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