WO1999008686A1 - Use of uridine to counter 5-fluorouracil toxicity - Google Patents
Use of uridine to counter 5-fluorouracil toxicity Download PDFInfo
- Publication number
- WO1999008686A1 WO1999008686A1 PCT/US1998/014179 US9814179W WO9908686A1 WO 1999008686 A1 WO1999008686 A1 WO 1999008686A1 US 9814179 W US9814179 W US 9814179W WO 9908686 A1 WO9908686 A1 WO 9908686A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tissue
- uridine
- fluorouracil
- pyrimidine analogue
- deoxyuridine
- 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 abstract description 137
- 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 abstract description 67
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229940045145 uridine Drugs 0.000 title claims abstract description 67
- 208000034428 5-fluorouracil toxicity Diseases 0.000 title 1
- 210000001519 tissue Anatomy 0.000 claims abstract description 51
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229960002949 fluorouracil Drugs 0.000 claims abstract description 44
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 33
- 208000003265 stomatitis Diseases 0.000 claims abstract description 15
- 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 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 8
- 231100000419 toxicity Toxicity 0.000 claims abstract description 6
- 230000001988 toxicity Effects 0.000 claims abstract description 6
- 210000004872 soft tissue Anatomy 0.000 claims abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 9
- 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
- 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
- 230000002496 gastric effect Effects 0.000 claims description 3
- 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
- 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
- 210000005178 buccal mucosa Anatomy 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
- 210000004195 gingiva Anatomy 0.000 claims 1
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- 238000002512 chemotherapy Methods 0.000 abstract description 4
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- 239000000243 solution Substances 0.000 description 14
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate 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=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 9
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- 241000699673 Mesocricetus auratus Species 0.000 description 3
- 206010028116 Mucosal inflammation Diseases 0.000 description 3
- 201000010927 Mucositis Diseases 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940045688 antineoplastic antimetabolites pyrimidine analogues Drugs 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
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- 239000008223 sterile water Substances 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000000089 arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 description 2
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- 230000003628 erosive effect Effects 0.000 description 2
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- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
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- 238000007910 systemic administration Methods 0.000 description 2
- 238000011200 topical administration Methods 0.000 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 description 1
- SSPYSWLZOPCOLO-UHFFFAOYSA-N 6-azauracil Chemical compound O=C1C=NNC(=O)N1 SSPYSWLZOPCOLO-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
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- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
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- 210000003679 cervix uteri Anatomy 0.000 description 1
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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
Definitions
- stomatitis is an inflammatory response of the oral mucosa and intraoral soft tissue structures.
- Stomatitis generally begins with erythema and edema of the buccal mucosa and tongue, and can progress to painful ulceration and secondary infections. Stomatitis makes eating and drinking painful and often results in malnutrition and dehydration.
- chemotherapy-induced stomatitis is managed with oral hygiene and pain relief.
- the present invention is a method for inhibiting, totally or partially, pyrimidine analogue-induced toxicity in a tissue of an individual, such as a patient, undergoing pyrimidine analogue therapy.
- the method comprises topically administering to the tissue a therapeutically effective amount of uridine .
- the tissue can be any accessible tissue which shows adverse effects of the pyrimidine analogue, for example, mucosal tissue, such as the gastrointestinal mucosa.
- the invention provides a method of inhibiting chemotherapy-induced stomatitis in a patient undergoing treatment with a pyrimidine analogue.
- the pyrimidine analogue is a chemotherapeutic agent, such as 5- fluorouracil or 5-fluoro-2 ' -deoxyuridine, which induces stomatitis
- the tissue is an intraoral tissue, such as an oral mucosal tissue or an intraoral soft tissue.
- the intraoral tissue is contacted with uridine by applying uridine or a composition comprising uridine directly to the surface of the intraoral tissue.
- the disclosed method is a method of inhibiting the toxic effects of a pyrimidine analogue within a selected tissue by the localized administration of uridine to the surface of the tissue.
- the method thus, provides local protection from pyrimidine analog toxicity without the limitations and difficulties associated with systemic administration of uridine, such as toxicity and limited availability .
- the present invention relates to the topical administration of uridine to a tissue, such as a tissue of a mammal, undergoing treatment with a pyrimidine analogue to inhibit pyrimidine analogue-induced toxicity.
- a tissue such as a tissue of a mammal
- a pyrimidine analogue to inhibit pyrimidine analogue-induced toxicity.
- topical administration of uridine to a mucosal tissue such as an intraoral tissue, inhibits, partially or totally, stomatitis in individuals to whom a pyrimidine analogue is administered .
- Applicants have made the surprising discovery that the visible erythema and ulceration produced by repeated application of 5-fluorouracil to the hamster cheek pouch is prevented by topical application of uridine.
- 5-fluorouracil 0.5 mg
- 20 ⁇ L water was applied twice daily to the right cheek pouch of 6 Syrian hamsters.
- the cheek epithelium in 5 of the animals had broken down completely, exposing the underlying stroma.
- a second group of 6 hamsters was treated with a solution of
- the median time to ulceration was 14 days.
- a group of 12 hamsters was treated with the 5-fluorouracil solution (1 mg 5- fluorouracil in 20 ⁇ L water) . Of these, 6 were immediately treated with a solution of 2 mg uridine in 20 ⁇ L water (low dose) , while the remaining 6 were treated with a solution of 10 mg uridine in 20 ⁇ L water (high dose) . After 14 days, none of the 12 uridine treated hamsters exhibited epithelial ulceration. The median time to ulceration was 20 days in the low dose group and 23 days in the high dose group, indicating a dose-related effect.
- Triacetyluridine is sparingly soluble in water. In two trials, the median time to ulceration of a group of hamsters administered 1 mg 5- fluorouracil and 20 ⁇ L of a saturated aqueous triacetyluridine solution was 22 and 17.5 days, while the median time to ulceration in a 5-fluorouracil -only (control) group was 21 days in both trials.
- the present invention provides a method of inhibiting the toxic effects of a pyrimidine analogue in a tissue of an individual, such as a human, undergoing pyrimidine analogue therapy.
- the method comprises directly contacting the tissue with an effective amount of uridine.
- directly contacting refers to methods of bringing uridine and at least one surface of the affected tissue into sufficient physical contact for the absorption of uridine by the tissue. Such methods exclude the systemic administration of uridine, wherein, for example, uridine can be delivered to the tissue via the bloodstream.
- the tissue will generally be a site of rapidly proliferating cells and have an accessible surface.
- Uridine or a uridine-containing composition can be applied directly, such as topically, to the tissue surface.
- pyrimidine analogue refers to a class of anticancer and antiviral agents comprising a pyrimidine ring or a heterocycle derived from a pyrimidine ring by the replacement of one nitrogen atom by carbon or the replacement of one carbon atom by nitrogen.
- Pyrimidine analogues can also include a glycosyl group, such as a ribosyl, deoxyribosyl or arabinosyl group.
- pyrimidine analogue therapy refers to the administration of a pyrimidine analogue to an individual in need of treatment for an illness (e.g., a patient) for which the pyrimidine analogue is indicated.
- the individual can be a mammal, such as a human.
- the pyrimidine analogue can be administered by any suitable method, for example, orally, intravenously, intraperitoneally, or intramuscularly, as is known in the art .
- the pyrimidine analogue can also be administered as a suitable prodrug, for example, a derivative of the pyrimidine analogue which is metabolized within the body to produce the active form of the drug.
- the pyrimidine analogue is a derivative of uridine or uracil.
- uridine or uracil include substituted derivatives of uridine and uracil, such as halogen-substituted uracil.
- Other examples include azauracil, deazauracil, azauridine and deazauridine .
- derivatives of uridine having a modified glycosyl group such as a deoxyribosyl , dideoxyribosyl or arabinosyl group.
- Pyrimidine analogues 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 .
- the pyrimidine analogue is 5-fluorouracil , 5-fluoro-2 ' -deoxyuridine or a prodrug thereof.
- 5-Fluorouracil can be administered intravenously or topically, while 5-fluoro-2 ' -deoxyuridine is usually administered intravenously.
- 5 -Fluorouracil prodrugs include 5-fluoro-1- (tetrahydrofurfuryl) uracil (tegafur) and 1- (n-hexylcarbamoyl) -5-fluorouracil (carmofur) .
- 5- Fluorouracil, 5-fluoro-2 ' -deoxyuridine and prodrugs thereof are used to treat a variety of cancer types, including metastatic carcinoma of the breast or gastrointestinal tract, hepatoma and carcinoma of the ovary, cervix, urinary bladder, prostate, pancreas, or oropharynx.
- a surface of the target tissue is contacted with an amount of uridine which is sufficient to inhibit the toxic effect (s) of the pyrimidine analogue on the tissue.
- the term "inhibition" of the toxic effeet (s) of a pyrimidine analogue is intended to include the prevention or reduction of the toxic effect (s) or the inhibition of an increase in the toxic effect (s); inhibition may be partial or complete.
- the quantity of uridine to be administered will be determined on an individual basis and will be determined, at least in part, by consideration of the individual's size, the dose of the pyrimidine analogue the patient is receiving, the severity of the symptoms to be treated and the result sought.
- the invention provides a method of inhibiting pyrimidine analogue- induced stomatitis.
- the pyrimidine analogue is a pyrimidine analogue which induces stomatitis.
- the pyrimidine analogue is 5-fluorouracil , 5-fluoro-2 ' -deoxyuridine or a prodrug thereof .
- an intraoral tissue such as an oral mucosal tissue or an oral soft tissue structure
- uridine in a manner and dose sufficient for absorption of sufficient uridine by the tissue to have the desired effect (inhibition of toxic effects of a pyrimidine analogue)
- uridine or a uridine-containing composition can be applied directly to the surface of the 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 can also be applied as a solid or in a viscous or gel composition.
- the tissue to be contacted with uridine is a gastrointestinal mucosal tissue, for example, the lining of the stomach or the intestinal lumen.
- tissue surface can be contacted with uridine via oral or rectal administration of uridine.
- the tissue to be contacted with uridine is the skin or the scalp.
- Pyrimidine analogues in particular 5-fluorouracil and 5-fluoro-2 ' -deoxyuridine, can have deleterious effects on the skin, resulting in, for example, dermatitis, increased pigmentation and atrophy.
- uridine or a uridine composition is applied directly to the surface of the skin in the region exhibiting or expected to be vulnerable to the toxic effects of the pyrimidine analogue.
- the target tissue can be contacted with uridine or a composition comprising uridine.
- the tissue is contacted with a composition comprising a solution of uridine in a suitable solvent, preferably water, an aqueous buffer or dimethylsulfoxide, or in another form appropriate to the target tissue.
- Uridine can be administered to an intraoral tissue in the form of an aqueous solution, lozenges, chewing gum, troches, gels, pastes, mouthwashes or rinses.
- Compositions for administration to the skin can comprise uridine dispersed in a suitable matrix. Examples of suitable matrices include mineral oil, petrolatum and waxes, such as paraffin wax and beeswax.
- the target tissue can be contacted with uridine subsequent to, concurrent with or prior to administration of the pyrimidine analogue.
- the timing of uridine administration can be based on the pyrimidine analogue treatment protocol.
- a 5-fluorouracil regimen can consist of a single continuous infusion, or a single daily infusion over a 5 day period.
- uridine is administered to the target tissue two or more times daily, for example, about every four hours, during the entire course of pyrimidine analogue treatment.
- Uridine and tri-O-acetyluridine were purchased from Sigma Chemical Co., St. Louis, MO.
- 5 -Fluorouracil also referred to herein as "5-FU" was used as a 50 mg/mL solution purchased from Pharmacia Inc., Columbus, OH.
- Uridine solutions were prepared by brief sonication in either sterile water or sterile water adjusted to pH 9.5 with NaOH.
- a saturated tri-o-acetyl uridine (TAU) solution was prepared by adding 1 gram of powder to 25 mL sterile water and mixing for 72 hours. After centrifugation at 2000 rpm for 5 minutes, any remaining particulate matter was removed by filtration through a 0.45 ⁇ m syringe filter (Acrodisc) . Spectroscopic analysis was performed on dilutions of this saturated solution, and the concentration determined on the basis of absorbance at 258 nm and comparison with standard solutions.
- Table 1 show the effects of uridine on 5-fluorouracil -induced oral mucositis.
- Group 1 was treated with 0.5 mg 5-fluorouracil twice per day. At day 14, 5 of the 6 hamsters in this group exhibited complete breakdown of the cheek epithelium, leaving the underlying stroma exposed.
- Group 2 was treated with 0.5 mg 5-fluorouracil mixed with 5 mg uridine twice a day. None of these animals (0/6) displayed visible erosion of the epithelial layer on day 14.
- Topical application 2 x per day in 20 ⁇ L water. *number of animals with ulceration of cheek pouch on day 14/number of animals in group.
- 5-fluorouracil was applied topically twice per day in 10 ⁇ L water. By day 12, four of the six hamsters in this group exhibited ulceration of the cheek epithelium. In contrast, in a group of six hamsters receiving twice daily doses of 5-fluorouracil followed immediately by 5 mg uridine in 10 ⁇ L water, none displayed ulceration at day 12.
- Table 3 shows the results of a third study which confirmed these initial results.
- Daily topical application of 1 mg 5-fluorouracil in 20 ⁇ L water followed immediately by 20 ⁇ L water resulted in 5 of 6 animals exhibiting complete epithelial breakdown after 14 days.
- animals receiving this dose of 5-fluorouracil immediately followed by high dose uridine (10 mg in 20 ⁇ L water) or low dose uridine (2 mg in 20 ⁇ L water) showed no ulceration on day 14. The median time to ulceration was longer for the animals receiving the high dose uridine and thus, indicated a dose related effect.
- Table 4 compares the protective effects of uridine and triacetyluridine in two studies.
- Daily topical application of 5-fluorouracil (1 mg in 20 ⁇ L water) followed immediately by 20 ⁇ L water resulted in a median time to ulceration of 21 days in both studies.
- Animals receiving 5-fluorouracil followed by low dose uridine (2 mg in 20 ⁇ L water) had median times to ulceration of 22 and 24 days, while animals receiving high dose uridine (10 mg in 20 ⁇ L water) had median times to ulceration of 27 and >29 days.
- administration of 5-fluorouracil followed by 20 ⁇ L of a saturated aqueous triacetyluridine solution failed to achieve meaningful protection against ulceration.
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Abstract
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU83881/98A AU8388198A (en) | 1997-08-21 | 1998-07-13 | Use of uridine to counter 5-fluorouracil toxicity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US91576997A | 1997-08-21 | 1997-08-21 | |
US08/915,769 | 1997-08-21 |
Publications (1)
Publication Number | Publication Date |
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WO1999008686A1 true WO1999008686A1 (en) | 1999-02-25 |
Family
ID=25436223
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/014179 WO1999008686A1 (en) | 1997-08-21 | 1998-07-13 | Use of uridine to counter 5-fluorouracil toxicity |
Country Status (4)
Country | Link |
---|---|
AR (1) | AR013424A1 (en) |
AU (1) | AU8388198A (en) |
HR (1) | HRP980436A2 (en) |
WO (1) | WO1999008686A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006073359A1 (en) * | 2005-01-03 | 2006-07-13 | Selectica Pharmaceuticals Ab | Topical compositions comprising one or more of 44-thiouridine, isomaltitol and uridine |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2016921A (en) * | 1978-03-27 | 1979-10-03 | Taiho Pharmaceutical Co Ltd | Anti cancer compositions containing uracil derivatives |
WO1991000081A2 (en) * | 1989-06-21 | 1991-01-10 | The Catholic University Of America | Anti-malarial composition and method of use |
WO1994026761A1 (en) * | 1993-05-14 | 1994-11-24 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
WO1996040165A1 (en) * | 1995-06-07 | 1996-12-19 | Pro-Neuron, Inc. | Methods of reducing toxicity of chemotherapeutic and antiviral agents with acylated pyrimidine nucleosides |
-
1998
- 1998-07-13 AU AU83881/98A patent/AU8388198A/en not_active Abandoned
- 1998-07-13 WO PCT/US1998/014179 patent/WO1999008686A1/en active Application Filing
- 1998-08-06 HR HRP980436 patent/HRP980436A2/en not_active Application Discontinuation
- 1998-08-18 AR ARP980104066 patent/AR013424A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2016921A (en) * | 1978-03-27 | 1979-10-03 | Taiho Pharmaceutical Co Ltd | Anti cancer compositions containing uracil derivatives |
WO1991000081A2 (en) * | 1989-06-21 | 1991-01-10 | The Catholic University Of America | Anti-malarial composition and method of use |
WO1994026761A1 (en) * | 1993-05-14 | 1994-11-24 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
WO1996040165A1 (en) * | 1995-06-07 | 1996-12-19 | Pro-Neuron, Inc. | Methods of reducing toxicity of chemotherapeutic and antiviral agents with acylated pyrimidine nucleosides |
Non-Patent Citations (9)
Title |
---|
C.J. GROENINGEN ET AL.: "MODULATION OF FLUOROURACIL TOXICITY WITH URIDINE", SEMINARS IN ONCOLOGY, vol. 2, no. S3, 1992, pages 148 - 154, XP002083217 * |
C.J. GROENINGEN ET AL.: "REVERSAL OF 5-FLUOROURACIL-INDUCED TOXICITY BY ORAL ADMINISTRATION OF URIDINE", ANNALS OF ONCOLOGY, vol. 4, 1993, pages 317 - 320, XP002083213 * |
D.S. MARTIN TE AL.: "USE OF ORAL URIDINE AS A SUBSTITUTE FOR PARENTERAL URIDINE RESCUE OF 5-FLUOROURACIL THERAPY, WITH AND WITHOUT THE URIDINE PHOSPHORYLASE INHIBITOR 5-BENZYLCYCLOURIDINE", CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. 24, no. 1, 1989, pages 9 - 14, XP002083216 * |
E.L. SWART ET AL.: "URIDINE", PHARMACEUTISCH WEEKBLAD, vol. 130, no. 39, 1995, pages 1036 - 1038, XP002083210 * |
G.K. SCHWARTZ ET AL.: "A PHASE I TRIAL OF A MODIFIED, DOSE INTENSIVE FAMTX REGIMEN (HIGH DOSE 5-FLUOROURACIL+DOXORUBICIN+HIGH DOSE METHOTREXATE+LEUCOVORIN) WITH ORAL URIDINE RESCUE", CANCER, vol. 78, no. 9, 1996, pages 1988 - 1995, XP002083215 * |
J. KRALOVANSZKY ET AL.: "BIOCHEMICAL CONSEQUENCES OF 5-FLUOROURACIL GASTROINTESTINAL TOXICITY IN RATS; EFFECT OF HIGH-DOSE URIDINE", CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. 32, no. 3, 1993, pages 243 - 248, XP002083212 * |
J. LAI-SIM ET AL.: "EFFECT OF URIDINE COADMINISTRATION ON 5-'DEOXY-5-FLUOROURIDINE DISPOSITION IN RATS", CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. 22, no. 1, 1988, pages 5 - 10, XP002083214 * |
S.P. ROBINSON ET AL.: "URIDINE THERAPY FOR 5FU INDUCED ORAL MUCOSITIS", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, vol. 39, March 1998 (1998-03-01), pages 608, XP002083209 * |
T. BAGRIJ ET AL.: "INFLUENCE OF URIDINE TREATMENT ON THE PROTECTION OF GASTROINTESTINAL TOXICITY CAUSED BY 5-FLUOROURACIL", ANTICANCER RESEARCH, vol. 13, no. 3, 1993, pages 789 - 793, XP002083211 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006073359A1 (en) * | 2005-01-03 | 2006-07-13 | Selectica Pharmaceuticals Ab | Topical compositions comprising one or more of 44-thiouridine, isomaltitol and uridine |
Also Published As
Publication number | Publication date |
---|---|
HRP980436A2 (en) | 1999-04-30 |
AR013424A1 (en) | 2000-12-27 |
AU8388198A (en) | 1999-03-08 |
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