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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention is directed to a method for favorably modulating the health-related quality of life and the health-related quality-adjusted time-to-disease progression in a patient with prostate cancer and a method for measuring of the health-related quality-adjusted time-to-disease progression in a patient with prostate cancer.
• Prostate cancer patients often face poor prognosis, limited treatment options, and a decline in their health-related quality of life (QoL) with disease progression.
• QoL quality of life
• a first embodiment of this invention is directed to a method for favorably modulating the health-related QoL of a patient with prostate cancer comprising administering thereto a therapeutically effective amount of an endothelin (ET) receptor antagonist.
• a second embodiment of this invention is directed to a method for favorably modulating the health-related QATTP of disease of a patient with prostate cancer comprising administering thereto a therapeutically effective amount of an ET receptor antagonist.
• ET endothelin
• endothelin receptor antagonist means a compound which binds to the endothelin receptor, which binding may be evaluated by the ability of the compound to inhibit endothelin from binding to its receptor, which inhibition is preferably between about 50%- 100% at 1 ⁇ m inhibitor concentration, more preferably about 80%- 100% at 1 ⁇ m inhibitor concentration, most preferably about 95%-100% at 1 ⁇ m inhibitor concentration.
• vorably modulating means sustaining and/or improving the health-related QoL and/or sustaining and/or improving and/or extending the health-related QATTP of disease in a patient with prostate cancer.
• quality-adjusted time-to-progression of disease or "QATTP of disease” means the interval between the initiation of chemotherapy in a patient with prostate cancer to the time of disease progression adjusted by the patient's health-related QoL score.
• health-related quality of life or “health-related QoL” means domains comprising physical functioning, emotional functioning, social/family functioning, role functioning, cognitive functioning, self-perception, and other domains for patients with prostate cancer, the other domains comprising pain, fatigue, nausea and vomiting, change in appetite, dyspnea, sleep disturbance, diarrhea, constipation, urinary function, and change in weight.
• a third embodiment of this invention is directed to a method for determining modulation of the health-related QATTP of disease in a patient undergoing endothelin antagonist chemotherapy for prostate cancer, the method comprising the steps of:
• the patient population comprises at least one patient with prostate cancer, preferably about 100 patients with prostate cancer, more preferably about 150 patients with prostate cancer, most preferably about 280 patients with prostate cancer;
• a fourth embodiment of this invention is directed to a method for increasing the survival time of a patient with prostate cancer comprising administering thereto a therapeutically effective amount of an ET receptor antagonist.
• ET receptor antagonist may be administered at any time during disease progression, such as, for example, at or near beginning of disease (such as, for example, progression indicated by elevation of prostate-specific antigen levels) or toward the end of disease (such as progression indicated by signs and symptoms consistent with the progression of prostate cancer or progression indicated by hormone refractoriness).
• the therapeutically effective amount of the ET receptor antagonist is between about 0.01 mg per day to about 100 mg per day, more preferably between about 1 mg per day to about 25 mg per day, most preferably about 2.5 mg or about 10 mg per day.
• the foregoing therapeutically effective amount of the ET receptor antagonist, or combinations of submultiples thereof may be administered once or twice per day, preferably without missing a day, more preferably once per day without missing a day.
• the ET receptor antagonist is an endothelin A (ETA) receptor antagonist, preferably an ETA receptor antagonist having formula (I)-a
• R 1 and R 2 are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or alkyl substituted with one cycloalkyl, halo, aryl, heteroaryl, heterocyclyl, -OH, or -O(alkyl) substituent;
• R 3 is R 4 S0 2 R 5 - or R 4 C(0)R 5 -;
• R is alkyl, -(CH 2 )alkenyl, -(CH 2 )alkynyl, -NR R , alkyl independently substituted with one or two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -NH 2 , -NH(alkyl), or -N(alkyl) 2 substituents, or alkenyl independently substituted with one or two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -NH 2 , -NH(alkyl), or -N(alkyl) 2 substituents;
• R is a covalent bond, alkylene, -N(H)(alkylene)-, or -N(alkyl)(alkylene)-,
• R and R are independently hydrogen, alkyl, -(CH 2 )alkenyl, -(CH 2 )alkynyl, cycloalkyl, aryl, or alkyl independently substituted with one or two cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -OH, -O(alkyl), -OCH 2 CF 3 , -OCH 2 CF 2 CF 3 , -NH 2 , -NH(alkyl), or -N(alkyl) 2 substituents; in which, for the foregoing, the term "alkenyl” means a monovalent, straight or branched hydrocarbon having two to ten carbon atoms and at least one carbon-carbon double bond, attached through a carbon atom; the term “alkynyl” means a monovalent, straight or branched hydrocarbon, having two to ten carbon atoms and at least one carbon-carbon triple bond, attached through a carbon atom; the term
• R moieties are ((N-(4-aminobutyl)-N-butylamino)carbonyl)methyl,
• R is alkyl, alkenyl, or phenyl, in which the phenyl is independently substituted with one or two halo, -OH, or -O(alkyl) substituents;
• R is phenyl fused with 1,3-dioxolane and unsubstituted or substituted with one -O(alkyl) substituent;
• R 3 is (alkyl)SO 2 N(alkyl)(alkylene)-, (alkyl)S0 2 N(H)(alkylene)-, or (R 7 )(R 8 )NC(O)(alkylene)-;
• R and R are independently hydrogen, alkyl, or alkyl substituted with one -NH 2 and -N(alkyl) 2 substituent; an ET receptor antagonist having formula (I)-a with the relative or absolute stereochemistry shown in the compound having formula (I)-b
• R is C 3 -C 8 -alkyl, C 6 -C 8 -alkenyl, or phenyl, in which the phenyl is independently substituted with one or two halo, -OH, or -O ⁇ -alky! substituents;
• R is phenyl fused with 1,3-dioxolane and unsubstituted or substituted with one -O(C ⁇ -alkyl) substituent; .
• R 3 is (C 2 -C 7 -alkyl)S0 2 N(C 1 -C 4 -alkyl)(C 2 -C 3 -alkylene)-, (C 2 -C 7 -alkyl)SO 2 N(H)(C 1 -C 2 -alkylene)-, or (R 7 )(R 8 )NC(0)(C 1 -C 4 -alkylene)-; and
• R and R are independently hydrogen, C**-C -alkyl, or C 2 -C -alkyl substituted with one -NH2 or -N(C ⁇ -alkyl)2 substituent; and an ET receptor antagonist having formula (I)-a with the relative or absolute stereochemistry shown in the compound having formula (I)-b, or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof, in which R is 2,2-dimethylpentyl;
• R is l,3-benzod ⁇ oxol-5-yl; and R is ((N,N-dibutylamino)carbonyl)methyl, ((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or 2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl; an ET receptor antagonist having formula (I)-a with the relative or absolute stereochemistry shown in the compound having formula (I)-b, or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof, in which R is 3-fluoro-4-methoxyphenyl; R 2 is l,3-benzodioxol-5-yl; andR 3 is
• R is 7-methoxy-l,3-benzodioxol-5-yl; and R is ((N,N-dibutylamino)carbonyl)methyl, ((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or 2-(N-((pentyl)sulfonyl)-N-propylamino)ethyl; an ET receptor antagonist having formula (I)-a with the relative or absolute stereochemistry shown in the compound having formula (I)-b, or a therapeutically acceptable salt, prodrug, or salt of a prodrug thereof, in which R is
• R 2 is 7-methoxy-l,3-benzodioxol-5-yl
• R 3 is ((N,N-dibutylamino)carbonyl)methyl
• R is ((N,N-dibutylammo)carbonyl)methyl, ((N-butyl-N-(4-(dimethylamino)butyl)amino)carbonyl)methyl, or
• the ET receptor antagonists of this invention comprise asymmetrically substituted carbon atoms in the R or S configuration, in which the terms "R” and "S” are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.
• ET receptor antagonists having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers of the ET receptor antagonists therein.
• relative stereochemistry refers to the direction of the variable R 1 and R 2 moieties in relation to the direction of the fixed carboxyl moiety to which each is adjacent.
• R 1 and R 2 are in the opposite direction of the carboxyl moiety and form the "trans,trans-" stereochemistry shown in the compound having formula (I)-b.
• the term "absolute stereochemistry,” as used herein, refers to the fixed direction of each fixed or variable moiety regardless of the orientation of the other substituents.
• the compounds having formula (I)-a and formula (I)-b may also contain carbon-carbon double bonds in the Z or E configuration, in which the term “Z” represents the larger two of the four substituents on same side of a carbon-carbon double bond and the term “E” represents the larger two of the four substituents on opposite sides of a carbon-carbon double bond.
• the compounds having formula (I)-a and formula (I)-b may also exist as an equilibrium mixture of Z and E configurations.
• prodrug-forming moieties may have attached thereto prodrug-forming moieties.
• the prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed hydroxyl, amino, or carboxylic acid in vivo.
• Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds, or their metabolites, as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.
• prodrugs of the compounds include ones in which the carboxyl moiety of the compounds have attached thereto a methyl, ethyl, isopropyl, or tert-butyl moiety.
• the compounds having formula (I)-a and formula (I)-b may be prepared by synthetic processes or metabolic processes. Metabolic processes include those processes occurring in vitro or in vivo. An example of a metabolite of the compounds is one in which R 1 is 4-methoxyphenyl; R2 is l,3-benzodioxol-5-yl; and R 3 is ((N-butylamino)carbonyl)methyl.
• the compounds having formula (I)-a and formula (I)-b may exist as acid addition salts, basic addition salts, or zwitterions. Salts of the compounds are prepared during their isolation or following their purification. Acid addition salts of the compounds are those derived from the reaction of the same with an acid.
• basic addition salts may be prepared therefrom by reaction with a base such as the hydroxide, carbonate, or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
• a base such as the hydroxide, carbonate, or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
• a preferred salt of the compounds is the hydrochloride salt.
• the compounds having formula (I)-a and formula (I)-b may be administered with or without an excipient and with or without another chemotherapeutic agent.
• Excipients include encapsulating materials or formulation additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof.
• Excipients for orally administered compounds in solid dosage forms include agar, alginic acid, cocoa butter, gelatin, isotonic saline, malt, powdered tragacanth, Ringer's solution, talc, water, aluminum hydroxide, magnesium hydroxide, sodium and potassium phosphate salts, cellulose, cellulose acetate, ethyl cellulose, sodium carboxymethyl cellulose, ethyl laureate, ethyl oleate, magnesium stearate, sodium lauryl sulfate, castor oil, com oil, cottonseed oil, germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, ethanol, ethyl acetate, ethyl carbonate, glycerol, isopropanol, propylene glycol, tetrahydrofurfury
• Excipients for ophthalmically and orally administered compounds in liquid dosage forms include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof.
• Excipients for osmotically administered compounds include water, ethanol, isopropanol, chlorofluorohydrocarbons, and mixtures thereof.
• Excipients for parenterally administered compounds include water, 1,3-butanediol, Ringer's solution, U.S.P. or isotonic sodium chloride solution, oleic acid, castor oil, corn oil, cottonseed oil, germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, liposomes, and mixtures thereof.
• Excipients for rectally administered compounds include cocoa butter, polyethylene glycol, wax, and mixtures thereof.
• the compounds having formula (I)-a and formula (I)-b may be administered as the sole active agent, or they may also be used co-therapeutically with one or more anticancer drugs or methods including hormonal agents such as leuprolide (Lupron ); gonadorelin antagonists such as goserelin (Zoladex ) and abarelix; bicalutamide; nilutamide; flutamide; vitamin D; vitamin D analogues; estrogen and estrogen analogues such as diethylstibestrol; prednisone; hydrocortisone; ketoconazole; cyproterone acetate; progesterone; 5-alpha reductase inhibitors such as fmasteride; bone-seeking radionuclides such as samarium (Quadramet ), strontium (Metastron ), and rhenium; external beam radiation such as three dimensional conformal radiation; brachytherapy (the implantation of radioactive seeds in the prostate); monoclonal antibodies such
• anti-angiogenic drugs such as thrombospondin peptide or kringle 5; matrix metalloproteinase inhibitors; farnesyl transferase inhibitors; lycopenes; urokinase; plasminogen activator inhibitors; plasminogen activator receptor blockers; apoptosis inducers; selective and non-selective alpha blockers; platinum agents such as cz ' s-platinum and carbo-platinum; taxane- class drugs such as docetaxil and paclitaxil; estramustine; gemcytabine; adriamycin; doxorubicin; daunorubicin; mitoxantrone; vinblastine; vincristine; capecitabine; irinotecan; topotecan; 5-fluorouracil; interferons; cytoxan; methotrexate; cytokines such as IL-2; PPAR
• combinations may be administered separately or singly in dosage forms containing both or all drugs.
• the drugs When administered as a combination, the drugs may be formulated as separate compositions, given at the same time or different times, or the therapeutic agents may be given as a single composition.
• the compounds having formula (I)-a and formula (I)-b may be administered parenterally (subcutaneously, intravenously, intramuscularly, and intrasternally), orally, osmotically, ophthalmically, rectally, topically, and transdermally.
• Orally administered compounds in solid dosage forms may be administered as capsules, dragees, granules, pills, powders, and tablets.
• Ophthalmically and orally administered compounds in liquid dosage forms may be administered as elixirs, emulsions, microemulsions, solutions, suspensions, and syrups.
• Osmotically and topically administered compounds may be administered as creams, gels, inhalants, lotions, ointments, pastes, powders, solutions, and sprays.
• Parenterally administered compounds may be administered as aqueous or oleaginous solutions or aqueous or oleaginous suspensions, the latter of which contains crystalline, amorphous, or otherwise insoluble forms of the compounds.
• Rectally administered compounds may be administered as creams, gels, lotions, ointments, and pastes. A preferred means of administration of the compounds is orally.
• the health-related QATTP of disease model for this invention expresses progression-free time as an equally preferable amount of time spent in full health. This is achieved by using patient-reported health-related QoL, as measured for the duration of observation or progression-free interval, to weight progression-free time.
• HRPCa hormone refractory prostate cancer
• EORTC QLQ-30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
• FACT-G Functional Assessment of Cancer Therapy
• FACT-P prostate cancer-specific module
• Patient-reported health-related QoL data were collected with the EORTC QLQ-30 and the FACT-G and FACT-P, both of which were administered at baseline, at six week intervals and at each patient's final visit. The results from the 10 mg and 2.5 mg treatment groups are reported relative to the placebo group.
• EORTC QLQ-30 and FACT were used to weight the time-to-progression outcome data.
• Transformed domain scores ranged between 0 and 1, so the reported health-related QATTP of disease outcome was never larger than the actual time-to-progression.
• the methods used for converting domain scores to weight adjustments are shown in TABLE 1.
• a higher score means a better health-related QoL.
• a higher transformed score means improved health-related QoL.
• a higher score means a worse health-related QoL.
• a higher transformed score means improved symptoms.
• Possible scores for the fourteen EORTC domains each range between 1 and 100.
• EORTC domains For the remaining eight EORTC domains, a higher score indicates worse symptoms (a worse health-related QoL). These domains are pain, fatigue, nausea and vomiting, appetite loss, dysnepa, sleep disturbance, diarrhea, and constipation. These eight scores were converted to weight adjustments by dividing them by 100 and subtracting the result from the integer 1 to provide consistent directionality of response. FACT domain scores were converted to weights using the linear affine transformation suggested in SF-36 Health Survey Manual and Interpretation Guide.
• Each patient's health-related QATTP of disease was computed as the sum of the health-related QoL weights multiplied by the duration for which that patient experienced that health-related QoL.
• results of the Kaplan-Meier product limit survival method analysis are reported in TABLE 2 (Intent to Treat) and TABLE 3 (Per Protocol Population). Mean and median health-related QATTP of disease are shown by treatment group. Log-rank tests comparing the differences between treatment groups are also reported.
• the Kaplan-Meier product limit method may provide biased results if study data are obtained under certain conditions such as staggered entry of subjects into the study and/or incomplete follow-up (Biometrics. 1989; 5:781-795). Thus, a second analysis was implemented to verify that the conclusions derived from the Kaplan-Meier method would remain robust to the length of follow-up. The assumption was that all patients were followed for one year.
• AUC Area under the Curve
• the data in TABLE 2 show significantly longer (p ⁇ 0.05) mean health-related QATTP's of disease for all health-related QoL domains except dyspnea, global score, emotional well-being, and social well-being in the 10 mg atrasentan treatment group.
• the trend favored the 10 mg atrasentan treatment group (p ⁇ 0.10).
• the 2.5 mg atrasentan treatment group also produced longer mean health-related QATTP of disease.
• Log rank tests showed these results to be statistically significant for all health-related QoL domains except dyspnea and functional well-being; and there were no statistical differences noted between the atrasentan treatment groups for any health-related QoL domain.
• the AUC analysis results were consistent with the health-related QATTP analyses in TABLES 2 and 3.
• atrasentan treatment and placebo groups showed no statistical differences.
• the AUC analysis of the per-protocol population showed strong trends in favor of the atrasentan treatment groups in every health-related QoL domain score when compared to placebo.
• the responses in the 10 mg and 2.5 mg treatment groups were not statistically differentiable.
• the AUC for the health-related QoL domain scores for physical functioning, social functioning, and pain were significantly longer (p ⁇ 0.05) for atrasentan.
• the 2.5 mg atrasentan group showed significantly improved AUC results except for dyspnea, social/family, functional well-being, and FACT-P domain scores.
• both the health-related QoL and the health-related QATTP of disease in patients with prostate cancer are favorably modulated by administration of an ET antagonist, preferably an ETA antagonist such as atrasentan.

Landscapes

• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Oncology (AREA)
• Urology & Nephrology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Measuring And Recording Apparatus For Diagnosis (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=26816420

Family Applications (1)

Country Status (10)

Families Citing this family (6)

Family Cites Families (1)

• 2002
  • 2002-04-11 CA CA002442591A patent/CA2442591A1/en not_active Abandoned
  • 2002-04-11 IL IL15807102A patent/IL158071A0/xx unknown
  • 2002-04-11 CN CNA028116720A patent/CN1514727A/zh active Pending
  • 2002-04-11 PE PE2002000305A patent/PE20021032A1/es not_active Application Discontinuation
  • 2002-04-11 JP JP2002582924A patent/JP2005503339A/ja active Pending
  • 2002-04-11 BR BR0205970-3A patent/BR0205970A/pt not_active IP Right Cessation
  • 2002-04-11 AR ARP020101335A patent/AR033465A1/es not_active Application Discontinuation
  • 2002-04-11 EP EP02726727A patent/EP1379238A1/de not_active Ceased
  • 2002-04-11 WO PCT/US2002/011397 patent/WO2002085351A1/en not_active Application Discontinuation
  • 2002-04-11 MX MXPA03009277A patent/MXPA03009277A/es unknown

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events