AmericanHeartAssociation

3" CC -9 ?P

StrokeA Journal of Cerebral Circulation

Volume 25, Number 4 April 1994

ContributionsCardiac Prognosis With Carotid Stenosis and No Coronary Disease • An Increase

in Carotid Lesions With Brain Ischemia in Japan • Paradoxical Embolism as a

Cause of Ischemic Stroke of Uncertain Etiology • Cardiac Sources of Embolism

With Pial Artery Infarcts and Lacunar Lesions • Patent Foramen Ovale and Brain

Infarct • Cardiovascular Autonomic Reflexes in Brain Infarction . Flow and

Velocity During Dynamic Autoregulation Testing • Major Depression With Silent

Cerebral Infarction • Probability of Stroke in the Copenhagen City Heart Study and

the Framingham Study • Influence of Age on Stroke Outcome • Elevated Serum

Cholesterol and Risk for Heart Disease and Stroke • Influence of Stroke Unit

Rehabilitation on Stroke Recovery . Lateralized CBF Response to CO2 in Crossed

Cerebellar Diaschisis • Regional CBF in Familial Hypercholesterolemia •

Mechanism of Anterior Choroidal Artery Territory Infarcts • Diffusion-Weighted

Imaging Differentiates Ischemic Tissue From Traumatized Tissue •

p53-lmmunoreactive Protein and p53 mRNA Expression After Arterial Occlusion •

Superoxide Dismutase Ameliorates Neuronal Death From Hypoxia in Culture •

Role of Superoxide Anions in Cerebral Vasospasm • Anti-Mac-1 Antibody Reduces

Cell Damage After Transient Artery Occlusion • Nitric Oxide Synthase Inhibition

Reduces Caudate Injury After Ischemia • Middle Cerebral Artery Occlusion Due to

Hydatid Cysts From the Heart • Neurovascular Manifestations of Heritable

Connective Tissue Disorders • Endothelin-1 and Pathogenesis of Cerebral

Vasospasm

Letters to the Editor • Abstracts of Literature

73-6105(SP) ISSN 0039-2499

AutomatedAssessment ofCerebrovascularCirculation

The MedaSonics CDSautomates the non-invasive assess-ment of cerebrovascular hemody-namics with transcranial Doppler.TCD is the only non-invasivemodality providing continuous,real-time, beat-to-beat cerebralblood flow velocity information.Automated TCD fromMedaSonics.. lor betterpatient care.

the

CALL: 1 (800) 227-8076 • in California: 1(800) 292-9966

CEREBROVASCULAR DIAGNOSTIC SYSTEM

MEDA /"CDS

FIFTH ANNUALDECADE OF THE BRAIN SYMPOSIUM

Significance and Basic Pathophysiology of StrokeDennis W. Choi, M.D., Ph.D.William A. Pulsinelli, M.D., Ph.D.Michael D. Walker, M.D.

Early Recognition and Diagnosis of StrokeThomas Brott, M.D.Louis R. Caplan, M.D.Richard E. Latchaw, M.D.

Early Treatment of StrokeThomas Brbtt, M.D.Dennis W. Choi, M.D., Ph.D.Myron D. Ginsberg, M.D.James C. Grotta, M.D.Roberto C. Heros. M.D.Edward D. Hall, Ph.D.Richard E. Latchaw, M.D.James T. Robertson, M.D.

OrganizersChairman: Dominick P. Purpura, M.D.

Dean, Albert Einstein College of MedicineModerator: Roberto C. Heros, M.D.

Lyle A. French Professor and Department Head,Department of NeurosurgeryUniversity of Minnesota Medical School

National Foundation for Brain ResearchLawrence S. Hoffheimer, Executive DirectorMorgan Downey, Associate DirectorTish Van Dyke, Symposium Director

"Stroke:Early Pathophysiology

and Treatment"

Sponsored byNational Foundationfor Brain Research

TUESDAY, MAY 10, 1994National Press Club

529 14th Street, N.W., 13th floorWashington, D.C.

Who Should Attend the Symposium?• Representatives of Voluntary Health Agencies• Representatives of Scientific and Professional

Societies• Representatives of Health Care Providers, including

Pharmaceutical Manufacturers, Medical Deviceand Equipment Manufacturers

• Health and Science Writers• Congressional Representatives and Staffs• Federal Officials and Staffs• Lay Public

FIFTH ANNUAL DECADE OF THE BRAIN SYMPOSIUM"Stroke: Early Pathophysiology and Treatment"

National Press Club, 529 14th Street, N.W., 13th floor, Washington, D.C.Tuesday, May 10, 1994

(Please print or type)

Name:*Mailing Address:*

Registration Fee: $40.00

Business Telephone:, , Affiliation:*.

*As you would like it to appear on name badge.The registration fee includes symposium materials, continental breakfast and lunch.Please make your check payable to NFBR and return by April 22. 1994 to:

The Fifth Annual Decade of the Brain SymposiumNational Foundation for Brain Research

1250 24th Street, N.W., Suite 30OWashington, D.C. 20037

If you have any questions, please call (202) 293-5453This Symposium is made possible by an educational grant from The Upjohn Company, with additional support from Du Pont

Radiopharmaceuticals and CIBA-GEIGY. The National Foundation for Brain Research acknowledges the American Heart Association for itscooperation with this symposium.

'American Heart AssociationNational Research Program

MinorityScientistDevelopmentAward

1995-1996To assist promising scientists who aremembers of ethnic groups under-represented in the fields of cardiovascularand stroke research (Black, Hispanic,Native American, and Pacific Islander) todevelop independent research programs.Junior faculty and clinical faculty seekingbasic research training may apply.

Application DeadlineReceipt June 1,1994for award activation July, 1995

Information: Division of Research AdministrationAmerican Heart Association7272 Greenville AvenueDallas, Texas 75231-4596

(214)706-1453(214)706-1341 (Fax)

4012 A

'American Heart AssociationNational Research Program

MedicalStudentResearchFellowship

1995-1996

Institutional award to attract promisingmedical students to careers incardiovascular or stroke research.Students engage in full-time research fora period of one year prior to graduation.

Application DeadlineReceipt June 1,1994for award activation July, 1995

Information: Division of Research AdministrationAmerican Heart Association7272 Greenville AvenueDallas, Texas 75231-4596

(214)706-1453(214)706-1341 (Fax)

Participation by women and minority candidates isencouraged.

4014 A

HARVARD MEDICAL SCHOOL: CONTINUING EDUCATION

CEREBRAL ANEURYSMS AND VASCULARMALFORMATIONS—1994 AND BEYOND

MAY 1&-21, 1994UNDER THE DIRECTION OF THE MASSACHUSETTS

GENERAL HOSPITAL BRAIN ANEURYSM/AVM CENTERDIRECTOR: ROBERT M. CROWELL, M.D.

CO-DIRECTORS: IN SUP CHOI, M.D., DARYL GRESS, M.D,CHRISTOPHER S. OGILVY, M.D.

LOCATION: SWISSOTEL, BOSTON, MAThis symposium includes the latest data on brain aneurysmsand vascular malformations. Special emphasis will be placedon efficacy and safety of current surgical or endovasculartechniques. Cooperation of neurologists, neurosurqeons,and interventional neuroradiologists will be stressed. Topicsinclude natural history and treatment of specific lesions. Weencourage faculty and participants to bring "routine" casesas well as complex problems to the course Tor the discussionsessions. CME credit awarded.

Bradley Buchbinder, M.D.Paul Chapman, M.D.In Sup Choi, M.D.

Issam Awad, M.D.Alex Berenstein, M.D.Robert Brown, M.D.Arthur Day, M D.Vmko Dolenc, M.D.Matthew Fink, M.D.

Harvard FacultyRobert Crowell, M.D.Daryl Gress, M.D.Christopher S. Ogilvy, M.D.

Guest FacultyJudah Folkman, M.D.Roberto Heros, M.D.Kevin Kiwak, M.D.Douglas Kondziolka. M.D.Jaques Moret, M.D.David Piepgras, M.D.

Robert Ojemann, M.D.Fred Scialabba, M.D.

Robert Solomon, M.D.Gary Steinberg, M.D.Philip Stieg, M.D.Charles Strother, M.D.Fernando Vinuela, M.D.David Wiebers, M.D.

FOR MORE INFORMATION CONTACT:The Harvard Medical School—Department of Continuing Education

Tel.: (617) 432-1525The MGH Brain Aneurysm/AVM Center

Massachusetts General Hospital, Boston, MA 02114Tel.: 1-800-888-1SAH

SECOND INTERNATIONALCONFERENCE ON

NEUROPROTECTIVE AGENTSClinical and Experimental Aspects

The Sagamore Resort, Lake George, New YorkSunday, July 31-Wednesday, August 3,1994ANNOUNCEMENT AND CALL FOR PAPERS

This conference will cover Clinical Syndromes,Mechanisms of Neuro-degeneration and injury,Antioxidants, Calcium Channel Antagonists,NMDA/Glutamate Antagonists, Sphingolipids,Animal Models of Neurodegeneration and otherresearch in Neuroprotective Agents.

We welcome and encourage contributions on allaspects of basic and clinical research in the fieldof neuroprotection.

This represents a satellite meeting of the XllthInternational Congress of Pharmacology, Mon-treal, July 24-30, 1994.

Contact: Bruce Trembly, M.D.Chief, NeurosurgeryUSVA Medical CenterTogus, Maine 04330TEL: 207-623-8411—FAX 207-623-5766

American HeartAssociationFighting Heart Disease

and Stroke

HypertensionPrimer Book

AvailableA new book entitled Hypertension Primer is now availablefrom the American Heart Association. The Primeris 370pages, and covers all aspects of hypertension from basicscience to clinical hypertension. It is also a useful adjuncttext for medical students. The editors are Joseph L. Izzo,MD and Henry R. Black, MD. There are 156 short, concisechapters divided into five major sections. The five sectionsand section editors are: Biochemistry and Cell Biology(Theodore L. Goodfriend, MD); Pathophysiology (James R.Sowers, MD and Franz H. Messerli, MD); Epidemiology,Prevention and Control (Jeffrey A. Cutler, MD, MPH);Evaluation of the Hypertensive Patient (Sheldon G. Sheps,MD); and Treatment of the Hypertensive Patient (DonaldVidt, MD). Each chapter is cross-referenced with otherlinked areas in different sections of the book. The Primeralso features extensive diagrams and tables.

The price is $34.95 plus $3.00 shipping and handling, forboth domestic and foreign orders. Foreign shipments will beby surface mail.

American HeartAssociationJFighting Heart Diseasem

Hypertension PrimerPlease Print

Name

Address

City State

Country

Master Card

Visa

Zip

_ Check/money orderenclosed (US dollarsdrawn on a US bank)

Account Number:

Expiration date: Month, Year

Signature as it appears on card HP94

Send order form to: Department of Finance,American Heart Association, 7272 Greenville Ave,Dallas, TX 75231.

3058

E THREAT OF STROK

EARLYINTERVENTION

TICLID...HELPS PREVENT STROKE(ticlopidine HCI)

• 48% more effective than aspirin (P=0.0004)to help prevent initial stroke in TIA patients at yeari*

• Effective first-line therapy for:Female TIA patients

Female patients at risk for recurrent strokeMale patients at risk for recurrent stroke

Although TICLID has been proven effective in male TIApatients (where aspirin is indicated to prevent stroke),it should be reserved as second-line therapy unless theyare intolerant to aspirin therapy.

In clinical trials, adverse effects were relatively frequent (over 50%).Most were mild, but 21% of patients taking TICLID discontinued therapy.The most serious adverse effect was neutropenia/agranulocytosis, whichmay be life threatening (see Warnings). CBC monitoring is required atbaseline and then every 2 weeks for at least the first 3 months of therapy.

*As demonstrated in TASS (Ticlopidine Aspirin Stroke Study).4

liclopidmeHCI 230mgTablets bid

HELPS SAVE LIVESPlease see brief summary ofprescribing informationon last page.

IclopidmeHCIZ7uEarly intervention with TICLID helps save lives• 48% more effective than aspirin " (P = 0.0004) to help prevent

initial stroke in TIA patients at year 1

The only drug indicated to help prevent recurrent stroke5

. Effective in women as well as men"

References: 1. Toote JF Cerebrovascular Disorders.4lhed New York Raven Press 1990 129.1452. Harbison JW Ticlopidme versus aspirin (or iheprevention of recurrent stroke analysis of patients withminor stroke from the TiclopiOine Aspirin Stroke StudyStroke 1992.23(12) 1723,1725 3. TICUD (ticiopidineHO) full prescribing information 4. Hass WK. EastonJD, Adams HP Jr et al A randomized trial comparingliclopidine hydrochloride with aspirin for trie preventionOf stroke m high-risk patients N Engl J Med 1989.321 (8)501-507 5. Geni M Easton JD Hachmski VC el alThe Canadian AmericanTiclopidtne Sludy (CATS)in thromboembolic stroke Lance! 1989,1 1215 1220

TICUD* (ticiopidine hydrochloride) TabletsBrief SummaryDESCRIPTION: TICUD' (ticiopidine hydrochloride) is a platelet aggregation inhibitor. Chemically it is 5-[{2-chlorophenyl) methyl]-4,5,6,7-tetrahydrothieno {3,2-c] pyridine hydrochloride.INDICATIONS AND USAGE TICUD is indicated to reduce the risk of thrombotic stroke (fatal or nonfatal) inpatients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke.Because TICUD is associated with a risk of neutropenia/agranulocytosis, which may be life-threatening (SeeWarnings), TICUD should be reserved for patients who are intolerant to aspirin therapy where indicated to pre-vent stroke. CONTRAINDICATIONS The use of T|CLID' is contraindicated in the following conditions:Hypersensitivity to the drug. Presence ot hematopoietic disorders such as neutropenia and thrombocytopenia.Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranialbleeding). Patients with severe liver impairment.

WARNINGS

NeutropeniaNeutropenia defined in these studies as an ANC <1200 neutrophils/mm* occurred in 50 of 2,048(2.4%) stroke patients who received TICLID in clinical trials.Severe Neutropenia (<450 neutrophlls/mm'):

Severe neutropenia and/or agranulocytosis occurred In 17 of the 2,048 (0.8%) patients whoreceived TICLID. When the drug was discontinued in these patients, the neutrophil countsreturned to normal (>1200 neutrophils/mm1) within 1-3 weeks.

Mild to Moderate Neutropenia (451-1200 neutrophilsimm'):Mild to moderate neutropenia occurred in 33 of the 2,048 (1.6%) patients who received TICUD.Eleven of the patients discontinued treatment and recovered within a few days. In the remaining22 patients, the neutropenia was transient and did not require discontinuation of therapy.

The onset of severe neutropenia occurred 3 weeks to 3 months after the start of therapy with TICLID,with no documented cases of severe neutropenia beyond that time in the large controlled trials. Thebone marrow typically showed a reduction In myelold precursors.

It is therefore essential that CBCs and white cell differentials be performed every two weeks, startingat baseline before treatment is initiated to the end of the third month of therapy with TICUD, butmore frequent monitoring is necessary for patients whose absolute neutrophil counts have beenconsistently declining or are 30% less than the baseline count. Because of the long plasma half-lifeof TICLID, it is recommended that any patient who discontinues TICLID for any reason within the first90 days continue to have CBC monitoring and white cell differential for at least another two weeksafter discontinuation of therapy.

Neutropenia (an absolute neutrophil count (ANC) of less than 1200 neutrophils/mm*) is calculated asfollows: ANC = WBC ¥ % neutrophils. If clinical evaluation and repeat laboratory testing confirm thepresence of neutropenia (<1200/mm>), the drug should be discontinued.In clinical trials, when therapy was discontinued immediately upon detection of neutropenia, theneutrophil counts returned to normal within 1-3 weeks.After the first three months of therapy, CBCs need be obtained only for patients with signs or symp-toms suggestive of Infection.

Thrombocytopenia Rarely, thrombocytopenia may occur in isolation or together with neutropenia. If clini-cal evaluation and repeat laboratory testing confirm the presence of thrombocytopenia (<80,000cells/mm1), the drug should be discontinued. Cholesterol Elevation: TICUD' therapy causes increasedserum cholesterol and triglycerides. Serum total cholesterol levels are increased 8-10% within one month of ther-apy and persist at that level. The ratios of the lipoprotein subtractions are unchanged. Other HematologicalEffects: Rare cases of pancytoperua and thrombotic thrombocytopenic purpura, some of which have been fatal,have been reported in Post-Marketing Surveillance. Anticoagulant Drugs: The tolerance and safety of coadmin-istration of TICLID with heparin, oral anticoagulants, or fibrinotytic agents has not been established. If a patient isswitched from an anticoagulant or fibrinotytic drug to TICUD, the former drug should be discontinued prior toTICUD administration. PRECAUTIONS General: TICUD should be used with caution in patients who may be atrisk of increased bleeding from trauma, surgery, or pathological conditions. If it is desired to eliminate theantiplatelet effects of TICLID prior to elective surgery, the drug should be discontinued 10-14 days prior tosurgery. Several controlled clinical studies have found increased surgical blood loss in patients undergoingsurgery during treatment with ticiopidine. In TASS and CATS it was recommended that patients have ticiopidinediscontinued prior to elective surgery. Several hundred patients underwent surgery during the trials, and noexcessive surgical bleeding was reported. Prolonged bleeding time is normalized within two hours after adminis-tration of 20 mg methylprednisolone i.v. Platelet transfusions may also be used to reverse the effect of TICUD onbleeding. Gl Bleeding: TICUD prolongs template bleeding time. The drug should be used with caution inpatients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesionsshould be used with caution in patients on TICLID. (See Contraindications.) Use in Hepatically ImpairedPatients: Because of limited experience in patients with severe hepatic disease, who may have bleeding diathe-ses, the use of TICLID is not recommended in this population. (See Clinical Pharmacology andContraindications.) Use in Renally Impaired Patients: There is limited experience in patients with renal impair-ment. In controlled clinical trials, no unexpected problems have been encountered in patients having mild renalimpairment and there is no experience with dosage adjustment in patients with greater degrees of renal impair-ment. Nevertheless, for renally impaired patients it may be necessary to reduce the dosage of ticfopidine or dis-continue it altogether, if hemorrhagic or hematopoietic problems are encountered. (See Clinical Pharmacology.)Information for the Patient (See PPI): Patients should be told that a decrease in the number of white bloodcelts (neutropenia) can occur with TICUD*, especially during the first three months of treatment, and that if neu-tropenia is severe, it could result in an increased risk of infection. They should be told ft is critically important toobtain the scheduled blood tests to detect neutropenia. Patients should also be reminded to contact their physi-cians if they experience any indication of infection such as fever, chills, and sore throat, aD of which may be con-sequences of neutropenia. AH patients should be told that it may take them longer than usual to stop bleedingwhen they take TICUD and that they should report any unusual bleeding to their physician. Patients should tedphysicians and dentists that they are taking TICUD before any surgery is scheduled and before any new drug isprescribed. Patients should be told to report promptly side effects of TICUD such as severe or persistent diar-rhea, skin rashes, or subcutaneous bleeding, or any signs of cholestasis, such as yellow skin or sctera, darkurine, or light colored stools. Patients should be told to take TICUD with food or just after eating in order to mini-mize gastrointestinal discomfort. Laboratory Tests: Liver Function: TICUD therapy has been associated withelevations of alkaline phosphatase and transamtnases which generally occurred within 1-4 months of therapy ini-tiation. In controlled clinical trials, the incidence of elevated alkaline phosphatase (greater than 2 times upperlimit of normal) was 7.6% in ticiopidine patients, 6.0% in placebo patients and 2.5% in aspirin patients. The inci-dence of elevated AST (SGOT) (greater than 2 times upper limit of normal) was 3.1% in ticiopidine patients, 4.0%in placebo patients and 2.1% in aspirin patients. No progressive increases were observed in closely monitoredclinical trials (e.g. no transaminase greater than 10 times the upper limit of normal was seen), but most patientswith these abnormalities had therapy discontinued. Occasionally patients had developed minor elevations inbilirubin. Based on post-marketing and clinical trials experiences, liver function testing should be consideredwhenever liver dysfunction is suspected, particularly during the first four months of treatment. DrugInteractions: Therapeutic doses of TICUD caused a 30% increase in the plasma half-life of antipyrine and maycause analogous effects on similarly metabolized drugs. Therefore the dose of drugs metabolized by hepaticmicrosomal enzymes with low therapeutic ratios, or being given to patients with hepatic impairment, may requireadjustment to maintain optimal therapeutic blood levels when starting ox stopping concomitant therapy withticiopidine. Studies of specific drug interactions yielded the following results: Aspirin: Aspirin did not modify thetidopidine-mediated inhibition of ADP-induced platelet aggregation, but ticiopidine potentiated the effect ofaspirin on collagen-induced platelet aggregation. The safety of this combination has not been established andconcomitant use of aspirin and ticiopidine is not recommended. (See Precautions - Gl Bleeding.) Antacids:Admirttstratton of TICUD after antacids resulted in an 18% decrease in plasma levels of ticiopidine. dmetidine:Chronic administration of cimetidine reduced the clearance of a single dose of TICUD by 50%. Digoxin: Co-admin-istration of TICUD with digoxin resulted in a slight decrease (approximately 15%) in digcodn plasma levels. Littleor no change in therapeutic efficacy of digoxin would be expected. Theophyttine: In normal volunteers, con-comitant administration of TICUD resulted in a significant increase in the theophyiline elimination half-life from

8.6 to 12.2 hr and a comparable reduction in total plasma clearance of theo-phyiline. Phenobarbital: In six normal volunteers, the inhibitory effects ofTICUD on platelet aggregation were not altered by chronic administration ofphenobarbital. Phenytoln: In vitro studies demonstrated that ticiopidinedoes not alter the plasma protein binding of phenytoin. However, the proteinbinding interactions of ticiopidine and its metabolites have not been studiedin vivo. Several cases of elevated phenytion plasma levels with associatedsomnolence and lethargy have been reported following co-adminsitrationwith TICUD. Caution should be exercised in coadministering this drug withTICUD and it may be useful to re-measure phenytoin blood concentrations.Propranolol: In vitro studies demonstrated that ticiopidine does not alter theplasma protein binding of propranolol. However, the protein binding interac-tions of ticiopidine and its metabolites have not been studied in vivo.Caution should be exercised in coadministering this drug with TICUD. OtherConcomitant Therapy: Although specific interaction studies were not per-formed, in clinical studies, TICUD was used concomitantJy with beta Mockers,calcium channel blockers, diuretics, and nonsterotdal anti-inflammatory drugswithout evidence of clinically significant adverse interactions. (SeePrecautions.) Food Interaction: The oral bioavailability of ticiopidine is

. increased by 20% when taken after a meal. Administration of TICUD withfood is recommended to maximize gastrointestinal tolerance. In controlled trials, TICUD was taken with meals.Carcinogenesis, Mutagenesis, Impairment of Fertility: In a two-year oral carcinogenictty study In rats, ticiopi-dine at daily doses of up to 100 mg/kg (610 mg/m*) was not tumorigenic. For a 70 kg person (1.73m* body sur-face area), the dose represents 14 times the recommended clinical dose on a mg/kg basis and 2 times the clini-cal dose on body surface area basis. In a 78 week oral carcinogenicity study in mice ticiopidine at dairy dosesup to 275 mg/kg (1180 mg/m*) was not tumorigenic. The dose represents 40 times the recommended clinicaldose on a mg/kg basis and 4 times the clinical dose on body surface area basis. Ticiopidine was not mutagenicin in vitro Ames test, rat hepatocyte DNA-repair assay, and Chinese hamster fibroblast chromosomal aberration testand in vivo mouse spermatozoid morphology test, Chinese hamster micronucleus test and Chinese hamster bonemarrow cell sister chromatid exchange test. Ticiopidine was found to have no effect on fertility of male and femalerats at oral doses up to 400 mg/kg/day. Pregnancy: Teratogenlc Effect: Pregnancy Category B. Teratologystudies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day) and rab-bits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice, and 100 mg/kg in rabbitsproduced maternal toxicity as well as fetal toxicity, but there was no evidence of a teratogenic potential of ticiopi-dine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal repro-duction studies are not always predictive of a human response, this drug should be used during pregnancy onlyif clearly needed. Nursing Mothers: Studies in rats have shown ticiopidine is excreted in the milk. It is not knownwhether this drug is excreted in human milk. Because many drugs are excreted in human milk and because ofthe potential for serious adverse reactions in nursing infants from ticiopidine, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother. Pediatric Use: Safety and efficacy in patients under the age of 18 have not been established. GeriatricUse: Clearance of ticiopidine is somewhat lower in elderly patients and trough levels are increased. The majorclinical trials with TICUD were conducted in an elderly population with an average age of 64 years. Of the totalnumber of patients in the therapeutic trials, 45% of patients were over 65 years old and 12% were over 75 yearsold. No overall differences in effectiveness or safety were observed between these patients and youngerpatients, and other reported clinical experience has not identified differences in responses between the elderlyand younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REAC-TION Adverse reactions were relatively frequent, with over 50% of patients reporting at least one. Most (30 to40%) involved the gastrointestinal tract. Most adverse effects are mild, but 21% of patients discontinued therapybecause of an adverse event, principally diarrhea, rash, nausea, vomiting, G.I. pain, and neutropenia. Mostadverse effects occur early in the course of treatment, but a new onset of adverse effects can occur after severalmonths. The incidence rates of adverse events listed in the following table were derived from multicenter, con-trolled clinical trials described above comparing TICUD, placebo, and aspirin over study periods of up to 5.8years. Adverse events considered by the investigator to be probably drug-related that occurred in at least onepercent of patients treated with TICUD are shown in the following table:

Percent of Patients with Adverse Events In Controlled Studies

Event

Any EventsDiarrheaNauseaDyspepsiaRashGIPainNeutropeniaPurpuraVomitingFlatulencePruritusDizzinessAnorexiaAbnormal liverFunction test

TICUD(n = 2048)Incidence

60.0 (20.9)12.5(6.3)7.0 (2.6)7.0(1.1)5.1 (3.4)3.7(1.9)2.4(1.3)2.2 (0.2)1.9(1.4)1.5(0.1)1.3 (0.8)1.1 (0.4)1.0(0.4)1.0(0.7)

Aspirin(n = 1527)Incidence

53.2 (14.5)5.2(1.8)6.2(1.9)9.0 (2.0)1.5(0.8)5.6(2.7)0.8(0.1)1.6(0.1)1.4(0.9)1.4(0.3)0.3(0.1)0.5 (0.4)0.5 (0 3)0.3 (0.3)

Placebo(n = 536)Incidence

34.3 (6.1)4.5(1.7)1.7(0.9)0.9 (0.2)0 6 (0.9)1.3(0.4)1.1 (0.4)0.0 (0.0)0.9 (0.4)0.0 (0.0)0.0 (0.0)0.0 (0.0)0.0 (0.0)0.0 (0.0)

Incidence of discontinuation, regardless of relationship therapy, is shown in parentheses.Neutropenta/Thrombocytopenia: See Warnings. Gastrointestlnal:TICUD therapy has been associated with avariety of gastrointestinal complaints including diarrhea and nausea. The majority of cases are mild, but about13% of patients discontinued therapy because of these. They usuaty occur within 3 months of initiation of thera-py and typically are resolved within 1-2 weeks without discontinuation of therapy. If the effect is severe or persis-tent therapy should be discontinued. Hemorrhagtc: TICUD has been associated with a number of bleedingcomplications such as eccnymosis, epcstaxis, hematuria, conjunctival hemorrhage, gastrointestinal bleeding andperioperative bleeding. intracerebraJ bleeding was rare in clinical trials with TICUD, with an incidence no greaterthan that seen with comparator agents. (Ticiopidine 0.5%, aspirin 0.6%. placebo 0.75%.) Rash: Ticiopidine hasbeen associated with a maculopapular or urticaria] rash (often with pruritus). Rash usually occurs within 3months of initiation of therapy, with a mean onset time of 11 days. If drug is discontinued, recovery occurs withinseveral days. Many rashes do not recur on drug rechallenge. There have been rare reports of severe rashes.Less Frequent Adverse Reactions (Probably Related): Clinical adverse experiences occurring in 0.5 to 1.0percent of patients in the controlled trials include: Digestive System: Gl fullness. Skin and Appendages: urticaria.Nervous System: headache. Body as a Whole: asthenia, pain. Hemostatic System: eptstaos. Special Senses:tinnitus. In addition, rarer, relatively serious events have also been reported, mainly from foreign post marketingexperience: Pancytopenta, hemotytic anemia with reticutocytosis, allergic pneumonitis, systemic lupus {positiveANA), peripheral neuropathy, vasculitis, serum sickness, arthropathy, hepatitis, cholestatic jaundice, nephroticsyndrome, myositis, hyponatremia, immune thrombocytopenia and thrombocytopenic thrombotic purpura(TTP). DOSAGE AND ADMINISTRATION The recommended dose of TICUD is 250 mg BID taken with food.Other doses have not been studied in controlled trials for these indications. CAUTION Federal law prohibits dis-pensing without prescription. See package insert for full prescribing information.

SYNTEXSYNTQC LABORATORIES, INC.PALO ALTO. CA 94304

U.S. Patent Nos. 4,051,1414; 4,591,59202-0431-0O01-BS AUGUST 1992

CB1993 SYNTEX LABORATORIES, INC.#205 Printed in USA.

International 6-DaySeminar on Congenital

Heart DiseasePathology and Cardiac

Development

American HeartAssociation^Fighting Heart Disease

and Stroke

Offered by the Council on Pediatric Cardiology of theInternational Society and Federation of Cardiology,

and The Councils on Cardiovascular Disease in theYoung and Cardio-Thoracic and Vascular Surgery of

the American Heart Association

The primary goal of the seminar is to provide an intensive intro-duction to the basic anatomy of the heart, the pathology ofcongenital heart disease and molecular genetic factors control-ling cardiac development There will be correlations betweenanatomy, angiocardiographic and 2-D ultrasound studiespresented. The seminar is designed for qualified health profes-sionals planning careers in research, teaching or practice inpediatric cardiology, cardiac surgery, cardiac pathology andcardiac development.

Faculty in pathology, pediatric cardiology, radiology, cardiacsurgery and cardiac development will present a series oflectures, discussions, laboratory and tutorial sessions. Up to 15international faculty and 30 selected candidates will participatein the seminar.

Candidates must ordinarily be at the postdoctoral level withsome residency training or its equivalent. Consideration forselection requires:

1) A completed signed application form (see attached form).

2) A letter of nomination from a sponsor from the candidate'sinstitution well acquainted with the candidate's experience,interests, fluency in spoken English and assuring the supportof the candidate's travel to and from the symposium.

3) A letter from the candidate indicating the basis for his or herinterest in the Seminar

4) The candidate's curriculum vitae.

Deadline for receipt of above materials is April 30,1994.

Note: Application represents a commitment to participate ifaccepted, in the full program, from Sunday July 17 throughFriday July 22, 1994. A deposit of $50 per person to covercurricular materials must be forwarded no later than June 15,1994 ($40 refundable until June 25, 1994).

Date: July 17-22,1994

Location: Minneapolis, Minnesota USA

Accommodations: The cost of single hotel accommodations,breakfast, luncheon and dinner will be paid by the organizationssponsoring the meeting.

Registration Fee: None

Accreditation: Meets the criteria for approximately 40 hours ofCategory I of the Physician's Recognition Award of the AMA.

For Additional Information, please contact Ronald M. Lauer, MD,Seminar Director, Scientific and Corporate Meetings, AmericanHeart Association, 7272 Greenville Avenue, Dallas, Texas75231-4596, Telephone: 214/706-1772, FAX: 214/373-3406.

Application Form:Please type or print the information requested below.

Name

Professional Title

Department/Division

University/Hospital/lnstitution

Street Address

City State. Zip Code.

Mailing Address_

(If different from above: where you can be reached between nowand the beginning of the Seminar)

Telephone _ Fax Number

Yes, my sponsor letter is enclosed.

Yes, my letter indicating the basis of my interest in theSeminar is enclosed.

Yes, a copy of my curriculum vitae is enclosed.

I, the undersigned, understand that the Seminar can accommo-date only a limited number of applicants and that an applicantwho declines after acceptance denies another worthy applicantthe opportunity to participate. I therefore assure the SeminarCommittee that, if accepted, I will participate in the full programof the Seminar beginning at 8:00 AM Sunday, July 17 through9:00 PM Friday, July 22,1994.

I understand that I or my sponsoring institution will be respon-sible for my travel costs to and from Minneapolis, Minnesota.

Signature. Date

Mail to: Ronald M. Lauer, MD , Seminar DirectorScientific and Corporate MeetingsAmerican Heart Association7272 Greenville AvenueDallas, TX 75231-4596Phone:214 706-1772

Applications must be received by April 30, 1994

3051

Transition to SI Units

At its October 1990 meeting the Scientific PublishingCommittee explored the use and prevalence of SystemeInternational (SI) units for reporting measures of clin-ical and laboratory data. The committee since hassanctioned the use of SI units in the American HeartAssociation (AHA) journals.

The SI, an update of the metric system, is theoutcome of a century of effort to provide a commonsystem of measurement between nations and among thesciences. To promote its use, which can reduce thepresent confusion about measurements, the WorldHealth Assembly in 1977 recommended the use of SIunits in medicine.

The SI base units are the meter, kilogram, second,ampere, kelvin, candela, and mole, respectively repre-senting length, mass, time, electric current, tempera-ture, luminous intensity, and amount of substance. Bymultiplying a base unit by itself, or by combining two ormore basic units by multiplication or division, manyunits can be formed, known as Si-derived units. Exam-ples of derived units are the square meter, cubic meter,mole per cubic meter, pascal (Pa), and joule (J).

Exceptions to the rule for SI unit conversion ascurrently applied to biomedical sciences include bloodpressure, oxygen pressure, and enzyme activity. Re-tained as presently used are temperature, the pH scale,and the use of liter for volume. Table 1 illustrates themeasurements excluded from SI unit conversion.

In the AHA journals, an average article contains fewitems that need conversion. Often the same conversionis made over and over in a manuscript and takes littleextra effort. It is our belief that, in return for a smalleffort, the AHA can take a large step, along with manyother international and domestic journals, toward per-petuating a common system for reporting medical andscientific measurements. The SI unit is to be used intext, followed by the presently used measurement inparentheses.

The accompanying conversion table (Table 2) lists themeasurements most commonly used in the AHA jour-

TABLE 1. Measurements Currently Not Convertedto Systeme International (SI) Units InBiomedical Applications

Measurement Current Unit

Blood pressure

Oxygen pressure

Enzyme activity

H+ concentration

Temperature

Volume

mm Hg

mm Hg

IU

PH

°C

L

nals and their corresponding SI units. A review of thistable may serve as an introduction to the forthcomingtransition to SI units.

TABLE 2. Examples of Measurement Conversions toSysteme International (SI) Units for American HeartAssociation Journals*

Normal LaboratoryValuest

ConversionCurrent Unit Factor SI Unit Current SI

Concentration

M (molar)

mM

Pressure

torr

atm

Hematocrit

Red bloodcell count

106/mm3

White bloodcell count

/mm3

Cholesterol

mg/dL

Sodium ion(Na+)

mEq/L

Potassium ion(K+)

mEq/L

Calcium ion(Ca2+)

mEq/L

Energy

Calories

Conductance

mho

1 mol/L

1 mmol/L

1 mm Hg

101.325 kPa

0.01 No units 36-54 0.36-0.54

1 10'2/L 4.0-6.0 4.0-6.0

0.001 109/L 5000-10 000 5.0-10.0

0.02586 mmol/L <200 <5.20

1 mmol/L 135-145 135-145

1 mmol/L 3.5-5.0 3.5-5.0

0.5 mmol/L 4.5-5.5 2.25-2.75

4.2 J

1 S*For a brief discussion of the development and use of SI units,

see World Health Organization: The SI for the Health Professions,Geneva, Switzerland: World Health Organization, 1982. For aconvenient list of commonly used laboratory measurement con-versions to SI units, see "SI unit implementation—the next step"(editorial) in JAMA (1988;260:73-76).

tFor illustration only; normal values may vary by laboratory.