WO2001012214A2 - MYCOPHENOLATE MOFETIL IN ASSOCIATION WITH PEG-IFN-$g(a) - Google Patents
MYCOPHENOLATE MOFETIL IN ASSOCIATION WITH PEG-IFN-$g(a) Download PDFInfo
- Publication number
- WO2001012214A2 WO2001012214A2 PCT/EP2000/007666 EP0007666W WO0112214A2 WO 2001012214 A2 WO2001012214 A2 WO 2001012214A2 EP 0007666 W EP0007666 W EP 0007666W WO 0112214 A2 WO0112214 A2 WO 0112214A2
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- WO
- WIPO (PCT)
- Prior art keywords
- ifn
- peg
- effective amount
- prodrug
- pharmaceutically acceptable
- Prior art date
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- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 title description 10
- 229960004866 mycophenolate mofetil Drugs 0.000 title description 5
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 claims abstract description 42
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229960000951 mycophenolic acid Drugs 0.000 claims abstract description 40
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- the invention relates to the field of treating liver diseases, in particular hepatitis C infections, by administering (i) interferon- ⁇ or pegylated interferon- ⁇ and (ii) a pharmaceutically acceptable salt or a prodrug of mycophenolic acid.
- HCV Hepatitis C virus
- Interferon is a family of naturally occurring small proteins and glycoproteins with characteristic biological effects such as antiviral, immunoregulatory and antitumoral activities. They are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.
- interferon system has a broader significance than that of more antiviral protective mechanism.
- IFNs have been shown in many different diseases of viral, malignant, angiogenic, allergic, inflammatory and fibrotic origin (A. Billiau (1984), Elsevier Sciences Publisher B.V., vol.l, 25-28).
- IFNs from natural sources as well as recombinant DNA technology have been the subject of many publications. Preparation of recombinant IFNs is known, for example from Nature 295, (1982), 503-508, Nature 284, (1980), 320-326, Nature 290, ( 1981), 20-26, Nucleic Acids Res. 8 ( 1980), 4057-4074, as well as from European Patents Nos. 32134, 43980 and 211148.
- IFN- ⁇ represent the predominant class of IFNs produced by stimulated peripheral blood leukocytes (Peska et al. loc. cit.; Have et al., ( 1975), Proc. Natl. Acad. Sci. USA 72, 2185-2187; Cavalieri et al., ( 1977), Proc. Natl. Acad. Sci. USA 74, 3287-3291), and lymphoblastoid and myeloblastoid cell lines (Familletti et al, ( 1981 ), Antimicrob. Agents. Chemother., 20, 5-9). IFN- ⁇ has emerged as an important regulator of growth and differentiation affecting cellular communication and immunology control. IFN- ⁇ is frequently used in the treatment of chronic hepatitis such as chronic hepatitis C.
- IFNs remain the only approved monotherapy for chronic HCV infection
- CHC chronic lung cancer
- the goal of treatment is to achieve a sustained virological response (that is non- detectable ( ⁇ 100 copies/ml) of HCV-RNA in peripheral blood) at 6 months after the end of treatment.
- IFN- ⁇ monotherapy results in a sustained response in only 5-20% of general CHC populations. (Fried et al., ( 1995), "Therapy of hepatitis C", Semin. Liver Dis., 15( 1), 82- 91).
- IFNs typically cause flu-like symptoms at the onset of treatment.
- IFNs do not attain maximum clinical potency because, inter alia, IFNs are rapidly cleared from the systemic circulation. It has been found that for IFN ⁇ conjugation with polyethylene glycol (PEG) reduces clearance. Furthermore, it has recently been shown that a PEG IFN- ⁇ 2A conjugate caused sustained reduction of the virus to undetectable levels in 36% of non cirrhotic with CHC in a phase II study. (Shiffman M, Pockros PJ, Reddy RK et al., "A controlled, randomized, multicenter, ascending dose phase II trial of pegylated interferon alfa-2a (PEG) vs.
- PEG polyethylene glycol
- Mycophenolic acid is an active agent that inhibits the proliferation of B and T lymphocytes through noncompetitive and reversible inhibition of inosine monophosphate dehydrogenase (IMP-DH), a key enzyme in the novo synthetic pathway of guanine nucleotides.
- IMP-DH inosine monophosphate dehydrogenase
- Mycophenolate mofetil the morpholinoethyl ester prodrug of MPA, has been demonstrated as an immunosuppressive agent which is effective in the treatment of refractory rejection, particularly, in liver transplant recipients. It has been used in monotherapy or in combination with cyclosporin and corticosteroids (J. Neyts and E. de Clercq, (1998), Antiviral Research 40, 53-56; Z.J. Gong et al., "The influences of immunosuppressive agents on HBV replication in vitro" and K. P. Platz et al., ( 1998), Elsevier Science Inc., 2232
- IFN- ⁇ in association with a pharmaceutically acceptable salt or a prodrug of mycophenolic acid may be of importance in the treatment of liver diseases and, in particularly, such as chronic viral hepatitis C.
- the present invention provides the use of IFN- ⁇ in association with a pharmaceutically acceptable salt or a prodrug of mycophenolic acid for the manufacture of medicaments for treating liver diseases patients.
- the present invention has also for object medicaments containing IFN- ⁇ and a pharmaceutically acceptable salt or a prodrug of mycophenolic acid as a combined preparation for simultaneous, part-simultaneous, separate or sequential use in therapy of liver diseases.
- the present invention concerns a method for treating liver diseases patient comprising administering to said patients IFN- ⁇ in association with MPA or one of its prodrugs e.g. mycophenolate mofetil.
- a dosage of IFN- ⁇ for practicing the combination therapy of this invention is from 3 to 6 million international units (IU) administered three times weekly.
- a preferred dosage for practicing the combination therapy of this invention is 3 million IU administered three times weekly.
- a dosage of PEG IFN- ⁇ for practicing the combination therapy of this invention is from 40 to 270 ⁇ g administered once per week.
- a preferred dosage is 180 ⁇ g administered once per week.
- a dosage for MPA or one of its prodrugs or salts (for example, MMF) for practicing the invention is from 250 to 2000 mg per day, preferably 500 - 1000 mg. This daily dosage may be administered in divided doses twice to four times per day.
- the present invention relates to the use of IFN- ⁇ in association with a pharmaceutically acceptable salt or a prodrug of mycophenolic acid for treating a patient infected with HCV to decrease the severity of the viral infection.
- the use comprises concomitantly administering to the patient a first component consisting of a pharmaceutical composition containing as an active ingredient a prodrug or pharmaceutically acceptable salt of MPA in a therapeutically effective amount to decrease the severity of the viral infection and a second component consisting of an injection solution containing as an active ingredient IFN- ⁇ or pegylated IFN- ⁇ conjugate in a therapeutically effective amount to decrease the severity of the viral infection.
- the components are administered over a period of time at least sufficient to reduce the amount of HCV-RNA present in the peripheral blood of the patient to less than 100 copies/ml after the period of time.
- the present invention relates to the use of IFN- ⁇ in association with a pharmaceutically acceptable salt or a prodrug of mycophenolic acid for treating a patient infected with a hepatitis C virus, comprising concomitantly administering to the patient:
- Z is hydrogen or -(CO)R and R is lower alkyl or aryl
- the sufficient effective amount of the first component is administered daily in an amount of from about 250 mg to about 2000 mg per day, and
- a second component consisting of an injection solution containing as an active ingredient interferon- ⁇ or pegylated interferon- ⁇ conjugate, wherein the active ingredient of the second component is administered three times weekly in amount of 3 to 6 million IU,
- said components being concomitantly administered over a period of time from about 24 weeks to about 72 weeks.
- the invention in another aspect, relates to a kit.
- the kit comprises a first compenent and a second component.
- the first component contains one or more oral unit dosage forms of an active ingredient, each unit containing the active ingredient in a amount of from about 250 mg to about 2000 mg, wherein the active ingredient is of pharmaceutically acceptable salt or prodrug of MPA.
- the second component contains a vial or series of vials each vial containing a single injectable solution dose or multiple injectable solution doses, each dose containing as an active ingredient about 40 ⁇ g to about 270 ⁇ g of interferon- ⁇ or pegylated interferon- ⁇ .
- the invention relates to a kit comprising a first component and a second component.
- the first component contains one or more oral unit dosage forms of an active ingredient, each unit containing about 250 mg to about 2000 mg of the active ingredient, wherein the active ingredient is a compound of the formula,
- the second component contains a vial or series of vials each vial containing a single injectable solution dose or multiple injectable solution doses, each dose containing as an active ingredient about 40 ⁇ g to about 270 ⁇ g of a pegylated interferon- ⁇ conjugate.
- MPA is a known compound of formula:
- the first component of the present invention consists of a pharmaceutical composition containing as an active ingredient a prodrug or pharmaceutically acceptable salt of MPA in a therapeutically effective amount to decrease the severity of the viral infection.
- pharmaceutically acceptable salt of MPA is any conventional salt or base addition salt that retains the biological effectiveness and properties of MPA and which is formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base.
- Preferred are cationic salts, for example, of alkali metals, especially sodium salts.
- Sodium mycophenolate salts are known, for example in WO 97/38689.
- prodrug of MPA refers to a compound that is converted under physiological conditions or by solvolysis to MPA.
- a prodrug of MPA may be inactive when administered to a subject but is converted in vivo to MPA.
- Preferred as a prodrug of MPA is a compound of the formula:
- Z is hydrogen or -(CO)R and R is lower alkyl or aryl.
- the second component consisting of an injection solution containing as an active ingredient IFN- ⁇ or pegylated IFN- ⁇ conjugate in a therapeutically effective amount to decrease the severity of the viral infection.
- IFN- ⁇ as used herein includes IFN- ⁇ s derived from any natural material
- IFN- ⁇ e.g., leukocytes, fibroblasts, lymphocytes
- material derived therefrom e.g. cell lines
- IFN- ⁇ there are many types of IFN- ⁇ such as IFN- ⁇ l, IFN- ⁇ 2; and further their subtypes including but not limited to IFN- ⁇ 2A, IFN- ⁇ 2B, IFN- ⁇ 2C and IFN- ⁇ ll (also designated IFN- ⁇ ll or w-IFN).
- IFN- ⁇ 2A the use of IFN- ⁇ 2A is preferred.
- the manufacture of IFN- ⁇ 2A is described in European Patents Nos. 43980 and 211148.
- the IFN- ⁇ used in this invention may be conjugated to a polymer such as a polyalkylene glycol (substituted or unsubstituted), for example polyethylene glycol, to form PEG-IFN- ⁇ .
- Conjugation may be accomplished by means of various linkers known in the art, in particularly by linkers such as those disclosed in European Patent Applications, Publication Nos. 0510356 and 593868 and European Patent Application No. 97108261.5.
- the molecular weight of the polymer, which is preferably polyethylene glycol may range from 300 to 30.000 Dalton, and one or more, preferably one to three, polymers may be conjugated to the IFN- ⁇ .
- the reagents attach to primary amino groups on for example lysine or to the N-terminus of the IFN- ⁇ .
- the reagents can also attach to a hydroxyl on for example serine.
- PEGs may be conjugated to the IFN- ⁇ .
- a most preferred reagent is of the formula
- a total of 2 monomethoxy PEG (m-PEG) chains is linked to lysine, one at the ⁇ and ⁇ amino groups via carbamate (urethane) bonds and the lysine carboxyl group is activated to a succinimidyl ester.
- This reagent may be obtained by conventional means, according to known procedures (Monfardini et al., "A branched monomethoxypoly(ethylene glycol) for protein modification", Bioconjugate Chem. 6:62, 1995) applicable to a reagent with R being lower alkyl and having a desired n.
- This reagent may be obtained from Shearwater Polymers, Inc. (Huntsville, Alabama).
- the preferred average molecular weight of the PEG is about 20,000 daltons, providing a total PEG mass of about 40,000 daltons in PEG2-NHS (other molecular weights may be obtained by varying n for the PEG-alcohol starting materials for the reagent of the above formula, by conventional means.
- a preferred pegylated-IFN- ⁇ conjugate has the formula:
- R and R' are independently lower alkyl; X is NH or O; n and n' are integers having a sum of from 600 to 1500; and the average molecular weight of the polyethylene glycol in said conjugate is from about 26,000 daltons to about 66,000 daltons.
- pegylated interferon- ⁇ is of the formula
- n and n' are independently 420 or 520.
- This pegylated IFN- ⁇ conjugate is known, for example in European Patent Application EP 809996, incorporated herein by reference.
- IFN- ⁇ and a pharmaceutically acceptable salt or a prodrug of mycophenolic acid are administered to patients suffering liver diseases.
- association of IFN- ⁇ with a pharmaceutically acceptable salt or a prodrug of mycophenolic acid as described in the present invention is efficacious for treating viral infections and, especially, chronic hepatitis C.
- sustained response is meant that the amount of HCV in peripheral blood set forth as copies of HCV-RNA in peripheral blood is less than 100 copies/ml, for example when measured at 24 weeks after the end of administration of the two components.
- the amount of HCV in peripheral blood set forth as copies of HCV-RNA/ml is determined by known methods.
- In vitro diagnostic kits for determining the amount are commercially available, such as the Amplicor® HCV Monitor Test (a quantitative test sensitive to 1000 copies/ml), the Amplicor® Hepatitis C Virus (HCV) Test (a qualitative test sensitive to 100 copies/ml), the Cobas AmplicorTM Hepatitis C Virus Test (an automated qualitative test sensitive to 100 copies/ml), and the Cobas AmplicorTM HCV Monitor Test (an automated quantitative test sensitive to 1000 copies/ml) (each Test may be obtained from Roche Diagnostic Systems, Inc., Branchburg, NJ).
- a preferred method for determining the amount is set forth in the Example.
- the injection solution of IFN- ⁇ or pegylated IFN- ⁇ is administered to the patient parenterally, preferably by subcutaneous (sc) or intramuscular (im) injection.
- the pharmaceutically acceptable salt to or prodrug of MPA is administered to the patient in an oral unit dosage form, more preferably in capsule, pill, sachet or tablet form in association with the parenteral administration of IFN- ⁇ or pegylated IFN- ⁇ .
- administration of the first component and the second component occur concomitantly for a period of from about 24 to about 72 weeks, preferably from about 24 to about 48 weeks, and most preferably for about 48 weeks.
- the dosage for the active ingredient of the injection solution is about 0.5 ⁇ g/kg to about 3.6 ⁇ g/kg of body weight, administered about 1 time per week.
- the dosage for the pharmaceutically acceptable salt or prodrug of MPA is about 3 mg/kg to about 40 mg/kg, preferably about 5 mg/kg to about 36 mg/kg, and most preferably about 12 mg/kg to about 25 mg/kg, administered daily.
- the dosage levels may be modified by the physician to be lower or higher than that stated herein depending on the needs of the patient, and the reaction of the patient to the treatment.
- the dosages may be administered according to any dosage schedule determined by the physician in accordance with the requirements of the patient.
- the dosages of each of the two components may be administered in single or in divided doses.
- the therapeutically effective amount of IFN- ⁇ or PEG IFN- ⁇ and the therapeutically effective amount of MPA or one of its prodrugs or salts (for example, MMF) may be administered simultaneous, part-simultaneous, separate or sequential.
- the therapeutically effective of MPA or one of its prodrugs or salts (for example, MMF) may be administered to the patient in association with the therapeutically effective amount of IFN- ⁇ or PEG IFN- ⁇ , that is the IFN- ⁇ or PEG IFN- ⁇ dose may be administered during the same or different periods of time that the patient receives doses of MPA or one of its prodrugs or salts (for example, MMF).
- a kit useful for treating hepatitis C.
- the kit comprises a first component and a second component.
- the first component contains one or more oral unit dosage forms of an active ingredient, each unit containing about 250 mg to about 2000 mg (preferably 500-1000 mg) of the active ingredient, wherein the active ingredient is a pharmaceutically acceptable salt or prodrug of MPA.
- the second component contains a vial or series of vials each vial containing a single injectable solution dose or multiple injectable solution doses, each dose containing as an active ingredient about 40 ⁇ g to about 270 ⁇ g (preferably 180 ⁇ g) of interferon- or a pegylated interferon- ⁇ conjugate.
- the first component contains a sufficient number of units so that a patient can administer about 2 grams per day of the active ingredient for a period of about 1 to about 4 weeks and the second component contains a sufficient number of doses so that a patient can administer about 180 ⁇ g per week of interferon- ⁇ or a pegylated interferon- ⁇ conjugate for a period of about 1 to about 4 weeks.
- the active ingredient of the first component is a prodrug of mycophenolate mofetil, having the formula
- Z is hydrogen or -(CO)R and R is lower alkyl or aryl.
- the active ingredient of the first component is a compound of the formula
- the active ingredient of each injectable solution dose is a pegylated interferon- ⁇ 2a conjugate, more preferably a pegylated interferon- ⁇ 2a conjugate of the formula
- R and R' are independently lower alkyl; X is NH or O; n and n' are integers having a sum of from 600 to 1500; and the average molecular weight of the polyethylene glycol in said conjugate is from about 26,000 daltons to about 66,000 daltons.
- each injectable solution dose is a pegylated interferon- ⁇ 2a conjugate of the formula
- n and n' are independently 420 or 520.
- the present invention may be exemplified by controlled clinical trials as shown in the Example below, which illustrates the invention without limitation.
- HCV-RNA quantifiable at > 2000 copies/ml have elevated serum alanine aminotransferase (ALT) activity documented during the 35 day period preceding the initiation of test drug dosing, and have chronic liver disease consistent with chronic HCV infection on a biopsy obtained within the 24 months preceding the initiation of test drug dosing.
- ALT serum alanine aminotransferase
- Patients may not have other forms of liver disease (including cirrhosis), anemia, hepatocellular carcinoma, pre-existing severe depression or other psychiatric disease, cardiac disease, renal disease, seizure disorders, or sever retinopathy.
- liver disease including cirrhosis
- anemia including cirrhosis
- hepatocellular carcinoma pre-existing severe depression or other psychiatric disease
- cardiac disease including cirrhosis
- renal disease CAD
- seizure disorders or sever retinopathy.
- Formulation 2 Ingredient Unit Formula per mL
- PEG-IFN Bulk PEG-IFN is supplied as an aqueous solution in 20 mM sodium acetate, buffered at pH 6, and containing 50 mM sodium chloride, the required amount is calculated using the actual protein content and the actual density of the bulk drug substance
- the theoretical protein content of PEG-IFN is 1 3 mg/mL and the theoretical density is 1 002 g/mL
- each patient is orally administered formulation 1, two times per day for 48 weeks. Concominantly, each patient is administered formulation 2 as a subcutaneous injection, once weekly for 48 weeks.
- the primary efficacy parameter is a sustained virological response rate (that is non- detectable ( ⁇ 100 copies/ml) HCV-RNA at the conclusion of a 24 week treatment- free follow up period).
- HCV-RNA is first isolated from serum or plasma by lysis of virus particles with a chaotropic agent followed by precipitation of the RNA with alcohol.
- a second target sequence (Standard) is introduced with the lysis reagent.
- the Standard is a non-infectous, 351 nucleotide in vitro transcribed RNA molecule with primer binding regions identical to those of the HCV target sequence.
- the Standard contains KY78 and KY80 primer binding regions and generates a product of the same length (244 bases) and base composition as the HCV target RNA.
- the probe binding region of the Standard amplicon is amplified to differentiate Standard amplicon from HCV target amplicon.
- the Standard is carried through the specimen preparation, reverse transcription, amplification and detection steps. The Standard compensates for effects of inhibition and controls for the amplification process to permit the accurate quantitation of HCV-RNA.
- RNA sequence for HCV depends on identification of regions within the HCV genome that show maximum conservation among the various HCV genotypes.
- the 5'-untranslated region of the HCV genome has been shown to have maximum conservation of RNA sequence among known HCV genotypes.
- primers KY78 and KY80 are primers to define a sequence of 244 nucleotides within the highly conserved 5'-untranslated region of the HCV genome. Young, K., Resnick, and Myers, T., 1992.
- thermostable recombinant enzyme Thermits thermophilus DNA Polymerase (rTth pol).
- rTth pol has both reverse transcriptase and DNA polymerase activity. This allows both reverse transcription and PCR amplification to occur in the same reaction mixture.
- Processed specimens are added to the amplification mixture in reaction tubes in which both reverse transcription and PCR amplification occur.
- the downstream or antisense primer (KY78) is biotinylated at the 5' end; the upstream or sense primer (KY80) is not biotinylated.
- the reaction mixture is heated to allow the downstream primer to anneal specifically to the HCV target RNA and to the HCV Standard RNA.
- rTth pol extends the annealed primer forming a DNA strand (cDNA) complementary to the RNA target.
- the reaction mixture is heated to denature the RNAxDNA hybrid and expose the primer target sequences.
- the upstream primer (KY80) anneals specifically to the cDNA strand, rTth pol extends the primer, and a second DNA strand is synthesized.
- uracil-N-glycosylase UNG and deoxyuridine triphosphate (dUTP).
- Uracil-N- glycosylase, UNG recognizes and catalyzes the destruction of DNA strands containing deoxyuridine, but not DNA containing thymidine.
- Deoxyuridine is not present in naturally occurring DNA, but is always present in amplicon due to the use of deoxyuridine triphospate in place of thymidine triphosphate as one of the dNTPs in the Master Mix reagent; therefore, only amplicon contain deoxyuridine.
- Deoxyuridine renders contaminating amplicon susceptible to destruction by uracil-N-glycosylase, UNG prior to amplification of the target DNA.
- Uracil-N-glycosylase, UNG which is included in the Master Mix reagent, catalyzes the cleavage of deoxyuridine containing DNA at the deoxyuridine residues by opening the deoxyribose chain at the C-l position.
- the amplicon DNA chain breaks at the position of the deoxyuridine, thereby rendering the DNA non-amplifiable.
- Uracil-N-glycosylase is inactive at temperatures above 55°C, i.e., throughout the thermal cycling steps, and therefore does not destroy target amplicon. Following amplification, any residual enzyme is denatured by the addition of a denaturation solution, thereby preventing the degradation of any target amplicon. Uracil-N-glycosylase, UNG has been demonstrated to inactivate at least 10 copies of deoxyuridine-containing HCV amplicon per PCR.
- the HCV amplicon and the Standard amplicon are chemically denatured to form single-stranded DNA by the addition of denaturation solution. Aliquots of denatured amplicon are added to separate wells of a microwell place (MWP) coated with HCV-specific (for example, KY150) and Standard-specific (for examaple, SK535) oligonucleotide probes. HCV and Standard amplicon are bound to HCV and Standard wells, respectively, by hybridization to the MWP-bound oligonucleotide probes. To achieve quantitative results over a large dynamic range, serial dilutions of the denatured amplicon are analyzed in the MWP.
- HCV-specific for example, KY150
- Standard-specific for examaple, SK535
- the MWP is washed to remove any unbound material and Avidin-horseradish peroxidase conjugate is added to each well of the MWP.
- the Avidin-horseradish peroxidase conjugate binds to the biotin-labeled amplicon captured by the target-specific oligonucleotide probes (HCV or Standard) bound to the MWP.
- HCV target-specific oligonucleotide probes
- the MWP is washed again to remove unbound conjugate and a substrate solution containing hydrogen peroxide and 3,3' > 5,5'-tetramethylbenzidine (TMB) is added to the wells.
- TMB 3,3' > 5,5'-tetramethylbenzidine
- the bound horseradish peroxidase catalyzes the oxidation of TMB to form a colored complex.
- the reaction is stopped by the addition of a weak acid and the optical density is measured at 450 nm using an automated microwell plate reader.
- the optical density (OD) in each well of the MWP is proportional to the amount of HCV amplicon or Standard amplicon in the well.
- the calculated total OD is proportional to the amount of HCV RNA or Standard RNA, respectively, present in each reverse transcription/PCR amplification reaction.
- the amount of HCV RNA in each specimen is calculated from the ratio of the total HCV OD to the total Standard OD and the input number of Standard RNA molecules using the following equation:
- Total HCV OD calculated total OD for HCV amplicon
- HCV QS copies/PCR the number of copies of QS in each reaction
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Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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PL00357367A PL357367A1 (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in association with peg-ifn-alpha |
EP00962297A EP1220683A2 (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in association with peg-ifn-alpha |
KR1020027001782A KR20020020809A (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in association with peg-ifn-alpha |
JP2001516559A JP2003507339A (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in combination with PEG-IFN-α |
AU74082/00A AU7408200A (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in association with peg-ifn-alpha |
IL14761200A IL147612A0 (en) | 1999-08-13 | 2000-08-08 | MYCOPHENOLATE MOFETIL IN ASSOCIATION WITH PREG-IFN-α |
CA002380653A CA2380653A1 (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in association with peg-ifn-.alpha. |
BR0013252-7A BR0013252A (en) | 1999-08-13 | 2000-08-08 | Mycophenolate mofetil in combination with peg-ifn-alfa |
MXPA02001296A MXPA02001296A (en) | 1999-08-13 | 2000-08-08 | MYCOPHENOLATE MOFETIL IN ASSOCIATION WITH PEG-IFN-alpha. |
NO20020704A NO20020704L (en) | 1999-08-13 | 2002-02-12 | Mycophenolate mofetil associated with PEG-IFN- <alfa> |
HK03101248.5A HK1048951A1 (en) | 1999-08-13 | 2003-02-19 | MYCOPHENOLATE MOFETIL IN ASSOCIATION WITH PEG-IFN-α |
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EP (1) | EP1220683A2 (en) |
JP (1) | JP2003507339A (en) |
CN (1) | CN1368887A (en) |
AU (1) | AU7408200A (en) |
BR (1) | BR0013252A (en) |
CA (1) | CA2380653A1 (en) |
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PE (1) | PE20010490A1 (en) |
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TR (1) | TR200200401T2 (en) |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006020720A3 (en) * | 2004-08-12 | 2006-06-01 | Schering Corp | Stable pegylated interferon formulation |
WO2007119889A1 (en) | 2006-04-18 | 2007-10-25 | Japan Tobacco Inc. | Novel piperazine compound, and use thereof as hcv polymerase inhibitor |
US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
EP2206715A1 (en) | 2004-02-24 | 2010-07-14 | Japan Tobacco, Inc. | Fused heterotetracyclic compounds and use thereof as hcv polymerase inhibitor |
US7977331B1 (en) | 2004-02-24 | 2011-07-12 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
US8809265B2 (en) | 2011-10-21 | 2014-08-19 | Abbvie Inc. | Methods for treating HCV |
US8853176B2 (en) | 2011-10-21 | 2014-10-07 | Abbvie Inc. | Methods for treating HCV |
US11192914B2 (en) | 2016-04-28 | 2021-12-07 | Emory University | Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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GB0307553D0 (en) * | 2003-04-01 | 2003-05-07 | Novartis Ag | Organic compounds |
JP5576928B2 (en) * | 2009-03-27 | 2014-08-20 | ジェイダブリュ ファーマシューティカル コーポレーション | IFN-α fusion protein comprising interferon-alpha and cytoplasmic residual cell membrane penetrating peptide |
HRP20231732T1 (en) * | 2014-11-06 | 2024-03-15 | Pharmaessentia Corporation | Dosage regimen for pegylated interferon |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998048840A1 (en) * | 1997-04-29 | 1998-11-05 | Schering Corporation | Polyethylene glycol-interferon alpha conjugates for therapy of infection |
WO2000050064A2 (en) * | 1999-02-26 | 2000-08-31 | Institute Of Molecular And Cell Biology | Synergistic combination for treatment of viral-mediated diseases |
-
2000
- 2000-08-08 RU RU2002105485/15A patent/RU2002105485A/en not_active Application Discontinuation
- 2000-08-08 CN CN00811397A patent/CN1368887A/en active Pending
- 2000-08-08 CA CA002380653A patent/CA2380653A1/en not_active Abandoned
- 2000-08-08 BR BR0013252-7A patent/BR0013252A/en not_active IP Right Cessation
- 2000-08-08 EP EP00962297A patent/EP1220683A2/en not_active Withdrawn
- 2000-08-08 PE PE2000000804A patent/PE20010490A1/en not_active Application Discontinuation
- 2000-08-08 JP JP2001516559A patent/JP2003507339A/en active Pending
- 2000-08-08 MX MXPA02001296A patent/MXPA02001296A/en unknown
- 2000-08-08 PL PL00357367A patent/PL357367A1/en not_active Application Discontinuation
- 2000-08-08 AU AU74082/00A patent/AU7408200A/en not_active Abandoned
- 2000-08-08 TR TR2002/00401T patent/TR200200401T2/en unknown
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- 2000-08-08 HU HU0202525A patent/HUP0202525A3/en unknown
-
2002
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998048840A1 (en) * | 1997-04-29 | 1998-11-05 | Schering Corporation | Polyethylene glycol-interferon alpha conjugates for therapy of infection |
WO2000050064A2 (en) * | 1999-02-26 | 2000-08-31 | Institute Of Molecular And Cell Biology | Synergistic combination for treatment of viral-mediated diseases |
Non-Patent Citations (3)
Title |
---|
KWO P Y ET AL: "Combination therapy with ribavirin plus alpha-interferon is beneficial for the treatment of chronic hepatitis C in patients who have failed treatment with alpha-interferon." GASTROENTEROLOGY, vol. 116, no. 4 PART 2, April 1999 (1999-04), page A1235 XP000990387 Digestive Disease Week and the 100th Annual Meeting of the American Gastroenterological Association;Orlando, Florida, USA; May 16-19, 1999 ISSN: 0016-5085 * |
PLATZ K P ET AL: "INDICATIONS FOR MYCOPHENOLATE MOFETIL THERAPY IN HEPATITIS C-PATIENTS UNDERGOING LIVER TRANSPLANTATION" TRANSPLANTATION PROCEEDINGS,US,ORLANDO, FL, vol. 30, no. 4, June 1998 (1998-06), pages 1468-1469, XP000889647 ISSN: 0041-1345 * |
POL S ET AL: "Ribavirin + Inerferon-alfa 2B combination shows increased efficiency compared to high doses alfa INF, alone in naive patients infected by genotype 1B" HEPATOLOGY,US,WILLIAMS AND WILKINS, BALTIMORE, MD, vol. 28, no. 4, PART 02, October 1998 (1998-10), page 507A XP002110250 ISSN: 0270-9139 * |
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US11192914B2 (en) | 2016-04-28 | 2021-12-07 | Emory University | Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto |
Also Published As
Publication number | Publication date |
---|---|
JP2003507339A (en) | 2003-02-25 |
CN1368887A (en) | 2002-09-11 |
TR200200401T2 (en) | 2002-06-21 |
PE20010490A1 (en) | 2001-04-27 |
MXPA02001296A (en) | 2002-07-22 |
WO2001012214A3 (en) | 2001-10-04 |
BR0013252A (en) | 2002-04-16 |
HUP0202525A3 (en) | 2003-11-28 |
PL357367A1 (en) | 2004-07-26 |
CA2380653A1 (en) | 2001-02-22 |
HUP0202525A2 (en) | 2002-11-28 |
EP1220683A2 (en) | 2002-07-10 |
RU2002105485A (en) | 2004-01-27 |
AU7408200A (en) | 2001-03-13 |
ZA200200280B (en) | 2003-04-11 |
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