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Practice Based ResearchPractice Based Research atat
Research Completed in a HospitalMedical / Clinical & Pharmacy Service Related Research
Examples of Some Researchto demonstrate the breadth of the work and the degree of opportunity & possibility
Pharmacy Practice ResearchPharmacy Practice ResearchSpecialty PracticeSpecialty Practice
Unique Role and OpportunityUnique Role and Opportunity
Specialty Practice Site in PharmacySpecialty Practice Site in PharmacyPractice Based Research in Hospital PharmacyPractice 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.
But who does the research…?But who does the research…?
Pharmacy leaders are very “knowledgeable” in particular areas
Cardiovascular Specialty – CPR/ICU/Care Teams Ambulatory Care
Anticoagulation ProgramsInfectious Diseases
Rise to that level of recognition through experience and reading/reviewing current literature (research)
related to their area of practice.
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 ProgramsInfectious Diseases
But … how do you get there?
PHARMACY DEPARTMENT with
Critical Mass with Common InterestAbility to Complete Research
Administrative SupportTime
Sunnybrook in the 70’sDirector: Jim MannAssociate Director: Bill Wilson
Coordinators: John IazzettaBill BartleTom Paton
Graduate Studies @ UofT: Dr. ThiessenKinetics
Residency
Return to Sunnybrook
Bench space grew to an 800 ft2
Quality Control Laboratory in early 80’s2 Research Assistants / laboratory technicians
Laboratory supplies, etcAnnual operating expenditure ~ 100K +
Current ResourcesCurrent Resources
1 LC – MS-MS; 2 LC - UV / Fl / ECFreezers, 1 – 80C; 1 -20C
3 computers in the lab plus 3 other computers
About 1500 ft2 in K-Basement
Lab
Equipment:
Research at Sunnybrook
Most Work has had anAnalytical Requirement
Pharmacokinetics IV additive Service
BioequivalenceDrug-Drug-Interactions
Pharmacodynamic Studies
Drug StabilityDrug Compatibility
Statistics
Tyramine Content of FoodHerbal Content/Label Claim
All studies have been completed through collaborationin fact for most … the idea/the need was generated by someone elsea pharmacist … a physician … someone with a practical question
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
Several types of ResearchBench Research * Clinical Research * Survey Research
Often at a UniversityFunding is often
for a programmultiple years
Generally at a HospitalFunding is for a specific
single projectwhich may take several months or several years
Can be done anywhere
Funding is often for a specific study
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.
Scientific Abstracts Papers
John Iazzetta 21 11Tom Paton 16 14Bill Bartle 11 12Sandra Tailor 5 26Brian Hardy 2 9Sharon Yamashita 1 5
Graduate StudentsLee DupuisYana BacjarIna SungailaDebra KwanCarrie Fung
Fran Paradiso-HardyRobert Lepage
All studies have been completed through collaborationin fact for most … the idea/the need was generated by someone elsea pharmacist … a physician … someone with a practical question
Information current to December 2001
Examples of studies completed
1. Compatibility Study2. Stability Studies3. Bioequivalence study Iron4. Tyramine in food5. Evaluation of content of Herbals6. Use of handhelds in Clinical Pharmacy
A pharmacist … a physician asks a question, we try to respond
Compatibility Studies.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
Hydromorphone2 mg/mL 10 mg/mL 40mg/mL
Cefazolin 20 mg/mL in D5W C C CCefazolin 300 mg/mL I recon vial I I I
Compatibility of dexamethasone sodium phosphate with hydromorphone hydrochloride or diphenhydramine hydrochlorideSCOTT 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 notvisually 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 & DiphenydramineDexamethasone & Diphenydramine
Equal volumes of D 50 & Dex 10
Equal volumes ofD 50 & Dex 4
Region of IncompatibilityRegion of Incompatibility
Region ofRegion ofCompatibilityCompatibility
Compatibility StudiesCompatibility StudiesSimilar graphs have been published for
Hydromorphone & HeparinDexamethasone & Diphenhydramine
Dexamethasone & MidazolamInsulin & Labetalol
Insulin & NorepinephrineInsulin & dopamineHeparin & LabetololHeparin & dopamine
Stability StudiesStability StudiesManufacturers 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.
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?
Can the expiry date be extended?
Stability StudiesStability StudiesEach 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).
Systematic evaluation of stability and completed the studies
which demonstrated expiry dates could be extended
to 7 days… or more.
Wastage was eventuallyreduced to less than 3%
But … can you move a drug along the line?
And why would you want to?
Savings in $Savings in $19861986 80,000.0020012001 148,000.00
Bioavailability StudiesBioavailability 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 CoatedFeSO4 tablets
had bioavailability
of less than 25%
… a negativebioavailability was estimated
for 1 brand
DQTC listing
Label Accuracy of Herbal ProductsLabel Accuracy of Herbal ProductsLabel Accuracy of Herbal ProductsLabel Accuracy of Herbal Products
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”
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?
Estimating the Concentration of Hypericin(s)Estimating the Concentration of Hypericin(s) in Commercial Productsin Commercial Products
Estimating the Concentration of Hypericin(s)Estimating the Concentration of Hypericin(s) in Commercial Productsin Commercial Products
54 different St John’s wort preparations were 54 different St John’s wort preparations were purchasedpurchased54 different St John’s wort preparations were 54 different St John’s wort preparations were purchasedpurchased
14 US preparations (no tinctures)14 US preparations (no tinctures) 4 Walmart (Pittsburgh)4 Walmart (Pittsburgh) 7 Rite Aid Pharmacy in Virginia Beach7 Rite Aid Pharmacy in Virginia Beach 3 From 2 other Pharmacies in Virginia 3 From 2 other Pharmacies in Virginia BeachBeach
40 Products purchased from Retail Stores 40 Products purchased from Retail Stores in GTAin GTAPharmacies, Health Food Stores, Grocery Pharmacies, Health Food Stores, Grocery
StoresStores12 Tablets 26 Capsules 16 Tinctures12 Tablets 26 Capsules 16 Tinctures
Hypericin and pseudohypericin concentrations were determined by chromatography
Hypericin and pseudohypericin concentrations were determined by chromatography
CAPSULE RESULTSCAPSULE RESULTS
Mean Potency:56.67%
Range:0 % - 108.62%
Canadian Potency:50.26%
US Potency:60.63%
p = 0.2611
NaturalifeNaturalife
HerbHerbTechTech
26 Formulations
16 Formulations
TABLETS TABLETS
Mean Potency:53.57%
Range:5.46% - 81.35%
12 Formulations
TINCTURESTINCTURES
Mean Concentration:23.1 g/mL
Range:0 - 110 g/mL
5 mL of Herbal Factors: delivers 550 g
Label Rec. 1 mL
Equivalent to average Tab or cap
The median concentration of a tincture was 6.49 g/ml.
In order to provide a dose similar to the
median capsule or tablet, you would have to ingest more than 70 mL / dose.
Most tinctures come in dropper bottles of 50 mL or less.
RESULTSRESULTS
LIMITATIONSLIMITATIONS
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 products14 brands of capsules (23 lots), 9 brands tablet/caplet (15 lots) and 6 Tinctures (8 lots)
All purchased in Southern Ontario, 1999
Analysis consisted of only 1 lot Only naphthodianthrones measured
Capsules 0-> 20 40 60 80 100 120 140 160 180 200 300 400ALBI (Migra Stress)Enzymatic Therapy (Mygracare)Herbal Factors (Feverfew Grand Camomile)Nature’s Way(Feverfew Leaf) 2Pharma Plus (feverfew)3Solaray (MigraGard)Solgar (Feverfew Leaf Extract)Swiss (Feverfew 125)Webber Naturals(Feverfew Extract)TabletsAshbury Biologics (Tanacet 125)Body Basics(Standardized Feverfew Leaf)Flora (Myranon Feverfew Extract)Jamieson (Migraban Feverfew) 2Life (Nomigraine Matricare)Nature’s Way (MygraFew)Nu-Source Quest (Herbal Migraine Formula)Wellsprings/Quest (Herbal Migraine Formula)
Feverfew Feverfew ProductsProducts
Percent of Label Percent of Label ClaimClaim
Feverfew Feverfew ProductsProducts
Percent of Label Percent of Label ClaimClaim
18 brands, 30 different lots with label claims
Brands: 14 Caps; 9 Tabs; 6 TincturesNo label claim for 5 Caps and all 6
Tinctures
Percent of label claim
Range of Label ClaimsAcross all brands< 8.4 % to 446%
Median ~72%2/3 are less than 100%
Range of Label ClaimsAcross all brands< 8.4 % to 446%
Median ~72%2/3 are less than 100%
Capsules 0-> 20 40 60 80 100 120 140 160 180 200 300 400ALBI (Migra Stress)Enzymatic Therapy (Mygracare)Herbal Factors (Feverfew Grand Camomile)Nature’s Way(Feverfew Leaf) 2Pharma Plus (feverfew)3Solaray (MigraGard)Solgar (Feverfew Leaf Extract)Swiss (Feverfew 125)Webber Naturals(Feverfew Extract)TabletsAshbury Biologics (Tanacet 125)Body Basics(Standardized Feverfew Leaf)Flora (Myranon Feverfew Extract)Jamieson (Migraban Feverfew) 2Life (Nomigraine Matricare)Nature’s Way (MygraFew)Nu-Source Quest (Herbal Migraine Formula)Wellsprings/Quest (Herbal Migraine Formula)
Feverfew Feverfew ProductsProducts
Percent of Label Percent of Label ClaimClaim
Feverfew Feverfew ProductsProducts
Percent of Label Percent of Label ClaimClaim18 brands, 30 different lots with label claims
Brands: 14 Caps; 9 Tabs; 6 TincturesNo label claim for 5 Caps and all 6 Tinctures
Percent of label claim
Range of Label ClaimsWithin a Brand
418 & 446%58, 65 & 66%
Range of Label ClaimsWithin a Brand
418 & 446%58, 65 & 66%
Range of Label Claimswithin a brand
17% 42% 110%101% 169% 184%
Range of Label Claimswithin a brand
17% 42% 110%101% 169% 184%
Alternative Product Content Result Summary
St Johns Wort.54 brands, single lots
Feverfew29 brands, 44 lots Content varies from < 8.4% to 446% of label Claim
Valerian19 brands, 30 lots
Content varies from 0-108% of Label Claim
Glucosamine53 brands, 77 lots
Content varies from 36% to 227% of label Claim
Content varies from 39% to 134% of label Claim
Tyramine Content of FoodTyramine 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.
QuestionExperimentation by patients is dangerous
Can we produce a list that contains only tryramine containing foods?
“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.
Tyramine Content of FoodTyramine Content of Food
Shulman KI, Walker SE, MacKenzie S and Knowles S.
Dietary restriction, tyramine and the use of monoamine oxidase inhibitors
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 samples38 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 ….
Medical based programsePocrates RxTM, Clinical Drug Database ePocrates RxTM, Infectious Disease Guide
Patient Tracking SoftwarePendragon software
ePatient 2000
Organization toolsEmail, Date/Appointments /
Addresses & phone Numbers
Handhelds in PharmacyHandhelds in Pharmacy
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 StudiesOther 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 metaboliteconcentrations in 32 subjects receiving multiple doses of 2%, 4%, & 8%
Stability / Compatibility / Analytical Studies:
Compatibility & Stability of PantoprazoleStability of a new formulation of Docetaxel
Sources of FundingPharmaceutical Firms
Peer - Review AgenciesOntario Ministry of Heath
Ontario HIV Treatment NetworkPhysician Services Incorporated
Canadian Institute of Health ResearchLocal Hospital Funding
Profit from Pharmaceutical Contract work
Collaborators at Sunnybrook John IazzettaTom PatonBill Bartle
Sandra TailorBrian Hardy
Sharon Yamashita