Practice Based Research
at
Pharmacy Practice Research
Specialty Practice
Unique Role and Opportunity
Research Completed in a Hospital
Medical / Clinical & Pharmacy Service Related Research
Examples of Some Research
to demonstrate the breadth of the work and the degree of opportunity & possibility
Specialty Practice Site in Pharmacy
Practice Based Research in Hospital Pharmacy
Each Profession must complete research to advance
Research improves the knowledge base & credibility
and is a method of improving a professions ability to stay current.
Pharmacy leaders are very “knowledgeable” in particular areas
Cardiovascular Specialty – CPR/ICU/Care Teams
Ambulatory Care
Anticoagulation Programs
Infectious Diseases
Rise to that level of recognition through experience
and reading/reviewing current literature (research)
related to their area of practice.
But who does the research…?
Most Pharmacy Research is completed by
pharmacists who are Pharm D or MSc trained
some with residencies and some with post-PharmD fellowships
Many work in a specialty environments
Cardiovascular Specialty – CPR/ICU/Care Teams
Ambulatory Care
Anticoagulation Programs
Infectious Diseases
But … how do you get there?
PHARMACY DEPARTMENT
with
Critical Mass with Common Interest
Ability to Complete Research
Administrative Support
Time
Sunnybrook in the 70’s
Director:
Associate Director:
Jim Mann
Bill Wilson
Coordinators:
John Iazzetta
Bill Bartle
Tom Paton
Residency
Graduate Studies @ UofT:
Dr. Thiessen
Kinetics
Return to Sunnybrook
Bench space grew to an 800 ft2
Quality Control Laboratory in early 80’s
2 Research Assistants / laboratory technicians
Laboratory supplies, etc
Annual operating expenditure ~ 100K +
Current Resources
About 1500 ft2
in K-Basement
Lab
Equipment:
1 LC – MS-MS; 2 LC - UV / Fl / EC
Freezers, 1 – 80C; 1 -20C
3 computers in the lab plus 3 other computers
Research at Sunnybrook
Most Work has had an
Analytical Requirement
IV additive Service
Pharmacokinetics
Statistics
Bioequivalence
Drug Stability
Drug-Drug-Interactions
Drug Compatibility
Pharmacodynamic Studies
Tyramine Content of Food
Herbal Content/Label Claim
All studies have been completed through collaboration
in fact for most … the idea/the need was generated by someone else
a pharmacist … a physician … someone with a practical question
Bench Research
Often at a University
Funding is often
for a program
multiple years
Several types of Research
* Clinical Research
*
Generally at a Hospital
Funding is for a specific
single project
which may take several
months or several years
Survey Research
Can be done
anywhere
Funding is often
for a specific study
These are questions which relate directly to patient care.
The questions result in single studies that answer a specific question.
The results can be used immediately in a patient
There are numerous clinical questions
for which there is no good data.
If you are a pharmacist
and you are asked such a question …where do you turn?
? In an HIV patient can we improve response to drug therapy
if we make sure that drug concentrations are within a certain range.
? If ciprofloxacin is given to a patient on dialysis, will dialysis
increase drug clearance, and if so,
what dose is required to replace losses.
? If a patient has an NG tube, can I crush a nifedipine PA tablet
Will the patient experience the same clinical response
… or must I convert to IV therapy.
Simpler questions
? If a patient is taking a herbal medication …
will it interfere with other drug therapy?
? If you have 10 different herbal preparations on the shelf –
what one is best?
? If the manufacturer of a $300 /IV dose drug says that the drug
must be discarded if it is not used immediately,
should I discard the medication?
? Can dolasetron and dexamethasone be mixed
in the same IV container
prior to administration to a patient.
All studies have been completed through collaboration
in fact for most … the idea/the need was generated by someone else
a pharmacist … a physician … someone with a practical question
Scientific
Papers
John Iazzetta
21
Tom Paton
16
Bill Bartle
11
Sandra Tailor
5
Brian Hardy
2
Sharon Yamashita 1
Abstracts
11
14
12
26
9
5
Graduate Students
Lee Dupuis
Yana Bacjar
Ina Sungaila
Debra Kwan
Carrie Fung
Fran Paradiso-Hardy
Robert Lepage
Information current to December 2001
Examples of studies completed
A pharmacist … a physician asks a question,
we try to respond
1.
2.
3.
4.
5.
6.
Compatibility Study
Stability Studies
Bioequivalence study Iron
Tyramine in food
Evaluation of content of Herbals
Use of handhelds in Clinical Pharmacy
Compatibility Studies.
In hospitals, most patients will only have
1 intravenous line running at anyone time.
What do you do when a patient has multiple intravenous drugs?
Can you give them together ? … or will they ppte in the line?
You could given them sequentially … and then flush the line
with saline. But this will require excessive nursing time.
You could start a second intravenous line …patient?
You could test the compatibility.
Most studies look at two drugs and present the results in a table
Hydromorphone
Cefazolin 20 mg/mL in D5W
Cefazolin 300 mg/mL I recon vial
2 mg/mL
10 mg/mL
40mg/mL
C
I
C
I
C
I
Compatibility of dexamethasone sodium phosphate
with hydromorphone hydrochloride or
diphenhydramine hydrochloride
SCOTT E. WALKER, CARLO DEANGELIS, JOHN IAZZETTA, J. GARY EPPEL
Am J Hosp Pharm 48: 2161-6; 1991
When equal volume of dexamethasone (10 mg/mL) and
diphenhydramine (50 mg/mL) are mixed a clear but water
immiscible liquid is observed. This incompatibility is not
visually apparent at lower concentrations.
… is this due to compatibility or visual acuity?
Equal vol. hydromorphone 50 mg/mL and dexamethasone 2 mg/mL
are compatible
… but hydromorphone 40 mg/mL
and dexamethasone 10 mg/mL
are incompatible
Are these examples of concentration dependant compatibilities?
Develop a method for
hydromorphone (H),
Dexamethasone (Dx),
methylparaben (M),
propyl paraben (P),
creatinine (C)
and
degradation products (Dx-1)
Then measure concentrations.
Dexamethasone & Diphenydramine
Equal volumes of
D 50 & Dex 10
Equal volumes of
D 50 & Dex 4
Region of Incompatibility
Region of
Compatibility
Compatibility Studies
Similar graphs have been published for
Hydromorphone & Heparin
Dexamethasone & Diphenhydramine
Dexamethasone & Midazolam
Insulin & Labetalol
Insulin & Norepinephrine
Insulin & dopamine
Heparin & Labetolol
Heparin & dopamine
Stability Studies
Manufacturers provide many intravenous drugs as lyophilized powders.
… monograph states that following reconstitution
that the product should be used immediately (with 24 hours).
In most hospital settings,
this can contribute to wastage.
24 hours is too little time
for a change in dose
or a discontinued (unused)
IV medication
to be re-labeled and given
to a second patient.
Can the expiry date be extended?
Wastage seems to be related to the Shelf-life.
You need time to get the IV dose to a second patient.
But … can you move a drug along the line?
Stability Studies
Each dose ~ $30.
The top dug on the list
in 1986 was cefazolin.
With wastage at only 4%
monthly expenditures > $16,500.
If we used a 24 hour expiry date,
wastage could have been
~2640 / month ($31,600 per year).
But … can you move a drug
along the line?
And why would you want to?
Systematic evaluation of stability
and completed the studies
which demonstrated
expiry dates could be extended
to 7 days… or more.
Wastage was eventually
reduced to less than 3%
Savings in $
1986
80,000.00
2001 148,000.00
Bioavailability Studies
Head of Hematology presents two cases of anemia
unresponsive to Enteric Coated Ferrous Sulfate tablets
Poor clinical response to enteric-coated iron preparations.
RUDINSKAS L, PATON TW, WALKER SE, DOTTEN DA, COWAN DH.
Can Med Assoc J. 1989. 141: 565-566.
Problem was that patients responded
well & quickly
to oral liquid formulations of ferrous sulfate.
Was it possible that Enteric Coated Ferrous Sulfate Tablets
were not being absorbed?
… but they had been on the market since the mid 60’s..!!
Bioavailability of oral ferrous sulfate
preparations in normal volunteers.
WALKER SE, PATON TW, COWAN DH, MANUEL MA, AND DRANITSARIS G.
Can Med Assoc J. 1989. 141: 543-547.
Enteric Coated
FeSO4
tablets
had
bioavailability
of less than
25%
… a negative
bioavailability
was estimated
for 1 brand
DQTC listing
Label Accuracy of Herbal Products
Your pharmacy stocks several brands of a particular herbal preparation.
What brand should you recommend to patients?
Or if you only have limited space … what brand should you stock?
A January 2000 STAR report
evaluated 10 brands
of each of ginseng, garlic and feverfew,
finding between 0% ~85%
of label claim in each.
“Its open season on the
consumer. When you buy
one of these products, it’s
an act of faith”
Estimating the Concentration of Hypericin(s)
in Commercial Products
54 different St John’s wort preparations were purchased
14 US preparations (no tinctures)
4 Walmart (Pittsburgh)
7 Rite Aid Pharmacy in Virginia Beach
3 From 2 other Pharmacies in Virginia Beach
40 Products purchased from Retail Stores in GTA
Pharmacies, Health Food Stores, Grocery Stores
12 Tablets 26 Capsules 16 Tinctures
Hypericin and pseudohypericin concentrations
were determined by chromatography
CAPSULE RESULTS
26 Formulations
Mean Potency:
56.67%
Naturalife
Herb
Tech
Range:
0 % - 108.62%
Canadian Potency:
50.26%
US Potency:
60.63%
p = 0.2611
TABLETS
TINCTURES
RESULTS
16 Formulations
The median
concentration
g/ml.
Mean
Potency: of a tincture was 6.49
Mean
Concentration:
12 Formulations
53.57%
23.1 g/mL
In order to provide a dose similar to the
Range:
Range: median capsule or tablet,
110 g/mL
you
5.46%
would
- 81.35%
have to ingest more than 70 mL0/-dose.
5 mL of
Herbalbottles
Factors: delivers 550 g
Most tinctures come in dropper
of 50 mL or less.
Label Rec. 1 mL
Equivalent to average Tab or cap
LIMITATIONS
 Analysis consisted of only 1 lot
 Only naphthodianthrones measured
Next study evaluated
the parthenolide content in
Feverfew products, looking at different lots.
Most Feverfew products are standardized to 0.2%
but some are as high as 0.7% parthenolide
44 different lots of Feverfew products
14 brands of capsules (23 lots), 9 brands tablet/caplet (15 lots) and 6 Tinctures (8 lots)
All purchased in Southern Ontario, 1999
Feverfew Products
Range of Label Claims
Percent of Label Claim
Across all brands
< 8.4 % to 446%
Brands: 14 Caps; 9 Tabs; 6 Tinctures
No label claim for 5 Caps and all 6 Tinctures
Median ~72%
2/3 are less than 100% 18 brands, 30 different lots with label claims
Percent of label claim
Capsules
0->
ALBI (Migra Stress)
Enzymatic Therapy (Mygracare)
Herbal Factors (Feverfew Grand Camomile)
Nature’s Way(Feverfew Leaf)
Pharma Plus (feverfew)3
Solaray (MigraGard)
Solgar (Feverfew Leaf Extract)
Swiss (Feverfew 125)
Webber Naturals(Feverfew Extract)
Tablets
Ashbury Biologics (Tanacet 125)
Body Basics(Standardized Feverfew Leaf)
Flora (Myranon Feverfew Extract)
Jamieson (Migraban Feverfew)
Life (Nomigraine Matricare)
Nature’s Way (MygraFew)
Nu-Source
Quest (Herbal Migraine Formula)
Wellsprings/Quest (Herbal Migraine Formula)
20
40
60
80
100
120
140
160
180
200
300
400
2
2
Feverfew Products
Range of Label Claims
within a brand
Percent of Label Claim
17%  42%  110%
Brands: 14 Caps; 9 Tabs; 6 Tinctures
101%  169% 184% No label claim for 5 Caps and all 6 Tinctures
18 brands, 30 different lots with label claims
Percent of label claim
Capsules
0->
ALBI (Migra Stress)
Enzymatic Therapy (Mygracare)
Herbal Factors (Feverfew Grand Camomile)
Nature’s Way(Feverfew Leaf)
Pharma Plus (feverfew)3
Solaray (MigraGard)
Solgar (Feverfew Leaf Extract)
Swiss (Feverfew 125)
Webber Naturals(Feverfew Extract)
Tablets
Ashbury Biologics (Tanacet 125)
Body Basics(Standardized Feverfew Leaf)
Flora (Myranon Feverfew Extract)
Jamieson (Migraban Feverfew)
Life (Nomigraine Matricare)
Nature’s Way (MygraFew)
Nu-Source
Quest (Herbal Migraine Formula)
Wellsprings/Quest (Herbal Migraine Formula)
20
40
60
80
100
120
140
160
180
200
300
400
2
2
Range of Label Claims
Within a Brand
418 & 446%
58, 65 & 66%
Alternative Product Content Result Summary
St Johns Wort.
54 brands, single lots
Content varies from 0-108% of Label Claim
Feverfew
29 brands, 44 lots Content varies from < 8.4% to 446% of label Claim
Valerian
19 brands, 30 lots Content varies from 36% to 227% of label Claim
Glucosamine
53 brands, 77 lots
Content varies from 39% to 134% of label Claim
Tyramine Content of Food
Why?
In normals, ~450 mg of tyramine increases BP 30 mmHg in 50% of subjects
In patient on MAO inhibitors, 8 mg increased blood pressure by 30 mmHg.
“cheese effect was reported in ~1963 …
hypertensive crisis following ingestion of cheese.
Severe headache … nausea …some deaths
Problem… case reports of patients on MAOI with headache
following ingestion of a food… restriction of the food
“restricted” food list grows to include 200+ items.
Question
Experimentation by patients is dangerous
Can we produce a list that contains only tryramine containing foods?
Tyramine Content of Food
Dietary restriction, tyramine and the use
of monoamine oxidase inhibitors
Shulman KI, Walker SE, MacKenzie S and Knowles S.
J clin Psychopharmacol. 1989. 9: 397-402.
Analysed 111 foods. Identified several foods
(some immature, non-aged cheeses and Chianti Wine)
that did not require restriction
Hypertensive Episode Associated with phenelzine and Tap Beer
A re-analysis of the Role of Pressor Amines in Beer.
Tailor, SAN, Shulman KI, Walker SE, Moss J, Gardner D.
J Clin Psycopharmacol 1994; 14: 5-14
79 brands of beer, 98 different samples
38 different brands of tap beers, 30 different canned & bottled beer,
11 dealcoholized beers
4 tap beers containing more than 27 mg/L of tyramine
Pizza, “combination foods” … sausage ….
Handhelds in Pharmacy
Organization tools
Email, Date/Appointments /
Addresses & phone Numbers
Medical based programs
ePocrates RxTM, Clinical Drug Database
ePocrates RxTM, Infectious Disease Guide
Patient Tracking Software
Pendragon software
ePatient 2000
Could you get these devices & programs
to help you work more efficiently?
Identify patients at risk, gather workload stats,
Calculate the cost savings of a clinical recommendation…
Other Current Studies
Clinical Trials:
Evaluation of the Effectiveness of TDM for PI in HIV patients
Weekly analysis of PI concentrations in plasma and integration of
concentration with HIV virus phenotype to adjust PI dosing.
Evaluation of THC to improve appetite in HIV patients
Development and analysis of THC, OH & COOH metabolite
concentrations in 32 subjects receiving multiple doses of 2%, 4%, & 8%
Stability / Compatibility / Analytical Studies:
Compatibility & Stability of Pantoprazole
Stability of a new formulation of Docetaxel
Sources of Funding
Pharmaceutical Firms
Peer - Review Agencies
Ontario Ministry of Heath
Ontario HIV Treatment Network
Physician Services Incorporated
Canadian Institute of Health Research
Local Hospital Funding
Profit from Pharmaceutical Contract work
Collaborators at Sunnybrook
John Iazzetta
Tom Paton
Bill Bartle
Sandra Tailor
Brian Hardy
Sharon Yamashita