WO2001078718A1 - Methods of use of penicillamines for the treatment of conditions resulting from dna damage - Google Patents
Methods of use of penicillamines for the treatment of conditions resulting from dna damage Download PDFInfo
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- WO2001078718A1 WO2001078718A1 PCT/US2001/012325 US0112325W WO0178718A1 WO 2001078718 A1 WO2001078718 A1 WO 2001078718A1 US 0112325 W US0112325 W US 0112325W WO 0178718 A1 WO0178718 A1 WO 0178718A1
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- WIPO (PCT)
- Prior art keywords
- penicillamine
- age
- reaction
- glycation
- fluorescence
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Classifications
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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
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a method of effectively preventing glycation-induced and other damage to proteins, lipids and DNA by scavenging dicarbonyl intermediates withpenicillamine, penicillamine derivatives and other ⁇ -amino- ⁇ , ⁇ -mercapto- ⁇ , ⁇ -dimethyl-ethane derivatives as dicarbonyl trapping agents.
- the dicarbonyl scavenging activity of this class of compounds renders them useful as therapeutic agents for the prevention of and treatment of conditions associated with reactive carbonyl compounds and photodamage.
- ROS reactive oxygen species
- RCS reactive carbonyl species
- the nonenzymatic reactivity of biomolecules is generally regarded as a major endogeneous source of damage to cells.
- Glycation is a nonenzymatic posttranslational modification of proteins by reducing sugars, which adversely affects protein function. These are subsequently converted to advanced glycosylation end products (AGEs) which represent a heterogenous class of reactive products which form spontaneously in vivo due to the reaction of glucose and other reducing sugars with amino groups of proteins in a concentration dependent manner. These undergo further rearrangements, dehydrations and cross-linking with other proteins to form the AGEs which play a role in long term complications of aging and diabetes.
- AGEs advanced glycosylation end products
- Lipid peroxidation is another deleterious reaction that targets membrane associated lipids by oxidative mechanisms. Damage to proteins, lipids and nucleic acids by the formation and cellular accumulation of AGEs and peroxidation products has been implicated in a number of age-related diseases including long term diabetic complications (see Thorpe, S:R., and J.W. Baynes. 1996. Role of the Maillard reaction in diabetes mellitus and diseases of aging. Drugs Aging. 9:69-77), atherosclerosis (see Ruderman, N.B., JR. Williamson, and
- Glycation and lipid peroxidation are characterized by the formation of very reactive, toxic dicarbonyl derivatives such as glyoxal, methylglyoxal, malondialdehyde, and 3-desoxyosones (Thornalley, P.J., Langborg, A., andMinhas, H.S. 1999. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem. J. 344, 109-116).
- Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependant mitogen-activated protein ldnase pathway regulated by oxidant stress. J. Biol. Chem 272:17810-4, 1997), the glyoxal-lysine dimer (GOLD) and the methylglyoxal-lysine dimer (MOLD) (Brinkmann, Frye E et al. , Role of Malliard reaction in aging tissue proteins, Advanced glycation end product-dependant increase in imidazolium cross-links in human lens proteins.
- UN- irradiation is another source of tissue carbonyl stress, as evidenced by the accumulation of CML in sun exposed lesions of actinic elastosis (Mizutari, K. et al., Photo- enhanced modification of human skin elastin in actinic elastosis by
- nucleophilic compounds acting as carbonyl traps like tenilsetam (Shoda, H et al., Inhibitory effects of tenilsetam on the Malliard reaction. Endocrinology 138:1886-92, 1997), pyridoxamine (Onorato, J. M. et al. J. Biol. Chem. 275:21177-21184, 2000) and metformin Ruggerio-Lopez et al. Reaction of metformin with dicarbonyl compounds. Possible implications in the inhibition of advanced glycation end product formation, Biochem. Pharm. 58:1765-1773, 1999) are being evaluated for prevention of secondary diabetic complications.
- Oxygen is not required for the browning and crosslinking of protein by pentoses: relevance to Malliard reactions in vivo. Int. J. of Biochem. Cell Biol 31:1297-1305, 1999.
- the assay described herein was developed to screen glycation inhibitors acting as carbonyl scavengers.
- the present invention provides a method for reducing protein, lipid, and DNA damage and change to skin cells by the administration of ⁇ -amino- ⁇ , ⁇ - mercapto- ⁇ , ⁇ -dimethyl-ethane derivatives, e.g., D-penicillamine, which react with dicarbonyls to prevent direct damage to important cellular macromolecules. Methods of inhibiting DNA and skin cell photodamage are also disclosed.
- ⁇ -amino- ⁇ , ⁇ - mercapto- ⁇ , ⁇ -dimethyl-ethane derivatives e.g., D-penicillamine
- the present invention also relates to a screening method for the identification of carbonyl scavengers via a rapid glycation system that proceeds independent of oxygen and therefore excludes identification of inhibitory compounds acting as antioxidants.
- Fig. 1 is a flow diagram showing the formation of AGE-products resulting from glycated proteins
- Fig. 2 is a more detailed flow diagram of the process shown in Fig. 1;
- Fig. 3 is a proposed pathway showing the nonenzymatic formation of
- Fig.4 is a graph showing AGE-fluorescence of H 1 -ADPR (standard), and reduction of AGE-fluorescent with aminoguanidine and various penicillamines;
- Fig. 5 is a schematic of the plate screening mechanism of the invention
- Fig. 6 are SDS-PAGE assays of Hl/ADPR crosslinking and inhibition by
- Fig. 7 are the reverse phase HPLC results showing the scavenging activity of D-penicillamine on the dicarboxyl phenylglyoxal;
- Fig. 8 is ! H- NMR spectrum of the thiazodine derivative of phenylglyoxal and
- Fig. 9 is a flow diagram showing reaction of D-penicillamine with phenylglyoxal.
- Fig. 10 show results of AGE-BS A photosensitized cleavage of ⁇ X-174 DNA from Example 3.
- Fig 11 is a graph of fluorescence v.s days showing the formation of AGE- fluorescence at pH 7.4.
- Fig. 12 shows aminoguanidine and D-penicillamine as inhibitors of non- oxidative advanced glycation of histone H-l by ADP-ribose.
- Fig 13 are the comparative reaction kinetics of alpha-oxoaldehyde scavenging by D-penicillamine and aminoguanidine.
- Fig. 14 shows the protection of HaCat human keratinocytes and CF3 fibroblasts from alpha-dicarbonyl stress in the presence of aminoguanidine and D-penicillamine.
- Fig. 15 shows the protection of HaCat keratinocytes and CF3 fibroblasts from methylglyoxal induced alpha-dicarbonyl stress by D-penicillamine.
- Fig. 16 shows the results of Example 4.
- Fig. 17 shows the results of Example 5.
- FIG 1 is a flow diagram of protein glycation and lipid peroxidation and shows the involvement of reactive dicarbonyls that lead to accumulation of AGE- products and other damage on proteins, nucleic acids and lipids.
- Figure 2 shows the process in more detail.
- Protein-AGE include protein N ⁇ -(carboxymethyl)lysine residues (CML) (Ahmed, M.U., S .R. Thorpe, and J. W. Baynes. 1986. Identification of N epsilon-carboxymethyllysine as a degradation product of fructoselysine in glycated protein. JBiol Chem.
- reactive dicarbonyl compounds may form by auto-oxidation of the sugar itself without requiring glycation, and the presence of trace amounts of transition metal ions (Fe, Cu) has been implicated in the formation of dicarbonyl compounds and reactive oxygen species such as hydrogen peroxide as reported by Elgawish, A., M. Glomb, M. Friedlander, and V.M. Monnier. 1996. Involvement of hydrogen peroxide in collagen cross-linking by high glucose in vitro and in vivo. JBiol Chem. 271:12964-12971.
- a simple reaction system was established allowing the assessment of nuclear glycation damage and its supression by inhibitory substances.
- aminoguanidine As mentioned above, glycation and subsequent protein- AGE formation plays a central role in glucose toxicity. Administering the glycation inhibitor aminoguanidine effectively suppresses secondary complications in rodents with experimental diabetes (Edelstein, D., and M. Brownlee. 1992. Aminoguanidine ameliorates albuminuria in diabetic hypertensive rats. Diabetologia. 35:96-97). Aminoguanidine is thought to act as a dicarbonyl scavenger, therefore inactivating toxic reactive dicarbonyl compounds. However, aminoguanidine is a hydrazine derivative that shows systemic toxicity upon long-term administration, since it is a potent inhibitor of catalase (Ou, P., and S.P.
- Aminoguanidine a drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem Pharmacol.46: 1139- 1144) and inducible nitric oxide synthase (Okuda, Y., S. Sakoda, H. Fujimura, and T. Yanagihara. 1998. Aminoguanidine, a selective inhibitor of the inducible nitric oxide synthase, has different effects on experimental allergic encephalomyelitis in the induction and progression phase. J Neuroimmunol. 81:201-210). The toxicity profile of aminoguanidine makes it a poor candidate for clinical use. Therefore, a need exists in the medical art for new compounds that effectively inhibit glycation and its associated pathological consequences.
- the following examples demonstrate the trapping reaction of the alpha- oxoaldehydes methylglyoxal and phenylglyoxal by ⁇ -amino- ⁇ , ⁇ -mercapto- ⁇ , ⁇ - dimethyl-ethane derivatives such as penicillamine for protection of human skin against carbonyl stress.
- AGE-BSA glycosylated bovine serum albumin
- Chromatin was isolated from fresh calf thymus by extraction with 0.14 M NaCl, 0.05 M Na 2 S 2 O 5 , as described earlier in Wondrak supra. After repeated extraction with 5% HC1) 4 and centrifugation (1500 g), histone HI was precipitated from the supernatant by addition of TCA (20% final concentration v/v). The histone HI precipitate was colleted by centrifugation (12,000 g) and deionized water. After extensive dialysis (MW cut-off: 12,000-14,000) against water for 48 h, the sample was lyophilized and the protein was stored at 4°C. SDS-PAGE (12%) was used to analyze the purity of the preparation.
- a number of different penicillamines and penicillamine derivatives were tested to determine the inhibition of AGE-fluorescence on histone HI at physiological pH.
- the reaction conditions for the glycation of histone HI by ADP-ribose mimic physiological conditions to the extent possible.
- Reaction mixtures contain 1.5 mg/ml histone HI, 1.0 mM ADP-ribose, 50 mM potassium phosphate buffer, pH 7.4, 37°C.
- D,L-penicillamine; L-penicillamine; D-penicllamine; D- penicillaminedisulfide and N,S- isopropylidine-D-penicillamine were tested in concentrations of 1 , 5 and 10 mM.
- the reaction volumes are 300 ⁇ l. Fluorescence on the 96-well microtiter plates was measured using an automated microtiter fluorescence reader.
- Fluoroskan II plate reader (Titertek, ICN) at the excitation/emission wavelengths set forth above at a bandwidth of 35 nm.
- AGE-fluorescence is determined at the beginning and after five days of incubation.
- Test compounds that are inherently fluorescent were identified by the initial fluorescence measurement (See Table 1 , NADH for example). Since these are compounds of uncertain activity, they are diverted directly to the second stage of the screen.
- Aminoguanidine a known glycation inhibitory agent, was used as a positive control for suppression of the increase on AGE-fluorescence.
- fluorescence quenchers (designated false positives) are excluded by measuring the quenching activity of the test compound by addition of AGE modified protein having known fluorescence activity to one microtiter plate well containing test compound in the complete reaction mixture.
- AGE-BSA is used as the AGE-type fluorescence standard.
- This AGE- BSA test excludes false positives compounds that function by fluorescence quenching. If fluorescence quenching occurs the test compound is excluded from further screening.
- Potential positive compounds are further analyzed by measuring inhibition of protein-crosslinking by 12% SDS-PAGE analysis of a 3 microliter aliquot taken from the reaction well on the plate. The protein is visualized by silver staining of the gel. Untreated histone HI and the positive control containing aminoguanidine are loaded onto the gel together with the samples of potential positive test compounds. A compound that passes the first and second stage of the screen is considered a glycation inhibitor and is further evaluated for biological activity as described below.
- D-penicillamine (5 mM) and aminoguanidine (5 mM) were shown to inhibit histone HI crosslinking measured by 12%-SDS-PAGE followed by silver staining as described ( Figure 6).
- Crosslinking was detected with high sensitivity in a histone HI, ADP-ribose reaction system paralleling formation of high AGE-type fluorescence (C), inhibition with aminoguanidine (AG), inhibition with D-penicillamine (P).
- Phenylglyoxal reaction product as 2-benzoyl-5,5-dimethyl- thiazolidine-4-carboxylic acid
- Phenylglyoxal (10 mM) and D-penicillamine (20 mM) were reacted in 50 mM KH2PO4 buffer, pH 7.4 at room temperature. The progress of he reaction was monitored by HPLC analysis of reaction aliquots at 254 nm. After 40 minutes reaction time more than 90% conversion of the phenylglyoxal peak into a single product peak of higher retention time was observed.
- the reaction product was obtained by preparative HPLC, lyophilized and analyzed by 1H- NMR spectroscopy. The spectrum exhibited the following signals: ( ⁇ H D2O in ppm): 1.38 (3H,s,CH3), 1.45 (3H,s,CH3), 4.12 (lH,s,CH-COOH), 7.42-7.82
- Penicillamines are effective dicarbonyl scavengers and may be administered to subjects to prevent AGE formation and other types of direct damage that result from dicarbonyls in vivo . Penicillamines will be administered to the subject in sufficient doses to accomplish these therapeutic goals, and will find particular use in the treatment of diabetics.
- reaction of phenylglyoxal with test compounds were carried out in 10 mM phosphate buffer, pH 7.4 at 37 °C and were followed by HPLC analysis.
- the reaction kinetics were studied at a phenylglyoxal concentration of 50 micromoles and at 250 and 500 micromolar carbonyl scavenger concentration (D- penicillamine, aminoguanidine). Over the course of the reaction, aliquots were analyzed by HPLC. In the case of D-penicillamine, which required shorter sampling periods, reaction aliquots were taken every 20 seconds, and kept on dry ice until analysis.
- the initial reaction rates of phenylglyoxal with the test compounds were monitored by following the disappearance of phenylglyoxal over time.
- the reaction was conducted in the presence of excess test compounds (ratio of 1:5 and 1:10 phenylglyoxal to test compound), to convert it to pseudo-first order reaction kinetics as demonstrated by the apparent dependency of the reaction rate constant (k lst ) on the concentration of the test compound.
- a continuous cell line of human epidermal keratinocytes (HaCat cells) and human dermal fibroblasts (CF-3 cells) were routinely cultured in 75 cm 2 flasks and split biweekly in DMEM containing 10% fetal bovine serum and kept in a humidified atmosphere containing 5% CO 2 at 37°C.
- Human keratinocytes were split using 5%trypsin and human fibroblasts employed 1% trypsin. All experiments were carried out on 6 well dishes (Falcon USA), where keratinocytes were seeded at 2x10 4 cells/well and fibroblasts at 4x10 4 cells/well.
- D-Penicillamine inhibits genotoxic consequences of AGE- photosensitization. Accumulation of AGEs on dermal elastin and collagen occurs during normal skin aging in humans. The hypothesis was tested that the intra- and extracellular accumulation of the complex yellow-brown AGE-chromophores contributes to skin aging and carcinogenesis induced by chronic exposure to sunlight. As a possible molecular mechanisms for a detrimental synergism of AGE-formation and exposure to sunlight, photosensitized DNA damage by AGEs was assessed in a simple in vitro system.
- Human skin consists of keratinocytes and fibroblasts growing in a collagen matrix. Skin aging, as well as certain pathological conditions, e.g. diabetes, leads to the collagen matrix becoming glycated.
- results from the above experiments show that ⁇ -amino- ⁇ , ⁇ -mercapto- ⁇ , ⁇ -dimethyl-ethane derivatives (pharmacophore), especially penicillamines, are useful in prevention of AGE-related damage to the skin of a subject, particularly mammals such as humans.
- results also show that these compounds provide effective protection of skin cells and genetic toxicity induced by photoaging. This can be accomplished, e.g., by systemic delivery through oral, parenteral, e.g., intravenous, topical or other suitable delivery means.
- a sufficient dose of the agent will be given to produce the desired effect in the subject, which can be any animal, mammal, reptile, etc.
- the dose will vary upon a variety of factors known to those skilled in the art, e.g., weight, desired therapeutic endpoint, weight of the subject, etc. Table 1. Screening of inhibitors of nonoxidative advanced glycation: AGE-fluorescence on 96 well-microtiter plate sample AGE-fluorescence 1 AGE-fluorescence 1 AGE-BSA test 1
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA02010182A MXPA02010182A (en) | 2000-04-14 | 2001-04-16 | Methods of use of penicillamines for the treatment of conditions resulting from dna damage. |
AU2001253539A AU2001253539B2 (en) | 2000-04-14 | 2001-04-16 | Methods of use of penicillamines for the treatment of conditions resulting from DNA damage |
JP2001576018A JP2003530434A (en) | 2000-04-14 | 2001-04-16 | Use of penicillamines in the treatment of conditions caused by DNA damage |
EP01927051A EP1274418A4 (en) | 2000-04-14 | 2001-04-16 | Methods of use of penicillamines for the treatment of conditions resulting from dna damage |
AU5353901A AU5353901A (en) | 2000-04-14 | 2001-04-16 | Methods of use of penicillamines for the treatment of conditions resulting from dna damage |
Applications Claiming Priority (2)
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US19721600P | 2000-04-14 | 2000-04-14 | |
US60/197,216 | 2000-04-14 |
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WO2001078718A1 true WO2001078718A1 (en) | 2001-10-25 |
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PCT/US2001/012325 WO2001078718A1 (en) | 2000-04-14 | 2001-04-16 | Methods of use of penicillamines for the treatment of conditions resulting from dna damage |
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Country | Link |
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EP (1) | EP1274418A4 (en) |
JP (1) | JP2003530434A (en) |
CN (1) | CN1431898A (en) |
AU (2) | AU5353901A (en) |
MX (1) | MXPA02010182A (en) |
WO (1) | WO2001078718A1 (en) |
Cited By (1)
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JP2006501146A (en) * | 2002-04-17 | 2006-01-12 | ダイナミス・セラピユーテイクス・インコーポレーテツド | 3-deoxyglucosone and skin |
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JP4985214B2 (en) * | 2007-08-20 | 2012-07-25 | ソニー株式会社 | Biological substance detection method using laser |
Family Cites Families (5)
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US4070483A (en) * | 1975-06-30 | 1978-01-24 | Sidney Lerman | Method of administering a human ocular treating agent and product therefor |
US5334617A (en) * | 1984-03-19 | 1994-08-02 | The Rockefeller University | Amino acids useful as inhibitors of the advanced glycosylation of proteins |
DE4228455A1 (en) * | 1992-08-26 | 1994-09-15 | Beiersdorf Ag | Cosmetic and dermatological sunscreen formulations containing thiols and / or thiol derivatives |
JPH1053516A (en) * | 1996-05-20 | 1998-02-24 | Shiseido Co Ltd | Aging resistant and collagen crosslinking preventing skin lotion |
DK1272843T3 (en) * | 2000-04-14 | 2007-10-08 | Niadyne Corp | Method for Identifying Regulators of Protein AGE Formation |
-
2001
- 2001-04-16 CN CN01810329A patent/CN1431898A/en active Pending
- 2001-04-16 EP EP01927051A patent/EP1274418A4/en not_active Withdrawn
- 2001-04-16 AU AU5353901A patent/AU5353901A/en active Pending
- 2001-04-16 AU AU2001253539A patent/AU2001253539B2/en not_active Ceased
- 2001-04-16 MX MXPA02010182A patent/MXPA02010182A/en unknown
- 2001-04-16 WO PCT/US2001/012325 patent/WO2001078718A1/en not_active Application Discontinuation
- 2001-04-16 JP JP2001576018A patent/JP2003530434A/en active Pending
Non-Patent Citations (7)
Title |
---|
DATABASE BIOSIS [online] VOGEL H.G.: "Strain of rat skin at constant load creep experiments influence of age and desmotropic agents", XP002945298, Database accession no. 1977:139942 * |
DATABASE CAPLUS [online] DILLON ET AL.: "In vitro and in vivo protection against phototoxic side effects of photodynamic therapy by radioprotective agents WR-2721 and WR-77913", XP002945297, Database accession no. 1988:545412 * |
DATABASE EMBASE [online] JAKUS V. ET AL.: "Inhibition of nonenzymatic protein glycation and lipid peroxidation by drugs with antioxidant activity", XP002945299, Database accession no. 1999376124 * |
GERONTOLOGY, vol. 23, no. 2, 1976, pages 77 - 86 * |
LIFE SCIENCES, vol. 65, no. 18-19, 1 October 1999 (1999-10-01), pages 1991 - 1993 * |
PHOTOCHEM. PHOTOBIOL., vol. 48, no. 2, 1988, pages 235 - 238 * |
See also references of EP1274418A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006501146A (en) * | 2002-04-17 | 2006-01-12 | ダイナミス・セラピユーテイクス・インコーポレーテツド | 3-deoxyglucosone and skin |
Also Published As
Publication number | Publication date |
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AU5353901A (en) | 2001-10-30 |
MXPA02010182A (en) | 2004-08-19 |
AU2001253539B2 (en) | 2005-08-04 |
JP2003530434A (en) | 2003-10-14 |
EP1274418A4 (en) | 2005-02-09 |
CN1431898A (en) | 2003-07-23 |
EP1274418A1 (en) | 2003-01-15 |
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