WO2000078316A1 - Use of nitroxides in wound healing and in the prevention of photodamage - Google Patents
Use of nitroxides in wound healing and in the prevention of photodamage Download PDFInfo
- Publication number
- WO2000078316A1 WO2000078316A1 PCT/US2000/016374 US0016374W WO0078316A1 WO 2000078316 A1 WO2000078316 A1 WO 2000078316A1 US 0016374 W US0016374 W US 0016374W WO 0078316 A1 WO0078316 A1 WO 0078316A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- skin
- containing compound
- nitroxide containing
- nitroxide
- wound
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—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
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
Definitions
- the ma or histopathologic alteration of photoaged skin is the accumulation of material which, on routine histopathologic examination, has the staining characteristics of elastm and is, thus, termed solar elastosis
- Immunohistochemical staining has shown the poorly-formed fibers comprising solar elastosis to be composed of elastm (Chen et al . , J. Invest . Dermatol . , 1986, 87:334-337; Mera et al . , Br. J. Dermatol . , 1987, 117:21- 27) fib ⁇ llm (Chen et al . , J. Invest . Dermatol .
- Miyachi Y., J. Dermatol . Sci . 1995, 9:75-86 provides a review of photoaging from a photo-oxidative standpoint and suggests that use of antioxidants as regulators of photoaging. Specifically studies with superoxide dismutase (SOD) are described. However, it was concluded that sunscreen agents provided better protection from ultraviolet radiation.
- SOD superoxide dismutase
- nitroxides are stable free radical components which react with a variety of biologically relevant compounds including other free radicals (Nilsson et al . J. Biol . Chem . , 1989, 264:11131-11135).
- free radicals specifically oxy radicals
- nitroxide containing compounds other than Tempol will prevent photoaging, and other skin damage resulting from exposure to solar, and more specifically, ultraviolet radiation, such as sunburn and skin cancer. Further, topical application of nitroxide containing compounds is believed to be effective in promoting healing of acute and chronic wounds.
- This patent also teaches the nitroxide containing compounds to be useful as protectants against: increased oxygen exposure so as to avoid pulmonary adult respiratory distress syndrome; oxygen- induced lenticular degeneration and hyaline membrane disease in infants; oxidative stress-induced cataracts; reperfusion injury in treating cardiovascular phenomena such as myocardial infarction and strokes, pancreatitis or intestinal ulceration and organ transplant; cytotoxicity due to excess oxidation in animal or plant cell cultures; cytotoxic effects of chemotherapeutic agents; and mutagenic and carcinogenic agents. Also taught in this patent is use of these compounds as anti-inflammatory agents effective against arthritic conditions.
- the nitroxide containing compositions are administered parenterally, intra-articularly or via oral ingestion. This patent also teaches use of these compounds as aging retardants when administered orally or parenterally and in weight reduction when administered orally or intravenously.
- U.S. Patents 5,824,781, 5,840,701 and 5,817,632 teach compositions and processes to alleviate free radical toxicity based on use of nitroxides in association with physiologically compatible macromolecules . These compositions are suggested to be useful as blood substitutes, radioprotective agents, imaging agents, agents to protect against ischemia and reperfusion injury, particularly cerebral stroke, and in vivo enzyme mimics.
- nitroxides or nitroxide containing compound
- stable nitroxide free radicals examples of nitroxide containing compounds are well known in the art and taught in prior art references such as U.S. Patent 5,462,946.
- a transgenic hairless mouse model has also been developed which permits the investigation of human elastin promoter activity in response to ultraviolet irradiation both in vivo by direct irradiation of mouse skin, and in vi tro by irradiation of cells derived from these mice. It is preferred that the hairless mouse used in the production of the transgenic mice for these experiment be of a strain Crl : SKHl-hrBR (Charles River) as this hairless strain of mice is well characterized and used routinely in preclinical dermatological and photobiological research. These transgenic hairless mice of are capable of expressing a full length or truncated elastin promoter.
- the cells may be derived from immortalized cell lines.
- the cells are treated with the nitroxide containing compound.
- the treated cells are then exposed to solar simulating, UVB or UVA radiation and human elastin promoter activity in the cells is determined.
- Addition of 8-methoxypsoralen prior to UVA exposure may be required in some cell culture experiments to achieve a significant increase in elastin promoter activity.
- the activity is then compared to control cells exposed to the same dose of solar simulating, UVB or UVA radiation but which were not treated with the nitroxide containing compound to demonstrate the ability of the nitroxide containing compound to provide protection against the exposure.
- a means for generating reactive oxygen species such as a ypoxanthine and xanthine oxidase system within these cell cultures provides a sensitive system for demonstrating the ability of the nitroxide containing compounds to prevent oxidative damage.
- nitroxide containing compounds are added to the cell cultures prior to addition of the means for generation of reactive oxygen species.
- the means for generating reactive oxygen species is then added and human elastin promoter activity is determined in the culture after a selected time period. The time period for determination of human elastin promoter can be selected in accordance with routine experiments wherein optimum time span for incubation of cells with a hypoxanthine and xanthine oxidase system is determined.
- compositions comprising a nitroxide containing compound are also useful in wound healing.
- the ability of nitroxide containing compounds to promote wound healing can be demonstrated in well- established wound healing animal models such as the guinea pig model described in Bernstein et al . J. Dermatologic Surgery and Oncology 1993, 19 (6) : 564-570 and Bernstein et al . J " . Invest . Dermatol . 1991, 97:430-434.
- a composition comprising a nitroxide containing compound can be topically applied to an irradiated skin flap wound of a guinea pig.
- compositions comprising a nitroxide containing compound are expected to be useful when applied topically as sunscreen agents and in promoting wound healing.
- topically applied compositions comprising a nitroxide containing compound include, but are not limited to creams, lotions and sprays. Methods of formulating nitroxide containing compounds into creams, lotions and sprays, as well as pharmaceutical additives for such formulations, are well known to those skilled in the art.
- compositions may further comprise secondary or additional sunscreens, free radical scavengers such as, but not limited to, Vitamin C and Vitamin E and analogs thereof, anti- inflammatory agents, or additional wound healing agents.
- sunscreens it is preferred that the composition be applied to the skin prior to exposure to the sun. However, application of these compositions subsequent to the exposure can also mitigate any damage resulting to the skin from this exposure.
- compositions of the present invention will be especially useful in protecting individuals with heightened sensitivities to the sun, such as, but not limited to, individuals undergoing psoralen treatment for cancer, psoriasis and other skin conditions; individuals undergoing photodynamic therapy for skin cancer, psoriasis and other skin conditions; individuals suffering from genetic repair defects such as xeroderma pigmentosa, albinism or other conditions resulting from decreased endogenous melanin pigment .
- the composition be applied directly to the wound.
- a homozygous line of transgenic mice expressing the 5.2- kb human elastin promoter linked to a CAT reporter gene can be used. Hsu-Wong et al . , J " . Biol . Chem . , 1994, 269:18072-18075. These mice express the human elastin promoter in a tissue- specific and developmentally regulated manner. Mice four or five days old must be used since at this age, visible hair growth is not yet present.
- Treatment sites are selected so that the center of the irradiated fold is 3.5 cm lateral to the midline.
- a skin fold is isolated and clamped in the same manner as the irradiated skin fold, but receives no irradiation. This serves as a control.
- Paired 5 cm linear incisions are made in each treatment area 3.5 cm from the midline with a scalpel blade . Incisions are closed with 6 Accustaple model 40R stainless steel surgical staples (Deknatel, Queens Village, NY) per incision. Seven guinea pigs are used, each receiving an incision in irradiated and non- irradiated skin.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Birds (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Toxicology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Cosmetics (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00941413A EP1194150A4 (en) | 1999-06-23 | 2000-06-15 | Use of nitroxides in wound healing and in the prevention of photodamage |
JP2001504379A JP2003502372A (en) | 1999-06-23 | 2000-06-15 | Use of nitroxides in wound healing and prevention of photoinjury |
US10/018,301 US6552040B1 (en) | 1999-06-23 | 2000-06-15 | Use of nitroxides in wound healing and in the prevention of photodamage |
CA002377621A CA2377621C (en) | 1999-06-23 | 2000-06-15 | Use of nitroxides in wound healing and in the prevention of photodamage |
AU56120/00A AU761674B2 (en) | 1999-06-23 | 2000-06-15 | Use of nitroxides in wound healing and in the prevention of photodamage |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14053799P | 1999-06-23 | 1999-06-23 | |
US60/140,537 | 1999-06-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000078316A1 true WO2000078316A1 (en) | 2000-12-28 |
Family
ID=22491708
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/016374 WO2000078316A1 (en) | 1999-06-23 | 2000-06-15 | Use of nitroxides in wound healing and in the prevention of photodamage |
Country Status (6)
Country | Link |
---|---|
US (1) | US6552040B1 (en) |
EP (1) | EP1194150A4 (en) |
JP (1) | JP2003502372A (en) |
AU (1) | AU761674B2 (en) |
CA (1) | CA2377621C (en) |
WO (1) | WO2000078316A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003022217A2 (en) * | 2001-09-06 | 2003-03-20 | Synzyme Technologies Llc | Treatment of excessive radiation (e.g. sunburn) exposure |
WO2004030623A2 (en) * | 2002-10-01 | 2004-04-15 | Mitos Pharmaceuticals, Inc. | Nitroxide radioprotector formulations and methods of use |
CN102584683A (en) * | 2012-02-29 | 2012-07-18 | 中国人民解放军第四军医大学 | Synthesis of Tempol derivative and radiation protection effect |
CN104817488A (en) * | 2015-02-04 | 2015-08-05 | 中国人民解放军第四军医大学 | Application of sulfone-type nitroxide free radical as radiation protectant |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006524701A (en) * | 2003-04-25 | 2006-11-02 | ミトス・インコーポレーテッド | Prophylactic pretreatment with antioxidants |
JP2007500227A (en) * | 2003-05-29 | 2007-01-11 | ミトス・ファーマシューティカルズ・インコーポレーテッド | Use of nitroxides in connection with photosensitizers and sound sensitizers |
US7285544B2 (en) * | 2003-11-18 | 2007-10-23 | Bernstein Eric F | Use of nitroxides in treating skin disease |
JP5191739B2 (en) * | 2004-12-22 | 2013-05-08 | チバ ホールディング インコーポレーテッド | Anti-radical agent |
US20110027200A1 (en) * | 2009-07-30 | 2011-02-03 | Bernstein Eric F | Methods to stabilize and prevent breakdown of sunscreen and other topical and oral preparations and compositions produced thereby |
US20120207687A1 (en) * | 2011-01-14 | 2012-08-16 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Topical formulations of targeted nitroxide agents |
CN103906756B (en) | 2011-09-26 | 2020-03-03 | 加莱拉实验室有限责任公司 | Methods for treating diseases |
US10231959B2 (en) | 2016-03-23 | 2019-03-19 | Louis Habash | Increasing expression level of apoptosis-related genes by treating a human subject with a nitroxide |
US20180078539A1 (en) | 2016-03-23 | 2018-03-22 | Louis Habash | T-cell regulation in t-cell mediated diseases by reducing pathogenic function of th17 in a human subject through treatment with a nitroxide |
WO2023009500A1 (en) * | 2021-07-27 | 2023-02-02 | Galera Labs, Llc | Pentaaza macrocyclic ring complex for enhanced surgical treatment |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5462946A (en) * | 1990-03-16 | 1995-10-31 | The United States Of America As Represented By The Department Of Health And Human Services | Nitroxides as protectors against oxidative stress |
US5840734A (en) * | 1997-05-06 | 1998-11-24 | Thomas Jefferson University | Use of tempol in the prevention of photoaging |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1362488A (en) * | 1987-01-28 | 1988-08-24 | Peter H. Proctor | Topical composition and method for stimulating hair growth with stable free radicals |
US5824781A (en) * | 1993-08-16 | 1998-10-20 | Hsia; Jen-Chang | Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules |
FR2714604B1 (en) * | 1993-12-30 | 1996-01-26 | Oreal | Use of a spin acceptor in a cosmetic or dermatological composition. |
-
2000
- 2000-06-15 US US10/018,301 patent/US6552040B1/en not_active Expired - Lifetime
- 2000-06-15 JP JP2001504379A patent/JP2003502372A/en active Pending
- 2000-06-15 EP EP00941413A patent/EP1194150A4/en not_active Withdrawn
- 2000-06-15 CA CA002377621A patent/CA2377621C/en not_active Expired - Fee Related
- 2000-06-15 AU AU56120/00A patent/AU761674B2/en not_active Ceased
- 2000-06-15 WO PCT/US2000/016374 patent/WO2000078316A1/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5462946A (en) * | 1990-03-16 | 1995-10-31 | The United States Of America As Represented By The Department Of Health And Human Services | Nitroxides as protectors against oxidative stress |
US5840734A (en) * | 1997-05-06 | 1998-11-24 | Thomas Jefferson University | Use of tempol in the prevention of photoaging |
Non-Patent Citations (1)
Title |
---|
See also references of EP1194150A4 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7229629B2 (en) | 2001-09-06 | 2007-06-12 | Synzyme Technologies, Llc | Carboxylate-gated-nitroxide (CGN) compounds and compositions and methods of use thereof |
WO2003022217A3 (en) * | 2001-09-06 | 2003-12-04 | Synzyme Technologies Llc | Treatment of excessive radiation (e.g. sunburn) exposure |
US7314633B2 (en) | 2001-09-06 | 2008-01-01 | Synzyme Technologies Llc | Carboxylate-gated-nitroxide (CGN) compounds and compositions and methods of use thereof |
WO2003022217A2 (en) * | 2001-09-06 | 2003-03-20 | Synzyme Technologies Llc | Treatment of excessive radiation (e.g. sunburn) exposure |
EP1429723A1 (en) * | 2001-09-06 | 2004-06-23 | Synzyme Technologies LLC | Treating effects of excessive reactive oxygen species |
EP1429723A4 (en) * | 2001-09-06 | 2005-06-15 | Synzyme Technologies Llc | Treating effects of excessive reactive oxygen species |
WO2004030623A3 (en) * | 2002-10-01 | 2004-05-13 | Mitos Corp | Nitroxide radioprotector formulations and methods of use |
WO2004030623A2 (en) * | 2002-10-01 | 2004-04-15 | Mitos Pharmaceuticals, Inc. | Nitroxide radioprotector formulations and methods of use |
US7625928B2 (en) | 2002-10-01 | 2009-12-01 | Mitos Pharmaceuticals, Inc. | Nitroxide radioprotector formulations and methods of use |
AU2003277075B2 (en) * | 2002-10-01 | 2009-12-17 | Mitos Pharmaceuticals, Inc. | Nitroxide radioprotector formulations and methods of use |
CN102584683A (en) * | 2012-02-29 | 2012-07-18 | 中国人民解放军第四军医大学 | Synthesis of Tempol derivative and radiation protection effect |
CN102584683B (en) * | 2012-02-29 | 2014-12-24 | 中国人民解放军第四军医大学 | Synthesis of Tempol derivative and radiation protection effect |
CN104817488A (en) * | 2015-02-04 | 2015-08-05 | 中国人民解放军第四军医大学 | Application of sulfone-type nitroxide free radical as radiation protectant |
CN104817488B (en) * | 2015-02-04 | 2018-04-24 | 中国人民解放军第四军医大学 | Application of the sulfone class NO free radical as radioprotectant |
Also Published As
Publication number | Publication date |
---|---|
CA2377621A1 (en) | 2000-12-28 |
CA2377621C (en) | 2009-05-19 |
EP1194150A1 (en) | 2002-04-10 |
JP2003502372A (en) | 2003-01-21 |
AU761674B2 (en) | 2003-06-05 |
US6552040B1 (en) | 2003-04-22 |
EP1194150A4 (en) | 2003-06-11 |
AU5612000A (en) | 2001-01-09 |
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