HRP980436A2 - Use of uridine to counter 5-fluorouracil toxicity - Google Patents
Use of uridine to counter 5-fluorouracil toxicityInfo
- Publication number
- HRP980436A2 HRP980436A2 HRP980436A HRP980436A2 HR P980436 A2 HRP980436 A2 HR P980436A2 HR P980436 A HRP980436 A HR P980436A HR P980436 A2 HRP980436 A2 HR P980436A2
- Authority
- HR
- Croatia
- Prior art keywords
- tissue
- uridine
- fluorouracil
- deoxyuridine
- pyrimidine analog
- Prior art date
Links
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 title claims description 133
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 title claims description 65
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 title claims description 65
- 229940045145 uridine Drugs 0.000 title claims description 65
- 208000034428 5-fluorouracil toxicity Diseases 0.000 title 1
- 210000001519 tissue Anatomy 0.000 claims description 48
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 41
- 229960002949 fluorouracil Drugs 0.000 claims description 41
- 150000003230 pyrimidines Chemical class 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 13
- 208000003265 stomatitis Diseases 0.000 claims description 12
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 231100000419 toxicity Toxicity 0.000 claims description 5
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- 210000002200 mouth mucosa Anatomy 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 claims description 3
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 claims description 3
- 239000012062 aqueous buffer Substances 0.000 claims description 3
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- KPQFKCWYCKXXIP-XLPZGREQSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(methylamino)pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(NC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 KPQFKCWYCKXXIP-XLPZGREQSA-N 0.000 claims description 2
- CBOKZNLSFMZJJA-PEBGCTIMSA-N 3-Deazauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)C=C(O)C=C1 CBOKZNLSFMZJJA-PEBGCTIMSA-N 0.000 claims description 2
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 2
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 claims description 2
- NEPYLBSUVIVISN-UHFFFAOYSA-N 5-fluoro-1-(oxolan-2-ylmethyl)pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(F)=CN1CC1OCCC1 NEPYLBSUVIVISN-UHFFFAOYSA-N 0.000 claims description 2
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 claims description 2
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 claims description 2
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 claims description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 2
- DRTQHJPVMGBUCF-CCXZUQQUSA-N arauridine Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-CCXZUQQUSA-N 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- QQOBRRFOVWGIMD-OJAKKHQRSA-N azaribine Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=N1 QQOBRRFOVWGIMD-OJAKKHQRSA-N 0.000 claims description 2
- 229950010054 azaribine Drugs 0.000 claims description 2
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 claims description 2
- 210000004877 mucosa Anatomy 0.000 claims description 2
- JTBBWRKSUYCPFY-UHFFFAOYSA-N 2,3-dihydro-1h-pyrimidin-4-one Chemical compound O=C1NCNC=C1 JTBBWRKSUYCPFY-UHFFFAOYSA-N 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 206010030113 Oedema Diseases 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
Description
Stanje tehnike State of the art
Mnogi oblici kemoterapije raka i terapije lokalne radijacije uzrokuju neželjene sporedne pojave (S.T. Sonis u Cancer Principles and Practice of Onco1ogy, 4. izdanje, šesto poglavlje, str. 2385-2394 (1993); Loprinzi et al., u Clinical Oncology 741-752 (1995)). Na primjer, antimetabolit 5-fluoruracil često izaziva stomatitis, koji je upalni odgovor oralne sluznice i intraoralne meke strukture tkiva. Stomatitis općenito započinje s crvenilom i edemom usne sluznice i jezika, i može napredovati do bolne ulceracije i sekundarnih infekcija. Zbog stomatitisa je uzimanje hrane i pića bolno i često ima za posljedicu slabu ishranu i dehidrataciju. Zasad se stomatitis uzrokovan kemoterapijom kontrolira oralnom higijenom i ublažavanjem bola. Many forms of cancer chemotherapy and local radiation therapy cause unwanted side effects (S.T. Sonis in Cancer Principles and Practice of Onco1ogy, 4th ed., ch. 6, pp. 2385-2394 (1993); Loprinzi et al., in Clinical Oncology 741-752 (1995)). For example, the antimetabolite 5-fluorouracil often causes stomatitis, which is an inflammatory response of the oral mucosa and intraoral soft tissue structures. Stomatitis generally begins with redness and edema of the oral mucosa and tongue, and may progress to painful ulceration and secondary infections. Because of stomatitis, taking food and drink is painful and often results in poor nutrition and dehydration. So far, stomatitis caused by chemotherapy is controlled by oral hygiene and pain relief.
Jasno, postoji potreba za poboljšanim metodama inhibicije stomatitisa i drugih neželjenih sporednih učinaka 5-fluoruracila ili predlijeka 5-fluoruracila. Clearly, there is a need for improved methods of inhibiting stomatitis and other unwanted side effects of 5-fluorouracil or 5-fluorouracil prodrugs.
Kratki opis izuma Brief description of the invention
Predloženi izum odnosi se na metodu za inhibiciju, potpunu ili djelomičnu, toksičnosti u tkivu pojedinca induciranu analogom pirimidina, kao u pacijenta koji se podvrgava terapiji s analogom pirimidina. Metoda uključuje površinsko davanje, na tkivo, terapeutski učinkovite količine uridina. Tkivo može biti bilo koje tkivo na kojem se pojavljuju štetne posljedice analoga pirimida, na primjer, tkivo sluznice kao što je gastrointestinalna sluznica. The proposed invention relates to a method for inhibiting, in whole or in part, toxicity in the tissue of an individual induced by a pyrimidine analog, such as in a patient undergoing therapy with a pyrimidine analog. The method involves topical administration, to the tissue, of a therapeutically effective amount of uridine. The tissue can be any tissue in which the adverse effects of the pyrimidine analog occur, for example, mucosal tissue such as the gastrointestinal mucosa.
U jednoj izvedbi izumom je data metoda inhibicije stomatitisa izazvanog kemoterapijom u pacijenata podvrgnutih liječenju s analogom pirimidina. Analog pirimidina je kemoterapeutsko sredstvo kao što je 5-fluor-uracil ili 5-fluor-2’-deoksiuridin, koji inducira stomatitis, a tkivo je intraoralno tkivo, kao što je tkivo oralne sluznice ili intraoralno meko tkivo. U toj, izvedbi intraoralno tkivo dolazi u dodiru s uridinom aplikacijom uridina ili sastava koji sadrži uridin izravno na površinu intraoralnog tkiva. In one embodiment, the invention provides a method of inhibiting chemotherapy-induced stomatitis in patients undergoing treatment with a pyrimidine analog. The pyrimidine analog is a chemotherapeutic agent such as 5-fluoro-uracil or 5-fluoro-2'-deoxyuridine, which induces stomatitis, and the tissue is intraoral tissue, such as oral mucosal tissue or intraoral soft tissue. In this embodiment, the intraoral tissue is contacted with uridine by applying uridine or a composition containing uridine directly to the surface of the intraoral tissue.
Obznanjena metoda je metoda inhibicije toksičnih učinaka analoga pirimidina u odabranom tkivu lokalnim davanjem uridina na površinu tkiva. Metodom je stoga data lokalna zaštita od toksičnosti analoga pirimidina bez ograničenja i teškoća povezanih sa sistemskim davanjem uridina, kao što je toksičnost i ograničena dostupnost. The known method is a method of inhibiting the toxic effects of pyrimidine analogs in a selected tissue by local administration of uridine to the tissue surface. The method thus provided local protection against the toxicity of pyrimidine analogs without the limitations and difficulties associated with systemic administration of uridine, such as toxicity and limited availability.
Opis izuma u pojedinostima Description of the invention in detail
Predloženi izum odnosi se na površinsko davanje uridina na tkivo, kao što je tkivo sisavca podvrgnutog liječenju s analogom pirimidina, za inhibiciju toksičnosti inducirane s analogom pirimidina. Kako je ovdje opisano, izumitelji su pokazali da površinsko davanje uridina na tkivo sluznice, kao što je intraoralno tkivo, inhibira, djelomično ili potpuno, stomatitis u pojedinaca kojima je dat analog pirimidina. The present invention relates to the topical administration of uridine to tissue, such as mammalian tissue subjected to pyrimidine analog treatment, to inhibit pyrimidine analog-induced toxicity. As described herein, the inventors have shown that topical administration of uridine to mucosal tissue, such as intraoral tissue, inhibits, partially or completely, stomatitis in individuals administered a pyrimidine analog.
Česta površinska aplikacija 5-fluoruracila na jabučice obraza sirijskog hrčka ima za posljedicu histološke i kliničke promjene (Cherrick et al., J. Invest. Derm. 63 : 284-286 (1974)). Pod tim uvjetima, izumitelji su opazili pogresivno stanjivanje oralnog epitela samo sa crvenilom i, na kraju, ulceraciju. Takovi razvoji karakteristični su za oralni mukozitis induciran kemoterapijom kod pacijenata s rakom (Sonis, gore (1993)). Stoga taj sistem sa hrčkom daje model za mukozitis induciran kemoterapijom kod pacijenata s rakom. Frequent topical application of 5-fluorouracil to the cheekbones of the Syrian hamster results in histological and clinical changes (Cherrick et al., J. Invest. Derm. 63: 284-286 (1974)). Under these conditions, the inventors observed a progressive thinning of the oral epithelium with only redness and, eventually, ulceration. Such developments are characteristic of chemotherapy-induced oral mucositis in cancer patients (Sonis, supra (1993)). Therefore, this hamster system provides a model for mucositis induced by chemotherapy in cancer patients.
Izumitelji su došli do iznenađujućeg otkrića da se vidljivo crvenilo i ulceracija nastala zbog ponovljene aplikacije 5-fluoruracila na jabučice obraza hrčka može spriječiti površinskom aplikacijom uridina. U početnoj sutidiji 5-fluoruracil (0,5 mg) u 20 μl vode apliciran je dva puta dnevno na desnu jabučicu obraza 6 sirijskih hrčaka. Nakon 14 dana epitel lica u 5 životinja bio je potpuno uništen, pri čemu se je vidjela stroma koja se nalazi ispod njega. Druga skupina od 6 hrčaka obrađena je s otopinom od 0,5 mg 5-fluoruracila i 5 mg uridina u 20 μl vode dva puta dnevno. Nakon 14 dana nijedna od tih životinja nije imala vidljivog propadanja epitela. The inventors made the surprising discovery that visible redness and ulceration caused by repeated application of 5-fluorouracil to the cheekbones of hamsters can be prevented by topical application of uridine. In the initial study, 5-fluorouracil (0.5 mg) in 20 μl of water was applied twice a day to the right cheekbone of 6 Syrian hamsters. After 14 days, the facial epithelium in 5 animals was completely destroyed, and the underlying stroma was visible. Another group of 6 hamsters was treated with a solution of 0.5 mg of 5-fluorouracil and 5 mg of uridine in 20 μl of water twice a day. After 14 days, none of these animals had visible epithelial deterioration.
U drugoj studiji, 6 hrčaka bilo je obrađeno dva puta dnevno s 0,5 mg 5-fluoruracila u 10 μl vode. Nakon 12 dana 4 životinje imale su vidljivu ulceraciju epitela obraza. Druga skupina od 6 hrčaka obrađena je dva puta dnevno s 0,5 mg 5-fluoruracila u 10 μl vode, i neposredno zatim s otopinom od 5 mg uridina u 10 μl vode. Nakon 12 dana nijedna od tih životinja nije imala vidljive ulceracije epitela obraza. In another study, 6 hamsters were treated twice daily with 0.5 mg of 5-fluorouracil in 10 μl of water. After 12 days, 4 animals had visible ulceration of the cheek epithelium. Another group of 6 hamsters was treated twice a day with 0.5 mg of 5-fluorouracil in 10 μl of water, and immediately after with a solution of 5 mg of uridine in 10 μl of water. After 12 days, none of these animals had visible ulceration of the cheek epithelium.
U trećoj studij i otopina od 1 mg 5-fluoruracila u 20 μl vode aplicirana je na jabučice obraza 6 hračaka jednom dnevno, i neposredno zatim aplicirano je 20 μl vode. Nakon 14 dana 5 od tih životinja imalo je potpuno uništeni epitel. U toj skupini prosječno vrijeme do ulceracije bilo je 14 dana. Skupina od 12 hrčaka bila je obrađena s otopinom 5-fluoruracila (1 mg 5-fluoruracila u 20 μl vode). Od tih, 6 životinja je bilo odmah obrađeno s otopinom od 2 mg uridina u 20 μl vode (niska doza), dok je preostalih 6 bilo obrađeno s otopinom od 10 mg uridina u 20 μl vode (visoka doza). Nakon 14 dana nijedan od tih 12 hrčaka obrađenih s uridinom nije imao vidljive ulceracije epitela. Prosječno vrijeme do ulceracije bilo je 20 dana u skupini koja je primila nisku dozu i 23 dana u skupini koja je primila visoku dozu, što pokazuje učinak povezan s dozom. In the third study, a solution of 1 mg of 5-fluorouracil in 20 μl of water was applied to the cheekbones of 6 hamsters once a day, and immediately after that, 20 μl of water was applied. After 14 days, 5 of these animals had completely destroyed epithelium. In that group, the average time until ulceration was 14 days. A group of 12 hamsters was treated with a solution of 5-fluorouracil (1 mg of 5-fluorouracil in 20 μl of water). Of these, 6 animals were immediately treated with a solution of 2 mg of uridine in 20 μl of water (low dose), while the remaining 6 were treated with a solution of 10 mg of uridine in 20 μl of water (high dose). After 14 days, none of the 12 uridine-treated hamsters had visible ulceration of the epithelium. The mean time to ulceration was 20 days in the low-dose group and 23 days in the high-dose group, indicating a dose-related effect.
Sposobnost uridina da spriječi oralni mikozitis induciran s 5-fluoruracilom bila je također uspoređena s onom kod uridinskog predlijeka, triacetiluridina. Triacetiluridin je slabo topiv u vodi. U dva pokusa prosječno vrijeme do ulceracije skupine hrčaka koji su primili 1 mg 5-fluoruracila i 20 μl zasićene vodene otopine triacetiluridina bilo je 22 i 17,5 dana, dok je prosječno vrijeme do ulceracije u skupini koja je primila samo 5-fluoruracil (kontrola) bilo 21 dan u obadva pokusa. Suprotno tome, prosječno vrijeme do ulceracije skupine hrčaka koji su primili 1 mg 5-fluoruracila i 2 mg uridina bilo je 24 i 22 dana, dok su hrčci obrađeni s 1 mg 5-fluoruracila i 10 mg uridina imali prosječno vrijeme do ulceracija od 27 i >29 dana. The ability of uridine to prevent 5-fluorouracil-induced oral mycositis was also compared with that of the uridine prodrug, triacetyluridine. Triacetyluridine is poorly soluble in water. In two experiments, the average time to ulceration in the group of hamsters that received 1 mg of 5-fluorouracil and 20 μl of a saturated aqueous solution of triacetyluridine was 22 and 17.5 days, while the average time to ulceration in the group that received only 5-fluorouracil (control ) was 21 days in both experiments. In contrast, the average time to ulceration of the group of hamsters that received 1 mg of 5-fluorouracil and 2 mg of uridine was 24 and 22 days, while the hamsters treated with 1 mg of 5-fluorouracil and 10 mg of uridine had an average time to ulceration of 27 and >29 days.
Predloženim izumom data je metoda inhibicije toksičnih učinaka analoga pirimidina u tkivu pojedinca, kao čovjeka podvrgnutog terapiji s analogom pirimidina. Metoda uključuje izravan dodir tkiva s učinkovitom količinom uridina. The proposed invention provides a method of inhibiting the toxic effects of pyrimidine analogs in the tissue of an individual, such as a person undergoing therapy with a pyrimidine analog. The method involves direct tissue contact with an effective amount of uridine.
Pojam “izravnog dodira” kako se ovdje rabi odnosi se na metode dovođenja uridina i najmanje jedne površine napadnutog tkiva u fizički dodir dovoljan da tkivo apsorbira uridin. Takove metode isključuju sistemsko davanje uridina, pri čemu se, na primjer, uridin može dovesti do tkivo putem krvotoka. Tkivo će općenito biti strana brze proliferacije stanica i s dostupnom površinom. Uridin ili sastav koji sadrži uridin može se aplicirati izravno, kao površinski, na površinu tkiva. The term "direct contact" as used herein refers to methods of bringing uridine and at least one surface of the affected tissue into physical contact sufficient for the tissue to absorb the uridine. Such methods preclude systemic administration of uridine, whereby, for example, uridine can be delivered to tissue via the bloodstream. The tissue will generally be the side of rapid cell proliferation and with available surface area. Uridine or a composition containing uridine can be applied directly, topically, to the tissue surface.
Pojam “analoga pirimidina”, kako se ovdje rabi, odnosi se na razred antikancernih i antivirusnih sredstava koja uključuju pirimidinski prsten ili heterocikl deriviran od pirimidinskog prstena zamjenom jednog dušikovog atoma ugljikom ili zamjenom jednog ugljikovog atoma dušikom. Analozi pirimidina mogu također uključiti glikozilnu skupinu, kao što je ribozilna, deoksiribozilna ili arabinozilna skupina. The term "pyrimidine analog" as used herein refers to a class of anticancer and antiviral agents that include a pyrimidine ring or a heterocycle derived from a pyrimidine ring by replacing one nitrogen atom with carbon or replacing one carbon atom with nitrogen. Pyrimidine analogs may also include a glycosyl group, such as a ribosyl, deoxyribosyl or arabinosyl group.
Pojam “terapije s analogom pirimidina”, kako se ovdje rabi, odnosi se na davanje analoga pirimidina osobi kojoj je to potrebno za liječenja bolesti (npr. pacijentu) za koju je indiciran analog pirimidina. Pojedinac može biti sisavac, kao čovjek. Analog pirimidina može se dati bilo kojom prikladnom metodom, na primjer oralno, intravenski, intraperitonealno ili intramuskularno, kako je poznato u struci. Analog pirimidina može se dati kao prikladan predlijek, na primjer derivat analoga pirimidina koji metabolizira u tijelu čime nastaje aktivan oblik lijeka. The term “pyrimidine analog therapy,” as used herein, refers to the administration of a pyrimidine analog to a person in need thereof for the treatment of a disease (eg, a patient) for which the pyrimidine analog is indicated. An individual can be a mammal, like a human. The pyrimidine analog can be administered by any suitable method, for example orally, intravenously, intraperitoneally or intramuscularly, as known in the art. A pyrimidine analog can be given as a suitable prodrug, for example a pyrimidine analog derivative that metabolizes in the body to form the active form of the drug.
U prednosnoj izvedbi analog pirimidina je derivat uridina ili uracil. Oni uključuju supstituirane derivate uridina i uracila, kao što je uracil supstituiran s halogenim. Drugi primjeri uključuju azauracil, deazauracil, azauridin i deazauridin. Ostali primjeri uključuju derivate uridina koji imaju modificiranu glikozilnu skupinu, kao što je deoksiribozilna, dideoksiribozila ili arabinozilna skupina. Analozi pirimidina uključuju ali nisu ograničeni samo na 5-fluoruracil, 5-fluor-2’-deoksiuridin, 5-fluoruridin, 6-azauridin, 5-azacitidin, 3-deazauridin, 5-joduracil, 5-jod-2’-deoksiuridin, 5-brom-2’-deoksiuridin, 5-etil-2’-deoksiuridin, 5-metilamino-2’-deoksiuridin, arabinoziluracil, azaribin i dideoksiuracil. In a preferred embodiment, the pyrimidine analog is a uridine derivative or uracil. These include substituted derivatives of uridine and uracil, such as halogen substituted uracil. Other examples include azauracil, deazauracil, azauridine and deazauridine. Other examples include uridine derivatives having a modified glycosyl group, such as a deoxyribosyl, dideoxyribosyl or arabinosyl group. Pyrimidine analogs include but are not limited to 5-fluorouracil, 5-fluoro-2'-deoxyuridine, 5-fluorouridine, 6-azauridine, 5-azacytidine, 3-deazauridine, 5-iodouracil, 5-iodo-2'-deoxyuridine, 5-bromo-2'-deoxyuridine, 5-ethyl-2'-deoxyuridine, 5-methylamino-2'-deoxyuridine, arabinosyluracil, azaribine and dideoxyuracil.
U posebnoj izvedbi analog pirimidina je 5-fluoruracil, 5-fluor-2’-deoksiuridin ili njihov predlijek. 5-fluoruracil se može dati intravenski ili površinski, dok se 5-fluor-2’-deoksiuridin obično daje intravenski. 5-fluoruracilni predlijekovi uključuju 5-fluor-1-(tetrahidrofurfuril)uracil (tegafur) i 1-(n-heksilkarbamoil)-5fluoruracil (karmofur). 5-fluoruracil, 5-fluor-2’-deoksiuridin i njihovi predlijekovi uporebljavaju se za liječenje raznih tipova raka, uključiv metastatične karcinome dojke ili gastrointestinalnog trakta i karcinom jajnika, cerviksa, mokraćnog mjehura, prostate, pankreasa ili orofarinska. In a special embodiment, the pyrimidine analog is 5-fluorouracil, 5-fluoro-2'-deoxyuridine or their prodrug. 5-fluorouracil can be given intravenously or topically, while 5-fluoro-2'-deoxyuridine is usually given intravenously. 5-fluorouracil prodrugs include 5-fluoro-1-(tetrahydrofurfuryl)uracil (tegafur) and 1-(n-hexylcarbamoyl)-5fluorouracil (carmofur). 5-Fluorouracil, 5-Fluoro-2'-deoxyuridine and their prodrugs are used for the treatment of various types of cancer, including metastatic cancers of the breast or gastrointestinal tract and cancers of the ovary, cervix, bladder, prostate, pancreas or oropharynx.
Površina ciljnog tkiva dolazi u dodir s količinom uridina koja je dovoljna za inhibiciju toksičnog efekta (efekata) analoga pirimidina na tkivu. Za svrhu predloženog izuma pojmom “inhibicija” toksičnog efekta (efekata) analoga pirimidina želi se obuhvatiti prevenciju ili redukciju toksičnog efekta (efekata) ili inhibiciju porasta toksičnog efekta (efekata); inhibicija može biti djelomična ili potpuna. The surface of the target tissue comes into contact with an amount of uridine that is sufficient to inhibit the toxic effect(s) of the pyrimidine analog on the tissue. For the purposes of the proposed invention, the term "inhibition" of the toxic effect(s) of pyrimidine analogs is intended to include the prevention or reduction of the toxic effect(s) or the inhibition of the increase in the toxic effect(s); inhibition can be partial or complete.
Količinu uridina koju će se dati određuje se na individualnoj osnovi i nju se barem djelomično određuje razmatranjem veličine pojedinca, doze analoga pirimidina koju pacijent prima, ozbiljnosti simptoma koji se liječe i željenog rezultata. The amount of uridine to be administered is determined on an individual basis and is determined at least in part by consideration of the individual's size, the dose of the pyrimidine analog the patient is receiving, the severity of the symptoms being treated, and the desired outcome.
U jednoj izvedbi, izumom je data metoda inhibicije stomatitisa induciranog s analogom pirimidina. Analog pirimidina je analog pirimidina koji inducira stomatitis. U specifičnoj izvedbi analog pirimidina je 5-fluoruracil, 5-fluor-2’-deoksiuridin ili njihov predlijek. In one embodiment, the invention provides a method of inhibiting stomatitis induced with a pyrimidine analog. A pyrimidine analog is a pyrimidine analog that induces stomatitis. In a specific embodiment, the pyrimidine analog is 5-fluorouracil, 5-fluoro-2'-deoxyuridine or a prodrug thereof.
U toj izvedbi intraoralno tkivo, kao što je oralno tkivo sluznice ili oralno tkivo meke strukture, je u dodiru s uridinom na način i dozom dovoljnom da tkivo apsorbira dovoljno uridina za postizanje željenog učinka (inhibicije toksičnih efekata analoga pirimidina). Na primjer, uridin ili sastav koji sadrži uridin može se aplicirati izravno na površinu oralnog tkiva kao otopina u vodi, vodenom puferu ili prikladnom organskom otapalu kao etanolu ili dimetilsulfoksidu, ili vodeno/organskoj mješavini. Uridin ili sastav koji sadrži uridin može se također aplicirati kao kruta tvar ili kao viskozni ili sastav u obliku gela. In this embodiment, intraoral tissue, such as oral mucosal tissue or oral soft tissue, is contacted with uridine in a manner and dose sufficient for the tissue to absorb enough uridine to achieve the desired effect (inhibition of toxic effects of pyrimidine analogs). For example, uridine or a composition containing uridine can be applied directly to the surface of oral tissue as a solution in water, an aqueous buffer, or a suitable organic solvent such as ethanol or dimethylsulfoxide, or an aqueous/organic mixture. Uridine or a uridine-containing composition may also be administered as a solid or as a viscous or gel-like composition.
U drugoj izvedbi tkivo koje se dovodi u dodir s uridinom je gastrintestinalno mukozno tkivo, na primjer, površina želuca ili intestinalne šupljine. U toj izvedbi površina tkiva može doći u dodir s uridinom oralnim ili rektalnim davanjem uridina. In another embodiment, the tissue contacted with the uridine is gastrointestinal mucosal tissue, for example, the surface of the stomach or intestinal cavity. In this embodiment, the tissue surface can be contacted with uridine by oral or rectal administration of uridine.
U drugoj izvedbi tkivo koje se dovodi u dodir s uridinom je koža ili skalp. Analozi pirimidina, posebno 5-fluoruracil i 5-fluor-2’-deoksiuridin, mogu imati štetne učinke na kožu, s posljedicom kao što je, na primjer, dermatitis, povećana pigmentacija i atrofija. U toj izvedbi uridin ili sastav koji sadrži uridin aplicira se izravno na površinu kože u području koje pokazuje ili gdje se očekuje osjetljivost prema toksičnim efektima analoga pirimidina. In another embodiment, the tissue that is brought into contact with the uridine is skin or scalp. Pyrimidine analogues, especially 5-fluorouracil and 5-fluoro-2'-deoxyuridine, can have adverse effects on the skin, with consequences such as, for example, dermatitis, increased pigmentation and atrophy. In this embodiment, the uridine or uridine-containing composition is applied directly to the surface of the skin in an area that exhibits or is expected to be sensitive to the toxic effects of the pyrimidine analog.
Ciljno tkivo može doći u dodir s uridinom ili sa sastavom koji sadrži uridin. U jednoj izvedbi tkivo dolazi u dodir sa sastavom koji sadrži otopinu uridina u prikladnom otapalu, ponajprije vodi, vodenom puferu ili dimetilsulfoksidu, ili u drugom obliku prikladnom za ciljno tkivo. Uridin se može dati na intraoralno tkivo u obliku vodene otopine, pastila, gume za žvakanje, pilula, gela, paste, otopine za pranje ili ispiranje ustiju. Sastavi za davanje na kožu mogu uključivati uridin dispergiran u prikladnoj matrici. Primjeri prikladnih matrica uključuju mineralno ulje, petrolatum ili voskove, kao parafinski vosak ili pčelinji vosak. The target tissue may come into contact with uridine or with a composition containing uridine. In one embodiment, the tissue is contacted with a composition comprising a solution of uridine in a suitable solvent, preferably water, aqueous buffer or dimethylsulfoxide, or in another form suitable for the target tissue. Uridine can be administered to the intraoral tissue in the form of an aqueous solution, lozenge, chewing gum, pill, gel, paste, wash solution or mouth rinse. Compositions for administration to the skin may include uridine dispersed in a suitable matrix. Examples of suitable matrices include mineral oil, petrolatum or waxes such as paraffin wax or beeswax.
Ciljno tkivo može doći u dodir s uridinom nakon, istovremeno ili prije davanja analoga pirimidina. Vremensko određivanje davanja uridina može se temeljiti na protokolu liječenja s analogom pirimidina. Na primjer, režim s 5-fluorailom može se sastojati u jednostrukoj trajnoj infuziji, ili u jednostrukoj dnevnoj infuziji tijekom perioda od pet dana. U jednoj izvedbi uridin se daje na ciljno tkivo dva ili više puta dnevno, na primjer, otprilike svaka četiri sata tijekom cijelog tijeka liječenja s analogom pirimidina. The target tissue may come into contact with uridine after, simultaneously with, or before administration of the pyrimidine analog. Timing of uridine administration may be based on the pyrimidine analog treatment protocol. For example, a 5-fluoroayl regimen may consist of a single continuous infusion, or a single daily infusion over a period of five days. In one embodiment, the uridine is administered to the target tissue two or more times per day, for example, approximately every four hours throughout the course of treatment with the pyrimidine analog.
Izum će se sada dalje i specifično opisati pomoću slijedećih primjera. The invention will now be further and specifically described by means of the following examples.
Primjeri Examples
Materijali i metode Materials and methods
Uridin i tri-O-acetiluridin nabavljeni su od tvrtke Sigma Chemical Co., St. Louis, MO. 5-fluoruracil (ovdje se također navodi i kao “5-FU”) upotrijebljen je kao otopina od 50 mg/ml nabavljena od tvrtke Pharmacia Inc., Columbus, OH. Uridine and tri-O-acetyluridine were purchased from Sigma Chemical Co., St. Louis. Louis, MO. 5-fluorouracil (also referred to herein as “5-FU”) was used as a 50 mg/ml solution obtained from Pharmacia Inc., Columbus, OH.
Otopine uridina pripravljene su kratkom sonikacijom u sterilnoj vodi ili u sterilnoj vodi namještenoj s NaOH na pH 9,5. 2asićena otopina tri-o-acetil uridina (TAU) pripravljena je dodatkom 1 grama praha u 25 ml sterilne vode i miješanjem 72 sata. Nakon centrifugiranja 5 minuta pri 2000 okr./min filtracijom kroz 0,45 μm tlačni filtar (Acrodisc) odstranjene su eventualno zaostale krute čestice. Spektroskopska analiza provedena je s razrijeđenim otopinama pripravljenim od ove koncentrirane, a koncentracija je određena na osnovi apsorbancije pri 258 nm i usporedbom sa standardnim otopinama. Uridine solutions were prepared by short sonication in sterile water or in sterile water adjusted with NaOH to pH 9.5. A saturated solution of tri-o-acetyl uridine (TAU) was prepared by adding 1 gram of powder to 25 ml of sterile water and stirring for 72 hours. After centrifugation for 5 minutes at 2000 rpm, any remaining solid particles were removed by filtration through a 0.45 μm pressure filter (Acrodisc). Spectroscopic analysis was performed with diluted solutions prepared from this concentrated solution, and the concentration was determined based on absorbance at 258 nm and comparison with standard solutions.
Mukozitis Mucositis
Sirijski zlatni hrčci (stari 6 do 23 tjedna; Harlan Sprague Dawley) umireni su inhalacijom metoksiflurana i okrenuta im je desna jabučica obraza. Otopina 5-FU aplicirana je površinski s pipetom i ravnomjerno poprskana na gornju površinu. Ispitna sredstva su slično aplicirana na isto područje. Životinje su vagane dnevno i ocijenjene s obzirom na mukozitis kako slijedi: 0 = normalno, - = blago crvenilo, 2 = značajno crvenilo, 3-edem ili nabiranje tkiva, 4 = ulceracija. Syrian golden hamsters (6 to 23 weeks old; Harlan Sprague Dawley) were sedated by inhalation of methoxyflurane and their right cheekbones were turned. The 5-FU solution was applied superficially with a pipette and evenly sprayed on the upper surface. Test means are similarly applied to the same area. Animals were weighed daily and scored for mucositis as follows: 0 = normal, - = mild redness, 2 = significant redness, 3-edema or tissue puckering, 4 = ulceration.
Rezultati the results
Podaci prikazani u tablici 1 pokazuju učinke uridina na oralni mukozitis induciran s 5-fluoruracilom. Skupina 1 bila je obrađena s 0,5 mg 5-fluoruracila dva puta dnevno. Nakon 14 dana, na 5 od 6 hrčaka u toj skupini vidjelo se je potpuno propadanje epitela obraza, ostavljaju izloženom stromu ispod epitela. Skupina 2 obrađena je s 0,5 g 5-fluoruracila pomiješanog s 5 mg uridina dva puta dnevno. The data shown in Table 1 show the effects of uridine on 5-fluorouracil-induced oral mucositis. Group 1 was treated with 0.5 mg of 5-fluorouracil twice a day. After 14 days, 5 out of 6 hamsters in that group showed complete decay of the cheek epithelium, leaving exposed stroma under the epithelium. Group 2 was treated with 0.5 g of 5-fluorouracil mixed with 5 mg of uridine twice a day.
Nijedna od tih životinja (0/6) nije pokazala vidljivog propadanja epitelnog sloja nakon 14 dana. None of these animals (0/6) showed visible deterioration of the epithelial layer after 14 days.
Tablica 1 Table 1
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Površinska aplikacija 2 x dnevno u 20 μl vode. Surface application 2 x a day in 20 μl of water.
*Broj životinja s ulceracijom jabučice obraza nakon 14 dana/broj životinja u skupini. *Number of animals with ulceration of the cheekbone after 14 days/number of animals in the group.
U drugoj studiji 5-fluoruracil je apliciran površinski dva puta dnevno u 10 μl vode. Nakon 12 dana četiri od šest hrčaka u toj skupini imali su vidljivu ulceraciju epitela obraza. Suprotno tome, u skupini od 6 hrčaka koji su primili dva puta dnevno dozu 5-fluoruracila i neposredno zatim 5 mg uridina u 10 μl vode, nijedan nije imao vidljive ulceraciju nakon 12 dana. In another study, 5-fluorouracil was applied topically twice a day in 10 μl of water. After 12 days, four out of six hamsters in that group had visible ulceration of the cheek epithelium. In contrast, in a group of 6 hamsters that received a twice-daily dose of 5-fluorouracil followed immediately by 5 mg of uridine in 10 μl of water, none had visible ulceration after 12 days.
Tablica 2 Table 2
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Površinska aplikacija 2 x dnevno u 10 μl vode. Surface application 2 x a day in 10 μl of water.
*Broj životinja s ulceracijom jabučice obraza nakon 12 dana/broj životinja u skupini. *Number of animals with ulceration of the cheekbone after 12 days/number of animals in the group.
Tablica 3 prikazuje rezultate treće studije koja je potvrdila te početne rezultate. Nakon dnevne površinske aplikacije od 1 mg 5-fluoruracila u 20 μl vode i neposredno zatim 20 μl vode 5 od 6 životinja imalo je potpuno uništen epitel nakon 14 dana. Međutim, životinje koje su primile tu dozu 5-fluoruracila neposredno nakon visoke doze uridina (10 mg u 20 μl vode) ili nižu dozu uridina (2 mg u 20 μl vode) imale su vidljivu ulceraciju nakon 14 dana. Prosječno vrijeme do ulceracije bilo je dulje za životinje koje su primile visoku dozu uridina, čime je indiciran učinak ovisan o dozi. Table 3 shows the results of a third study that confirmed these initial results. After a daily topical application of 1 mg of 5-fluorouracil in 20 μl of water and immediately followed by 20 μl of water, 5 out of 6 animals had completely destroyed epithelium after 14 days. However, animals that received that dose of 5-fluorouracil immediately after a high dose of uridine (10 mg in 20 μl of water) or a lower dose of uridine (2 mg in 20 μl of water) had visible ulceration after 14 days. The mean time to ulceration was longer for animals that received the high dose of uridine, indicating a dose-dependent effect.
Tablica 3 Table 3
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Površinska aplikacija jednom dnevno u 20 μl vode. Surface application once a day in 20 μl of water.
*Broj životinja s ulceracijom jabučice obraza nakon 14 dana/broj životinja u skupini. *Number of animals with ulceration of the cheekbone after 14 days/number of animals in the group.
U tablici 4 uspoređeni su zaštitni učinci uridina i triacetiluridina u dvije studije. Dnevna površinska aplikacija 5-fluoruracila (1 mg u 20 μl vode) i neposredno zatim 20 μl vode dalo je prosječno vrijeme do ulceracije od 21 dana u obje studije. Životinje koje su primile 5-fluoruracil popraćen s niskom dozom uridina (2 mg u 20 μl vode) imale su prosječno vrijeme do ulceracije od 22 do 24 dana, dok su životinje koje su primile visoku dozu uridina (10 mg u 20 μl vode) imale prosječno vrijeme do ulceracije od 27 i >29 dana. Suprotno tome, davanje 5-fluroacila popraćeno s 20 μl zasićene vodene otopine triacetiluridina nije dalo značajniju zaštitu od ulceracije. Table 4 compares the protective effects of uridine and triacetyluridine in two studies. Daily topical application of 5-fluorouracil (1 mg in 20 μl of water) followed immediately by 20 μl of water gave a mean time to ulceration of 21 days in both studies. Animals that received 5-fluorouracil accompanied by a low dose of uridine (2 mg in 20 μl of water) had an average time to ulceration of 22 to 24 days, while animals that received a high dose of uridine (10 mg in 20 μl of water) had average time to ulceration of 27 and >29 days. In contrast, administration of 5-fluoroacyl followed by 20 μl of saturated aqueous triacetyluridine did not provide significant protection against ulceration.
Tablica 4 Table 4
[image] [image]
*Površinska aplikacija jednom dnevno u 20 μl vode. Najprije je dat 5-FU i zatim je slijedio uridin ili triacetiluridin. *Surface application once a day in 20 μl of water. 5-FU was given first followed by uridine or triacetyluridine.
Ekvivalenti Equivalents
Budući da je ovaj izum bio posebno prikazan i opisan pomoću njegovih prednosnih izvedbi, razumljivo je da stručnjak može učiniti brojne promjene u obliku i pojedinostima a da se time ne udaljava od duha i svrhe izuma, kako je definiran u priloženim patentnim zahtjevima. Stručnjak će prepoznati ili će pomoću samo rutinskih pokusa naći mnoge ekvivalente specifičnim izvedbama posebno ovdje opisanog izuma. Takovi ekvivalenti se smatraju obuhvaćeni opsegom patentnih zahtjeva. Since this invention has been specifically shown and described using its preferred embodiments, it is understood that one skilled in the art may make numerous changes in form and detail without departing from the spirit and purpose of the invention as defined in the appended claims. Many equivalents to specific embodiments of the invention particularly described herein will be recognized by one skilled in the art, or will be found by only routine experimentation. Such equivalents are considered within the scope of the patent claims.
Claims (15)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US91576997A | 1997-08-21 | 1997-08-21 |
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| HRP980436A2 true HRP980436A2 (en) | 1999-04-30 |
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| HRP980436 HRP980436A2 (en) | 1997-08-21 | 1998-08-06 | Use of uridine to counter 5-fluorouracil toxicity |
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| AR (1) | AR013424A1 (en) |
| AU (1) | AU8388198A (en) |
| HR (1) | HRP980436A2 (en) |
| WO (1) | WO1999008686A1 (en) |
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| SE529064C2 (en) * | 2005-01-03 | 2007-04-24 | Selectica Pharmaceuticals Ab | Topical compositions |
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| GB2016921B (en) * | 1978-03-27 | 1982-08-18 | Taiho Pharmaceutical Co Ltd | Anti cancer compositions containing uracil derivatives |
| US5968914A (en) * | 1987-10-28 | 1999-10-19 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
| EP0445239A4 (en) * | 1989-06-21 | 1992-03-25 | The Catholic University Of America | Anti-malarial composition and method of use |
| AU6081294A (en) * | 1993-05-14 | 1994-12-12 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
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1998
- 1998-07-13 WO PCT/US1998/014179 patent/WO1999008686A1/en active Application Filing
- 1998-07-13 AU AU83881/98A patent/AU8388198A/en not_active Abandoned
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| WO1999008686A1 (en) | 1999-02-25 |
| AU8388198A (en) | 1999-03-08 |
| AR013424A1 (en) | 2000-12-27 |
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