HRP940429A2 - New combination of active substances - Google Patents
New combination of active substances Download PDFInfo
- Publication number
- HRP940429A2 HRP940429A2 HRP4325435.7A HRP940429A HRP940429A2 HR P940429 A2 HRP940429 A2 HR P940429A2 HR P940429 A HRP940429 A HR P940429A HR P940429 A2 HRP940429 A2 HR P940429A2
- Authority
- HR
- Croatia
- Prior art keywords
- esupron
- levodopa
- active substances
- tablets
- new combination
- Prior art date
Links
- 239000013543 active substance Substances 0.000 title description 6
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 17
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 17
- 229960004502 levodopa Drugs 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 6
- 208000018737 Parkinson disease Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
- -1 carrageenates Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 210000003523 substantia nigra Anatomy 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- QEEXKPYVMOIPKR-UHFFFAOYSA-N 7-hydroxy-3,4-dimethylchromen-2-one Chemical compound C1=C(O)C=CC2=C1OC(=O)C(C)=C2C QEEXKPYVMOIPKR-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- HLKZFSVWBQSKKH-UHFFFAOYSA-N but-3-enoic acid;1-ethenylpyrrolidin-2-one Chemical compound OC(=O)CC=C.C=CN1CCCC1=O HLKZFSVWBQSKKH-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CHDGAVDQRSPBTA-UHFFFAOYSA-N esuprone Chemical compound CC1=C(C)C(=O)OC2=CC(OS(=O)(=O)CC)=CC=C21 CHDGAVDQRSPBTA-UHFFFAOYSA-N 0.000 description 1
- 229950007673 esuprone Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
Description
Ovaj izum odnosi se na jednu novu kombinaciju aktivnih tvari za liječenje poremećaja ekstrapiramidnih motoričkih sustava. This invention relates to a new combination of active substances for the treatment of extrapyramidal motor system disorders.
Esupron je ester etansulfonske kiseline i 7-hidroksi-3,4-dimetilkumarina: Esupron is an ester of ethanesulfonic acid and 7-hydroxy-3,4-dimethylcoumarin:
[image] [image]
Ova tvar poznata je kao aktivna tvar za farmakoterapiju psihičkih poremećaja, osobito kao antidepresiv (EP-PS 111 746). This substance is known as an active substance for the pharmacotherapy of mental disorders, especially as an antidepressant (EP-PS 111 746).
Levodopa je odavna poznata tvar (Merck Index, 11. Auflage, Nr. 5344), koja se upotrebljava kao sredstvo protiv Parkinsonove bolesti: Levodopa is a long-known substance (Merck Index, 11. Auflage, Nr. 5344), which is used as a means against Parkinson's disease:
[image] [image]
Sada je pronađeno da se kombinacijom obaju tvari može postići učinak koji se ne može objasniti zbrajanjem pojedinačnih učinaka. It has now been found that the combination of both substances can produce an effect that cannot be explained by the sum of the individual effects.
Predmet izuma su lijekovi koji sadrže Esupron i Levodopu. The subject of the invention are medicines containing Esupron and Levodopa.
Lijekovi mogu biti pripremljeni kao kombinirani pripremci za istovremenu primjenu u nepromjenjivoj kombinaciji ili odvojeno za istovremenu ili vremenski postupnu primjenu. Medicines can be prepared as combined preparations for simultaneous administration in an unchanging combination or separately for simultaneous or time-gradual administration.
Kombinacije su vrlo prikladne za liječenje poremećaja ekstrapiramidnog motoričkog sustava, osobito Parkinsonove bolesti. Combinations are very suitable for the treatment of disorders of the extrapyramidal motor system, especially Parkinson's disease.
Esupron i Levodopa daju se u kombinaciji i količinama koje su ispod dolnje granice doziranja obaju tvari kod njihovih pojedinačnih aplikacija. Dnevna doza Esuprona u pravilu je od 100 do 200 mg po pacijentu i daje se jednokratno. Dnevna doza Levodope iznosi u pravilu 25 do 200 mg po pacijentu. Ona se može dati zajedno s Esupronom ili također i s vremenskim razmakom. Dnevna doza Levodope može se također podijeliti i na 2 do 3 pojedinačna davanja tijekom jednog dana. Esupron and Levodopa are given in combination and in amounts that are below the lower dosage limit of both substances in their individual applications. As a rule, the daily dose of Esupron is from 100 to 200 mg per patient and is given once. The daily dose of Levodopa is usually 25 to 200 mg per patient. It can be given together with Esupron or also with a time gap. The daily dose of Levodopa can also be divided into 2 to 3 individual doses during one day.
Kombinacija se može davati na uobičajen način, npr. oralno ili intravenozno. The combination can be administered in a conventional manner, eg orally or intravenously.
Aktivne tvari mogu se primjenjivati u uobičajenim galenskim aplikacijskim oblicima kao što su tablete, kapsule, prašak, granule, dražeje ili otopine. Oni se pripremaju na uobičajen način. Pri tome aktivne tvari mogu se preraditi s uobičajenim galenskim pomoćnim sredstvima (uglavnom nosiocima i sredstvima za razređenje) kao što su talk, gumirabika, saharoza, laktoza, žitni ili kukuruzni škrob, krumpirovo brašno, magnezijev stearat, alginati, tragant guma, karagenati, polivinil alkohol, polivinil pirolidon, vodeni ili nevodeni nosioci, sredstva za kvašenje, sredstva za dispergiranje, emulgatori i/ili konzervansi (usporediti H. Sucker et. al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978). Tako dobiveni pripremci uobičajeno sadrže aktivnu tvar u količini od 10 do 93% težinski. The active substances can be used in the usual galenic application forms such as tablets, capsules, powder, granules, dragees or solutions. They are prepared in the usual way. In this case, the active substances can be processed with the usual galenic aids (mainly carriers and diluents) such as talc, gum arabic, sucrose, lactose, wheat or corn starch, potato flour, magnesium stearate, alginates, gum tragacanth, carrageenates, polyvinyl alcohol, polyvinyl pyrrolidone, aqueous or non-aqueous carriers, wetting agents, dispersing agents, emulsifiers and/or preservatives (compare H. Sucker et. al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978). The preparations thus obtained usually contain an active substance in an amount of 10 to 93% by weight.
Također je moguće pojedinačne sastojke kombinacije preraditi u aplikacijske oblike i te onda pakirati zajedno, npr. protiskivanjem. It is also possible to process the individual ingredients of the combination into application forms and then package them together, for example by pressing.
Terapeutsko i profilaktičko djelovanje kombinacije kod poremećaja ekstrapiramidnog motoričkog sustava dokazano je slijedećim pokusima: The therapeutic and prophylactic action of the combination in disorders of the extrapyramidal motor system was proven by the following experiments:
Omamljenim štakorima (mužjaci, 180 - 200 g) dat je unilateralno injekcijom 6-OH-dopamin (8 μg u 4 μl u 4 minute) u supstantia nigra. Anesthetized rats (males, 180 - 200 g) were given a unilateral injection of 6-OH-dopamine (8 μg in 4 μl in 4 minutes) into the substantia nigra.
Kod tako oštećenih životinja postsinaptička dopaminergična stimulacija, npr. pomoću apomorfina ili L-dopa, izaziva kontralateralno okretanje (Brain Research 24, 485 (1970). In such damaged animals, postsynaptic dopaminergic stimulation, eg by apomorphine or L-dopa, induces contralateral turning (Brain Research 24, 485 (1970).
Frekvencija okretanja je mjera za veličinu stimulacije. 10 dana nakon operacije ispitane su životinje dva do tri puta s 0,5 mg/kg tj.tež. apomorfina. Životinje koje su reagirale sa 70 ili više okretaja u 15 minuta bile su podvrgnute ispitivanju tvari. The turning frequency is a measure of the magnitude of the stimulation. 10 days after surgery, the animals were tested two to three times with 0.5 mg/kg, i.e. weight. apomorphine. Animals that responded with 70 or more revolutions in 15 minutes were subjected to the test substance.
Jednostrane aplikacije 6-OH-dopamina u supstantia nigra na štakorima dovodi do degeneracije dopaminergičkih neurona koji se tamo nalaze i do njihove projekcije u striatum. Te promjene odgovaraju patološkim anatomskim nalazima kako oni izgledaju kod Parkinsonove bolesti muškaraca. Na taj način dobije se dakle životinjski model za Parkinsonovu bolest. Samo jednostrano oštećenje u životinjskom modelu dovodi do asimetrije pokretanja (okretanja), koje omogućuje kvantificiranje oštećenja odnosno djelovanja tvari. Unilateral application of 6-OH-dopamine in the substantia nigra of rats leads to the degeneration of dopaminergic neurons located there and to their projection into the striatum. These changes correspond to pathological anatomical findings as they appear in Parkinson's disease in men. In this way, an animal model for Parkinson's disease is obtained. Only one-sided damage in the animal model leads to an asymmetry of starting (turning), which enables the quantification of the damage or the action of the substance.
L-DOPA u tom modelu u dozama od približno 200 do 300 mg/kg ip izaziva kontralateralno okretanje, što se može uzeti kao ekvivalent klinički poznatog djelovanja L-DOPA kod Parkinsonove bolesti. Doza od 21,5 mg/kg nedjelotvorna je (vidi tablicu). L-DOPA in this model at doses of approximately 200 to 300 mg/kg ip induces contralateral turning, which can be taken as equivalent to the clinically known effect of L-DOPA in Parkinson's disease. A dose of 21.5 mg/kg is ineffective (see table).
Rezultati the results
[image] [image]
Istovremenim davanjem Esuprona uspjeva se pojačati učinak L-DOPA. 2,15 i 4,64 mg/kg p.o. Esuprona (doze koje su, date same, također neučinkovite) u kombinaciji s L-DOPA izazivaju izrazita okretanja. Ovaj porast statistički je signifikantan. The simultaneous administration of Esupron succeeds in enhancing the effect of L-DOPA. 2.15 and 4.64 mg/kg p.o. Esuprone (doses which, given alone, are also ineffective) in combination with L-DOPA cause pronounced turns. This increase is statistically significant.
Primjer 1 Example 1
Na preši za tablete na uobičajen način isprešane su tablete slijedećeg sastava: Tablets with the following composition were pressed on the tablet press in the usual way:
[image] [image]
Primjer 2 Example 2
Bile su pripremljene tablete s filmom slijedećeg sastava: Tablets with a film of the following composition were prepared:
[image] [image]
Masa jezgre sastoji se od 9 dijelova kukuruznog škroba, 3 dijela mliječnog šećera i 1 dijela Luviskola® VA 64 (miješani polomerizat vinilpirolidon-vinilacetata 60:40, usporedi Pharm. Ind. 1962, 586). The core mass consists of 9 parts corn starch, 3 parts milk sugar and 1 part Luviskol® VA 64 (mixed polymerizate of vinylpyrrolidone-vinylacetate 60:40, compare Pharm. Ind. 1962, 586).
Sloj filmske prevlake sastoji se od: The film coating layer consists of:
50% metilhidroksipropil celiloze 50% methylhydroxypropyl cellulose
10% PEG-a 400 10% PEG 400
20% talka 20% talc
15% PEG-a 15% PEG
8000 5% bojila (od toga 4% TiO2) 8000 5% dyes (of which 4% TiO2)
Primjer 3 Example 3
U jednom protisnom pakovanju za 28 tableta složeno je 14 tableta sa po 100 mg Esuprona i 14 tableta sa po 100 mg Levodopa u redove tako da se uvijek jedna tableta Esuprona nalazi pored jedne tablete Levodopa. In one blister pack for 28 tablets, 14 tablets with 100 mg of Esupron each and 14 tablets with 100 mg of Levodopa are stacked in rows so that one Esupron tablet is always next to one Levodopa tablet.
Primjer 4 Example 4
U jednom protisnom pakovanju za 36 tableta složeno je 12 tableta sa po 100 mg Esuprona i 50 mg Levodopa, te 24 tableta sa po 50 mg Levodopa tako da se jedna tableta koja sadrži Esupron uvijek nalazi pored dvije tablete Levodopa. One blister pack for 36 tablets contains 12 tablets with 100 mg of Esupron and 50 mg of Levodopa each, and 24 tablets with 50 mg of Levodopa each, so that one tablet containing Esupron is always next to two tablets of Levodopa.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4325435A DE4325435A1 (en) | 1993-07-29 | 1993-07-29 | New combination of active ingredients |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP940429A2 true HRP940429A2 (en) | 1997-08-31 |
Family
ID=6493978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP4325435.7A HRP940429A2 (en) | 1993-07-29 | 1994-07-27 | New combination of active substances |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU7457594A (en) |
| DE (1) | DE4325435A1 (en) |
| HR (1) | HRP940429A2 (en) |
| IL (1) | IL110336A0 (en) |
| WO (1) | WO1995003796A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7208010B2 (en) | 2000-10-16 | 2007-04-24 | Conor Medsystems, Inc. | Expandable medical device for delivery of beneficial agent |
| US20040254635A1 (en) | 1998-03-30 | 2004-12-16 | Shanley John F. | Expandable medical device for delivery of beneficial agent |
| US6241762B1 (en) | 1998-03-30 | 2001-06-05 | Conor Medsystems, Inc. | Expandable medical device with ductile hinges |
| EP2292190B1 (en) | 2000-10-16 | 2017-11-08 | Conor Medsystems, Inc. | Expandable medical device for delivery of beneficial agent |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3243158A1 (en) * | 1982-11-23 | 1984-05-24 | Basf Ag, 6700 Ludwigshafen | NEW SULPHONIC ACID ESTERS OF HYDROXYCUMARINES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
| ATE76747T1 (en) * | 1986-06-10 | 1992-06-15 | Chiesi Farma Spa | PHARMACEUTICAL COMPOSITIONS CONTAINING LEVODOPA METHYL ESTER, THEIR PREPARATION AND THERAPEUTIC USES. |
-
1993
- 1993-07-29 DE DE4325435A patent/DE4325435A1/en not_active Withdrawn
-
1994
- 1994-07-05 WO PCT/EP1994/002196 patent/WO1995003796A1/en active Application Filing
- 1994-07-05 AU AU74575/94A patent/AU7457594A/en not_active Withdrawn
- 1994-07-15 IL IL11033694A patent/IL110336A0/en unknown
- 1994-07-27 HR HRP4325435.7A patent/HRP940429A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE4325435A1 (en) | 1995-02-02 |
| IL110336A0 (en) | 1994-10-21 |
| WO1995003796A1 (en) | 1995-02-09 |
| AU7457594A (en) | 1995-02-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| ODBC | Application rejected |