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EP1124558A2 - Nouvel inhibiteur de formation de cataracte - Google Patents

Nouvel inhibiteur de formation de cataracte

Info

Publication number
EP1124558A2
EP1124558A2 EP99949910A EP99949910A EP1124558A2 EP 1124558 A2 EP1124558 A2 EP 1124558A2 EP 99949910 A EP99949910 A EP 99949910A EP 99949910 A EP99949910 A EP 99949910A EP 1124558 A2 EP1124558 A2 EP 1124558A2
Authority
EP
European Patent Office
Prior art keywords
hydrogen
amino
chloro
halogen
dimethylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99949910A
Other languages
German (de)
English (en)
Other versions
EP1124558A4 (fr
Inventor
Maria Emanuel Ryan
Lorne M. Golub
Nungavaram S. Ramamurthy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Foundation of the State University of New York
Original Assignee
Research Foundation of the State University of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Research Foundation of the State University of New York filed Critical Research Foundation of the State University of New York
Publication of EP1124558A2 publication Critical patent/EP1124558A2/fr
Publication of EP1124558A4 publication Critical patent/EP1124558A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/65—Tetracyclines
    • 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
    • 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

Definitions

  • Cataracts are an abnormal progressive condition of the lens of the eye, characterized by loss of transparency. A gray- white opacity can be seen within the lens, behind the pupil. Most cataracts are caused by degenerative changes, occurring most often after fifty years of age, however in susceptible patients such as diabetics, cataracts can occur at a much earlier age.
  • cataracts Two types have been described: (1) metabolic or juvenile cataracts, which are observed in children and young adults with uncontrolled diabetes, and (2) senile cataracts which are more common than metabolic cataracts.
  • the cataracts in diabetics are similar to the senile cataracts observed in non-diabetic patients but tend to occur at a younger age (e.g. the aging process is accelerated).
  • cataracts The tendency to develop cataracts is inherited and can be accelerated by diseases such as diabetes. If cataracts are untreated, sight is eventually lost. First, vision is blurred, then bright lights glare diffusely, and finally, distortion and double vision may develop.
  • cataracts have been treated according to the progressive condition of the lens of the eye.
  • senile cataracts are usually treated with excision of the lens and prescription of special contact lenses or glasses.
  • the soft cataracts of children and young adults can either be incised and drained or fragmented by ultrasound, followed by irrigation and aspiration of the fragments through a minute incision.
  • diseases such as diabetes. Diabetes is the leading cause of blindness in adults and accounts for loss of vision in 8% of those who are legally blind in the United States (Klein and Klein, 1995). Sixty-five percent of diabetic patients develop blindness within five years after detection of proliferative retinopathy (Lavine, 1990).
  • tetracycline Using compounds approved for use in humans and available in the oral, injectable and topical routes, such as tetracycline, to treat diseases or conditions such as cataracts has not been suggested.
  • the compound, tetracycline exhibits the following general structure:
  • the numbering system of the ring nucleus is as follows:
  • Tetracycline as well as the 5-OH (Terramycin) and 7-C1 (Aureomycin) derivatives exist in nature, and are well known antibiotics.
  • Natural tetracyclines can be modified without losing their antibiotic properties, although certain elements of the structure must be retained.
  • the modifications that can and cannot be made to the basic tetracycline structure have been reviewed by Mitscher in The Chemistry of Tetracyclines, Chapter 6, Marcel Dekker, Publishers, New York (1978). According to Mitscher, the substituents at positions 5-9 of the tetracycline ring system may be modified without the complete loss of antibiotic properties.
  • CMT chemically modified tetracycline
  • tetracyclines have been described as having a number of other uses.
  • tetracyclines are also known to inhibit the activity of collagen destructive enzymes such as mammalian collagenase, gelatinase, macrophage elastase and bacterial collagenase.
  • tetracyclines have been known to inhibit wasting and protein degradation in mammalian skeletal muscle, U.S. Pat. No. 5,045,538. Furthermore, tetracyclines have been shown to enhance bone protein synthesis in U.S. Pat. No. Re. 34,656 and to reduce bone resorption in organ culture in U.S. Pat. No. 4,704,383.
  • U.S. Pat. No. 5,532,227 to Golub et al. discloses that tetracyclines can ameliorate the excessive glycosylation of proteins.
  • tetracyclines inhibit the excessive collagen cross linking which results from excessive glycosylation of collagen in diabetes.
  • tetracyclines Suppress Metalloproteinase Activity in Adjuvant Arthritis and, in Combination with Flurbiprofen, Ameliorate Bone Damage," Journal of Rheumatology 19:927-938(1992); Greenwald et al., “Treatment of Destructive Arthritic Disorders with MMP Inhibitors: Potential Role of Tetracyclines in, Inhibition of Matrix Metalloproteinases: Therapeutic Potential, "
  • Tetracyclines have also been suggested for use in treating skin diseases.
  • White et al. Lancet, Apr. 29, p. 966 (1989) reports that the tetracycline minocycline is effective in treating dystrophic epidermolysis bullosa, which is a life- threatening skin condition believed to be related to excess collagenase.
  • the effectiveness of tetracycline in skin disorders has also been studied by Elewski et al., Journal of the American Academy of Dermatology 8:807-812 (1983). Elewski et al. disclosed that tetracycline antibiotics may have anti-inflammatory activity in skin diseases.
  • Plewig et al. Journal of Investigative Dermatology 65:532 (1975), disclose experiments designed to test the hypothesis that antimicrobials are effective in treating inflammatory dermatoses.
  • the experiments of Plewig et al. establish that tetracyclines have anti-inflammatory properties in treating pustules induced by potassium iodide patches.
  • tetracyclines in combination with non-steroidal anti-inflammatory agents has been studied in the treatment of inflammatory skin disorders caused by acne vulgaris. Wong et al., Journal of American Academy of Dermatology 1 : 1076- 1081 (1984), studied the combination of tetracycline and ibuprofen and found tetracycline to be an effective agent against acne vulgaris and ibuprofen to be useful in reducing the resulting inflammation by inhibition of cycloxygenase. Funt et al.,
  • doxycycline An antimicrobial tetracycline derivative, doxycycline has been used to inhibit nitrate production.
  • D'Agostino et al., Journal of Infectious Diseases: 177:489-92 (1 98) discloses experiments where doxycycline, administered to mice injected with bacterial lipopolysaccharide (hereinafter LPS), exerted a protective effect by inhibiting nitrate production by an IL-10 independent mechanism.
  • LPS bacterial lipopolysaccharide
  • Experiments carried out in vitro also showed that doxycycline inhibited nitric oxide synthesis by LPS activated macrophages without enhancing endogenous IL-10 release.
  • tetracyclines have been found to be effective in different treatments. However, there has been no suggestion whatsoever that tetracyclines can be used to reduce the risk of cataract development in a mammal. Accordingly, it is one of the purposes of this invention, among others, to provide an economical and relatively uncomplicated method of reducing the risk of cataract development.
  • the methods of the present invention provide for reducing the risk of cataract development in a mammal by administering to the mammal an effective amount of a tetracycline derivative.
  • a preferred method of the present invention provides that the tetracycline derivative is a non-antimicrobial tetracycline.
  • Another preferred method of the present invention provides for reducing the risk of cataract development by administering to a mammal an effective amount of a chemically-modified tetracycline derivative, for example dedimethylaminotetracycline.
  • a chemically-modified tetracycline derivative for example dedimethylaminotetracycline.
  • a preferred dedimethylaminotetracycline derivative is
  • Other dedimethylaminotetracyclines which can be administered according to the methods of the present invention have D ring substituents at the C7 and/or C9 positions on the 4-dedimethylaminotetracycline molecule.
  • These compounds include 7-azido-6-demethyl-6-deoxy-4-dedimethylamino tetracycline, 7-dimethylamino-9- azido-6-demethyl-6-deoxy-4-dedimethylamino tetracycline, 9-amino-6-demethyl-6- deoxy-4-dedimethylaminotetracycline, 9-azido-6-demethyl-6-deoxy-4- dedimethylaminotetracycline, 9-nitro-6-demethyl-6-deoxy-4- dedimethylaminotetracycline, 9-amino-7-dimethylamino-6-demethyl-6-deoxy-4- dedimethylaminotetracycline, 7-acetamido-6-demethyl-6-deoxy-4-dedimethylamino tetracycline, 9-acetamido-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 7- amino-9-nitro-6-demethyl-6-deoxy-4-dedi
  • the D ring may be halogenated at the C8 position to provide 8- halo-dedimethylaminotetracycline derivatives.
  • halogens can be chlorine, fluorine, bromine, and iodine.
  • 8-halo- dedimethylaminotetracycline derivatives are 9-amino-8-chloro-7-dimethylamino-6- demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-amino-8-chloro-7- dimethylamino-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline and 9-amino-8- chloro-6-demethyl-6-deoxy-4-dedimethylaminotetracycline.
  • Another preferred method of the present invention provides for reducing the risk of cataract development in a mammal by administering a tetracycline derivative selected from the group consisting of 6a-benzylthiomethylenetetracycline, tetracyclinotrile, the mono-N-alkylated amide of tetracycline, 6-fluoro-6- demethyltetracycline, l la-chlorotetracycline, tetracycline pyrazole and 12a- deoxytetracycline and its derivatives.
  • a tetracycline derivative selected from the group consisting of 6a-benzylthiomethylenetetracycline, tetracyclinotrile, the mono-N-alkylated amide of tetracycline, 6-fluoro-6- demethyltetracycline, l la-chlorotetracycline, tetracycline pyrazole and 12a- deoxytetracycline and its derivatives.
  • tetracycline derivative is an antimicrobial tetracycline.
  • Antimicrobial tetracycline derivatives which can be used with the methods of the present invention include tetracycline, minocycline and doxycycline.
  • Another method of the present invention provides for reducing the risk of cataract development in a mammal by administering a tetracycline derivative systemically.
  • the tetracycline derivative is administered systemically by a controlled release delivery system.
  • Additional methods of the present invention provide for reducing the risk of cataract development in a mammal by administering a tetracycline derivative orally or topically.
  • Figure 1 is a bar graph illustration of the development of cataracts in untreated Type II ZDF/GMI diabetic rats and diabetic rats treated with doxycycline, CMT-3
  • Figure 2 is a photographic illustration of the development of cataracts in untreated Type II ZDF/GMI diabetic rats in comparison with healthy control rats.
  • Figure 3 is a photographic illustration of the development of cataracts in Type
  • the present invention provides for methods of reducing the risk of cataract development in a mammal.
  • the methods provide for administering to a mammal an effective amount of a tetracycline derivative.
  • Mammals include, for example, humans, as well as pet animals such as dogs and cats, laboratory animals, such as rats and mice, and farm animals, such as horses and cows.
  • the numbering system of the multiple ring nucleus is as follows:
  • Tetracycline as well as the 5-OH (oxytetracycline, e.g. Terramycin) and 7-C1
  • chlorotetracycline e.g., Aureomycin
  • Semisynthetic tetracyclines include, for example, doxycycline, minocycline and methacycline.
  • a class of compounds has been defined which are structurally related to the antibiotic tetracyclines, but which have had their antibiotic activity substantially or completely eliminated by chemical modification. Substantial elimination of antibiotic activity occurs when the antibiotic activity is substantially less than that of tetracycline.
  • the antibiotic activity is at least approximately two times less than that of tetracycline, more preferably at least approximately five times less than that of tetracycline, and even more preferably at least approximately ten times less than that of tetracycline.
  • Chemically modified tetracyclines (CMT's) derivatives include, for example, 4-dedimethylaminotetracycline (CMT-1), tetracyclinonitrile (CMT-2), 6-demethyl-6-deoxy-4-dedimethylaminotetracycline (CMT-3), 7-chloro-4-dedimethylaminotetracycline (CMT-4), tetracyclinopyrazole (CMT-5), 4-hydroxy-4-dedimethylamino tetracycline (CMT-6), 12 ⁇ -deoxy-
  • CMT-7 4-dedimethylaminotetracycline
  • CMT-8 5-hydroxy-6- ⁇ -deoxy-4-dedimethylamino tetracycline
  • CMT-9 4-dedimethylamino- 12- ⁇ -deoxyanhydrotetracycline
  • CMT-10 7-dimethylamino-6-demethyl-6-deoxy-4- dedimethylaminotetracycline
  • a particularly preferred tetracycline derivative suitable for use according to the present invention is CMT-8.
  • Tetracycline derivatives which possess antibacterial activity are also contemplated by the present invention.
  • such compounds are preferably employed in an amount which has substantially no antibacterial activity but which is effective for reducing the risk of cataract formation in a mammal.
  • Preferred compounds of this type include tetracycline, minocycline and doxycycline.
  • the chemically modified and antimicrobial tetracycline derivatives can be made by methods known in the art. See, for example, Mitscher, L.A., The Chemistry of the Tetracycline Antibiotics, Marcel Dekker, New York (1978), Ch. 6 and U.S. Pat. Nos. 4,704,383 and 5,532,227.
  • an effective amount of a tetracycline derivative is administered.
  • An "effective amount” as used herein is that amount effective to achieve the specified result of reducing the risk of cataract formation.
  • the tetracycline derivative is provided in an amount which has little or no antimicrobial activity.
  • a tetracycline derivative is not effectively antimicrobial if it does not significantly prevent the growth of microbes.
  • the methods of the present invention can beneficially employ a tetracycline derivative which has been modified chemically to reduce or eliminate its antimicrobial properties.
  • CMT's are preferred in the present invention since they can be used at higher levels than antimicrobial tetracyclines, while avoiding certain disadvantages such as the indiscriminate killing of beneficial microbes and the emergence of resistant microbes, which often accompanies the use of antimicrobial or antibacterial amounts of such compounds.
  • Tetracycline derivatives which are useful according to the methods of the present invention appear to exhibit their beneficial effect in a dose-dependent manner although CMT-8 exhibits its best effect when absorbed.
  • administration of larger quantities of a tetracycline derivative has been observed to further reduce the risk of cataract formation than does administration of smaller amounts.
  • efficacy has been observed at dosages below the level at which toxicity is seen.
  • Maximal dosage for a subject is the highest dosage which does not cause undesirable or intolerable side effects.
  • the tetracycline compound can be administered in an amount of from about 0.1 mg/kg/day to about 30 mg/kg/day, and preferably from about 1 mg/kg/day to about 18 mg/kg/day.
  • side effects can include clinically significant antimicrobial or antibacterial activity, as well as toxic effects.
  • a dose in excess of about 50 mg/kg/day would likely produce side effects in most mammals, including humans.
  • the practitioner is guided by skill and knowledge in the field, and the present invention includes without limitation dosages which are effective to achieve the described effect.
  • the methods of the present invention involve administering a tetracycline derivative in an amount which is effective for reducing the risk of cataract formation in a mammal.
  • Administering tetracycline derivatives can be accomplished in a variety of ways.
  • tetracycline derivatives can be administered systemically by the parenteral and enteral routes, and include controlled release delivery systems.
  • a tetracycline derivative can easily be administered intravenously (e.g., intravenous injection) which is a preferred route of delivery.
  • Intravenous administration can be accomplished by mixing the tetracycline derivative in a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art.
  • Oral or enteral use is also contemplated, and formulations such as tablets, capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like can be employed to provide a tetracycline derivative.
  • delivery of a tetracycline derivative can include topical application.
  • the carrier is preferably suited for topical use.
  • Compositions deemed to be suited for such topical use include gels, salves, lotions, creams, ointments and the like.
  • the tetracycline derivative can also be incorporated with a support base or matrix or the like to provide a pre-packaged surgical or burn dressing or bandage which can be directly applied to skin.
  • Topical application of tetracycline derivatives in amounts of up to about 25% (w/w) in a vehicle are therefore appropriate. More preferably, application of tetracycline derivatives in amounts of from about 0.1% to about 10% is believed to effectively reduce the risk of cataract formation according to the present invention. It is believed that these quantities do not induce significant toxicity in the subject being treated.
  • tetracycline derivatives are also contemplated under the invention.
  • a non-absorbable tetracycline compound such as CMT-2 or CMT-6
  • a tetracycline compound capable of substantial absorption and effective systemic distribution in a subject such as CMT-1, CMT-3, CMT-7 or CMT-8, can be administered systemically.
  • the invention has been developed based on the unexpected observation by Applicants that tetracycline derivatives reduce the risk of cataract formation in a mammal. Applicants are unaware of any physiological or biochemical basis for expecting that tetracyclines would reduce the risk of cataract formation in a mammal. It is, therefore, surprising that tetracycline derivatives are found to reduce the risk of cataract formation in a mammal.
  • Diabetics develop posterior subcapsular cataracts, characterized by a central opacity in the nucleus and cortex.
  • non- diabetic controls did not develop clinically-detectable cataracts, whereas 65% of the untreated Type II diabetic rats developed these ocular lesions by 5 months of age, an increase in incidence that was statistically significant (p ⁇ .001).
  • treatment with CMT-8 appeared to prevent the development of these cataracts at five months while the antimicrobial parent compound doxycycline was not as effective.
  • CMT-8 administration to the Type II diabetic rats reduced the incidence of cataract development by 37% at five months.
  • Figure 1 shows the development of cataracts in untreated Type II ZDF/GMI diabetic rats and Type II ZDF/GMI diabetic rats treated with different tetracycline analogues. Specifically, approximately 60% of untreated Type II ZDF/GMI diabetic rats developed cataracts whereas approximately 42% of Type II ZDF/GMI diabetic rats treated with CMT-8 developed cataracts.
  • Type II ZDF/GMI diabetic rats treated with other tetracycline analogues did not exhibit as low a percentage of cataract development in comparison to Type II ZDF/GMI diabetic rats treated with CMT-8.
  • approximately 60% of Type II ZDF/GMI diabetic rats treated with doxycycline developed cataracts and approximately 70% of Type II ZDF/GMI diabetic rats treated with CMT-3 developed cataracts.
  • FIGS. 2 and 3 provide a comparison of healthy untreated rats with untreated Type II ZDF/GMI diabetic rats and Type II ZDF/GMI diabetic rats treated with doxycycline and CMT-8. Cataracts do not appear to have developed in the CMT-8 treated diabetic rats as they appear very similar to the non-diabetic control rats. Treating diabetic rats with doxycycline to prevent cataract development does not appear to be effective although it is believed that the lack of efficacy was due to the low serum concentration as discussed above.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des méthodes de réduction du risque de cataracte chez un mammalien, les méthodes consistant à administrer au mammalien une quantité effective d'un dérivé de tétracycline. De préférence, un dérivé de tétracycline administré selon les méthodes de la présente invention consiste en 6α-désoxy 5-hydroxy-4-dédiméthylaminotétracycline.
EP99949910A 1998-09-28 1999-09-28 Nouvel inhibiteur de formation de cataracte Withdrawn EP1124558A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10205698P 1998-09-28 1998-09-28
US102056P 1998-09-28
PCT/US1999/022354 WO2000018353A2 (fr) 1998-09-28 1999-09-28 Nouvel inhibiteur de formation de cataracte

Publications (2)

Publication Number Publication Date
EP1124558A2 true EP1124558A2 (fr) 2001-08-22
EP1124558A4 EP1124558A4 (fr) 2004-10-27

Family

ID=22287890

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99949910A Withdrawn EP1124558A4 (fr) 1998-09-28 1999-09-28 Nouvel inhibiteur de formation de cataracte

Country Status (7)

Country Link
EP (1) EP1124558A4 (fr)
JP (1) JP2002525299A (fr)
KR (1) KR20010073190A (fr)
AU (1) AU759372B2 (fr)
CA (1) CA2343038A1 (fr)
NZ (1) NZ510628A (fr)
WO (1) WO2000018353A2 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69932846T2 (de) * 1998-11-18 2007-03-15 Collagenex Pharmaceuticals, Inc. Neue 4-dedimethylaminotetracyclinderivate
US6506740B1 (en) 1998-11-18 2003-01-14 Robert A. Ashley 4-dedimethylaminotetracycline derivatives
WO2002080932A1 (fr) * 2001-04-05 2002-10-17 Collagenex Pharmaceuticals, Inc. Methodes de traitement de l'acne
WO2002083106A1 (fr) * 2001-04-05 2002-10-24 Collagenex Pharmaceuticals, Inc. Delivrance controlee de composes de tetracycline et de derives de tetracycline
US7056902B2 (en) * 2002-01-08 2006-06-06 Paratek Pharmaceuticals, Inc. 4-dedimethylamino tetracycline compounds
CA2521885C (fr) 2003-04-07 2013-06-25 Shire Laboratories, Inc. Formulations de tetracyclines en dose quotidienne unique
HRP20130928T1 (hr) 2008-08-08 2013-11-22 Tetraphase Pharmaceuticals, Inc. C7-fluor supstituirani spojevi tetraciklina
US9315451B2 (en) 2009-05-08 2016-04-19 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
DK2470500T3 (en) 2009-08-28 2018-01-08 Tetraphase Pharmaceuticals Inc tetracycline
CN108329312B (zh) 2012-08-31 2021-12-31 四相制药公司 四环素化合物
HUE066360T2 (hu) 2016-10-19 2024-07-28 Tetraphase Pharmaceuticals Inc Eravaciklin kristályformái

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS275231B2 (en) * 1989-09-29 1992-02-19 Ustav Makormolekularni Chemie Medicine bottle
JPH0515954A (ja) * 1991-07-10 1993-01-26 Harima Ceramic Co Ltd ポーラス質スライデイングノズルプレート
US5340572A (en) * 1993-02-08 1994-08-23 Insite Vision Incorporated Alkaline ophthalmic suspensions
US5814655A (en) * 1996-11-14 1998-09-29 Insite Vision Incorporated Non-steroidal ophthalmic mixtures
US5929055A (en) * 1997-06-23 1999-07-27 The Research Foundation Of State University Of New York Therapeutic method for management of diabetes mellitus

Also Published As

Publication number Publication date
NZ510628A (en) 2003-08-29
AU759372B2 (en) 2003-04-10
WO2000018353A3 (fr) 2000-07-06
JP2002525299A (ja) 2002-08-13
EP1124558A4 (fr) 2004-10-27
KR20010073190A (ko) 2001-07-31
CA2343038A1 (fr) 2000-04-06
WO2000018353A2 (fr) 2000-04-06
AU6268499A (en) 2000-04-17

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