EP1162963A1 - Mittel zur diagnose und therapie von karzinomen - Google Patents
Mittel zur diagnose und therapie von karzinomenInfo
- Publication number
- EP1162963A1 EP1162963A1 EP00912602A EP00912602A EP1162963A1 EP 1162963 A1 EP1162963 A1 EP 1162963A1 EP 00912602 A EP00912602 A EP 00912602A EP 00912602 A EP00912602 A EP 00912602A EP 1162963 A1 EP1162963 A1 EP 1162963A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hypericin
- preparation
- carcinoma
- instillation
- bladder
- 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- Withdrawn
Links
- 201000009030 Carcinoma Diseases 0.000 title claims abstract description 24
- BTXNYTINYBABQR-UHFFFAOYSA-N hypericin Chemical compound C12=C(O)C=C(O)C(C(C=3C(O)=CC(C)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 BTXNYTINYBABQR-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229940005608 hypericin Drugs 0.000 claims abstract description 66
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 claims abstract description 66
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000012530 fluid Substances 0.000 claims abstract description 10
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims abstract description 6
- 210000003741 urothelium Anatomy 0.000 claims abstract description 5
- 208000009458 Carcinoma in Situ Diseases 0.000 claims description 19
- 201000004933 in situ carcinoma Diseases 0.000 claims description 19
- 238000003745 diagnosis Methods 0.000 claims description 14
- 102000004506 Blood Proteins Human genes 0.000 claims description 7
- 108010017384 Blood Proteins Proteins 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 210000000621 bronchi Anatomy 0.000 claims description 4
- 210000003200 peritoneal cavity Anatomy 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 210000001635 urinary tract Anatomy 0.000 claims description 4
- 102000009027 Albumins Human genes 0.000 claims description 3
- 108010088751 Albumins Proteins 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 3
- 229920000388 Polyphosphate Polymers 0.000 claims description 3
- 239000012062 aqueous buffer Substances 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 3
- 210000005002 female reproductive tract Anatomy 0.000 claims description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000001205 polyphosphate Substances 0.000 claims description 3
- 235000011176 polyphosphates Nutrition 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 210000003932 urinary bladder Anatomy 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 201000001531 bladder carcinoma Diseases 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 150000005846 sugar alcohols Polymers 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 206010005006 Bladder cancer stage 0, with cancer in situ Diseases 0.000 claims 1
- 238000005538 encapsulation Methods 0.000 claims 1
- 238000001179 sorption measurement Methods 0.000 claims 1
- 238000004659 sterilization and disinfection Methods 0.000 claims 1
- 238000009434 installation Methods 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 description 14
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 9
- 229960002749 aminolevulinic acid Drugs 0.000 description 9
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000001574 biopsy Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000035945 sensitivity Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 241000546188 Hypericum Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000003504 photosensitizing agent Substances 0.000 description 4
- 235000017309 Hypericum perforatum Nutrition 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000002574 cystoscopy Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000002165 photosensitisation Effects 0.000 description 3
- 239000012460 protein solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000282461 Canis lupus Species 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- 206010058314 Dysplasia Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001839 endoscopy Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000005751 tumor progression Effects 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 244000141009 Hypericum perforatum Species 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 231100000674 Phytotoxicity Toxicity 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004882 non-tumor cell Anatomy 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000002215 photochemotherapeutic effect Effects 0.000 description 1
- 229940109328 photofrin Drugs 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- 231100000760 phototoxic Toxicity 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 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
- A61K49/0013—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
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the diagnosis and treatment of carcinoma, in particular of carcinoma of hollow organs, such as the urinary tract, including the bladder, bronchi, peritoneal cavity, gastrointestinal tract, female genital tract.
- carcinoma in particular of carcinoma of hollow organs, such as the urinary tract, including the bladder, bronchi, peritoneal cavity, gastrointestinal tract, female genital tract.
- the invention relates in particular to diagnosis and treatment of carcinoma of the urothelium with a special interest of carcinoma of the bladder.
- Bladder cancer is the sixth most common malignant disease worldwide. When first diagnosed, 75 to 85% of the patients have superficial tumors. More than 70% of patients with superficial bladder tumors will have one or more recurrences after initial therapy and in about one third tumor progression is observed. The cause for this high recurrence rate is the fact that small papular lesions can be overlooked. Progression is mostly due to the presence of flat carcinoma in situ.
- Carcinoma in situ (CIS) of the bladder is a confounding disease that is difficult to recognize clinically as well as histopathologically. Many studies have suggested its relationship with subsequent invasive disease.
- a study of natural history of untreated CIS has been reported by Wolf et al . (Wolf et al . , Scand. J. Urol. Nephrol. Suppl . 157:147-151 (1994)).
- CIS Carcinoma in situ
- the object of the invention to provide a new way of diagnosing carcinoma in general, carcinoma of hollow organs in particular and of the urothelium more in particular and specifically CIS without the drawbacks of the known methods described above .
- hypericin as a diagnostic or therapeutic agent.
- analogues or derivatives thereof can be used.
- Such analogues or derivatives contain modifications that are intended to modify the solubility or other physical parameters of the hypericin, but are not intended to change the fluorescent nature of hypericin. This means that for example hypericin polyacetate and hypericin polyphosphate, derivatives that are no longer fluorescent per se, are excluded for the use of the invention.
- Hypericin is the hexahydroxydimethyl derivative of phenantroperylene dione and is one of the major photosensitizing constituents present in Hypericum extracts.
- the extract of Hypericum is used in the treatment of mild to moderately depressive disorders, especially in German speaking countries. Hypericin shows a bright red fluorescence when excited.
- the photodynamic characteristics of the compound on human cell lines have been shown in vitro (Hadjur et al . , J. Photochem. Photobiol . B. Biol . 27, 139-146 (1995); Canwell et al . , Neurosurgery 35, 705-709 (1994); Zhang et al . , Neurosurgery 38, 705-709 (1996); Zhang et al .
- Vandenbogaerde et al . (Anticancer Res. 16, 1619-1626 (1996) ) reported the selective accumulation and antitumoral activity of photosensitized hypericin in A431 cell xenografts in athymic nude mice. The accumulation in the tumor in this case took place after hypericin was illuminated.
- hypericin exhibited in vitro a differential phototoxicity against several human tumor cell lines depending on the uptake of the compound by the cells (Vandenbogaerde et al . , J. Photochem. Photobiol. B. 38, 136-142 (1997)).
- hypericin topically as photochemotherapeutic agent in squamous cell and basal cell carcinoma (Alecu et al . , Anticancer Res. 18, 4651-4654 (1998)). For this hypericin was injected into the tumor and illuminated afterwards.
- Hypericin derivatives have been used for diagnosis of tumors.
- WO97/03697 for example describes that tumor cells contain enzymes that convert non- fluorescent compounds, such as hypericin polyacetate or hypericin polyphosphate, into fluorescent compounds.
- Non- tumor cells do not contain the same (amount) of enzymes. Tumor cells are thus preferentially stained because they can convert the substrate into a fluorescent form.
- the present invention does not rely on a fluorogenic compound, but starts out with hypericin per se, which is already fluorescent, and which is now surprisingly found to preferentially accumulate in the tumor tissues.
- W094/14956 relates to the use of an energy donating chemical together with a photosensitizing chemical, such as hypericin or porphyrin.
- the energy donating chemical is used as a molecular flashlight to photoactivate the photosensitizing chemical and is in turn activated by an activating chemical.
- the activating chemical must be regulated such that activation occurs solely in tumor cells. For this additional, rather complicated methods are needed.
- the present invention relies solely on the direct activation of hypericin by light and its specificity is based on the surprising finding that tumor cells preferentially accumulate hypericin.
- the present inventors were the first to identify hypericin as a selective tumor marker, in particular for bladder cancer. Surprisingly, it was found that hypericin was capable of concentrating very specifically into the tumor. Except for the tumor no other tissues showed fluorescence after illumination thus demonstrating the specificity. The advantage of this is that the amount of false positives will be lower than with the known markers, such as ALA.
- the diagnostic method and treatment of the invention can be applied to various hollow organs, such as the urinary tract, including the bladder, bronchi, peritoneal cavity, gastrointestinal tract, female genital tract .
- urinary tract including the bladder, bronchi, peritoneal cavity, gastrointestinal tract, female genital tract .
- the diagnostic or therapeutic preparation can take the form of an inhaler and the diagnosis or therapy can be made through endoscopy.
- peritoneal cavity laparoscopy is a suitable technique for applying the preparation and for illumination thereof and observation of the fluorscence.
- the preparation can be taken orally.
- oesophagus When the oesophagus is to be diagnosed or treated use can be made of two balloons that close of the oesophagus and in between which the fluid can be kept for a certain period of time. Diagnosis and treatment can again be made through endoscopy.
- a diagnostic preparation of the invention comprises hypericin and a suitable carrier or excipient and preferably takes the form of an instillation fluid.
- the instillation fluid is brought into the bladder and left there for a predetermined period of time. After removal of the fluid, the bladder can be illuminated with light that excites hypericin, e.g. blue light.
- the hypericin that is accumulated in the bladder carcinoma When excited the hypericin that is accumulated in the bladder carcinoma will emit orange-red fluorescence of 600-640 nm. This fluorescence can be detected with slightly modified lenses to enhance the blue/red contrast.
- diagnosis can be coupled to local treatment by longer illumination times . Because the specificity of hypericin is so high, the treatment can also be highly specific and localised to the actual place of the tumor. Treatment without direct preceding diagnosis is also part of the invention. In that case, a higher total light dose should be used, reaching typically 15 J/cm 2 (unscattered) .
- hypericin is admixed with inter alia a plasma protein solution.
- a preparation that is obtainable by dissolving hypericin in PEG 400 and subsequently diluting the thus obtained solution with an aqueous buffer of bladder-compatible pH, containing mannitol, sorbitol or other poly-alcohols.
- the thus obtained concentrated preparation is stable and can be diluted in a desired buffer solution.
- a lyophilized preparation of buffer, additives and hypericin may be used, which is reconstituted with water prior to use.
- Example 1 will show that hypericin has various advantages over the commonly used ALA.
- the use of hypericin for diagnosis according to the invention leads to a specificity in case of instillations of 98% with a negative predictive value (probability of a patient not having the disease when the test is negative) of 91%.
- the sensitivity after hypericin instillations is comparable to ALA.
- Hypericin induced by ALA is rapidly bleached out and exposure to blue light has to be limited to short illumination periods in order to inspect the whole bladder.
- Hypericin induced fluorescence on the contrary is very stable, and the bladder can be fully inspected during the whole procedure .
- Another advantage of hypericin as compared to ALA is the very slow fluorescence decay as a result of which patients can be instilled up to 16 hours prior to endoscopic inspection.
- hypericin can be used in lower concentrations than are used for other applications such as the treatment of depression or phytotoxicity .
- the amount to be administered for diagnosis according to the invention is about a tenfold lower than the oral dose of total hypericin used to treat depression and approximately a 100 times lower than the phototoxic dose after oral administration of the Hypericum extract .
- an instillation solution for example plasma proteins in an isotonic buffered solution (pH 7.4)
- an instillation solution for example plasma proteins in an isotonic buffered solution (pH 7.4)
- the total amount of hypericin instilled lies between 25 and 250 ⁇ g. Higher concentrations lead to loss of specificity wheras no fluorescence is detected when lower concentrations are used.
- Hypericin is a lipophilic molecule and will therefore not readily dissolve in an aqueous medium.
- hypericin is preferably adsorbed to a protein, in particular albumin or a plasma protein preparation for solubilisation.
- a protein in particular albumin or a plasma protein preparation for solubilisation.
- solubilisation means such as cyclodextrin or liposomes.
- Hypericin (as salt) for use in the invention can be either isolated from Hypericum species (e.g. H.perforatum) or synthetically prepared.
- hypericin as used in this application is intended to encompass hypericin (as salt) itself, but also modified versions (analogues) or derivatives thereof.
- a preferred modification is a modification that leads to a higher hydrophilicity, thus facilitating dissolution of the compound in an aqueous medium.
- Such modifications can be formation of ethers or esters on the phenols or substitution of the aromatic rings .
- the instillation solution was prepared as follows. 1 to 10 mM hypericin in absolute ethanol was diluted a thousand fold in a 1% plasma protein solution and sterile membrane filtered. 29 patients were included in the study. 22 presented with visible exophytic transitional cell carcinoma. One patient had interstitial cystitis. 7 patients had repeated positive urinary cytology, without detectable lesions at cystoscopy, sonography or urogram. Random biopsies previously performed without hypericin instillation had been negative in 2 of them.
- Instillation time varied between 1 and 4 hours (1, 2, 3 and 4 hours) .
- the system used for fluorescence diagnostics was developed by Storz company (D Light system) . It consists of a small light source, with a Xenon arc lamp with a corresponding band pass filter (380-450 nm) . By switching the foot pedal, the filter is placed or removed and blue or white light is produced, respectively.
- a conventional cystoscope is used for endoscopic examination, but the telescopes (0° and 30°) are provided with a long wavelength pass filter (>520 nm) to cut off the reflected blue excitation light without blocking the red fluorescence light.
- the telescopes are compatible with all Storz endoscopes .
- Biopsies were performed from fluorescent positive and negative areas. The instillation did not provoke any side effects nor symptoms.
- Carcinoma in situ could be correctly diagnosed in all of the patients with a suspicious cytology, without detectable tumor.
- 66 biopsies confirmed the presence of carcinoma in situ (Table 1) . 56 of those biopsies had shown red fluorescence at cystoscopy.
- the sensitivity is the chance that the test will give a positive result in case a pathology is present and is obtained by dividing the amount of exact positives by the total of exact positives and false negatives.
- the specificity is the chance that a malignancy is present when the test is positive and is obtained by dividing exact negative by the sum of exact negatives and false positives .
- a concentrated preparation for installation was prepared as follows. Hypericin was dissolved in PEG 400 to a final concentration of 5 mM. The thus obtained solution is further diluted while stirring to 80 ⁇ M in an aqueous phosphate buffer, containing 4.2% mannitol (pH
- the content of the vials can be added to 45 ml of an aqueous buffer of choice.
- the final concentration of the 50 ml installation fluid thus obtained is 8 ⁇ M.
- the concentrate was kept in the dark at room temperature for 1 month before use. Its diagnostic potential was then found to be identical to preparations containing a plasma protein solution.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00912602A EP1162963A1 (de) | 1999-03-11 | 2000-03-10 | Mittel zur diagnose und therapie von karzinomen |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99200747A EP1040825A1 (de) | 1999-03-11 | 1999-03-11 | Mittel zur Diagnostik von Harnblasenkarzinom |
EP99200747 | 1999-03-11 | ||
EP00912602A EP1162963A1 (de) | 1999-03-11 | 2000-03-10 | Mittel zur diagnose und therapie von karzinomen |
PCT/EP2000/002193 WO2000053170A1 (en) | 1999-03-11 | 2000-03-10 | Means for diagnosing and treating carcinoma |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1162963A1 true EP1162963A1 (de) | 2001-12-19 |
Family
ID=8239974
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99200747A Withdrawn EP1040825A1 (de) | 1999-03-11 | 1999-03-11 | Mittel zur Diagnostik von Harnblasenkarzinom |
EP00912602A Withdrawn EP1162963A1 (de) | 1999-03-11 | 2000-03-10 | Mittel zur diagnose und therapie von karzinomen |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99200747A Withdrawn EP1040825A1 (de) | 1999-03-11 | 1999-03-11 | Mittel zur Diagnostik von Harnblasenkarzinom |
Country Status (7)
Country | Link |
---|---|
EP (2) | EP1040825A1 (de) |
JP (1) | JP2002538201A (de) |
KR (1) | KR20020008124A (de) |
AU (1) | AU3429300A (de) |
BR (1) | BR0008914A (de) |
WO (1) | WO2000053170A1 (de) |
ZA (1) | ZA200107345B (de) |
Families Citing this family (5)
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KR100450523B1 (ko) * | 2002-03-13 | 2004-10-01 | 이종근 | 애완견용 신발 주걱 |
GB0723124D0 (en) * | 2007-11-26 | 2008-01-02 | Univ Leuven Kath | Targeted radiotherapy |
AT508680B1 (de) * | 2009-05-19 | 2011-03-15 | Onkotec Gmbh | Verfahren zur qualitativen und/oder quantitativen bestimmung von tumorzellen |
DE102014204138A1 (de) * | 2014-03-06 | 2015-09-24 | Briu Gmbh | Pharmazeutische Formulierung, Verfahren zur Herstellung der pharmazeutischen Formulierung und Infusionslösung sowie deren Verwendung als Medizinprodukt und/oder als Medikament |
US9629932B2 (en) * | 2015-09-28 | 2017-04-25 | Sanochemia Pharmazeutika Ag | Photodynamic diagnosis, formulations usable as photosensitizers for this purpose, method for the production and use thereof |
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DE4228106A1 (de) * | 1992-08-24 | 1994-03-03 | Medac Klinische Spezialpraep | Verwendung von £-Aminolävulinsäure zur Herstellung eines topischen Arzneimittels zur integralen Diagnose und/oder Therapie von Tumoren in Hohlorganen |
AU5959994A (en) * | 1992-12-23 | 1994-07-19 | Iowa State University Research Foundation Inc. | Molecular flashlight |
US6576784B1 (en) * | 1993-05-27 | 2003-06-10 | Yeda Research And Development Co. Ltd. | Antiviral agents |
JP3394566B2 (ja) * | 1993-07-16 | 2003-04-07 | 富士写真フイルム株式会社 | 癌の光化学療法用医薬組成物 |
IT1275571B (it) * | 1995-07-19 | 1997-08-07 | Consiglio Nazionale Ricerche | Substrati fluorogenici suscettibili di fotoattivazione previa trasformazione per via enzimatica atti alla diagnosi ed alla terapia fotodinamica dei tumori |
ATE353019T1 (de) * | 1995-12-01 | 2007-02-15 | Molecular Insight Pharm Inc | Stereoisomere von fettsäureanalogen zur diagnostischen bildgebung |
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1999
- 1999-03-11 EP EP99200747A patent/EP1040825A1/de not_active Withdrawn
-
2000
- 2000-03-10 JP JP2000603659A patent/JP2002538201A/ja active Pending
- 2000-03-10 KR KR1020017011495A patent/KR20020008124A/ko not_active Application Discontinuation
- 2000-03-10 BR BR0008914-1A patent/BR0008914A/pt not_active Application Discontinuation
- 2000-03-10 EP EP00912602A patent/EP1162963A1/de not_active Withdrawn
- 2000-03-10 AU AU34293/00A patent/AU3429300A/en not_active Abandoned
- 2000-03-10 WO PCT/EP2000/002193 patent/WO2000053170A1/en not_active Application Discontinuation
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2001
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Also Published As
Publication number | Publication date |
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EP1040825A1 (de) | 2000-10-04 |
AU3429300A (en) | 2000-09-28 |
ZA200107345B (en) | 2002-11-27 |
KR20020008124A (ko) | 2002-01-29 |
BR0008914A (pt) | 2002-01-29 |
WO2000053170A1 (en) | 2000-09-14 |
JP2002538201A (ja) | 2002-11-12 |
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