DE3026402A1 - Non-steroidal antiinflammatory agents - for treatment of micro:vascular disease, e.g. diabetic retinopathy or diabetic nephropathy - Google Patents
Non-steroidal antiinflammatory agents - for treatment of micro:vascular disease, e.g. diabetic retinopathy or diabetic nephropathyInfo
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- DE3026402A1 DE3026402A1 DE19803026402 DE3026402A DE3026402A1 DE 3026402 A1 DE3026402 A1 DE 3026402A1 DE 19803026402 DE19803026402 DE 19803026402 DE 3026402 A DE3026402 A DE 3026402A DE 3026402 A1 DE3026402 A1 DE 3026402A1
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
Description
Die Verwendung analgetischer und nicht-hormonaler,The use of analgesic and non-hormonal,
entzündungshemmender Mittel bei der Behandlung von mikrovaakulären Erkrankungen Die vorliegende Erfindung bezieht sich auf die Verwendung von Analgetika und nicht-hormonalen, entzUndungshemmenden Mitteln bei der Behandlung mikrovaskulärer Erkrankungen bei Mensch und Säuctier, insbesondere mikrovaskuläre Erkrankungen der Haut, Nieren und Retina, die aus Komplikationen von Diabetes mellitus resultieren.anti-inflammatory agents in the treatment of microvaacular Diseases The present invention relates to the use of analgesics and non-hormonal anti-inflammatory agents in treatment microvascular diseases in humans and animals, especially microvascular diseases Skin, kidney and retinal disorders arising from complications of diabetes mellitus result.
Diabetische Retinopathie, eine häufige Komplikation eines langandauernden Diabetes mellitus, ist ein Grund für Sicht.-beeinträchtigung und Erblindung bei Diabetes-Patienten.Diabetic retinopathy, a common complication of a long-term Diabetes mellitus is a cause of visual impairment and blindness Diabetes patient.
Viele pathophysiologische Mechanismen sollen angeblich zur Entwicklung diabetischer Retinopathie und anderer mikrovaskulärer Erkrankungen führen. Auch verschiedene Stoffwechsel-, Hormon- und physiologische Störungen sowie genetische Faktoren sind mit diabetischer Mikroangiopathie in Verbindung gebracht worden. Es sind jedoch keine Ursache-und Wirkung-Beziehungen nachgewiesen worden. Viele, bei Diabetes-Patienten identifizierte, biologische Abnormalitäten, die nachgewiesenermaßen mit mikrovaskulären Komplikationen verbunden sind, können, was die vaskuläre Erkrankung betrifft, sekundär und nicht primär sein.Many pathophysiological mechanisms are supposed to lead to development diabetic retinopathy and other microvascular diseases. Even various metabolic, hormonal and physiological disorders, as well as genetic ones Factors have been implicated in diabetic microangiopathy. It however, no cause and effect relationships have been established. Many, at Diabetes patients identified biological abnormalities that have been proven Associated with microvascular complications, what can be the vascular disease concerns, be secondary and not primary.
Einige der bei Diabetes beschriebenen, vaskulären Abnormalitäten umfassen eine erhöhte vaskuläre Permeabilität, die Degeneration von Pericyten, vaskuläre Mikroaneurysmen und die Verdickung der Basalmembran, um nur einige zu nennen.Some of the vascular abnormalities described in diabetes include increased vascular permeability, the degeneration of pericytes, vascular Microaneurysms and basement membrane thickening, to name a few.
Während bestimmte dieser Schädigungery charakteristisch mit den bekannten klinischen Komplikationen von Diabetes (z.B.While certain of this damage is characteristic of the known clinical complications of diabetes (e.g.
Basalmembranverdickung bei diabetischer Nephropathie und vaskuläre Mikroaneurysmen bei diabetischer Retinopathie) in Verbindung gebracht werden, sind alle diese pathologischen Veränderungen im Mikrogefäßsystem praktisch aller Körpergewebe beschrieben worden. Das Ausmaß der Schädigung variiert Jedoch von Gewebe zu Gewebe und sogar innerhalb derselben Gewebeart in unterschiedlichen Körperteilen (DIABETES 26:65-75, 1977).Basement membrane thickening in diabetic nephropathy and vascular Microaneurysms in diabetic retinopathy) all these pathological changes in the microvasculature of practically all body tissues has been described. However, the extent of the damage varies from tissue to tissue and even within the same type of tissue in different parts of the body (DIABETES 26: 65-75, 1977).
Powell et al haben festgestellt, daß eine geringe Inzidenz und hohe Regression der diabetischen Retinopathie bei Patienten angetroffen wird, bei welchen Diabetes und rheumatoide Arthritis gleichzeitig vorliegen (LANCET, 14.Juli 1974, Seite 17 und 18). Es wurde angenommen, daß es eine Beziehung zwischen der Behandlung des Arthritis-Patienten mit Asprin und der Regression der diabetischen Retinopathie geben könne mit der Vermutung, daß Aspirin eine positive Wirkung auf die Behandlung der Retinopathie hat.Powell et al have found that the incidence is low and high Regression of diabetic retinopathy is encountered in patients in which Diabetes and rheumatoid arthritis are present at the same time (LANCET, July 14, 1974, Pages 17 and 18). It was believed that there was a relationship between treatment of arthritis patient with asprin and regression of diabetic retinopathy could give with the suggestion that aspirin had a beneficial effect on the treatment who has retinopathy.
Es wurde nun gefunden, daß sich bestimmte analgetische oder entzündungshemmende Verbindungen bei der Behandlung diabetischer Retinopathie und anderer mikrovaskulärer Erkrankungen, wie Nephropathie, eignen, die mit Komplikationen aus Diabetes mellitus in Verbindung gebracht werden oder diese sind. Obgleich es bekannt ist, daß sich diese Verbindungen als Analgetika, Aggregationsinhibitoren der Thrombocyten und entzündungshemmende Mittel (einschließlich der Behandlung von Entzündungen des Auges; vgl. die US PS 3 998 966) eignen, ist es dennoch überraschend festzustellen, daß sie bei Mensch und Tier zu einer Verhütung oder Regression mikrovaskulärer Erkrankungen führen, wobei berücksichtigt werden muß, daß einige dieser Verbindungen Störungen im gastrointestinalen Trakt verursachen können.It has now been found that certain analgesic or anti-inflammatory Compounds in the treatment of diabetic retinopathy and other microvascular Diseases, such as nephropathy, are useful with complications from diabetes mellitus be associated or these are. Although it is known that these compounds as analgesics, platelet aggregation inhibitors and anti-inflammatory agents (including treating inflammation of the eye; See US Pat. No. 3,998,966), it is nevertheless surprising to find that they help prevent or regression microvascular diseases in humans and animals , taking into account that some of these connections are interference in the gastrointestinal tract.
Somit bezieht sich die vorliegende Erfindung auf die Verwendung der Verbindungen bei der Behandlung mikrovaskulärer Erkrankungen bei Mensch unt M Wer, wobei dem Patienten eine therapeutisch wirksame Menge eines im folgenden genau definierten Anlgetikums oder entzündung8hemmenden Mittels verabreicht wird. Die in dieser Hinsicht besonders wertvollen Verbindung sind allgemein als Naproxen [2-(6-Meth- # oxy-2-naphthyl ) propionsäurej und Ibuprofen 2-(4-Isobutylphenyl)-propionsäurev bekannt; weiterhin geeignet sind auch ihre pharmazeutisch annehmbaren Salze. Weiterhin bezieht sich die vorliegende Erfindung auch auf die Verwendung dieser analgetischen oder entzündungshemmenden, im folgendes beschriebenen Mittel zur Herstellung pharmazeutischer Präparate für die Behandlung und Verhütung von mikrovaskulären Erkrankungen.Thus, the present invention relates to the use of the Compounds in the treatment of microvascular diseases in humans and M who, providing the patient with a therapeutically effective amount of one of the following as precisely defined An anti-inflammatory or anti-inflammatory agent is administered. The ones in that regard Particularly valuable compounds are generally called naproxen [2- (6-meth- # oxy-2-naphthyl ) propionic acid and ibuprofen 2- (4-isobutylphenyl) propionic acid are known; Farther their pharmaceutically acceptable salts are also suitable. Furthermore relates the present invention also relates to the use of these analgesic or anti-inflammatory, in the following described means for the manufacture of pharmaceutical Preparations for the treatment and prevention of microvascular diseases.
Die vorliegende Erfindung richtet sich auch auf ein Verfahren zur Besserung, Inhibierung oder Verhütung mikrovaskulärer Erkrankungen bei Mensch und Tier. Diese Erkrankungen können z.B. solche der Haut, Nieren oder Retina sein und treten oft als Symptome in Verbindung mit akuten Komplikationen von Diabetes mellitus, z.B. diabetische Retinopathie oder diabetische Nephropathie, auf. Das erfindungsgemäße Verfahren ist sowohl kurativ als präventiv. Ohne an einen theoretischen Wirkungsmechanismus gebunden werden zu wollen,wirkt das erfindungsgemäße Verfahren vermutlich durch Verhütung der Bildung neuer Kapillaren oder Blutgefäße. Daher eignet sich das Verfahren besonders zur Behandlung eines (insbesondere menschlichen) Patienten mit Diabetes mellitus, ob der Patient nun die Symptome bereits aufweist oder ob diese noch nicht feststellbar sind.The present invention is also directed to a method for Amelioration, inhibition or prevention of microvascular diseases in humans and Animal. These diseases can be, for example, those of the skin, kidneys or retina and often appear as symptoms in connection with acute complications of diabetes mellitus, e.g. diabetic retinopathy or diabetic nephropathy. The inventive Procedure is both curative and preventive. Without a theoretical mechanism of action wanting to be bound, the method according to the invention presumably works Preventing the formation of new capillaries or blood vessels. The method is therefore suitable especially for the treatment of a (especially human) patient with diabetes mellitus, whether the patient already has the symptoms or not yet are detectable.
Erfindungsgemäß geeignete Verbindungen werden folgenden entsprechend dem ersten, chemischen, in"USAN and USP Dictionary of Drug Namen für 1980 (falls die Verbindung dort aufgeführt ist) angegebenen Namen aufgeführt, wobei der in den USA angenommene Name in Klammern gesetzt ist: 2-Naphthyl-propionsäurederivate, wie 6-Methoxy-drmethyl-2-naphthalinessigsäure (Naproxen, vgl. US PS 3 637 767 und 3 904 682 für eine vollständigere Beschreibung der Verb in dungen und ihrer Herstellung); 4-Alkylphenylpropionsäuren, in welchen Alkyl sich auf gerade.Compounds suitable for the present invention are as follows the first, chemical, in "USAN and USP Dictionary of Drug Names for 1980 (if the connection is listed there) listed, whereby the name in the USA adopted name in brackets is: 2-naphthyl-propionic acid derivatives, such as 6-methoxydromethyl-2-naphthaleneacetic acid (naproxen, see US Pat. No. 3,637,767 and 3 904 682 for a more complete description of the compounds and how to make them); 4-alkylphenylpropionic acids, in which alkyl is based on straight.
und verzweigte, gesättigte Kohlenwasserstoffgruppen mit 1 bis 4 Kohlenstoffatomen bezieht, wie z.B. -Methyl-4-(2-methylpropyl)-benzolessigsäure und 2-(4-Isopropylphenyl) propionsäure (Ibuprofen; vgl. z.B. die US PS 3 228 831 und 3 385 886).and branched, saturated hydrocarbon groups having 1 to 4 carbon atoms refers, such as -Methyl-4- (2-methylpropyl) -benzeneacetic acid and 2- (4-isopropylphenyl) propionic acid (ibuprofen; see e.g. U.S. Patents 3,228,831 and 3,385,886).
Phenoxyphenylpropionsäuren, wie M-Methyl-3-phenoxybenzolessigsäure (Fenoprofen; US PS 3 600 437); 3-Benzoyl-α-methylbenzolessigsäure (Ketoprofen; US PS 3 641 127); 2-Fluor-α-mesthyl[1,1'-biphenyl]-4-essigsäure (Flurbiprofen; US PS 3 755 427); 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-i-methylbenzolessigsäure (Indoprofen; US PS 3 767 805); 2-[(2,6-Dichlorphenyl)-amino]benzolessigsäure (Diclofenac; US PS 3 558 690); (+)2-(4-Chlorphenyl 4-methyl-5-benzoxazol)e8sigsäure (Benoxaprofen); 5-(4-Chlorbenzoyl)-1,4-dimethyl-1H-pyrrol-2-essigsäure (Zomepirac); #-Oxo-(1,1-biphenyl)-4-buttersäure (Fenbufen); 2-(2,4-Dichlorphenoxy)-benzolessigsäure (Fenclofenac); 1-(4-Chlorbenzoyl)-5-methoy-2-methyl-1H-indol-3-essigsäure (Indomethacin; US PS 3 161 654); 4,5-Diphenyl-2-oxazolpropionsäure (Oxaprozin); 4-Hydroxy-2-methyl-N-(2-pyridinyl)-ZH-1,2-benzothiazin-3-carboxamid-1,1-dioxid (Piroxicam); 3-Chlor-4-(2,5-dShydro-1H-pyrrol-1-yl) 4-methylbenzole8sigsäure (Pirprofen); 7-Methyl-1-(1-methylen)-4-phenyl-2-(1H)-chinazolinon (Proquazon); 5-Fluor-2-methyl1-tS -(methylsulfinyl)-phenyl7-methylen-1H-inden-3-essigsäure (Sulindac; US PS 3 654 349); 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-essigsSure (Tolmetin; FR-PS 1 574 570); 4-(2-Methylpropyl)-benzolessigsäure (Ibufenac; GB PS 971 7O0; 3-Chlor-4-( 2-propenyloxy) -benzolessigsäure (Alclofenac; BE PS 704 368); 2-Amino-3-benzoylbenzolessigsäuremonohydrat (Amfenac); 1-(p-Chlorbenzoyl)-5methoxy-2-naphthylindol-3-essigsäureester mit Glykolsäure (Acemetacin); (#)-6-Chlor-α-methyl-9H-carbazol-2-essigsäure (Carprofen); 1-Cinnamoyl-5-methoxy-2-methylindol-3-essigsäure (Cinmetacin; α-Methyl-9H-fluoren-2-essigsäure (Cicloprofen); 3-Chlor-α-Methyl-4-(2-thienylcarbonyl)-benzolessigsäure (Cliprofen); 1-(4-Chlorphenyl)-2,5-dimethyl-1H-pyrrol-3-essigsäure (Clopirac; DE-PS 2 261 965); (#)-α-Methyl-3-phenyl-7-benzofuranessigsäure (Enprofen); 2-(2,4-Dichlorphenoxy)-benzolessigsäure (Fenclofenac); α,3-Dichlor-4-cyclohexybenzolessigsäure (Fenclorac); 4-p-Chlorphenyl-2-phenyl-thiazolessigsäure (Fentiazac); 4'-ilthinyl-2-fluor-1,7'-biphenyl (Fluretofen); 6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-essigsäure (Isoxepac); 4-Hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazin-3-carboxamid-1 ,1-dioxid (Isoxicam); 1-(5H-1)-Benzopyrano(2,3-b)pyridin-7-yl-propionsäure (Pranoprofen); 7-Methoxy- ob 1 0-dimethylphenothiazin-2-essigsäure (Protizinsäure); α-Methyl-4-(2-thienylcarbonyl)-benzolessigsäure (Suprofen); 6,11-Dihydro-11-oxodlbenzoth,eXoxepin-3-essigsäure (Oxepinac); 1-(4-Azidobenzoyl)-5-methoxy-2-methyl-1H-indol-3-essigsäure (Zidometacin); und die geeigneten, pharmazeutisch annehmbaren Salze derselben, wie Alkali- und Erdalkalisalze, z.B. Natrium-, Kalium-, Lithium-, Magnesium-, Calciumsalze, und Aminsalze, wie Isopropylamin-, Trimethylamin-,Diäthylamin- Triäthylamin-, Tripropylamin-, Äthanolamin-, 2-Dimethylaminoäthanol-, 2-Diäthylaminoäthanol-, Tromethamin-, Dicyclohexylamin-, Lysin-, Arginin-, Histidin-, Coffein-, Procain-, Hydrabamin-, Cholin-, Betain-, Äthylendiamin-, Glucosamin-, N-Alkyl-(1-1B)-D-glucamin-(insbesondere N-Methyl-D-glucamin)-salz.Phenoxyphenylpropionic acids such as M-methyl-3-phenoxybenzene acetic acid (Fenoprofen; U.S. Patent 3,600,437); 3-benzoyl-α-methylbenzene acetic acid (ketoprofen; U.S. Patent 3,641,127); 2-fluoro-α-methyl [1,1'-biphenyl] -4-acetic acid (flurbiprofen; U.S. Patent 3,755,427); 4- (1,3-Dihydro-1-oxo-2H-isoindol-2-yl) -i-methylbenzene acetic acid (Indoprofen; U.S. Patent 3,767,805); 2 - [(2,6-dichlorophenyl) amino] benzene acetic acid (diclofenac; U.S. Patent 3,558,690); (+) 2- (4-chlorophenyl 4-methyl-5-benzoxazole) acetic acid (benoxaprofen); 5- (4-chlorobenzoyl) -1,4-dimethyl-1H-pyrrole-2-acetic acid (zomepirac); # -Oxo- (1,1-biphenyl) -4-butyric acid (Fenbufen); 2- (2,4-dichlorophenoxy) benzene acetic acid (fenclofenac); 1- (4-chlorobenzoyl) -5-methoy-2-methyl-1H-indole-3-acetic acid (Indomethacin; U.S. Patent 3,161,654); 4,5-diphenyl-2-oxazole propionic acid (oxaprozin); 4-hydroxy-2-methyl-N- (2-pyridinyl) -ZH-1,2-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam); 3-chloro-4- (2,5-d-hydro-1H-pyrrol-1-yl) 4-methylbenzenesetic acid (Pirprofen); 7-methyl-1- (1-methylene) -4-phenyl-2- (1H) -quinazolinone (Proquazon); 5-Fluoro-2-methyl1-tS - (methylsulfinyl) -phenyl-7-methylene-1H-indene-3-acetic acid (Sulindac; U.S. Patent 3,654,349); 1-methyl-5- (4-methylbenzoyl) -1H-pyrrole-2-acetic acid (Tolmetin; FR-PS 1,574,570); 4- (2-methylpropyl) benzene acetic acid (Ibufenac; GB PS 971 700; 3-chloro-4- (2-propenyloxy) benzene acetic acid (Alclofenac; BE PS 704 368); 2-amino-3-benzoylbenzene acetic acid monohydrate (Amfenac); 1- (p-Chlorobenzoyl) -5-methoxy-2-naphthylindole-3-acetic acid ester with glycolic acid (acemetacin); (#) - 6-Chloro-α-methyl-9H-carbazole-2-acetic acid (Carprofen); 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid (cinmetacin; α-methyl-9H-fluorene-2-acetic acid (cycloprofen); 3-chloro-α-methyl-4- (2-thienylcarbonyl) benzene acetic acid (Cliprofen); 1- (4-chlorophenyl) -2,5-dimethyl-1H-pyrrole-3-acetic acid (Clopirac; DE-PS 2,261,965); (#) - α-methyl-3-phenyl-7-benzofuranacetic acid (enprofen); 2- (2,4-dichlorophenoxy) benzene acetic acid (Fenclofenac); α, 3-dichloro-4-cyclohexybenzene acetic acid (Fenclorac); 4-p-chlorophenyl-2-phenyl-thiazole acetic acid (Fentiazac); 4'-ilthynyl-2-fluoro-1,7'-biphenyl (Fluretofen); 6,11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid (Isoxepac); 4-Hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-1,2-benzothiazine-3-carboxamide-1 , 1-dioxide (isoxicam); 1- (5H-1) -Benzopyrano (2,3-b) pyridin-7-yl-propionic acid (pranoprofen); 7-methoxy-ob 10-dimethylphenothiazine-2-acetic acid (protic acid); α-methyl-4- (2-thienylcarbonyl) benzene acetic acid (Suprofen); 6,11-dihydro-11-oxodlbenzoth, eXoxepin-3-acetic acid (Oxepinac); 1- (4-Azidobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid (Zidomethacin); and the suitable pharmaceutically acceptable salts thereof, such as Alkali and alkaline earth salts, e.g. sodium, potassium, lithium, magnesium, calcium salts, and amine salts, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, Ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, Lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, Ethylenediamine, glucosamine, N-alkyl (1-1B) -D-glucamine (especially N-methyl-D-glucamine) salt.
Erfindungsgemäß wird eine wirksame Menge der erfindungsgemaßen Verbindungen oder ihrer pharmazeutischen Präparate in üblicher Weise einzeln oder in Kombination mit einer oder mehreren anderen erfindungsgemäßen Verbindungen oder anderen pharmazeutischen Mitteln, wie Antibiotika, hormonelle Mittel zur Behandlung wikrovaskulärer Erkrankungen, wie Insulin usw., auf eine übliche und anerkannte Weise vorabreicht. Somit können die Verbindungen oder Präparate oral, örtlich, parenteral oder durch Inhalation und in fester, flüssiger oder gasförmiger Form einschließlich Tabletten, Suspensionen und Aerosolen verabreicht werden. Es wird darauf hingewiesen, daß die Verabreichung der erfindungsgemäßen aktiven Bestandteile nicht auf eine besondere Art und Weise beschränkt ist. Zur Behandlung von Retinopathie können die Verbindungen z.B. in Form von Tropfen steriler, gepufferter,ophthalmischer Lösungen (vorzugsweise wässriger Lösungen) mit einem pH Wert von 7,2 bis 7,8 örtlich direkt ins Auge gegeben werden. Die Verabreichung kann in Einzeldosisform mit kontinuierlicher Therapie oder als Einzeldosistherapie ad kl zum erfolgen. Es gibt auch andere, wirksame Verabreichungsweisen zur Behandlung von Retinopathie und Nephropathie. In den bevorzugten Ausführungsformen der vorliegenden Erfindung erfolgt die Behandlung, wenn eine Besserung der Symptome speziell erforderlich oder auch imminent ist. Das erfindungsgemaße Verfahren kann auch als kontinuierliche oder prophylaktische Behandlung erfolgen.In accordance with the invention, an effective amount of the compounds of the invention is used or their pharmaceutical preparations in the usual way, individually or in combination with one or more other compounds according to the invention or other pharmaceutical Agents such as antibiotics, hormonal agents used to treat microvascular diseases, such as insulin, etc., in a customary and recognized manner. Thus can the compounds or preparations orally, topically, parenterally or by inhalation and in solid, liquid or gaseous form including tablets, suspensions and aerosols are administered. It should be noted that the administration of the active ingredients of the invention not in any particular way is limited. For the treatment of retinopathy, the compounds can e.g. In the form of drops of sterile, buffered, ophthalmic solutions (preferably aqueous Solutions) with a pH value of 7.2 to 7.8 are given locally directly into the eye. Administration can be in single dose form with continuous therapy or as Single dose therapy ad kl to take place. There are other effective modes of administration as well for the treatment of retinopathy and nephropathy. In the preferred embodiments According to the present invention, treatment occurs when there is improvement in symptoms is especially necessary or also imminent. The inventive method can can also be done as continuous or prophylactic treatment.
Aufgrund der obigen Aussagen sowie unter Berücksichtigung der Schwere der zu behandelnden Erkrankung, des Alters des Patienten, seines Körpergewichtes usw. - wobei alle diese Faktoren vom Fachmann durch Routine feststellbar sind -kann die erfindungsgemäß wirksame Dosis über einen weiten Bereich variieren. Gewöhnlich liegt eine wirksame Menge zwischen etwa 0,005 bis etwa 100 mgZkg Körpergewicht/Tag, vorzugsweise zwischen etwa 0,01 bis etwa 20 mgZkg Körpergewicht/Tag. Anders ausgedrückt, liegt die erfindungsgemaßte wirksame Menge zwischen etwa 0,350 bis etwa 7000, vorzugsweise zwischen etwa 7 bis 1400 mg, pro Tag fUr einen 70 kg wiegenden Patienten. Selbstverständlich erfolgt die Dosierung jeder Verbindung - wo bekannt - entsprechend Angaben für das formulierte Arzneimittel oder andernfalls gemäß üblicher medizinischer Praxis. Im wesentlichen können die Verbindungen erfindungsgemäß zur Behandlung von mikrovaskulären Erkrankungen in praktsich denselben Mengen verabreicht werden, die auch zur Behandlung von Entzündungen oder bei Störungen, wo ein Analgetikum indiziert ist, gegeben werden.Based on the above statements and taking into account the severity the disease to be treated, the age of the patient, his body weight etc. - all of these factors being routinely detectable by those skilled in the art vary the effective dose according to the invention over a wide range. Usually an effective amount is between about 0.005 to about 100 mgZkg body weight / day, preferably between about 0.01 to about 20 mgZkg body weight / day. Expressed differently, is the inventive effective amount between about 0.350 up to about 7000, preferably between about 7 to 1400 mg, per day for a 70 kg weighing patient. It goes without saying that each compound is metered - where known - according to information for the formulated medicinal product or otherwise in accordance with standard medical practice. In essence, the compounds according to the invention administered in practically the same amounts for the treatment of microvascular diseases That can also be used to treat inflammation or disorders where an analgesic is used is indicated to be given.
Geeignete pharmazeutische Träger zur Herstellung der-erfindungsgemäßen Präparate können Feststoffe, Flüssigkeiten oder Gase sein. So können die Präparate die Form von Tabletten, Pillen, Kapseln, Pulvern; Depot-Formulierungen, Lösungen, Suspensionen, Elixieren, Aerosolen usw. annehmen.Suitable pharmaceutical carriers for the production of those according to the invention Preparations can be solids, liquids or gases. This is how the preparations can the form of tablets, pills, capsules, powders; Depot formulations, solutions, Accept suspensions, elixirs, aerosols, etc.
Als Träger kann ein Öl, z.B. ein solches von Erdöl-, tierischem, pflanzlischem oder synthetischem Ursprung, wie Erdnußöl, Sojabohnenöl, Mineralöl, Sesamöl usw., verwendet werden. Wasser, Salzlösung, wässrige Dextrose und Glykole sind bevorzugte flüssige Träger, insbesondere für in3izierbare Lösungen. Geeignete pharmazeutische Streckmittel umfassen Stärke, Cellulose Talkum, Glucose, Lactose, Suct>oSe, Gelatine, Malz, heiß, Mehl, Kreide, Kieselsäuregel, Magnesiumstearat, Natriumstearat, Glycerylmonostearat, Natriumchlorid, Trockenmagermilch, Glycerin, Propylenglykol, Wasser, Äthanol usw. Geeignete pharmazeutische Träger und ihre Formulierung sind in "Remingston's Pharmaceutical Sciences, Easton, Pa., Mack Publishing Comp., 5. Auflage, 1975, beschrieben. Die Präparate enthalten in jedem Fall eine wirksame Menge der aktiven Verbindung zusammen mit einer geeigneten Trägermenge, um die für die jeweilige Verabreichung richtige Dosierungsform herzustellen. Gewöhnlich ist der aktive Bestandteil in einer Menge von 0,1 bis 99, vorzugsweise 5 bi8 75, Gew.-96 anwesend, während die pharmazeutischen Streckmittel in einer Menge von etwa 99,9 bis etwa 1 Gew. -%, vorzugsweise etwa 95 bis etwa 25 Gew.-%, anwesend sind.An oil, e.g. petroleum, animal, vegetable, can be used as a carrier or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc., be used. Water, saline, aqueous dextrose and glycols are preferred liquid carriers, especially for injectable solutions. Suitable pharmaceutical Extenders include starch, cellulose, talc, glucose, lactose, suct> oSe, gelatin, Malt, hot, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, Sodium Chloride, Dry Skimmed Milk, Glycerin, Propylene Glycol, Water, Ethanol, etc. Suitable pharmaceutical carriers and their formulation are in "Remingston's Pharmaceutical Sciences, Easton, Pa., Mack Publishing Comp., 5th Edition, 1975. the In each case, preparations contain an effective amount of the active compound together with an appropriate amount of carrier to be appropriate for the particular administration Manufacture dosage form. Usually the active ingredient is in an amount from 0.1 to 99, preferably 5 to 8 75, 96 wt. present, while the pharmaceutical Extenders in an amount of from about 99.9 to about 1 percent by weight, preferably about 95 to about 25% by weight, are present.
Die folgenden Beispiele veranschaulichen die vorliegende Erfindung.The following examples illustrate the present invention.
Beispiel 1 Bei klinischen Untersuchungen an Diabetes-Patienten wurde gefunden, daß es vor irgendeiner sichtbaren Veränderung der retinalen Blutgefäße ein Durchsickern aus den Blutgefäßen in den Glaskörper gibt. Dies kann nachgewiesen werden, indem man Fluorescein in die Blutbahn des Patienten injiziert und den Glaskörper auf Anwesenheit von Fluorescein beobachtet. Die im Glaskörper anwesende Fluoresceinmenge kann dann durch Fluorphotometrie gemäß Cunha-Vaz et al (Brit.J.Phthal.Example 1 In clinical studies on diabetic patients found that there was any visible change in the retinal blood vessels there is leakage from the blood vessels into the vitreous humor. This can be proven by injecting fluorescein into the patient's bloodstream and vitreous humor observed for the presence of fluorescein. The amount of fluorescein present in the vitreous humor can then by fluorophotometry according to Cunha-Vaz et al (Brit. J. Phthal.
59:649-656, 1975) bestimmt werden.59: 649-656, 1975).
Dasselbe Phänomen zeigt sich auch im Laboratorium an diabetischen Ratten. Daher wurden in diesem Versuch Ratten verwendet, um die Wirkung von Naproxen und Ibuprofen bei diabetischer Retinopathie zu bestimmen.The same phenomenon is also evident in the laboratory on diabetic patients Rats. Therefore, rats were used in this experiment to test the effects of naproxen and to determine ibuprofen in diabetic retinopathy.
40 männliche Long-Evans-Ratten von 200 bis 250 g Gewicht wurden in 4 Gruppen von je 10 Tieren geteilt. Drei der 4 Gruppen erhielten intravenös 65 mg/kg Streptozotocin zur Induzierung von Diabetes. Die verbleibende Gruppe erhielt nur den Träger (einen Citratpuffer) und diente als Kontrolle. Es handelte sich um die 4 folgenden Gruppen Gruppe , ~ Diät I Kontrolle Purina Lab Chow II Diabetes Purina Lab Chow III Diabetes/Ibuprofen 0,05 % Ibuprofen in Purina Lab Chow IV Diabetes/Naproxen 0,015 % Naproxen in Purina Lab Chow Jede Gruppe blieb 3 Wochen auf der obigen Diät. Es wurde angenommen, daß die Ratten in Gruppe III etwa 50 mg Ibuprofen/Tag und die Ratten in Gruppe IV etwa 15 mg/kg Naproxen/ Tag zu sich nahmen. Nach 3 Wochen erhielt jede Ratte 10 mg/kg,intravenös verabreicht, Fluorescein und wurde eine Stunde später getötet. Zum Zeitpunkt der Tötung wurde durch Kardialpunktur eine Blutprobe entnommen. Die Augen wurden entfernt und in einer Trockeneis/Isopropanol-Bad gefroren.40 male Long-Evans rats weighing 200 to 250 g were in 4 groups of 10 animals each divided. Three of the 4 groups received 65 mg / kg intravenously Streptozotocin, used to induce diabetes. The remaining group only received the vehicle (a citrate buffer) and served as a control. It was about the 4 following groups group, ~ Diet I control Purina Lab Chow II diabetes Purina Lab Chow III Diabetes / Ibuprofen 0.05% ibuprofen in Purina Lab Chow IV Diabetes / Naproxen 0.015% naproxen in Purina Lab Chow Each group stayed on the above diet for 3 weeks. It was assumed that the rats in group III about 50 mg ibuprofen / day and the Rats in Group IV consumed approximately 15 mg / kg naproxen / day. Received after 3 weeks every rat 10 mg / kg, administered intravenously, fluorescein and was killed an hour later. At the time of killing it was done by cardiac puncture a blood sample taken. The eyes were removed and placed in a dry ice / isopropanol bath frozen.
Der Glaskörper wurde aus dem gefrorenen Auge extrahiert, jede Probe wurde gewogen und in 1 ml 0,1 n Natraiumhydroxid gelöst. Der Fluoresceingehalt wurde fluoronetrisch bei Wellenlängen von 460 nrn Exzitation und 510 nm Emission bestimmt. Die Fluoreszenblesungen wurden in Fluoresceineiii beiten Manogramm (ng) mittels einer Standardkurve umgerechnet. Auch das Plasmafluorescein wurde bestimmt und als /ug Fluorescein pro ml Plasma ausgedr.ickt. Die Ergebnisse wurden als Durchsindern wie folcg, definiert: Durchsickem= n Fluorescein pro g Glaskörper Fluorescein pro ml Plasma Je höher somit der Durchsickerwert ist, umso größer ist das Verhältnis von Fluorescein im Glaskörper im Vergleich zu der im Plasma anwesenden Menge. Dies zeigt, daß das Fluorescein leicht durch das Zusammenbrechen der Blut/Retina-Schranke und durch Durchsickern desselben durch die Mikrogefäße in den Glaskörper gelangen konnte.The vitreous was extracted from the frozen eye, each sample was weighed and dissolved in 1 ml of 0.1 N sodium hydroxide. The fluorescein content was determined fluoronetrically at wavelengths of 460 nm excitation and 510 nm emission. The fluorescence readings were made in fluorescein using manograms (ng) converted from a standard curve. The plasma fluorescein was also determined and found to be / ug fluorescein expressed per ml plasma. The results were called thawing Defined as follows: Leakage = n fluorescein per g of vitreous fluorescein per ml plasma The higher the seepage value, the greater the ratio of fluorescein in the vitreous compared to the amount present in the plasma. this shows that fluorescein can easily break through the breakdown of the blood / retina barrier and get into the vitreous body by seeping through the microvessels could.
In allen Gruppen wurde die Plasmaglucose bestimmt, um zu bestätigen, daß Tiere in den diabetischen Gruppen tatsächlich Diabetes hatten. Die Glucose wurde durch ein besonderes, für Glucose spezifisches, enzymatisches Hexokinase-Verfahren bestimmt.Plasma glucose was determined in all groups to confirm that animals in the diabetic groups, in fact, had diabetes. The glucose was by a special, glucose-specific, enzymatic hexokinase process certainly.
Die Ergebnisse der Untersuchung sind in der folgenden Tabelle II aufgeführt. Der durchschnittliche Durchsickerwert bei den Diabetikern war deutlich höher als der durchschnittliche Wert der Kontrolltiere. Sowohl Ibuprofen (0,05 % im Futter) und Naproxen (0,015 % im Futter) konnten das mit Diabetes in Verbindung stehende, erhöhte Durchsickern verhindern. Obgleich der durchschnittliche Durchsickerwert der Ibuprofengruppe etwas niedriger als der durchschnittliche Wert der Kontrolle war, ist er von diesem nicht deutlich verschieden (p ist größer als 0,5). Die durchschnittlichen Werte des Durchsickerns sind in der folgenden Tabelle II aufgeführt.The results of the study are shown in Table II below. The average leakage rate among diabetics was significantly higher than the average value of the control animals. Both ibuprofen (0.05% in feed) and naproxen (0.015% in feed) were able to reduce the diabetes-related, prevent increased leakage. Although the average leakage value the Ibuprofen group slightly lower than the average value was the control, it is not significantly different from this (p is greater than 0.5). The average values of the leakage are in the following table II listed.
Tabelle II Gruppe durchschnittl,Durchsickerwerte I Kontrolle 13,44 + 1,52 SF* II Diabetes 28,55 + 4,92 SF III Diabetes/Ibuprofen 12,05 + 2,71 SF IV Diabetes/Naproxen 13,05 + 1,86 SF *SF = Standardfehler Beispiel 2 Gemäß dem Verfahren von Beispiel 1 wurde festgestellt, daß auch andere Verbindungen erfindungsgemäß wirksam sind, ein mit Diabetes in Verbindung stehendes, erhöhtes Durchsickern 1 in die Glaskörper zu verhinden. Diese Verbindungen umfassen u.a.: 2-(4-Isopropylphenyl)-propionsäure; 2-Fluor-α-methyl-[1,1'-biphenyl]-4-essigsäure (Flurbiprofen); 3-Benzoyl-α-methylbenzolessigsäure (Ketoprofen); o(-Methyl-3-phenoxybenzolessigsäure (Fenoprofen); 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-«-methylbenzolessigsäure (Indoprofen); 2- g 2,6-Dichlorphenyl)amino7-benzolessigsäure-mononatriumsalz (Diclorfenoc-natrium); (l)2-(4-Chlorphenyl-i-methyl-5-benzoxazol)-essigssure (benoxaprofen); 5-(4-Chlorbenzoyl)-1,4-dimethyl-1H-pyrrol-2-essigsäure (Zomepirac oder dessen Natriumsalz); #-Oxo-(1,1-biphenyl)-4-buttersäure (Fenbufen); 2-(2,4-Dichlorphenoxy)-benzolessigsäure (Fenclofenac); 1-(4-Chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-essigsäure (Indomethacin); 4, 5-Diphenyl-2-oxazolpropionsäure (Oxaprozin); 4-Hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid (Piroxicam); 3-Chlor-4(2,5-dihydro-1H-pyrrol-1-yl)-«-methylbenzolessigsäure (Pirprofen); 7-Methyl-1-(1-methyläthyl)-4-phenyl-2(1H)-chinazolinon (Proquazon); 5-Fluor-2-rnethyl-1 ff4- ( methylsulfinyl) -phenylj-methylenj-1H-inden-3-essigsäure (Sulindac); 1-Methyl-5-84-methylbenzoyl)-1H-pyrrol-2-essigsäure (Tolmetin). Table II Group Avg, Leakage Values I Control 13.44 + 1.52 SF * II diabetes 28.55 + 4.92 SF III diabetes / ibuprofen 12.05 + 2.71 SF IV Diabetes / Naproxen 13.05 + 1.86 SF * SF = Standard Error Example 2 According to the procedure from Example 1 it was found that other compounds according to the invention diabetes-related increased leakage 1 to prevent in the vitreous humor. These compounds include, but are not limited to: 2- (4-isopropylphenyl) propionic acid; 2-fluoro-α-methyl- [1,1'-biphenyl] -4-acetic acid (flurbiprofen); 3-benzoyl-α-methylbenzene acetic acid (Ketoprofen); o (-Methyl-3-phenoxybenzeneacetic acid (fenoprofen); 4- (1,3-dihydro-1-oxo-2H-isoindol-2-yl) - «- methylbenzeneacetic acid (Indoprofen); 2- g 2,6-dichlorophenyl) amino7-benzene acetic acid monosodium salt (diclorfenoc sodium); (l) 2- (4-chlorophenyl-i-methyl-5-benzoxazole) acetic acid (benoxaprofen); 5- (4-chlorobenzoyl) -1,4-dimethyl-1H-pyrrole-2-acetic acid (Zomepirac or its sodium salt); # -Oxo- (1,1-biphenyl) -4-butyric acid (Fenbufen); 2- (2,4-dichlorophenoxy) benzene acetic acid (fenclofenac); 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid (Indomethacin); 4,5-diphenyl-2-oxazole propionic acid (oxaprozin); 4-Hydroxy-2-methyl-N- (2-pyridinyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (Piroxicam); 3-chloro-4 (2,5-dihydro-1H-pyrrol-1-yl) - «- methylbenzene acetic acid (Pirprofen); 7-methyl-1- (1-methylethyl) -4-phenyl-2 (1H) -quinazolinone (Proquazon); 5-fluoro-2-methyl-1 ff4- (methylsulfinyl) -phenylj-methylenj-1H-indene-3-acetic acid (Sulindac); 1-methyl-5-84-methylbenzoyl) -1H-pyrrole-2-acetic acid (Tolmetin).
Beispiel 3 Bestandteile Menge pro Tablette; mg Naproxen 250 Maisstärke 50 Lactose 198 Magnesiumstearat 2 Die obigen Bestandteile wurden in den angegebenen Verhältnissen innig gemischt und zu einzelnen, gekerbten Tabletten gepreßt. In ähnlicher Weise können andere, hier genannte Verbindungen in der obigen Formulierung in entsprechenden Mengen anstelle des Naproxens verwendet werden.Example 3 Ingredients Amount per tablet; Naproxen 250 mg corn starch 50 Lactose 198 Magnesium Stearate 2 The above ingredients were in the specified Proportions intimately mixed and compressed into individual, notched tablets. In a similar way In the above formulation, other compounds mentioned here can be used in corresponding Amounts can be used in place of the naproxen.
Beispiel 4 Aus gleichen Teilen Ibuprofen und einer Tablettengrundlage, die Stärke umfaßt, wurde unter Zugabe von 1 % Magnesiumstearat als Schmiermittel eine innige Mischung hergestellt und diese zu 400 mg Ibuprofen enthaltenden Tabletten komprimiert.Example 4 From equal parts of ibuprofen and a tablet base, which comprises starch, was made with the addition of 1% magnesium stearate as a lubricant an intimate mixture prepared and this to tablets containing 400 mg ibuprofen compressed.
Weitere Tabletten können hergestellt werden, indem man als aktive Bestandteile andere, oben genannte Verbindungen in entsprechenden Mengen verwendet.More tablets can be made by being active Ingredients other compounds mentioned above are used in appropriate amounts.
Beispiel 5 Aus 50 Teilen Indomethacin, 149 Teilen Maisstärke und 1 Teil Magnesiumstearat wurde eine innige Mischung hergestellt und diese in 50 mg aktiven Bestandteil enthaltende Kapseln eingeführt.Example 5 From 50 parts of indomethacin, 149 parts of corn starch and 1 Part of magnesium stearate, an intimate blend was made and this in 50 mg Capsules containing active ingredient were introduced.
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US4423074A (en) * | 1980-06-19 | 1983-12-27 | Ayerst, Mckenna & Harrison Inc. | Aldose reductase inhibition by 5-fluoro-2-methyl-1-[[4-(methylthio)phenyl]me]-1H-indene-3-acetic acid |
DE3329265A1 (en) * | 1983-06-14 | 1984-12-20 | Syntex Pharmaceuticals International Ltd., Hamilton | NAPROXEN AND NAPROXEN SODIUM TABLETS WITH CONTROLLED ACTIVE SUBSTANCE RELEASE |
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EP0130524A2 (en) * | 1983-07-05 | 1985-01-09 | Troponwerke GmbH & Co. KG | Depot antiphlogistics |
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BE1000148A3 (en) * | 1986-10-29 | 1988-05-17 | Ibis Ist Biochim Speriment | Ophthalmic compositions. |
EP0306984A1 (en) * | 1987-09-11 | 1989-03-15 | Syntex (U.S.A.) Inc. | Preservative system for ophtalmic formulations |
US4968718A (en) * | 1988-01-25 | 1990-11-06 | University Of Iowa Research Foundation | Topically effective, nonsteroidal drug for use in external and internal eye inflammations |
US5110493A (en) * | 1987-09-11 | 1992-05-05 | Syntex (U.S.A.) Inc. | Ophthalmic NSAID formulations containing a quaternary ammonium preservative and a nonionic surfactant |
US5179124A (en) * | 1988-01-25 | 1993-01-12 | University Of Iowa Research Foundation | Anti-inflammatory for use in external and internal eye inflammations |
WO1995024901A1 (en) * | 1994-03-17 | 1995-09-21 | Ciba-Geigy Ag | Treatment of diabetic nephropathy with valsartan |
WO1995033457A1 (en) * | 1994-06-06 | 1995-12-14 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
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WO2002013805A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
WO2002013804A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating angiogenesis-related disorders using benzoyl phenylacetic acid |
EP1216980A1 (en) * | 1999-10-01 | 2002-06-26 | Eisai Co., Ltd. | Carboxylic acid derivatives and drugs containing the same |
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US4423075A (en) * | 1980-06-19 | 1983-12-27 | Ayerst, Mckenna & Harrison Inc. | Aldose reductase inhibition by 5-fluoro-2-methyl-1-[[4-(methylsulfonyl)phenyl]methylene]-1H-indene-3-acetic acid |
US4423074A (en) * | 1980-06-19 | 1983-12-27 | Ayerst, Mckenna & Harrison Inc. | Aldose reductase inhibition by 5-fluoro-2-methyl-1-[[4-(methylthio)phenyl]me]-1H-indene-3-acetic acid |
DE3329265A1 (en) * | 1983-06-14 | 1984-12-20 | Syntex Pharmaceuticals International Ltd., Hamilton | NAPROXEN AND NAPROXEN SODIUM TABLETS WITH CONTROLLED ACTIVE SUBSTANCE RELEASE |
EP0130524A3 (en) * | 1983-07-05 | 1986-08-13 | Troponwerke Gmbh & Co. Kg | Depot antiphlogistics |
EP0130524A2 (en) * | 1983-07-05 | 1985-01-09 | Troponwerke GmbH & Co. KG | Depot antiphlogistics |
EP0130514A3 (en) * | 1983-07-05 | 1986-08-13 | Troponwerke GmbH & Co. KG | Depot antiphlogistics |
EP0130514A2 (en) * | 1983-07-05 | 1985-01-09 | Troponwerke GmbH & Co. KG | Depot antiphlogistics |
FR2560523A1 (en) * | 1984-03-01 | 1985-09-06 | Yoshitomi Pharmaceutical | OPHTHALMIC SOLUTION CONTAINING PRANOPROFEN AND BORIC ACID |
DE3507024A1 (en) * | 1984-03-01 | 1985-09-12 | Senju Pharmaceutical Co., Ltd., Osaka | EYE TREATMENT SOLUTION |
EP0242328A3 (en) * | 1986-04-14 | 1988-04-06 | Dispersa Ag | Pharmaceutical composition for treating inflammation in the eye |
EP0242328A2 (en) * | 1986-04-14 | 1987-10-21 | Ciba Vision AG, Hettlingen | Pharmaceutical composition for treating inflammation in the eye |
US4829088A (en) * | 1986-04-14 | 1989-05-09 | Dispersa Ag | Medicament for the treatment of inflammations of the eye |
EP0265858A1 (en) * | 1986-10-29 | 1988-05-04 | L.B.S. S.r.l. LABORATORIO BIOCHIMICO SPERIMENTALE | Topical antiinflammatory compositions |
BE1000148A3 (en) * | 1986-10-29 | 1988-05-17 | Ibis Ist Biochim Speriment | Ophthalmic compositions. |
EP0306984A1 (en) * | 1987-09-11 | 1989-03-15 | Syntex (U.S.A.) Inc. | Preservative system for ophtalmic formulations |
US5110493A (en) * | 1987-09-11 | 1992-05-05 | Syntex (U.S.A.) Inc. | Ophthalmic NSAID formulations containing a quaternary ammonium preservative and a nonionic surfactant |
US4968718A (en) * | 1988-01-25 | 1990-11-06 | University Of Iowa Research Foundation | Topically effective, nonsteroidal drug for use in external and internal eye inflammations |
US5179124A (en) * | 1988-01-25 | 1993-01-12 | University Of Iowa Research Foundation | Anti-inflammatory for use in external and internal eye inflammations |
WO1995024901A1 (en) * | 1994-03-17 | 1995-09-21 | Ciba-Geigy Ag | Treatment of diabetic nephropathy with valsartan |
WO1995033457A1 (en) * | 1994-06-06 | 1995-12-14 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
US6552077B2 (en) | 1996-02-20 | 2003-04-22 | Exocell, Inc. | Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies |
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WO1998025597A3 (en) * | 1996-12-09 | 2000-10-12 | Warner Lambert Co | Method for treating and preventing heart failure and ventricular dilatation |
WO2001003684A3 (en) * | 1999-07-08 | 2002-06-06 | Exocell Inc | Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies |
WO2001003684A2 (en) * | 1999-07-08 | 2001-01-18 | Exocell, Inc. | Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies |
JP2003504328A (en) * | 1999-07-08 | 2003-02-04 | エグゾセル・インコーポレーテッド | Albumin binding compounds that prevent non-enzymatic saccharification and can be used in the treatment of saccharification-related diseases |
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EP1216980A4 (en) * | 1999-10-01 | 2010-12-08 | Eisai R&D Man Co Ltd | Carboxylic acid derivatives and drugs containing the same |
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EP1251862A1 (en) * | 2000-01-18 | 2002-10-30 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
WO2002013805A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
WO2002013804A3 (en) * | 2000-08-14 | 2002-06-06 | Alcon Universal Ltd | Method of treating angiogenesis-related disorders using benzoyl phenylacetic acid |
US6638976B2 (en) * | 2000-08-14 | 2003-10-28 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
WO2002013804A2 (en) * | 2000-08-14 | 2002-02-21 | Alcon, Inc. | Method of treating angiogenesis-related disorders using benzoyl phenylacetic acid |
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