CA2030525A1

CA2030525A1 - Method and means for inducing, resp., preventing constriction of the pupil in the eye

Info

Publication number: CA2030525A1
Application number: CA002030525A
Authority: CA
Inventors: Anders Bill
Original assignee: Individual
Current assignee: Pfizer Health AB
Priority date: 1989-04-03
Filing date: 1990-04-03
Publication date: 1990-10-04
Also published as: SE8901149D0; AU627570B2; HU903583D0; HUT55994A; BG93398A; FI905952A0; WO1990011773A1; KR920700044A; AU5428290A; EP0422181A1; JPH03505224A; HU206185B

Abstract

The use of cholecystokinin and derivatives of cholecystokinin for inducing miosis in the eye (pupil constriction) after certain types of examinations and operations. Furthermore, the use of antagonists to cholecystokinin and derivatives of these for preventing miosis in the eye, for example during surgery and in cases of uveitis. The invention moreover also comprises ophthalmological compositions containing an active amount of cholecystokinin or of its derivatives or antagonists.

Description

WO 90/117~3 PCI'/SE90/00219 o ? ~ ~ j 2 ~J

ME5'HOD AND MEI~NS FO~ INDUCING ~ RESP ., PRE;VE~ING CONSTRICTION
OF TXE PUPI~ N ~HE F'f E

The invention relates to the use of cholecystokinin and derivatives of cholecystokinin for inducing miosis in the eye (constriction of the pupil) after certain types of examinations and operat_ons. Moreover the invention comprises the use of antagonists to cholecystokinin and derivatives of said antagonists for preventing moisis in the eye, for example during surgery and in cases of uveitis. Also, the invention relates to ophthalmological compositions containing an active amount of cholecystokinin, its derivatives or antagonists.

The size of the pupil in the eye is governed by two muscles in the iris, opposite in character in respect of their mode of action. One of these muscles when undergoing contraction will produce a dilatation of the pupil (dilatator muscle);
it is controlled by nerve fibers from the sympathetic nervous system. The other muscle (sphincter muscle sltuated near the iris edge region, i.e. near the pupil) will cause a diminution of the pupil. ~his muscle is governed by parasympathetic nerves which utilize acetylcholine as transmitter.

It has been known for a long time that constriction of the pupil, i.e. mlosis, can be caused by mechanisms other than acetylcholine relea~e. In particular this occurs as part of the eye's response to various kinds of irritation. Such miosis cannot be prevented by antagonists of acetylcholine such as e.g. atropine. Clinically miosis of the type produced by irritation oten implies substantial complications, e.g.
in intraocular surgery, In cases of uveites (inflammation o the u~ea), especiall~ iritis, this type o miosis will sometime~ gi-ve rise to very undesirable s~ynechiae between 90/11773 2 ~ 3 i~ 3 PCT/SE90/00~19 the lris and the lens. Miosl~ caused by lrrltation has been studied thoroughly in experimental animals; as reported in a paper from my laborato~y (Bill et al., 1979) lt was ound that such irrltatlon causes a peptide very slmilar to substance P to be released in the eye. When synthetically produced substance P was injected into the anterior chamber this produced a substantial contractive response of the sphincter muscle of the iris, thus suggestlng that thls miosis is brought about by the said peptide or a closely related substance.

It should be noted however that there are considerable variations from species to species as regards pupillary responses to substance P - despite the fact that this neuropeptide has been detected lmmunohistochemically ln the eyes of many species, including primates. It has been found inter alia that this response is totally absent ln primates (Mandahl et al., 1980) and that therefore in primates irritation-caused miosis must be due to some other substance.
Thus, the effect of certain neuropeptides is dependent on the presence or absence o~ receptors in the tlssue innervated by sensory nerves, and such presence or absence o~ receptors differs very much between animal species. For this reason it i8 entirely impossible to predict whether conditions valid in e.g. rabbit iris will be valid to the iris of monkeys or humans, and vice versa, even though the same peptide may have been identified in sensory nerves of the iris in different species.

In the rabbit, irritation will cause substance P to be released from the sensory nerve fibers in the iris. The iris sensory nerves contain a number of other potential trans-mitters, one of these being cholecystokinin (CCK) or a substance related to CCX; see Kuwayama et al., 1987. In my laboratory we have found that CCK does not induce miosis in the rabbit, despite its presence in sensory nerves.

WO90/11773 ~ 3 ~ PCT/SE90/00219 h~ile looking for the substance that i~ responsible in primates for the miosis response to local irritation we have unexpectedly found in my laboratory that CCK has a very potent miotic effect t n monkeys (Macaca fascicularis), A
dose of about 0.21 pmol (~800 picograms) in~ected into the anterior chamber will glve a half-maximal effect; a nearly maximal effect is seen at 1 pmol (-3.9 nanograms).. Fragments of the C-terminal portion of the peptide are also active:
The sulfated terminal 8-aminoacid sequence is about 10 time~
more potent than the whole CCK molecule (Figure 1 which shows how in three monkey eyes injection of CCK-8 into the anterior chamber will affect the size of the pupil). This fragment results in a decrease of pupil size also upon administration in the form of eye drops (Figure 2 which shows how corneal application of CCK-8 will affect pupil size). The amino acid sequence of CCK, its C-terminal octapeptide, and its C-terminal tetrapeptide are as follows:

Lys-Ala-Pro-Ser-Gly-Arg-Val-Ser-Met-Ile-Lys-Asn-Leu-G}n-Ser--Leu-Asp-Pro-Ser-His-Arg-Ile-Ser-Asp-Arg-Asp-Tyr-(S03H)-Met-Gly-l~rp-Met-Asp-Phe-NH2 CCK 26-33 (octaDe~tide) Asp-Tyr-(S03H~-Met-Gly-Trp-Met-Asp-Phe-NH2 CCK 30-33 (tetrapeptide~
-~rp-Met-Asp-Phe-NH2 In other experiments, in vitro, we have shown that CCK, its C-terminal octapeptide but not its C-terminal tetrapeptide will contract ~he iri8 sph~ncter mugcle isolated ~rom monkey (Pigure 3 which æhows a cumulated dose-responSe curve of the W090/1l773 - 4 - PCT/SE90/~219 ~3~ 3 ' f-cholecys inin e~fect on monkey iris ln vitro (3A) and cumulated dose-response curve of the cholecystokinln C-terminal octapeptide effect ~26-33) on monkey irl~ in vitro (3B).

It appear~ that the C-terminal octapeptlde is the more potent one of these two. Furthermore we have shown that several antagonists to CCK (CCK blockers) as e.g. CR 1409, also called "Lorglumide" (D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pentanoic acid), Proglumide DL4-benzamido-N,N-dipropyl-glutaramic acid and N-(4-chlorobenzoyl)-L-tryptophan will effectively cause the dose-response curve of CCK and its C-terminal octapeptide to be shifted to the right, or will totally block the effect of CCK on isolated iris sphincter from monkey (Figure 4 which shows cumulated dose-response curves of CCK and of its C-terminal octapeptide with and without antagonists). This means that the CC~
receptors on the smooth muscles of the iris sphincter are sub~ect to direct competitive blockage. Experiments carried out in my laboratory moreover show that Lorglumide antagonlzes CCK also in vivo with respect to the miosis response. Upon injection of 0.75 ~g of Lorglumide into the anterior chamber the dose-response curve of CCK-8 was shifted to the right by more than one order of magnitude (Figure 5 which shows CCK-8 dose-response curves with and without pretreatment with the antagonist ~orglumide).

In addition, we have found that CCK has a direct effect on a receptor pre~ent on the sphincter muscle. This may be concluded from the ~act that nerve bloc~ade with tetrodotoxin and pretreatment with indomethacin do not cause a decrease in the miosis response. These experiments show that the receptors are not located on other nerves and that cyclo-ox.ygenas~ products of arachidonic acid metabolism are not involved in the miosis response to CCK. I n addition an effect on isolated human pupil sphincter comparable to the in vitro efect on monkeyY has also been found (Figure 6 ~hich shows ~ cumulated dose-re~ponse curve of the CCK

WO90/11773 ~ 5 ~ P~/SE90/00219 J ~ ^.; "
~-termin~l octapeptlde on the sphinct~r muscle of human iris in vltro), thus confirming that the same mechanism also exists in the human eye. Capsalcln (8~methyl-N-vanlllyl-6-nonenamide) is a highly irrltative substance which in the eye of the rabbit ~Jill produce miosis due to release o substance P from sensory nerves of the iris (Mandahl et al., 1984). Experiments that have now been carried out have revealed a miotic response to capsaicin in monkeys, although this is less consistent and less pronounced as compared to the response in rabbits. Very probably this response ln the monkey is secondary to the release of a substance from the iridial sensory nerves.

The nature of the substance is still unknown, but there is good reason to believe that this substance is CCK or a closely related substance with a terminal portion similar to the C-terminal portion of CCK. This assumption is supported by experiments with animals that have shown sensitivity to capsalcin. After pretreatment with Lorglumide, a CCK an~agonist, most of the effect on the pupil was eliminated (Figure 7 which sho~s the effect of capsaicin on pupil size with and without pretreatment with 7.5 ~g Lorglumide).

It now seems highly probable that the miosis seen in human beings in irritative conditions such as iritis, uveitis, and in cases of surgery in the anterior chamber, is due to the release of a substance similar to or consisting of CCK.
Consequently it ought to be possible to prevent this miosis by means of CCK antagonists. Cholecystokinin antagonists have been subdivided into a number of different classes, i.e. such CCK antagonists that are derivatives of cyclic nucleotides and such that are derivatives of amlno ac~ds and C-termlnal and N-terminal fragments of CCK. N2,O2-dibutyryl cyclic gua~osine 3',5'-monophosphate is an example of cyclic nucleotide derivati~es that have been described as having an antagonistic effec~ against CCK.

WO90/11773 - 6 - PCT/SE~O/O~I9

2 ~ 3~ 73 Proglumide, and ( D, L-4 ~ 3, 4-dichlorobenzoylamino)-5-(~-3-methoxypropyl-pentylamino)-5-oxo-pentanolc ac~d) also called Loxiglumide or CR-1505, a~ well a3 other derivativeQ of glutaramlc acid have been ound to have a very good in-hibitory effect on CCK receptors. Lorglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pentanoic acid, also called CR-1409, as well as other derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid have also been ound to have a very good CCK-antagonistic effect. Furthermore, various synthetic peptide derivative~ of CCK and its fragments e.g. t-butyloxycarbonyl-Tyr(S~3)-Met-Gly-D-Trp-Nle-Asp-2-pheny~ethyl ester, CCK 27-33 and even peptide derivatives of substance P developed for blocking substance P receptors, e.g. (D-Pro4,D-Trp7 9 1O)-substance P4-11, have been found to have a CCK-blocking effect. It is moreover known from the literature that esters of beta-carbolines such as methyl or ethyl beta-carboline-3-carboxylate may exert an inhibitory effect on CCK. A fact that is very interesting is that there are various benzodiazepine derivatives such as e.g. 3-substi-tuted 1,4-benzodiazepine-2-amines and 4-substituted 4H-(1,2,4)-triazolo(4,3-a)(1-4)-benzodiazepines which have an inhibitory effect on CCK. Benzodiazepines such as chlordiazepoxide, diazepam and medazepam may also be active. It has also been reported recently that substances deri~ing from Aspergillus alliaceus, which are called "A~perlicins", are CCK receptor inhibitors. Starting from this group of substances additional potent derivatives have been prepared which exhibit a strong CCK receptor antagonistic effect. One of these substances is 3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-lH-1,4-benzodiazep-ine-3-yl)-lH-indole-2-carboxamide, also called L-364,718.
Thi3 suostance is one of the most efficient CCK inhibitors hithe~to known. Other inhibitors of CCK also mentioned in the literature are benzotript znd CR-1392, and A-64718.

Among the a~oresaid su~stances may be mentioned expecially the ~ollowing antagonists: Lorglumide ( CR 1409) (Makovec et al., l9a7a; 1987b), L-364,718 ~Lotti et al., 1987), Proglumide, Lo~iglumide (CR-1~5 ) and N~4-chlorobenzoyl)-L-t~ptophan.

3 ~ 7 ~ PCT/S~9OJ00219 2r~,r) .~ j .
L~W toxicity and good bioavailabillty have been reported a~
propertles of several cholecystokinln antagonists. More ~uch substances may be expected to come orth, wlth additlonal useful properties.

Substances to be used according to the present invention are previously known to be pharmaceutlcally active. So has for instance the octapeptide of CCK been utilized for emptying the gallbladder. Cholecystokinin antagonists have been studied primarily in gastroenterological disorders e.g. for the treatment of pancreatitis and to prevent contractions ln the gallbladder as well as in the central nervous system as appetite enhancing agents, see also WO 8805774.

The possibility of preventing undesired noncholinergic miosis by means of antagonists to CCK is now presenting itself as a highly interesting, novel concept for potential therapies of practical importance, in the first place in such contexts where the lens is being extracted and thls is then followed by insertion of an artificial lens, but also in contexts of other intraocular surgeries, for instance surgery in the posterior segment. Blockage here can be effected by way of local and/or optionally general admin-istration of the antagonist. There are also situations where a miosis is desirable - for example after a lens implantation has been made if the pupil width is then too great, or after examination of the fundus of eye under cholinergic blockade.
A possibility to then bring about miosis with the aid of CCK
or fragments thereof appears to be a very attractive concept.
LoGal administration directly into the aqueous humor when surgery is being perfomed, topically on the cornea, or subconjunctivally, may be expected to produce the effect desired.

A factor of some importance in these conditions is probably the release of a ~eptide having a terminal sequence similar to CC~ or CC~-8 from ner~es or a protein degradation product WO90/11773 ~ PCT/SE90/OOZIg '~,a3~'~'3'')~"~
comprising a similar sequence. In such a case treatment with CCx antagonists presents itself as a highly at~ract~ve possibility for preventing miosis.

The present invention thus relates to cholecystokinin, and derivatives and analogues of thls peptide, especlally its C-terminal portion, for inducing miosis in the eye after certain types of examinations and intraocular operations.
The invention also relates to antagonists o cholecystokinin, derivatives and analogues of this peptide, for preventing such miosis as is liable to occur as a consequence of intraocular surgery, trauma, or uveitis and iritis. Only pharmaceutically active and physiologically acceptable CCK
dsrivatives and analogues as well as antagonists of these are of course intended to be used according to this invention.

Furthermore, the invention comprises compositions containing an effective amount of cholecystokinin or derivatives or analogues of this peptide in an ophthalmologically compatible vehicle for inducing miosis after certain types of examin-ations and intraocular surgery. The term ~effective amount"
here means that the composition contalns from 10 pg to 100 ~g thereof depending on whether it i8 introduced directly into the anterior chamber in connection with the o~eratlonal procedure, or whether it is applied topically or applied subcon~unctivally. The invention moreover also relates to compositions which contain an effective amount of antagonists to cholecystoktnin or derivatives or analogues of this''' peptide in an ophthalmologically compatible vehicle for preventing miosis during intraocular surgery or as a con-sequence to trauma and uveitis or iritis- The term n Sl;
includes also treatment of the eye with laser beams of various kinds. The term "effective amount" here means that the ~om~08iton contains from 10 ng to 10 mg of one or re antagonists, depending on whether it 18 introduced directly into the anterior chamber o~ the eye, for in~tance af~er an W~ ~/11773 ~ ~ ~ PCT/SEgO/00219 2~ 3 ~
~peration, or whether lt is applied topically on the cornea or ~s applied subconjunctivally. If the antagonist ls administered systemically the dose range 18 preferen~ially about 0.01-S0 mg/kg body weight.

The ophthalmologically compatible vehicle that may be employed for preparing compositions according to this inventlon consists of aqueous solutions such as for example physiological salines for compogitions to be inserted into the eye, e.g. into the anterior chamber or subcon~unctivally.

The ophthalmologically compatible vehicle that may be employed for preparing compositions for topical use consists of aqueous solutions such as for instance physiological salines, oil solutions or ointments. Furthermore the vehicle may contain - especially in cases where the composltion is intended for topical use - ophthalmologically compatible preservatives such as e~g. benzal~onium chloride, sur-factants, liposomes or polymers, e.g. methyl cel~ulose, polyvinyl alcohol, polyvinyl ~yrrolidone, hyaluronlc acid, which may be employed for the purpose of lncreasin~ viscosity.
Also soluble and insoluble drug inserts may be included in the vehicle when the cholecystokinln, its derlvativeg or analogues, or antagonists, are to be administered topically, The invention moreover also relates to a method of inducing miosis after certain types of examinations and intraocular ~urgery, and a method of preventing miosis induced by surgery (including also laser treatment), trauma, uveitis or iritis. The method consists in administration of a thera-peutically active amount of a composition containing at least one of the substances defined above. In a preferred embodiment a composition as described above is contacted with ~he eye 80 as to either induce or prevent miosis. The com~ostlon contains cholecystokinin or derlvatives or analogues of this ~ubstance for inducing miosis, and cont-ains antagonists to cholecystokinln or to derivatives or analogues of this substance for preventing miosls.

The invention is illustrated by a series of non-llmitating examples; results are set forth in Figures 1-7 as follows:

Figure 1: The effect of inJection of CCK-8 on pupil size in three monkey eyes.

Figure 2: The effect on pupil size when CCK-8 is applied on the cornea.

Figure 3A: Cumulated dose-response curve of cholecystokinin on monkey iris in vitro.

Figure 3B: Cumulated dose-response curve of the C-terminal octapeptide (26-33) of cholecystokinin on monkey iris in vitro.

Figure 4A: Cumulated dose-response curve of cholecystokinin on monkey iris in vitro in the presence and absence of Proglumide, a CCK receptor antagonist.

Figure 4B: Cumulated dose-response curve o CCK on monkey lris in vitro in the presence and absence of N~4-chlorobenzoyl)-L-tryptophan, a CCK receptor antagonist.

Pigure 4C: Cumulated dose-response curve of cholecystokinin on monkey iris in vitro in the presence and absence of Lorglumide, a CCK receptor antagonist.

Figure 4D: Cumulated dose-response curve o the C-terminal octapeptide (26-33) of cholecystokinin on monkey lris in vitro in the presence and absence of Proglumide.

,. 20~0~32~ .
~igure 4E: Cumulated dose-response curve of the C-terminal octapeptide (26-33) of cholecystoklnin on monkey lris in vitro in the presence and absence of N( 4-cholobenzoyl)-L-tryptophan.

Figure 4F: Cumulated dose-response curve of the C-terminal octapeptlde (26-33) of cholecystokinin on monkey iris in vitro in the presence and absence of Lorglumide.

Figure,5: Dose-response curve of CCK-8 with and without pretreatment with the.antagonist Lorglumide in the monkey eye in vlvo.

Figure 6: Cumulated dose-response curve of the C-terminal octapeptide of CCK on tha sphincter muscle of human iris in vitro.

Figure 7: The effect of Capsaicin on pupil size with and without pretreatment with 7.5 ~g Lorglumide.

W090/ll773 - 12 - PC~/~E90/00219 2~
Experiments Example 1: Monkeys employed in these experlments (Macaca fascic~lIaris) were anesthesized wlth pentobarbital. The anterior chambers of the eyes were cannulated with 2 special needles each. Substance could be injected through one of the need7es which was connected via a polyethylene tube to a syringe for small volumes (100~1). A corresponding volume of aqueous humor could be drawn off via the other needle to thus avoid eye pressure alterations due to the intracameral inj ection of the test substances. The test substance, CCK or CCK-8, was dissolved in isotonic saline.

The animals were first treated with atropine to induce maximal dilatation of the pupil. The dose-response relation-ship was then determined for one eye. Pupil size was recorded as obtained by measuring the horizontal diameter of the pupil by means of a graduated ruler, these measurements being made at regular intervals and under standard light conditions. Typical examples of these experiments are shown in Flgure 1.

Example 2: Atropine treated monkeys which had been anesthesized with pentobarbital were given every ten minutes a drop of 6-12 ul of a solution containing 250 ng/yl CCK-8, on the cornea of the left eye. This was carried on during a time span 100 minutes from start; at that stage 100 ,ul were administered, followed by 10 ~1 every ten minutes. 60 minutes after start, pupil size decrease was observed in the treated eye. The pupil then went on decreasing during the course of the experiment (Figure 2). No e~ect was seen in the untreated control eye.

Fxample 3: Iris tissues from monkeys (Macaca fascicularis) were obtained immediately after the animals had been sac-rificed. The tigsues were transported in saline on ice and WO90/1~73 2 ~ PCT/SE90/~lg nere mounted in a conventional muscle bath system. Increase of tension in the tissue, which was held ln a fixed position at each end of the cut muscle, was measured isometrlcally by means of Grass Transducers coupled to a Grass 7D polygraph and was expressed as mm recordings on the polygraph, The pieces of tissue were lying immersed in a bath consisting of a standard Ringer solution for muscle baths, with-continuous oxygen supply and controlled temperature (35). Indomethacin, propranolol and atropine were added to the solution in order to eliminate the effects of prostaglandin, beta-adrenergic receptors and muscarinic receptors. Varying amounts of CCK, CCK-8 dissolved in isotonic saline were added to the bath, and the cumulated dose-response curves obtained with CCK and CCK-8 were drawn up. These curves are illustrated in Figure 3. With the tetrapeptide of the C-terminal portion of CCK, 30-33, no muscle contraction was obtained - not even with a total dose of 86 ~g dispersed in the 10 ml tissue bath.

Example 4: When the cumulated dose-response curves had been obtained the preparations were carefully rinsed and one of three antagonists, viz., Lorglumide or Proglumide or N(4-chlorobenzyl)-1-tryptophan, was added to the baths.
About 10 to 20 minutes later a corresponding cumulated dose-response curve was drawn up for CCK and CCK-8 in the presence of one of the antagonists in the bath. After completion of this dose-response curve in the presence of antagonist the baths again were carefully rinsed; then again a sp2cified amount of CCK or CCK-8 was tested without the presence of an antagonist in order to thus investigate reversibility propertles. Figure 4 illustrates the results obtained in experiments with the aforèsaid three antagonists to CCK and CCK-8 on in vitro monkey iris. The volume of the tissue baths was 10 ml, Fxample 5: Dose-response determination of CCK-8 was carried out on one eye of a~ropine treated, pentobarbital anesthesized W090/11~73 2~ 14 - PCT/S~ t~
.,~,~, i monke~s in accordance with the description ln E~ample 1.
Thereafter 0.75~g of Lorglumide in 15~1 o~ isotonic saline was injected into the anterior chamber of the other eye. The CCK-8 dose-response relationship was then determlned in the same way as in the case of the first eye. The CCK antagonist produced a shift of the dose-response curve by more than one Grder of magnitude (F~gure 5~.

ExamQle 6: Iris tissue from an enucleated human eye was obtained immediately after operation. The sphincter muscle was isolated and mounted in a tissue bath as has been described in Example 3. A cumulated dose-response curve for CC~-8 was drawn up in a manner analogous to that described in Example 3. The result is illustrated in Figure 6.

Exam~le 7: Monkeys (Macaca fascicularis) were anesthesized, pretreated with atropine and cannulated as described in E~ample 1. Then 10 ~1 of a 1% solution of Capsaicin was in~ected into the anterior chamber; the diameter of the pupil was measured 15 minutes later. Thé decrease in pupil size obtained with this dose varled from 0 to 1.5 mm.
Animals that had been found to be sensitive to Capsaicin in one eye were later injected with the same dose of Capsaicin in the other eye a~ter pretreatment of that other eye with Lorglumide, 7.5 ~g in 15 ~1. The CCK antagonist decreased the response to Capsaicin (Figure 7).

Our experiments thus show that cholecystokinin or its octapeptide, and probably some closely related derivatives as well, induce miosis in primates ~including humans) by stimulating cholecystokinin receptors in the iris. Selective blockade of said receptcrs, using any of a variety of antagonists, will counteract this miosis. (It also appears that the blockage of CCK receptors prior to irritative stimull will diminish irritation miosls in the monkey.) Consequently lt seems probable that the mechanism responsible for irritatlon mlosi3 in primates resides in a release of CCK or a closely related substance which produces mlosis by W~90/117~3 - 15 - PCTJSE9OJ0021'~
- 2~0~
wa~ of stimulatins CCK receptors on smooth muscle cells in the iris sphincter muscle. This miosls is lndependent of acetylcholine.

The above examples show that CCK or closely related substances acting upon CCK receptors can be utilized for inducing miosis for therapeutical purposes, e.g. after cataract surgery with implantation of an artificial lens, and inversely, antagonists to CCK or closely related substances acting through the same receptors can be used for preventing miosis during the operation itself, or they may be utilized for inhibiting such miosis as will occur in association with iritis, u~veitis and trauma.

W090/11773 ~a ~ Cj ~ PCT/SE90/00219 REFERENCES

Bill, A. Stjernschantz, J., Mandahl, A., Brodin, E. &
Nilsson, G. 1979. Substance P: Release on trigeminal nerve stimulation, effects in the eye. Acta Physiol Scand 106:371~373.

Kuwayama, Y., Terenghl, G., Polak, J.M., Tro~anowski, J.Q. &
Stcne, R.A. 1987. A quantitative correlation of substance P-, calcltonin gene-related peptide- and cholecystokininlike immunoreactivlty with retrogradely labelled trigeminal ganglion cells innervating the eye. Brain Res. 405:220-226.

~otti, V.J., Pendleton, R.G., Gould, R.J., Hanson, H.M., Chang, R.S.L. & Clineshmidt, B.V. 1987. In vivo pharmacology of L-364, 718, a new potent non-peptide peripherial chole-cystokinin antagonist . J Pharmacol and Exp Therap. 241:103-109.

Makovec, F., Bani, M., Cereda, R., Chiste', R., Pacini, M.A., Revel, L., Rovati, L.C. & Setnikar, I. 1987a. Pharmacological properties o f lorglumide as member of a new class of cholecysto-kinin antagonists . Arzneim.forsch./Drug Res. 37(11), No. 11, pp. 1265-1268.

Makovec, F., Bani, M., Cereda, R., Chiste', R., Pacini, .A., Revel, L. & Rovati, L.C. 1987b. Antispasmodic activity on the gallbladder of the mouse of CR 1409 (lorglumide) a potent antagonist of peripheral CCK. Pharmacol Res Comm.
19:41-51.

Mandahl, A., Brodin, E., Nilsson, G. & 8ill, A. 1980.
Substance P, release and effects in the eye. Acta Physiol Scand. 108:18A.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Use of cholecystokinin, its C-terminal octapeptide, other pharmaceutically active and physiologically acceptable derivatives and analogues, and antagonists thereto, for the manufacture of a composition for controlling pupil constriction in the eye.

2. Use of cholecystokinin or therapeutically active derivatives or analogues thereof, according to claim 1 in order to induce pupil constriction after certain types of examinations and operations in the eye.

3. Use of the C-terminal octapeptide (CCK 26-33) of cholecystokinin, according to claim 1 in order to induce pupil constriction after certain types of examinations and operations in the eye.

4. Use of antagonists to cholecystokinin, therapeutically active derivatives or analogues of cholecystokinin, or the C-terminal octapeptide (CCK 26-33) of cholecystokinin, for use according to claim 1 in order to block pupil constriction during certain types of eye surgery.

5. Use of Lorglumide (CR-1409), Loxiglumide (CR-1505), L-364,718, Proglumide, N(4-chlorobenzoyl)-1-tryptophan or derivatives of these, according to claim 4.

6. Ophthalmological composition for the control of pupil constriction, characterized by containing a therapeutically active amount of cholecystokinin, its C-terminal octapeptide or a pharmaceutically active and physologically acceptable derivative or an analogue or an antagonist of these, in an ophthalmologically compatiblevehicle.

7. Ophthalmological composition according to claim 6, characterized in that the ophthalmologically compatible vehicle is a physiological salt solution, an oil solution or ointment, and optionally contains also ophthalmologically compatible preservatives, surfactants, liposomes or polymers.