WO1990011773A1 - Method and means for inducing, resp., preventing constriction of the pupil in the eye - Google Patents
Method and means for inducing, resp., preventing constriction of the pupil in the eye Download PDFInfo
- Publication number
- WO1990011773A1 WO1990011773A1 PCT/SE1990/000219 SE9000219W WO9011773A1 WO 1990011773 A1 WO1990011773 A1 WO 1990011773A1 SE 9000219 W SE9000219 W SE 9000219W WO 9011773 A1 WO9011773 A1 WO 9011773A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cck
- eye
- cholecystokinin
- antagonists
- derivatives
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2207—Gastrins; Cholecystokinins [CCK]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/595—Gastrins; Cholecystokinins [CCK]
Definitions
- 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 operations. 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 situated near the iris edge region, i.e. near the pupil
- This muscle is governed by parasympathetic nerves which utilize acetylcholine as transmitter.
- Miosis caused by irritation has been studied thoroughly in experimental animals; as reported in a paper from my laboratory (Bill et al., 1979) it was found that such irritation causes a peptide very similar to substance P to be released in the eye.
- substance P 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 suggesting that this miosis is brought about by the said peptide or a closely related substance.
- CCK cholecystokinin
- CCK blockers 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).
- CCK has a direct effect on a receptor present on the sphincter muscle. This may be concluded from the fact that nerve blockade 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- oxygenase products of arachidonic acid metabolism are not involved in the miosis response to CCK.
- 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 amino acids and C-terminal and N-terminal fragments of CCK.
- N 2 ,0 2 -dibutyryl cyclic guanosine 3' ,5'-monophosphate is an example of cyclic nucleotide derivatives that have been described as having an antagonistic effect against CCK.
- Lorglumide D,L-4-(3,4- dichlorobenzoylamino)'-5-(dipentylamino)-5-oxo-pentanoi ⁇ acid, also called CR-1409, as well as other derivatives of. 5-(dipentylamino)-5-oxo-pentanoic acid have also been found to have a very good CCK-antagonistic effect. Furthermore, various synthetic peptide derivatives of CCK and its fragments e.g.
- Lorglumide (CR 1409) (Makovec et al., 1987a; 1987b), L-364,718 (Lotti et al., 1987), Proglumide, Loxiglumide (CR-1505) and N(4-chlorobenzoyl)-L-tryptophan.
- Low toxicity and good bioavailability have been reported as properties of several cholecystokinin antagonists. More such substances may be expected to come forth, with additional useful properties.
- Substances to be used according to the present invention are previously known to be pharmaceutically 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 in the gallbladder as well as in the central nervous system as appetite enhancing agents, see also WO 8805774.
- the present invention thus relates to cholecystokinin, and derivatives and analogues of this peptide, especially its C-terminal portion, for inducing miosis in the eye after certain types of examinations and intraocular operations.
- the invention also relates to antagonists of 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 ulceris. Only pharmaceutically active and physiologically acceptable CCK derivatives and analogues as well as antagonists of these are of course intended to be used according to this invention.
- 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.
- effective amount here means that the composition contains from 10 pg to 100 ⁇ g thereof depending on whether it is introduced directly into the anterior chamber in connection with the operational procedure, or whether it is applied topically or applied subconjunctivally.
- the invention moreover also relates to compositions which contain an effective amount of antagonists to cholecystokinin 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 ulceris.
- the term "effective amount” here means that the compositon contains from 10 ng to 10 mg of one or more antagonists, depending on whether it is introduced directly into the anterior chamber of the eye, for instance after an operation, or whether it is applied topically on the cornea or is applied subconjunctivally. If the antagonist is administered systemically the dose range is preferentially about 0.01-50 mg/kg body weight.
- the ophthalmologically compatible vehicle that may be employed for preparing compositions according to this invention consists of aqueous solutions such as for example physiological salines for compositions to be inserted into the eye, e.g. into the anterior chamber or subconjunctivally.
- 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 composition is intended for topical use - ophthalmologically compatible preservatives such as e.g. benzalkonium chloride, sur ⁇ factants, liposomes or polymers, e.g. methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, which may be employed for the purpose of increasing viscosity. Also soluble and insoluble drug inserts may be included in the vehicle when the cholecystokinin, its derivatives or analogues, or antagonists, are to be administered topically.
- ophthalmologically compatible preservatives such as e.g. benzalkonium chloride, sur ⁇ factants, liposomes or polymers, e.g. methyl
- the invention moreover also relates to a method of inducing miosis after certain types of examinations and intraocular surgery, and a method of preventing miosis induced by surgery (including also laser treatment), trauma, uveitis or ulceris.
- the method consists in administration of a thera- Chamberically active amount of a composition containing at least one of the substances defined above.
- a composition as described above is contacted with the eye so as to either induce or prevent miosis.
- the compostion contains cholecystokinin or derivatives or analogues of this substance for inducing miosis, and contains antagonists to cholecystokinin or to derivatives or analogues of this substance for preventing miosis.
- 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 of CCK on monkey iris in vitro in the presence and absence of N(4-chlorobenzoyl)-L-tryptophan, a CCK receptor antagonist.
- Figure 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 of the C-terminal octapeptide (26-33) of cholecystokinin on monkey iris in vitro in the presence and absence of Proglumide.
- Figure 4E Cumulated dose-response curve of the C-terminal octapeptide (26-33) of cholecystokinin on monkey iris in vitro in the presence and absence of N(4-cholobenzoyl)-L-tryptophan.
- Figure 4F Cumulated dose-response curve of the C-terminal octapeptide (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 vivo.
- Figure 6 Cumulated dose-response curve of the C-terminal octapeptide of CCK on the 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.
- Example 1 Monkeys employed in these experiments (Macaca fascicularis) were anesthesized with pentobarbital.
- the anterior chambers of the eyes were cannulated with 2 special needles each.
- Substance could be injected through one of the needles which was connected via a polyethylene tube to a • syringe for small volumes (lOO ⁇ l).
- a corresponding volume of aqueous humor could be drawn off via the other needle to thus avoid eye pressure alterations due to the intracameral injection of the test substances.
- the test substance, CCK or CCK-8 was dissolved in isotonic saline.
- Example 2 Atropine treated monkeys which had been anesthesized with pentobarbital were given every ten minutes a drop of 6-12 ⁇ l of a solution containing 250 ng/ ⁇ l 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 ⁇ l were administered, followed by 10 ⁇ l 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 effect was seen in the untreated control eye.
- Example 3 Iris tissues from monkeys (Macaca fascicularis) were obtained immediately after the animals had been sac ⁇ rificed. The tissues were transported in saline on ice and were mounted in a conventional muscle bath system. Increase of tension in the tissue, which was held in a fixed position at each end of the cut muscle, was measured isometrically 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°).
- 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)-l-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 specified amount of CCK or CCK-8 was tested without the presence of an antagonist in order to thus investigate reversibility properties.
- Figure 4 illustrates the results obtained in experiments with the aforesaid three antagonists to CCK and CCK-8 on in vitro monkey iris. The volume of the tissue baths was 10 ml.
- Example 5 Dose-response determination of CCK-8 was carried out on one eye of atropine treated, pentobarbital anesthesized monkeys in accordance with the description in Example 1. Thereafter 0.75 ⁇ g of Lorglumide in 15 ⁇ l of isotonic saline was injected into the anterior chamber of the other eye. The CCK-8 dose-response relationship was then determined 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 order of magnitude (Figure 5).
- Example 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 CCK-8 was drawn up in a manner analogous to that described in Example 3. The result is illustrated in Figure 6.
- Example 7 Monkeys (Macaca fascicularis) were anesthesized, pretreated with atropine and cannulated as described in Example 1. Then 10 ⁇ l of a 1% solution of Capsaicin was injected into the anterior chamber; the diameter of the pupil was measured 15 minutes later. The decrease in pupil size obtained with this dose varied 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 after pretreatment of that other eye with Lorglumide, 7.5 ⁇ g in 15 ⁇ l. The CCK antagonist decreased the response to Capsaicin ( Figure 7).
- 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 crizis, uveitis and trauma.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO905069A NO905069D0 (en) | 1989-04-03 | 1990-11-22 | PROCEDURE AND MEASURES FOR INDUCTION, RESP. PREVENTION OF PREVENTION OF THE PUPILL IN THE EYE. |
KR1019900702506A KR920700044A (en) | 1989-04-03 | 1990-11-23 | Methods and means for inducing and preventing pupillary contraction of the eye |
SU904894239A RU2003331C1 (en) | 1989-04-03 | 1990-12-03 | Agent for controlling contraction of the pupils |
FI905952A FI905952A0 (en) | 1989-04-03 | 1990-12-03 | FOERFARANDE OCH MEDEL FOER INDUCERING ELLER FOERHINDRANDE AV SAMMANDRAGNING AV PUPILLEN I OEGAT. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8901149-8 | 1989-04-03 | ||
SE8901149A SE8901149D0 (en) | 1989-04-03 | 1989-04-03 | AGENTS FOR INDUCTION RESPECTIVE PREVENTION OF PUPILL CONSTRUCTION IN OEGAT |
Publications (1)
Publication Number | Publication Date |
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WO1990011773A1 true WO1990011773A1 (en) | 1990-10-18 |
Family
ID=20375526
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1990/000219 WO1990011773A1 (en) | 1989-04-03 | 1990-04-03 | Method and means for inducing, resp., preventing constriction of the pupil in the eye |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0422181A1 (en) |
JP (1) | JPH03505224A (en) |
KR (1) | KR920700044A (en) |
AU (1) | AU627570B2 (en) |
CA (1) | CA2030525A1 (en) |
FI (1) | FI905952A0 (en) |
HU (1) | HU206185B (en) |
SE (1) | SE8901149D0 (en) |
WO (1) | WO1990011773A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5177071A (en) * | 1991-06-17 | 1993-01-05 | Merck & Co., Inc. | 1,4-benzodiazepines with 6-membered heterocyclic rings to treat panic and anxiety disorder |
US5185331A (en) * | 1991-05-14 | 1993-02-09 | Merck & Co., Inc. | Triazolobenzodiazepines |
US5189050A (en) * | 1991-06-03 | 1993-02-23 | Merck & Co., Inc. | Fermentation analogs of virginiamycin m1 to treat panic and anxiety disorder |
US5206237A (en) * | 1991-05-14 | 1993-04-27 | Merck & Co., Inc. | Benzodiazepine analogs |
US5210082A (en) * | 1991-05-16 | 1993-05-11 | Merck & Co., Inc. | 2-benzazepines with 5- and 6-membered heterocyclic rings to treat pain and anxiety disorders |
WO1993021911A1 (en) * | 1992-05-06 | 1993-11-11 | Kabi Pharmacia Ab | Method and means for preventing constriction of the pupil in the eye |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4400377A (en) * | 1980-09-26 | 1983-08-23 | Farmitalia Carlo Erba, S.P.A. | Use of polypeptides as analgesic drugs |
US4517180A (en) * | 1982-10-27 | 1985-05-14 | Amano Pharmaceutical Co., Ltd | Peptides, process for preparing the same and psychodepressant compositions containing the same |
WO1986003489A1 (en) * | 1984-12-12 | 1986-06-19 | Rotta Research Laboratorium S.P.A. | Pharmaceutically active derivatives of tryptophan and pharmaceutical compositions containing them |
WO1986003968A1 (en) * | 1984-12-27 | 1986-07-17 | Rotta Research Laboratorium S.P.A. | Proglumide and pharmaceutical compositions containing it for use in the treatment of neoplastic affections |
US4794103A (en) * | 1986-01-10 | 1988-12-27 | Alfio Bertolini | Pharmaceutical compositions containing peptides of the cholecystokinin-cerulein group for the therapy of shock conditions and of respiratory and cardiocirculatory insufficiencies |
DD272653A1 (en) * | 1987-02-09 | 1989-10-18 | Akad Wissenschaften Ddr | METHOD FOR PRODUCING NEW ANTAGONISTS OF CHOLECYSTOKININE |
-
1989
- 1989-04-03 SE SE8901149A patent/SE8901149D0/en unknown
-
1990
- 1990-04-03 AU AU54282/90A patent/AU627570B2/en not_active Ceased
- 1990-04-03 CA CA002030525A patent/CA2030525A1/en not_active Abandoned
- 1990-04-03 HU HU903583A patent/HU206185B/en not_active IP Right Cessation
- 1990-04-03 EP EP90906391A patent/EP0422181A1/en not_active Withdrawn
- 1990-04-03 JP JP2506058A patent/JPH03505224A/en active Pending
- 1990-04-03 WO PCT/SE1990/000219 patent/WO1990011773A1/en not_active Application Discontinuation
- 1990-11-23 KR KR1019900702506A patent/KR920700044A/en not_active Application Discontinuation
- 1990-12-03 FI FI905952A patent/FI905952A0/en not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4400377A (en) * | 1980-09-26 | 1983-08-23 | Farmitalia Carlo Erba, S.P.A. | Use of polypeptides as analgesic drugs |
US4517180A (en) * | 1982-10-27 | 1985-05-14 | Amano Pharmaceutical Co., Ltd | Peptides, process for preparing the same and psychodepressant compositions containing the same |
WO1986003489A1 (en) * | 1984-12-12 | 1986-06-19 | Rotta Research Laboratorium S.P.A. | Pharmaceutically active derivatives of tryptophan and pharmaceutical compositions containing them |
WO1986003968A1 (en) * | 1984-12-27 | 1986-07-17 | Rotta Research Laboratorium S.P.A. | Proglumide and pharmaceutical compositions containing it for use in the treatment of neoplastic affections |
US4794103A (en) * | 1986-01-10 | 1988-12-27 | Alfio Bertolini | Pharmaceutical compositions containing peptides of the cholecystokinin-cerulein group for the therapy of shock conditions and of respiratory and cardiocirculatory insufficiencies |
DD272653A1 (en) * | 1987-02-09 | 1989-10-18 | Akad Wissenschaften Ddr | METHOD FOR PRODUCING NEW ANTAGONISTS OF CHOLECYSTOKININE |
Non-Patent Citations (4)
Title |
---|
CHEMICAL ABSTRACTS, Volume 102, No. 21, 27 May 1985, (Columbus, Ohio, US), THIER, PETER et al: "Cholecystokinin in the Cat Retina. Action of Exogenous CCK8 and Localization of Cholecystokinin-Like Immunoreativity", see page 108, Abstract 179697g, & Invest. Ophthalmol. Visual Sci. 1985, 26 (3), 266- 272 * |
CHEMICAL ABSTRACTS, Volume 112, No. 21, 21 May 1990, (Columbus, Ohio, US), BILL, ANDERS et al: "Cholecystokinin Causes Contraction of the Pupillary Sphincter in Monkeys but not in Cats, Rabbits, Rats and Guinea Pigs: Antagonism by Lorglumide", see page 118, Abstract 192316h, & Acta Physiol. Scand. 1990, 138 (4), 479-485 * |
Dialog Information Services, File 155, Medline 66-90 Dialog Accession No. 06160370, LUTSIK NV et al: Spike Activity of Neurons of the Ventromedial Hypothalamus of the Rabbit in Response to Cholecystokinin Application to the Cornea", Fiziol Zh SSSR Nov 1986, 72 (11) p 1493-6, Abstract * |
Dialog Information Services, File 155, Medline 66-90 Dialog Accession No. 06509302, GIBBINS I L et al: "Co-Existence of Neuropeptides in Sympathetic, Cranial Autonomic and Sensory Neurons Innervating the Iris of the Guinea-Pig, J Auton Nerv Syst Nov 1987, 21 (1) p 67-82 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5185331A (en) * | 1991-05-14 | 1993-02-09 | Merck & Co., Inc. | Triazolobenzodiazepines |
US5206237A (en) * | 1991-05-14 | 1993-04-27 | Merck & Co., Inc. | Benzodiazepine analogs |
US5210082A (en) * | 1991-05-16 | 1993-05-11 | Merck & Co., Inc. | 2-benzazepines with 5- and 6-membered heterocyclic rings to treat pain and anxiety disorders |
US5189050A (en) * | 1991-06-03 | 1993-02-23 | Merck & Co., Inc. | Fermentation analogs of virginiamycin m1 to treat panic and anxiety disorder |
US5177071A (en) * | 1991-06-17 | 1993-01-05 | Merck & Co., Inc. | 1,4-benzodiazepines with 6-membered heterocyclic rings to treat panic and anxiety disorder |
WO1993021911A1 (en) * | 1992-05-06 | 1993-11-11 | Kabi Pharmacia Ab | Method and means for preventing constriction of the pupil in the eye |
Also Published As
Publication number | Publication date |
---|---|
KR920700044A (en) | 1992-02-19 |
HUT55994A (en) | 1991-07-29 |
FI905952A0 (en) | 1990-12-03 |
CA2030525A1 (en) | 1990-10-04 |
JPH03505224A (en) | 1991-11-14 |
AU5428290A (en) | 1990-11-05 |
EP0422181A1 (en) | 1991-04-17 |
SE8901149D0 (en) | 1989-04-03 |
HU206185B (en) | 1992-09-28 |
HU903583D0 (en) | 1991-05-28 |
AU627570B2 (en) | 1992-08-27 |
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