NO179312B - Anv. of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical composition, as well as the pharmaceutical. prep. - Google Patents
Anv. of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical composition, as well as the pharmaceutical. prep. Download PDFInfo
- Publication number
- NO179312B NO179312B NO920063A NO920063A NO179312B NO 179312 B NO179312 B NO 179312B NO 920063 A NO920063 A NO 920063A NO 920063 A NO920063 A NO 920063A NO 179312 B NO179312 B NO 179312B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- active ingredient
- methionine
- adenosyl
- group
- Prior art date
Links
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 title claims description 44
- 239000004480 active ingredient Substances 0.000 title claims description 28
- 150000003839 salts Chemical class 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 title claims description 10
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 title claims description 4
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 title description 34
- 229940105150 5-methyltetrahydrofolic acid Drugs 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 43
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 21
- 208000030507 AIDS Diseases 0.000 claims description 20
- 208000012902 Nervous system disease Diseases 0.000 claims description 20
- 208000025966 Neurological disease Diseases 0.000 claims description 13
- 230000000750 progressive effect Effects 0.000 claims description 11
- 206010012289 Dementia Diseases 0.000 claims description 8
- 206010003591 Ataxia Diseases 0.000 claims description 7
- 208000034800 Leukoencephalopathies Diseases 0.000 claims description 6
- 206010028570 Myelopathy Diseases 0.000 claims description 6
- -1 S-adenosyl-L-methionine salt Chemical class 0.000 claims description 6
- 206010014599 encephalitis Diseases 0.000 claims description 6
- 206010021639 Incontinence Diseases 0.000 claims description 5
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 5
- 206010033885 Paraparesis Diseases 0.000 claims description 5
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 5
- 208000018198 spasticity Diseases 0.000 claims description 5
- 208000027232 peripheral nervous system disease Diseases 0.000 claims description 4
- 235000007635 levomefolic acid Nutrition 0.000 description 33
- 239000011578 levomefolic acid Substances 0.000 description 33
- 235000019152 folic acid Nutrition 0.000 description 12
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 11
- 241000725303 Human immunodeficiency virus Species 0.000 description 10
- 210000003169 central nervous system Anatomy 0.000 description 10
- BMQYVXCPAOLZOK-UHFFFAOYSA-N Trihydroxypropylpterisin Natural products OCC(O)C(O)C1=CN=C2NC(N)=NC(=O)C2=N1 BMQYVXCPAOLZOK-UHFFFAOYSA-N 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 239000011724 folic acid Substances 0.000 description 9
- BMQYVXCPAOLZOK-XINAWCOVSA-N neopterin Chemical compound OC[C@@H](O)[C@@H](O)C1=CN=C2NC(N)=NC(=O)C2=N1 BMQYVXCPAOLZOK-XINAWCOVSA-N 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000007812 deficiency Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 229940014144 folate Drugs 0.000 description 6
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 6
- 230000000926 neurological effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000006872 improvement Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 4
- 208000016192 Demyelinating disease Diseases 0.000 description 4
- 206010012305 Demyelination Diseases 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 229960004452 methionine Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001755 vocal effect Effects 0.000 description 4
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 3
- 229960003237 betaine Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- 150000002224 folic acids Chemical class 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000003340 mental effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010060860 Neurological symptom Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000009593 lumbar puncture Methods 0.000 description 2
- 230000001343 mnemonic effect Effects 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 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
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- KVDQMARGGBLIJM-UHFFFAOYSA-N 6,7-dihydropteridine Chemical compound N1=CN=CC2=NCCN=C21 KVDQMARGGBLIJM-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 230000002407 ATP formation Effects 0.000 description 1
- 206010003084 Areflexia Diseases 0.000 description 1
- 208000031504 Asymptomatic Infections Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000014912 Central Nervous System Infections Diseases 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 206010015727 Extensor plantar response Diseases 0.000 description 1
- 206010016880 Folate deficiency Diseases 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000027626 Neurocognitive disease Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010049025 Persistent generalised lymphadenopathy Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- QWARKYOPJRNOOU-RLUFNZFXSA-N [(3s)-3-amino-3-carboxypropyl]-[[(2s,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl]-methylsulfanium;butane-1,4-disulfonate;butane-1,4-disulfonic acid Chemical compound OS(=O)(=O)CCCCS(O)(=O)=O.OS(=O)(=O)CCCCS(O)(=O)=O.[O-]S(=O)(=O)CCCCS([O-])(=O)=O.O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1.O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 QWARKYOPJRNOOU-RLUFNZFXSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960001570 ademetionine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000025222 central nervous system infectious disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000002987 choroid plexus Anatomy 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 208000016290 incoordination Diseases 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000006422 monoaminergic transmission Effects 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000010984 neurological examination Methods 0.000 description 1
- 210000002569 neuron Anatomy 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
- 229960002748 norepinephrine Drugs 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 201000003450 persistent generalized lymphadenopathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 108010064332 quinonoid dihydropterin reductase Proteins 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 229940046001 vitamin b complex Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører anvendelse av minst en forbindelse valgt fra gruppen omfattende et salt av S-adenosyl-L-metionin, 5-metyltetrahydrofolinsyre og 5-formyltetrahydrofolinsyre eller saltene derav som den aktive bestanddel til fremstilling av et farmasøytisk preparat for behandling av nevrologiske forstyrrelser i AIDS-pasienter. The present invention relates to the use of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolinic acid and 5-formyltetrahydrofolinic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical preparation for the treatment of neurological disorders in AIDS - patients.
Oppfinnelsen vedrører likeledes et farmasøytisk preparat inneholdende et salt av S-adenosyl-L-metionin i kombinasjon med 5-metyltetrahydrofolinsyre eller 5-formyltetrahydrofolinsyre som den aktive bestanddel. The invention likewise relates to a pharmaceutical preparation containing a salt of S-adenosyl-L-methionine in combination with 5-methyltetrahydrofolinic acid or 5-formyltetrahydrofolinic acid as the active ingredient.
Disse og andre trekk ved oppfinnelsen fremgår av patent-kravene. These and other features of the invention appear in the patent claims.
AIDS (Acquired Immunodeficiency Syndrome) er en overførbar infeksjonssykdom med høy dødelighet som hovedsakelig påvirker cellene i immunsystemet slik at individet er utsatt for risikoen for en rekke infeksjoner og visse typer tumorer. Viruset som er ansvarlig for AIDS, nemlig HIV (Human Immuno-def iciency Virus) er et retrovirus med elektiv tropisme for T-lymfocytter, særlig av fenotypen 0KT4/Leu 3 (hjelper/inducer), hvorfra det kan isoleres. AIDS (Acquired Immunodeficiency Syndrome) is a transmissible infectious disease with a high mortality rate which mainly affects the cells of the immune system so that the individual is exposed to the risk of a number of infections and certain types of tumours. The virus responsible for AIDS, namely HIV (Human Immuno-deficiency Virus) is a retrovirus with elective tropism for T-lymphocytes, particularly of the 0KT4/Leu 3 (helper/inducer) phenotype, from which it can be isolated.
En praktisk talt konstant hendelse hos individer som er infisert med HIV er involveringen av sentralnervesystemet (CNS), som kommer til uttrykk ved demyelinisering, i form av multifokal progressiv leukoencefalopati, med en rekke symptomer som strekker seg fra lette psykiske forstyrrelser til et klart nevrologisk syndrom. A virtually constant event in individuals infected with HIV is the involvement of the central nervous system (CNS), manifested by demyelination, in the form of multifocal progressive leukoencephalopathy, with a range of symptoms ranging from mild mental disturbances to a clear neurological syndrome .
Omtrent 10 % av AIDS-pasienter viser alvorlige nevrologiske symptomer (afasi, ataksi og arefleksi helt til motorisk ukoordinering med paralyse og tap av lukkemuskelkontroll), og i 75 % av tilfellene viser obduksjon tydelige tegn på involvering av nervesystemet. I 62 % av de HIV-positive individer er det beskrevet organiske mentale forstyrrelser som fører til forandring av de kognitive funksjoner og til dementi, men så mange som 83 % har forstyrrelser i sinnsstemning (depresjon). About 10% of AIDS patients show severe neurological symptoms (aphasia, ataxia and areflexia up to motor incoordination with paralysis and loss of sphincter control), and in 75% of cases autopsy shows clear signs of involvement of the nervous system. In 62% of the HIV-positive individuals, organic mental disturbances have been described which lead to changes in cognitive functions and to dementia, but as many as 83% have disturbances in mood (depression).
I litteraturen er det rapportert at HIV-positive individer med ledsagende nevrologiske komplikasjoner kan utvise 5-metyltetrahydrof olat (MTHF) og S-adenosylmetionin (SAMe) mangel. Disse pasienter utviser særlig en redusert konsentrasjon av totale folater, av SAMe og metionin, og en økning i neopterin-nivåer i cerebrospinalfluidet. In the literature, it has been reported that HIV-positive individuals with accompanying neurological complications may exhibit 5-methyltetrahydrofolate (MTHF) and S-adenosylmethionine (SAMe) deficiency. In particular, these patients show a reduced concentration of total folates, of SAMe and methionine, and an increase in neopterin levels in the cerebrospinal fluid.
På grunnlag av disse data er det foreslått at en endring i metabolismen av transmetylerende forbindelser er grunnlaget for den nevrologiske forstyrrelse hos disse individer. Dette vil faktisk føre til multifokal og perivenulær demyelinisering av sentralnervesystemet. Disse er skader som er helt like dem som er forårsaket av vitamin Bl2-mangel (E.G. Lever et al., On the basis of these data, it has been proposed that a change in the metabolism of transmethylating compounds is the basis for the neurological disorder in these individuals. This will actually lead to multifocal and perivenular demyelination of the central nervous system. These are damages that are quite similar to those caused by vitamin Bl2 deficiency (E.G. Lever et al.,
J. Neurologi, Neurosurgery and Psychiatry, 49: 1203-1207, 1986) . To metabolske mekanismer med indirekte toksisitet vil være involvert: 1) Mikrofagene som stimuleres vedvarende ved x-interferonet indusert ved virusinfeksjon syntetiserer store mengder dihydropteridin. Ved å virke som en "antifolic" er denne substans i stand til å inhibere de metabolske spor som fører til syntesen av MTHF og følgelig SAMe (MTHF er den fysiolog-iske forløper til SAMe i sentralnervesystemet) (R. Surtees et al., The Lancet, vol 335, mars 1990). 2) I tillegg, idet folatkatabolisme skjer ved kjemisk oksydasjon, vil folatmangel i cerebrospinal-fluidet også kunne følge av økt oksidativ aktivitet (I. Smith et al., The Lancet, 25. juli 1987). J. Neurology, Neurosurgery and Psychiatry, 49: 1203-1207, 1986). Two metabolic mechanisms with indirect toxicity will be involved: 1) The microphages that are continuously stimulated by the x-interferon induced by viral infection synthesize large amounts of dihydropteridine. By acting as an "antifolic", this substance is capable of inhibiting the metabolic tracks that lead to the synthesis of MTHF and consequently SAMe (MTHF is the physiological precursor to SAMe in the central nervous system) (R. Surtees et al., The Lancet, vol 335, March 1990). 2) In addition, since folate catabolism occurs by chemical oxidation, folate deficiency in the cerebrospinal fluid could also result from increased oxidative activity (I. Smith et al., The Lancet, 25 July 1987).
Disse data foreslår at folat (MTHF) og SAMe-mangel kan være en årsak til nevrologisk degenerering i AIDS-pasienter. Tilførsel av metionin og betain er foreslått for å korrigere denne metabolske mangel (The Lancet, mars 1990). Nevrologiske forstyrrelser som behandles i henhold til EP-A-388827 med metyltetrahydrofolinsyre (MTHF) eller med formyltetrahydrofolinsyre (FTHF), som senil og presenil primær degenerativ demens av Alzheimer type med depresjon og multi-infarkt demens med depresjon, med andre ord patologier som er typisk for eldre mennesker og som alltid ledsages av depresjon, er forskjellige fra og kan på ingen måte sammenlignes med de nevrologiske forstyrrelser som forefinnes hos AIDS-pasienter, nemlig subakutt encefalitt assosiert med demens, vakuolær myelopati med progressiv paraparese, ataksi, spastisitet og inkontinens, multifokal progressiv leukoencefalopati, perifere nevropartier. Dette bekreftes også ved det faktum at det i henhold til EP-A-388827 kun er nødvendig å administrere MTHF eller FTHF i form av farmasøytiske preparater med kontrollert frigivelse. I motsetning til dette og i henhold til den foreliggende oppfinnelse er det ikke avgjørende å administrere MTHF og FTHF på en form med kontrollert frigivelse. These data suggest that folate (MTHF) and SAMe deficiency may be a cause of neurological degeneration in AIDS patients. Supply of methionine and betaine has been suggested to correct this metabolic deficiency (The Lancet, March 1990). Neurological disorders treated according to EP-A-388827 with methyltetrahydrofolinic acid (MTHF) or with formyltetrahydrofolinic acid (FTHF), such as senile and presenile primary degenerative dementia of the Alzheimer type with depression and multi-infarct dementia with depression, in other words pathologies which are typical of elderly people and always accompanied by depression, are different from and in no way comparable to the neurological disorders found in AIDS patients, namely subacute encephalitis associated with dementia, vacuolar myelopathy with progressive paraparesis, ataxia, spasticity and incontinence, multifocal progressive leukoencephalopathy, peripheral neuropathies. This is also confirmed by the fact that according to EP-A-388827 it is only necessary to administer MTHF or FTHF in the form of pharmaceutical preparations with controlled release. In contrast and according to the present invention, it is not essential to administer MTHF and FTHF in a controlled release form.
Det skal videre bemerkes at SAMe og saltene derav, når de anvendes i henhold til DE off. skr. 40 05 275 som antivirus midler mot retroviruser og spesielt mot HIV virus, har en virkningsmekanisme som er forskjellig fra mekanismen til SAMe som anvendt i overensstemmelse med den foreliggende oppfinnelse. It should further be noted that SAMe and its salts, when used according to DE off. skr. 40 05 275 as antiviral agents against retroviruses and especially against the HIV virus, have a mechanism of action which is different from the mechanism of SAMe as used in accordance with the present invention.
De såkalte nevrologiske forstyrrelser behandlet med SAMe og omtalt i norske patenter NO 161262, NO 153370 og NO 139523, m.a.o. depressive tilstander, søvnforstyrrelser og Parkinson's sykdom (for behandling av den sistnevnte nevrologiske forstyrrelse blir SAMe alltid administrert sammen med levodopa), er hel-t forskjellige fra de ovennevnte nevrologiske forstyrrelser som er typisk for AIDS-pasienter. The so-called neurological disorders treated with SAMe and discussed in Norwegian patents NO 161262, NO 153370 and NO 139523, m.a.o. depressive states, sleep disorders and Parkinson's disease (for the treatment of the latter neurological disorder, SAMe is always administered together with levodopa), are completely different from the above-mentioned neurological disorders that are typical for AIDS patients.
Man har nå funnet at tilførsel av metionin og betain i doser på 6 g/dag i 14 dager ikke var i stand til å øke MTHF- og SAMe-nivåene betydelig i kroppsvæskene. Man fant spesielt at tilførsel av metionin og betain til 4 individer angrepet av AIDS og som hadde nevrologiske komplikasjoner, ikke ga forbedring i de nevrologiske kliniske symptomer, eller i modifikasjoner i de undersøkte parametere relatert til symptomatologien, eller i en økning i SAMe- og MTHF-nivåene i kroppsfluidene (tabell I). It has now been found that administration of methionine and betaine at doses of 6 g/day for 14 days was unable to significantly increase MTHF and SAMe levels in body fluids. In particular, it was found that the administration of methionine and betaine to 4 individuals attacked by AIDS and who had neurological complications did not produce an improvement in the neurological clinical symptoms, or in modifications in the investigated parameters related to the symptomatology, or in an increase in SAMe- and MTHF -the levels in the body fluids (table I).
Man har imidlertid overraskende funnet at tilførsel av MTHF og SAMe parenteralt eller oralt i minst 7 døgn gir en signifikant økning av verdien av disse forbindelsene i cerebrospinal-fluidet og følgelig i sentralnervesystemet. Det kliniske forsøk som er angitt i det etterfølgende har klart vist at behandling med MTHF (eller FTHF) og SAMe i en gruppe på 2 0 HIV-positive individer er forbundet med generell klinisk forbedring, positive modifikasjoner av de undersøkte nevrologiske parametere og en signifikant økning av SAMe og MTHF i cerebrospinalfluidet. However, it has surprisingly been found that administration of MTHF and SAMe parenterally or orally for at least 7 days results in a significant increase in the value of these compounds in the cerebrospinal fluid and consequently in the central nervous system. The clinical trial described below has clearly shown that treatment with MTHF (or FTHF) and SAMe in a group of 20 HIV-positive individuals is associated with general clinical improvement, positive modifications of the examined neurological parameters and a significant increase of SAMe and MTHF in the cerebrospinal fluid.
For gi en bedre forståelse og for enkelhets skyld vil betegnelsen "5-metyltetrahydrofolinsyre" henholdsvis "MTHF" i den foreliggende beskrivelse referere til forbindelser med følgende kjemiske betegnelse: (±)L-5-metyl-5,6,7,8-tetrahydrofolinsyre, og (-)L-5-metyl-5,6,7,8-tetrahydrofolinsyre, og deres salter, mens betegnelsen 5-formyltetrahydrofolinsyre og forkortelsen FTHF refererer til forbindelser med følgende kjemiske navn: (±)L-5-formyl-5,6,7,8-tetrahydrofolinsyre og (-)L-5-formyl-5,6,7,8-tetrahydrofolinsyre og deres salter. To give a better understanding and for the sake of simplicity, the term "5-methyltetrahydrofolinic acid" or "MTHF" in the present description will refer to compounds with the following chemical designation: (±)L-5-methyl-5,6,7,8-tetrahydrofolinic acid , and (-)L-5-methyl-5,6,7,8-tetrahydrofolinic acid, and their salts, while the designation 5-formyltetrahydrofolinic acid and the abbreviation FTHF refer to compounds with the following chemical names: (±)L-5-formyl- 5,6,7,8-tetrahydrofolinic acid and (-)L-5-formyl-5,6,7,8-tetrahydrofolinic acid and their salts.
Den foreliggende oppfinnelse vedrører således anvendelse av minst en forbindelse valgt fra gruppen omfattende et salt av The present invention thus relates to the use of at least one compound selected from the group comprising a salt of
S-adenosyl-L-metionin, 5-metyltetrahydrofolinsyre og 5-formyltetrahydrofolinsyre eller saltene derav som den aktive bestanddel til fremstilling av et farmasøytisk preparat for behandling av nevrologiske forstyrrelser i AIDS-pasienter valgt fra gruppen av subakutt encefalitt assosiert med demens, vakuolær myelopati med progressiv paraparese, ataksi, spastisitet og inkontinens, multifokal progressiv leukoencefalopati og perifere nevropatier. S-adenosyl-L-methionine, 5-methyltetrahydrofolinic acid and 5-formyltetrahydrofolinic acid or their salts as the active ingredient for the preparation of a pharmaceutical preparation for the treatment of neurological disorders in AIDS patients selected from the group of subacute encephalitis associated with dementia, vacuolar myelopathy with progressive paraparesis, ataxia, spasticity and incontinence, multifocal progressive leukoencephalopathy and peripheral neuropathies.
Oppfinnelsen vedrører også et farmasøytisk preparat inneholdende et salt av S-adenosyl-L-metionin i kombinasjon med 5-metyltetrahydrofolinsyre eller 5-formyltetrahydrofolinsyre som den aktive bestanddel som er kjennetegnet ved at vektforholdet S-adenosyl-L-metioninsalt/5-metyltetrahydrofolinsyre eller S-adenosyl-L-metioninsalt/5-formyltetrahydrofolinsyre er mellom 10/1 og 4/1. The invention also relates to a pharmaceutical preparation containing a salt of S-adenosyl-L-methionine in combination with 5-methyltetrahydrofolinic acid or 5-formyltetrahydrofolinic acid as the active ingredient which is characterized by the fact that the weight ratio S-adenosyl-L-methionine salt/5-methyltetrahydrofolinic acid or S -adenosyl-L-methionine salt/5-formyltetrahydrofolinic acid is between 10/1 and 4/1.
Det farmasøytiske preparat kan også inneholde passende farmasøytisk tålbare hjelpestoffer. The pharmaceutical preparation may also contain suitable pharmaceutically acceptable excipients.
Det farmasøytiske preparat i henhold til oppfinnelsen er særlig aktivt for behandling av subakutt encefalitt assosiert med demens og av vakuolær myelopati assosiert med nevrologiske forstyrrelser som ofte forekommer ved infeksjon med HIV (Human Immunodeficiency Virus). Til nå er der ingen tilgjengelig effektiv behandling i terapi av nevrologiske komplikasjoner som oppstår i forbindelse med AIDS. 5-metyltetrahydrofolinsyre, -5-formyltetrahydrofolinsyre og deres salter er en gruppe substanser som hører til vitamin B komplekset, strukturelt relatert til pteroyl-glutaminsyre (folinsyre). Denne syre syntetiseres ikke av pattedyrceller og er av særlig biologisk viktighet. Den intervenerer i en rekke kjemiske reaksjoner i forbindelse med overføring av monokarbongrupper, og særlig i syntesen av purinringen, av tymidylat og i neogenesen av metylgrupper. The pharmaceutical preparation according to the invention is particularly active for the treatment of subacute encephalitis associated with dementia and of vacuolar myelopathy associated with neurological disorders which often occur with infection with HIV (Human Immunodeficiency Virus). Until now, there is no effective treatment available in the therapy of neurological complications arising in connection with AIDS. 5-methyltetrahydrofolinic acid, -5-formyltetrahydrofolinic acid and their salts are a group of substances belonging to the vitamin B complex, structurally related to pteroyl-glutamic acid (folinic acid). This acid is not synthesized by mammalian cells and is of particular biological importance. It intervenes in a number of chemical reactions in connection with the transfer of monocarbon groups, and particularly in the synthesis of the purine ring, of thymidylate and in the neogenesis of methyl groups.
I blodsirkulasjonen er folat for det meste representert ved MTHF-syren, men også ved FTHF. MTHF representerer den viktigste transportformen av folater i blodet. Den passerer fra blodet til fluidet i plexus choroidei, og deretter ved passiv diffusjon inn i vev og nerveceller. I sentralnervesystemet deltar folatene og særlig MTHF i fundamentale bio-kjemiske prosesser ved å intervenere i syntesen av S-adenosyl-L-metionin (SAMe), i metabolismen av bestemte aminosyrer (glycin, serin, glutaminsyre), i modulerende aktivitet av de monoaminergiske transmisjonssystemer (noradrenalin, serotonin, dopamin), i nukleinsyresyntese og i produksjon av ATP og GTP. In the blood circulation, folate is mostly represented by the MTHF acid, but also by FTHF. MTHF represents the most important transport form of folates in the blood. It passes from the blood to the fluid in the choroid plexus, and then by passive diffusion into tissues and nerve cells. In the central nervous system, folates and especially MTHF participate in fundamental biochemical processes by intervening in the synthesis of S-adenosyl-L-methionine (SAMe), in the metabolism of specific amino acids (glycine, serine, glutamic acid), in modulating activity of the monoaminergic transmission systems (noradrenaline, serotonin, dopamine), in nucleic acid synthesis and in the production of ATP and GTP.
Den terapeutiske anvendelse av folinsyre og dens kofaktorer har til nå vært begrenset til forebygging og behandling av mangler av dette vitamin, dvs. til behandling av hypofola-temiske individer. The therapeutic use of folic acid and its cofactors has until now been limited to the prevention and treatment of deficiencies of this vitamin, i.e. to the treatment of hypofolateemic individuals.
I forbindelse med den foreliggende oppfinnelse muliggjøres effektiv terapi av nevrologiske forstyrrelser relatert til sykdommen AIDS ved tilveiebringelse av farmasøytiske preparater som er klinisk effektive i forbindelse med terapi av slike forstyrrelser og som ikke har bivirkninger. Man har nå funnet at oral eller parenteral tilførsel av farmasøytiske preparater inneholdende, som aktivt substans minst en forbindelse valgt fra gruppen bestående av S-adenosyl-L-metioninsalt, 5-metyl-tetrahydrofolinsyre og 5-formyltetrahydrofolinsyre eller deres salter sammen med passende farmasøytisk tålbare hjelpestoffer viser uventet farmakologisk aktivitet når de anvendes for behandling av individer med AIDS-relaterte nevrologiske forstyrrelser. For SAMe kan ethvert av dennes stabile salter anvendes, og særlig dem som er beskrevet i søkernes tidligere italienske patentsøknader med nummer 1.022.016, 1.043.885, 1.054.175, 1.137.640, 1.137.892, 1.169.772, 1.169.773, 1.169.774, 1.173.990, 1.173.991 og 1.173.992. In connection with the present invention, effective therapy of neurological disorders related to the disease AIDS is made possible by providing pharmaceutical preparations which are clinically effective in connection with the therapy of such disorders and which do not have side effects. It has now been found that oral or parenteral administration of pharmaceutical preparations containing, as active substance, at least one compound selected from the group consisting of S-adenosyl-L-methionine salt, 5-methyl-tetrahydrofolinic acid and 5-formyltetrahydrofolinic acid or their salts together with suitable pharmaceutically acceptable adjuvants show unexpected pharmacological activity when used to treat individuals with AIDS-related neurological disorders. For SAMe, any of its stable salts can be used, and in particular those described in the applicants' previous Italian patent applications with numbers 1,022,016, 1,043,885, 1,054,175, 1,137,640, 1,137,892, 1,169,772, 1,169,773 , 1,169,774, 1,173,990, 1,173,991 and 1,173,992.
De tre aktive substanser kan tilføres sammen eller separat. The three active substances can be added together or separately.
Dosen som anvendes er mellom 2 0 og 200 mg/dag og foretrukket 50 mg/dag for MTHF (eller FTHF) og mellom 100 og 2000 mg/dag og foretrukket 400 mg/dag for SAMe. Fra kliniske forsøk er det i tillegg funnet at de beste resultater oppnås med et SAMe/MTHF (eller FTHF) vektforhold mellom 10/1 og 4/1, foretrukket omtrent 8/1. The dose used is between 20 and 200 mg/day and preferably 50 mg/day for MTHF (or FTHF) and between 100 and 2000 mg/day and preferably 400 mg/day for SAMe. From clinical trials, it has additionally been found that the best results are obtained with a SAMe/MTHF (or FTHF) weight ratio between 10/1 and 4/1, preferably about 8/1.
De nevrologiske forstyrrelser under AIDS-forløpet kan være sekundære til en patogen skade av infeksiøs natur, eller primært involvere sentralnervesystemet ved en etiopatogen mekanisme som fremdeles ikke er spesielt godt kjent. The neurological disturbances during the course of AIDS may be secondary to a pathogenic injury of an infectious nature, or primarily involve the central nervous system by an etiopathogenic mechanism which is still not particularly well known.
I dette andre tilfellet er pasientene rammet av: In this second case, the patients are affected by:
1) subakutt encefalitt assosiert med demens (se kode 2 94.10, Axis I, organiske mentale forstyrrelser assosiert med fysiske forstyrrelser, se Axis III, eller for hvilke etiologien er ukjent, i overensstemmelse med kriteriene inneholdt i the Diagnostic and Statistical Manual of Mental Disorders, 3. utgave, publisert av the American Psychiatric Association i 1987) 2) vakuolær myelopati med progressiv paraparese, ataksi, spastisitet og inkontinens 1) subacute encephalitis associated with dementia (see code 2 94.10, Axis I, organic mental disorders associated with physical disorders, see Axis III, or for which the etiology is unknown, in accordance with the criteria contained in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, published by the American Psychiatric Association in 1987) 2) vacuolar myelopathy with progressive paraparesis, ataxia, spasticity and incontinence
3) multifokal progressiv leukoencefalopati 3) multifocal progressive leukoencephalopathy
4) perifer nevropati. 4) peripheral neuropathy.
I forbindelse med punktene 1, 2, 3 og 4 er der særlig en assosiert konstant reduksjon av forbindelsene som er essen-sielle for metabolismen av myelinstrukturene (MTHF og SAMe) i cefalorachidian-fluidet, med perivenulær og multifokal demyel-inisering av sentralnervesystemet som en følge derav. In connection with points 1, 2, 3 and 4, there is in particular an associated constant reduction of the compounds essential for the metabolism of the myelin structures (MTHF and SAMe) in the cephalorachidian fluid, with perivenular and multifocal demyelination of the central nervous system as a follow from it.
På grunnlag av en rekke allerede publiserte data er det ingen tvil om den terapeutiske effektiviteten av MTHF og FTHF og deres farmakologiske tålbare salter i pasienter med spesifikke genetiske metabolske feil, som mangel på 5,10-tetrahydrofolat og dihydropterinreduktase, som er assosiert med demyelinisering av sentralnervesystemet og mental retardasjon (R. Surtees et al., The Lancet, vol. 335, mars 1990). Egenskapene og fordelene ved den foreliggende oppfinnelse vil fremkomme klarere ut fra beskrivelsen av et signifikant klinisk forsøk som er valgt fra forsøk gjennomført ved anvendelse av preparatene i henhold til oppfinnelsen. On the basis of a number of already published data, there is no doubt about the therapeutic effectiveness of MTHF and FTHF and their pharmacologically tolerated salts in patients with specific genetic metabolic defects, such as deficiency of 5,10-tetrahydrofolate and dihydropterin reductase, which are associated with demyelination of the central nervous system and mental retardation (R. Surtees et al., The Lancet, vol. 335, March 1990). The properties and advantages of the present invention will appear more clearly from the description of a significant clinical trial which has been selected from trials carried out using the preparations according to the invention.
Eksperimentell del Experimental part
Formålet med det kliniske forsøk som er angitt i det etter-følgende ved anvendelse av en dobbel blindprøvemetode med placebokontroller, var å bekrefte de terapeutiske virkninger, 1 forbindelse med tilførsel av MTHF og FTHF, ved kliniske utslag og ved MTHF, SAMe og neopterin fluidkonsentrasjonen i AIDS-pasienter med nevrologiske komplikasjoner. 2 0 sykehuspasienter deltok idet disse var av begge kjønn og hadde en alder mellom 24 og 41 år (gjennomsnittlig alder 30,5) og hvor sykdommen AIDS var diagnostisert i henhold til definisjonen fra the Center for Disease Control, Atlanta, USA (Revision of the case definitions of acquired immunodeficiency syndrome for national reporting - United States Morbidity and Mortality Weekly Report 34:373-75, 1985). I henhold til denne definisjonen hørte pasientene til gruppen IV, undergruppe B (tabell II). Alle pasienter hadde vist klare kliniske tegn og symptomer på at sentralnervesystemet var involvert i minst 1 måned. De kliniske og demografiske egenskaper hos de 2 0 pasienter ved begynnelsen av undersøkelsen er vist i tabell III. Ingen av pasientene var under behandling med antivirus-midler, antibiotika og/eller sulfamid og immunomodulerende medikamenter ved begynnelsen av studiet. The purpose of the clinical trial stated below, using a double blind test method with placebo controls, was to confirm the therapeutic effects, 1 in connection with the administration of MTHF and FTHF, by clinical results and by the MTHF, SAMe and neopterin fluid concentration in AIDS patients with neurological complications. 20 hospital patients participated as they were of both sexes and had an age between 24 and 41 years (average age 30.5) and where the disease AIDS was diagnosed according to the definition from the Center for Disease Control, Atlanta, USA (Revision of the case definitions of acquired immunodeficiency syndrome for national reporting - United States Morbidity and Mortality Weekly Report 34:373-75, 1985). According to this definition, the patients belonged to group IV, subgroup B (Table II). All patients had shown clear clinical signs and symptoms of central nervous system involvement for at least 1 month. The clinical and demographic characteristics of the 20 patients at the beginning of the study are shown in Table III. None of the patients were being treated with antiviral agents, antibiotics and/or sulfamide and immunomodulating drugs at the beginning of the study.
Ved begynnelsen av det kliniske forsøk ble pasientene underkastet lumbarpunktur for å utelukke tilstedeværelsen av infeksjoner i sentralnervesystemet og/eller for å komplettere diagnosen. Ved samme anledning ble SAMe, MTHF og neopterin-konsentrasjonene i fluidet bestemt ved hjelp av HPLC. De opp-nådde verdier ble sammenlignet med verdiene for en referanse-populasjon av voksne individer underkastet lumbalpunktur-diagnose for andre nevrologiske sykdommer som ikke er relatert til endringer i neopterinmetabolismen eller av transmetyl-eringsprosessene. At the start of the clinical trial, patients underwent lumbar puncture to rule out the presence of central nervous system infections and/or to complete the diagnosis. On the same occasion, the SAMe, MTHF and neopterin concentrations in the fluid were determined using HPLC. The values obtained were compared with the values for a reference population of adult individuals subjected to lumbar puncture diagnosis for other neurological diseases not related to changes in neopterin metabolism or transmethylation processes.
Folatfluidkonsentrasjonen i 20 HIV-positive pasienter ble undersøkt og det ble funnet at nivåene av 5-MTHF og SAMe var lave mens neopterinfluidnivåene var høye i forhold til referansepopulasjonen (tabell IV). The folate fluid concentration in 20 HIV-positive patients was investigated and it was found that the levels of 5-MTHF and SAMe were low while the neopterin fluid levels were high compared to the reference population (Table IV).
TABELL II TABLE II
KLASSIFISERINGSSYSTEM FOR HIV-INFEKSJON CLASSIFICATION SYSTEM FOR HIV INFECTION
Gruppe I Akutt infeksjon Group I Acute infection
Gruppe II Asymtomatisk infeksjon Group II Asymptomatic infection
Gruppe III Vedvarende generalisert lymfoadenopati Group III Persistent generalized lymphadenopathy
Gruppe IV Andre sykdommer Group IV Other diseases
Undergruppe A Konstitusjonelle sykdommer Subgroup A Constitutional diseases
Undergruppe B Nevrologiske sykdommer Subgroup B Neurological diseases
Undergruppe C Sekundære infeksjonssykdommer Subgroup C Secondary infectious diseases
Kategori C-l Spesifikke sekundære infeksjonssykdommer Category C-l Specific secondary infectious diseases
som er angitt i the Center for Disease Control Surveillance Definition for AIDS as stated in the Center for Disease Control Surveillance Definition for AIDS
Kategori C-2 Andre spesifikke sekundære infeksjonssykdommer Undergruppe D Sekundære tumorer Category C-2 Other specific secondary infectious diseases Subgroup D Secondary tumors
Undergruppe E Andre tilstander. Subgroup E Other conditions.
Gruppe 1: pasienter 1, 2, 5, 8. Gruppe 2: pasienter 3, 4, 6, 7. Gruppe 3: pasienter 10, 11, 12, 15. Gruppe 4: pasienter 9, 13, 14, 16. Gruppe 5: pasienter 17, 18, 19, 20. Group 1: patients 1, 2, 5, 8. Group 2: patients 3, 4, 6, 7. Group 3: patients 10, 11, 12, 15. Group 4: patients 9, 13, 14, 16. Group 5 : patients 17, 18, 19, 20.
Referansepopulasi on Reference population on
Pasientene ble tilfeldig fordelt i 5 grupper for behandling som varte i 4 uker: gruppe 1 pasienter mottok SAMe 1,4-butan-disulfonat i en dose på 5-10 mg/kg/dag intravenøst pluss MTHF i en dose på 0,5-1 mg/kg/dag. Gruppe 2 pasienter mottok placebo, som ikke kan skjelnes, ved samme tilførselsmetode som SAMe og MTHF. Gruppe 3 pasienter mottok MTHF, gruppe 4 pasienter mottok SAMe i samme dose som anvendt for behandlingen i forbindelse med gruppe 5 pasienter som mottok FTHF. Patients were randomly divided into 5 groups for treatment lasting 4 weeks: group 1 patients received SAMe 1,4-butane disulfonate at a dose of 5-10 mg/kg/day intravenously plus MTHF at a dose of 0.5- 1 mg/kg/day. Group 2 patients received placebo, indistinguishable, by the same delivery method as SAMe and MTHF. Group 3 patients received MTHF, group 4 patients received SAMe in the same dose as used for the treatment in connection with group 5 patients who received FTHF.
Biokjemisk evaluering ble gjennomført på begynnelsen og slutten av studiet. Etter 4 uker med behandling ble folat og neopterin-nivåene i cefalorachidian-fluidet målt (tabell IV). Statistisk behandling viste at SAMe og MTHF-verdiene var økt signifikant og neopterin-verdiene var avtatt i pasientene 1, 2, 5, 8, 10, 11, 12, 15, 17, 18, 19 og 20 (gruppene 1, 3 og 5). Pasientene 9, 13, 14 og 16 (gruppe 4) viste en signifikant økning i SAME-nivåene og en reduksjon i neopterinfluidnivåene men ingen signifikant økning i MTHF-verdiene sammenlignet med de andre gruppene. Pasientene 3, 4, 6 og 7 (gruppe 2) viste ingen signifikant variasjon i verdiene for folat, SAMe eller neopterin i cefalorachidian-fluidet sammenlignet med de andre gruppene (fig. 1, 2). Biochemical evaluation was carried out at the beginning and end of the study. After 4 weeks of treatment, folate and neopterin levels in the cephalorachidian fluid were measured (Table IV). Statistical treatment showed that the SAMe and MTHF values were significantly increased and the neopterin values were decreased in patients 1, 2, 5, 8, 10, 11, 12, 15, 17, 18, 19 and 20 (groups 1, 3 and 5 ). Patients 9, 13, 14 and 16 (group 4) showed a significant increase in SAME levels and a decrease in neopterin fluid levels but no significant increase in MTHF values compared to the other groups. Patients 3, 4, 6 and 7 (group 2) showed no significant variation in the values for folate, SAMe or neopterin in the cephalorachidian fluid compared to the other groups (Figs. 1, 2).
Bestemte skalaer foreslått for å undersøke opptreden og mentale funksjoner ble anvendt for å evaluere psykiske symptomer. Evalueringen av nevrologiske symptomer er basert på en klinisk evaluering som ble gjennomført ved starten av behandlingen (T0) og deretter periodisk hver uke (Tlx T2, T3 og T4). Certain scales proposed to examine behavior and mental functions were used to evaluate psychological symptoms. The evaluation of neurological symptoms is based on a clinical evaluation that was carried out at the start of treatment (T0) and then periodically every week (Tlx T2, T3 and T4).
De følgende skalaer ble spesielt benyttet: The following scales were used in particular:
1) Wechsler Adult Intelligence Scale (WAIS) 1) Wechsler Adult Intelligence Scale (WAIS)
2) Digit Span (Wechsler Adult Intelligence Scale Manual, Psychological Corporation, New York 1955), som består av en frem- og tilbake repetisjon av nummersekvenser av økende lengde lest for pasienten av den som behandler. 2) Digit Span (Wechsler Adult Intelligence Scale Manual, Psychological Corporation, New York 1955), which consists of a back and forth repetition of number sequences of increasing length read to the patient by the therapist.
Det etterfølgende ble også evaluert som parametere for spesifikk nevrologisk forstyrrelse: The following were also evaluated as parameters for specific neurological disorder:
a) babinski refleks a) babinski reflex
b) overfladisk og "profundus" sensitivitetsforstyrrelser. b) superficial and "profundus" sensitivity disorders.
Disse tester ble gjennomført før behandlingen (T0) og etter These tests were carried out before the treatment (T0) and after
behandlingen (T4) . the treatment (T4) .
De psykometriske tester viste generell reduksjon av intellek-tuell, mnemisk og verbal kapasitet omfattende alvorlig reduksjon av kortidsminne hos de 20 pasientene før studiet. The psychometric tests showed a general reduction of intellectual, mnemonic and verbal capacity including severe reduction of short-term memory in the 20 patients before the study.
W.A.I.S. gjennomsnittlig verdi for de 20 pasientene som ble undersøkt var: W.A.I.S. the average value for the 20 patients examined was:
verbal: 84 verbal: 84
opptreden: 89 appearance: 89
totalt: 85 total: 85
Innen den første behandlingsuken viste pasientene i gruppene 1, 3, 4 og 5 en markert bedre sinnsstemning og en forbedret mnemisk kapasitet og bedre oppmerksomhet. I løpet av to ukers behandling viste den nevrologiske undersøkelse en forbedring i pyramidal svakhet og en reduksjon i patologiske reflekser. Ved tiden T4 var W.A.I.S. gjennomsnittsverdiene for gruppene 1, 3, 4 og 5: Within the first week of treatment, the patients in groups 1, 3, 4 and 5 showed a markedly better mood and an improved mnemonic capacity and better attention. During two weeks of treatment, the neurological examination showed an improvement in pyramidal weakness and a reduction in pathological reflexes. By the time T4 was W.A.I.S. the average values for groups 1, 3, 4 and 5:
verbal 104 (+20) verbal 104 (+20)
opptreden: 98 (+9) appearance: 98 (+9)
totalt: 102 (+18) total: 102 (+18)
I motsetning til dette viste gruppe 2 (placebo) ingen signifikant forbedring i W.A.I.S. verdiene, idet gjennom-snittet var som følger: In contrast, group 2 (placebo) showed no significant improvement in the W.A.I.S. the values, the average being as follows:
verbal: 83 verbal: 83
opptreden: 88 appearance: 88
totalt: 84 total: 84
Det ble likeledes ikke målt signifikante modifikasjoner i nevrologisk symptomatologi for denne gruppen (tabell V). Likewise, no significant modifications in neurological symptomatology were measured for this group (table V).
Resultater Results
De psykometriske tester som inkluderer W.A.I.S. viste statistisk signifikante forbedringer i gruppene 1, 3, 4 og 5 ved effekten av behandlingen med MTHF, FTHF og SAMe tilført sammen eller individuelt. Ved tidspunktene T3 og T4 viste spesielt W.A.I.S. testen, "the forward Digit Span" testen og "the backward Digit Span" testen en statistisk signifikant forskjell. The psychometric tests that include the W.A.I.S. showed statistically significant improvements in groups 1, 3, 4 and 5 in the effect of the treatment with MTHF, FTHF and SAMe administered together or individually. At times T3 and T4, W.A.I.S. in particular showed test, "the forward Digit Span" test and "the backward Digit Span" test a statistically significant difference.
I motsetning til dette viste gruppen av pasienter som var behandlet med placebo (gruppe 2) ingen modifikasjon av noe slag. Toleranse under behandling var god for nærmest alle pasientene unntatt for et individ i gruppe 1 (pasient 2) som klaget over lett kvalme under de første dagene med behandling. Denne tilstand ble løst spontant og forsvant senere selv om tilførsel av medikamentet fortsatte. In contrast, the group of patients treated with placebo (group 2) showed no modification of any kind. Tolerance during treatment was good for almost all patients except for one individual in group 1 (patient 2) who complained of slight nausea during the first days of treatment. This condition resolved spontaneously and later disappeared even though administration of the drug continued.
Tabell VI viser den totale bedømmelse av effektiviteten av behandlingen ved tidspunktene Tx, T2 og T4, som uttrykt av den praktiserende lege som gjennomførte terapien. Ved utforming av denne bedømmelse tok den praktiserende lege også hensyn til indikasjonene fra pasientens slektninger og fra førstehjelps-personalet . Antall positive responser overfor behandlingen med MTHF og SAMe som enten ble anvendt sammen for terapi eller hver for seg, ble funnet til å være statistisk signifikant allerede ved T2 og økte videre ved T4 (68 % positive responser til behandlingen). Table VI shows the overall assessment of the effectiveness of the treatment at the time points Tx, T2 and T4, as expressed by the practitioner who carried out the therapy. When formulating this assessment, the practitioner also took into account the indications from the patient's relatives and from the first aid staff. The number of positive responses to the treatment with MTHF and SAMe, which were either used together for therapy or separately, was found to be statistically significant already at T2 and further increased at T4 (68% positive responses to the treatment).
De farmasøytiske preparater i henhold til oppfinnelsen som inneholder de tre produkter som aktive prinsipper, alene eller i blanding, også med farmasøytisk tålbare, faste eller flytende tilsetningsmidler og hjelpestoffer er passende for anvendelse i injiserbar eller oral form. Da kombinasjonen av de tre aktive prinsipper i en blanding generelt ikke er tilstrekkelig stabil over tid, er det tilrådelig at kombinasjonen fremstilles ekstemporært i anvendelsesøyeblikket ut fra farmasøytiske preparater av de individuelle aktive bestanddeler. De tre separate aktive bestanddeler kan også tilføres til pasienten enten samtidig eller med korte mellomrom. The pharmaceutical preparations according to the invention which contain the three products as active principles, alone or in mixture, also with pharmaceutically acceptable, solid or liquid additives and auxiliaries are suitable for use in injectable or oral form. As the combination of the three active principles in a mixture is generally not sufficiently stable over time, it is advisable that the combination be prepared extemporaneously at the time of use from pharmaceutical preparations of the individual active ingredients. The three separate active ingredients can also be administered to the patient either simultaneously or at short intervals.
De farmasøytiske preparater i henhold til oppfinnelsen kan være i form av et frysetørket rør til bruk sammen med et passende løsningsmiddel, frysetørkede flasker som også brukes sammen med passende oppløsningsmidler, injiserbare oppløsning-er, tabletter, piller, kapsler, kapsler med forlenget frigivelse, tabletter med forlenget frigivelse, gastroresistente tabletter, poser, ekstemporære siruper, siruper med forlenget frigivelse og andre former som normalt anvendes innen det farmasøytiske området, idet totalt innhold av aktiv bestanddel er mellom 2 0 og 2000 mg. The pharmaceutical preparations according to the invention can be in the form of a freeze-dried tube for use with a suitable solvent, freeze-dried bottles which are also used with suitable solvents, injectable solutions, tablets, pills, capsules, extended-release capsules, tablets with extended release, gastro-resistant tablets, bags, extemporaneous syrups, syrups with extended release and other forms normally used in the pharmaceutical field, the total content of active ingredient being between 20 and 2000 mg.
I de etterfølgende eksempler er det vist farmasøytiske preparater inneholdende de individuelle aktive bestanddeler SAMe, 5-MTHF og 5-FTHF som eventuelt kan blandes sammen ved tids-punktet for tilførselen til å gi blandingen av aktive bestanddeler. In the following examples, pharmaceutical preparations are shown containing the individual active ingredients SAMe, 5-MTHF and 5-FTHF which can optionally be mixed together at the time of administration to give the mixture of active ingredients.
EKSEMPEL 1 EXAMPLE 1
Injiserbare preparater som inneholder 2 00 mg SAMe som aktiv bestanddel. Injectable preparations containing 200 mg SAMe as active ingredient.
A) En flaske inneholder: A) One bottle contains:
EKSEMPEL 2 EXAMPLE 2
Injiserbare preparater som inneholder 400 mg SAMe som aktiv bestanddel. Injectable preparations containing 400 mg SAMe as active ingredient.
A) En flaske inneholder: A) One bottle contains:
EKSEMPEL 3 EXAMPLE 3
Injiserbare preparater som inneholder 50 mg 5-metyl-tetrahydrofolinsyre som aktiv bestanddel. Injectable preparations containing 50 mg of 5-methyl-tetrahydrofolinic acid as active ingredient.
A) En flaske inneholder: A) One bottle contains:
EKSEMPEL 4 EXAMPLE 4
Injiserbare preparater som inneholder 50 mg (±)L-5-formyl-5,6,7,8-tetrahydrofolinsyre (eller folinsyre) som aktiv bestanddel. Injectable preparations containing 50 mg (±)L-5-formyl-5,6,7,8-tetrahydrofolinic acid (or folic acid) as active ingredient.
A) En ampulle inneholder: A) One ampoule contains:
EKSEMPEL 5 EXAMPLE 5
Injiserbare preparater som inneholder 50 mg (-)L-5-formyl-5,6,7,8-tetrahydrofolinsyre som aktiv bestanddel. Injectable preparations containing 50 mg (-)L-5-formyl-5,6,7,8-tetrahydrofolinic acid as active ingredient.
A) En ampulle inneholder: A) One ampoule contains:
Orale preparater Oral preparations
EKSEMPEL 6 EXAMPLE 6
Orale preparater som inneholder 200 mg SAMe som aktiv bestanddel. Oral preparations containing 200 mg SAMe as active ingredient.
A) KJERNE: A) CORE:
EKSEMPEL 7 EXAMPLE 7
Oralt preparat som inneholder 400 mg SAMe som aktiv bestanddel. Oral preparation containing 400 mg SAMe as active ingredient.
A) KJERNE: A) CORE:
EKSEMPEL 8 EXAMPLE 8
Oralt preparat som inneholder 50 mg 5-metyl-tetrahydrofolinsyre som aktiv bestanddel. Oral preparation containing 50 mg of 5-methyl-tetrahydrofolinic acid as active ingredient.
A) KJERNE: A) CORE:
EKSEMPEL 9 EXAMPLE 9
Oralt preparat inneholdende 50 mg (±)L-5-formyl-5,6,7,8-tetrahydrofolinsyre. Oral preparation containing 50 mg (±)L-5-formyl-5,6,7,8-tetrahydrofolinic acid.
A) KJERNE: A) CORE:
EKSEMPEL 10 EXAMPLE 10
Oralt preparat som inneholder 50 mg metyltetrahydrofolinsyre som aktiv bestanddel. Oral preparation containing 50 mg methyltetrahydrofolinic acid as active ingredient.
A) KJERNE: A) CORE:
EKSEMPEL 11 EXAMPLE 11
Oralt preparat som inneholder 50 mg (-)L-5-formyl-5,6,7,8-tetrahydrofolinsyre som aktiv bestanddel. Oral preparation containing 50 mg (-)L-5-formyl-5,6,7,8-tetrahydrofolinic acid as active ingredient.
A) KJERNE: A) CORE:
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO920063A NO179312C (en) | 1992-01-06 | 1992-01-06 | Anv. of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical composition. as well as the pharmaceutical preparation. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO920063A NO179312C (en) | 1992-01-06 | 1992-01-06 | Anv. of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical composition. as well as the pharmaceutical preparation. |
Publications (4)
Publication Number | Publication Date |
---|---|
NO920063D0 NO920063D0 (en) | 1992-01-06 |
NO920063L NO920063L (en) | 1993-07-07 |
NO179312B true NO179312B (en) | 1996-06-10 |
NO179312C NO179312C (en) | 1996-09-18 |
Family
ID=19894755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO920063A NO179312C (en) | 1992-01-06 | 1992-01-06 | Anv. of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical composition. as well as the pharmaceutical preparation. |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO179312C (en) |
-
1992
- 1992-01-06 NO NO920063A patent/NO179312C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO920063L (en) | 1993-07-07 |
NO179312C (en) | 1996-09-18 |
NO920063D0 (en) | 1992-01-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6093703A (en) | Pharmaceutical compositions, containing S-adenosyl-L-methionine salt, 5-methyl-tetrahydrofolic acid and 5-formyltetrahydrofolic acid | |
EP0388827B1 (en) | Use of 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in the preparation of pharmaceutical compositions in controlled release form active in the therapy of organic mental disturbances, and the relative pharmaceutical compositions | |
Betts et al. | Human safety of lamotrigine | |
US11110104B2 (en) | Glutamine antagonists for the treatment of cognitive deficits and psychiatric disorders | |
Guilleminault et al. | HVA and 5HIAA CSF measurements and 5HTP trials in some patients with involuntary movements | |
CN105311033B (en) | Antiviral therapy | |
CA2339934C (en) | Medicine for multiple sclerosis | |
Looareesuwan et al. | Treatment of acute, uncomplicated, falciparum malaria with oral dihydroartemisinin | |
Pialoux et al. | Pharmacokinetics of R 82913 in patients with AIDS or AIDS-related complex | |
Stellar et al. | L-Dopa in the Treatment of Parkinsonism A Preliminary Appraisal | |
US5011841A (en) | Treatment of depression | |
NO179312B (en) | Anv. of at least one compound selected from the group comprising a salt of S-adenosyl-L-methionine, 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid or the salts thereof as the active ingredient for the preparation of a pharmaceutical composition, as well as the pharmaceutical. prep. | |
EP0362162B1 (en) | Pharmaceutical composition comprising zidovudine and inosiplex or components thereof for the treatment of aids and aids-related syndromes | |
Granerus et al. | CLINICAL ANALYSES OF FACTORS INFLUENCING L‐DOPA TREATMENT OF PARKINSON'S SYNDROME | |
US20220096486A1 (en) | Compounds for use in the treatment of adcy5-related dyskinesia | |
WO2018220457A1 (en) | Vitamin b1 in high doses for use in the medical treatment of motor symptoms of some sporadic neurodegenerative diseases, of genetic origin, and of cluster headache and of migraine headache | |
WO2019002542A1 (en) | Combination of a mps1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof | |
CN112294834B (en) | Application of decitabine in preparing medicament for treating herpes simplex virus | |
Storey et al. | Some considerations of cycloserine toxicity | |
US8927600B2 (en) | Compound for use in the treatment of peripheral neuropathies | |
Stein et al. | The man who turned bad | |
NO179602B (en) | Use of a NADH or NADPH in the preparation of an antidepressant | |
Collignon et al. | Neurological toxicity associated with vidarabine (adenine arabinoside) therapy | |
WO1993025203A1 (en) | Method of treating and protecting against central nervous system ischemia, hypoxia, degeneration, and trauma with a 5-aminocarbonyl-sh-dibenzo[a,d]cyclohepten-5,10-imine | |
CN112154151A (en) | Treatment or prevention of infection of Coronaviridae |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM1K | Lapsed by not paying the annual fees |