AmericanHeartAssociation

DMPCINFORMATION SERViC

—y

ensionVolume 21, Number 6, Part 2 June 1993

Proceedings of the Council for HighBlood Pressure Research, 1992

Gregory D. Fink, PhDGuest Editor

Preface: Proceedings of the High Blood Pressure Council, 1992

Corcoran Lecture: Sympathetic Activity and Coronary Risk

Original Contributions: Gene Transfer into Vascular Cells • Prostaglandin Release in SHR

Smooth Muscle • Cardiac Distribution of Cytosolic 5'-Nucleotidase • Adrenal Kallikrein •

Endothelin Gene Expression in DOCA-Satt Rats • Captopril Inhibits Endothelin-1 Secretion •

Inactivatjon of Endothelin-1 by Endothelial Cells • Endothelial Function in Human

Hypertension • Nitric Oxide Synthase Expression in the Rat • Ethanol and Endothelial

Nitric Oxide Synthase • Sodium, Angiotensin, and Nitric Oxide Blockade • Nitric Oxide in

Angiotensin IHnduced Renal Vasoconstrictjon • Renal Interstitial Pressure and Nitric Oxide •

Wnin Effects on Renal Blood Row • Bradykinin and Atrial NatriuretJc Factor • Low Calorie

Diet and Progression of Renal Injury • Angiotensin II Blockade and Renal Injury • Wnins and

MineraJocortJcoid Hypertension • Clofibrate Lowers Pressure in Dahl Rats • Cations and

Adolescent Blood Pressure • Prazosin-lnduced Salt-Sensitive Hypertension •

Sympathoinhibibon by 2-Methylserotonin • /3-Receptor and Membrane Potential in

Hypertension • CGRP in the Spontaneously Hypertensive Rat • Insulin and Sympathetic

Vascconstriction • Thiazolidinedlones, Calcium Metabolism, and Hypertension •

Magnesium Deficiency and Insulin Resistance • Vascular Metabolism of Angiotenslnogen •

Adenytyl Cyclase and Renal Angiotensin • Angiotensin Receptor in Genetic Obesity •

Angiotensin IHnduced Hyperplasia • Fructose-induced Cardiac Hypertrophy • Intrarenai

Angiotensin II Antagonism • Angiotensin Receptor Antibody and Brain • Mitochondrial DNA

Divergence • Y Chromosome and Blood Pressure • Blood Pressures in Pedigreed Baboons

Awards: CIBA Award for Hypertension Research • Third Bnstol-Myers Squibb Lifetime

Achievement Award in Hypertension • Ninth Annual Marion Merreli Dow Hypertension Research

Clinical Fellowship Award • Harry GoWWatt Award in Cardiovascular Research • Merck Travel

Fellowship Award • New Fellows, Council for High Blood Pressure Research

73-2122(SP) ISSN 0194-911X

Now for heart rate control during atrial fibrillation and flutter

Injectablehydrochloricle][diltiozem

BO L U S

Heart rate control that is

FAST, SAFE, AND CONTINUOUS1

Cardlzem Injectable Is Indicated for temporary control of rapid ventricular rate during atrial fibrillation and flutter:rarely converts to normal sinus rhythm; should be used with continuous monitoring of ECG and blood pressure to avoid

hypotension or bradycardia. Infusion rate/dose should be regulated accordingly.A deflbrlllator and emergency equipment should be readily available.

'Symptomatic hypotension (3.2%) or flushing (1.7%) occurs most often during or immediately following bolus Injection.'Contraindications: atrial fibrillation and flutter patients with WPW or short PR syndrome; sick sinus syndrome or

second- or third-degree AV block, except with a functioning pacemaker; severe hypotension or shock: hypersensitMty:recent IV beta-blockers; ventricular tachycardia.

Please see the prescribing information on an adjacent page.

CIVAH058/A6584 0313C2

Mxaum us n m t nCAROiarin|«ctiUa(«tai»ydrod«rta)

CAHXZEM* ( o B t a a n h y * o d * ) r n a | < l a f c l m « rtn kraSIW | d w dunta 1 Mocbc orc a o j n c a n a l a t a j o a t t ) Charrtaly, M e n hydroatoirk k 1 M l ! : >ita1HHit**tyF!Jh»rt;*otack-.Ttadmlcaltraank:

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d

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ol CAADtZEa11) uprodroWy 305 L CAfJUZBi a U n M y iMbobd a tka har ««fi IPfTOnK QaWCV 01 a^il^d fluffy 05 L L

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n i l hioar coacattiwoni Oon t m d dHun aid n wri riadBictMy k itout 20 hoan ctnpnd B 2 B S Iran tor oVom.CARDLZEU It 70% to 10% boiod to p U w prottint IP Wtro ttudkl uggttt HpUriddgrfsaraaa trta nTtodnaaj 40% o( tte *ug a etaaly ajalart coanntkra. Aba*vpan to aal tppradraKy 30% ol la *uc » * otar raoauna t M la nranhg boadtridto. Contatt« k *ni lond b h * ( n d a ton tfon tot CAfBCai Mafeg k notatnd by tttmartt tmetmSoo ol dJooin, pranytoh, hyorocNororJaudl, hdoratdadn,phmytotraai, propnooU, afeyfc idd, t*ao™tt or w M iRanal nsiQdtncy, or tm md-filgt nnal diMtu, doa not ippor to ntlutnct dltiuwi

nldtotci and protoap Ki M Bt.

CWSIGEM h|aMk (olanii «y*«t*irlda) k h t a d tar la MMag.t • W F a a a a a > a M F M i r . TanoDn^criMolra^vtjMAnjkhiMbtafenor

n 9*r . I ahouU an bt aid a paaan «a arU bttfen a mi H*r saxaad »tt ai

a i i a tk i l a T « * r t » * . °J& corHnkm ol Hrmrml n i n a d c a utstyctnSn (PSVT) lo m a rnytln. ThU tadurja AV mxU nwrtiut tacrqrctrdla md

d l n g acfeycaito otodaai wDi ai o r t x d l m a n y Httmy tadi o t» WPW

bt at imal prior to i lnWtmoi ol CAAQCBi l nmha

or mi Mar or comnfen to >r«l rlytfcn h pdaO aU PSVT *o»J ba aidaraba »«iaJon • * » at paal k uimiomaad ' a i u ^ n r m r ot a atag otar angi l a Jtctaaay or H ol d» tatwhg; paiphtra1 roaaaca, nyoonlU ahg, mrooittaJ corftKXty, orMctncs hnputtt j y * ajVaajj TTTW In tit rvyocvou^F« Man Wot* aal Rrtcalali atai taaltTBf c a t a

r codtTDW trktt hi prihnti trifi (rW i x U k i i of atU bLK, taaaf rirnMiii'iUfin dCAKOIZai IM>diUi n (ItidM to ndgdag hurtrabyi lBBt2O%at:%gl onrxCAHXZEHI nUdMa ra«V COMA «rU rertHUn or mta U t » tg Hrral t a o rhythn

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Mat raaaaad a ast 120% tart Mi ndaam data la r i m c o% ot paMs. Upo»tftc^iftnutfrw ol arnBc a m nil ndKtJoa ray ktt ton 0J hotn B nun na to bon(nadon duress 7 boat) HypolonODi 11 oton, nay bt «a*rly [anktatto aa cotnlad drical M A 12% ol Hand nquhd tona torn of namattia (lypbly, aaot I r tmwf* ftuUl or t j | Tnad««nbirg potWoi) for brood irmort lupport folnrtogCAKXZM nkdtsk.)• domic codniaU tiUL botu irtattntiji olCAAOtZBil anfEtatit vsFWtlirtt»%dB>]rtta<rtWlynrrtrTfn mnrtilil wtti Iht iitrjf i i j win i^iniiti hi psjEncdoi atS dKrHMd I w i rrii orcorfrtnlon to nonTiaa t t u rtiyfci fcita^BOMlaiiaiiiiliutotCAflDtZBI l^tct^ii

CAPOZn h j u i a k rMtihotaM a.

3. Pr ta t t id ifart l^^ttkJuic

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f C M I l C i i « r ^ t i t i t r a *uAjalJng my btmpjbb.

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p fl * ( a b . i <k> compai ORE odyanb ot tusrnarirtoor onga Iron «alof»Ota*rongn prior to B * B r t n ol CAfCEa I r t t U

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B a iCvaoja d^

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or AV ink cotdodki Ita WAPJlieS)Ai rtl * drtot, e n no* ) bt cardHd i t« i taring pnantl artl luttoa mlcckm.CAADIZQI mdargon rakmln l U M n by ft* cytodnn FMiO nbad fUKttot oiktot

k - m t t d t i t v » ) t t b a 3 l>tti thuk arrnrtnoa n»an i « ctraanl rttt n t n v H M tafnioa, cradnlnritnrKi olCARDIZEH la|«ctJb(t vttl ottiir tgiott wtildi irtmrlry radlrgo tht wr* roatl of

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d ta d k f Uy

ootafad ta i flujy aartorraad a mak ati amak ran a oral doaapo of op to 1ri iaiatr. Coj-xr C fupmirto rodao t n are coaduaad ta ralci, no, and rtbob.AdrrlrutaUai tt crt dota ragtag ron tit to ta ttan ftala (oa I mo*J aaa) k a ta daa>iMiarmlad it Ktaagtoa1 l a n n draa ko vutad ta atryo ad tea1 kltally Tootdoao. k u a H j d n , Ima bsai nporiadto cacao djatt rinomaHat. a ta pvtatal/foatnttam tan ao a n rataaji ta arty bMrtal m aabta aal u n W ran Taai ao atmaad taddan ot OUrta a dow ol 20 ano ta ranan ora1 oaagka dot or grati*r a n n K aal^ontrolid Badat ta m e a d «onacr. rjantat, lat CADOZtM k anr/aalauianorty l l a iMaia1 kaak judla ta poannj rka to talabihnlaj l a l a t . M m k raaad ta IM ua nft. Ctae nxrt atA ora1 JKuai I ^ ^ J I dadn n n t m ta braot na\ my ffmirjk m laiaO. tl B I of OBCUZQI o dantdmailkl ai tfffwa'Yi svliod ol Wat ladBD ahraid bt todtatad.M a t * Ua. Saaly n l afKhaaa ti d*tan B M an ban oaeaaad.

mtaamxntmTat tofcarag antru r a d W M o a i boa) oe tta ua of CAROtZH to^daaa ta mar 400tmmXctocM<Mt**B+<'rtto*li».'batirZfitir****i*<iaQrm-<**rnartHd'iii Wur^aaJi nparanca n OMT IJOOpaiaiimBiitar/MYara n a n raportad ta cot tnM a t uauntrolid dtakU Utah i n gttaraly md a*JtJWJaot HypootdoD tro Aa rwal eornamly raportad adwta mrtdviag dWolMia .A t i c typotansiaa t e a m * t i n d paUrtt Srottanat hyfjotattoo octomd ta

feB wt t t I h ld It B

ypABnpboaticp yp p rot y f j t t o o

n ufeiB w t u uutxmt IM hnotaotam a n rtqilnd. It gmnBy contiud oln f ^ ^ b U k M T d ^ a C n j a

at atd 1% of h oUaaHndtd pEarb aara nadon da rodka (ig, kaag, imttrq31%, modlluloe (flaiktcn})—1.7%. n ) urtfmnti (juocltoial rtytta or torhyUnlc

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t i t ^ J L t o t t a t o f c t o d t t la cmbdhd ddctl btb, ttmpy rti lolarttytwic igtrD to naitata tadnd baaimik Mialfbtttan or Ota1 mm or to prtptyej* d PSVT aaa garanly Bawl aaTai 3 hon tm lota•taaotatton of CAHKZBi lajdatai. Ttcn artartyan* ajaati wrt attmaaou or oaloXrjdrt, CBB I aajntrttraa (K. toHrta, prtakaax), caUaa ctaaal Ucckn, ail era1

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or i r x t i t t i a t t aad val cotafatag SO ng datoao byarjJUrJi (S ragarl) (DC COB-179O-3JJ-

SlaatUSE CWTUaBB. OtSCAH) IJUSED PORTW,

STOW rHOOUCT la t f f l REFfflaATW 2-fC (3(r4»n DO HOT FPHZL MAY BE STOfrffl ATROOD TEMPERATURE FOR UP TO I MONTH DESTROY AFTER 1 MOUTH AT ROOaTEWBUTURE.

Pradad adtrranai o ol Odobar 1»1

MARION MERRELL DOW INC

Referrjnco: 1. Cardlzem InJgctaUe prascrlUng Informatjon2 EltenbwnKA,DlasVC,RumbVJ,H3ywoo<JJT,MlrvtsDM.J>(mCol CanUoL 1991:18891-897

CIVAH058/A6S64 0 3 1 X 2

I/-WA/ FADT T

THE ONECARDIZEM CD( d i l t i aZem 1-fCf) 120-,180-, 240-, 300-ms Capsules

PROVEN* 24-HOUR CONTROLOF BOTH ANGINAAND HYPERTENSIONReduces the frequency of angina attacks—through i 1

Tbtat angina attacks!'

s 6

b 3a1 2z

1

6.331.W

I I Baseline

^ B Post-treatment

3.781.09

4.21±0.99

Baseline

Post-treatment

3.40±0.53

-

».73±0.71

Placebo Cardlzcm CO Cardizem CD(n=39) 120mgqd 360mgqd

(n=37) (n=40)f At rest and on exertion.

Placebo Cardlzcm CD Cardlzcm CD(n=39) 120mgqd 360mgqd

(n=37) (n=40)

Consistent antihypertensive effect seenthroughout 24 hours9

100-

90

80

70 •

60

Ambulatory BP subset: 4 of 9 sites performedambulatory BP monitoring- The 47 patients enrolledat tnese sites were clinically and demosraphicallyrepresentative of the total study population.Mean supine cuff DBP at baseline 99.3 ± 0.6 placebo;99.4± 0.7 Cardizem CD

8 am 11am 2 pm 5 pm 8 pm 11pm

TIME OF DAY

2 am 5 am 8 am

Adapted from Massk et al .s

• Overall study results (127 patients) show a sisnificant mean chanse at24 hours in both diastolic (p =0.0075) and systolic (p =0.0009) bloodpressure vs placebo2

• Cardizem CD averase daily dose 268 ms/day•Proven efficacy throush 24-hour ambulatory blood pressure recording, peak/trough blood pressure evaluation, and Bruce treadmill protocol

CCDAJ277/A7858

EXTREMELY WELL TOLERATED

CARDIZEM CD Placebo-ControlledAngina and Hypertension

Adverse Reaction

HeadacheDizzinessBradycardiaAV Block First DegreeEdemaECG AbnormalityAsthenia

Trials Combined3

Cardizem CDn=607

5.4%3.0%3.3%3.3%2.6%1.6%1.8%

Placebon=301

5.0%3.0%1.3%0.0%1.3%2.3%1.7%

In clinical trials of Cardizem CD capsules, Cardizem tablets, and Cardizem SRcapsules involving over 3200 patients, the most common events (ie, greaterthan 1%) were edema (4.6%), headache (4.6%), dizziness (3.5%), asthenia(2.6%), first-desree AV block (2.4%), bradycardia (1.7%), flushins (1.4%),nausea (1.4%), and rash (1.2%).

LOWER PRICEBased on average wholesale prices* using equivalentmg/day doses4:• 35% lower cost than Cardizem® (diltiazem HCI)

tablets for angina(Cardizem tablets are available as 30, 60,90, and 120 mg)

• 25% lower cost than Cardizem® SR (diltiazem HCI)capsules for hypertension(Cardizem SR is available as 60-, 90-, and 120-mg capsules)

Please see prescnbins information on adjacent page.

*Red Book Update. 1992;11(10>7

C E-A-DAYDIZEM CD

(diltiazem HCI)0113A3

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Prescribing Information as of January 1991

CARDIZEM*(dlnJiram bydrachlortde)TaMtta

DESCRIPTIONCARDIZEM* (dNtlazam hydrochtrxide) It i calcium loci Influx Inhibitor (flowchannel blocker or calcium antagonist) Chemically, dlltiazem hydrochlorideIs 1, 5-Benzothlazepln-4(5H)one, 3-(acetyloxy)-5-[2-(dlmothylimlno)ethyll-2, 3-dihydro-2-(4-metboxyphenyl)-, monohydrochlorlde, (+)-cls-The chemical structure a

,OCH,

CH,CH,N(Cty,

Dltllazem hydrochloride It I whits to off-white crystalline powder with abttter tiita It Is soluble In water, methanol, and ctiloroform. It has i molec-ular weight oi 450 98 Eacfi tablet oi CARDIZEM contains 30 mg, 60 mg, 90mo, or 120 mg dllUazem hydrochlorideAlso contains, D&C Yellow #10, FO&C Yellow rt (60 mg and 120 mg). orFDSC Blue #1 (30 mg ind 90 mg), hydroxypropylcellulOM, bydroxypropylmethytceltulose, lactose, magnesium stearate, methyl pa raben, polyethyleneotycd. talc, and other IngredientsFor oral ad mil 1st rationaimCJU.PHARMACW.CWY

The therapeutic benefits achieved with CARDIZEM are believed to be relatedto Its ability to Inhibit the Influx of calcium Ions during membrane depolar-ization of cardiac and vascular smooth muscleMusmtasM of A t l l i Although precise mechanisms of its antlanglcalactions are still being delineated, CARDIZEM is believed to act In thefollowing ways1. Aagkta D M to Canary A H H T Spain: CARDIZEM has been shown to

be a potent dilator of coronary arteries both eptcirdlal and subendocar-dial. Spontaneous and trgonovlne-lnduced coronary artery spasm areInhibited by CARDIZEM

2. Enfttoul Aagrna. CARDIZEM hts been shown to produce Increases Inexercise tolerance, probably due to its aoffity to reduce myocardlal oxygendemand. This is accomplished via reductions In heart rate and systemicblood pressure at submwlmal and maximal exercise work loads

In animal models, dltJazem Interferes with the slow Inward (depolarizing)current In excitable tissue It causes excltatJon-contrtction uncoupling Invarious myocardial tissues without changes In the configuration of theaction potential. Dllttazem produces relaxation of coronary vascular smoothmuscle and dlatlon of both large and small coronary arteries at drug levelswhich came little or no negative Inotroplc effect The resultant Increases Incoronary blood flow (eplcardlal and subendocardlal) occur In Ischemic andnonlschemlc models and are accompanied by dose-dependent decreases Insystemic blood pressure and decreases inpeftpheral resistanceHamadinaasllc wti ^LupotwalnlMk Epatft LJke other caJcaim antago-nists, dotlazefn decreases MWfltnal arn atnovertrlcular conduction In isolatedtissues and has a negative inotroplc effect in Isolated preparations In theIntact animal, prolongation of the AH Interval can be seen at higher dosesIn man, ditjazem prevents spontaneous and ergonovtne-provoked coronaryartery spasm It causes a decrease In peripheral vascular resistance and amodest fall in blood pressure and, in exercise tolerance studies In patientswith Ischemic heart disease, reduces the heart rate-blood pressure productfor any given work load Studies to date, primarily In patients with goodventricular function, have not revealed evidence of a negative Inotropiceffect; cardiac output election fraction, and left ventricular end dlastolicpressure have not been affected. There are as yet few data on the Interac-tion ol dlltiazem and beta-blockers. Resting heart rate is usually unchangedor slightly reduced by rjltlazsm.

Intravenous dlltlazem In doses of 20 mg prolongs AH conduction time andAV node functional and effective refractory periods approximately 20% Ina study Involving single oral doses of 300 mg of CARDIZEM in six normalvolunteers, the average maximum PR prolongation was 14% with noInstances of greater than first-degree AV block Dlltlazem-assoclatedprolongation ol the AH interval Is not more pronounced in patients wtthfirst-degree heart block. In patients with sick sinus syndrome, dlltlazemsignificantly prolongs sinus cycle length (up to 50% In some cases)Chronic oral administration of CARDIZEM In doses of up to 240 mgAtay hasresulted In small Increases In PR interval, but has not usually producedabnormal prolongation~ ilimtci aiK Hatumisfli Dlrtlazem is absorbed from the tabletformulation to about 80% of a reference capsule and is subject to an exten-sive first-pass effect giving an absolute btoava I lability (compared to intra-venous dosing) of about 40% CARDIZEM undergoes extensive hepaticmetaboflsm in which 2% to 4% of the unchanged drug appears In the urine.In vitro binding studies show CARDIZEM is 70% to 80% bound to plasmaproteins. Competitive ligand binding studies have also shown CARDIZEMbinding Is not altered by therapeutic concentrations of dlgoxln,hydrochlorothlazide, phenylbutazono, propranotol, salicylic acid, or warfarin.Single oral doses of 30 to 120 mg of CARDIZEM result In detectable plasmalevels within 30 to 60 minutes and peak plasma levels two to three hoursafter drug admbilstratlon. The plasma efimJnarJon haff-llfe following single ormultiple drug administration Is approximately 3 5 hours Desacetyl dlltazemIs aHo present In the plasma at levels of 10% to 20% of the parent drug andIs 25% to 50% as potent as a coronary vasodBator as dlttjazem TherapeuticWood levels of CARDIZEM appear to be in the range of 50-200 ng/mL ThereIs a departure from dose-linearity when single doses above 60 mg are given,a 120-mg dose gave blood levels three times that of the 60-mg dose ThereIs no Information about the effect of renal or hepatic Impairment on excre-tion or metabolism of dlrtlazemINDICATIONS AMD USA8E

1 Aoflna Pwstrti Om ID Carman Artny i m CARDIZEM Is IndicatedIn tha treatment of angina pectorls dua to coronary artery spasmCARDIZEM has besn shown effective In the treatment of spontaneouscoronary artery spasm presenting as Prinzmetal's variant angina (restingangina with ST-segment elevation occurring during attacks)

is Indicated mi the management of chronic stable"anginam patients whoctnnot tolerate therapy wtth beta-Mockers and/or nitrates or who remainsymptomatic despite adequate doses ol these scants CARDIZEM hasbeen effective in short-term controlled trials In reducing angina frequencyand Increasing exercise tolerance, but confirmation of sustained effec-tiveness Is incomplete

There are lew controlled studies of the effectiveness of tha concomitant useof diltiazem and bela-blockere or of the safety of this combination Inpatients with Impaired ventricular function or conduction abnormalitiesCO HTRAWDI CATIONSCARDIZEM Is contralndlcated In (1) patients with sick sinus syndromeexcept in the presence of a functioning ventricular pacemaker, (2) patientswith second- or third-degree AV block except In the presence ol afunctioning ventricular pacemaker, (3) patients with hypotension (less than90 mm Hg systolic), (4) patients who have demonstrated hypersensltlvtty

CCDAJ577/A7858

to the drug, and (5) patients with acute myocardlal infarction andpulmonary congestion documented by x-ray on admission.

WAHMN8St Cardiac CnndntHon CARDIZEM prolongs AV node relractory periods

without significantly prolonging sinus node recovery time, except Inpatients with sick sinus syndrome. This effect may rarery result in sbnor-maly slow heart rates (parficulariy In patients with sick sinus syndrome)or second- or third-degree AV block (six of 1,243 patients for 0 48%)Concomitant use ol dlltiazsm wtth beta-blockers or digitalis may result Inadditive eflects on cardiac conduction. A patient with Prinzmetal's anginadeveloped periods ol asystole (2 to 5 seconds) after a single dose of 60mg of dlltiazem.

2. Crjimatlw Htart Fallari Although dlltlazem has a negative Inotroplceffect In Isolated animal tissue preparations, hemodynamlc studies Inhumans with normal ventricular function have not shown a reduction Incardiac Index nor consistent negative effects on contractility (dp/dt).Experience with the use of CARDIZEM alone or in combination with beta-blockers In patients with Impaired ventricular function is very limitedCaution should be exercised when using the drug In such patterns

3 Hrantunlon Decreases In Wood pressure associated wtth CARDIZEMtherapy may occasionally result hi symptomatic hypotension

4.Acata Haiatlc Injury In rare instances, significant elevations in enzymessuch as alkaline phosphatase. LDH, SGOT\ SGPT, and other phenomenaconsistent with acute hepatic Injury have been noted These reactionshave been reversible upon discontinuation of drug therapy The relation-ship to CARDIZEM Is uncertain in most cases, but probable in some (SeePRECAUTIONS)

PRECAUTIONS

B M r O l CARDIZEM (dlltiazem hydrochloride) Is extensively metabolizedby tha liver and excreted by the kidneys and In bile. As wtth any drug givenover prolonged periods, laboratory parameters should be monitored atregular Intervals. The drug should be used wtth caution In patients withimpaired renal or hepatic function In subacute and chronic dog and ratstudies designed to produce toiJdty, high doses of dBttazem were associ-ated with hepatic damage In special subacute hepatic studies, oral dosesol 125 mg/kg and higher In rats were associated with hlstotogkaJ changesIn the liver which were reversible when the drug was discontinued Indogs, doses of 20 mgAg were also associated with hepatic changes,however, these changes were reversible with continued dosrngDarmatological events (see ADVERSE REACTIONS section) may betransient and may disappear despite continued use of CARDIZEMHowever, skin eruptions progressing to erythema multlforme and/orexlollatlve dermatitis have also been Infrequently reported Should adermatologlc reaction persist the drug should be discontinued.Dnw litatTacttwu Due to the potential for additive effects, caution andcareful ttaitwn are warranted hi patients receiving CARDIZEM concomi-tauitry with any agents known to affect cardiac contractility and/or conduc-tion. (See WARNINGS)

Pharmacologlc studies Indicate that there may be additive effects Inprolonging AV conduction when using beta-Mockers or digitalis concoml-tarttty with CARDIZEM (See WARNINGS)As with all drugs, care should be exercised when treating patients withmultiple medications. CARDIZEM undergoes blotransformation bycytochrome P-450 mixed function oxldau' Coadministration of CARDIZEMwith other agents which follow the same route of biotranstormatJon mayresult In the competitive Inhibition ol metabolism Dosages ol similarlymetabolLzed drugs, particularly those of low therapeutic ratio or In patientswith renal and/or hepatic impairment, may require adjustment whenstarting or stopping concomltantty administered CARDIZEM to maintainoptimum therapeutic blood levelsM a - i t o d n r r Controlled and uncontroled domestic studies suggest thatconcomitant use ol CARDIZEM and beta-blockers or cSgrtalts is usualy welltolerated. Avalable data are not sufficient however, to predict the effectsof concomitant treatment particularly in patlsnts with left ventriculardysfunction or cardiac conduction abnormalitiesAdministration of CARDIZEM (dlrtlazem hydrochloride) concomltantly wtthpropranolol In five normal volunteers resulted In Increased propranolollevels In all subjects and bloavallablllty of propranolol was Increasedapproximately 50% If combination therapy Is Initiated or withdrawn Inconjunction with propranolol an adjustment In the propranolol dose maybe warranted. (See WARNINGS )ClMlldlnt A study In stx healthy volunteers has shown a significantIncrease in peak dlltiazem plasma levels (58%) and area-under-the curve(53%) after a 1-week course of clmebdine at 1,200 mg per day and dBti-azem 60 mg per day Ranltldlne produced smaller, nonsignificant IncreasesThe effect may be mediated by dmetldine's known Inhibition of hepaticcytochrome P-450, the enzyme system probably responsible tor the first-pass metabolism of dlltiazem Patients currently receiving diltiazem therapyshould be carefully monitored for a change In pharmacological effect wheninitiating and discontinuing therapy with dmetJdlne An adjustment in thedlltiazem dose may be warranted.Digitalis Administration of CAflDIZEM wtth dlgoxln In 24 healthy malesubjects Increased plasma dlgoxin concentrations approximately 20%.Another investigator tound no Increase In dlgoxln levels In 12 patients wtthcoronary artery disease Since there have been conflicting results

" g the effect of dlgoxln levels, it Is recommended that dlgoxln leversbe monitored when Initiating, adjusting, and discontinuing CARDIZEMtherapy to avoid possible over- or under-dtgitallzatjon (See WARNINGS)AwtTJitlcs Jhe depression ol cardiac contractility, conductivity, andautomatlclty as well as the vascular dilation associated with anestheticsmay be potentiated by calcium channel blockers When used concoml-tantry, anesthetics and calcium blockers should be titrated carefulyCarclnuua—tla. Mitaaarwsrs. IrnnaHntMl i l FartJIItf A 24-month studyin rats and a 21 -monm study In mice showed no evidence of carclno-genidty There was also no mutagenlc response In in vitro bacterial testsNo intrinsic effect on fertility was observed In rats.Pran nancy Category C Reproduction studies have been conducted inmice, rats, and rabbits. Administration of doses ranging Iran live to tentimes greater (on a mg/kg basis) than the dally recommended therapeuticdose has resulted In embryo and fetal lethality These doses, In somestudies, have been reported to cause skeletal abnormalities In theperinatal/postnatal studies, there was some reduction In early Individualpup weights and survival rates There was an increased Incidence ol still-births at doses of 20 times the human dose or greaterThere are no well-controlled studies in pregnant women, therefore, useCARDIZEM in pregnant women only If the potential benefit justifies thepotential risk to the fetus.

Wiralin Mothtrs Dlltiazem is excreted in human milk One reportsuggests that concentrations In breast milk may approximate serum levels.II use of CARDIZEM Is deemed essential, an alternative method of Infantfeeding should be Instituted

PutetrlcUn Safety and effectiveness In chBdren have not been established.

ADVERSE REACTIONSSerious adverse reactions have been rare In studies carried out to date, butIt should be recognized that patients wtth Impaired ventricular function andcardiac conduction abnormalities have usually been excludedIn domestic placebo-controlled angina trials, the Incidence ot adversereactions reported during CARDIZEM therapy was not greater than thatreported during ptacebo therapyThe following represent occurrences observed in clinical studies of anginapatients In many cases, the relationship to CARDIZEM has not been estab-

lished The most common occurrences from these studies, as well as theirfrequency of presentation, are: edema (2 4%), headache (2.1%), nausea(1.9%). dizziness (1 5%). rash (1 3%), asthenia (1.2%) In addition, thefollowing events were reported Infrequently (less than 1%).Cardlmasmlar Angina, arrhythmia, AV block (first degree), AV block(second or third degree - see conduction warning) bradycardia, bundlebranch block, congestive heart failure, ECG abnormality, flushing, hypoten-sion, palpitations, syncope, tachycardia, ventricular axtruystolesNamua System: Abnormal dreams, amntsla, depression, gait abnor-mality, hallucinations, Insomnia, nervousness, pareslhesla, personalitychange, somnolence, tremorBattrolatntial. Anorexia, constipation, diarrhea^ dysoeiaia, dyspepsia,mild elevations ol afcstlne phosphatase. SCOT, SGPT, and LDH (see hepaticwarnings), thirst, vomiting, weight Increase.Dwmafcloglcal Petechtae, photosensitMty, prurtus, urticaria.M a r Amolyopta, CPK elevation, dry mourn, dyspnea, epistaxls, eye Irrita-tion, hyperglycemla, hyperurlcemla. Impotence, muscle cramps, nasalcongestion, nocturia, osteoartlcular pain, poryurta, sexual dlmcutttes, tinnitus.The following postmarketlng events have been reported infrequently inpatients receiving CARDIZEM: alopecia, erythema multltorme, extrapyra-mldal symptoms, glngival hyperptasa, hemoMIc anemia, Increased bleedingtime, leukopenla, purpura, retjnopathy, and mrombocytopenia. Thtre havebeen observed cases of a generalized rash, characterized as teukocytodasttcvasculltls In addition, events such as myocardlal infarction have beenobserved which are not readly rjstlngulshable from the natural history ofthe disease in these patients. A definitive cause and effect relationshipbetween these events and CARDIZEM therapy cannot yet be established.Exidlalivt dermatitis (proven by rechallenge) has also been reported.0VERD0SA6E OR EXAGGERATED RESPONSEThe oral LDuj's in mice and rats range from 415 to 740 mgAg and from 560to 810 mg/tg, respectively The Intravenous U W s In these species were60 and 38 mg/kg, respectively. The oral LD» In dogs Is considered to ba mexcess ol 50 mg/kg, write lethality was seenTn monkeys at 380 mg/kgThe toxic dose In man is not known. Due to extensive metabolism, bloodlevels after a standard dose of ditto:m can vary over tenfold, limiting theusefulness of blood levels hi overdose cases.

There have been 29 reports of dlltlazem overdose In doses ranging fromlass than 1 g to 10.8 g. Sixteen ot these reports involved multtpH drugIngestionsTwenty-two reports Indicated patients had recovered from dUttazem overdoseranging from less than 1 g to 10.6 g. There were seven reports with a fataloutcome; although the amount ol dltianm Ingested was unknown, multipledrug Ingestions were confirmed In six of the seven reportsEvents observed following dlltlazem overdose Included bradycardia,hypotension, heart Mock, and cardiac failure Most reports of overdosedescribed some supportive medical measure and/or drug treatmentBradycardia frequently responded favorably to alroplne, as did heart block,although cardiac pacing was also frequently utilized to treat heart block.Fluids and vasopressors were used to maintain blood pressure, and Incases ol cardiac failure inotroplc agents were administered. In addition,some patients received treatment wtth ventltatory support gastric lavage,activated charcoal, and/or Intravenous calcium Evidence of the effective-ness of Intravenous calcium administration to reverse the pharmacologicaleffects of duttazem overdose was contacting.In the event of overdose or exaggerated response, appropriate supportivemeasures should be employed In addition to gastrointestinal decontamina-tion Diltlazom does not appear to be removtd by peritoneal or hamo-dlalysls Based on the known pharmacological effects ot diltiazem and/orreported clinical experiences, the folowtng measures may be consideredBradycardia Administer atroplne (0.60 to 1 0 mg) If there is no responseto vagal blockade, administer Isoproterenol cautiouslyHtan-Dtgrs* AV Mock. Treat as for bradycardia above. Ftxtd high-degreeAV Wort should be treated with cardiac pacingCardiac Fallan Administer Inotroplc agents (isoproterenol, dopamlne, ordobutamlne) and diuretics.Hrpotanstoar. Vasopressors (eg, dopamlne or ktvarterenol bitartrate).Actual treatment and dosage should depend on tha severity of the cUnlcalsituation and the judgment and experience of the treating physician,DOSASE AND AS M M STRATI OilEiirtlonal Ani lni Pattnrli P i t to Attirniclirptlc Cnronnr ArumD l f i a a or Anilni Pattona at Rest Dia Fn Cqronanf Arttr* S I M I B .

nrll Di» to Attirnicllrptlc Cnritons at Rest p i a In Cqronanf Aito eadi pattern's needs Starting wit.e must be adjusted to each patient's needs Starting with 30 mg tour

times daily, before meals and at bedtime, dosage should be Increasedgradually (gtven in divided doses three or four times dally) at one- to two-day Intervals until optimum response Is obtained Although Individualpatients may respond to any dosage level, the average optimum dosagerange appears to be 180 to 380 mg/day. There are no available dataconcerning dosage requirements in patients wtth Impaired renal or hepaticfunction. II the drug must be used In such patients, titration should becarried out with particular caution.Contafaltanl UMwWi Ottnf Canlhrmajrir A « i t i1 Hblaaaal HTQ may be taken as required to abort acute anginal attacks

durtngCARDIZEM(dltaem hydrochloride)therapy2 Proflniactfc Nrtratu Tttenirf-CARDIZEM may be safely coadmlnlstered

with short- and long-acting nitrates, but there have been no controlledstudies to evaluate trie irrtanrjlnsl effectiveness of this combination.

3 Ma-blodtan. (See WARNINGS and PRECAUTIONS)

HOW SUPPLIEDCARDIZEM 30-mo tablets are luppted In bottles ol 100 (NDC 0088-1171-47) and 500 (NDC 0088-1771-55), and In Untl Dose Identification Paks ol100 (NDC 0038-1771-49). Each green tablet Is engraved wtth MARION onone sida and 1771 engraved on the otherCARDIZEM 60-mg scored tablets are supplied In bottles of 90 (NDC 0088-1772-42), 100 (NDC 0088-1772-47), 500 (NDC 0088-1772-55), and In UnitDose Identification Paks of 100 (HOC 0088-1772-49) Each yellow tablet Isengraved wtth MARION on one side and 1772 engraved on tha otherCARDIZEM 90-mg scored tablets are supplied In bottles of 90 (NDC 0088-1791-42), and 100 (NDC 0088-1791-47), and In Unit Dose IdentificationPaks of 100 (NDC 0088-1791-49). Each green oolong tablet is engravedwith CARDIZEM on one side and 90 mg engraved on the other.CARDIZEM 120-mg scored tablets are supplied m bottles ot 90 (NBC 0088-1792-42), and 100 (NDC 0088-1792-47). and m Unit Dose IdentificationPaks of 100 (NDC 0088-1792-49). Each yellow oblong tablet Is engravedwtth CARDIZEM on one side and 120 mg engraved on the other.Store at controlled room temperature 59-86T (15-30"C).Prescribing Information as of January 1991Marlon Merrel Dow Inc.Kan sasClty.MO 64114

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Rir tmos: 1. DUa on IU, Marion Merrill Dow Inc. t. MatsU BU, Der E,Htrman TS, Topoild P, Park GD, Stewart WH. G * Cirrfty 1W2:15:Ja5-368.I . CirtUam CD pracrilxng Inforrrattan. 4. Rtd Boat UfXta 1992:11(10).7.

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MARION MERRELL DOW INC

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 clinicaland laboratory data. The committee since has sanctionedthe use of SI units in the American Heart Association(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 conversion ismade over and over in a manuscript and takes little extraeffort. It is our belief that, in return for a small effort, theAHA can take a large step, along with many otherinternational and domestic journals, toward perpetuatinga common system for reporting medical and scientificmeasurements. The SI unit is to be used in text, followedby the presently used measurement in parentheses.

TABLE 1. Measurements Currently Not Converted to SystemeInternational (SI) Units in Biomedical Applications

Measurement Current unit

Blood pressure

Oxygen pressure

Enzyme activity

H+ concentration

Temperature

Volume

mm Hg

mm Hg

IU

pH

°C

liter

The accompanying conversion table (Table 2) lists themeasurements most commonly used in the AHA jour-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 to SystemeInternational (SI) Units for American Heart Association Journals*

Conversion Normal laboratory valuesf

Current unit factor SI unit Current SI

Concentration

M (molar)

mM

Pressure

torr

atm

Hematocrit

%

Red blood cellcount

1

1

1

101.325

mol/L

mmol/L

mm Hg

kPa

0.01 no units 36-54

4.0-6.0

036-034

4.0-6.0

White bloodcell count

/mnr

Cholesterol

mg/dLSodium ion(Na+)

mEq/L

Potassium ion(K+)

mEq/L

Calcium ion(Ca2+)

mEq/L

Energy

Calories

Conductance

mho

0.001 107L 5,000-10,000 5.0-10.0

0.02586 mmol/L <200 <5.20

1 mmol/L 135-145 135-145

1 mmol/L 33-5.0 33-5.0

03 mmol/L 43 -53 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.

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