The Pharmacology

C. Greenwood, M.B., B.Ch.,

of Ketotifen

Dip.Phar,n.Med.*

K etotifen
(Fig basis blocking showed models

is a benzocycloheptathiophene 1) which was selected for clinical and selective histamine pharmacologic activity. Subsequent

derivative trials on the receptor studies

of its powerful that ketotifen of anaphylaxis

was active in experimental which are not usually influenced

by antihistamines, histaminic activity, ketotifen also had

and during clinical tests for antithe observation was made that properties which indicated that it bronchial ketotifen will experi-

could be effective as a prophylactic against asthma. The early pharmacologic findings with have ments been with well documented. more recent This communication concentrate on the ketotifen.
OF

pharmacologic

DISSOCIATION ANTIHISTAMINIC

ANTI-ANAPHYLACTIC PROPERTIES
OF KETOTIFEN

AND

The model (PCA).

best of

recognized properties

test

for of

the a

identification compound in is the by

of the rat inrich

antianaphylactic passive The rats

cutaneous anaphylaxis are passively sensitized of a homologous sites antigen separate of the on their triggers

tracutaneous in IgE travenous reaction visible injected diameter reaction serotonin intradermal challenge. at

injection three injection

antiserum

back. Inan allergic becomes has been The of the

FIGURE

I
CH3
1. Chemical structure of Wander, Ltd). Hydrogen fumarate den-4H-benzo [4,5] cyclohepta [1,2-bI ketotifen (Zaditen, Sandoz] of 4-(1-methyi-4-piperidylithiophene-lO (9H)-one.

in the sensitized through exudation intravenously of the blue

skin sites, which of the blue dye that

together with the antigen. spots is taken as a measure

intensity. Antagonism of histamine and of can be estimated in the same animal by injection of the amine immediately before compound two pure disodium antihistaminic cromoglycom-

The ketotifen

time on

course the skin

of

the reaction

inhibitory induced

activity either

of by
and

If the anti-allergic cate (DSCG) and

Table 1-Effect of Ketotifen, Clemastine, Mepyramine Disodium Cromoglycate (DSCG) in the Rat Skin Test
Percent Dose mg/kg Test No rats 12 10 10 12 given DSCG percent case in the PCA 665 173 243 638 before was given

pounds, clemastine and mepyramine, with ketotifen in the rat PCA test and

are compared rat histamine and ketotifen reactions DSCG

compound*

inhibition Serotonin Reaction 33 52 33 0 of the before. formation animal for per skin

serotonin skin reactions, it can be seen that inhibits the PCA and the histamine-induced to a similar extent (Table 1). As expected, inhibits mine, have PCA, despite but having neither strong effect on influences clemastine antihistaminic the the PCA. skin

Histamine Reaction 703 834 943 0 induction 1 mm SE

iv 0.1 1.0 5.6 3.2

nor mepyraproperties, None reaction of the in-

Ketotifen Clemastine Mepyramine DSCC The compounds except represent per animal and were for mean

a significant

compounds tested duced by serotonin.

6dlmnicai Reprint Research requests:

5 mm which

reactions, Sandoz Ltd., Basle, 386/949 Sandoz Switzerland. AG, Rasel tValues CH at 3 sites histamine-

Department, Dr Greenwood,

inhibition of PCA and reactions,

of spot

at 2 sites

4002,

Su,itzerland

serotonmn-induced

respectively.

CHEST

/ 82 I 1 I July.

1982

I Supplement

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j T

T
Ui XZ 5O%

. #{149}

:
0% 4 8 16 64

:
FIGURE

2. lime

course

of the

anti-anaphylactic

(0)

r28

56

512 PRETREATMENT INTERVAL (MIN)

and the antihistammnic (0) actions of ketotifen. Ketotifen was administered at a dose of 1 mg/kg iv to animals which were sensitized passively 24 hours in advance by the intracutaneous injection of antiserum (at three sites). Histamine skin reactions (at two sites) and PCA (by intravenous administation of the antigen) were then induced between 5 and 512 minutes after administration of ketotifen. Each point represents the mean percent inhibition SE of spot formation in five animals.

antigen or by histamine in the rat is demonstrated Figure 2. Maximum inhibition of both antigen histamine reactions is obtained between four and

in and eight

other does

showing that the anti-allergic not depend on its histamine

INHIBITION OF MEDIATOR

action blocking
RELEASE

of ketotifen activity.

minutes after an intravenous dose of 1 mg/kg of ketotifen. The protection against the antigen-induced effect decreases progressively with time, having disappeared almost completely trast, the inhibition of
starting

and

The release of mediators, in particular histamine slow reacting substance of anaphylaxis (SRS-A) is to play It a major role in the pathogenesis of has been established that histamine is stored in the cytoplasmic granules of mast basophils, and released by exocytosis. SRShand, a mixture ofleukotrienes,23 is not cell and formed from In addition, arachidonic acid upon SRS-A is also produced

after four hours. By conthe histamine reaction is some skin

eight

thought asthma. preformed, cells and

administration In the

to decrease only of ketotifen. same combined

hours ketotifen

after and

test,

A, on the other stored but stimulation.4

clemastine, the latter a classic H1-antagonist, to rats separately or in combination, and and The

are given the allergen

histamine skin reactions induced one hour later. results are presented in Table 2. Both compounds the histamine skin reaction and when show an additive effect. In the allergen given test,

inhibit together

released by cells which do not store or release histamine.5 The effect of ketotifen on anaphylactically-induced mediator release is investigated in the chopped human
100

however, ketotifen alone is effective and the addition of clemastine does not produce any greater inhibition. These results indicate that ketotifen has both antihistaminic and anti-allergic properties, clemastine is a pure antihistamine. The antihistaminic and antiallergic ketotifen Table can 2-Effects
and

whereas properties from each of

r.

#{149}J; ::
#{149}#{149}
5-4 S.
S. U U)

thus

be

clearly

dissociated

of Combined Administratkm Clemastine in the Rat Skin

Percent Dose mg/kg No rats 5 5 5 PCA 538 154 524

of
Test

Ketotfen

50
00
00

..

ui
mnhibitiont Histamine Reaction 865 474 1000
-j U

00 LI
0

#{149}#{149}

on
03

#{149}#{149} #{149}#{149}
#{149}#{149}I

freatment* Ketotifen Clemastine Ketotifent

po 10 18 10/18

z
0

cc
U-,

00
00

I-

00
00

00

Clemastmne
5The compounds were given 1 hour beibre induction of the skin

z
0 10 -6

C(J

#{149}#{149}I #{149}#{149}I
10 -4

:3

reaction. tValues 3 sites histaminerepresent per animal and mean percent in the case serotonin-induced inhibition of PCA, and reactions,

SE of spot formation at 2 sites per animal respectively.

at for

KETOTIFEN
FIGURE

(M0L/L)
release of

3.
(0)

histamine

Effects of and SRS-A

ketotifen on antigen-induced (#{149}) from chopped human

lung.

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lung

preparation.

Released

SRS-A

is determined

in a of is

Table

bioassay on strips of the longitudinal smooth muscle the guinea-pig ileum. The release of histamine

3-Effect of prenali ne-induced

Ketotifen on Antagonism

Tachphylaxis of Rat PCA

of isoTest
% Inhibition

estimated by an automated fluorometric assay. The release of SRS-A isinhibited to a large extent by preincubation with 10 mol/L ketotifen (Fig 3). InhibiPretreatment NaCI Drug Isoprenaline

Dose (mg/kg) 0.0032 1 10 10 iv po po ip po 0.0032 1 iv po iv 1 0.0032 10 0.0032 1 10 0.0032 po iv po iv po ip iv

of spot diameter 52 13 3 6

tion of the release of histamine is less prominent. These results are in agreement with those published by Ross et al6 who tested the effects of ketotifen on anaphylactically-induced pig and human chopped inhibits considerably SRS-A more release potent mediator release in guinealung preparations. Ketotifen from in the both human sources, lung but prepararespecwas less fact that the by different cellular is

Ketotifen
Mepyramine Propranolol Isoprenalmne (10 tds mg/kg for Ketotifenl NaCl Ketotifen/ days) NaCl/ Isoprenaline

20

tions (38 percent tively). Inhibition

and 100 percent inhibition, of release of histamine

4 consecu-

tive

14

prominent in both preparations. These effects of ketotifen underline the two mediators of anaphylaxis are released mechanisms sources.
FUNCTIONAL ANTAGONISM OF

Isoprenaline
Mepyramine/

61

and

possibly

from

different

Isoprenaline
ICetotifen/ Propranolol/

25

SRS-A

Isoprenalmne

21

More myotonic purified

recently, the influence and bmnchoconstrictor SRS were tested. SRS

of ketotifen on the activities of partially was obtained from a rat prenaline, ited, by By thus the antigen-induced that weal ketotifen is again can isoprenaline confirmed reverse inhibthe action in an of demonstrating stimulation The SRS-insmooth

basophilic leukemia with the calcium duced muscle ketotifen comparison, inhibitory SRS contraction strip at

cell line following ionophore A-23187.7 of the isolated longitudinal

of the guinea-pig concentrations SRS-antagonist micromolar in vivo

ileum is inhibited above 0.1 mmol/L.

isoprenaline-induced tachyphylaxis. That the reestablishment of this is mediated additional propranolol, plus ketotifen by the 3-receptor group of rats. Following neither isoprenaline inhibited the PCA presented Meeting applied

was

the in the the

FPL 55712 is already range. In contrast, when to artificially-ventilated is reproducilow doses is obtained after of

the application nor isoprenaline test (Table 3). his results with in Paris in 1981. in vivo and

is administered

guinea-pigs,8 bly attenuated ketotifen. intravenous

ensuing bronchospasm by pretreatment with

Szentivanyi recently ketotifen at the Interasma He has shown that ketotifen increased the number eral lymphocytes and

An inhibition of 50 percent doses of 1 mg/kg.

CALCIUM ANTAGONISM

in vitro periphclinical have to

of 3-receptors pulmonary interesting

in canine tissue. The findings will

Ketotifen calcium the could since ated muscle ions smooth

has also been which muscle follows cell

shown

to inhibit

the These

influx results

of of

implications be investigated.

of these

sustained membrane.9

depolarization of ketotifen or by libersmooth

CONCLUSIONS

be relevant contractions autacoids membrane.

to the anti-allergic effect induced by anaphylaxis involve depolarization

Pharmacologic ketotifen Earlier acts results via

findings a number histamine show

available

so far suggest pathways. inhibition

that

of different antagonism, blockade document

of the

of phosphodiesterases nels.9 More recent

OF KETOTIFEN WiTH

and results

of Ca2 chaninhibition of

INTERFERENCE

ISOPRENALINE

The some tions.

most

recent

findings rat

indicate it

that

ketotifen

in reacthat With

mediator release A.#{176} In addition, suggest receptors,

and functional however, there

antagonism of SRSis now evidence to by action 13of

way influences Using the inhibits

the 35-receptor PCA test, the antigen-induced

mediated is shown weal.

that a more indirect effect, mediated may be involved in the therapeutic

isoprenaline

repeated administration tory effect disappears lactic. produce

of isoprenaline, and the rat becomes

this inhibitachyphynot iso-

ketotifen. Considering pathogenesis properties

the multifactorial etiology and complex of asthma, the different pharmacologic of ketotifen make it a valuable prophylactic

If a dose of ketotifen, that by itself does any inhibition, is given together with the

agent for this condition.

CHEST / 82 / I / JuI 1982 / Supplement 41S

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REFERENCES 1 Martin orally 28:770-82 2 Murphy slow Natl 3 Orning slow Nat! 4 Morris arachidonate pig 5 Aced HR. Aced L, reacting Sci RC, reacting Hammarstr#{246}m substance Sci (USA) HammarstrOm substance (USA) Piper lipoxygenase PJ, 1980; from 1979; from ihylor in the 5, Samuelsson murmne 76:4275-79 5, Samuelsson rat basophilic 77:2014-17 GW, release Tippins JR. B. Leukotriene leukemic cells. D: Proc a B. Leukotriene mastocytoma cells. C: a Proc U, R#{246}merD. active The pharmacological compound: Arzneim ForschlDrug properties ketotifen, Research of a new, a ben1978;

6 Ross Med 7 Jakschik

WJ, Chem

Harrison 1979;

RG,

Jolley

MRS, agents.

Neville

MC,

Todd

A, Verge oxazoles.

JP, et al. Anti-anaphylactic 22:412-17

1. 2-(acylamino)

anti-anaphylactic

zocycloheptathiophene.

BA, reacting cells. H,

Kulczycki substances

A, MacDonald (SRS) 1977; from

HH,

Parker

CW.

Release
leukemia

of slow (RBL-1) 8 Konzett an der 195:71-4 9 Lowe ketotifen calcium 1980; 10 stimulates Martin American cal and 3:424-60

rat basophilic

J Immunol

119:618-22 zu Untersuchungen exp Path Pharm 1940;

R#{246}sslerR. Versuchsanordnung Arch

Bronchialmuskulatur.

DA, and uptake 14:134-40 U,

Richardson sodium in guinea-pig

BE nitroprusside

The

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of

cyproheptadine, activity Prog M. and

mechanical in vitro.

The
from

role
guinea-

of

Taenia
Craps

Resp Res
Ketotifen. 1981;

of SRS-A 19:371-83 Phagocytosis

chopped lung. Prostaglandins 1980; Bretz U, Dewald B, Payne T, SchnyderJ.

Creenod Academy

C,

Baggiolmni Sciences, Drug

of Pharmaceutical Properties

PharmacologiSubstances.

the release
Br

of a slow reacting
1980;

substance

in cultured

macrophages.

Biochemical

Pharmacol

71:631-34

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