CZ300540B6 - Farmaceutický prostredek obsahující ribavirin v kombinaci s interferonem alfa pro lécbu pacientu s chronickou infekcí hepatitidy C genotypu 1 - Google Patents
Farmaceutický prostredek obsahující ribavirin v kombinaci s interferonem alfa pro lécbu pacientu s chronickou infekcí hepatitidy C genotypu 1 Download PDFInfo
- Publication number
- CZ300540B6 CZ300540B6 CZ20004177A CZ20004177A CZ300540B6 CZ 300540 B6 CZ300540 B6 CZ 300540B6 CZ 20004177 A CZ20004177 A CZ 20004177A CZ 20004177 A CZ20004177 A CZ 20004177A CZ 300540 B6 CZ300540 B6 CZ 300540B6
- Authority
- CZ
- Czechia
- Prior art keywords
- weeks
- patients
- interferon alpha
- hcv
- rna
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 126
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 title claims abstract description 92
- 229960000329 ribavirin Drugs 0.000 title claims abstract description 90
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 title claims abstract description 90
- 108010047761 Interferon-alpha Proteins 0.000 title claims abstract description 89
- 102000006992 Interferon-alpha Human genes 0.000 title claims abstract description 89
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 208000005176 Hepatitis C Diseases 0.000 title claims description 24
- 208000006154 Chronic hepatitis C Diseases 0.000 title claims description 21
- 208000010710 hepatitis C virus infection Diseases 0.000 title claims description 21
- 208000015181 infectious disease Diseases 0.000 title claims description 19
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 36
- 230000003612 virological effect Effects 0.000 claims description 83
- 102000014150 Interferons Human genes 0.000 claims description 47
- 108010050904 Interferons Proteins 0.000 claims description 47
- 229940079322 interferon Drugs 0.000 claims description 45
- 210000002966 serum Anatomy 0.000 claims description 37
- 102100040018 Interferon alpha-2 Human genes 0.000 claims description 22
- 108010079944 Interferon-alpha2b Proteins 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 15
- 230000003442 weekly effect Effects 0.000 claims description 9
- 238000003753 real-time PCR Methods 0.000 claims description 8
- 230000006378 damage Effects 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims 1
- 238000002648 combination therapy Methods 0.000 abstract description 109
- 208000020403 chronic hepatitis C virus infection Diseases 0.000 abstract description 13
- 230000004044 response Effects 0.000 description 138
- 230000002459 sustained effect Effects 0.000 description 89
- 239000000902 placebo Substances 0.000 description 41
- 229940068196 placebo Drugs 0.000 description 41
- 238000009097 single-agent therapy Methods 0.000 description 37
- 238000001574 biopsy Methods 0.000 description 29
- 230000006872 improvement Effects 0.000 description 22
- 238000011529 RT qPCR Methods 0.000 description 20
- 229940065638 intron a Drugs 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 238000002560 therapeutic procedure Methods 0.000 description 15
- 230000009265 virologic response Effects 0.000 description 15
- 206010061218 Inflammation Diseases 0.000 description 13
- 230000004054 inflammatory process Effects 0.000 description 13
- 230000002440 hepatic effect Effects 0.000 description 11
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 10
- 229920001223 polyethylene glycol Polymers 0.000 description 10
- 238000012317 liver biopsy Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 108010078049 Interferon alpha-2 Proteins 0.000 description 8
- 208000006454 hepatitis Diseases 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000010606 normalization Methods 0.000 description 8
- 238000002203 pretreatment Methods 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 230000002035 prolonged effect Effects 0.000 description 7
- 206010016654 Fibrosis Diseases 0.000 description 6
- 238000000729 Fisher's exact test Methods 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 230000007882 cirrhosis Effects 0.000 description 6
- 208000019425 cirrhosis of liver Diseases 0.000 description 6
- 238000000611 regression analysis Methods 0.000 description 6
- 238000010839 reverse transcription Methods 0.000 description 6
- 229960003507 interferon alfa-2b Drugs 0.000 description 5
- 208000018191 liver inflammation Diseases 0.000 description 5
- 230000002085 persistent effect Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 5
- 239000002775 capsule Substances 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229940047124 interferons Drugs 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229950000038 interferon alfa Drugs 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- -1 polyethylene Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 101000959794 Homo sapiens Interferon alpha-2 Proteins 0.000 description 2
- 102100023915 Insulin Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002105 Southern blotting Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108020003215 DNA Probes Proteins 0.000 description 1
- 239000003298 DNA probe Substances 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 206010019837 Hepatocellular injury Diseases 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108020005719 Species specific proteins Proteins 0.000 description 1
- 102000007397 Species specific proteins Human genes 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 108010006785 Taq Polymerase Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- YDQXYRCYDMRJGD-UHFFFAOYSA-N chloroform;phenol;thiocyanic acid Chemical compound SC#N.ClC(Cl)Cl.OC1=CC=CC=C1 YDQXYRCYDMRJGD-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- FFYPMLJYZAEMQB-UHFFFAOYSA-N diethyl pyrocarbonate Chemical compound CCOC(=O)OC(=O)OCC FFYPMLJYZAEMQB-UHFFFAOYSA-N 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000008935 histological improvement Effects 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229960003521 interferon alfa-2a Drugs 0.000 description 1
- 108010055511 interferon alfa-2c Proteins 0.000 description 1
- 108010006088 interferon alfa-n1 Proteins 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008593 response to virus Effects 0.000 description 1
- 238000011268 retreatment Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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]
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7956698A | 1998-05-15 | 1998-05-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CZ20004177A3 CZ20004177A3 (cs) | 2001-04-11 |
| CZ300540B6 true CZ300540B6 (cs) | 2009-06-10 |
Family
ID=22151354
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ20004177A CZ300540B6 (cs) | 1998-05-15 | 1999-05-13 | Farmaceutický prostredek obsahující ribavirin v kombinaci s interferonem alfa pro lécbu pacientu s chronickou infekcí hepatitidy C genotypu 1 |
Country Status (22)
| Country | Link |
|---|---|
| EP (3) | EP0956861B1 (https=) |
| JP (2) | JP5281726B2 (https=) |
| KR (1) | KR100694345B1 (https=) |
| CN (1) | CN1230198C (https=) |
| AR (1) | AR019551A1 (https=) |
| AT (1) | ATE216591T1 (https=) |
| AU (2) | AU766597B2 (https=) |
| BR (1) | BR9910505A (https=) |
| CA (1) | CA2331823A1 (https=) |
| CZ (1) | CZ300540B6 (https=) |
| DE (1) | DE69901321T2 (https=) |
| DK (1) | DK0956861T3 (https=) |
| ES (1) | ES2172288T3 (https=) |
| HU (1) | HU230432B1 (https=) |
| IL (3) | IL139220A0 (https=) |
| MY (1) | MY129244A (https=) |
| NO (1) | NO330715B1 (https=) |
| NZ (1) | NZ507621A (https=) |
| PT (1) | PT956861E (https=) |
| SK (1) | SK288038B6 (https=) |
| TW (1) | TWI277424B (https=) |
| WO (1) | WO1999059621A1 (https=) |
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2686899B1 (fr) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
| AR021876A1 (es) * | 1998-12-18 | 2002-08-07 | Schering Corp | Terapia de combinacion para vhc por induccion de ribavirina - interferon alfa pegilado |
| KR20030032908A (ko) * | 1999-12-23 | 2003-04-26 | 아이씨엔 파마슈티컬스, 인코포레이티드 | Ｌ-누클레오시드, ｌ-누클레오티드 및 이들의 유사체에대한 조성물 및 방법 |
| JP4536194B2 (ja) * | 2000-02-17 | 2010-09-01 | 大日本住友製薬株式会社 | 安定な注射用製剤 |
| EP2206720A1 (en) | 2000-04-12 | 2010-07-14 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| KR20080021797A (ko) | 2000-05-26 | 2008-03-07 | 이데닉스(케이만)리미티드 | 플라비바이러스 및 페스티바이러스의 치료방법 및 조성물 |
| EP1326594A2 (en) * | 2000-10-18 | 2003-07-16 | Schering Corporation | Ribavirin-pegylated interferon alfa hcv combination therapy |
| AU2002330154A1 (en) | 2001-09-28 | 2003-04-07 | Centre National De La Recherche Scientifique | Methods and compositions for treating hepatitis c virus using 4'-modified nucleosides |
| IL161889A0 (en) * | 2001-11-09 | 2005-11-20 | Biomedicines Inc | Method for treating diseases with omega interferon |
| EP2261250B1 (en) | 2001-12-21 | 2015-07-01 | Human Genome Sciences, Inc. | GCSF-Albumin fusion proteins |
| PL374781A1 (en) | 2002-06-28 | 2005-10-31 | Idenix (Cayman) Limited | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| BR0312271A (pt) | 2002-06-28 | 2007-11-06 | Idenix Cayman Ltd | compostos, composições e seus usos para o tratamento de infecções por flaviviridae |
| US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| NZ537662A (en) | 2002-06-28 | 2007-10-26 | Idenix Cayman Ltd | 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| HUE033832T2 (en) | 2002-11-15 | 2018-01-29 | Idenix Pharmaceuticals Llc | 2'-methyl nucleosides in combination with interferon and Flaviviridae mutation |
| RU2005121904A (ru) | 2002-12-12 | 2006-01-20 | Айденикс (Кайман) Лимитед (Ky) | Способ получения 2`-разветвленных нуклеозидов |
| CA2513213C (en) | 2003-01-22 | 2013-07-30 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| RU2005133093A (ru) * | 2003-03-28 | 2006-07-27 | Фармассет, Инк. (Us) | Соединения для лечения флавивирусных инфекций |
| JP2006528679A (ja) * | 2003-04-01 | 2006-12-21 | インターミューン インコーポレイテッド | コロナウイルス感染症及びサースを治療するための組成物及び方法 |
| US20070026014A1 (en) * | 2003-04-17 | 2007-02-01 | Ares Trading S.A. | Interferon beta in severe acute respiratory syndrome (sars) |
| EP2345657A1 (en) | 2003-05-30 | 2011-07-20 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
| EP1641485A4 (en) * | 2003-06-09 | 2009-06-24 | Genome Inst Of Singapore | INHIBITION OF SARS CORONAVIRUS INFECTION USING ANTIVIRAL DRUGS CLINICALLY TESTED |
| JP2007501806A (ja) * | 2003-08-13 | 2007-02-01 | ハワード ジェイ． スミス アンド アソシエイツ ピーティーワイ エルティーディー | ウィルス感染を治療する方法 |
| AR045870A1 (es) * | 2003-10-11 | 2005-11-16 | Vertex Pharma | Terapia de combinacion para la infeccion de virus de hepatitis c |
| CN101023094B (zh) | 2004-07-21 | 2011-05-18 | 法莫赛特股份有限公司 | 烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备 |
| AU2005285045B2 (en) | 2004-09-14 | 2011-10-13 | Gilead Sciences, Inc. | Preparation of 2'fluoro-2'- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
| TWI437990B (zh) * | 2004-10-29 | 2014-05-21 | Vertex Pharma | Vx-950之醫藥用途 |
| AP2907A (en) | 2006-01-09 | 2014-05-31 | Romark Lab Lc | Viral hepatitis treatment |
| US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
| EP2175865A4 (en) | 2007-07-25 | 2012-01-11 | Biolex Therapeutics Inc | INTERFERON DRUG PRODUCTS WITH CONTROLLED RELEASE AND TREATMENT OF HCV INFECTIONS THEREWITH |
| TW200946541A (en) | 2008-03-27 | 2009-11-16 | Idenix Pharmaceuticals Inc | Solid forms of an anti-HIV phosphoindole compound |
| RU2369403C1 (ru) * | 2008-05-22 | 2009-10-10 | Сергей Юрьевич Родионов | Способ лечения хронических вирусных гепатитов |
| KR20110098849A (ko) | 2008-12-23 | 2011-09-01 | 파마셋 인코포레이티드 | 뉴클레오시드 유사체 |
| PT2376088T (pt) | 2008-12-23 | 2017-05-02 | Gilead Pharmasset Llc | Fosforamidatos de nucleósidos de 2-amino-purina 6-osubstituída |
| SG194404A1 (en) | 2008-12-23 | 2013-11-29 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
| EP2427213B1 (en) | 2009-05-08 | 2015-04-01 | Sciclone Pharmaceuticals, Inc. | Alpha thymosin peptides as vaccine enhancers |
| US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| TWI598358B (zh) | 2009-05-20 | 2017-09-11 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
| PT2609923T (pt) | 2010-03-31 | 2017-08-30 | Gilead Pharmasset Llc | Processo para a cristalização de 2-(((s)- (perfluorofenoxi)(fenoxi)fosforil)amino)propanoato de (s)-isopropilo |
| JP2013542206A (ja) * | 2010-10-05 | 2013-11-21 | ノバルティス アーゲー | Ｃ型肝炎ウイルス感染症の新規治療 |
| AU2011336632B2 (en) | 2010-11-30 | 2015-09-03 | Gilead Pharmasset Llc | Compounds |
| KR20190060879A (ko) * | 2011-03-02 | 2019-06-03 | 제롬 쉔타그 | 단독으로 또는 c형 간염 바이러스 감염과 결합되는 간 지방증의 치료를 위한 조성물, 방법 및 진단 |
| PL2709613T5 (pl) | 2011-09-16 | 2020-12-14 | Gilead Pharmasset Llc | Metody leczenia hcv |
| US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
| PT2950786T (pt) | 2013-01-31 | 2020-03-03 | Gilead Pharmasset Llc | Formulação de combinação de dois compostos antivirais |
| EA201690473A1 (ru) | 2013-08-27 | 2017-03-31 | ГАЙЛИД ФАРМАССЕТ ЭлЭлСи | Комбинированный состав двух противовирусных соединений |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0707855A2 (en) * | 1995-05-19 | 1996-04-24 | Schering Corporation | Combination therapy for chronic hepatitis C infection |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4211771A (en) | 1971-06-01 | 1980-07-08 | Robins Ronald K | Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide |
| US4530901A (en) | 1980-01-08 | 1985-07-23 | Biogen N.V. | Recombinant DNA molecules and their use in producing human interferon-like polypeptides |
| US6936694B1 (en) | 1982-05-06 | 2005-08-30 | Intermune, Inc. | Manufacture and expression of large structural genes |
| US4492537A (en) | 1982-12-10 | 1985-01-08 | Awerkamp John B | Fluid-operated oil or water well pump |
| US4917888A (en) | 1985-06-26 | 1990-04-17 | Cetus Corporation | Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation |
| US4766106A (en) | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
| JP2514950B2 (ja) | 1986-03-10 | 1996-07-10 | エフ・ホフマン―ラ ロシユ アーゲー | 化学修飾蛋白質，その製造法および中間体 |
| US5595732A (en) | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
| US5382657A (en) | 1992-08-26 | 1995-01-17 | Hoffmann-La Roche Inc. | Peg-interferon conjugates |
| KR960705579A (ko) * | 1993-11-10 | 1996-11-08 | 에릭에스. 딕커 | 개선된 인터페론 중합체 결합체(Improved interferon polymer conjugates) |
| US5766582A (en) | 1994-10-11 | 1998-06-16 | Schering Corporation | Stable, aqueous alfa interferon solution formulations |
| US5824784A (en) * | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
| TW426523B (en) | 1995-04-06 | 2001-03-21 | Hoffmann La Roche | Interferon solution |
| PT858343E (pt) * | 1995-11-02 | 2004-07-30 | Schering Corp | Terapia por infusao continua de uma dose baixa de citoquina |
| US5908621A (en) * | 1995-11-02 | 1999-06-01 | Schering Corporation | Polyethylene glycol modified interferon therapy |
| TW517067B (en) | 1996-05-31 | 2003-01-11 | Hoffmann La Roche | Interferon conjugates |
| CA2298543A1 (en) | 1997-08-13 | 1999-02-25 | James Barry | Loading and release of water-insoluble drugs |
| DK1136075T3 (da) * | 1997-09-21 | 2003-04-28 | Schering Corp | Kombinationsterapi til udryddelse aff detekterbart HCV-RNA i patienter med kronisk hepatitis C infektion |
-
1999
- 1999-05-13 CA CA002331823A patent/CA2331823A1/en not_active Abandoned
- 1999-05-13 HU HU0103423A patent/HU230432B1/hu unknown
- 1999-05-13 IL IL13922099A patent/IL139220A0/xx unknown
- 1999-05-13 SK SK1710-2000A patent/SK288038B6/sk not_active IP Right Cessation
- 1999-05-13 MY MYPI99001891A patent/MY129244A/en unknown
- 1999-05-13 AT AT99303729T patent/ATE216591T1/de active
- 1999-05-13 EP EP99303729A patent/EP0956861B1/en not_active Expired - Lifetime
- 1999-05-13 PT PT99303729T patent/PT956861E/pt unknown
- 1999-05-13 DE DE69901321T patent/DE69901321T2/de not_active Expired - Lifetime
- 1999-05-13 CZ CZ20004177A patent/CZ300540B6/cs not_active IP Right Cessation
- 1999-05-13 AU AU38600/99A patent/AU766597B2/en not_active Withdrawn - After Issue
- 1999-05-13 ES ES99303729T patent/ES2172288T3/es not_active Expired - Lifetime
- 1999-05-13 TW TW088107774A patent/TWI277424B/zh not_active IP Right Cessation
- 1999-05-13 JP JP2000549285A patent/JP5281726B2/ja not_active Expired - Lifetime
- 1999-05-13 CN CNB998085960A patent/CN1230198C/zh not_active Expired - Lifetime
- 1999-05-13 WO PCT/US1999/007037 patent/WO1999059621A1/en not_active Ceased
- 1999-05-13 KR KR1020007012784A patent/KR100694345B1/ko not_active Expired - Lifetime
- 1999-05-13 DK DK99303729T patent/DK0956861T3/da active
- 1999-05-13 EP EP01130613A patent/EP1213029A1/en not_active Withdrawn
- 1999-05-13 EP EP10181927A patent/EP2305287A1/en not_active Withdrawn
- 1999-05-13 BR BR9910505-5A patent/BR9910505A/pt not_active Application Discontinuation
- 1999-05-14 AR ARP990102303A patent/AR019551A1/es unknown
-
2000
- 2000-10-18 NZ NZ507621A patent/NZ507621A/xx not_active IP Right Cessation
- 2000-10-23 IL IL139220A patent/IL139220A/en not_active IP Right Cessation
- 2000-11-14 NO NO20005755A patent/NO330715B1/no not_active IP Right Cessation
-
2005
- 2005-10-10 AU AU2005220271A patent/AU2005220271B9/en not_active Expired
-
2010
- 2010-07-27 IL IL207259A patent/IL207259A/en not_active IP Right Cessation
-
2011
- 2011-04-07 JP JP2011085606A patent/JP2011173898A/ja not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0707855A2 (en) * | 1995-05-19 | 1996-04-24 | Schering Corporation | Combination therapy for chronic hepatitis C infection |
Non-Patent Citations (9)
| Title |
|---|
| Dig. Dis. Sci 41(12 Suppl) 131S-134S (1996) (abstrakt) * |
| Dig. Dis. Sci. 1996 DEc 41 (12 Suppl) 131S-134S (abstrakt) * |
| Hepatology 26 (2) s. 500- 504 (1997) * |
| Hournal of Hepatology 23 (Suppl. 2) 32-36 (1995) (abstrakt) * |
| Journal of Hepatology 23 (SUP2) s. 17-21 (1995) (abstrakt) * |
| Journal of Hepatology 23 (SUP2) s. 3-7 (1995) (abstrakt) * |
| Pathologie Biologie43 (8 s. 716-724 (1995) (abstrakt) * |
| Scnadinavian Journal of Gastroenterology 32 (Suppl. 223) s. 46-49 (1997) (abstrakt) * |
| The Lacet 351 10.1.1998s. 83-87 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CZ300540B6 (cs) | Farmaceutický prostredek obsahující ribavirin v kombinaci s interferonem alfa pro lécbu pacientu s chronickou infekcí hepatitidy C genotypu 1 | |
| US6472373B1 (en) | Combination therapy for eradicating detectable HCV-RNA in antiviral treatment naive patients having chronic hepatitis C infection | |
| US20020127203A1 (en) | Ribavirin-pegylated interferon alfa HCV combination therapy | |
| SK3922000A3 (en) | The use of ribavirin for the manufacture of a pharmaceutical composition, the use of interferon alpha for the manufacture of a pharmaceutical composition and pharmaceutical compositions | |
| US20030039630A1 (en) | Combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection | |
| CA2354536A1 (en) | Ribavirin-pegylated interferon alfa induction hcv combination therapy | |
| US6824768B2 (en) | Ribavirin-pegylated interferon alfa induction HCV combination therapy | |
| HUP0200942A2 (hu) | Humán hepatitisz-C kezelése antioxidánsokkal társított ribavirint tartalmazó kombinációkkal | |
| WO2000037097A1 (en) | Ribavirin-interferon alfa induction hcv combination therapy | |
| MXPA00011198A (en) | Combination therapy comprising ribavirin and interferon alpha in antiviral treatment naive patients having g chronic hepatitis c infection | |
| HK1154495A (en) | Combination therapy for eradicating detectable hcv-rna in antiviral treatment naive patients having chronic hepatitis c infection | |
| HK1021131B (en) | Combination therapy comprising ribavirin and interferon alpha in antiviral treatment naive patients having chronic hepatitis c infection | |
| HK1044464A (en) | Combination therapy for eradicating detectable hcv-rna in antiviral treatment naive patients having chronic hepatitis c infection | |
| CZ2000788A3 (cs) | Použití ribavirinu pro výrobu farmaceutických prostředků, použití interferonů alfa pro výrobu farmaceutických prostředků a farmaceutické výrobky | |
| MXPA01006161A (en) | Ribavirin-pegylated interferon alfa induction hcv combination therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4A | Patent expired |
Effective date: 20190513 |