any signs and symptoms of any other disease, satisfying
the third presentation for possible Alzheimer’s disease and criterion D.

WORKING DIAGNOSIS

MILD NEUROCOGNITIVE DISORDER DUE TO ALZHEIMER’S DISEASE

PATHOPHYSIOLOGY

Study of the familial forms of Alzheimer’s Disease (AD) supports a model in

which a peptide called beta amyloid, or Aβ, accumulates in the brain over time, initiating
a chain of events that result in AD. Aβ is created when the transmembrane protein
amyloid precursor protein (APP) is sequentially cleaved by the enzymes β-amyloid
converting enzyme (BACE) and γ-secretase. APP also can be cleaved by α-secretase
and γ-secretase, which liberates a different peptide that is nonpathogenic.

Mutations in APP or in components of γ-secretase (presenilin-1 or presenilin-2)

lead to familial AD by increasing the rate at which Aβ is generated. The APP gene is
located on chromosome 21, and the risk of AD also is higher in those with an extra copy
of the APP gene, such as patients with trisomy 21 (Down syndrome) and persons with
small interstitial duplications of APP, presumably because this too leads to greater Aβ
generation. The other major genetic risk factor is a variant of apolipoprotein E called ε4
(ApoE4). Each ApoE4 allele that is present increases the risk of AD by approximately 4
fold and also appears to lower the age of onset. How ApoE4 influences Aβ accumulation
is unknown. It may increase Aβ aggregation or deposition, or decrease Aβ clearance.

While large deposits of Aβ are a feature of end-stage AD, small aggregates of Aβ

may also be pathogenic, as they alter neurotransmission and are toxic to neurons and
synaptic endings. Large deposits, in the form of plaques, also lead to neuronal death,
elicit a local inflammatory response that can result in further cell injury, and may cause
altered region-to-region communication through mechanical effects on axons and
dendrites.

The presence of Aβ also leads to hyperphosphorylation of the neuronal

microtubule binding protein tau. This increased level of phosphorylation causes tau to
redistribute from axons into dendrites and cell bodies, where it aggregates into tangles,
which also contribute to neuronal dysfunction and cell death.

THERAPEUTIC OBJECTIVES

1. To improve quality of life

2. To stabilize cognitive and functional symptoms
3. To slow the progression of cognitive, functional, and behavioral decline
4. To maximize function in daily activities
5. To reduce the burden of caregiving

ESNA CRITERIA

EFFICACY CRITERIA
Criteria # Condtiion Points
1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvements in daily living 1
activities
3 Ability to maintain efficacy for more than 6 months 1
4 Ability to slow disease progression 1
TOTAL 4
SAFETY CRITERIA

Criteria # Condtiion Points

1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 4

NECESSITY CRITERIA

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 1
relation to the patient’s case
2 Ease of administration (available as transdermal 1
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 4

AFFORDABILITY CRITERIA

Monthly regimen < P 1,000 5

Monthly regimen P1,000-1,999 4
Monthly regimen P2,000 – 2,999 3
Monthly regimen P3,000- 3,9999 2
Monthly regimen > P4,000 1

SELECTION OF DRUG GROUP

I. Cholinesterase Inhibitors (Donepezil, Rivastigmine, Galantamine)

EFFICACY

Criteria # Condtiion Points

1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvements in daily living 1
activities
3 Ability to maintain efficacy for more than 6 months 1
4 Ability to slow disease progression 1
TOTAL 4

Cholinesterase is a family of enzymes that catalyzes the hydrolysis of the

neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow
a cholinergic neuron to return to its resting state after activation. According to the mode
of action, cholinesterase inhibitors can be divided into two groups: irreversible and
reversible. Reversible inhibitors, competitive or noncompetitive, mostly have therapeutic
applications, while toxic effects are associated with irreversible cholinesterase activity
modulators. It is the reversible cholinesterase inhibitors that are the mainstay of
Alzheimer’s disease treatment.

Cholinesterase inhibitors are indicated for the treatment of Alzheimer’s disease

beginning from the mild stages onwards (Parsons et al, 2013). By inhibiting the action of
acetylcholinesterase, the predominant cholinesterase in the brain, the cholinesterase
inhibitors aim to boost acetylcholine levels. Thus, alleviating disease symptoms
associated with the progressive loss of cholinergic function in Alzheimer’s disease.
Studies have shown that lowered synthesis of acetylcholine (including reduced choline
acetyltransferase activity, required for acetylcholine synthesis) is associated with greater
cognitive impairment in dementia, including Alzheimer’s disease. However, despite clear
evidence of efficacy in the clinical setting, the exact mechanisms and pathways that link
acetylcholinesterase inhibition and acetylcholine activity with symptomatic improvements
in Alzheimer’s disease are not fully understood.

Reversible cholinesterase inhibitors employed in the therapy of Alzheimer’s disease

treat symptoms related to memory, thinking, language, judgement, and other thought
processes. Different physiological processes related to Alzheimer’s disease damage or
destroy cells that produce and use acetyl choline, thereby reducing the amount available
to deliver messages to other cells. Cholinesterase inhibitor drugs, maintain acetylcholine
level by decreasing its breakdown rate. Therefore, they boost cholinergic
neurotransmission in the forebrain regions and compensate for the loss of functioning
brain cells (Colovic et al, 2013).

According to a study by Rountree et al (2009), patients who received more persistent

exposure to cholinesterase drugs over the course of their illness had a significantly
slower rate of decline in key measures of cognition (as assessed using Mini Mental
Status Examination [MMSE] and Alzheimer’s Disease Assessment Scale-Cognitive),
global functioning (as measured using Clinician Interview Based Impression of Change
sale), and basic activities of daily living. These effects are cumulative over time.

In a study by Nakagawa et al (2017), they demonstrated the long-term efficacy of

cholinesterase inhibitors in maintaining cognitive function and clinical state of patients
with mild-to-moderate Alzheimer’s disease in comparison with the natural disease
trajectory predicted using a mathematical model. In this study, they observed that MMSE
score improved over 24 weeks and was stable up to 1 year. Furthermore, there was a
long-term beneficial effect on cognitive function measured by the MMSE compared with
the predicted outcome without treatment.

Activities of daily living are an essential part of the diagnostic criteria for Alzheimer’s
disease. A decline in activities of daily living affects independent living and has a strong
negative impact on caregiver burden. Wattmo et al (2012), in their study, have shown
that patients taking cholinesterase inhibitors had better functional response compared to
those who took placebo.
 SAFETY

Criteria # Condtiion Points

1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 4

Adverse effects of inhibitors of acetylcholinesterase such as donepezil notably

include nausea, vomiting, anorexia, diarrhea, fatigue and dizziness. Other common side
effects include abdominal pain, dyspepsia, rash, pruritus, headache, muscle cramps,
sweating, tremors and syncope, while some documented upper respiratory tract and
urinary tract infections. (ADAP, 2007)

Some cases of angina, sinus node and AV nodal blocks, bradycardia, peptic ulcers,
GI bleeding, extrapyramidal symptoms and seizures have been noted. Psychiatric
disturbances including depression, hallucination and agitations were also reported.
There is a potential for bladder outflow obstruction. Minor increase in serum creatinine
kinase have also been observed with the use of donepezil.

Anti-acetylcholinesterase has a fairly wide therapeutic index and it can be used on a

long term basis. Precaution must be done in GI and urinary obstruction, asthma, COPD,
Parkinson’s disease and in those with risk of developing PUD. In line with its mechanism
of action, theoretically, it has the potential to worsen parkinsonism symptoms,
particularly tremors.

NECESSITY

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 1
relation to the patient’s case
2 Ease of administration (available as transdermal 1
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 4

Patients treated with donepezil, rivastigmine and galantamine show modest but
statistically significant improvement in cognitive function. In the Alzheimer’s Disease
Assessment Scale-Cognitive subscale (ADAS-cog), average improvements of about 2 to
4 points over 6 months were observed in cholinesterase inhibitors-treated patients
compared with an average decline of 5 to 6 points per year observed in placebo-treated
patients (Alzheimer's Disease Association of the Philippines, 2007).
 Rivastigmine has an oral preparation (capsule) as well as transdermal patch
preparation. For Alzheimer’s dementia, initial dose for oral preparation is 1.5mg every 12
hours increased by 1.5mg/dose every 2 weeks. Maintenance dose is 3-6mg every 12
hours. For the transdermal patch, initial dose is 4.6mg every 24 hours, which may be
increased to 9.5mg every 24 hours after a minimum 4 weeks if well-tolerated, may be
further increased to 13.3mg if needed. For mild to moderate Alzheimer’s disease, the
effective dose range is 9.5-13.3mg/24 hr. The patch is replaced every 24 hours.

AFFORDABILITY

Monthly regimen < P 1,000 5

Monthly regimen P1,000-1,999
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000

DONE-10 manufactured by Innogen Pharmaceuticals is listed as the most affordable

drug brand under this drug group. It’s available at P4,000.00 for 100 pcs. of 10mg tablet.
Initial dose is 5mg once a day; increased after 4-6 weeks to a maximum of 10mg once
daily if necessary. A monthly regimen can be estimated to cost: P560.00

II. NMDA antagonists (Memantine)

EFFICACY

Criteria # Condtiion Points

1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvements in daily living 0
activities
3 Ability to maintain efficacy for more than 6 months 1
4 Ability to slow disease progression 1
TOTAL 3

Memantine is an uncompetitive NMDA receptor antagonist, and thus relies on

glutamate's activation of the NMDA receptor to take effect. Designed to block
pathological levels of glutamate activity, memantine prevents damage caused by
excitotoxicity but also permits the maintenance of physiological glutamate activity when
given in lower doses. It is most effective when more channels are open (which is
maximized under pathological conditions of excess glutamate), which suggests that
memantine is more effective at blocking the channels in cases of moderate or severe
neurodegenerative disease severity rather than during milder stages. Memantine has a
shorter dwell time (or faster off-rate) than some of the earlier NMDA antagonists that
were not tolerated, but a longer dwell time than Mg2+, which can be ineffective at
blocking the channel. It has been shown to preferentially block extrasynaptic NMDA
receptors over synaptic receptors in physiological conditions as well as in pathological
conditions, when Mg2+ is repelled from the NMDA channel. These factors make
memantine a good candidate for the prevention of excessive glutamate activity.
 As a currently approved drug, memantine is indicated for the symptomatic treatment
of moderate to severe Alzheimer’s disease, and has been associated with a moderate
decrease in clinical deterioration in Alzheimer’s disease (Olivares et al, 2016). Several
systematic reviews of randomized controlled trials have established that memantine has
small but helpful actions on cognition, mood, behavior, and the ability to perform daily
activities in patients with moderate-to-severe Alzheimer’s disease. s. In mild-to-moderate
AD, memantine has only a marginal beneficial effect on cognition, without any benefit in
terms of activities of daily living, behavior and clinical impression of change (Chu, 2012).

In a clinical effectiveness observational study comparing combination therapy

(memantine plus a cholinesterase inhibitor), cholinesterase inhibitor alone, and no
treatment with a mean observational period of 30 months (mean cumulative medication
treatment = 22.5 months), it was found that the group receiving combination therapy had
significantly lower mean annualized rates of deterioration on the Blessed Dementia
Scale (BDS) and the Weintraub Activities of Daily Living scores compared with
cholinesterase inhibitors alone and the no-treatment group (Olivares et al, 2016).

SAFETY
Criteria # Condtiion Points
1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 4

The kinetics of memantine action in the NMDA receptor associated ion channel
explains the favorable clinical safety profile that has been seen to date. The
neuroprotective properties of memantine have been studied in a large number of in vitro
and in vivo animal models by several laboratories (Hamidreza et al., 2014). NMDA
antagonists, especially Memantine, has less toxicity in comparison with
acetylcholinesterase inhibitors. Most common adverse drug reactions associated with
memantine include constipation, dizziness and headache. Less common are found to be
confusion, anxiety, hallucinations, coughing and hypertension. The most serious reaction
associated can be Steven-Johnson Syndrome.

Memantine can be given even in patients with renal impairment, with creatinine
clearance of 5 to 29 mL/min. Lack of adverse effects was consistent with findings in
other memantine monotherapy studies (Winslow et al., 2011).

In one double-blind, randomized clinical trial of 404 patients with moderate to severe
Alzheimer’s disease with an MMSE score between 5 and 14 on a stable dose of
donezepil, 203 received memantine and 201 received placebo. In patients with moderate
to severe AD, memantine resulted in significantly better outcomes than placebo on
measures of cognition and behavior. (ADAP, 2007)
 NECESSITY

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 0
relation to the patient’s case
2 Ease of administration (available as transdermal 0
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 2

Memantine, an NMDA-receptor anatagonist, has long been used as treatment for

moderate to severe Alzheimer’s disease (AD). Several studies show statistically
significant result in slowing the rate of deterioration and in improving cognition in patients
with moderate to severe AD (Alzheimer's Disease Association of the Philippines, 2007).
However, there is lack of evidence in the benefit of memantine in mild AD (Schneider et
al., 2011). There were studies suggesting that memantine has potential benefits in
patients with mild to moderate AD. However, NICE recommendations indicate that
memantine is not cost effective and that it should be prescribed only as part of clinical
studies (Tampi & Dyck, 2007).

Memantine exists as oral preparation. In the studies showing potential benefit of

memantine in mild AD, the dosage used is 10mg tablet twice daily (Tampi & Dyck,
2007).

AFFORDABILITY

Monthly regimen < P 1,000

Monthly regimen P1,000-1,999 4
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000

MEMANTINE HCl (Memry) manufactured by Medichem is available at P902.52/ box for

30 pcs. of 10mg film coated tablet. This medicine is to be taken twice a day. A monthly
regimen can be estimated to cost P 1, 811.04.

III. MAO inhibitors (Selegeline)

EFFICACY
Criteria # Condtiion Points
1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvements in daily living 0
activities
3 Ability to maintain efficacy for more than 6 months 0
4 Ability to slow disease progression 0
TOTAL 1
 Monoamine oxidase (MAO) catalyzes the oxidative deamination of biogenic and
xenobiotic amines and has an important role in the metabolism of neuroactive and
vasoactive amines in the central nervous system (CNS) and peripheral tissues. The
enzyme preferentially degrades benzylamine and phenylethylamine and targets a wide
variety of specific neurotransmitters involved in the primary substrates of MAO in the
brain, including epinephrine (EP), norepinephrine (NE), dopamine (DA), serotonin (5-
HT), and β-phenylethylamine (PEA).

An increasing number of molecular biology and pharmacology studies have shown

the neuroprotective effects of MAO inhibitors on the prevention and treatment of
Alzheimer’s disease (Drozak and Kozłowski, 2006). The main neuroprotective
mechanisms of MAO inhibitors in Alzheimer’s disease include the following: (1)
Improvement of cognitive impairment, where MAO inhibitors correct chemical
imbalances in the brain (Delumeau et al, 1994) and (2) antioxidant activities and
enhancement of iron-chelating activities where chelators can modulate Aβ accumulation,
protect against tau hyperphosphorylation and block metal-associated oxidative stress,
thereby holding considerable promise as effective anti-Alzheimer’s disease drugs. It
must be noted that MAO inhibitors are not able to demonstrate improvement in activities
of daily living, not able to maintain long-term efficacy, and not able to slow disease
progression (Drozak and Kozłowski, 2006).

SAFETY

Criteria # Condtiion Points

1 Absent to minimal side effects
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction
TOTAL 2

In the trials included in the Cochrane Dementia and Cognitive Impairment Group
Register of Clinical Trials, there is ample evidence on the adverse effects caused by
selegiline, and few had withdrawn from the trials. (Birks, J., Flicker, L., 2003). Letufo-
Neto et al., 1999, described moclobemide with another RIMA, brofaromine as more
effective compared to SSRIs based on the results from 8 clinical studies. Both
moclobemide and brofaromine had a safety profile similar to SSRIs.

Some adverse effects were recorded but very few patients left a trial as a direct
result. In 1991, Mangoni reported poor tolerability for 3 out of 68 patients on treatment
and 1 out of 51 on placebo. Small numbers found equally in both groups reported
anxiety, agitation, dizziness, nausea and dyspepsia. Selegiline was also well tolerated
with few adverse reactions like dizziness and orthostatic hypotension as reported by
Piccinin in 1990.

Unlike nonspecific inhibitors of MAO, selegiline does not inhibit peripheral

metabolism of catecholamines and can be taken safely with levodopa. It does not cause
lethal potentiation of indirectly acting sympathomimetic amines such as dietary tyramine.
(Brunton, et al., 2008) Selegiline, like the nonspecific MAO inhibitors, can lead to the
development of stupor, rigidity, agitation, and hyperthermia after administration of the
analgesic meperidine. There are reports of adverse effects resulting from interactions
between selegiline and tricyclic antidepressants and between selegiline and SSRIs.
(Brunton, et al., 2008)

NECESSITY

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 0
relation to the patient’s case
2 Ease of administration (available as transdermal 1
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 3

In a clinical study done by Wilcock et al. (2002), there was some evidence of
improvement with selegiline in the short term in cognition and activities of daily living.
However, the magnitude of the effect did not reach clinical importance. Moreover, there
was no evidence of long-term effects. Based on a meta-analysis of 17 RCTs by Birks &
Flicker (2003), there is no evidence of clinically meaningful benefit for AD sufferers.
Therefore, there would seem to be no justification to use it in the treatment of people
with AD or for any further studies of its efficacy.

Selegiline exists in both oral form (tablet/capsule) and as transdermal patch.

Concomitant meperidine, and possibly other opioids, as well as antidepressants are
contrainidicated to selegiline due to drug-drug interaction. The patient’s history did not
mention any illness which require the use of these drugs.

AFFORDABILITY

Monthly regimen < P 1,000 5

Monthly regimen P1,000-1,999
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000

SELEGELINE HCl (Selegos) manufactured by Medichemie is available at P1, 250 for 50

pcs. of 5 mg tablets. A monthly regimen can be estimated to cost: P 750.00.
 IV. Peroxisome Proliferator-activated Receptor Gamma (PPAR-Ƴ) agonists
(Pioglitazone)

EFFICACY

Criteria # Condtiion Points

1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvements in daily living 1
activities
3 Ability to maintain efficacy for more than 6 months 0
4 Ability to slow disease progression 0
TOTAL 2

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR)

is a newly recognized therapeutic target for the treatment of Alzheimer’s disease. The
PPARs are a family of three related nuclear receptors that act as whole body lipid
sensors, and each member functions to regulate a unique subset of genes responsible
for lipid and energy metabolism. The receptors act by mediating the body’s response to
dietary intake. PPAR is of particular importance as this nuclear receptor acts to regulate
both lipid and carbohydrate metabolism and participates in the regulation of serum
glucose levels, as well as regulating insulin sensitivity.

There is ample evidence that multiple physiological functions are altered in

Alzheimer’s disease. PPAR-gama exhibits pleiotropic physiological functions in multiple
systems. Therefore, PPAR-gamma agonists could exert their salutary effects in treating
Alzheimer’s disease by regulating multiple aspects involved in the disease, including
insulin insensitivity, energy metabolism, lipid metabolism, and inflammation.

In a study by Watson et al (2005) involving patients with mild-to-moderate

Alzheimer’s disease, they found that after 6 months of drug treatment, there was
enhanced memory and cognitive function compared with placebo-treated control
patients. A study demonstrated the effect of 15 - 30 mg of piogliatzone daily in patients
with mild Alzheimer’s disease. The pioglitazone group improved agitation and regional
cerebral blood flow in the parietal lobe. The study demonstrated that pioglitazone
exhibited cognitive and functional improvement (Sato et al., 2009).

SAFETY

Criteria # Condtiion Points

1 Absent to minimal side effects 0
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 3

PPARy agonists have a generally favorable adverse drug reaction profile and are
well-tolerated in the elderly as reported by Keating & Waugh in 2006. Recently, however,
Rosiglitazone usage was found to be related with an increase in the risk for
cardiovascular side effects (Nissen & Wolksi, 2007). In comparison with this,
pioglitazone has some cardioprotective capacity (Lincoff et al., 2007). In another drug-
drug interaction study, PPARy agonists had no effect on the activities of the P450s
tested, signifying that in the clinical sense, minimal drug interactions should be expected
(Kim et al., 2008).

NECESSITY

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 0
relation to the patient’s case
2 Ease of administration (available as transdermal 0
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 2

There is insufficient evidence to support the use of rosiglitazone in improving

cognitive performance in Alzheimer’s disease patients. On the other hand, the efficacy of
pioglitazone in improving cognitive performance seems to be promising, particularly for
patients with comorbid diabetes. However, this needs to be further confirmed by well-
designed trials with large sample sizes (Liu, Wang, & Jia, 2015).

Both rosiglitazone and pioglitazone exists only as an oral form (tablet). In the studies
reviewed, the dosages used were 2, 4 and 8mg rosiglitazone (Liu, Wang, & Jia, 2015).
In both rosiglitazone and pioglitazone, the contraindications are congestive heart failure,
diabetic ketoacidosis, and acute liver disease. None of which exists in our patient.

AFFORDABILITY

Monthly regimen < P 1,000 5

Monthly regimen P1,000-1,999
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000

PIOGLITAZONE HCl (Prialta) is available at P 794.18/box for 50 pcs. of 15mg tablet.

This medicine is to be taken once daily. A monthly regimen can be estimated to cost P
476.51
 V. HMG-CoA reductase inhibitors (Atorvastatin, Fluvastatin, Rosuvastatin)

EFFICACY

Criteria # Condtiion Points

1 Ability to stabilize cognitive symptoms 0
2 Ability to demonstrate improvements in daily living 0
activities
3 Ability to maintain efficacy for more than 6 months 0
4 Ability to slow disease progression 1
TOTAL 1

One of the most widely accepted theories of Alzheimer’s disease pathology is the
aggregation of amyloid-beta (Aβ) into extracellular cortical and hippocampal plaques. It
has also been postulated that excessive cholesterol build-up in the brain plays an
integral role in Aβ aggregation and using HMG-CoA reductase inhibitors may reduce Aβ
accumulation by lowering brain cholesterol levels.

Statins are well-known for their cardiovascular benefits. However, the cognitive
effects of statins are not well understood. In a study by Simons et al (17), it was found
that MMSE scores were significantly better for the statin-treated group than the placebo
group. However, the ADAS-cog scores were not significantly different. While the MMSE
was an easier test to administer, the ADAS-cog test is more comprehensive and should
be the gold standard when evaluating cognitive functions in patients with Alzheimer’s
disease. Time to initiate therapy and the duration of treatment are still unknown.

SAFETY

Criteria # Condtiion Points

1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 0
4 Few drug-drug interaction 0
TOTAL 2

Disturbances associated with the use of statins include GI upset, headache, skin
rashes, dizziness, blurred vision and raised liver enzymes with elevated liver enzymes
and muscle problems being the most common.
In some randomized clinical trials, reported side effects are low, but higher in studies
using data from commercial use. Adverse drug reactions include myopathy (muscle
tenderness, pain, generalized weakness in skeletal muscles), hepatic dysfunction
(elevated liver enzymes), renal impairment from myoglobinuria (Hu et al., 2012).

Special precautions should be taken when given in patients with hepatic

parenchymal disease and in the geriatric population. Contraindications with the use of
statins include active liver disease, myopathy, pregnancy and lactation. Drugs that inhibit
or block the action of liver enzymes increase the levels of simvastatin, lovastatin,
fluvastatin and atorvastatin in the blood and can lead to the development of
rhabdomyolysis (Banach et al., 2015).
 Finally, concerning the safety of the statin therapy, the KDIGO Work Group suggests
that, due to lack of evidence that the risk of liver dysfunction differs in people with CKD,
baseline levels of transaminases should be measured before initiating statin treatment,
however routine follow-up measurements are not recommended (KDIGO, 2013)

NECESSITY

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 0
relation to the patient’s case
2 Ease of administration (available as transdermal 0
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 2

There has been a pilot proof-of-concept study of atorvastatin in mild to moderate

AD showing significant cognitive benefit observed at 6 months. However, this cognitive
benefit did not persist at the end of 1 year (Sparks, et al., 2005). Evidence from
retrospective case control studies suggests a beneficial role of statins in the prevention
of AD. However, a similar benefit has not been established in prospective cohort studies
or clinical trials (Nagaendran Kandiah, 2009). Since there are no randomized trials for
review, there is not enough clinical data to support the use of statins for treating AD.
Thus, currently, it is not recommended as treatment for Alzheimer’s disease (Alzheimer's
Disease Association of the Philippines, 2007).

Atorvastatin exists only in oral form (tablet). In the abovementioned study, the
dosage used is atorvastatin calcium 40mg twice daily (Sparks, et al., 2005).
Contraindication for atorvastatin is liver disease, which does not exist in our patient.

AFFORDABILITY

Monthly regimen < P 1,000 5

Monthly regimen P1,000-1,999
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000

RiteMED Atorvastatin is available at P 1,600/ box for 100 pcs of 10mg film coated tablet.
This medication shall be taken once daily. A monthly regimen would cost P 480.00.
SUMMARY OF SCORES

DRUG CLASS E S N A TOTAL

Cholinesterase 4 4 4 5 17
Inhibitors
NMDA 3 4 2 4 13
Receptor
Antagonist
MAO Inhibitor 1 2 3 5 11
PPAR-gamma 2 3 2 5 12
Agonist
HMG-CoA 1 2 2 5 10
reductase

P-DRUG SELECTION

CHOLINESTERASE INHIBITORS

According to Alzheimer’s Association, only two types of medications are approved

by the U.S. Food and Drug Administration: cholinesterase inhibitors and memantine.
Among cholinesterase inhibitors, these are Donepezil, Rivastigmine, and Galantamine.
Previous pair-wise meta-analyses and adjusted indirect comparisons showed the
modest efficacy of ChEIs on cognition, but there has been no evidence of any
differences between them. Present studies by Koboyashi et al. (2016) also
demonstrated essentially the same result. Taken together, these drugs have modest but
robust efficacy on cognition, although, identifying hierarchies of efficacy for cognition
among them are not yet well-defined (Koboyashi et al., 2016). In comparison with
placebo, all three cholinesterase inhibitors donezepil, galantamine, and rivastigmine
have the ability to stabilize or slow decline in different domains: cognition, function,
behavior, and global change (Hansen et al., 2008). Cholinesterase inhibitors delay or
slow symptom worsening, although this effect varies from person to person (Alzheimer’s
Association).

EFFICACY

A. DONEPEZIL

Criteria # Condtiion Points

1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvement of daily living 1
activities
3 Ability to maintain efficacy for more than 6 months 1
4 Ability to slow disease progression 1
TOTAL 4

The donepezil treated group evidenced significantly better performance on measures

of working memory and attention when compared to the no treatment control group and
also performed significantly better than the rivastigmine group on three of our four
measures (Foster et al., 2016). According to Foster et al. (2016), whereas patients who
respond to donepezil exhibit increased cerebral blood flow to the anterior frontal lobe
and the parietal lobe, patients who respond to rivastigmine exhibit increased blood flow
to hippocampal structures and the prefrontal cortex. These findings suggest that
donepezil increases regional cerebral blood in those regions of the brain associated with
vigilant attentional processing and working memory. These collective findings could
potentially explain why donepezil was associated with better performance on the tests of
working memory-attention used in their study. With regards to clinical global change
comparing donepezil with galantamine, superior efficacy is attributed to the former
(Koboyashi et al., 2016). Global change refers to clinicians’ observations of change in
the patient’s cognitive, functional, and behavioral performance since the start of a trial
(Alzheimer’s Disease Research Center).

Studies of 6 months duration in patients with mild to moderate AD treated with

donepezil have demonstrated the improvement on cognition to persist even at end of six
months and long term studies have demonstrated the improvement in cognition on
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) to be above
baseline values for as long as 38 weeks and at any point-of-time retained better than the
placebo in long term studies over 5 years of duration (Mehta et al., 2012).

B. RIVASTIGMINE

Criteria # Condtiion Points

1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvement of daily living 1
activities
3 Ability to maintain efficacy for more than 6 months 1
4 Ability to slow disease progression 1
TOTAL 4

The efficacious effects of treatment with rivastigmine on various behavioral

disturbances provide supporting evidence that cholinergic mechanisms, among other
neurotransmitters, are involved in the manifestation of some behavioral and
psychological symptoms of dementia (Figiel and Sadowsky, 2008). According to Figiel
and Sadowsky (2008), rivastigmine has shown efficacy in treating behavioral
disturbances in patients with a wide range of dementias, including Alzheimer's disease,
vascular dementia, fronto-temporal dementia, mixed dementia, Lewy body dementia,
Parkinson's disease with dementia, and schizophrenia with dementia. Most of the
studies have been open-label clinical trials with behavior as a secondary endpoint. The
behavior domains that most consistently showed improvement were apathy/indifference,
anxiety, delusions (psychosis), and hallucinations.

C. GALANTAMINE
Criteria # Condtiion Points
1 Ability to stabilize cognitive symptoms 1
2 Ability to demonstrate improvement of daily living 1
activities
3 Ability to maintain efficacy for more than 6 months 1
4 Ability to slow disease progression 1
TOTAL 4
 Clinical outcomes of cognition in the group switched to galantamine after not
responding to donepezil were not inferior to outcomes in the group naïve to galantamine.
Findings of this study (Hwang et al., 2016) may contribute to the evidence-based clinical
approach for managing patients with AD of mild-moderate severity who are non-
responders to donepezil. Compared with placebo, galantamine significantly improved
cognition and global function in patients with mild to moderate Alzheimer’s disease.
These therapeutic effects were associated with significant benefits on patients’ activities
of daily living (Wilcock et al., 2000).

SUMMARY OF EFFICACY

EFFICACY
# Criteria Donepezil Rivastigmine Galantamine
1 Ability to stabilze cognitive 1 1 1
symptoms
2 Ability to demonstrate improvement 1 1
of daily living activities
3 Ability to maintain efficacy for more 1 1 1
than 6 months
4 Ability to slow disease progression 1 1 1
Total 4 4 4

SAFETY

CHOLINESTERASE INHIBITORS

Alzheimer’s Association states that adverse effects of these medications are well
tolerated. They commonly include nausea, vomiting, loss of appetite, and increased
frequency of bowel movements.

A. DONEPEZIL

Criteria # Condtiion Points

1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 4

Koboyashi et al. (2016) cited a study (Hansen et al., 2008) which essentially yielded
similar results: all drugs, except donezepil, had a significantly higher risk and frequency
of nausea, vomiting, diarrhea, dizziness, and withdrawals due to adverse effects
compared to placebo. In a previous study long-term efficacy and safety of donepezil (up
to 10 mg/day) was evaluated on 133 patients up to 192 weeks and found out that
donepezil was well tolerated, with no evidence of hepatotoxicity. It has been proposed
that donepezil is effective and well tolerable in AD patients, even in difficult clinical
conditions such as hepatic or renal impairment (Erbayraktar, 2016).

B. RIVASTIGMINE

Criteria # Condtiion Points

1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 4

Rivastigmine patch showed superior tolerability. Koboyashi et al. (2016) also cited
Winblad et al. (2007), stating that rivastigmine patch shows superior tolerability than that
of the oral. This could be explained by the differences in formulation. Patch version is
much preferred by caregivers due to its greater ease of use, greater ease of following
the schedule, and more convenient handling. In a study involving 1,059 caregivers, more
than 70% preferred the patch after 24 weeks of use and reported greater overall
satisfaction. Also cited in this study is another research including 88.2% of caregivers
preferring patch over oral due to the said reasons and in addition, there is less
interference with daily activities, promoting adherence and long term use (Nieto et al.,
2016). Oral rivastigmine treatment may be associated with a number of gastrointestinal
adverse events, which may limit the maximum therapeutic dose for some patients (Su et
al., 2015). First meta-analysis by Su et al. (2015) reveals that rivastigmine treatment
shows a positive result of improving the condition of patients with mild-to-severe AD.

C. GALANTAMINE

Criteria # Condtiion Points

1 Absent to minimal side effects 1
2 Possible for long-term administration of more than 6 1
months
3 Less risk for systemic or organ damage 1
4 Few drug-drug interaction 1
TOTAL 4

There was an improved core Alzheimer’s Disease symptoms or slowing of the rate of
cognitive decline in AD after at least 6 months of galantamine treatment (Hwang et al,
2016). Contraindicated in severe hepatic impairment (Child-Pugh Score >9) and in
patients with Creatinine clearance of <9mL/min. Adverse drug reactions include
abdominal pain, bradycardia, decreased appetite, depression, diarrhoea, dizziness,
dyspepsia, fall, fatigue, hallucination, headache, HTN, laceration, malaise, muscle
spasm, nausea, syncope, tremor, vomiting, weightt loss. Arrhythmias, blurred vision,
dehydration, 1st degree AV block, flushing, hypersensitivity, hypersomnia, hypotension,
muscular weakness, palpitation, paraesthesia, retching, seizures, sweating, taste
disturbance, tinnitus. Rarely, exacerbation of Parkinson’s disease, hepatitis (MIMS
Philippines 2018). May antagonize the effect of other cholinomimetics (e.g. donepezil,
neostigmine, systemic pilocarpine). Pharmacodynamic interaction with drugs that
significantly reduce the heart activity (e.g. digoxin, β-blockers, certain Ca-channel
blocking agents and amiodarone) (MIMS Philippines 2018).

SUMMARY OF SAFETY

SAFETY
# Criteria Donepezil Rivastigmine Galantamine
1 Absent to minimal side effects 1 1 1
2 Possible for long-term administration 1 1 1
of more than 6 months
3 Less risk for systemic or organ 1 1 1
damage
4 Few drug-drug interaction 1 1 1
Total 4 4 4

NECESSITY

A. DONEPEZIL

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 1
relation to the patient’s case
2 Ease of administration (available as transdermal 0
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 3

Donepezil has the advantages of improved tolerability and once-daily

administration due to its half-life of 70 hours. Its absorption is neither affected by food or
time of administration. According to 12 randomized controlled trials, there is a
statistically significant difference favoring donepezil over placebo and with four of these
reporting a statistically significant difference on two different cognitive scales. Donepezil
has been approved by the US FDA for the treatment of all stages of Alzheimer’s.
B. RIVASTIGMINE

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 1
relation to the patient’s case
2 Ease of administration (available as transdermal 1
patch)
3 Less frequent dosing regimen that promotes 1
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 4

Three new studies for rivastigmine were identified by the assessment group of
NICE that measure cognition by two different cognitive scales and showed significant
improvement of cognition with use of rivastigmine compared to placebo. In four head-to-
head randomized controlled trials, there was no significant difference seen between
donepezil and rivastigmine for behavioral and cognitive outcomes.

C. GALANTAMINE

Criteria # Criteria considered in rating for the drug group's Points

necessity are the following:
1 Effective stand-alone drug as treatment regimen in 1
relation to the patient’s case
2 Ease of administration (available as transdermal 0
patch)
3 Less frequent dosing regimen that promotes 0
compliance to treatment (once daily dosing)
4 No contraindications for use in relation to the patient’s 1
case
TOTAL 2

According to the recommendations of National Institute for Health and Carel

Excellence (NICE) on dementia, their assessment group included a systematic review,
including a meta-analysis, that concluded that the AchE inhibitors provided benefits in
terms of cognitive function and activities of daily living, and galantamine improved
psychological symptoms in mild to moderate dementia. Galantamine has also been
approved in the US for the treatment of mild dementia.

SUMMARY OF NECESSITY

# Criteria Donepezil Rivastigmine Galantamine

1 Effective stand-alone drug as 1 1 1
treatment regimen in relation to
the patient’s case
2 Ease of administration (available 0 1 0
 as transdermal patch)
3 Less frequent dosing regimen 1 1 0
that promotes compliance to
treatment (once daily dosing)
4 No contraindications for use in 1 1 1
relation to the patient’s case
TOTAL 3 4 2

AFFORDABILITY

A. DONEPEZIL

Monthly regimen < P 1,000

Monthly regimen P1,000-1,999 4
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000

According to MIMS Drug Reference 2017, Donepezil is available in 5mg capsule

in Php 1,821.09 per box of 30. This would cost the patient Php 1,821.09 for one month
of 5mg once daily dosing in the initial treatment of mild dementia.

B. RIVASTIGMINE

Monthly regimen < P 1,000

Monthly regimen P1,000-1,999
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000 1

According to MIMS Drug Reference 2017, only the Exelon Patch is available.
Initial dosing using the Patch 5 (4.6mg/24 hours) would cost the patient Php 6550 for
one month.

C. GALANTAMINE

Monthly regimen < P 1,000

Monthly regimen P1,000-1,999
Monthly regimen P2,000 – 2,999
Monthly regimen P3,000- 3,9999
Monthly regimen > P4,000 1

Galantamine is not found in the MIMS Drug Reference Philippines 2017. Price for
30 tablets according to RX Online Pharmacy Asia is Php 4324.98.
SUMMARY OF AFFORDABILITY

# Criteria Donepezil Rivastigmine Galantamine

1 Monthly regimen < P 1,000
2 Monthly regimen P1,000-1,999 4
3 Monthly regimen P2,000 – 2,999
4 Monthly regimen P3,000- 3,9999
5 Monthly regimen > P4,000 1 1
TOTAL 4 1 1

SAMPLE PRESCRIPTION

JANE DOE, MD
Ospital ng Maynila Medical Center
Quirino Ave., Manila

Name: CTC Date: March 9,

Age/Sex: 72/F 2018

Donepezil HCl
(Dopezil)
5mg tablet
# 30

Sig: Take 1 tab once daily for 1

month. Follow up after 1 month.

Refill: 0

Warning: Watch out for nausea,

vomiting, diarrhea. Consult
immediately if hypersensitivity
reaction occurs.

Jane Doe
Jane Doe, MD
Lic. No.
050794
PTR No.
478532
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