University of Toronto Medical Journal, May 2001

100 Pages·2001·11.1 MB·English

by  Medical Society of the University of Toronto

University of Toronto Medical Journal
Volume 78, Number 3/May, 2001
A student-run s c i e n t ifi c publication. Established in 1 923.
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180 Preface 206 News and Views
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184 The Human Genome Project 213 Awards d
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239 Clinicopathological Correlation y
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190 Acromegaly: A Review and Case Presentation ra
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Yael Friedman, Andrea K. Boggild, and Ivy Fettes 244 Morning Report i
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196 Assessing Health-Related Quality of Life 247 Quick Diagnosis o
200 CMraorch nK'se rDbai sease in Children 254 Technology Review rchives Toronto r Rare B e St. rio M5S
205 CKirroasns wKo. rKd undhal, Pavi S. Kundhal and Anne M. Griffiths 226539 CBoaonka dRiaenv ieHwesa lth Care versity Aersity of mas Fishe St. Georgnto, Onta
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ATDRVASTATIN CALCIUM
EFFICACY
Possible delays ahead TO
LIPITOR* is
an HMG-CoA
reductase inhibitor
REACH
(statin). LIPITOR is
indicated as an adjunct
to diet for the reduction
of elevated total cholesterol,
LDL-C, triglycerides, and
apolipoprotein B in hyperlipidemic
and dyslipidemic conditions TARGET
(including primary hypercholestero¬
lemia, combined [mixed] hyperlipi¬
demia, dysbetalipoproteinemia,
hypertriglyceridemia, and familial
hypercholesterolemia) when response to
diet and other non-pharmacological
measures alone has been inadequate. See THE
prescribing information for complete
warnings, precautions, dosing and admini¬
stration. LIPITOR is contraindicated during
pregnancy and lactation. Lipid levels should
be monitored periodically and, if necessary, the
dose of LIPITOR adjusted based on target lipid
FIRST
levels recommended by guidelines. Caution
should be exercised in severely hypercholestero-
lemic patients who are also renally impaired,
elderly, or are concomitantly being administered
digoxin or CYP 3A4 inhibitors. Liver function tests
should be performed before the initiation of
treatment, and periodically thereafter. Special
TIME
attention should be paid to patients who develop
elevated serum transaminase levels, and in these
patients measurements should be repeated promptly
and then performed more frequently. The effects of
atorvastatin induced changes in lipoprotein levels,
including reduction in serum cholesterol, on cardio¬
vascular morbidity, mortality, or total mortality have not
been established.
Recent clinical data showed that LIPITOR actually gets patients to target
with fewer titrations and fewer repeat visits than PrZocor® (simvastatin),
pPravachol® (pravastatin) or PrLescol® (fluvastatin).1*
Exceptional LDL-C reductions of SEBfliES (Type I la and Mb) over the full dose range
2
Significantly better LDL-C and TC/HDL-C ratio reductions compared to Zocor or
Pravachol at starting doses
3451
T^gp(l
The added benefit of excellent TG reductions of (Type IV) over the full
dose range
2
• Competitive price - LIPITOR costs less than Zocor or Pravachol at usual starting dose1’*
• Less than 2% of patients discontinued therapy due to adverse experiences. Most
common adverse effects were myalgia, headache, constipation, diarrhea, dyspepsia,
flatulence and nausea
2
fomized, open-label, treat-to-target study with 336 patients enrolled Patients were treated with LIPITOR 10 mg (n=140). Lescol 20 mg (n=58). Pravachol 20 mg (n=72) or Zocor 10 mg
C target was achieved. Cholestyramine was added for patients not reaching LDL-C target at maximum dose p<0 005
ly of 177 hypercholesterolemic patients taking LIPITOR 10 mg or Zocor 10 mg in a one-year, randomized, double blind study. The LIPITOR group had LDL-C andTC reductions of 37%
% while the Zocor group had LDL C and TC reductions of 30% and 24% respectively ip<0 05) and an HDL-C increase of 7%. ^
ly of 305 hypercholesterolemic patients taking LIPITOR 10 mg or Pravachol 20 mg in a one year randomized, double-blind study. The LIPITOR group had LDL C and TC reductions PAABW
-- the Pravachol group had LDL-C and TC reductions of 23% and 17% respectively (/> 0 05) and an HDL-C increase of 8%.
deluding dispensing fees for a 30 day script of the statin at the usual starling dose, LIPITOR (10 mg) costs S48, and Zocor (10 mg) and Pravachol (20 mg) each cost $53.40. Mcmbc
UTMJ
University of Toronto Medical Journal
Volume 78, Number 3/May, 2001
A student-run s c i e n t ifi c publication. Established in 1923
Table ot Contents
180 Preface 232 Back to Basics VII: Minor Burns Injuries
Michael Bezuhly, Manuel Gomez, Joel S. Fish
Biomedical Research
184 The Human Genome Project Clinicopathological Correlation
Nicholas Tan 239 Furuncular Myiasis: A Case of an Unexpected
Traveling Companion
Cardiovascular Andrea K. Boggild, Yael Friedman and Kevin C. Kain
190 Acromegaly: A Review and Case Presentation
Yael Friedman, Andrea K. Boggild, and Ivy Fettes Morning Report
244 A Suspicious Jaundice
Health Assessment Martin C. Chang and Catherine Chung
196 Assessing Health-Related Quality of Life
Marc Kerba Quick Diagnosis
247 Piero Tartaro, Steven W.H. Hwang and Shoba Subramanian
Pediatrics
200 Crohn's Disease in Children Technology Review
Kiran K. Kundhal, Pavi S. Kundhal and Anne M. Griffiths 254 Handheld Computers and Medicine:
A Brief Review of Hardware and Software Options
205 Crossword Feisal A. Adatia and Anthony D. LoFaro
Sarah Shaikh
Canadian Health Care
News and Views 259 Canada's "Brain Drain" and Its Impact on Health Care
206 In the Literature Vlad Miropolsky
Philippe L. Bedard
Book Reviews
208 Prolific Scientist Profiles: 263 Doing Good: the Life of Toronto's General Hospital
A Conversation with Dr. Tirone David, M.D., Rizwan Haq
F.R.C.S.(C), F.A.C.S.
Innovation, Passion & Cardiac Surgery 263 Code Blue: Reviving Canada's Health Care System
Steve K. Singh Chris Chong
213 Awards 264 Clear Answers: the Economics and Politics of For-
Profit Medicine
214 Law and Ethics in Medicine: Ifran Dhalla
When to Speak Out: The Dilemma for Medical
Students 265 Infections and Inequalities: The Modern Plagues
Anil J. Misir Darrell Tan
216 Forum: 266 A Review of Anatomy Books
Exploring the Use of Physician Report Cards Paolo Mazzotta and Anil J. Misir
Christopher J. Hall and Ann M. Stewart
267 The House of God
220 Evidence-Based Medicine: Andrea Waddell
The Value of Mammography in Screening for Breast
Cancer
Ann M. Stewart
226 Back to Basics VI: An Approach to the Patient with a
Life-Threatening Acid-Base Disturbance: the
Alkalemias and Mixed Disturbances
Manish Shah, Murray Beuerlein and Karoon Danayan
Front cover illustration by Andree Jenks and Victoria Rowsell
Department of Biomedical Communications, University of Toronto.
volume 78, number 3, May 2001 177
UTMJ
University of Toronto Medical Journal
Room 2141, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario M5S 1A8
A s tu d e n t - r u n s c i e n t ifi c p u b I i c a t i o n . E s t a b l i s bed in 1 923.
UTMJ Staff
Editors-In-Chief CPC Editors Editorial Board
Prateek k. Lala, M.Sc. (0T3) Andrea k. Boggild, M.Sc. (0T3) Sylvia Asa, M.D., Ph.D.
Valerie Panct-Raymond, M.Sc. (0T3) Yael Friedman, M.Sc. (0T3) kathy Barnard, B.Sc. (0T2)
Andrew S.-P. Lim, B.Sc. (0T3)
Sam Bederman, M.Sc. (0T1)
Senior Assoclate Editors
Michael Chang, M.Sc. (0T2)
Michael A. Levesque, Ph.D. (0T3) Quick Diagnosis Editors
Jonathan Dostrovsky, Ph.D.
kenji S. Mivata, Ph.D. (0T3) Steven W.H. Hwang, B.Sc. (0T3)
Carol Durno, M.D.
Shoba Subramanian, B.Sc. (0T3)
Patrick Gullane, M.D.
Junior Associate Editors Piero Tartaro, B.Sc. (0T3)
Stanley Liu, Ph.D. (0T4) Mohammed T. 1 Iussain, B.Sc. (0T2)
.Andrea Molckovsky, M.Sc. (0T4) Morning Report Editors Nancy McKee, M.D.
(amic 1. Spiegelman, B.Sc. (0T4) Martin C. Chang, Ph.D. (0T3) Maria Muraca, M.Sc. (0T3)
karol Wroblewski, M.Sc. (0T4) Catherine Chung, B.Sc. (0T3) Ted Myers, Ph.D.
David Naylor, M.D., D.Phil.
Layout Editor Senior Technology Review Editor Blake Papsin, M.D.
Andrea E. Waddell, B.Sc. (0T3) Victor X.D. Yang, M.A.Sc. (MD/PhD3)
Sarah Pinto, B.Sc. (0T3)
Peter Ray, M.D., Ph.D.
Managing Editors Book Review Editor
Steve Scherer, Ph.D.
Mohammed Ali Warsi, M.Sc. (0T3) Irfan A. Dhalla, B.A.Sc. (0T3)
Andrew Schumacher, Ph.D. (0T1)
Sharon Cushing, B.Sc. (0T3)
Anand GoAindarajan, B.Sc. (0T3) Senior Copy Editors Nicholas Tan, B.Sc. (0T3)
Natalie kontakos, B.Sc. (0T3) Paul ). Belletruttd, B.Sc. (0T3) David B. Yan, M.D.
Philip M. Buckler, B.Sc. (0T3)
Dawn Owen, B.Sc., (MD/PhD2)
Junior Managing Editor Faculty Advisory Board
Larry' Pan, B.Sc. (0T4)
Chair, Allan S. Dctsky, M.D., Ph.D.
Junior Copy Editors
Jane Aubin, Ph.D.
Timothy 1 lanna, B.Sc. (0T4)
Treasurer
Tony Lee, B.Sc. (0T4) Michael Baker, M.D.
Christopher A.k.Y. Chong, B.Sc. (0T3)
Amv E. Lin, B.Sc. (0T4) John Challis, Ph.D., D.Sc.
Anil J. Misir, B.Sc. (0T4) Jay S. keystone, M.D.
Art Directors
Christina R. Tunzi, M.Sc. (0T4)
Murray krahn, M.D.
Andree |enks, B.Sc. (M.Sc. BMC, 0T1)
June Ma, B.Sc. (0T4)
Victoria Rowsell, B.Sc. (M.Sc. BMC, 0T1) Anthony Lang, Ph.D.
David Naylor, M.D., D.Phil.
Webmaster
Senior News and Views Editors Errol Colak, B.Sc. (0T3) Donald Redelmeier, M.D.
Philippe L. Bedard, B.ArtsSc. (0T3) Duncan Stewart, M.D.
Steve k. Singh, B.Sc. (0T3)
Junior Webmasters Sharon E. Straus, M.D.
Olivia Y.Y Cheng, B.Sc. (0T4) Donald Stuss, Ph.D.
News and Views Series Editors
Ian Tannock, Ph.D.
Murrav J. Beuerlein, M.Sc. (0T3)
Historical Review Editors
Bryce Taylor, M.D.
Christopher ). Hall, (0T3) Jewel Samadder, B.Sc. (0T3)
John Trachtenberg, M.D.
Manish Shah, B.Sc. (0T3) Vladislav Miropolsky, B.Sc. (0T3)
Rohit Bose, B.Sc. (MD/PhD2) Donald Wasylenki, M.D.
Junior H istorical Review Editors
Ji nior News and Views Editors Charis kepron, M.Sc. (0T4)
karoon C. Danavan, B.Sc. (0T4) Peter Zakrzewski, B.Sc. (0T4) T\ tesetting
Ann M. Stewart, M.Sc. (0T4) Type and Graphics
UTMJ
Crossword Editors
Sarah A. Shaikh, B.Sc. (0T3)
rail: [email protected] • http://www.utmj.org • Phone: [phone] • Fax: [phone]
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The Editors apologise for any
Dr. Jay S. Keystone Dr. James Mahoney Hospital for Sick Children
omissions to the above list;
Dr. Peter Liu Dr. Jack Mandel Dr. Richard J. Inman
this list represents our final
Dr. Hugh D. McGowan Dr. Jaanus Marley Dr. Michael A.S. Jewett
version at press time. We
Dr. Martin McKneally Dr. J. T. Marotta Dr. Moira Kapral
will update the list in future
Dr. Murray Krahn
Dr. David McNeely Dr. R. Maunder
issues.
Dr. Bernard Langer
volume 78, number 3, May 2001 179
Preface from the Editors
The final 2000-2001 issue of the l TMJ showcases a wide vari¬ a classic case of an unusual metabolic disease. For the
ety of articles that are sure to provide topics of interest for technophiles among us, hardware and software aspects of hand¬
everyone. It begins with an overview of the Human Genome held personal digital assistants (“PDAs”) are explored, with a
Project that separates fact from fiction in discussing the impact thorough review of the technology to date. Rounding off this
ot the project's results on biomedical research. Friedman et al. final issue is an examination of the realities and misconceptions
review acromegaly, from its molecular pathophysiology to its surrounding Canada’s postulated brain drain, followed by a
clinical presentation and recent advances in treatment. The series of book reviews, ranging from pathophysiology to fiction
review’s scope will engage everyone from the undifferentiated - books that would be welcome additions to any collection.
reader to the experienced endocrinologist. Kerba then provides
us with an in-depth analysis of health-related quality of life and With this last issue of the 78th volume, our tenure as editors
utility theory'. The final review article by Kundhal et al, probes comes to an end. We would like to take this opportunity to
the issues surrounding Crohn’s disease in the pediatric popula¬ acknowledge those who ha\^e played a part in the continuing
tion, and reports on the numerous etiological factors implicat¬ success of the UTMJ. Our staff, writers and editors alike, truly
ed in this form ot inflammatory bowel disease. From human form the heart and soul of the journal, and without their con¬
genetics to internal medicine to community health, these feature tributions this venture would have been impossible. Their
articles arc sure to appeal to a broad range of medical trainees commitment to the UTMJ over this past year has been instru¬
and professionals. mental to the journal’s success, and we commend their efforts.
As well, we would like to acknowledge our faculty advisory
In our Prolific Clinician Profile, we interview esteemed board for their support, especially the chair of the board. Dr.
Professor of Surgery', Tirone David. As a world-class cardiac Allan Detsky, who has provided invaluable support for the
surgeon. Dr. David has gained internadonal acclaim for his clin¬ UTMJ since his mandate began. This issue features a newly-cre¬
ical research. The Law and Ethics section features a timely dis¬ ated Awards page to acknowledge those individuals who have
cussion on the issue of medical students’ ability to speak out gone above and beyond the call of duty to enhance the quality
about their supervisors’ improprieties. In this piece, Misir dis¬ of the journal. Lasfiy, we would like to thank our subscribers
cusses the intricacies of coping with unethical behaviour as a who, with their continued contributions, have allowed Canada’s
medical trainee. The Forum probes the issue of physician report oldest student-run medical journal to thrive and blossom into a
cards, with perspectives from both medical students and physi¬ highly regarded publication for all health professionals and stu¬
cians. ()ur News and Views section concludes with back-to- dents to enjoy.
back Back-to-Basics articles. The first is the conclusion of a
two-part series on acid-base disturbances, this time reviewing As we hand off the editorial torch, wc look forward to the
alkalemias and mixed disturbances. The second primer explores promising future of the UTMJ. With its newly revamped web¬
the management of burn injuries, and provides an excellent site (yvww.utmj.org) and its growing subscriber base, its ascent
approach for treating minor burns. has only begun. We feel confident that the journal will con¬
tinue to grow in its role as a medium for student publishing and
In this issue, the Clinicopathological Correlation examines an medical education.
unwanted traveling companion, as it deh'es into the differential
diagnosis of a fixed, painful cutaneous nodule. Quick Prateek Lala
Diagnosis takes a pediatric turn with case reports taken from Valerie Panet-Raymond
Hospital for Sick Children; fascinating dermatological, Editors-in-Chief
at’.logical and infectious disease cases are also presented.
■ Morning Report takes the reader to the bedside, reviewing
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Lipitofc
ATORVASTAT/N CALCIUM
EFFICACY TO REACH TARGET THE FIRST TIME
-LIPITOR* LIPITOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past
history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of
10 mg, 20 nig and 40 mg tablets LIPITOR; if such a condition should develop during therapy, the drug should be discontinued.
THERAPEUTIC CLASSIFICATION: Lipid Metabolism Regulator Muscle Effects
ACTIONS AND CLINICAL PHARMACOLOGY Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokmase (CPK)
LIPITOR atorvastatin calcium) is a synthetic lipid lowering agent It is a selective, competitive inhibitor of 3-hydroxy 3- values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse
inethyigiutaryl coenzyme A (HMG-CoA) reductase This enzyme catalyzes the conversion of HMG-CoA to mevalonate, myalgia, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report
which is an early and rate-limiting step in the biosynthesis of cholesterol. promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. LIPITOR
therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
l IPITOR owers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in
the liver and by increasing the number of hepatic Low Density Lipoprotein (LDL) receptors on the cell-surface for The risk of myopathy and rhabdomyolysis during treatment with HMG CoA reductase inhibitors is increased with
enhanced uptake and catabolism of Low Density Lipoprotein (LDL). concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, clarithromycin, niacin (nicotinic acid), azole
antifungals or nefazodone. As there is no experience to date with the use of LIPITOR given concurrently with these drugs,
LIPITOR reduces LDL Cholesterol (LDL C) and the number of LDL particles. LIPITOR also reduces Very Low Density
with the exception of pharmacokinetic studies conducted in healthy subjects with erythromycin and clarithromycin, the
Lipoprotein Cholesterol (VLDL-C), serum tnglycendes (TG) and Intermediate Density Lipoproteins (IDL), as well as the
benefits and risks of such combined therapy should be carefully considered (see PRECAUTIONS, Pharmacokinetic
number of apolipoprotein B (apo B) containing particles, but increases High Density Lipoprotein-Cholesterol (HDL-C).
Interaction Studies and Potential Drug Interactions). Rhabdomyolysis has been reported in very rare cases with LIPITOR
Elevated serum cholesterol due to elevated LDL C is a major risk factor for the development of cardiovascular disease.
(see PRECAUTIONS, Drug Interactions).
Elevated plasma TG is also a nsk factor for cardiovascular disease, particularly if due to increased IDL, or associated with
decreased HDL-C or increased LDL-C. Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has also been reported with HMG-CoA reductase
inhibitors. LIPITOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within t to 2 hours.
suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to
Atorvastatin tablets are 95% to 99% bioavailable compared to solutions.
rhabdomyolysis (such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and
Mean distribution of atorvastatin is approximately 381 litres. Atorvastatin is >98% bound to plasma proteins. Atorvastatin
electrolyte disorders, and uncontrolled seizures).
is extensively metabolized by cytochrome P-450 3A4 to ortho and para hydroxylated derivatives and to various beta-
oxidation products. Approximately 70% of circulating inhibitory activity for HMG Co-A reductase is attributed to active PRECAUTIONS
metabolites General
Atorvastatin and its metabolites are eliminated by biliary excretion. Less than 2% of a dose of atorvastatin is recovered The effects of atorvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol
in urine following oral administration. Mean plasma elimination half-life of atorvastatin in humans is approximately on cardiovascular morbidity or mortality or total mortality have not been established.
14 hours, but the half life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of longer- Before instituting therapy with LIPITOR (atorvastatin calcium), an attempt should be made to control elevated serum
lived active metabolites. lipoprotein levels with appropriate diet, exercise, and weight reduction in overweight patients, and to treat other
INDICATIONS AND CLINICAL USE underlying medical problems (see INDICATIONS AND CLINICAL USE). Patients should be advised to inform subsequent
LIPITOR (atorvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the American Heart Association physicians of the prior use of LIPITOR or any other lipid-lowering agents.
(AHA) Step 1 diet, for the reduction of elevated total cholesterol, (total-C), LDL-C, TG and apolipoprotein B (apo B) in Effect on the Lens
hyperlipidemic and dyslipidemic conditions, when response to diet and other nonpharmacological measures alone has
Current long-term data from clinical trials do not indicate an adverse effect of atorvastatin on the human lens.
been inadequate, including:
Effect on Ubiquinone (CoQio) Levels
• Primary hypercholesterolemia (Type lla).
• Combined (mixed) hyperlipidemia (Type lib), including familial combined hyperlipidemia, regardless of whether Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been
cholesterol or triglycerides are the lipid abnormality of concern; observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been
established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac
• Dysbetalipoproteinemla (Type III)
function in patients with borderline congestive heart failure (see SELECTED BIBLIOGRAPHY).
• Hypertriglyceridemia (Type IV).
Effect on Lipoprotein (a)
• Familial hyiiercholesterolemia (homozygous and heterozygous). For homozygous familial hypercholesterolemia, LIPITOR
should be used as an adjunct to treatments such as LDL apheresis, or as monotherapy if such treatments are not available. In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a
concomitant increase in Lp(a) levels. Until further experience is obtained, it is suggested, where feasible, that
In clinical trials. LIPITOR (10 to 80 mg/day) significantly improved lipid profiles in patients with a wide variety of
measurements of serum Lp(a) be followed up in patients placed on atorvastatin therapy (see SELECTED BIBLIOGRAPHY).
hyperlipidemic and dyslipidemic conditions In 2 dose-response studies in mildly to moderately hyperlipidemic patients
(Fredrickson Types lla and lib), LIPITOR reduced the levels of total cholesterol (29-45%), LDL-C (39-60%), apo B Hypersensitivity
(32-50%), TG (19-37%), and increased high density lipoprotein cholesterol (HDL-C) levels (5-9%). Comparable responses An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included
were achieved in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, 1 or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia
combined hyperlipidemia, including familial combined hyperlipidemia and patients with non-insulin dependent diabetes rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA. ESR increase,
mellitus In patients with hypertriglyceridemia (Type IV), LIPITOR (10 to 80 mg daily) reduced TG (25 - 56%) and LDL-C eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic
levels (23 ■ 40%). Chylomicrons, which characterize Types I and V, have not been measured in clinical studies In patients epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Although to date hypersensitivity
with high TG levels (>11 mmol/L). syndrome has not been described as such, LIPITOR should be discontinued if hypersensitivity is suspected.
In an open-label study in patients with dysbetalipoproteinemia (Type III), LIPITOR (10 to 80 mg daily) reduced total-C
Use in Pregnancy
(40-57%), TG (40-56%) and IDL-C + VLDL-C levels (34-58%).
LIPITOR is contraindicated during pregnancy (see CONTRAINDICATIONS).
In an open label study in patients with homozygous familial hypercholesterolemia (FH) LIPITOR (10 to 80 mg daily)
reduced mean LDL-C levels (22%). In a pilot study, LIPITOR 80 mg/day showed a mean LDL-C lowering of 30% for Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little
patients not on plasmapheresis and of 31 % for patients who continued plasmapheresis. A mean LDL-C lowering of 35% impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of
was observed in receptor defective patients and of 19% in receptor negative patients (see PHARMACOLOGY, Clinical cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell
Studies). membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other
biologically active substances derived from cholesterol, they may cause harm to the fetus when administered to pregnant
For more details on efficacy results by pre defined classification and pooled data by Fredrickson types, see
women.
PHARMACOLOGY, Clinical Studies.
There are no data on the use of LIPITOR during pregnancy. LIPITOR should be administered to women of childbearing
Prior to initiating therapy with LIPITOR. secondary causes should be excluded for elevations in plasma lipid levels
age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient
(e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease,
and alcoholism), and a lipid profile performed to measure total cholesterol, LDL-C, HDL-C, and TG. For patients with becomes pregnant while taking LIPITOR, the drug should be discontinued and the patient apprised of the potential risk
TG <4.52 mmol/L (<400 mg/dL), LDL-C can be estimated using the following equation: to the fetus.
LDL-C (mmol/L) = total-C - [(0.37 x (TG) + HDL-C)] Nursing Mothers
LDL-C (mg/dL) = total-C - [(0.2 x (TG) + HDL-C)]1 In rats, milk concentrations of atorvastatin are similar to those in plasma. It is not known whether this drug is excreted
For patients with TG levels >4.52 mmol/L (>400 mg/dL), this equation is less accurate and LDL-C concentrations should in human milk. Because of the potential for adverse reactions in nursing infants, women taking LIPITOR should not
be measured directly or by ultracentrifugation. breast-feed (see CONTRAINDICATIONS).
The Atorvastatin Versus Revascularization Treatments (AVERT) study examined the effect of intensivre lipid-lowering Pediatric Use
in patients with stable coronary artery disease and LDL-C at least 3.0 mmol/L in patients referred for percutaneous Treatment experience in a pediatric population is limited to doses of LIPITOR up to 80 mg/day for 1 year in 8 patients
transluminal coronary angioplasty (PTCA). Patients were randomised for 18 months to LIPITOR 80 mg daily or to PTCA with homozygous familial hypercholesterolemia. No clinical or biochemical abnormalities were reported in these patients.
with usual medical care which could include lipid metabolism regulators. The results of the AVERT study should be
Geriatric Use
considered as exploratory since several limitations may affect its design and conduct. In the medical-treated group with
LIPITOR there was a trend for a reduced incidence of ischemic events and time to first ischemic event. The results also Treatment experience in adults 70 years or older (N=221) with doses of LIPITOR up to 80 mg/day has demonstrated that
suggest that intensive treatment to target LDL -C levels with LIPITOR is additive and complementary to angioplasty the safety and effectiveness of atorvastatin in this population was similar to that of patients <70 years of age.
and would benefit patients referred for this procedure (see SELECTED BIBLIOGRAPHY). Pharmacokinetic evaluation of atorvastatin in subjects over the age of 65 years indicates an increased AUC. As a
precautionary measure, the lowest dose should be administered initially (see PHARMACOLOGY, Human
CONTRAINDICATIONS Pharmacokinetics; SELECTED BIBLIOGRAPHY).
Hypersensitivity to any component of this medication.
Renal Insufficiency
Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of
normal (see WARNINGS). Plasma concentrations and LDL-C lowering efficacy of LIPITOR was shown to be similar in patients with moderate renal
Pregnancy and lactation (see PRECAUTIONS) insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have
been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and
WARNINGS pending further experience in renal disease, the lowest dose (10 mg/day) of LIPITOR should be used in these patients.
Pharmacokinetic Interactions Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mLYmin (<0.5 ml_/sec)];
The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rtiabdomyolysis, which the lowest dosage should be used and implemented cautiously (see WARNINGS, Muscle Effects; PRECAUTIONS,
may be mote frequent when they are co administered with drugs that inhibit the cytochrome P-450 enzyme system. Drug Interactions).
Atorvastatin is metabolized by cytochrome P-450 isoform 3A4 and as such may interact with agents that inhibit this Refer also to DOSAGE AND ADMINISTRATION.
enzyme. (See WARNINGS, Muscle effects and PRECAUTIONS, Drug Interactions and Cytochrome P-450-mediated
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or
Hepatic Effects gonadal steroid production. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that
■ i s. pe'sistent increases in serum transaminases greater than three times the upper limit of normal occurred these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma
i 1% ' patients who received LIPITOR When the dosage of LIPITOR was reduced, or when drug treatment was testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in
■ or discontinued, serum transaminase levels returned to pretreatment levels. The increases were adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.
■ assrx ated with jaundice or other clinical signs or symptoms. Most patients continued treatment with a Patients treated with atorvastatin who develop clinical evidence of endocrine dysfunction should be evaluated
- . ed dose of LIPITOR without clinical sequelae. appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol
on : u- ;;>ert.-i-ni.!d before the initiation of treatment, and periodically thereafter. Special attention levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may
1 ■!'!-- : > who develop elevated serum transaminase levels, and in these patients measurements should decrease the levels of endogenous steroid hormones.
>- • • ■ ’: ironptty and then performed more frequently
Pharmacokinetic Interaction Studies and Potential Drug Interactions
i alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of Pharmacokinetic interaction studies conducted with drugs in healthy subjects may not detect the possibility of a
'icularly if they rise to greater than 3 times the upper limit of normal and are persistent, the potential drug interaction in some patients due to differences in underlying diseases and use of concomitant medications
Mould be reduced or the drug discontinued. (see also Geriatric Use; Renal Insufficiency; Patients with Severe Hypercholesterolemia).
Bitii 489 5C
Concomitant Therapy with Other Lipid Metabolism Regulators: Combined drug therapy should be approached (AHA) Step 1 diet] before receiving LIPITOR, and should continue on this diet during treatment with LIPITOR.
with caution as information from controlled studies is limited. If appropriate, a program of weight control and physical exercise should be implemented.Primary Hypercholesterolemia
and Combined (Mixed) Hyperlipidemia, Including Familial Combined Hyperlipidemia The recommended dose of LIPITOR
Bile Acid Sequestrants:
is 10 mg once a day. The majority of patients achieve and maintain target cholesterol levels with LIPITOR 10 mg/day.
Patients with mild to moderate hypercholesterolemia: LDL-C reduction was greater when LIPITOR 10 mg and colestipol 20 g
A significant therapeutic response is evident within two weeks, and the maximum response is usually achieved within two
were coadministered (-45%) than when either drug was administered alone (-35% for LIPITOR and -22% for colestipol).
to four weeks. The response is maintained during chronic therapy.
Patients with severe hypercholesterolemia: LDL-C reduction was similar (-53%) when LIPITOR 40 mg and colestipol 20 g
Doses can be given at any time of the day, with or without food, and should preferably be given in the evening. Doses should
were coadministered when compared to that with LIPITOR 80 mg alone. Plasma concentration of atorvastatin was lower
be individualized according to baseline LDL-C and/or TG levels, the desired LDL-C and/or TG target (see the Detection and
(approximately 26%) when LIPITOR 40 mg plus colestipol 20 g were coadministered compared with LIPITOR 40 mg alone.
Management of Hypercholesterolemia. Working Group on Hypercholesterolemia and other Dyslipidemias [Canada] and/or
However, the combination drug therapy was less effective in lowering the triglycerides than LIPITOR monotherapy in both the US National Cholesterol Education Program (NCEP]), the goal of therapy and the patient's response. Adjustments of
types of hypercholesterolemic patients (see PHARMACOLOGY, Clinical Studies), dosage, if necessary, should be made at intervals of four weeks or more. The recommended dose range for most patients
When LIPITOR is used concurrently with colestipol or any other resin, an interval of at least two hours should be is 10 to 40 mg/day. The maximum dose is 80 mg/day, which may be required in a minority of patients (see section below).
maintained between the two drugs, since the absorption of LIPITOR may be impaired by the resin.
Lipid levels should be monitored periodically and, if necessary, the dose of LIPITOR adjusted based on
Fibric Acid Derivatives (Gemfibrozil, Fenofibrate, Bezafibrate) and Niacin (Nicotinic Acid): Although there is no target lipid levels recommended by guidelines.
experience with the use of LIPITOR given concurrently with fibric acid derivatives and niacin, the benefits and risks of such The following reductions in total cholesterol and LDL-C levels have been observed in two dose-response studies, and may
combined therapy should be carefully considered. The risk of myopathy during treatment with other drugs in this class is serve as a guide to treatment of patients with mild lo moderate hypercholesterolemia.
increased with concurrent administration (see WARNINGS, Muscle Effects)
TABLE 2. Dose-Response in Patients With Mild to Moderate Hypercholesterolemia
Coumarin Anticoagulants: LIPITOR had no clinically significant effect on prothrombin time when administered to (Mean Percent Change from Baseline)1
patients receiving chronic warfarin therapy (see SELECTED BIBLIOGRAPHY).
LIPITOR Dose (mq/day)
Digoxin: In healthy subjects, digoxin pharmacokinetics at steady-state were not significantly altered by coadministration
of digoxin 0.25 mg and LIPITOR 10 mg daily, However, digoxin steady-state concentrations increased approximately 20% 10 20 40 80
following coadministration of digoxin 0.25 mg and LIPITOR 80 mg daily (see Human Pharmacokinetics). Patients taking (N=22) (N=20) (N=21) (N=23)
digoxin should be monitored appropriately. Total-C: 7.1 mmol/L1
-29 -33 -37 -45
Antihypertensive agents (amlodipine): In clinical studies, LIPITOR was used concomitantly with antihypertensive (273 mq/dL)1'
agents without evidence to date of clinically significant adverse interactions. In healthy subjects, atorvastatin LDL-C: 4.9 mmol/L' -39 -43 -50 -60
pharmacokinetics were not altered by the coadministration of LIPITOR 80 mg and amlodipine 10 mg at steady state (190 mq/dL)"
(see Human Pharmacokinetics).
Results are pooled from 2 dose-response studies.
Oral Contraceptives and Hormone Replacement Therapy: Coadministration of LIPITOR with an oral contraceptive,
"Mean baseline values.
containing 1 mg norethindrone and 35pg ethinyl estradiol, increased plasma concentrations (AUC levels) of norethindrone
and ethinyl estradiol by approximately 30% and 20%, respectively. These increases should be considered when selecting
Severe Dyslipidemias:
an oral contraceptive. In clinical studies, LIPITOR was used concomitantly with estrogen replacement therapy without
In patients with severe dyslipidemias, including homozygous and heterozygous familial hypercholesterolemia and
evidence to date of clinically significant adverse interactions.
dysbetalipoproteinemia (Type III), higher dosages (up to 80 mg/day) may be required (see WARNINGS, Pharmacokinetic
Antacids: Administration of aluminum and magnesium based antacids, such as MaaloX" TO Suspension, with LIPITOR Interactions, Muscle Effects; PRECAUTIONS, Drug Interactions)
decreased plasma concentrations of LIPITOR by approximately 35%, LDL-C reduction was not altered but the triglyceride¬
Concomitant Therapy
lowering effect of LIPITOR may be affected
See PRECAUTIONS, Drug Interactions.
Cimetidine: Administration of cimetidine with LIPITOR did not alter plasma concentrations or LDL-C lowering efficacy of
LIPITOR, however, the triglyceride-lowering effect of LIPITOR was reduced from 34% to 26%. Dosage in Patients With Renal Insufficiency
See PRECAUTIONS.
Cytochrome P-450-mediated Interacbons: Atorvastatin is metabolized by the cytochrome P-450 isoenzyme, CYP 3A4.
Erythromycin, a CYP 3A4 inhibitor, increased atorvastatin plasma levels by 40%. Coadministration of CYP 3A4 inhibitors, such PHARMACEUTICAL INFORMATION
as grapefruit juice, some macrolide antibiotics (i.e. erythromycin, clarithromycin), immunosuppressants (cyclosporine), azole
Drug Substance
antifungal agents (i.e. itraconazole, ketoconazole), or the antidepressant, nefazodone, may have the potential to increase
Proper Name: Atorvastatin calcium
plasma concentrations of HMG-CoA reductase inhibitors, including LIPITOR (see SELECTED BIBLIOGRAPHY). Caution should
Chemical Name: [R-(R',R*)]-2-(4-fluorophenyl)-B, 5-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-
thus be exercised with concomitant use of these agents (see WARNINGS, Pharmacokinetic Interactions, Muscle Effects;
1 H-pyrrole-1 -heptanoic acid, calcium salt (2:1) trihydrate
PRECAUTIONS, Renal Insufficiency and Endocrine Function; DOSAGE AND ADMINISTRATION; SELECTED BIBLIOGRAPHY)
Empirical Formula: (C, ,HMFN;,0,,) ,Ca»3H.-,0
In healthy subjects, coadministration of maximum doses of both atorvastatin (80 mg) and terfenadine (120 mg), a
CYP 3A4 substrate, was shown to produce a modest increase in terfenadine AUC. The QTc interval remained unchanged. Molecular Weight: 1209.42
However, since an interaction between these two drugs cannot be excluded in patients with predisposing factors for Structural Formula: r ->
arrhythmia, (e.g. pre-existing prolonged QT interval, severe coronary artery disease, hypokalemia), caution should be
JL
exercised when these agents are coadministered (see WARNINGS, Pharmacokinetic Interactions; DOSAGE AND
ADMINISTRATION).
Antipyrine: Antipyrine was used as a non-specific model for drugs metabolized by the microsomal hepatic enzyme
system (cytochrome P-450 system), LIPITOR had no effect on the pharmacokinetics of antipyrine, thus interactions with
other drugs metabolized via the same cytochrome isozymes are not expected.
Macrolide Antibiotics (azithromycin, clarithromycin, erythromycin): In healthy adults, coadministration of
LIPITOR (10 mg QD) and azithromycin (500 mg QD) did not significantly alter the plasma concentrations of atorvastatin.
However, coadministration of atorvastatin (10 mg QD) with erythromycin (500 mg QID) or clarithromycin (500 mg BID),
which are both CYP 3A4 inhibitors, increased plasma concentrations of atorvastatin approximately 40% and 80%,
respectively (see WARNINGS, Muscle Effects; Human Pharmacokinetics). Description: Atorvastatin calcium is a white to off-white crystalline powder that is practically insoluble in aqueous
Patients with Severe Hypercholesterolemia: Higher drug dosages (80 mg/day) required for some patients with solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer and
severe hypercholesterolemia (including familial hypercholesterolemia) are associated with increased plasma levels of acetonitrile, slightly soluble in ethanol, and freely soluble in methanol.
atorvastatin Caution should be exercised in such patients who are also severely renally impaired, elderly, or
Tablet Composition:
are concomitantly being administered digoxin or CYP 3A4 inhibitors (see WARNINGS, Pharmacokinetic
Each tablet contains either 10 mg, 20 mg or 40 mg atorvastatin as the active ingredient. Each tablet also contains the
Interactions, Muscle Effects; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).
following non-medicinal ingredients: calcium carbonate, candelilla wax, croscarmellose sodium, hydroxypropyl cellulose,
Druq/Laboratorv Test Interactions lactose monohydrate, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol,
LIPITOR may elevate serum transaminase and CPK levels (from skeletal muscle). In the differential diagnosis of chest pain talc, titanium dioxide, polysorbate 80 and simethicone emulsion.
in a patient on therapy with LIPITOR, cardiac and noncardiac fractions of these enzymes should be determined.
Stability and Storage Recommendations:
ADVERSE REACTIONS
Store at controlled room temperature 15 to 25' C.
LIPITOR is generally well-tolerated. Adverse reactions have usually been mild and transient. In controlled clinical studies
(placebo-controlled and active-controlled comparative studies with other lipid-lowering agents) involving 2502 patients, AVAILABILITY OF DOSAGE FORMS
<2% of patients were discontinued due to adverse experiences attributable to LIPITOR. Of these 2502 patients, LIPITOR (atorvastatin calcium) is available in dosage strengths of 10 mg, 20 mg and 40 mg atorvastatin per tablet
1721 were treated for at least 6 months and 1253 for 1 year or more. 10 mg: White, elliptical, film-coated tablet, coded "10” on one side and "PD 155" on the other. Available in bottles of
Adverse experiences occurring at an incidence >1 % in patients participating in placebo-controlled clinical studies of 90 tablets.
LIPITOR and reported to be possibly, probably or definitely drug related are shown in Table 1 below: 20 mg: White, elliptical, film-coated tablet, coded "20" on one side and "PD 156" on the other. Available in bottles of
TABLE 1. Associated Adverse Events Reported in >1% of Patients in Placebo-Controlled Clinical Trials 90 tablets.
Placebo % (n=270) LIPITOR % (n=1122) 40 mg: White, elliptical, film-coated tablet, coded ”40" on one side and "PD 157" on the other. Available in bottles of
90 tablets.
GASTROINTESTINAL
Constipation 1 1 References:
1. Smith et at. Cost of Treating to a Modified European Atherosclerosis Society LDL-C Target - Comparison of Atorvastatin
Diarrhea 1 1
with Fluvastatin, Pravastatin and Simvastatin. Clin Drug Invest 1999 Mar.l 7(3):185-193. 2. LIPITOR (atorvastatin
Dyspepsia 2 1 calcium) Product Monograph, Pfizer Canada Inc., June 2000, 3, Bertolini S, Bitollo Bon G, Campbell LM, Farnier M,
Flatulence 2 1 Langan J, Mahla G, Pauciullo P, Sirtori C, Egros F, Fayyad R, Nawrocki J. The efficacy and safety of atorvastatin compared
Nausea 0 1 to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997:130:191 -197.4. Dart A, Jerums G, Nicholson
G, d'Emden M, Hamilton-Craig I, Tallis G, Best J, West M, Sullivan D, Braes P, Black D. A multicenter, double-blind, 1 -year
NERVOUS SYSTEM
study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol
Headache 2 1 1997;80:39-44. 5. Ontario Drug Benefit Formulary, April 1999.
MISCELLANEOUS
For a copy of the Product Monograph or full Prescribing Information, please contact:
Pain <1 1
Myalgia 1 1
Asthenia <1 1
The following additional adverse events were reported in clinical trials; not all events listed below have been associated
with a causal relationship to LIPITOR therapy: Muscle cramps, myositis, myopathy, paresthesia, peripheral neuropathy,
pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, rash, impotence, hyperglycemia, and
hypoglycemia.
Post-marketing experience: Very rare reports: severe myopathy with or without rhabdomyolysis (see WARNINGS, Muscle
Effects; PRECAUTIONS, Renal Insufficiency and Drug Interactions). Isolated reports: thrombocytopenia, arthralgia and allergic
reactions including urticaria, angioneurotic edema, anaphylaxis and bullous rashes (including erytheme multiforme,
Stevens-Johnson syndrome and toxic epidermal necrolysis). These may have no causal relationship to atorvastatin.
Ophthalmologic observations: see PRECAUTIONS.
Laboratory Tests: Increases in serum transaminase levels have been noted in clinical trials (see WARNINGS).
Life is our life's work
SYMPTOMS AND TREATMENT OF OVERDOSAGE ©2001
There is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient should be treated Pfizer Canada Inc.,
symptomatically and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, Kirkland, Quebec
hemodialysis is not expected to significantly enhance atorvastatin clearance. H9J 2M5
DOSAGE AND ADMINISTRATION *TM Pfizer Ireland Pharmaceuticals
Patients should be placed on a standard cholesterol-lowering diet [at least equivalent to the American Heart Association P(i“r Canada Inc., licensee
Biomedical Research
The Human Genome Project
Nicholas Tan, B.Sc. (0T3)
Abstract Introduction
Throughout this past year, the Human Genome Project has The Human Genome Project (HGP) was first conceived in the
attracted considerable public attention. Movie scriptwriters, mid-1980s by two prominent scientists, Robert Sinsheimer and
science fiction authors and the popular press alike have all Nobel laureate Renatto Dulbecco, to help in the fight against can¬
elaborated, inaccurately more often than not, the significance cer. In 1990, the HGP kicked off as a public joint international
of the Human Genome Project. This article seeks to present consortium including the United States of America, Asia, and
the facts concerning the history and results of the Human Europe, with funding coming from both government agencies and
Genome Project, as well as to discuss its immediate impact public charities (see Box l).1
on biomedical research.
Box 1
Member institutions of the Human Genome Sequencing Consortium
Baylor College of Medicine, Houston, Texas, USA
Beijing Human Genome Center, Institute of Genetics, Chinese Academy of Sciences, Beijing, China
Department of Molecular Biology, Keio University, Tokyo, Japan
Gesellschaft fur Biotechnologische Forschung GmbH, Braunschweig, Germany
Genome Analysis Group, International.
Genome Therapeutics Corporation, Waltham, MA, USA
Genoscope, Evry, France
Human Genome Center, Stanford, Palo Alto, CA, USA
Institute of Molecular Biotechnology, Department of Genome Analysis, Jena, Germany
Joint Genome Institute, U.S. Department of Energy, Walnut Creek, CA, USA
Lita Annenberg Hazen Genome Center, Cold Spring Harbor Laboratory, New York, USA
Max Planck Institute for Molecular Genetics, Berlin, Germany
National Human Genome Research Institute, NIH, MD, USA
RIKEN Genomic Sciences Center, Saitama, Japan
Stanford Genome Technology Center, Palo Alto, CA, USA
The Sanger Centre, Hinxton, U.K.
University of Oklahoma's Advanced Center for Genome Technology, OK, USA
The Institute for Systems Biology: Multimegabase Sequencing Center, Seattle, WA, USA
University of Texas Southwestern Medical Center at Dallas, Texas, USA
University of Washington Genome Center, Seattle, WA, USA
Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, USA
Washington University Genome Sequencing Center, St. Louis, MO, USA
84 University of Toronto Medical Journal