WO2003066049A1 - Combinaisons pour le traitement des infections fongiques - Google Patents

Combinaisons pour le traitement des infections fongiques Download PDF

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Publication number
WO2003066049A1
WO2003066049A1 PCT/US2003/003039 US0303039W WO03066049A1 WO 2003066049 A1 WO2003066049 A1 WO 2003066049A1 US 0303039 W US0303039 W US 0303039W WO 03066049 A1 WO03066049 A1 WO 03066049A1
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WIPO (PCT)
Prior art keywords
aminopyridine
triazole
phenazopyridine
administered
fluconazole
Prior art date
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PCT/US2003/003039
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English (en)
Inventor
George N. Serbedzija
Benjamin A. Auspitz
Grant R. Zimmermann
Curtis Keith
M. James Nichols
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Combinatorx, Incorporated
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Application filed by Combinatorx, Incorporated filed Critical Combinatorx, Incorporated
Priority to AU2003212888A priority Critical patent/AU2003212888A1/en
Publication of WO2003066049A1 publication Critical patent/WO2003066049A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088—Liquid substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases

Definitions

  • the invention relates to the treatment of fungal infections.
  • mycoses In animals, fungal infections (mycoses) may be superficial or systemic. Superficial mycoses include tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, and other candidoses such as vaginal, respiratory tract, biliary, eosophageal, and urinary tract candidoses.
  • Systemic mycoses include systemic and mucocutaneous candidosis, cryptococcosis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, and sporotrichosis.
  • AIDS Acquired Immunodeficiency Syndrome
  • amphotericin B a macrolide polyene that interacts with fungal membrane sterols, flucytosine, a fluoropyrimidine that interferes with fungal protein and DNA biosynthesis
  • azoles e.g., ketoconazole, itraconazole, and fluconazole
  • amphotericin B has a broad range of activity and is viewed as the standard of antifungal therapy, its use is limited due to infusion-related reactions and nephrotoxicity (Wamock, J. Antimicrob. Chemother., 41 :95, 1998).
  • Flucytosine usage is also limited due to the development of resistant microbes and its narrow spectrum of activity.
  • the widespread use of azoles is causing the emergence of clinically-resistant strains of Candida spp. Due to the problems associated with the current treatments, there is an ongoing search for new treatments.
  • the invention features a method for treating a patient who has, or is at risk for developing, fungal infection, by administering to the patient (i) a triazole; and (ii) an aminopyridine, in amounts that treat the patient.
  • the triazole and the aminopyridine may be administered separately or as components of a pharmaceutical composition.
  • the triazole and aminopyridine can be administered within ten days of each other (e.g, within five days, twenty- four hours, or one hour of each other, or simultaneously). Administration of each compound can occur 1-4 times each day, or as necessary to produce a therapeutic effect.
  • the invention also features a method of preventing, stabilizing, or inhibiting the growth of fungal cells.
  • the method includes contacting fungal cells (or a site susceptible to growth of fungal cells) with a combination of compounds of the invention in amounts sufficient to prevent, stabilize, or inhibit the growth of the fungal cells.
  • the method of contacting fungal cells with a combination of the invention can be used, for example, for the preservation of food, beverages, cosmetics, deodorants, contact lens products, food ingredients, enzyme compositions, grains, or animal feed.
  • the compound is incorporated into cleaning compositions or disinfectants for hard surface cleaning or water treatment.
  • the combinations can be applied to bioimplants, such as in-dwelling catheters, surgical implants, prosthetic devices, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, and continuous ambulatory peritoneal dialysis (CAPD) catheters.
  • bioimplants such as in-dwelling catheters, surgical implants, prosthetic devices, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, and continuous ambulatory peritoneal dialysis (CAPD) catheters.
  • the specific amounts of the triazole and aminopyridine administered depend on the specific combination of components (i.e., the specific triazole/aminopyridine combination) and the mode of administration.
  • fluconazole when orally, topically or intravenously administered to a human, fluconazole is administered at a dosage of 0.001 mg to 2000 mg per day, desirably 1 mg to 1600 mg per day, and most desirably 50 mg to 800 mg per day.
  • itraconazole is administered at a dosage of 0.001 mg to 1600 mg/ day, desirably 1 mg to 1200 mg per day, and most desirably 25 mg to 800 mg per day.
  • PZP is desirably administered at a dosage of 0.001 mg to about 2400 mg per day, desirably 0.5 mg to 1600 mg per day, and most desirably 10 mg to 1200 mg per day.
  • the ratio of fluconazole to PZP is 4:1 by weight, while the ratio of itraconazole to PZP is desirably 10:1 to 20:1 by weight.
  • higher doses of each component may be used.
  • a combination of the invention can also be used to treat a fungal infection in a vertebrate animal, particularly a domestic animal, such as those bred for food or kept as pets (e.g., horses, cows, sheep, poultry, fish, pigs, cats, and dogs).
  • a domestic animal such as those bred for food or kept as pets (e.g., horses, cows, sheep, poultry, fish, pigs, cats, and dogs).
  • the combinations can be applied as a cleaning agent, a treatment, or impregnated into or on surgical tools and endoscopy equipment.
  • the fungal infection or mycosis to be targeted by a combination of the invention may be caused, for example by a fungus selected from the group consisting o ⁇ Absidia corymbifera, Acremoniumfalciforme, A. kiliense, A. recifei, Ajellomyces dermatitidis, A. capsulata, Aspergillus spp., (e.g., A.flavus, A. fumigatus ', A. nidulans, A. niger, A. terreus), Candida spp. (e.g., C. albicans, C. glabrata, C. guillermondii, C. krusei, C.
  • a fungus selected from the group consisting o ⁇ Absidia corymbifera, Acremoniumfalciforme, A. kiliense, A. recifei, Ajellomyces dermatitidis, A. capsulat
  • the invention discloses a method of treating infections by the above fungi, among others.
  • the invention also features a method for identifying compounds useful for treating a patient having a fungal infection.
  • the method includes the steps of: contacting fungal cells in vitro with (i) a triazole and/or an aminopyridine; and (ii) a candidate compound, and determining whether the growth of the fungal cells is modulated relative to (a) fungal cells contacted with the triazole and/or aminopyridine but not contacted with the candidate compound, and (b) fungal cells contacted with the candidate compound but not with the triazole and/or aminopyridine.
  • a candidate compound that, when combined with the triazole and/or aminopyridine, modulates the growth of fungal cells to a greater degree than controls, is a compound that is potentially useful for treating a patient having a fungal infection.
  • Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures of the compounds described herein.
  • triazole is meant any member of the class of anti- fungal compounds having a five-membered ring of two carbon atoms and three nitrogen atoms. A compound is considered “antifungal” if it inhibits growth of a species of fungus by at least 25%.
  • Exemplary triazoles include, for example, fluconazole, terconazole, itraconazole, posaconazole (SCH 56592), ravuconazole (BMS 207147), and voriconazole (UK- 109,496), the structures of which are depicted in Table 1, below.
  • aminopyridine is meant any pyridine ring-containing compound in which the pyridine has one, two, or three amino group substituents.
  • aminopyridines include, for example, phenazopyridine, 4-aminopyridine, 3,4-diaminopyridine, 2,5- diamino-4-methylpyridine, 2,3,6-triaminopyridine, 2,4,6-triaminopyridine, and 2,6-diaminopyridine, the structures of which are depicted in Table 2, below.
  • treating is meant administering a pharmaceutical composition for prophylactic and/or therapeutic purposes, wherein the growth of fungal cells is prevented, stabilized, or inhibited, or wherein fungal cells are killed.
  • prevent disease refers to prophylactic treatment of a subject who is not yet infected, but who is susceptible to, or otherwise at risk of, a particular infection.
  • therapeutic treatment refers to administering treatment to a subject already suffering from an infection to improve the subject's condition.
  • subject is meant any animal.
  • fungal infection is meant the invasion of a host animal by fungal cells.
  • the infection may include the excessive growth of fungi that are normally present in or on the animal, or growth of fungi that are not normally present in or on the animal.
  • a fungal infection can be any situation in which the presence of a fungal population is detrimental or damaging to a host animal.
  • an animal is “suffering" from a fungal infection when an excessive amount of a fungal population is present in or on the animal, or when the presence of a fungal population is damaging the cells or tissue of the animal.
  • the number of a particular genus or species of fungus is at least 2, 4, 6, or 8 times the number normally found in the plant or animal.
  • an effective amount is meant the amount of a compound, in a combination of the invention, required to treat or prevent a fungal infection.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic or prophylactic treatment of conditions caused by or contributed to by a fungal infection varies depending upon the manner of administration, the age, body weight, and general health of the subject.
  • the combination of a triazole with an aminopyridine for the treatment of fungal infections allows for the administration of a low dose of each compound and less total active compound, thus providing similar efficacy with less toxicity, and reduced costs.
  • Another advantage is that the combinations of the invention are effective against fluconazole-resistant strains of Candida spp.
  • Antifungal triazoles as described herein refers to any member of the class of anti- fungal compounds having a five-membered ring of two carbon atoms and three nitrogen atoms.
  • Exemplary triazoles include, for example, fluconazole, terconazole, itraconazole, posaconazole (SCH 56592), ravuconazole (BMS-207147), and voriconazole (UK-109,496) (Table 1).
  • aminopyridine any pyridine ring-containing compound in which the pyridine has one, two, or three amino group substituents. Other substituents may optionally be present.
  • exemplary aminopyridines include, for example, phenazopyridine, 4-amino-pyridine, 3,4-diaminopyridine, 2,5- diamino-4-methylpyridine, 2,3,6-triaminopyridine, 2,4,6-triaminopyridine, and 2,6-diaminopyridine (Table 2).
  • Combination therapy according to the invention may be performed alone or in conjunction with another therapy and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital.
  • Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed.
  • the duration of the combination therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. Additionally, a person having a greater risk of developing a fungal infection (e.g., a person who is to undergo a surgical procedure) may receive prophylactic treatment to inhibit or delay the onset of symptoms.
  • the dosage, frequency and mode of administration of each component of the combination can be controlled independently.
  • one compound may be administered orally three times per day, while the second compound may be administered topically once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side-effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • Suitable modes of administration include oral, rectal, intravenous, topical or transdermal, vaginal, and ophthalmic.
  • Administration of each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other compound, is effective.
  • Each compound can be admixed with a suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A.R. Gennaro, 2000, Lippencott Williams & Wilkens, Philadelphia, PA, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • compositions according to the invention may be formulated to release the active compound substantially immediately upon administration or at any predetermined time period after administration, using controlled release formulations.
  • Administration of compounds in controlled release formulations is useful where the compound, either alone or in combination, has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )); ( ⁇ ) a narrow absorption window in the gastro-intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level. Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound.
  • a narrow therapeutic index e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )
  • controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings.
  • appropriate controlled release compositions and coatings include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • compositions suitable for topical application include conventional anhydrous or aqueous preparations including ointments, lotions, creams, pastes, jellies, sprays, aerosols, and oils.
  • preparations can include oleaginous, aqueous, or emulsion-type bases.
  • topically applied formulations can be covered with an occlusive or semi-occlusive dressing.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
  • the two compounds may be mixed together in a tablet or other vehicle, or may be partitioned.
  • the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.
  • each compound of the " claimed combinations used in any given therapeutic method depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect dosage used.
  • the compound(s) may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories.
  • Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes.
  • a solubilizer such as ethanol can be applied.
  • the dosages for triazoles and aminopyridines are described.
  • fluconazole when orally, topically or intravenously administered to a human, fluconazole is administered at a dosage of 0.001 mg to 2000 mg per day, desirably 1 mg to 1600 mg per day, and most desirably 50 mg to 800 mg per day.
  • itraconazole is administered at a dosage of 0.001 mg to 1600 mg/ day, desirably 1 mg to 1200 mg per day, and most desirably 25 mg to 800 mg per day.
  • PZP is desirably administered at a dosage of 0.001 mg to about 2400 mg per day, desirably 0.5 mg to 1600 mg per day, and most desirably 10 mg to 1200 mg per day.
  • the ratio of fluconazole to PZP is 4:1 by weight, while the ratio of itraconazole to PZP is desirably 10:1 to 20:1 by weight.
  • higher doses of each component may be used.
  • Combinations of the invention may also be used for the preservation of food, beverages, cosmetics such as lotions, creams, gels, ointments, soaps, shampoos, conditioners, antiperspirants, deodorants, mouthwash, contact lens products, enzyme formulations, or food ingredients.
  • Methods for use as a preservative include incorporating a compound of the invention into, for example, unpreserved food, beverages, cosmetics, contact lens products, or food ingredients in an amount effective for killing or inhibiting the growth of fungi.
  • a compound of the invention may be useful as a disinfectant, e.g., in the treatment of acne, eye infections, mouth infections, fingernail infections, toenail infections, skin infections, or wounds. It is also contemplated that a compound of the invention is useful for cleaning, disinfecting, or inhibiting fungal growth on any hard surface.
  • surfaces which may advantageously be contacted with a compound of the invention are surfaces of process equipment used in dairies, chemical or pharmaceutical process plants, water sanitation systems, paper pulp processing plants, water treatment plants, cooling towers, cooking utensils, or surfaces in any area in which food is prepared (e.g., hospitals, nursing homes, or restaurants).
  • the composition of the invention should be used in an amount that is effective for cleaning, disinfecting or inhibiting microbial growth on the relevant surface.
  • combinations of the invention are useful for cleaning, disinfecting, or inhibiting fungal growth on or in an in-dwelling device in a patient.
  • In-dwelling devices include, but are not limited to, surgical implants, prosthetic devices, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, and continuous ambulatory peritoneal dialysis (CAPD) catheters.
  • the combinations can be applied as a cleaning agent, a treatment, or impregnated into or on surgical tools and endoscopy equipment.
  • a combination of the invention may be used to bathe an in-dwelling device immediately before insertion. Alternatively, the combination may be administered by injection to achieve a local or systemic effect against relevant fungi shortly before insertion of an in-dwelling device. Treatment may be continued after surgery during the in-body time of the device.
  • Table 4 percent inhibition of proliferation of fluconazole-resistant C. albicans strain MYA 573
  • Fluconazole-resistant C. albicans strain 17 was obtained from the culture collection of the Seattle Biomedical Research Institute (Seattle, WA). Fluconazole-resistant C. albicans strain MYA 573 was obtained from the American Type Culture Collection (Manassas, NA). Yeast were stored in 15% glycerol at -70°C. Isolates were cultured in growth medium (RPMI; 2% glucose w/o ⁇ aC0 2 and phenol red, buffered with 0.165M MOPS to pH 7.0) at 35°C for 24 hours prior to in vitro susceptibility testing. All media reagents were purchased from Sigma Chemical Co. (St. Louis, MO).
  • amphotericin B was used as a positive control for antifungal activity.
  • Stock solutions of each compound were prepared and stored at -20°C. Prior to use, stock solutions were diluted in growth medium to produce 10X solutions.
  • 10X fluconazole or itraconazole (0- 7 ⁇ L) and 10X PZP (0-7 ⁇ L) were then plated in 45 ⁇ L of test medium (growth medium with 18% Alamar Blue; BioSource Intl., Camerillo, CA) in 384 well microtiter plates to form a matrix of compound combinations, as indicated in Tables 3-5.

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Abstract

L'invention concerne des procédés et des réactifs pour le traitement d'un patient ayant contracté une infection fongique, ou risquant d'en contracter une. On administre au patient un triazole et une aminopyridine, simultanément ou à 14 jours d'intervalle, en quantités suffisantes pour réduire ou inhiber la prolifération fongique. L'invention concerne également des procédés et des réactifs permettant de prévenir, de stabiliser ou d'inhiber la prolifération des cellules fongiques dans le corps ou sur le corps d'un mammifère, ou bien sur une surface.
PCT/US2003/003039 2002-02-06 2003-01-31 Combinaisons pour le traitement des infections fongiques WO2003066049A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2863273A1 (fr) * 2003-12-03 2005-06-10 Univ Nantes Milieu, dispositif et procede de test de la sensibilite d'un inoculum de champignons a un agent antifongique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817321A (en) * 1992-10-08 1998-10-06 Supratek Pharma, Inc. Biological agent compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817321A (en) * 1992-10-08 1998-10-06 Supratek Pharma, Inc. Biological agent compositions

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2863273A1 (fr) * 2003-12-03 2005-06-10 Univ Nantes Milieu, dispositif et procede de test de la sensibilite d'un inoculum de champignons a un agent antifongique

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