MXPA02002184A - Rhodamine diagnostic agent and diagnostic methods for detection of epithelial cancer. - Google Patents
Rhodamine diagnostic agent and diagnostic methods for detection of epithelial cancer.Info
- Publication number
- MXPA02002184A MXPA02002184A MXPA02002184A MXPA02002184A MXPA02002184A MX PA02002184 A MXPA02002184 A MX PA02002184A MX PA02002184 A MXPA02002184 A MX PA02002184A MX PA02002184 A MXPA02002184 A MX PA02002184A MX PA02002184 A MXPA02002184 A MX PA02002184A
- Authority
- MX
- Mexico
- Prior art keywords
- rhodamine
- composition
- tissue
- cancerous
- diagnostic
- Prior art date
Links
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 title claims description 17
- 238000002405 diagnostic procedure Methods 0.000 title claims description 5
- 201000009030 Carcinoma Diseases 0.000 title claims description 4
- 238000001514 detection method Methods 0.000 title claims description 4
- 229940039227 diagnostic agent Drugs 0.000 title description 3
- 239000000032 diagnostic agent Substances 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 17
- 210000000981 epithelium Anatomy 0.000 claims abstract description 12
- 210000001519 tissue Anatomy 0.000 claims description 12
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 claims description 11
- 238000001727 in vivo Methods 0.000 claims description 7
- 238000010186 staining Methods 0.000 claims description 6
- 230000000717 retained effect Effects 0.000 claims description 4
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 230000009841 epithelial lesion Effects 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000003535 biological staining Substances 0.000 claims 1
- 239000001022 rhodamine dye Substances 0.000 abstract description 4
- 239000000975 dye Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 229950003937 tolonium Drugs 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100309716 Arabidopsis thaliana SD18 gene Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000025157 Oral disease Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- QTWZICCBKBYHDM-UHFFFAOYSA-N leucomethylene blue Chemical compound C1=C(N(C)C)C=C2SC3=CC(N(C)C)=CC=C3NC2=C1 QTWZICCBKBYHDM-UHFFFAOYSA-N 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000003458 metachromatic effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 210000004895 subcellular structure Anatomy 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 239000001016 thiazine dye Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- AURFVNDXGLQSNN-UHFFFAOYSA-K trisodium 2-hydroxypropane-1,2,3-tricarboxylic acid phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O AURFVNDXGLQSNN-UHFFFAOYSA-K 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0071—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form solution, solute
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biodiversity & Conservation Biology (AREA)
- Optics & Photonics (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Rhodamine dye compositions and methods for detecting and/or delineating cancerous and precancerous epithelial tissue.
Description
RODAMINE DIAGNOSTIC AGENT AND DIAGNOSTIC METHODS TO DETECT EPITHELIAL CANCER
This invention relates to a novel diagnostic agent for the detection of precancerous and cancerous epithelial tissue.
According to another aspect, the invention pertains to novel methods for detecting and / or delineating cancerous and / or precancerous epithelial tissue.
In another aspect the invention relates to such diagnostic methods and agents useful in these which are especially useful for in vivo screening of patients for possible oral cancer as part of the usual examinations or procedures of dentists or doctors, such as examinations. dental or periodic physical, dental cleaning, et cetera.
In yet another aspect, the invention relates to such methods and compositions useful therein, which use dyeings with dyes that are more readily available and / or that are less expensive and less complicated to synthesize and / or purify than dyes that they are used in the prior art processes.
In still another aspect, the invention relates to in vivo methods and compositions employing a dye which, despite the teachings of the prior art, is sufficiently non-toxic that it can be used by rinsing the entire oral cavity and / or gargle. In vivo diagnostic procedures for detecting epithelial lesions are known in the art.
• premalignants, such as oral lesions and oral carcinomas, using coloring compositions that are
15 selectively retain in tissues that have become abnormal by dysplasia, hyperplasia, tumorigenesis and other lesions with surface activity. For example, procedures employing fluorescein or fluorescein derivatives are described in Chenz, Chinese Journal
20 of Stomatology (27: 44-47 (1992)) and Filurin
• (Stomagologiia (Russian) 72; 44-47 (1993)). These procedures include the application of the dye, followed by the visual examination in ultraviolet light to detect cancerous / precancerous tissue, which is
25 selectively fluorescent.
Another method of the prior art includes in vivo application by rinsing with toluidine blue O, followed by normal visual examination to detect any selectively stained tissue. Such procedures are described, for example, in U.S. Patent No. 5,372,801 to Tucci et al. and in U.S. Patent No. 4,321,251 to Mashberg. Toluidine blue has been used for decades as a histopathological staining for in vitro use. This use has been known as a metachromatic dye, which stains nuclei rich in DNA and RNA from purple to pink. The deep blue color of toluidine blue O changes to purple or pink when the dye binds to the nucleic acid or other acid cell macromolecules. Of course, this type of staining depends on the dye having access to internal subcellular structures such as the nucleus. Such access is easily obtained only by "fixing" a sample of tissue with formaldehyde or another reagent that breaks the cell membrane without destroying the overall cellular structure.
Contrary to the mechanism involved in in vitro use, in vivo oral tissue staining by toluidine blue O is due to its ability to penetrate cell walls and bind to mitochondria, which retain the dye for longer than the components of the extracellular matrix.
The Mashberg procedure involves the application of the toluidine blue solution 0 as a rinse in the entire oral cavity, with gargling, followed by rinses with water and acetic acid to remove the dye that is not retained by the cancerous or precancerous tissue. The preliminary diagnosis by the Mashberg procedure is then confirmed by the direct application of the toluidine blue O composition to the suspect site 10 to 14 days later, the '801 patent of Tucci discloses an improved composition of toluidine blue O for Use according to the general procedure taught by Mashberg.
An in vivo procedure includes the use of Lugol's solution (iodine) and toluidine blue 0 was proposed to detect esophageal cancer at the same time with cancers in the upper aerodigestive tract in Papazian,
Gastroenterologic Clinique et Biologique 9: 16-22 (1985).
Recently, U.S. Patent No. 5,882,627 to Pomerantz describes a class
The structurally defined oxazine and thiazine dyes are generally useful according to the Mashberg diagnostic protocol.
Bernal et al., Cancer Research 43, 716-720 (1983) describe that rhodamine dye selectively inhibits the growth of and kills carcinoma cells in vitro. Gaboury et al., US Patent No. 5,773,460 discloses that rhodamine is preferentially retained by multiple tumor cells and proposes that certain rhodamine esters are useful for in vitro photodynamic inhibition of certain tumor cell lines, but indicates that systemic toxicity may limit its use in chemotherapy.
Rhodamine, the 2- (6-amino-3-imino-3H-xanten-9-yl) benzoic acid methyl ester and the ionic salts thereof, for example, the hydrochloride salts, is a lipophilic cationic dye of the class pyriilio [sic]. This is effective to selectively identify and / or delineate cancerous and precancerous epithelial tissue by topical application to the epithelium, followed by normal visual examination, generally in accordance with the protocol described by the Mashberg patent 251.
Suitable compositions of rhodamine for application of the dye to the epithelial tissue are prepared by mixing the dye with a solvent suitable for pharmaceutical use, convenient. Preferably, the pH of the rhodamine solution is adjusted with a convenient, pharmaceutically acceptable buffer system to produce a final solution that is practically isotonic and has a pH in the range of from about 2.5 to 7.0, preferably 4.0-5.0. . This can be done by a buffer system acetic acid-sodium acetate. Other suitable buffer systems include citric acid-sodium citrate or mixed systems of acid salts such as citric acid-sodium phosphate and the like.
The solvent is used to produce the liquid rhodamine dye compositions of the invention is an aqueous solvent. According to the currently preferred embodiment of the invention, the solvent includes an alcohol acceptable for pharmaceutical use, ie non-toxic, non-reactive, for example ethyl alcohol. Solvents like this do not interfere appreciably with the staining mechanism and do not contribute to the reduction of the chromium forms of the dye to the leuco forms.
The flavor, stable with the other components of the coloring composition, can be added to improve the flavor of the composition if it is to be used as an oral "rinse". The amount of the rhodamine dye in the liquid composition is preferably adjusted to produce a concentration of about 1% by weight of the final composition, although it is possible to employ
10 higher concentrations, and the lower concentrations are at least partially effective. At present I prefer to employ coloring compositions containing from about 0.5 to about 3.5% by weight of the rhodamine component. The invention also contemplates the compositions for use according to the methods of the invention, in which any leuco form of the dye present in the composition is oxidized to the chromium form, by the
20 inclusion of an acceptable oxidizing agent for pharmaceutical use, in the same way as described in the '801 patent of Tucci.
25
ÍtaÉÉM --- -á - ^ - i ---- ¿--í.
EXAMPLES
The following examples are presented to illustrate the practice of the invention to the person skilled in the art and not as a limitation of the scope thereof, which is defined only by the attached clauses.
•
Example 1 Preparation of the diagnostic composition
A diagnostic composition is prepared by mixing each of the indicated components in the following 15 proportions (% by weight):
Purified water U. S. P. 83.85 Glacial acetic acid U. S. P. 4.61 Sodium acetate trihydrate U. S. P. 2.45 Ethyl alcohol SD18 7.48 Hydrogen peroxide 30%, U. S. P. 0.41 Raspberry IFF IC563457 0.20 Rhodamine 1.00 Example 2
Preparation of solution for rinsing
5 A solution for rinsing is prepared by mixing the following components in the proportions indicated (% by weight):
Purified water U. S. P. 98.70 Glacial acetic acid U. S. P. 1.00 Sodium benzoate U. S. P. 0.10 Raspberry IFF IC563457 0.20 • 10 Example 3
Clinical efficacy
The clinical efficacy of the compositions of Examples 1 and 2 is compared with the compositions for the diagnostic control of toluidine blue O prepared according to the '801 patent of Tucci, using the diagnostic protocol described in the' 251 patent. from
20 Mashberg.
First, patients with oral pathology are detected using the TBO control composition. After identifying the potential precancerous or cancerous pathology, all traces of the TBO are removed by repeatedly rinsing the suspect sites with water and with the acetic acid rinse of Example 2.
Those patients having oral pathology 10 are then taken as the test subjects for the rhodamine diagnostic composition of Example 1. 2-3 cc of the rhodamine composition is applied by rubbing the pathological mucosal surface, followed by rinsing with the rinse and water mixture to remove excess rhodamine composition.
Histological examination of the tissue of the areas stained by the rhodamine diagnostic composition of Example 1 confirms that the rhodamine composition is at least as effective as toluidine blue O for
• identification and delineation of cancerous and precancerous epithelial tissue.
25
M * í "* ß? *? Ím < s u * ^ 'iA. ¿.?? J- - ?.
Example 4
The procedures of Example 3 are repeated, except that the test and control compositions are applied to the
5 oral mucosa rinsing with gargles, instead of direct application to the place of suspicious sites. Equivalent results are obtained.
Having described my invention in such terms 10 to enable those skilled in the art to understand and practice it, and having described the currently preferred mode, I claim:
^^ Aßiiitt
Claims (3)
1. A diagnostic method for identifying and delineating cancerous epithelial tissue comprises: (a) apply rhodamine to the epithelium, to mark • selectively cancerous tissue; Y 10 (b) visually examine the epithelium, to identify and delineate the suspicious cancerous tissue sites, comparing the color of the suspect sites with the color of the adjacent tissue.
2. In a method for in vivo detection of premalignant epithelial lesions and carcinomas, which includes the steps of: in sequence 20 • rinsing the epithelium with the composition of the dye which is selectively retained by the precancerous and cancerous tissue, where the dye composition consists mainly of toluidine blue O, and ^ e & * mt? »^ ^, ^ ^ ^ ^ rinse the epithelium with a rinse composition to remove the composition for non-retained staining, 5 the improvement in which the staining composition contains rhodamine. •
3. A composition for biological staining for in vivo detection of cancerous and precancerous tissue, 10 contains (a) rhodamine, • (b) an aqueous solvent acceptable for pharmaceutical use, and (c) an oxidizing agent acceptable for pharmaceutical use for leuco rhodamine. twenty •
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2000/018126 WO2002002149A1 (en) | 2000-06-30 | 2000-06-30 | Rhodamine diagnostic agent and diagnostic methods for detection of epithelial cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA02002184A true MXPA02002184A (en) | 2002-09-30 |
Family
ID=21741551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MXPA02002184A MXPA02002184A (en) | 2000-06-30 | 2000-06-30 | Rhodamine diagnostic agent and diagnostic methods for detection of epithelial cancer. |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1294408A4 (en) |
| JP (1) | JP2004501982A (en) |
| CN (1) | CN1371290A (en) |
| AU (1) | AU784558B2 (en) |
| BR (1) | BR0013636A (en) |
| CA (1) | CA2383697A1 (en) |
| IL (1) | IL148341A0 (en) |
| MX (1) | MXPA02002184A (en) |
| NO (1) | NO20020958L (en) |
| NZ (1) | NZ517445A (en) |
| WO (1) | WO2002002149A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109768151B (en) * | 2019-01-04 | 2020-05-08 | 浙江大学 | Multi-color LED for illumination and display and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69229471T2 (en) * | 1991-10-31 | 1999-11-25 | Zila Inc | BIOLOGICAL DYE COMPOSITION, PROCESS FOR ITS PRODUCTION AND USE FOR MARKING THE OUTLINE OF EPITHELIC CARSINOMAS |
| US5618831A (en) * | 1992-11-17 | 1997-04-08 | Fuji Photo Film Co., Ltd. | Composition and method for treating cancer |
| CA2214829C (en) * | 1996-01-16 | 2002-05-14 | Edwin Pomerantz | Methods and compositions for in-vivo detection of oral cancers and precancerous conditions |
| WO2001064110A1 (en) * | 2000-02-28 | 2001-09-07 | Zila, Inc. | Method for detecting and killing epithelial cancer cells |
-
2000
- 2000-06-30 BR BR0013636-0A patent/BR0013636A/en not_active Application Discontinuation
- 2000-06-30 EP EP00946949A patent/EP1294408A4/en not_active Withdrawn
- 2000-06-30 JP JP2002506770A patent/JP2004501982A/en active Pending
- 2000-06-30 AU AU16752/02A patent/AU784558B2/en not_active Ceased
- 2000-06-30 CA CA002383697A patent/CA2383697A1/en not_active Abandoned
- 2000-06-30 MX MXPA02002184A patent/MXPA02002184A/en not_active Application Discontinuation
- 2000-06-30 IL IL14834100A patent/IL148341A0/en unknown
- 2000-06-30 CN CN00812220.2A patent/CN1371290A/en active Pending
- 2000-06-30 WO PCT/US2000/018126 patent/WO2002002149A1/en active IP Right Grant
- 2000-06-30 NZ NZ517445A patent/NZ517445A/en unknown
-
2002
- 2002-02-27 NO NO20020958A patent/NO20020958L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1294408A1 (en) | 2003-03-26 |
| NO20020958D0 (en) | 2002-02-27 |
| IL148341A0 (en) | 2002-09-12 |
| CN1371290A (en) | 2002-09-25 |
| NO20020958L (en) | 2002-04-24 |
| JP2004501982A (en) | 2004-01-22 |
| AU784558B2 (en) | 2006-05-04 |
| AU1675202A (en) | 2002-01-14 |
| NZ517445A (en) | 2004-03-26 |
| BR0013636A (en) | 2005-01-11 |
| EP1294408A4 (en) | 2005-01-05 |
| WO2002002149A1 (en) | 2002-01-10 |
| CA2383697A1 (en) | 2002-01-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| GB | Transfer or rights |
Owner name: ZILA BIOTECHNOLOGY, INC. |
|
| FA | Abandonment or withdrawal |