SE468213B - Use of podophyllotoxin or a derivative thereof for producing a pharmacological preparation for treating collagenoses, especially rheumatoid arthritis - Google Patents
Use of podophyllotoxin or a derivative thereof for producing a pharmacological preparation for treating collagenoses, especially rheumatoid arthritisInfo
- Publication number
- SE468213B SE468213B SE8602880A SE8602880A SE468213B SE 468213 B SE468213 B SE 468213B SE 8602880 A SE8602880 A SE 8602880A SE 8602880 A SE8602880 A SE 8602880A SE 468213 B SE468213 B SE 468213B
- Authority
- SE
- Sweden
- Prior art keywords
- podophyllotoxin
- rheumatoid arthritis
- collagenoses
- derivative
- treating
- Prior art date
Links
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
15 20 25 30 35 468 215 2 den högrena formen enligt föreliggande uppfinning, vilket har möjliggjort dess användning på människa och djur vid nya indikationsområden. Vid tidigare arbeten har oftast använts ett orent extrakt från Podophyllum- arter, s.k. "podophy1lin", vilket endast innehållit 20- 40 % podophyllotoxin. Vidare innehåller extraktet ett stort antal andra komponenter, såsom desoxipodophyllo- toxin, dehydropodophyllotoxin, a och B-peltatin, m fl, beroende av vilka arter som extraktet har utvunnits från. Flera av dessa andra komponenter har visat sig vara avsevärt mutagena. The highly pure form of the present invention, which has enabled its use in humans and animals in new indications. In previous works, an unclean extract from Podophyllum species, so-called "podophyllin", which contained only 20-40% podophyllotoxin. Furthermore, the extract contains a large number of other components, such as deoxypodophyllotoxin, dehydropodophyllotoxin, α and β-peltatin, etc., depending on the species from which the extract has been extracted. Several of these other components have been shown to be significantly mutagenic.
Föreningen podophyllotoxin har i rent tillstånd följande fysikaliska data: Smältpunkt: 183-184°C Två kristallina modifika- 160-16l°C tioner med lösningsmedels- fri substans optisk vridning [a]2°: - 132,5 (c 0,2 cHc13) Löslighet i vatten: 120 mg/l Podophyllotoxin och dess derivat kan utvinnas ur växtdelar, speciellt då rötter eller rhizomer, från olika arter av släktet Podophyllum, såsom P. emodi Wall. och P. peltatum L. Föreningen förekommer även i andra växtarter, t ex av släktet Juniperus, såsom J. virginiana L.The compound podophyllotoxin has in its pure state the following physical data: Melting point: 183-184 ° C Two crystalline modifications 160-16l ° C ions with solvent-free substance optical rotation [a] 2 °: - 132.5 (c 0.2 cHc13 ) Solubility in water: 120 mg / l Podophyllotoxin and its derivatives can be extracted from plant parts, especially roots or rhizomes, from different species of the genus Podophyllum, such as P. emodi Wall. and P. peltatum L. The compound also occurs in other plant species, for example of the genus Juniperus, such as J. virginiana L.
Vid framställning av högrent podophyllotoxin eller dess derivat enligt uppfinningen extraheras torkade och finmalda rhizomer av exempelvis Podophyllum emodi eller Podophyllum peltatum med t ex etylacetat, och extraktet koncentreras och filtreras genom kiselgel. Den önskade fraktionen av podophyllotoxin och derivat därav kroma- tograferas sedan på sur aluminiumoxid, och ger därvid en fraktion, som huvudsakligen innehåller de fem ligna- nerna deoxipodophyllotoxin, podophyllotoxon, isopikro- podophyllon, podophyllotoxin och 4'-demetylpodophyllo- toxin. Från denna blandning isoleras podophyllotoxin eller ett annat önskat derivat genom en omsorgsfull kromatografering på kiselgel, varefter den önskade n; 10 15 20 25 30 35 468 213 3 fraktionen omkristalliseras.In the preparation of high-purity podophyllotoxin or its derivatives according to the invention, dried and finely ground rhizomes of, for example, Podophyllum emodi or Podophyllum peltatum are extracted with, for example, ethyl acetate, and the extract is concentrated and filtered through silica gel. The desired fraction of podophyllotoxin and derivatives thereof is then chromatographed on acidic alumina to give a fraction which mainly contains the five lines deoxypodophyllotoxin, podophyllotoxone, isopicropodophyllone, podophyllotoxin and 4'-demethylpodophylloxine. From this mixture, podophyllotoxin or another desired derivative is isolated by careful chromatography on silica gel, after which the desired n; 10 15 20 25 30 35 468 213 3 the fraction is recrystallized.
Högrent podophyllotoxin och dess derivat enligt uppfinningen har visat sig ha ett flertal framstående farmakologiska verkningar, och kan användas mot ett flertal sjukdomstillstånd. I enlighet med detta inne- fattar föreliggande uppfinning användning av podophyl- lotoxin eller ett derivat därav till framställning av farmakologiska beredningar, vilka innehåller podo- phyllotoxin och/eller dess derivat, tillsammans med ett eller flera farmakologiskt godtagbara bärarmaterial.High-purity podophyllotoxin and its derivatives according to the invention have been shown to have a number of outstanding pharmacological effects, and can be used against a variety of disease states. Accordingly, the present invention encompasses the use of podophyllotoxin or a derivative thereof for the preparation of pharmacological preparations containing podophyllotoxin and / or its derivatives, together with one or more pharmacologically acceptable carrier materials.
Som bärarmaterial kan användas alla de material som är kända för att vara användbara vid framställning av farmakologiska beredningar, förutsatt att de icke oför- delaktigt reagerar med den verksamma föreningen eller tillsammans med den utövar någon olämplig verkan. De farmakologiska beredningarna kan vara utformade för enteral, parenteral eller dermal administrering, och de kan exempelvis föreligga i form av fasta beredningar, såsom tabletter, pulver, kapslar, suppositorier eller vagitorier, mer eller mindre halvflytande beredningar, såsom salvor, geler eller krämer, eller vätskeformiga beredningar, såsom lösningar, suspensioner eller emul- sioner. De kan även innehålla ytterligare, vanliga tillsatsmedel, och även andra, terapeutiskt verksamma medel. Det ligger inom fackmannens kompetens att fram- ställa en lämplig komposition, när administrerings- sättet och andra betingelser för administreringen är kända.As the carrier material, all the materials known to be useful in the preparation of pharmacological preparations can be used, provided that they do not adversely react with the active compound or together with it exert any unsuitable effect. The pharmacological preparations may be designed for enteral, parenteral or dermal administration, and may be, for example, in the form of solid preparations, such as tablets, powders, capsules, suppositories or vagitori, more or less semi-liquid preparations, such as ointments, gels or creams, or liquid preparations, such as solutions, suspensions or emulsions. They may also contain additional, common additives, and also other, therapeutically active agents. It is within the competence of the person skilled in the art to prepare a suitable composition, when the method of administration and other conditions of administration are known.
Den använda dosen kan fastställas av fackmannen med utgående från konventionella kriterier, såsom sjukdoms- tillståndets allvarlighet, administreringssättet, pati- entens ålder och tillstånd, etc.The dose used can be determined by those skilled in the art based on conventional criteria, such as the severity of the disease state, the mode of administration, the age and condition of the patient, etc.
Farmakologiska beredningar, innehållande podophyllo- toxin och dess derivat enligt uppfinningen kan användas till behandling av ett flertal olika sjukdomstillstånd, vilka kan sammanfattas som kollagenoser (bindvävssjuk- domar). Exempel på sådana utgöres av reumatoid artrit, 10 15 20 25 30 35 468 213 4 systemisk lupus erytematosus disseminatus, sklerodermí, polvarteritis nodosa och sarkoidos.Pharmacological preparations, containing podophyllotoxin and its derivatives according to the invention can be used for the treatment of a number of different disease states, which can be summarized as collagenoses (connective tissue diseases). Examples of these are rheumatoid arthritis, systemic lupus erythematosus disseminatus, scleroderma, polar varteritis nodosa and sarcoidosis.
De av de nämnda sjukdomstillstånden angripna organis- merna kan utgöras av människor eller djur.The organisms infected by the mentioned disease states can be human or animal.
Podophyllotoxin och dess derivat enligt uppfinningen har underkastats ett antal farmakologiska, toxikologis- ka och kliniska undersökningar för att fastlägga dess terapeutiska egenskaper. Resultaten från dessa under- sökningar beskrives i det följande.Podophyllotoxin and its derivatives according to the invention have been subjected to a number of pharmacological, toxicological and clinical studies to determine its therapeutic properties. The results of these surveys are described below.
Akut toxicitet Den akuta toxiciteten hos podophyllotoxin har be- stämts på olika försöksdjur och med olika administre- ringssätt. Resultaten framgår av följande tabell 1.Acute toxicity The acute toxicity of podophyllotoxin has been determined in different experimental animals and with different routes of administration. The results are shown in the following Table 1.
TABELL 1 iFörsöks- Administre- Akut toxicitet! djur ringssätt LD50 mg/kg; « I *Rätta i.v. 10 i šMus i.v. 20 I šMus p.o. 100 i Rätta dermalt son šKanin dermalt 200 Verkan mot reumatoid artrit En dos-responsundersökning av podophyllotoxin genom- fördes med avsikt att undersöka den terapeutiska verk- ningsgraden, säkerheten och toleransen för olika doser av podophyllotoxin hos vuxna patienter med reumatoid artrit.TABLE 1 iTry- Administre- Acute toxicity! animal ring method LD50 mg / kg; «I * Correct i.v. 10 i šMus i.v. 20 I šMus p.o. 100 i Correct dermal son šKin dermal 200 Action against rheumatoid arthritis A dose-response study of podophyllotoxin was performed with the aim of investigating the therapeutic efficacy, safety and tolerance of different doses of podophyllotoxin in adult patients with rheumatoid arthritis.
Totalt undersöktes 15 patienter med tydlig reumatoid artrit. De uppdelades i tre grupper om vardera 5 pa- tienter, vilka erhöll doser på 0,99 mg/dygn, resp. 1,5 och 3,0 mg/dygn. Proven utfördes som dubbelblindprov.A total of 15 patients with clear rheumatoid arthritis were examined. They were divided into three groups of 5 patients each, who received doses of 0.99 mg / day, respectively. 1.5 and 3.0 mg / day. The tests were performed as double-blind tests.
Podophyllotoxin administerades som mjuka gelatin- kapslar, innehållande 0,33 mg, 0,5 mg eller l,O mg aktiv substans per kapsel, löst i en löslighetsförmed- 10 15 20 25 30 35 468 213 lare.Podophyllotoxin was administered as soft gelatin capsules, containing 0.33 mg, 0.5 mg or 1.0 mg of active substance per capsule, dissolved in a solubility mediator.
“För utvärdering av resultatet användes de objektiva parametrarna C-reaktivt protein (CRP) och erytrocyter- nas sedimenteringsgrad (ESR). Dessa utgör de mest accepterade parametrarna vid bedömning av antireumatis- ka läkemedel. För dessa utvärderingar sammanfattas resultatet i följande tabell.“For evaluation of the results, the objective parameters C-reactive protein (CRP) and the degree of sedimentation of the erythrocytes (ESR) were used. These are the most accepted parameters when assessing antirheumatic drugs. For these evaluations, the results are summarized in the following table.
För 6 patienter av 12 observerades kliniska förbätt- ringar med avseende på CRP, ESR, Ritchies modifierade index, greppstyrka och aktiviteter i dagligt liv. Inga biverkningar observerades. En patient utgick på grund av ineffektiv terapi, och 5 patienter förbättrades icke under undersökningsperioden. Kliniska förbättringar kunde vanligtvis observeras efter endast 2-6 veckor.For 6 patients out of 12, clinical improvements were observed with respect to CRP, ESR, Ritchie's modified index, grip strength, and activities of daily living. No side effects were observed. One patient was discontinued due to ineffective therapy, and 5 patients did not improve during the study period. Clinical improvements could usually be observed after only 2-6 weeks.
ESR (mm/h) CRP (mg%) Patient Baslinje lg veckor Baslinje 12 veckor Dos: 0,33 mg X 3 2 17 25 1,28 1,7 4 47 40 2,8 , 7 50 50 2,0 , 10 35 30 3,8 , 13 Ingick ej i undersökningen Dos: _ M 0,5 mg x 3 123 54 ll 6,7 25 80 1,1 2,7 46 81 1,2 2,6 ll 19 20 20,5 20,5 14 Ingick ej i undersökningen Dos: 1,0 mg x 3 65 45 4,7 3,2 38 51 2.09 - 22 24 4,5 2,5 12 50 utgickESR (mm / h) CRP (mg%) Patient Baseline lg weeks Baseline 12 weeks Dose: 0.33 mg X 3 2 17 25 1.28 1.7 4 47 40 2.8, 7 50 50 2.0, 10 35 30 3.8, 13 Not included in the study Dose: _ M 0.5 mg x 3 123 54 ll 6.7 25 80 1.1 2.7 46 81 1.2 2.6 ll 19 20 20.5 20 , 5 14 Not included in the study Dose: 1.0 mg x 3 65 45 4.7 3.2 38 51 2.09 - 22 24 4.5 2.5 12 50 discontinued
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8602880A SE468213B (en) | 1986-06-27 | 1986-06-27 | Use of podophyllotoxin or a derivative thereof for producing a pharmacological preparation for treating collagenoses, especially rheumatoid arthritis |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8602880A SE468213B (en) | 1986-06-27 | 1986-06-27 | Use of podophyllotoxin or a derivative thereof for producing a pharmacological preparation for treating collagenoses, especially rheumatoid arthritis |
Publications (3)
Publication Number | Publication Date |
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SE8602880D0 SE8602880D0 (en) | 1986-06-27 |
SE8602880L SE8602880L (en) | 1987-12-28 |
SE468213B true SE468213B (en) | 1992-11-23 |
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SE8602880A SE468213B (en) | 1986-06-27 | 1986-06-27 | Use of podophyllotoxin or a derivative thereof for producing a pharmacological preparation for treating collagenoses, especially rheumatoid arthritis |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002102805A1 (en) * | 2001-06-19 | 2002-12-27 | Axelar Ab | NEW USE Of CYCLOLIGNANS AND NEW CYCLOLIGNANS |
-
1986
- 1986-06-27 SE SE8602880A patent/SE468213B/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002102805A1 (en) * | 2001-06-19 | 2002-12-27 | Axelar Ab | NEW USE Of CYCLOLIGNANS AND NEW CYCLOLIGNANS |
US7709526B2 (en) | 2001-06-19 | 2010-05-04 | Biovitrum Ab | Use of cyclolignans and new cyclolignans |
Also Published As
Publication number | Publication date |
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SE8602880D0 (en) | 1986-06-27 |
SE8602880L (en) | 1987-12-28 |
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