CA2594202C - Use of resiniferatoxin (rtx) for producing an agent for treating joint pains and method for applying said agent - Google Patents
Use of resiniferatoxin (rtx) for producing an agent for treating joint pains and method for applying said agent Download PDFInfo
- Publication number
- CA2594202C CA2594202C CA 2594202 CA2594202A CA2594202C CA 2594202 C CA2594202 C CA 2594202C CA 2594202 CA2594202 CA 2594202 CA 2594202 A CA2594202 A CA 2594202A CA 2594202 C CA2594202 C CA 2594202C
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- rtx
- joint
- pain
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- DSDNAKHZNJAGHN-MXTYGGKSSA-N resiniferatoxin Chemical compound C1=C(O)C(OC)=CC(CC(=O)OCC=2C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]34[C@H](C)C[C@@]5(O[C@@](O4)(CC=4C=CC=CC=4)O[C@@H]5[C@@H]3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-MXTYGGKSSA-N 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title description 24
- 208000006820 Arthralgia Diseases 0.000 title description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 4
- IKYCZSUNGFRBJS-UHFFFAOYSA-N Euphorbia factor RL9 = U(1) = Resiniferatoxin Natural products COC1=CC(O)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 IKYCZSUNGFRBJS-UHFFFAOYSA-N 0.000 claims description 53
- DSDNAKHZNJAGHN-UHFFFAOYSA-N resinferatoxin Natural products C1=C(O)C(OC)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-UHFFFAOYSA-N 0.000 claims description 53
- 229940073454 resiniferatoxin Drugs 0.000 claims description 53
- 239000007924 injection Substances 0.000 claims description 47
- 238000002347 injection Methods 0.000 claims description 47
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 239000007853 buffer solution Substances 0.000 claims description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910001424 calcium ion Inorganic materials 0.000 claims description 5
- -1 ethoxyethylene diglycol Chemical compound 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 239000005526 vasoconstrictor agent Substances 0.000 claims description 3
- SGRCVQDBWHCTIS-UHFFFAOYSA-N 2-nonanoyloxypropyl nonanoate Chemical compound CCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCC SGRCVQDBWHCTIS-UHFFFAOYSA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 claims 1
- 230000003444 anaesthetic effect Effects 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims 1
- 208000002193 Pain Diseases 0.000 abstract description 26
- 230000036407 pain Effects 0.000 abstract description 22
- 239000003589 local anesthetic agent Substances 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000013543 active substance Substances 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 32
- 239000000126 substance Substances 0.000 description 20
- 210000000988 bone and bone Anatomy 0.000 description 14
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 206010034464 Periarthritis Diseases 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 206010006002 Bone pain Diseases 0.000 description 10
- 230000006378 damage Effects 0.000 description 10
- 210000001503 joint Anatomy 0.000 description 10
- 210000000281 joint capsule Anatomy 0.000 description 10
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 9
- 235000017663 capsaicin Nutrition 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 230000005499 meniscus Effects 0.000 description 9
- 210000005036 nerve Anatomy 0.000 description 9
- 208000007538 neurilemmoma Diseases 0.000 description 9
- 206010039667 schwannoma Diseases 0.000 description 9
- 208000004371 toothache Diseases 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 8
- 206010028851 Necrosis Diseases 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 230000007850 degeneration Effects 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 230000017074 necrotic cell death Effects 0.000 description 8
- 206010058029 Arthrofibrosis Diseases 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 201000010603 frozen shoulder Diseases 0.000 description 7
- 210000000629 knee joint Anatomy 0.000 description 7
- 229960005015 local anesthetics Drugs 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- 238000001356 surgical procedure Methods 0.000 description 7
- 238000009826 distribution Methods 0.000 description 6
- 208000000112 Myalgia Diseases 0.000 description 5
- 238000011010 flushing procedure Methods 0.000 description 5
- 230000002887 neurotoxic effect Effects 0.000 description 5
- 210000000689 upper leg Anatomy 0.000 description 5
- 208000008035 Back Pain Diseases 0.000 description 4
- 206010007710 Cartilage injury Diseases 0.000 description 4
- 206010016654 Fibrosis Diseases 0.000 description 4
- 206010061159 Foot deformity Diseases 0.000 description 4
- 208000001963 Hallux Valgus Diseases 0.000 description 4
- 206010023230 Joint stiffness Diseases 0.000 description 4
- 201000009859 Osteochondrosis Diseases 0.000 description 4
- 206010053692 Wound complication Diseases 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229960002504 capsaicin Drugs 0.000 description 4
- 208000002849 chondrocalcinosis Diseases 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 208000002925 dental caries Diseases 0.000 description 4
- 238000002674 endoscopic surgery Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000004761 fibrosis Effects 0.000 description 4
- 238000002695 general anesthesia Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000007443 liposuction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 208000013465 muscle pain Diseases 0.000 description 4
- 230000003387 muscular Effects 0.000 description 4
- 230000002981 neuropathic effect Effects 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 230000001148 spastic effect Effects 0.000 description 4
- 201000004595 synovitis Diseases 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 206010072970 Meniscus injury Diseases 0.000 description 3
- 208000004983 Phantom Limb Diseases 0.000 description 3
- 206010056238 Phantom pain Diseases 0.000 description 3
- 208000004550 Postoperative Pain Diseases 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 230000001741 anti-phlogistic effect Effects 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 229910052788 barium Inorganic materials 0.000 description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 3
- 229960002537 betamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 229960003160 hyaluronic acid Drugs 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 210000001087 myotubule Anatomy 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 231100000189 neurotoxic Toxicity 0.000 description 3
- 230000003040 nociceptive effect Effects 0.000 description 3
- 201000001245 periodontitis Diseases 0.000 description 3
- 238000000554 physical therapy Methods 0.000 description 3
- 210000003281 pleural cavity Anatomy 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 210000000323 shoulder joint Anatomy 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010002153 Anal fissure Diseases 0.000 description 2
- 208000016583 Anus disease Diseases 0.000 description 2
- 241001260012 Bursa Species 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 208000009531 Fissure in Ano Diseases 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- 206010020565 Hyperaemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000004575 Infectious Arthritis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010039491 Ricin Proteins 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- 230000002638 denervation Effects 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 210000001624 hip Anatomy 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 210000003041 ligament Anatomy 0.000 description 2
- 238000002690 local anesthesia Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 210000004126 nerve fiber Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 201000001223 septic arthritis Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 108010025083 TRPV1 receptor Proteins 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 150000003868 ammonium compounds Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 238000011882 arthroplasty Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 238000001804 debridement Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 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
- 239000012153 distilled water Substances 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 210000001145 finger joint Anatomy 0.000 description 1
- 210000000527 greater trochanter Anatomy 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000008349 purified phosphatidyl choline Substances 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000001170 unmyelinated nerve fiber Anatomy 0.000 description 1
- 239000000105 vanilloid receptor agonist Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Surgery (AREA)
- Anesthesiology (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CH2004/000756 WO2006069451A1 (de) | 2004-12-28 | 2004-12-28 | Verwendung von resiniferatoxin (rtx) für die herstellung eines mittels zur behandlung von gelenkschmerzen und verfahren zur applikation dieses mittels |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2594202A1 CA2594202A1 (en) | 2006-07-06 |
| CA2594202C true CA2594202C (en) | 2013-12-03 |
Family
ID=34959549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2594202 Expired - Lifetime CA2594202C (en) | 2004-12-28 | 2004-12-28 | Use of resiniferatoxin (rtx) for producing an agent for treating joint pains and method for applying said agent |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US20080139641A1 (enExample) |
| EP (1) | EP1838301B1 (enExample) |
| JP (1) | JP5775246B2 (enExample) |
| CA (1) | CA2594202C (enExample) |
| DK (1) | DK1838301T3 (enExample) |
| ES (1) | ES2533256T3 (enExample) |
| PL (1) | PL1838301T3 (enExample) |
| WO (1) | WO2006069451A1 (enExample) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100076037A1 (en) | 2006-11-02 | 2010-03-25 | Chiang Lillian W | Methods of Treating Neuropathic Pain with Agonists of PPAR-gamma |
| WO2010011597A2 (en) * | 2008-07-22 | 2010-01-28 | Mayo Foundation For Medical Education And Research | Treatment of obesity and related disorders |
| US8870876B2 (en) | 2009-02-13 | 2014-10-28 | Tarsus Medical Inc. | Methods and devices for treating hallux valgus |
| US8277459B2 (en) | 2009-09-25 | 2012-10-02 | Tarsus Medical Inc. | Methods and devices for treating a structural bone and joint deformity |
| US8652141B2 (en) | 2010-01-21 | 2014-02-18 | Tarsus Medical Inc. | Methods and devices for treating hallux valgus |
| US8696719B2 (en) | 2010-06-03 | 2014-04-15 | Tarsus Medical Inc. | Methods and devices for treating hallux valgus |
| EP3269371A1 (en) | 2011-06-10 | 2018-01-17 | Queen Mary University of London | Artemisinin and its derivatives for use in the treatment of myocardial infarction or coronary heart disease |
| EP2879660A1 (de) * | 2012-08-03 | 2015-06-10 | Mestex AG | Resiniferatoxin-lösung |
| JP6144775B2 (ja) | 2012-12-12 | 2017-06-07 | クイーン マリー アンド ウエストフィールド カレッジ, ユニバーシティー オブ ロンドン | 腎臓病の治療に使用されるアーテミシニンおよびその誘導体 |
| US10076384B2 (en) | 2013-03-08 | 2018-09-18 | Symple Surgical, Inc. | Balloon catheter apparatus with microwave emitter |
| JP7100635B2 (ja) | 2016-11-02 | 2022-07-13 | セントレクシオン セラピューティクス コーポレイション | 安定な水性カプサイシン注射製剤およびその医学的使用 |
| EP3641746B1 (en) * | 2017-06-19 | 2024-11-20 | President And Fellows Of Harvard College | Methods and compositions for treating a microbial infection |
| IL272036B2 (en) | 2017-07-20 | 2025-01-01 | Centrexion Therapeutics Corp | Methods and compositions for treating pain using capsaicin |
| KR20200051771A (ko) * | 2017-09-11 | 2020-05-13 | 소렌토 쎄라퓨틱스, 인코포레이티드 | 레시니페라톡신 제형 |
| SG11202105938RA (en) * | 2018-12-21 | 2021-07-29 | Sorrento Therapeutics Inc | Perineural administration of resiniferatoxin for treatment of maladaptive pain |
| US11447444B1 (en) | 2019-01-18 | 2022-09-20 | Centrexion Therapeutics Corporation | Capsaicinoid prodrug compounds and their use in treating medical conditions |
| US11254659B1 (en) | 2019-01-18 | 2022-02-22 | Centrexion Therapeutics Corporation | Capsaicinoid prodrug compounds and their use in treating medical conditions |
| TW202042802A (zh) | 2019-01-22 | 2020-12-01 | 美商索倫多醫療公司 | 藉由投與樹脂毒素(resiniferatoxin)治療骨關節炎疼痛之方法 |
| CN110123833A (zh) * | 2019-05-31 | 2019-08-16 | 龚啸元 | 一种关节镜手术用灌流液及其制备方法 |
| EP4487872A3 (en) * | 2020-04-15 | 2025-03-26 | Grünenthal GmbH | Resiniferatoxin compositions |
| WO2025153517A1 (en) | 2024-01-15 | 2025-07-24 | Grünenthal GmbH | Treating knee joint pain by injecting resiniferatoxin at ultra low doses |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3104085A (en) | 1960-07-18 | 1963-09-17 | Ind Paper Log Inc | Compressed fibrous articles |
| US4939149A (en) * | 1988-10-24 | 1990-07-03 | The United States Of America As Represented By The Department Of Health And Human Services | Resiniferatoxin and analogues thereof to cause sensory afferent C-fiber and thermoregulatory desensitization |
| US4997853A (en) * | 1988-12-02 | 1991-03-05 | Galenpharma, Inc. | Method and compositions utilizing capsaicin as an external analgesic |
| AU5744490A (en) * | 1989-05-15 | 1990-12-18 | Afferon Corporation | Composition and method for neural desensitization |
| ATE219674T1 (de) | 1997-03-13 | 2002-07-15 | James N Campbell | Zusammensetzung enthaltend capsaicin oder seine analogen und lokalanästhetika |
| GB9711962D0 (en) | 1997-06-10 | 1997-08-06 | Reckitt & Colmann Prod Ltd | Therapeutically active compositions |
| US6780650B2 (en) * | 2000-10-16 | 2004-08-24 | Ortho-Mcneil Pharmaceutical, Inc. | Ligand binding assays for vanilloid receptors |
| US20040047807A1 (en) * | 2001-01-24 | 2004-03-11 | Dominik Meyer | Use of neurotoxic substances in producing a medicament for treating joint pains |
| WO2002076444A1 (en) | 2001-03-22 | 2002-10-03 | The Government Of The United States, As Represented By The Secretary Of The Department Of Health And Human Services | Molecular neurochirurgerie for pain control administering locally capsaicin or resiniferatoxin |
| US20030104085A1 (en) * | 2001-12-05 | 2003-06-05 | Yeomans David C. | Methods and compositions for treating back pain |
| JP2006513267A (ja) * | 2002-12-18 | 2006-04-20 | アルゴルクス ファーマスーティカルズ,インク | カプサイシノイドの投与 |
| ES2355109T3 (es) * | 2004-12-22 | 2011-03-22 | Mestex Ag | Mezcla de un agonista de receptor de vainilloide con una sustancia inhibidora de la regeneración nerviosa, su utilización para la fabricación de un analgésico y procedimiento de aplicación de este fármaco. |
-
2004
- 2004-12-28 PL PL04802396T patent/PL1838301T3/pl unknown
- 2004-12-28 ES ES04802396.4T patent/ES2533256T3/es not_active Expired - Lifetime
- 2004-12-28 US US11/722,779 patent/US20080139641A1/en not_active Abandoned
- 2004-12-28 WO PCT/CH2004/000756 patent/WO2006069451A1/de not_active Ceased
- 2004-12-28 DK DK04802396.4T patent/DK1838301T3/en active
- 2004-12-28 EP EP04802396.4A patent/EP1838301B1/de not_active Expired - Lifetime
- 2004-12-28 JP JP2007548653A patent/JP5775246B2/ja not_active Expired - Lifetime
- 2004-12-28 CA CA 2594202 patent/CA2594202C/en not_active Expired - Lifetime
-
2010
- 2010-04-07 US US12/755,994 patent/US9044452B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| US9044452B2 (en) | 2015-06-02 |
| PL1838301T3 (pl) | 2015-08-31 |
| DK1838301T3 (en) | 2015-04-27 |
| ES2533256T3 (es) | 2015-04-08 |
| JP5775246B2 (ja) | 2015-09-09 |
| EP1838301A1 (de) | 2007-10-03 |
| US20100196281A1 (en) | 2010-08-05 |
| JP2008525504A (ja) | 2008-07-17 |
| EP1838301B1 (de) | 2015-01-28 |
| US20080139641A1 (en) | 2008-06-12 |
| CA2594202A1 (en) | 2006-07-06 |
| WO2006069451A1 (de) | 2006-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9044452B2 (en) | Use of resiniferatoxin (RTX) for producing an agent for treating joint pains and method for applying said agent | |
| CA2592086C (en) | Mixture of a vanilloid receptor agonist and a substance inhibiting nerve regeneration, use thereof for producing a painkiller, and method for applying said painkiller | |
| US8703741B2 (en) | Method of treating articular pain using a vanilloid receptor agonist together with a glycosaminoglycan or proteoglycan | |
| EA011708B1 (ru) | Применение транс- капсаицина | |
| JP2004521112A (ja) | 関節痛治療薬を製造することへの神経毒性物質の使用 | |
| JP2008525504A5 (enExample) | ||
| JP2008533140A (ja) | 術後鎮痛剤の低減 | |
| CA2493041C (en) | Injectable pharmaceutical composition for treating post-operative joint pain comprising an amide local anesthetic | |
| RU2299733C1 (ru) | Способ лечения дегенеративно-дистрофических заболеваний опорно-двигательного аппарата и посттравматических спаечных процессов | |
| RU2845795C1 (ru) | Способ лечения ранних стадий остеохондральных поражений нижних конечностей | |
| EP1176967A1 (en) | Management of pain after joint surgery | |
| RU2027433C1 (ru) | Способ лечения мицетомы стоп | |
| RU2352339C2 (ru) | Способ лечения артралгии |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |