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US3781429A - Method of inhibiting ulcerogenesis induced by non-steroidal anti-inflammatory agents - Google Patents

Method of inhibiting ulcerogenesis induced by non-steroidal anti-inflammatory agents Download PDF

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US3781429A
US3781429A US00293710A US3781429DA US3781429A US 3781429 A US3781429 A US 3781429A US 00293710 A US00293710 A US 00293710A US 3781429D A US3781429D A US 3781429DA US 3781429 A US3781429 A US 3781429A
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inhibiting
inflammatory agents
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steroidal anti
induced
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US00293710A
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R Partridge
M Weiss
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Wyeth Holdings LLC
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American Cyanamid Co
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    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins

Definitions

  • non-toxic pharmaceutically acceptable cationic salts of the prostanoic acid derivatives of the above general formulae when R is hydrogen.
  • the cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tr i(lower alkyl)amine cations (e.g., trimethylamine), procaine, and the like.
  • the risks of continuing Indocin therapy in the face of such symptoms must be weighed against the possible benefits to the individual patient.
  • the gastrointestinal effects may be reduced by giving the drug immediately after meals, with food, or with antacids. As advancing years appear to increase the possibility of adverse reactions, Indocin should be used with concomitantly greater care in the aging.
  • prostaglandins in general are not effective when administered by the oral route.
  • the subject prostaglandins are indeed effective orally and at relatively low doses.
  • the assay to determine the protective effect of these compounds is carried out in the following manner.
  • Rats were starved for 48 hours (water was given ad libitum).
  • Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After three hours, the second half of the test compound was administered, also by gavage.
  • Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed.
  • the stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled Water.
  • the stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of ulcers was as previ ously reported. [Abdel-Galil et al., Brit. J. Pharmac. Chemotherapy 33:1-14 (1968).]
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit.
  • compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 0.05 and 20 milligrams of active compound. It may also be desirable to combine a protective compound of the present invention with indomethacin, aspirin, phenyl'butazone, or the like in one capsule or tablet for convenience of administration.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as cornstarch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may he added or a. flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, cornstarch, or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as cornstarch, potato starch, alginic acid, and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin may he added or
  • any material may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • tablets, pills or capsules may be coated with shellac, sugar, or both.
  • a syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • racemic active agents of the novel compositions of this invention can be resolved at appropriate stages into their optically active components by a number of methods of resolution well known in the art. It is to be understood that the above pictorial representation of the active compounds of the present invention is to be construed as inclusive of other forms including enantiomers and racemates, and not to be construed as limited to the particular form shown.
  • EXAMPLE 1 Preparation of capsule formulation Ingredient: Milligrams per capsule Prostaglandin A 5 Starch Magnesium stearate 5 The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of milligrams per capsule.
  • EXAMPLE 2 Preparation of tablet formulation
  • the active ingredient, lactose and corn starch (for mix) are blended together.
  • the sorn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste.
  • This paste is then used to granulate the mixed powders.
  • the Wet granules are passed through a No. 8 screen and dried at 120 F.
  • the dry granules are passed through a No. 16 screen.
  • the mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 2 milligrams of active ingredient.
  • the sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein.
  • the sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution.
  • the volume is adjusted to 100 milliliters with distilled water.
  • a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buifers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.
  • EXAMPLE 4 Magnesium stearate 5 Preparation of tablet formulation Ingredient: Milligrams per tablet ll-deoxy-prostaglandin E 2 Lactose 200 Corn starch (for mix) 50 Corn starch (for paste) 50 Magnesium stearate 6
  • the active ingredient, lactose and corn starch (for mix) are blended together.
  • the corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 screen and dried at 120 F.
  • the dry granules are passed through a No. 16 screen.
  • the mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 2 milligrams of active ingredient.
  • R is hydrogen or alkyl having up to 12 carbon atoms, R is hydrogen or hydroxy, the moiety C C is ethylene or cis-vinylene, and the moiety -C -C is ethylene or cis-vinylene with the proviso that when the moiety -C -C is ethylene then the moiety C -C must be ethylene, and the non-toxic pharmaceutically acceptable cationic salts thereof when R is hydrogen; in association with a pharmaceutical carrier to provide a daily dosage of from about 0.003 mg. to about 0.7 mg. per kilogram of body Weight of said mammal.
  • the method of inhibiting the ulcerogenic effect induced by non-steroidal anti-inflammatory agents in a mammal which comprises administering concomitantly with said agents and orally to said mammal an effective amount of a compound selected from the group consisting of those of the formula:
  • R is hydrogen or alkyl having up to 12 carbon atoms, the moiety -C C is ethylene or ci s-vinylene, and the moiety -C C is ethylene or cis-vinylene, with the proviso that when the moiety C C is ethylene then the moiety --C -C must be ethylene, and the non-toxic pharmaceutically acceptable cationic salts thereof when R is hydrogen; in association with a pharmaceutical carrier to provide a daily dosage of from about 0.003 mg. to about 0.7 mg. per kilogram of body Weight of said mammal.
  • the method of inhibiting the ulcerogenic effect induced by non-steroidal anti-inflammatory agents in a mammal which comprises administering concomitantly with said agents and orally to said mammal an effective amount of a compound selected from the group consisting of 13,14-dihydro-prostaglandin E and the non-toxic pharmaceutically acceptable cationic salts thereof; in association with a pharmaceutical carrier to provide a daily dosage of from about 0.003 mg. to about 0.7 mg. per kilogram of body weight of said mammal.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

THIS DISCLOSURE DESCRIBES THE METHOD OF INHIBITING THE ULCEROPGENIC EFFECT INDUCED BY NON-STEROIDAL ANTI-INFLAMMATORY AGENTS IN MAMMALS BY ADMINISTERING ORALLY THE PROSTAGLANDINS OF THE E SERIES AND CERTAIN 11-DEOXY DERIVATIVES THEREOF AND THE PROSTAGLANDINS OF THE A SERIES.

Description

United StatesPatent O 3,781,429 METHOD OF INHIBITlNG ULCEROGENESIS IN- DUCED BY NON-STEROIDAL ANTl-INFLAM- MATORY AGENTS Ruth Partridge, Pearl River, N.Y., and Martin Joseph Weiss, Oradell, NJ., assignors to American Cyanamid Company, Stamford, Conn. No Drawing. Filed Sept. 29, 1972, Ser. No. 293,710 Int. Cl. A61k 27/00 US. Cl. 424-234 9 Claims ABSTRACT OF THE DISCLOSURE This disclosure describes the method of inhibiting the ulcerogenic effect induced by non-steroidal anti-inflammatory agents in mammals by administering orally the prostaglandins of the E series and certain ll-deoxy derivatives thereof and the prostaglandins of the A series.
BRIEF SUMMARY OF THE INVENTION H OH wherein R is hydrogen or alkyl having up to 12 carbon atoms, R is hydrogen or hydroxy, the moiety C -C is ethylene or cis-vinylene, and the moiety C C is ethylene or cis-vinylene with the proviso that when the moiety --C C is ethylene then the moiety C1'7 C18 must be ethylene.
Also embraced within the scope of the present invention are the non-toxic pharmaceutically acceptable cationic salts of the prostanoic acid derivatives of the above general formulae, when R is hydrogen. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tr i(lower alkyl)amine cations (e.g., trimethylamine), procaine, and the like.
DETAJLED DESCRIPTION OF THE INVENTION We have found that the substances of the above general formulae are useful when administered by the oral route as protective agents against the ulcerogenic and gastrointestinal effects induced by certain otherwise valuable pharmaceutical agents, particularly non-steroidal anti-inflammatory agents such as indomethacin, phenylbutazone, and aspirin. Thus, with the concomitant use of the protective agents of this invention, it should be possible to administer larger and potentially more eflicacious doses of these anti-inflammatory agents without increasing the danger of increased ulcerogenic or gastrointestinal side effects. Indicative of the serious nature of this problem are the following statements concerning indomethacin (Indocin) taken from Physicians Desk Reference, 1972 (Medical Economics Inc., Oradell, NJ p. 964.
Gastrointestinal effects-Because of the occurrence and, at times, severity of gastrointestinal reactions to indocin, the prescribing physician must be continuously alert for any sign or symptom signalling a possible gastrointestinal reaction. The risks of continuing Indocin therapy in the face of such symptoms must be weighed against the possible benefits to the individual patient. The gastrointestinal effects may be reduced by giving the drug immediately after meals, with food, or with antacids. As advancing years appear to increase the possibility of adverse reactions, Indocin should be used with concomitantly greater care in the aging.
Gastrointestinal reactions.%ingle or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small intestines. Fatalities have been reported to occur in some instances. Gastrointestinal bleeding without obvious ulcer formation. Perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.). Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely. Gastritis may persist after the cessation of the drug. Nausea, vomiting, anorexia, epigastric distress, abdominal pain and diarrhea.
It is further to be noted that prostaglandins in general are not effective when administered by the oral route. Thus, it is most unexpected that for the novel use of this invention the subject prostaglandins are indeed effective orally and at relatively low doses. The assay to determine the protective effect of these compounds is carried out in the following manner.
Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After three hours, the second half of the test compound was administered, also by gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled Water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of ulcers was as previ ously reported. [Abdel-Galil et al., Brit. J. Pharmac. Chemotherapy 33:1-14 (1968).]
Score:
0-Norm'al stomach 1Petechial hemorrhage or pin point ulcer 2-1 or 2 small ulcers 3Many ulcers, a few large 4--Many ulcers, mainly large Control animals treated with indomethacin but not test compound usually give scores of about 2.5-3.7. Compounds which reduce the ulcer score by 0.7 unit are considered active. Control animals treated with neither indomethacin nor test compound give scores of about 0.5-
0.8. The results obtained in this assay with typical protective compounds of the present invention are set forth in the Table I below.
TABLE I Total oral dose (mg./ kg. of bed weight Ulcer score Treated animals Compound Controls l-Prostaglandin El--...'..'.-'.'-'-'------ l-Prostaglandln E 5 rs PP The active compounds of the present invention and the non-toxic pharmaceutically acceptable cationic salts thereof when R is hydrogen have thus been found to be highly useful for inhibiting the ulcerogenic effect induced by relatively high doses of non-steroidal anti-inflammatory agents in mammals when administered orally. A preferred dosage regimen for optimum results would be from about 0.003 mg. to about 0.7 mg. per kilogram of body weight per day and such dosage units are employed that a total of from about 0.20 mg. to about 50.0 mg. of active ingredient for a subject of about 70 kg. body weight are administered in a 24-hour period.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit. The amount of active ingredient in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 0.05 and 20 milligrams of active compound. It may also be desirable to combine a protective compound of the present invention with indomethacin, aspirin, phenyl'butazone, or the like in one capsule or tablet for convenience of administration.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as cornstarch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may he added or a. flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
The racemic active agents of the novel compositions of this invention can be resolved at appropriate stages into their optically active components by a number of methods of resolution well known in the art. It is to be understood that the above pictorial representation of the active compounds of the present invention is to be construed as inclusive of other forms including enantiomers and racemates, and not to be construed as limited to the particular form shown.
The invention will be described in greater detail in conjunction with the following specific examples.
EXAMPLE 1 Preparation of capsule formulation Ingredient: Milligrams per capsule Prostaglandin A 5 Starch Magnesium stearate 5 The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of milligrams per capsule.
EXAMPLE 2 Preparation of tablet formulation The active ingredient, lactose and corn starch (for mix) are blended together. The sorn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The Wet granules are passed through a No. 8 screen and dried at 120 F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 2 milligrams of active ingredient.
Sorbitol solution (70% NE): 40 ml. Distilled water: q.s. to ml.
The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buifers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.
EXAMPLE 4 Magnesium stearate 5 Preparation of tablet formulation Ingredient: Milligrams per tablet ll-deoxy-prostaglandin E 2 Lactose 200 Corn starch (for mix) 50 Corn starch (for paste) 50 Magnesium stearate 6 The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120 F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 2 milligrams of active ingredient.
What is claimed is:
1. The method of inhibiting the ulcerogenic eliect induced by non-steroidal anti-inflammatory agents in a mammal which comprises administering concomitantly with said agents and orally to said mammal and effective amount of a compound selected from the group consisting of those of the formula:
wherein R is hydrogen or alkyl having up to 12 carbon atoms, R is hydrogen or hydroxy, the moiety C C is ethylene or cis-vinylene, and the moiety -C -C is ethylene or cis-vinylene with the proviso that when the moiety -C -C is ethylene then the moiety C -C must be ethylene, and the non-toxic pharmaceutically acceptable cationic salts thereof when R is hydrogen; in association with a pharmaceutical carrier to provide a daily dosage of from about 0.003 mg. to about 0.7 mg. per kilogram of body Weight of said mammal.
2. The method according to claim 1 wherein R and R are 'both hydrogen, the moiety -C C is cis-vinylene, and the moiety C C is ethylene; ll-deoxyprostaglandin E 3. The method according to claim 1 wherein R and R are both hydrogen, and the moieties C -C and --C C are both cis-vinylene; ll-deoxy-prostaglandin 4. The method according to claim 1 wherein R is hydrogen, R is hydroxy, the moiety C C is ethylene, and the moiety C -C is cis-vinylene; prostaglandin E 5. The method of inhibiting the ulcerogenic effect induced by non-steroidal anti-inflammatory agents in a mammal which comprises administering concomitantly with said agents and orally to said mammal an effective amount of a compound selected from the group consisting of those of the formula:
wherein R is hydrogen or alkyl having up to 12 carbon atoms, the moiety -C C is ethylene or ci s-vinylene, and the moiety -C C is ethylene or cis-vinylene, with the proviso that when the moiety C C is ethylene then the moiety --C -C must be ethylene, and the non-toxic pharmaceutically acceptable cationic salts thereof when R is hydrogen; in association with a pharmaceutical carrier to provide a daily dosage of from about 0.003 mg. to about 0.7 mg. per kilogram of body Weight of said mammal.
6. The method according to claim 5 wherein R is hydrogen, and the moieties C -C and -C -C are both ethylene; prostaglandin A 7. The method according to claim 5 wherein R is hydrogen, the moiety -C C is cis-vinylene, and the moiety C -C is ethylene; prostaglandin A 8. The method according to claim 5 wherein R is hydrogen, and the moieties C -C and -C -C are both cis-vinylene; prostaglandin A 9. The method of inhibiting the ulcerogenic effect induced by non-steroidal anti-inflammatory agents in a mammal which comprises administering concomitantly with said agents and orally to said mammal an effective amount of a compound selected from the group consisting of 13,14-dihydro-prostaglandin E and the non-toxic pharmaceutically acceptable cationic salts thereof; in association with a pharmaceutical carrier to provide a daily dosage of from about 0.003 mg. to about 0.7 mg. per kilogram of body weight of said mammal.
References Cited Horton: Physiological Reviews, vol. 49 (1969), pp. 127, 131 and 143.
SAM ROSEN, Primary Examiner US. Cl. X.R.
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3911124A (en) * 1974-01-28 1975-10-07 Upjohn Co Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors
US3917828A (en) * 1974-01-28 1975-11-04 Upjohn Co Method of reducing the undesirable gastraintestinal effects of prostaglandin synthetase inhibitors
US3927213A (en) * 1973-07-10 1975-12-16 American Home Prod Prostaglandin E{HD 2 {B and derivatives for reducing the side effects of anti-inflammatory agents
US3928588A (en) * 1974-02-22 1975-12-23 Upjohn Co Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors
US4089951A (en) * 1976-04-14 1978-05-16 Imperial Chemical Industries Limited Oestrus or menstrual regulation
US4359465A (en) * 1980-07-28 1982-11-16 The Upjohn Company Methods for treating gastrointestinal inflammation
EP0029247B1 (en) * 1979-11-20 1983-04-13 A. Nattermann & Cie. GmbH Alkenyl thienyl alkane carboxylic acids and their derivatives, process for their preparation and medicaments containing them
EP0108452A1 (en) * 1982-11-05 1984-05-16 The Procter & Gamble Company Treatment of gastric inflammatory disease with cytoprotective prostaglandins and histamine-2 blocking anti-secretory agents
EP0159784A1 (en) 1984-03-08 1985-10-30 The Upjohn Company Carbacyclin analogues
WO1992006684A1 (en) * 1990-10-18 1992-04-30 Syntex (Usa) Inc. A new use of enprostil
US6183779B1 (en) 1999-03-22 2001-02-06 Pharmascience Inc. Stabilized pharmaceutical composition of a nonsteroidal anti-inflammatory agent and a prostaglandin
US6410595B1 (en) 1997-07-09 2002-06-25 Androsolutions, Inc. Methods and compositions for treating male erectile dysfunction
US6414027B1 (en) 1997-07-09 2002-07-02 Androsolutions, Inc. Methods and compositions for treating male erectile dysfunction
WO2004004738A1 (en) * 2002-07-02 2004-01-15 Wakamoto Pharmaceutical Co.,Ltd. Remedy or preventive for keratoconjunctival epithelial cell injury
US20050124699A1 (en) * 2002-07-02 2005-06-09 Wakamoto Pharmaceutical Co., Ltd. Drugs for treating or preventing disorders of corneal and/or conjunctival epithelial cells
WO2009005172A1 (en) * 2007-07-03 2009-01-08 Sucampo Ag Pharmaceutical combination of nsaid and prostaglandin compound

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927213A (en) * 1973-07-10 1975-12-16 American Home Prod Prostaglandin E{HD 2 {B and derivatives for reducing the side effects of anti-inflammatory agents
US3911124A (en) * 1974-01-28 1975-10-07 Upjohn Co Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors
US3917828A (en) * 1974-01-28 1975-11-04 Upjohn Co Method of reducing the undesirable gastraintestinal effects of prostaglandin synthetase inhibitors
US3928588A (en) * 1974-02-22 1975-12-23 Upjohn Co Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors
US4089951A (en) * 1976-04-14 1978-05-16 Imperial Chemical Industries Limited Oestrus or menstrual regulation
EP0029247B1 (en) * 1979-11-20 1983-04-13 A. Nattermann & Cie. GmbH Alkenyl thienyl alkane carboxylic acids and their derivatives, process for their preparation and medicaments containing them
US4359465A (en) * 1980-07-28 1982-11-16 The Upjohn Company Methods for treating gastrointestinal inflammation
EP0108452A1 (en) * 1982-11-05 1984-05-16 The Procter & Gamble Company Treatment of gastric inflammatory disease with cytoprotective prostaglandins and histamine-2 blocking anti-secretory agents
EP0159784A1 (en) 1984-03-08 1985-10-30 The Upjohn Company Carbacyclin analogues
WO1992006684A1 (en) * 1990-10-18 1992-04-30 Syntex (Usa) Inc. A new use of enprostil
US6410595B1 (en) 1997-07-09 2002-06-25 Androsolutions, Inc. Methods and compositions for treating male erectile dysfunction
US6414027B1 (en) 1997-07-09 2002-07-02 Androsolutions, Inc. Methods and compositions for treating male erectile dysfunction
US6559184B2 (en) 1997-07-09 2003-05-06 Androsolutions, Inc. Methods and compositions for treating male erectile dysfunction
US6183779B1 (en) 1999-03-22 2001-02-06 Pharmascience Inc. Stabilized pharmaceutical composition of a nonsteroidal anti-inflammatory agent and a prostaglandin
US6287600B1 (en) 1999-03-22 2001-09-11 Pharmascience Inc. Stabilized pharmaceutical composition of a nonsteroidal anti-inflammatory agent and a prostaglandin
WO2004004738A1 (en) * 2002-07-02 2004-01-15 Wakamoto Pharmaceutical Co.,Ltd. Remedy or preventive for keratoconjunctival epithelial cell injury
US20050124699A1 (en) * 2002-07-02 2005-06-09 Wakamoto Pharmaceutical Co., Ltd. Drugs for treating or preventing disorders of corneal and/or conjunctival epithelial cells
WO2009005172A1 (en) * 2007-07-03 2009-01-08 Sucampo Ag Pharmaceutical combination of nsaid and prostaglandin compound
US20090012165A1 (en) * 2007-07-03 2009-01-08 Sucampo Ag Pharmaceutical combination of nsaid and prostaglandin compound

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