Nitroglycerin and Other Nitrites of Angina · in vasodilating action on sublingual administration is seen also with mannitol hexanitrate and triethanolamine trinitrate and to a lesser

Nitroglycerin and Other Nitrites in the Treatmentof Angina Pectoris

Comparison of Six Preparations and Four Routes of AdministrationBy JOSEP11 E. F. RISEMAN, M.D., GEORGE E. ALTMIAN, M.D., AND SIDNEY KORETSKY, M.D.

The close chemical relationship between glyceryl trinitrate and erythrol tetranitrate suggeststhat these 2 drugs, despite clinical evidence to the contrary, should be equally effective inpreventing attacks of angina pectoris. This proved to be true when the drugs were admin-istered by the same route. Thus, erythrol tetranitrate when administered sublingually (insteadof being swallowed, as is the custom) behaves like nitroglycerin and is one of the most effec-tive vasodilators available. Conversely, nitroglycerin when swallowed (instead of being takensublingually, as is the custom) is ineffective and erratic in activity. A similar striking increasein vasodilating action on sublingual administration is seen also with mannitol hexanitrate andtriethanolamine trinitrate and to a lesser extent with pentaerythritol tetranitrate but not withsodium nitrite.

The prolonged effect of erythrol tetranitrate, when administered sublingually or in the buccalpouch, makes it particularly valuable in the clinical management of patients with anginapectoris.

OF ALL the drugs available for preventingattacks of angina pectoris nitroglycerin,

amyl nitrite, and octyl nitrite are by far themost effective. Of these 3, nitroglycerin isthe most widely used, primarily because of itsdefinite dosage, simplicity of administration,and low cost. The one drawback to its clinicalusefulness is the short duration of action.Measurements in this laboratory' demon-strated that, although the prophylactic benefitof sublingual nitroglycerin may persist for anhour in some patients, its action persists forminutes only in most patients. Similar studieswith other drugs' 6 showed that nitroglycerinis of prophylactic benefit to more patients andto a greater degree than any other medication.The present report is concerned with a searchfor drugs as effective as nitroglycerin, butwith more prolonged activity.The graphic chemical formulas of the 6

Froas the Medical Research Department of theYamins Research Laboratory, Beth Israel Hospitaland the Departments of Medicine, Harvard MiedicalSchool, and Tufts Medical School, Boston, Mass.

This study was aided by grants from ThomasLeeming & Co., Inc., and Brewer & Co., Inc.

Presented in part before the New England Cardio-vascular Society, February 8, 1954.

22

nitrites studied in the present series are shownin figure 1. If the action of nitroglycerin isdue to the presence of -ONO2 groups, all 6should have therapeutic value in anginapectoris.Two problems were of particular interest.

First, since the chemical structures of nitro-glycerin and erythrol tetranitrate are similar,why is the former much more effective forpreventing attacks of angina pectoris? Sec-ond, since laboratory studies show that sodiumnitrite has a highly effective vasodilating ac-tion, why is this drug of such limited clinicalvalue in treating angina pectoris? A studyof the extensive literature suggests that partof the difference in clinical effectiveness ofthese 6 drugs may be due to the various routesof administration employed.

Nitroglycerin or glycerol trinitrate is anoily liquid and, originally, was used in alco-holic solution, i.e., tincture glanoin. The vividdescription by Field in 18587 showed that thissolution, when dropped on the tongue, wasreadily absorbed by the mucous membranesof the mouth with striking effects. One of thepatients treated by Field may well have suf-fered from angina pectoris, but Murrell isgenerally given credit for first advocating the

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NITRITES IN THE TREATMENT OF ANGINA PECTORIS

MANNITO.TE NEXANITRATE102 H2- C-O-NO2

02 H-C-0-NOI02 H- C-O-NO2

02 H-C-O-NO0

H- C-0-NOt

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RlE THANOLAMINETRINITRATE

CH2-CHa-0-NO2

N-COt- CH2- O-NO2.2Hp

CHt-COO-O-NO2

FIG. 1. Graphic chemical formulas of amyl nitriteanid the 6 nitrites stuilied in the present series.

use of nitroglycerin (1879) for the treatmentof this condition. Murrell prescribed 10minims of a 1 per cent solution of nitroglyc-erin in water to be swallowed several timesdaily. Although in the past9 there was some

difference of opinion as to the best route ofadministration, nitroglycerin has been usually

lrescribed for sublingual use.

Recently, a slow release preparation fororal use was made available. This material( Nitroglyni) is a porous plastic tablet im-pregiiated with nitroglycerin, designed so thatthe drug leaches out of the matrix slowly;thus, swallowing a single tablet makes themedication available to the patient for severalhours. Few evaluations of the effectivenessof Nitroglyn are available. Russek et al.1('found it of little value in correcting the exer-

cise electrocardiogram although Huppert andBoyd1" reported that its use decreased thenecessity for nitroglycerin in 16 out of 25patients.

Nitroglycerin is readily absorbed from thlskin.'2' 13 An ointment containing nitroglyc-erin has recently been made available conimer-

cially for the treatment of peripheral vaseulardisease. This preparation has been us-ed withsome clinical success in some patients withangina pectoris.'4 '1

Erythrol tetranitrate, according to thegraphic formula, should be an ideal drug be-cause it is identical with glycerol trinitrateexcept that its molecule is 1/.3 larger; thismight well prolong its activity without de-

tracting from its effectiveness. Bradbury 'searly studies'6 and also subsequent measure-ments'7-19 showed that both drugs are effectivein lowering the blood pressure of laboratoryanimals but erythrol tetranitrate has a moreprolonged action. However, exercise toleranceand electrocardiographic measurements4' 6, 20showed that although erythrol tetranitrate isof some prophylactic value in some patientswith angina pectoris, it is considerably lesseffective than nitroglycerin, both in the degreeto which the exercise tolerance is increased andin the number of patients benefited.One possible reason for this discrepancy

might lie inl the different routes of administra-tion used with these 2 drugs. Erythrol tetrani-trate is a solid and hence, unlike nitroglycerin,is administered in tablets to be swallowed. Instudying the comparative value of the differ-ent nitrites, therefore, it is necessary to com-pare the effect of oral, sublingual, and paren-teral administration.

Maniiitol hexainitrate resembles glyceroltrinitrate and erythrol tetranitrate in that itis prepared by nitration of a straight chainalcohol; in this instance the alcohol contains6 carbon atoms and the nitrate contains 6-ONO2 groups. Mannitol hexanitrate, likeerythrol tetranitrate and the other compoundsto be described, is a solid and is prescribed tobe swallowed. Studies in this laboratory5' 21indicated that mannitol hexanitrate whengiven in this manner is only of moderate bene-fit to patients with angina pectoris.

Pentaerythritol tetranitrate like erythroltetranitrate, has 4 -ONO2 groups; the struc-tural configuration and physical characteris-tics of pentaerythritol tetranitrate, however,are quite different from those of erythroltetranitrate or nitroglycerin. 12'13

This drug has been the subject of a numberof clinical investigations. The purely sub-jective methods of study22-28 uniformly in-dicated good results but this is true of mostevaluations of therapy in angina pectoris,where purely subjective criteria are employed.Several objective studies showed improvementin the exercise electrocardiogram or clinical

NITROGLYCERINH2-C- 0- NOt

H- C-0-NO2

H2- C- O - NO2

ERYTHROLTETRANITRA-H2-C-O-N

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0e N-O-CH2 CH2-0-NO2

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RISEMAN, ALTMAN, AND KORETSKt

exercise tolerance in a high percentage of pa-tients.1'0 29-33 In other instances" 34-36 similarobjective studies gave less favorable results.Winsor and Scott33 found the drug to be effec-tive when administered sublingually.

Triethanolamine trinitrate biphosphate, likenitroglycerin, has 3 -ONO2 groups; the struc-tural configuration, however, resembles penta-erythritol tetranitrate rather than nitroglyc-erin.

This nitrite was introduced following favor-able reports from Europe.37-39 Experimentson the isolated rabbit heart demonstratedcoronary vasodilatation.40 Several clinicalevaluations reported favorable subjective re-sults.41-43 However, poor results have beenreported by one group of workers, who alsoevaluated the drug by clinical observation,44and by another group,10 who evaluated thedrug by electrocardiographic measurementsafter exercise and compared the results withthose following other preparations includingpentaerythritol tetranitrate and Nitroglyn.Sodium nitrite is the simplest nitrite avail-

able. Studies in laboratory animals45 indi-cated that it is a highly effective coronaryvasodilator but it has proved ineffective whengiven in 60 mg. doses to patients with anginapectoris.' In laboratory studies the drug isgiven parenterally and in doses (consideringthe weight of the subjects) considerably largerthan those given orally to human subjects.

METHODSThe methods of study have been described in

detail elsewhere." 6 46 In brief, they involved thefollowing steps:SubjectsA group of typical patients with angina pectoris

were observed for many weeks, both without treat-ment and while taking placebos, in order to evalu-ate the severity and relative constancy of symp-toms.The 34 subjects of the present study included

20 men and 14 women. All but 2 patients were51 years of age or older. In each instance theangina pectoris was due to coronary artery disease.These 34 patients were similar to other groupspreviously studied in this laboratory except for ahigher percentage of women and a higher pgrcent-age of patients who responded favorably to nitro-glycerin.

Methods of Observation. At weekly intervals,for many months, the clinical response to therapywas evaluated by 2 physicians while another phy-sician independently measured the amount of exer-cise necessary to induce angina under standardizedconditions. The standardized conditions of theexercise tolerance test are important. "' ' 47 Theyinvolve repeated trips over a 2-step staircase ina relatively cold environment (45 to 55 F.) untilan attack of angina, typical for that patient, isprecipitated.

Medication. The 6 nitrites were administeredin at least 21 different shapes, colors, vehicles, orconcentrations. Placebos in at least 10 differentforms were also administered.The first medication prescribed was invariably

a placebo. Thereafter, there was no uniform orderexcept that each beneficial response was followedby a placebo and later by re-administration of theapparently effective medication in disguised form.As a result of these precautions, neither the pa-tient nor the observer who measured the standard-ized exercise tolerance could recognize the medica-tion. Thus, the conditions of the "double-blindtest" were fulfilled.Routes of Administration, Dosage and Time ofMeasurementsThe 6 nitrites were given sublingually (or

buccally), subcutaneously (or intramuscularly), bymouth (to be swallowed), and by inunction. Thedoses employed were those recommended by themanufacturer as adequate and several times largerif the recommended dose proved inadequate. Ex-cept when given parenterally, the medication wastaken several times daily for at least 1 week be-fore the response was measured. The Standard-ized Exercise Tolerance was measured at a timeappropriate for demonstrating the effect of themorning dose.

Sublingual or Buccal Therapy. Medication wastaken 3 times daily after meals. The StandardizedExercise Tolerance Test was performed 2 minutesafter an 0.3 mg. "hypodermic tablet" of nitro-glycerin had dissolved under the patient's tongue;in most instances from 20 to 30 seconds were re-quired for complete solution of the tablet.

Since the only available preparations of theother 5 nitrites were meant to be swallowed, thesetablets were used for the sublingual or buccal pouchstudies also. The exercise tolerance was measuredwithin 20 minutes after these tablets had dissolvedexcept when the duration of action was studied.The erythrol tetranitrate was obtained from 3

sources. The tablets contained 15 mg. of erythroltetranitrate when prepared. Some deteriorationmust have taken place because freshly openedbottles gave off a distinct odor of nitric acid andthe cotton wadding in 1 preparation had disinte-

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grated to powder. Two of the preparations (thosemarketed by Burroughs Wellcome Co. and Merckand Co.) usually required from 1 to 11/2 hours incontact with the oral mucosa for disintegration;the latter product is no longer available com-mercially. The third preparation (a Merek prod-uct, marketed by Sharpe and Dohme Co.) disin-tegrated more rapidly, usually in 1/2 to 1 hour,and contained 15 mg. of active drug in a 230-mg.tablet.The mannitol hexanitrate contained 32.5 mg.

of the drug in a tablet weighing 494 mg. Thesetablets were quite large. They dissolved or disin-tegrated sublingually in about 15 minutes. Thedose used was 65 mg. 3 times daily.Two preparations, each containing 2 mg. of tri-

ethanolamine trinitrate biphosphate (Metamine)were used in doses of 1 to 4 tablets 3 times daily.

Pentaerythritol tetranitrate (Peritrate) was ob-tained from 2 sources' as tablets of 10 or 20 mg.The doses were usually 40 to 50 mg. 3 times aday; several subjects also received 10 mg., 3 timesa day. The exercise tolerance tests were performedwithin 1/2 hour after sublingual solution of thetablets.

In most instances, the dose of sodium nitritewas 0.3 Gm. (5 tablets). Patients who experi-enced faintness with this dose were given smallerdoses but usually had similar untoward reactionswith as little as 60 mg.

Parenteral Administration. The StandardizedExercise Tolerance Test was performed 20 minutesto 1/2 hour after a single injection of medication.During the preceding week these patients hadtaken placebos by mouth, 3 times daily.

Nitroglycerin was given subcutaneously in dosesof 0.3 mg.

Erythrol tetranitrate used for subcutaneous ad-ministration was obtained by extraction of theactive principle from the tablets with alcohol andether. This extract was then mixed with lactose,made into hypodermic tablets, and assayed forpotency. Erythrol tetranitrate is only slightlysoluble in water, so that much of the 15 mg. dosewas probably in suspension when injected hypo-dermically.The solution of triethanolamine trinitrate bi-

phosphate for parenteral administration was sup-plied by the manufacturer. The dose employedwas 4 mg., administered intramuscularly. Un-fortunately, its use was followed by considerable,although temporary, local pain, which may havedecreased its efficacy.Sodium nitrite was administered intramuscularly

in doses of 0.06 to 0.18 Gm.Mannitol hexanitrate and pentaerythritol tetra-

nitrate were not given parenterally.

*Maltbie Laboratories and Warner Chilcott Co.

Oral or Swallowed Medication. Nitroglyn wasgiven twice daily, all others 3 times daily (onarising, at 2:00 to 3:00 p.m., and on retiring)for 1 week and the Standardized Exercise Toler-ance Test was performed from 1 to 2 hours afterthe last morning dose.

Nitroglycerin was given in 2 forms. In orderto prevent absorption from the oral mucous mem-branes, hypodermic nitroglycerin tablets were en-cased in gelatin capsules before being swallowed.The minimum dose used in these studies was 0.45mg. t.i.d. In order to determine the effective doseof nitroglycerin when swallowed, doses of 1 to 15mg. (in capsules containing 1 mg. or 3 mg. each)were given to 13 patients. Studies with Nitro-glyn were also carried out with varying doses.

Erythrol tetranitrate was administered in dosesof 30 mg. 3 times daily for at least 1 week.

Mannitol hexanitrate was given in doses of 65ng.After preliminary studies with 2 mg. tablets,

the dosage of triethanolamine trinitrate biphos-phate used was 6 mg., 3 times daily for at leasta week.The dosage of pentaerythritol tetranitrate used

was 40 to 50 mg. 3 times a day; several subjectsalso took 10 mg. 3 times a day.

Twenty-nine patients were requested to take300 mg. of sodium nitrite 3 times daily for 1week. Patients who developed untoward effectsto this dose were given smaller doses.

Inunction. These studies were carried out withnitroglycerin and erythrol tetranitrate ointments.Four inches of Nitrol Ointment (containing ap-

proximately 43 mg. of nitroglycerin) were rubbedin well twice daily for 1 week. The StandardizedExercise Tolerance Test was performed approxi-mately 2 hours after the last dose.The erythrol tetranitrate material for inunction

was made by incorporating the specially preparedhypodermic tablets in a water soluble ointmentbase. An amount containing approximately 65mg. of erythrol tetranitrate was rubbed in well,morning and night for 1 week and the exercisetest carried out 2 hours after the last application.

Analysis of ResultsThe results were evaluated by studying the pa-

tient's record of the number of attacks experiencedduring each period of therapy; by asking the pa-tient's opinion of the effectiveness of the treat-ment; and, most important, by measurement ofthe patient's exercise tolerance under the stand-ardized conditions of the test. The following de-grees of response were recognized.Marked response. The patient was able to per-

form at least 25 per cent more work withoutangina than when taking placebos and stoppedexercise because of dyspnea or fatigue, rather

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RISEMAN, ALTMAN, AND KORETSKY

than pain; or angina was induced but only aftera 50 per cent increase in exercise above the levelwith placebos.

Moderate Response. Angina did not occur butthe increased work was no more than 24 percent; or angina was induced after an improve-ment of exercise tolerance of 20 to 49 per cent.

Slight response. This implied a 10 to 19 percent increase in exercise tolerance before anginawas precipitated.No response. Angina was induced after no

more exercise than the maximum that could beperformed during the placebo period. A de-crease in exercise tolerance was not infrequentin these cases. In such instances the medicationfailed to improve the patient's condition sufficient-ly to overcome the deleterious effects of factorsthat increase the tendency to attacks (emotion, in-tercurrent illness, etc.). This apparent decreasein exercise tolerance does not imply that theclinical condition was made worse; it must beremembered that the change in exercise tolerancewas determined by comparison with the maximumamount of work that the patient could performwhile taking placebos.

All positive and many negative results werechecked by re-administering the drug at a laterdate in disguised form or by comparison with theresponse to larger doses, except in a few instanceswhere a change in the patient's condition (com-plete remission of symptoms, progression of dis-ease, unavailability of the patient, etc.) prevent-ed repetition.As in previous studies2' 4` , 47-S the patients

were divided into 3 groups according to the in-crease in their exercise tolerance 2 minutes afterthe solution sublingually of 0.3 mg. nitroglycerin.Group 1 included those patients who had a

"marked response" to sublingual nitroglycerin.Group 2 patients had a "moderate response" to

sublingual nitroglycerin.Group 3 patients showed "slight response" or

"no response" to sublingual nitroglycerin.

Electrocardiographic Studies.These were carried out in a few patients to

demonstrate coronary vasodilator activity accord-ing to methods previously described.` 6, 48, 51 Cor-onary vasodilatation was indicated by preventionof S-T depression in lead 4R after the sameamount of work that caused definite S-T depres-sion plus an attack of angina pectoris when thepatient was taking placebos.

RESULTSThe results are presented in tables 1 and 2.

As in previous studies2-6' 47, 50, 52 the 20 group1 subjects were far more likely to respond to

other medication than were the 5 group 2 orthe 9 group 3 patients. Comparison of theeffects of medication, therefore, is best ob-served in group 1 subjects (fig. 2).

Nitroglycerin

Sublingual Administration. The dosage usedcaused no untoward effects in the 34 subjects.Thirteen of the 20 group 1 patients were ableto exercise until fatigued without developingangina. The remaining 7 were able to increasetheir exercise tolerance by 62 to 135 per centbefore they developed angina.

Subcutaneous Administration. In 7 of the10 group 1 subjects, the degree of beneficialresponse was comparable to that followingsublingual administration of the same dose.

Oral Administration. Thirteen of the 15group 1 subjects who swallowed capsules con-taining 0.45 mg. of nitroglycerin showed nosignificant response while only 2 showed"moderate" increases in exercise tolerance.The swallowed dose of nitroglycerin neces-

sary to increase the ability to exercise isshown in table 3. In 11 group 1 subjects, a"marked response" required a minimum of2 or 3 mg. in 3 patients, 5 or 6 mg. in 2 pa-tients, and 15 mg. in 2 patients. Two otherpatients showed a moderate response to 2 or4 mg. but did not receive larger doses. Theremaining 2 subjects failed to show a responseafter 15 mg. There were no untoward effects.

Fourteen group 1 subjects received Nitro-glyn (table 3). Six showed a "marked re-sponse;" 1, after 1 tablet (6 mg.) ; 2, follow-ing 12 mg.; 3 required 18, 24, and 30 mg.,respectively. Two additional patients showeda "moderate response" after 12 and 24 mg.,respectively. Two patients showed no responseto as much as 30 mg. The remaining 4 showedno response after 12 mg., but received nolarger doses.

Administration by Inunction (table 4). Oneof 6 group 1 patients showed a "marked re-sponse " to Nitrol Ointment and 3 othersshowed responses that were "moderate" butappreciably less than followed sublingualnitroglycerin in the same patients.

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NITRITES IN TIlE TREATMENT OF ANGINA PECTORIS

Erythrol Tetranitrate

Sublingual or Buccal Administration. In the20 group 1 patients the magnitude of the re-

sponse to 15 mg. was comparable to that fol-lowing nitroglycerin in 9 subjects, somewhatless, but of considerable benefit in 8, and of

little value in the remaining 3 patients. Inaccordance with previous studies, the clinicalresponse during the weeks of administrationwas uniformly excellent in those patients whoshowed a "imarked" or a "moderate re-

sponse. "

Patients did not object to sublingual or

buccal use of the drug during the compara-

tively short period of study. Severe poundingheadache similar to that experienced by some

patients after nitrogylcerin was reported by2 of the total 34 patients. This was relievedby aspirin. More severe headache, sufficientto cause the patient to discontinue the medi-cation, was reported by 4 patients who took 2tablets (30 mg.).The beneficial action of the drug did not

become evident until 6 to 10 minutes afterthe drug was placed under the tongue. Theduration of action persisted for at least 1 to2 hours after dissolution of the tablet (table5) .

Siubeittan eoius Administration. Five out of7 group 1 patients responded to parenteralinjection but the increase in exercise tolerancewas somewhat less than what followed sub-lingual administration.

Oral Adninlistration. Swallowing 30 mg. oferythrol tetranitrate was distinctly less bene-ficial than sublingual or subcutaneous admin-istration of 15 mg. (table 2).Administration by Inunction. The results

were similar to those obtained with nitroglye-erin ointment in 6 of the 7 patients studied(table 4).

M1annitol Hexanitratc

Here again the nitrite was comparativelyineffective when swallowed but highly effectivewhen given by the sublingual route. Therewere no untoward effects.

Triethanolamine Trivit rate BiphosphateSublingual Administration. Of 12 group 1

subjects, 2 showed a "marked response," 3 a"moderate response," 4 "no response," and3 discontinued the therapy because of painfulsublingual stomatitis. One additional patient(who showed a "moderate response") had asimilar stomatitis but continued therapy. Ingeneral, the increase in exercise tolerance wasless than after sublingual erythrol tetranitrateor nitroglycerin.

Oral Administration. All 21 patients whoswallowed 6 mg. of Metamine 3 times a dayfor at least 1 week showed "no response."There were no headaches or other untowardeffects.

Parenteral Administration. One out of a

group 1 patients had a "moderate response."

Pentaerythritol TetranitrateThis drug was not administered parenteral-

ly or by inunction.Sublingual Administration. Two out of 15

group 1 subjects showed a "marked re-sponse, " and 6 a "moderate response." Therewere no untoward reactions. In general themagnitude of the response was less than thatfollowing nitroglycerin, but somewhat greaterthan when pentaerythritol tetranitrate wasswallowed.

Oral Administration. Out of 17 group 1patients 1 showed a "marked response," and4 a "moderate response." There were no uti-toward reactions.

Sodium NitriteThe route of administration did not affect

the results as strikingly as with other prepara-tions used in this study, but untoward effectswvere frequent and related to peripheral ratherthan intracranial dilatation.

Sublingual Administration. This was em-ployed in 16 group 1 patients. No patient hada "marked response," while 4 had a "moder-ate response." Four patients omitted thedrug because of faintness; 1 additional pa-tient continued the drug despite faintness andshowed no therapeutic response.

Subcutaneous Administration. One of the 6group 1 subjects had a "marked response," 2

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TABLE 4.-Comparative Effect of Nitrites Given Sublingually and by Inunction

Increase in exercise tolerance (per cent)Placebos(orally) Nitroglycerin Ointment

Patient Sex Age S.L.S.E.T.T. trips Erythrol

Nitroglycerin tetranitrate

H.N. M 67 24-28 142t 71 50tI.K. M 63 16-23 135 - 4 -7

t M.R. M 51 29-34 106t 47 0£ E.W. F 65 19-23 93 26 18: F.D. F 50 26-30 76 -13

M.F. M 69 54-76 45t 29 24

0

T.Mc.F.B.

MF

6554

33-3630-34

6-12

-17-18

-17-21

S.E.T.T., Standardized Exercise Tolerance Test; S.L., Medication administered sublingually.tNo attack of angina pectoris induced.- A decrease in exercise tolerance as compared with the maximum amount that could be performedduring the placebo trial.

TABLE 5.-Speed of Onset and Duration of Action of Erythrol Tetranitrate Administered Sublingually toGroup 1 Subjects

Increase in S. E. T. after sublingual administration of erythrol tetranitrate (per cent)

S.E.T.T. Minutes after sublingualwhile taking administration (before dissolved) Hours after solution of tablet

Patient Sex Age placebos || -

trips Im-3 6 10 15 20 medi- %4 V4 1 2 3 4

ately

H.N. M 67 24 -28 - l 36t52t 50t 50t 50 46I.K. M 63 16 - 23 - - 74 - - 106 39 30 13M.Ke. F 60 25 -30 47 - - -57 - -

M.R. M 51 29 - 34 12 50 24 184 146 41t - - 40 - 36 26E.W. F 65 19 - 35 40 82 57 78t 78t44 13 13 -

M.B. M 74 29-33 15 3 70 100t 70t 94t 88t 39 9A.T. F 64 18218- 27 - - 74t - - 74 - 93 -18

S.E.T., Standard Exercise Tolerance; S.E.T.T., Standardized Exercise Tolerance Test.t No attack of angina pectoris induced.- A decrease in exercise tolerance compared with the maximum amount that could be performed duringing the placebo trial.

showed "moderate response," and 1 was notexercised because of faintness. Five subjectswho had untoward reactions when given thedrug by other routes did not receive it par-enterally.

Oral Administration. Of 18 group 1 subjectswho swallowed this drug 2 showed a "markedresponse," and 3 a "moderate response."Three discontinued the drug because of faint-ness, pallor, and sweating. Doses of 180 mg.and 6() mg. caused similar but less severe re-

actions, accompanied by a fall in blood pres-sure in these 3 patients, even when the 60-mg.tablet was disguised. One additional patientnoted faintness but continued the drug.

Electrocardiographic StudiesElectrocardiographic studies before and

after exercise were carried out in 8 subjects(4 in group 1, 1 in group 2, 3 in group 3),following the administration of placebos,nitroglycerin sublingually, and both erythrol

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TABLE 6.-Effect of Medication on the Degree of S-T Depression Induced by Exercise

Placebo Nitroglycerin Erythrol tetranitrate Triethanolaminetrinitrate biphosphate

S.L. or P.O. S.L. S.L. P.O. 3.L. P.O.

S-T S-T S-T S-T S-T S-TSubject Number depres- Number depres- Number depres- Number depres- Number depres- Number depres-

of sion* of sion* of sion* of sion* of sion* of sion*trips (mm.) trips (mm.) trips (mm.) trips (mm.) trips (mm.) trips (mm.)

Group 1H.N. 28 0.8 28t 0.0 - 28t 1.15 _ 28 0.82M.B. 33 0.95 33t 0.15 -A.T. 27 2.5 27t 1.45 27t 1.8 27 1.25M.P. 32 0.85 32t 0.0 30t 0.12 32 0.0 30t 0.67 30 -1.0

Group 2E.R. 20 1.6 20t 0.45 20 0.5 20 1.85 20 1.5

Group 3T.Mc. 30 6.4 30t 3.25 30t 2.72 28 4.0 32 2.25 30 2.85A.Z. 22 0.95 22 0.15 - - - -

F.B. 30 0.95 30t 1.0 - - 25 0.7 25 0.55

S.L., Medication administered sublingually or in* Average of 10 consecutive complexes.t No attack of angina pectoris induced.

tetranitrate and triethanolamine trinitratebiphosphate administered sublingually and byswallowing (table 6).The S-T depression in lead 4R after exercise

was appreciably less in 6 out of 7 subjects whoreceived nitroglycerin sublingually, in all 4subjects who received erythrol tetranitratesublingually, in 3 out of 5 who received thisdrug by mouth, in 2 out of 4 who receivedMetamine sublingually, and in 2 out of 4 whotook this drug by mouth.

DISCUSSIONIn this study, as in previous studies,2'5'6'48-50

a "marked response " or a "moderate re-sponse" to medication as measured by theStandardized Exercise Tolerance Test, was ofclinical significance. Patients who showed thisdegree of response experienced no attacks oralmost no attacks in daily life while takingthe medication, and such results were repro-duced even when the medication was dis-guised. In contrast, a "slight response" tomedication was of no clinical significance andany apparent clinical improvement was fortui-tous or due to the patient's faith in therapyand was not likely to be persistent or repro-ducible. Since group 1 subjects (those who

buccal pouch; P.O., Medication administered by mouth.

show a " marked response " to nitroglycerinadministered sublingually) are the ones mostlikely to respond to other efective medication,study of this group makes it possible to com-pare the effectiveness of medication with aminimum of confusing data (fig. 2).Not only do patients differ greatly in their

response to treatment, but drugs also differconsiderably in their effectiveness in prevent-ing attacks of angina pectoris. In accord withprevious studies2' 3 5, 6 therapeutic measurescan be divided into 3 groups. Group A in-cludes drugs that are highly effective bothclinically and by exercise tolerance studies ina large number of patients, especially group1 subjects (those responding to sublingualnitroglycerin). Group B includes drugs ofonly moderate value in such subjects. GroupC drugs are of little or no value.

Nitroglycerin. When administered sublin-gually, nitroglycerin is the most effective ofall group A drugs in common use. Not onlydo more patients show a response to this formof treatment, but the degree of response (i.e.,the amount by which the patients' exercisetolerance can be increased before angina isinduced) is greater than is observed after anyother medication. Because of its short dura-

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NITRITES IN THE TREATMENT OF ANGINA PECTORIS3

0

Ia_z 60-

o 40

0

W

NITROGLYCERIN ERY THROLTETRANITRATE

Ie SUBLINGUAL

c SUBCUTANEOUS

a] ORAL

MANNITOL TRETHANOLAMINE PENTA- SoM

HEXANITRATE TRIt4TRATE ERYThRITOL NITRITEBAPHOSPIATE TETRANITRATE

FIG. 2i. Frequency of moderate or marked response of group 1 subjects to 6 nitrites administcredslub)lingually, subcutaneously, and when swallowed.

tion of action, the prophylactic use of thisdrug is usually limited to administration im-mediately before undertaking any task.

Nitroglycerin administered by mouth, onthe other hand, is a group C drug and is oflittle clinical value to most patients in thedoses usually employed. To be effective whenswallowed, a single dose of nitroglycerin mustlie many times larger than the usual sublingualone (table 3). The reasons for this markeddifference in effectiveness is not known. Theequal effectiveness of nitroglycerin given sub-cutaneously and sublingually suggests thatthe drug is inactivated in the gastrointestinaltract. Hypodermic administration of nitro-glyeerin has limited value in clinical practicebecause of the inconvenience of self-medica-tion; it might be of value in the treatment ofacute exacerbations of the disease, but sub-lingual administration is as effective andsimpler to use.The results with Nitroglyn, a pharmnaceu-

tical preparation of nitroglycerin intended fororal use, are in accord with these findings.Nitroglyn is a group B drug. It was of markedor moderate value in 57 per cent of 14 group1 patients, but only in doses that were 2 to 4

times larger than that advocated by the manu-facturer and many times larger than original-ly advised. At least part of the lack of objec-tive evidence of the usefulness of nitroglycerinwhen given by mouth may be due to the shortduration of action, if so, it limits further theclinical value of this form of treatment.The effectiveness of nitroglycerin by inunc-

tioin (group B) is of interest because itillustrates the well-known fact that this drugcan be absorbed through the unbroken skin.This characteristic is responsible for the head-aches of workers manufacturing dynamite.The lack of popularity of treatment by inunc-tion further limits its value in present dayclinical therapy of angina pectoris.Erythrol Tetranitrate. According to the

present and previous studies in this labora-toryi' 2 erythrol tetranitrate, when swallowed,is a group B therapeutic agent, i.e., it is effec-tive to a moderate degree in a small percentageof patients. In marked contrast, however, arethe results of the present investigation thaterythrol tetranitrate, given sublingually, isone of the most highly effective group Aagents. The frequency of this beneficial actionand the degree of increase in exercise tolerance

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after sublingual erythrol tetranitrate approxi-mate the effects of nitroglycerin, amyl nitrite,and octyl nitrite more closely than do anyother of the approximately 100 preparationstested in this laboratory. Furthermore, theduration of this beneficial action is prolongedsufficiently to make this method of treatmentof practical clinical value. On the other hand,the speed of onset of action is too slow topermit its use for the treatment of individualattacks. Further studies of the speed of onsetand duration of action are advisable withtablets especially prepared for sublingual orbuccal use, but the solubility of erythroltetranitrate in water is much less than thatof nitroglycerin and it is unlikely that it canreplace the latter drug for the treatment ofindividual attacks. The slow disintegrationtime of the available tablets may be of someadded value in prolonging the duration ofaction. The absence of local discomfort makesit possible to retain the tablet in the buccalpouch for prolonged periods without interfer-ing with normal activity (including speech);for obvious convenience, it is probably advis-able to use the drug after meals.With the doses used (15 mg. t.i.d.) head-

ache was infrequent; with larger doses (30mg.) severe pulsating headache was oftentroublesome. This is probably due to intra-cranial vasodilatation and is additional evi-dence of the drug's activity; it is seen fre-quently with large doses of the active nitritessuch as nitroglycerin, amyl nitrite, and octylniitriterb53-' as well as with erythrol tetrani-trate, but it is not seen with the other weakernitrites used in this study, nor with otherweak vasodilators such as the purines and thecinchona alkaloids.1' 6, 52The beneficial results of erythrol tetrani-

trate when given subcutaneously or by inunc-tion are additional evidence of its absorptionparenterally and from the skin respectively.This action is probably of limited clinicalapplication.Man nitol Hexanitrate. It is evident from

the present as well as previous exercise toler-a'e studies2' 21 that this is a group B drug

when swallowed in doses of 65 mg. 3 timesdaily. In contrast, although the number ofsubjects in the present series is small, it isevident that mannitol hexanitrate is a groupA drug when administered sublingually.The practical clinical value of this thera-

peutic procedure is decreased considerably bythe size of the tablets available on the market.The commercially available tablets are largebecause the Bureau of Explosives has advisedthat mannitol hexanitrate be diluted with atleast 10 parts of inert material to assure safetyin transportation. This degree of dilutionmay not be essential, however, for although theAmerican preparation of its close relative,erythrol tetranitrate (Merck) also is marketedin a dilution of 1 :15, the British preparation(Burroughs Wellcome) has been marketed foryears in approximately a 1:2 dilution.

It is evident that as the number of carbonatoms in the chain, or as the size of the mole-cule is increased, the vasodilator activity isdecreased even though the number of -ONO2groups may be increased. Thus the effectivesublingual dosages for nitroglycerin, erythroltetranitrate, and mannitol hexanitrate is 0.3,15, and 65 mg., respectively, while the effec-tive sublingual doses for Peritrate and Meta-mine are considerably larger than that ofnitroglycerin.

T'riethanolamninl e T r in it rate Biphosphate(Alletaniine). Here again the drug was muchmore effective when given sublingually or byinjection than when given by mouth. Head-ache was not experienced; this suggests thatits vasodilating action is comparatively weak.Other untoward effects, however, (e.g., stoma-titis when given sublingually and pain whengiven intramuscularly) limit its usefulness bythese more effective routes.

Pentaerythritol Tetranitrate. This drug isof definite but moderate value in a small per-centage of patients. It is classified, therefore,as a group B drug. There was no great differ-ence in the frequency or degree of its effec-tiveness by the sublingual or by the oral route.This is in accordance with the fact that it isnot readily absorbed from the skin or gastro-

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intestinal tract ;12, 13 and also with the reportthat munitions workers who handle the chemi-cal do not develop the typical nitrite headache.The frequency of beneficial results with

pentaerythritol tetranitrate in the subjects ofthe present series would seem to be less thanthat demonstrated by the objective electro-cardiographic studies of Russek et al.10' 31 Thisdifference, however, is probably not as greatas would appear, because Russek 's subjectswere limited to those whose electrocardio-graphic changes following exercise could beprevented by the administration of nitroglyc-erin. It would appear, therefore, that Rus-sek's subjects corresponded to the more sus-ceptible group 1 patients of the present seriesand such patients are likely to respond topentaerythritol tetranitrate.Sodium Nitrite. The discrepancy between

the striking responses reported in animal ex-periments45 where the drug was given paren-terally and the comparative ineffectiveness ofthe drug when given orally to patients withangina pectoris' is probably due at least inpart to the different routes of administrationemployed in these 2 studies and in part tothe much smaller doses usually given clinical-ly.

It is evident that larger doses (300 mg.t.i.d.) are much more eSective than the 60mg. doses usually employed in men. Thedrug is equally effective when absorbed fromeither the buccal mucosa or the gastroin-testinal tract, but it is more effective whengiven parenterally. The frequency of effec-tiveness parenterally would probably havebeen greater in the present series if it hadbeen administered to the 5 additional patientswho developed untoward reactions when tak-ing the drug sublingually or by mouth. Theuntoward reactions from this drug are quitedifferent from, and more frequent than, thoseseen following the other nitrites. Headachewas not encountered but hypotensive reactionsoccurred in over one third of the group 1patients. This further limits the clinical use-fulness of the drug in the treatment of anginapectoris.

Electrocardiographic Studies. Nitroglycerin,erythrol tetranitrate, and Metamine in thepresent series and with pentaerythritol tetra-nitrate in other series10' 31 yield objectiveelectrocardiographic evidence of a true phar-macodynamic activity indicating that theyprevent or diminish myocardial anoxia, pre-sumably by coronary vasodilatation. Suchelectrocardiographic studies cannot be ac-cepted as evidence of therapeutic efficiency,however, for the following reasons: 1. Thereis no constant relationship between the occur-rence of the electrocardiographic changes andthe occurrence of cardiac pain. 2. Only asmall percentage of angina patients are suit-able for such studies.4' 31 51 Thus, althoughelectrocardiographic studies after exercise oranoxemia demonstrate a pharmacologic effect,they yield no information concerning the fre-quency of beneficial clinical effect in the pre-ponderant percentage of patients who are notsuitable for such electrocardiographic studies.3. Technical difficulties make it difficult toreproduce identical results on repeated tests.This is especially true in patients with anginapectoris because the electrocardiogram at restmay show varying degrees of S-T depressionspontaneously on different days.Untoward Effects. The occurrence of head-

ache with nitrate therapy has been discussed.It is of short duration and can be avoided bydecreasing the dose or can be treated withaspirin. The possibility of other untowardeffects with prolonged use of the nitrites, al-though unlikely, must be kept in mind.Early reports56' 57 suggested the possibility

of methemaglobinemia because of cyanosis ora brown discoloration of the blood. Earlyspectrophotometric methods, although morespecific than these clinical observations, weresubject to inaccuracies and inconsistencies.58-62Modern hemoglobin spectrophotometry,63-65which permits precise diagnosis, has shownmethemaglobinemia in cases of sodium nitritepoisoning,66' 67 but it has been pointed out thatthis is unlikely with therapeutic doses.62Angina pectoris and even cardiac deaths

have been encountered in young munitions

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RISEMAN, ALTAMAN, AND KORETSKY

workers who manufacture dynamite froninitroglycerin. This may be due to reactivevasoconstriction that may occur when the drugis withdrawn abruptly after prolonged expo-

sure to large doses. The necessity for indus-trial safeguards for munitions and pharmaceu-tical workers who have prolonged or frequentexposure to nitrites has been stressed."1' 68 Thistype of withdrawal reaction has not been re-

ported following therapeutic doses.Hypotension, cardiovascular collapse, and

myocardial infarction have been reported fol-lowing nitroglyeerin69-71 or octyl nitrite,=)especially in patients consuming significantamounts of alcohol while taking nitrites.61'Such reactions are readily avoided by adjust-ing the dosage and especially by avoiding over-

dosage such as may occur if the rapidly actingnitrites are administered repeatedly with onlya few minutes between doses.

SIJTMMARY

The comparative value of 6 different nitritesill the treatment of angina pectoris when ad-ministered by the oral, sublingual, subcutan-eous, and percutaneous routes was studied in34 patients by measuring the amount of workthat could be performed under standardizedconditions without inducing angina and alsoby observing the clinical response and thelexercise electrocardiogram.

Glycerol trinitrate, erythrol tetranitrate,mannitol hexanitrate. and triethanolaminltrinitrate biphosphate were all much more

effective sublingually than when swallowed.Nitroglycerin and erythrol tetranitrate

when administered sublingually are among

the most effective of all prophylactic agentsavailable for the treatment of patients withangina pectoris. The comparatively prolongedduration of action of erythrol tetranitratewhen given sublingually makes it especiallyvaluable for clinical use.

Nitroglycerin and erythrol tetranitrate were

also effective when administered parenterallyor by inunction but their value was markedlylimited when swallowed. This suggests thatthese nitrites are inactivated in the gastroin-testinal tract. Mannitol hexanitrate also was

more effective sublingually than when swal-lowed but was of limited clinical value becauseof the large size of the tablets available. Tri-ethanolamine trinitrate was moderately effec-tive wheu administered sublingually but of nodemonstrable value when swallowed. Sub-lingual therapy with this drug is limited be-cause of the frequent glossitis that follows itsuse.

Pentaerythritol tetranitrate showed littledifference in the frequency of response whenadministered sublingually or when swallowed,but the increase in exercise tolerance wassomewhat greater following sublingual admin-istration. This drug was only of moderatevalue in the treatment of patients with anginapectoris.

Sodium nitrite was more effective whengiven subcutaneously than when given sub-lingually or when swallowed, but the degreeof value was low and the frequency of un-toward reactions was too high to indicateclinical value.

SUMMAmR1 IN INTERLINGUALe valor comparative de 6 differente nitritos

in le tractamento de angina de pectore, admin-istrate per via oral, sublingual, subcutanee, epercutanee, esseva studiate in 34 patientesper mnesurar le quantitate de labor que potevaesser executate sub conditioners standardisatesin induction de angina e etiam per observarle responses clinic e le electrocardiogrammasa exercitio.

Glycerol trinitrate, erythrol tetranitrate,mnannitol hexanitrate, e triethanolamino trini-trate biphosphate esseva omnes plus efficace inadministration sublingual que post inglutition.Nitroglycerina e erythrol tetranitrato, quandoadministrate per via sublingual, es inter leplus efficace de omne le agentes prophylacticdisponibile pro le tractamento de patientescon angina de pectore. lie comnparativementeprolongate duration del action de erythroltetranitrate post administration sublingualrende iste agente specialmente utile pro usosclinic.

Nitroglycerina e erythrol tetranitrate essevaetiam efficace quando administrate per via

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parenteral o per inunetion, sed lor valor essevamulto restringite post inglutition. Iste ob-servation suggere que le duo nitritos es inac-tivate in le vias gastrointestinal. Etiam man-nitol hexanitrate esseva plus efficace post usosublingual que post inglutition, sed iste agenteesseva de limitate valor clinic a causa delgrande dimensiones del tablettas in que illoesseva disponibile. Triethanolamino trinitrateesseva moderatemente effieace quando admin-istrate sublingualmente e sin valor demon-strabile quando inglutite. Le uso therapeuticde iste droga es restringite a causa del fre-quentia de glossitis que seque su administra-tion sublingual.

Pentaerythritol tetranitrate differeva paucoin le frequentia del responsa post administra-tion sublingual e post inglutition, sed leaugmento del toleration de exercitio essevalevemente plus marcate post administrationessublingual. Iste droga esseva solmentemoderatemente utile in le tractamento de pa-tientes con angina de pectore.

Nitrito de natrium esseva plus efficacequando administrate subcutaneemente quequando administrate sublingualmente o peringlutition, sed le grado de su valor essevabasse, e le incidentia de reactiones adverseesseva troppo frequente pro indicar un valorclinic.

REFERENCES1. RISEMAN, J. E. F. AND BROWN, M. G.: Medic-

inal treatment of angina pectoris. Arch. Int.Med. 60: 100, 1937.

2. -: The treatment of angina pectoris: A sum-mary of ten years' objective study. NewEngland J. Med. 229: 670, 1943.

3. -: The present status of treatment in an-gina pectoris. Connecticut State M. J. 9:99, 1945.

4. FREEDBERG, A. S., SPIEW,, E. D. AND RISE-MAN, J. E. F.: Objective evidence of the ef-ficacy of medicinal therapy in angina pec-toris. Am. Heart J. 22: 494, 1941.

5. -, RISEMAN, J. E. F., AND SPIEGL, E. D.:Octyl nitrite in the treatment of anginapectoris. Am. Heart J. 22: 519, 1941.

6. RISEMAN, J. E. F., STEINBERG, L. A. ANDALTMAN, G. E.: Treatment of angina pee-tOris with cinehona alkaloids. Circulation 10:809, 1954.

7. FIELD, A. G.: On the toxical and medicinal

properties of nitrate of oxyde of glycyl. Med.Times & Gazette 16: 291, 1858.

8. MURRELL, W.: Nitro-glycerine as a remedy forangina pectoris. Lancet 1: 80, 1879.

9. EVANS, W. AND HOYLE, C.: Prevention andtreatment of individual attacks of angina pec-toris. Quart. J. Med. 3: 105, 1934.

10. RUSSEK, H. I., ZOHMAN, B. L., DRUMma, A. E.,WEINGARTEN, W., AND DORSET, V. J.: Longacting coronary vasodilator drugs: Metamine,Paveril, Nitroglyn, and Peritrate. Circulation12: 169, 1955.

11. HUPPERT, V. F. AND BOYD, L. J.: Sustained-action nitroglycerin (Nitroglyn) in anginapectoris due to coronary sclerosis. Bull. NewYork M. Coll. 18: 58, 1956.

12. VON OETTINGEN, W. F., DONAHUE, D. D.,LAWTON, A. H., MONACO, A. R., YAGODA, H.AND VALAER, P. J.: Toxicity and potentialdangers of penta-erythritol tetranitrate(PETN). Public Health Service Bulletin No.282, U. S. Public Health Service, 1944.

13. -: The effects of aliphatic nitrous and nitricacid esters on the physiological functions withspecial reference to their chemical constitution.National Institute of Health Bulletin No. 186,U. S. Public Health Service, 1946.

14. DAVIS, J. A. AND WIESEL, B. H.: The treat-ment of angina pectoris with a nitroglycerinointment. Am. J. M. Sc. 230: 259, 1955.

15. HEFNER, L. L., FRIEDMAN, B., REEVES, T. J.,EDDLEMAN, E. E., AND HARRISON, T. J.: Sym-posium on coronary dilator drugs. Circulation15: 111, 1957.

16. BRADBURY, J. B.: The Bradshaw lecture onsome new vaso-dilators. Brit. M. J. 2: 1213,1895.

17. KRANTZ, J. C., CARR, C. J., FORMAN, S. E.AND ELLIS, F. W.: Alkyl nitrites. IV. Thepharmacology of isomannide dinitrate. J.Pharmacol. & Exper. Therap. 67: 191, 1939.

18. -, , -, AND CONE, N.: Alkyl nitrites. VI.A contribution to the mechanism of the actionof organic nitrates. J. Pharmacol. & Exper.Therap. 70: 323, 1940.

19. BOYER, N. A. AND GREEN, H. P.: The effectsof nitrites and xanthines on corona 'y inflowand blood pressure in anesthetized dogs. Am.Heart J. 21: 199, 1941.

20. LEVY, R. L., BRUENN, H. G. AND WILLIAMS,N. E.: The modifying action of certain drugs(aminophyllin, nitrites, digitalis) upon theeffects of induced anoxemia in patients withcoronary insufficiency, with remarks on ther-apy. Am. Heart J. 19: 639, 1940.

21. SPIEGL, E. D., RISEMAN, J. E. F., AND FREED-BERG, A. S.: Unpublished data.

22. BJERLOV, H.: Nitropent, ett nytt medel mot

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angina pectoris. Svenska lik.-tidning. 40:694, 1943.

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21. DAILHEU-GEOFFREY, P.: Action comparee dela pentanitrine (penta-erythrite tetranitree)et des autres vaso-dilateurs coronariens dgns1'angine de poitrine; Etude de 258 cas per-sonnels, dont 97 traites par la pentanitrine.Quest m6d. 3: 319, 1950.

25. MARCHE, J.: Le traintement des coronariteschroniques par les esters nitres des polyalcools.Fiches med. 144: 1, 1950.

26. PERLMAN, A.: A study of the therapeutic ac-tion and toxicity of pentaerythritol tetrani-trate. Angiology 3: 16, 1952.

27. PLOTZ, M.: Pentaerythritol tetranitrate: Anew drug for the treatment of coronary in-sufficiency. New York State J. Med. 52: 16,1952.

28. ROSENBERG, H. N. AND MICHELSON, A. L.: Theuse of pentaerythritol tetranitrate in chroniccoronary insufficiency. Am. J. M. SC. 230:254, 1955.

29. WINSOR, T. AND HuJMPHREYS, P.: Influence ofpentaerythritol tetranitrate (Peritrate) onacute and chronic coronary insufficiency. An-giology 3: 1, 1952.

30. WEITZMAN, D.: Pentaerythritol tetranitrate inthe treatment of angina. Brit. M. J. 2: 1409,1953.

31. RUSSEK, H. I., URBACH, K. F., DOERNER, A.A. AND ZOHMAN, B. L.: Choice of a coronaryvasodilator drug in clinical practice. J. A. M.A. 153: 207, 1953.

32. Rossi, B.: Clinical and electrocardiographicstudy of some cases of hypertension and an-gina pectoris treated with peritrate. Angi-ology 6: 59, 1955.

33. WINsoR, T. AND SCOTT, C. C.: Further ob-servations of the cardiovascular effects ofpentaerythritol tetranitrate in animals andman. Am. Heart J. 49: 414, 1955.

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JOSEPH E. F. RISEMAN, GEORGE E. ALTMAN and SIDNEY KORETSKYComparison of Six Preparations and Four Routes of AdministrationNitroglycerin and Other Nitrites in the Treatment of Angina Pectoris:

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Nitroglycerin and Other Nitrites of Angina · in vasodilating action on sublingual administration is seen also with mannitol hexanitrate and triethanolamine trinitrate and to a lesser