NO138852B - PROCEDURES FOR THE PRODUCTION OF A NEW HORMONE, LITORALON - Google Patents
PROCEDURES FOR THE PRODUCTION OF A NEW HORMONE, LITORALON Download PDFInfo
- Publication number
- NO138852B NO138852B NO2758/72A NO275872A NO138852B NO 138852 B NO138852 B NO 138852B NO 2758/72 A NO2758/72 A NO 2758/72A NO 275872 A NO275872 A NO 275872A NO 138852 B NO138852 B NO 138852B
- Authority
- NO
- Norway
- Prior art keywords
- litoralone
- litoralon
- substance
- parathyroid
- effect
- Prior art date
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/55—Glands not provided for in groups A61K35/22 - A61K35/545, e.g. thyroids, parathyroids or pineal glands
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
- A61K8/981—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of mammals or bird
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Birds (AREA)
- Zoology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Endocrinology (AREA)
- Virology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av et hittil ukjent, av biskjoldbruskkjertelen produsert hormon, kalt litoralon. The present invention relates to a method for the production of a hitherto unknown hormone produced by the parathyroid gland, called litoralone.
Et av biskjoldbruskkjertelens hormoner, det såkalte One of the parathyroid hormones, the so-called
parathormon (molvekt 8.500) med forhøynende effekt på blodkonsentrasjon av kalsium, er hyppig omtalt i de senere års litteratur. parathormone (molecular weight 8,500) with an elevating effect on the blood concentration of calcium, is frequently mentioned in the literature of recent years.
(The Journ. of Biol. Chem. 236 : 759, 196l. Rasmussen et al.:. Isolation and Cha raet erization of Bovine Parathyroid Hormone; Biochemistry 5 : 344, 1966. Hawker et al.: Further Studies on (The Journ. of Biol. Chem. 236 : 759, 196l. Rasmussen et al.:. Isolation and Cha raet erization of Bovine Parathyroid Hormone; Biochemistry 5 : 344, 1966. Hawker et al.: Further Studies on
the Isolation and Cha raeterization of Parathyroid Polypeptides; the Isolation and Cha raeterization of Parathyroid Polypeptides;
Calc. Tiss. Res. 4 : 67, 1970. 0'Riordan et al.: The Properties Calc. Pee. Res. 4 : 67, 1970. O'Riordan et al.: The Properties
of Porcine Parathyroid Hormone; Annals of Int. Med. 70 : 1243, of Porcine Parathyroid Hormone; Annals of Int. Med. 70 : 1243,
1969. Aurbach et al.: Polypeptide Hormones and Calcium Meta- 1969. Aurbach et al.: Polypeptide Hormones and Calcium Meta-
bolism; Hoppe Seylers Zrscht. fUr Phys. Chem. 351 : 1581, 1970. bolism; Hoppe Seyler's Zrscht. for Phys. Chem. 351 : 1581, 1970.
Nial et al.: The amino acid sequence of Bovine Parathyroid Nial et al.: The amino acid sequence of Bovine Parathyroid
Hormone; Proe. Nat. Acad. Sei. (USA) 67 : 1862, 1970. Brewer et Hormone; Pro. Nat. Acad. Pollock. (USA) 67 : 1862, 1970. Brewer et
al.: Bovine Parathyroid Hormone: Amino Acid Sequence; Proe. Nat. al.: Bovine Parathyroid Hormone: Amino Acid Sequence; Pro. Nat.
Acad. Sei. (USA) 68 : 63, 1971. Potts et al.: Synthesis of the Biological Active N-terminal Part of Parathyroid Hormone). Acad. Pollock. (USA) 68 : 63, 1971. Potts et al.: Synthesis of the Biologically Active N-terminal Part of Parathyroid Hormone).
Dette hormon har en polypeptidlignende struktur. Frem- This hormone has a polypeptide-like structure. forward
stilling foregår ved ekstraksjon av avfettede, findelte biskjoldbruskkjertler med varm saltsyre eller fenol, eller med vann ved en pH-verdi mellom 6,5 og 7,5 (BDR utlegningsskrift 1 193 64l). position takes place by extraction of defatted, finely divided parathyroid glands with hot hydrochloric acid or phenol, or with water at a pH value between 6.5 and 7.5 (BDR explanatory note 1 193 64l).
Fra ekstraktet erholdes det urene produkt som ved en pH på An impure product is obtained from the extract which at a pH of
4,8 er utfellbar ved tallrike fraksjoneringer med et løsnings- 4.8 is precipitated by numerous fractionations with a solution
middel og ved utsalting og utfelling med trikloreddiksyre.» Det kjemisk rene kalsiumaktive parathormon, henholdsvis dets aktive isohormon, kan fremstilles ved komplisert gelfilt reringsteknologi . agent and by salting out and precipitation with trichloroacetic acid." The chemically pure calcium-active parathyroid hormone, or its active isohormone, can be produced by complicated gel filtration technology.
Grunnlaget for den foreliggende oppfinnelse er den er- The basis of the present invention is the
kjennelse av biskjoldbruskkjertelen i tillegg til de allerede ruling of the parathyroid gland in addition to those already
kjente hormoner inneholder én eller flere stoffer med en hormonell virkning, og som er vesentlig forskjellig fra de tidligere kjente stoffer. I denne beskrivelse kalles det nye hormon "litoralon". known hormones contain one or more substances with a hormonal effect, which are significantly different from the previously known substances. In this description, the new hormone is called "litoralon".
Den kjemiske struktur av litoralon er ikke klarlagt. Det The chemical structure of litoralone has not been clarified. The
er ikke entydig klart om det her dreier seg om en enkelt forbindelse eller en gruppe forbindelser, eller om en mer fysikalsk eller fysisk-kjemisk modifikasjon av en enkelt kjemisk forbindelse. is not unequivocally clear whether this concerns a single compound or a group of compounds, or a more physical or physico-chemical modification of a single chemical compound.
Det nye stoff med hormonell virkning er kalsiuminaktivt, dvs. at det i motsetning til de tidligere kjente hormoner ikke innvirker på blodkalsiumkonsentrasjonen hverken i positiv eller negativ retning, men det høyner blodets siliciuminnhold. The new substance with a hormonal effect is calcium-inactive, i.e. unlike the previously known hormones, it does not affect the blood calcium concentration in either a positive or negative direction, but it increases the blood's silicon content.
Biologisk utviser de sterkt rensede fraksjoner allerede i ganske svak konsentrasjon (under 1 ug pr. kg kroppsvekt) en bred farmakologisk og terapeutisk virkning som senere vil nærmere be-skrives . Biologically, the highly purified fractions already in a rather weak concentration (below 1 ug per kg body weight) exhibit a broad pharmacological and therapeutic effect which will be described in more detail later.
Det nye hormon, litoralon, som fremstilles ifølge oppfinnelsen, er et oligopeptid. Det er vannoppløselig og uoppløselig The new hormone, litoralone, which is produced according to the invention, is an oligopeptide. It is water soluble and insoluble
i apolare oppløsningsmidler, gir ingen feining med trikloreddiksyre, det inneholder en peptidbinding, ninhydrinreaksjonen er positiv. Litoralon er hydrolyserbar med syrer og baser. Karakteristiske grupper er carboxyl- og aminogruppen og en gruppe med sur karakter, som ennu ikke er identifisert. Stoffet har en sur karakter, ved 1500 V spenning og pH 1,8 vandrer det i løpet av elektroforesen i retning mot anoden. Det inneholder sikkert serin og aminocarboxylsyrer bundet peptidaktig. Molekylvekt: 500-2000. Litoralon utøver også sin virkning ved oral administra-sjon. Elementærsammensetning C, N, O, H og S og/eller P. in apolar solvents, gives no feigning with trichloroacetic acid, it contains a peptide bond, the ninhydrin reaction is positive. Litoralon is hydrolysable with acids and bases. Characteristic groups are the carboxyl and amino group and a group with an acidic character, which has not yet been identified. The substance has an acidic character, at 1500 V voltage and pH 1.8 it migrates during the electrophoresis in the direction towards the anode. It certainly contains serine and aminocarboxylic acids bound peptide-like. Molecular weight: 500-2000. Litoralon also exerts its effect by oral administration. Elemental composition C, N, O, H and S and/or P.
Molekylet består av minst 5 og maksimalt 15 fragmenter. The molecule consists of at least 5 and a maximum of 15 fragments.
Fosfor er derfor ikke utelukket, da den ukjente gruppe med sur karakter også kan være en fosfatgruppe. Phosphorus is therefore not excluded, as the unknown group with an acidic character can also be a phosphate group.
De mest karakteristiske farmakologiske virkninger: Vektøkning av Harder-kjertler hos rotter (økning av funk-sjonen) , økning av konsentrasjonen av sporelementene Si, Cu, Zn og Mn i blodet. The most characteristic pharmacological effects: Weight increase of Harder's glands in rats (increase in function), increase in the concentration of the trace elements Si, Cu, Zn and Mn in the blood.
Blodsukkersenkende virkning. Blodkalsiumnivået påvirkes ikke. Blood sugar-lowering effect. The blood calcium level is not affected.
AMP og fosfatuttømmende virkning i urinen. AMP and phosphate-depleting effect in the urine.
Litoralon forhindrer,, henholdsvis minsker symptomene på for-søkslathyrismus og fluorosis. Litoralon prevents or reduces the symptoms of experimental lathyrismus and fluorosis.
De mest karakteristiske kliniske virkninger; The most characteristic clinical effects;
Litoralon minsker symptomene på Rhinolaryngo-pharyngitis, Sjøgren-syndromet, Parodontit is, Mucovisci-dosen, Vitiligos og strålingsskader. Litoralon reduces the symptoms of Rhinolaryngo-pharyngitis, Sjøgren syndrome, Periodontitis, Mucovisci dose, Vitiligos and radiation damage.
Oppfinnelsen angår en fremgangsmåte ved fremstilling av et konsentrat som inneholder det nye hormon litoralon som produseres av biskjoldbruskkjertelen, ved hvilken biskjoldbruskkjertler isolert fra pattedyr, tørres, findeles, og eventuelt avfettes, og det således erholdte produkt ekstraheres med en vandig oppløsning, fortrinnsvis med vann, og fremgangsmåten kjennetegnes ved at derpå fjernes først eggehvitestoffer og polypeptider med molekyl - vekt over 1O0O fra ekstraktet, fortrinnsvis ved feining med trikloreddiksyre, og derpå fjernes overskudd av felningsmiddel' og det erholdte råkonsentrat renses eventuelt. Som utgangsmaterialer egner seg også cellekulturer som stammer fra biskjoldbruskkjertler fra pattedyr. The invention relates to a method for the production of a concentrate containing the new hormone litoralone which is produced by the parathyroid gland, in which parathyroid glands isolated from mammals are dried, minced and possibly defatted, and the product thus obtained is extracted with an aqueous solution, preferably with water, and the method is characterized by the fact that egg whites and polypeptides with a molecular weight above 1000 are first removed from the extract, preferably by fining with trichloroacetic acid, and then the excess fining agent is removed and the crude concentrate obtained is optionally purified. Cell cultures derived from mammalian parathyroid glands are also suitable as starting materials.
Ved kjente ekstraksjoner av biologisk aktive stoffer fra biskjoldbruskkjertler ekstraheres der ikke med vann alene, og det vil allerede herav forståes at det fra fremgangsmåten ifølge oppfinnelsen utvundne produkt er forskjellig fra de kjente. Om forholdet mellom litoralon og stoffene utvunnet ved de kjente fremgangsmåter skal kort tilføyes at der fra dansk patentskrift nr. 48044 kjennes en fremgangsmåte til fremstilling av væsker inneholdende hormoner fra biskjoldbruskkjertler; det aktive prinsipp uttrekkes med vandig alkohol surgjort til pH 4,6-5; det vil av det ovenstående sees at der ved foreliggende fremgangsmåte ekstraheres i nøytralt medium. US patentskrift nr. 1 680 660 angår en fremgangsmåte ved fremstilling av et konsentrat av parathormonet som hever blodets kalsiuminnhold og hindrer tetanisymptomer. Ekst raksjonen skjer med en vandig oppløsning av metafosforsyre fulgt av nøytralisering, filtrering og fjern-else av uorganiske salter. Litoralon er kalsiuminaktivt. In known extractions of biologically active substances from parathyroid glands, they are not extracted with water alone, and it will already be understood from this that the product obtained from the method according to the invention is different from the known ones. Regarding the relationship between litoralone and the substances extracted by the known methods, it should be briefly added that a method for the production of liquids containing hormones from parathyroid glands is known from Danish patent document no. 48044; the active principle is extracted with aqueous alcohol acidified to pH 4.6-5; it will be seen from the above that in the present method extraction is carried out in a neutral medium. US Patent No. 1 680 660 relates to a method for the production of a concentrate of the parathormone which raises the calcium content of the blood and prevents tetany symptoms. The extraction takes place with an aqueous solution of metaphosphoric acid followed by neutralization, filtration and removal of inorganic salts. Litoralon is calcium inactive.
US patentskrift nr. 1 890 851 beskriver utvinning av parathormonet ved varm, sur ekstraksjon. US patentskrift nr. 3 256 151 angår fremstilling av hormonet calcitonin fra kjertelvev fra biskjoldbruskkjertelen. Hormonet nedsetter blodets kalsiuminnhold og har således delvis motsatt virkning av parathormonet. Det har senere vist seg at calcitonin som har polypeptidkarakter, dannes av C-cellene i skjoldbruskkjertelen, ikke i biskjoldbruskkjertelen. Calcitonin kan lett skilles fra litoralon på kjemiske kriterier, bl.a. kan det felles med trikloreddiksyre og andre proteinfel-ningsmidler, og det har større molekylvekt enn litoralon. Litoralon kan derimot utvinnes ved vannekstraksjon ved nøytral pH-verdi. US Patent No. 1,890,851 describes recovery of the parathormone by hot, acidic extraction. US Patent No. 3,256,151 relates to the production of the hormone calcitonin from glandular tissue from the parathyroid gland. The hormone lowers the blood's calcium content and thus partially has the opposite effect of the parathormone. It has later been shown that calcitonin, which has a polypeptide character, is formed by the C cells in the thyroid gland, not in the parathyroid gland. Calcitonin can be easily distinguished from litoralone on chemical criteria, i.a. it can be combined with trichloroacetic acid and other protein precipitants, and it has a higher molecular weight than litoralone. Litoralon, on the other hand, can be recovered by water extraction at a neutral pH value.
De ved foreliggende fremgangsmåte fremstilte konsentrater (vandige løsninger eller lyofiliserte pulvere) er vel egnet til fremstilling av farmasøytiske preparater, som utviser de i det etterfølgende beskrevne, farmasøytiske eller biologiske virkninger . The concentrates produced by the present method (aqueous solutions or lyophilized powders) are well suited for the production of pharmaceutical preparations, which exhibit the pharmaceutical or biological effects described below.
Det kan også fremstilles mere aktive konsentrater, idet det tilstrebes et produkt som inneholder den aktive forbindelse i mere konsentrert eller renere form, og/eller at det ledsagende kalsiumaktive hormon deaktiveres. De renere produkter er bedre egnet til fremstilling av farmasøytiske preparater både fra et estetisk synspunkt som fra et doseringssynspunkt (de renere produkter gir mere entydig dosering). More active concentrates can also be produced, with the aim being a product that contains the active compound in a more concentrated or purer form, and/or that the accompanying calcium-active hormone is deactivated. The cleaner products are better suited to the manufacture of pharmaceutical preparations both from an aesthetic point of view and from a dosage point of view (the cleaner products give a more unambiguous dosage).
Som fellingsmiddel for eggehvitestoffer kan f.eks. anvendes trikloreddiksyre eller ,sulfosalicylsyre. Fjerning av eggehvite-stoffene kan også foretaes ved hjelp av løsningsmidler og ved utsalting. Utfelling med trikloreddiksyre er funnet å være mest hensiktsmessig og heldig. En ulempe er imidlertid at det er for-holdsvis vanskelig å fjerne overskudd av fellingsmiddel. Dette kan hensiktsmessig foretaes ved serievise ekst raksjoner med ether, eller også ved oppvarming av den vandige løsning befridd for eggehvitestoffer (erfaring har vist at litoralon ikke er særlig varmeømfintlig). På denne måte er 90% av trikloreddiksyren blitt spaltet. (Ved oppvarming dannes kloroform og C02). As a precipitating agent for egg whites, e.g. trichloroacetic acid or sulfosalicylic acid is used. Removal of the egg white substances can also be done with the help of solvents and by salting out. Precipitation with trichloroacetic acid has been found to be most convenient and successful. A disadvantage, however, is that it is relatively difficult to remove excess precipitating agent. This can conveniently be done by serial extractions with ether, or also by heating the aqueous solution freed from egg whites (experience has shown that litoralon is not particularly sensitive to heat). In this way, 90% of the trichloroacetic acid has been split. (When heated, chloroform and C02 are formed).
Det er også erfart at separasjon av eggehvitestoffer, polypeptider og andre fraksjoner utføres med godt resultat ved hjelp av gelfiltrering. It is also known that separation of egg whites, polypeptides and other fractions is carried out with good results by means of gel filtration.
I dette tilfelle kan det ønskede stoff lett fåes i relativt høy grad av renhet i den tilsvarende fraksjon. Særlig hensiktsmessig er rensing ved gelfiltrering av den vandige løsning etter fjerning av eggehvitestoff, hvor det fra en snever fraksjon på en søyle med stor fraksjoneringsevne, eventuelt ved gjentatte gel-filtreringer, kan utvinnes en litoralonfraksjon av relativt høy renhetsgrad. In this case, the desired substance can easily be obtained in a relatively high degree of purity in the corresponding fraction. Purification by gel filtration of the aqueous solution after removal of egg white is particularly suitable, where a littoralone fraction of relatively high purity can be recovered from a narrow fraction on a column with high fractionation capability, possibly by repeated gel filtration.
Konsentratet av aktivt stoff kan også renses på andre måter, eksempelvis ved kromatografi, dialyse, ekstraksjon, utfelling, adsorpsjon eller ved kombinasjoner av disse metoder. The concentrate of active substance can also be purified in other ways, for example by chromatography, dialysis, extraction, precipitation, adsorption or by combinations of these methods.
For tilintetgjørelse av det kalsiumaktive parathormon er den mest hensiktsmessige metode å behandle med forbindelser som lett reagerer med eggehvitestoffer, henholdsvis polypeptider. For the destruction of the calcium-active parathormone, the most appropriate method is to treat with compounds that easily react with egg whites, respectively polypeptides.
For dette formål kan anvendes salpetersyre, ethylenoxyd, For this purpose, nitric acid, ethylene oxide,
formalin osv. formalin etc.
Som tidligere angitt, er de forskjellige enkeltheter ved-rørende litoralon ikke klarlagt. Det er fastlagt at det ved forskjellige kjemiske og fysiokjemiske behandlinger kan separeres forskjellige aktive "litoralonfraksjoner". således kan det erholdes forskjellige fraksjoner ved utfelling av løsningsmidler, forskjellige kromatografiske metoder, gelfiltrering, dialyse, ekstraksjon, fraksjonert utsalting, behandling ved ionebyttere. For finere separasjon kan kombinasjoner av disse metoder benyttes. As previously stated, the various details concerning litoralon have not been clarified. It has been established that different active "litoralone fractions" can be separated by different chemical and physiochemical treatments. thus different fractions can be obtained by precipitation of solvents, different chromatographic methods, gel filtration, dialysis, extraction, fractional salting out, treatment with ion exchangers. For finer separation, combinations of these methods can be used.
Litoralon eller litoralonfraksjoner fremstilt ifølge foreliggende oppfinnelse, kan anvendes som aktiv bestanddel i terapeutiske og/eller preventive preparater. Mengden av aktiv bestanddel kan varieres innen vide grenser og avhenger av de angitte be-tingelser. Mengden av aktiv bestanddel kan være 0,05-10 mg pr. dose. Disse preparater fremstilles etter kjente metoder fra litoralonholdige faste eller flytende konsentrater, hhv. blandinger, i form av tabletter, stikkpiller, løsninger, salver, pulverbland-inger eller spray. Litoralone or litoralone fractions produced according to the present invention can be used as an active ingredient in therapeutic and/or preventive preparations. The amount of active ingredient can be varied within wide limits and depends on the stated conditions. The amount of active ingredient can be 0.05-10 mg per dose. These preparations are produced according to known methods from litoralone-containing solid or liquid concentrates, respectively. mixtures, in the form of tablets, suppositories, solutions, ointments, powder mixtures or sprays.
Med litoralonholdige preparater ble etterfølgende omfattende, klinisk-terapeutiske undersøkelser foretatt. Preparatet ble i alminnelighet administrert peroralt i doser på 3 ganger 0,1 - With preparations containing litoralone, extensive, clinical-therapeutic investigations were subsequently carried out. The preparation was generally administered orally in doses of 3 times 0.1 -
0,5 mg litoralonkonsentrat. Skadelige bivirkninger ved et pasientmateriale på 3000 ble praktisk talt ikke observert, »i enkelte tilfeller var imidlertid et urticaria-artig utslag på hud-overflaten merkbar, hhv. kvalme og brekninger. Dette oppsto maksimalt hos 5% av de behandlede pasienter. 0.5 mg litoralone concentrate. Harmful side effects with a patient material of 3,000 were practically not observed, »in some cases, however, an urticaria-like rash on the skin surface was noticeable, resp. nausea and vomiting. This occurred in a maximum of 5% of the treated patients.
Karakteristisk for den nye forbindelse, hhv. forbindelser med hormonvirkning, er følgende fysiologiske virkninger: Characteristic of the new connection, resp. compounds with hormonal action, the following physiological effects are:
a) Farmakologisk virkning a) Pharmacological effect
Blodserumkonsentrasjon av kalsium blir praktisk talt ikke Blood serum concentration of calcium is practically not
påvirket. Forhoyelse av blodsiliciumkonsentrasjon og forandringer i konsentrasjonen av andre viktige sporelementer (f.eks. kopper, fluor osv.). affected. Increase in blood silicon concentration and changes in the concentration of other important trace elements (e.g. copper, fluoride, etc.).
Det nye stoff bevirker fosfaturi og forhoyelse av organisk monofosfat og cyclisk monofosfatkonsentrasjon (cyclisk AMP) i urin. The new substance causes phosphaturia and an increase in organic monophosphate and cyclic monophosphate concentration (cyclic AMP) in urine.
Senkning av blodsukkerkonsentrasjon. Lowering blood sugar concentration.
Innvirkning på blodets koagulasjonsfaktorer, oket lypolyse. Effect on blood coagulation factors, increased lypolysis.
Innvirkning på hypothalamus-hypofysebinyresystemet. Impact on the hypothalamic-pituitary-adrenal system.
(Frembringelse av en adoptasjonssyndrom-resistenstilstand: Okning av serumcortisonkonsentrasjoner, sensitivisering av binyrebark mot ACTH, beskyttelse mot sjokk fra overproduksjon av steroider fra binyrebark, inhibering av endogen ACTH-frigivelse av hypofysen, beskyttelse mot binyrebarkhyp.ertrofl. fra vedvarende ACTH dosering). (Production of an adoption syndrome resistance state: Increase in serum cortisone concentrations, sensitization of the adrenal cortex to ACTH, protection against shock from overproduction of steroids by the adrenal cortex, inhibition of endogenous ACTH release by the pituitary gland, protection against adrenal cortical hypertrophy from sustained ACTH dosing).
Ved kronisk (årlig) dosering hypertroferer zonaglomerulosa svakt, zonafascikulata viser derimot svak hypofunksjon. Dette er påvist ved spesielle histologiske undersøkelser. Myeloid og erythroid substansforholdet i knokkelmargen forhoyes. With chronic (annual) dosing, the zonaglomerulosa hypertrophies slightly, the zonafasciculata, on the other hand, shows a slight hypofunction. This has been proven by special histological examinations. The myeloid and erythroid substance ratio in the bone marrow is increased.
Utovelse av mesenchymaktiverende virkning: ansporing til vekst og formering av fibroblaste, oppbygning av bindevevsubstans og fasesystemets fibriller, bket sårhelbredelse som forhindres ved cortisonbehandling. Repetition of mesenchyme-activating effect: stimulation of growth and proliferation of fibroblasts, build-up of connective tissue substance and fibrils of the phase system, delayed wound healing which is prevented by cortisone treatment.
Oket konsentrasjon av glycoprotein og seromucoidinnhold i serum. Increased concentration of glycoprotein and seromucoid content in serum.
Innvirkning på helbredelsen av knokler og knokkelsubstans Impact on the healing of bones and bone substance
og i mindre konsentrasjoner aktivisering av osteoblaster og chondro-scyther. Det er nodvendig for fysiologisk funksjon av knokkelmatrix-brusk såvel som sener i bånd og synovialmembraner. Ved intracellu-lær effekt oker den elektrontettheten i. Golgiapparatet og det endo-plastiske reticulum i celler som knokler og brusk bygger opp. Det forhindrer eksperimentell lathyrisme. Senkning av serumcitratkon-sentrasjonen og bking av alkalisk fosfatasekonsentrasjon. and in smaller concentrations activation of osteoblasts and chondro-scythes. It is necessary for the physiological function of bone matrix cartilage as well as tendons in bands and synovial membranes. In the case of an intracellular effect, it increases the electron density in the Golgi apparatus and the endoplastic reticulum in cells that build up bones and cartilage. It prevents experimental lathyrism. Lowering the serum citrate concentration and lowering the alkaline phosphatase concentration.
Den beskytter organismen mot skadelige virkninger fra elektro-magnetisk bestrålinger. Det forårsaker raskere tilbakegangstid av huderythem, og øker betydelig levetiden for rotter som er bestrålt med dødelige røntgendoser. Forminskning av røntgenstrålers mitose-hemmende effekt på knokkelmarg og myelozytter. Den har ikke bare profylaktisk, men også terapeutisk effekt på stråleskader. It protects the organism against harmful effects from electro-magnetic radiation. It causes faster regression of skin erythema, and significantly increases the lifespan of rats irradiated with lethal doses of X-rays. Reduction of the mitosis-inhibiting effect of X-rays on bone marrow and myelocytes. It not only has a prophylactic, but also a therapeutic effect on radiation damage.
Betraktelig økning i vekt av rottens Harder-kjertler, Considerable increase in weight of the rat's Harder glands,
hvilke kjertler inneholder de extra retinale fotoreseptorer i rotta. which glands contain the extra retinal photoreceptors in the rat.
Innflytelse på den biologiske-energetiske virkning av ly s (sol)-best råling . Øket konsentrasjon av C, , merket glucos-aminer i dypt liggende (metulare) nyretubuler, og uttrykt øking i mucopolysaccharidkonsentrasjon i nyrevev. Øket diurese. Influence on the biological-energetic effect of light (solar) best rawling. Increased concentration of C, , labeled glucos-amines in deep-lying (metular) kidney tubules, and pronounced increase in mucopolysaccharide concentration in kidney tissue. Increased diuresis.
Vesentlig forminskning av histaminers nedsettende effekt på rektaltemperaturen og regulerende virkning på arteriovenøse anastomoser. Substantial reduction of histamines' lowering effect on rectal temperature and regulatory effect on arteriovenous anastomoses.
Den innvirker på åreveggens endothel, henholdsvis mucopoly-saccharidsyntese i intima. It affects the endothelium of the vein wall, respectively mucopolysaccharide synthesis in the intima.
b) Klinisk virkning b) Clinical effect
Resultatene av undersøkelser ved 7 forskjellige ungarske universi-tetsinstitutter kan oppsummeres som følger: 1) Litoralon hadde god terapeutisk virkning i 63% av til-fellene på sykdommer i bevegelsesorganene som reagerer dårlig på behandling med de vanlig anvendte droger. 2) Litoralon er egnet for symptomatisk behandling av sicca-syndrom av en hvilken som helst opprinnelse i de øvre luftveier. Ved de ikke-konstitusjonelle former for lidelsen, dvs. sicca-symptomer som ledsager infeksjoner, tracheostomy, begynner virkningen efter relativt kort tid. Ved konstitusjonell sicca-syndrom begynnende i ung alder, kreves kronisk behandling for å opprettholde en symptomfri tilstand. Ved ozaena fører behandling med litoralon selv ved de alvorligste former, til lindring av lidelser og forbedring av den objektive tilstand. 3) Litoralon er virksom i subakutte og kroniske sykdommer i respirasjonsorganene. Oral behandling med 5 mg tolereres godt . 4) Den lokaliserte form for scleroderma reagerte gunstig på litoralon, mens den systemiske form viste dårlig reaksjon. I mere enn halvparten av vitiligo-pasientene forekom repigmentering i en grad som ikke har vært iakttatt ved andre droger. 5) Ved milde former av xerofthalmi hadde litoralon en gunstig innflytelse. I ekte sicca-tilfeller kan litoralon anvendes som substitusjonsterapi, men efter avslutning av behandlingen kommer symptomene tilbake efter fra 1 uke til 1 måned. Forandringer av de generelle symptomer, f.eks. The results of investigations at 7 different Hungarian university institutes can be summarized as follows: 1) Litoralon had a good therapeutic effect in 63% of the cases of diseases of the locomotor organs that respond poorly to treatment with the commonly used drugs. 2) Litoralon is suitable for the symptomatic treatment of sicca syndrome of any origin in the upper respiratory tract. In the non-constitutional forms of the disorder, i.e. sicca symptoms accompanying infections, tracheostomy, the effect begins after a relatively short time. In constitutional sicca syndrome beginning at a young age, chronic treatment is required to maintain a symptom-free state. In the case of ozaena, treatment with litoralone, even in the most severe forms, leads to relief of suffering and improvement of the objective condition. 3) Litoralon is effective in subacute and chronic diseases of the respiratory organs. Oral treatment with 5 mg is well tolerated. 4) The localized form of scleroderma responded favorably to litoralon, while the systemic form showed a poor response. In more than half of the vitiligo patients, repigmentation occurred to a degree that has not been observed with other drugs. 5) In mild forms of xerophthalmia, litoralon had a beneficial influence. In true sicca cases, litoralone can be used as substitution therapy, but after the end of the treatment, the symptoms return after 1 week to 1 month. Changes in the general symptoms, e.g.
Sjøgren<*>s syndrom, forløper ikke alltid parallelt med den oculære tilstand. Iatrogen xerofthalmi bevirket av steroide øyendråper og salver bedres hurtigere hvis, efter avslutning av behandlingen, litoralon anvendes parallelt med kausal terapi enn hvis, efter avslutning av steroid-behandlingen, kausal terapi anvendes alene. Det synes å være en kausal forbindelse mellom litoralonbehandling og xerofthalmi. Gastrisk bivirkning forekommer. 6) Den radiobeskyttende virkning av litoralon kunne påvises ved måling av lokale dermale reaksjoner som forekom ved nedsatt intensitet og ble restituert i kortere tid. 7) Ved parodontal atrofi av 1. og 2. grad oppnådde man efter 1 måneds behandling en optimal effekt bestående i 50% reduksjon av løsheten av tannfestet. Sjøgren's syndrome does not always run parallel to the ocular condition. Iatrogenic xerophthalmia caused by steroid eye drops and ointments improves more quickly if, after the end of the treatment, litoralone is used in parallel with causal therapy than if, after the end of the steroid treatment, causal therapy is used alone. There appears to be a causal link between litoralone treatment and xerophthalmia. Gastric side effect occurs. 6) The radioprotective effect of litoralon could be demonstrated by measuring local dermal reactions that occurred at reduced intensity and were restored in a shorter time. 7) In the case of periodontal atrophy of the 1st and 2nd degree, an optimal effect was achieved after 1 month of treatment consisting of a 50% reduction in the looseness of the tooth attachment.
De farmakologiske og kjemiske undersøkelser er hittil blitt gjennomfbrt ved 8 universitetslæresteder, statlige institutter og farmakologiske fabrikker, mens de kliniske undersøkelser har pågått systematisk i 20 universitetsklinikker, statlige institutter og Budapest-sykehus i 2 år. De terapeutiske undersøkelser av forskjellige sykdomsbilder har hittil funnet sted med registrert syk-domsmateriell av ^ 000 personer. The pharmacological and chemical investigations have so far been carried out at 8 university teaching sites, state institutes and pharmacological factories, while the clinical investigations have been carried out systematically in 20 university clinics, state institutes and Budapest hospitals for 2 years. The therapeutic investigations of various disease patterns have so far taken place with registered medical records of ^ 000 people.
Den terapeutiske effekt kan i visse sykdomstilfeller ta flere uker eller måneder for den manifesterer seg (f.eks. Bechterew' s sykdom), men den kan også gi relativt rask virkning, (f. eks. ozena). In certain disease cases, the therapeutic effect can take several weeks or months to manifest (eg Bechterew's disease), but it can also produce a relatively quick effect (eg ozena).
I visse tilfeller er remisjonen vedvarende, i andre tilfeller oppstår sterk hormonavhengighet og ved avbrudd i behandlingen, får den syke raskt tilbakefall Cf.eks. rhinopharingitis sicca). In certain cases the remission is persistent, in other cases strong hormone dependence occurs and if the treatment is interrupted, the patient quickly relapses Cf.eg. rhinopharyngitis sicca).
Den renere fraksjon av hormoner fremviser sin terapeutiske effekt allerede i ganske små konsentrasjoner. (I en konsentrasjon på 0,001 ppm eller derunder som tilsvarer en oral dose på 1 mikrogram pr. kg kroppsvekt). The purer fraction of hormones exhibits its therapeutic effect already in fairly small concentrations. (At a concentration of 0.001 ppm or less which corresponds to an oral dose of 1 microgram per kg of body weight).
Overraskende er det brede spektrum og de tilsynelatende ube-slektede sykdommer som litoralon har hatt en gunstig terapeutisk innvirkning på. I denne sammenheng kan man henvise til cortison og dets derivater som har utvist en terapeutisk effekt på hundrevis av sykdommer. Den terapeutiske virkning av litoralon kan i sitt omfang og viktighet bare sammenlignes med cortisonderivater, og åpner et nytt kapitel i terapeutisk farmakologi og biokjemi. De skiller seg ikke bare fra cortisonderivater i de vesentlig avvikende indikasjonene (indikasjon for dosering av medikamentet), disse er i flere tilfelle motsatte av hydrocortison, men også i deres vesentlig lavere toksisi-tet og virkningsmåte. I sin alminnelighet forårsaker litoralon en trinnvis utviklende effekt i motsetning til den ofte raske virkning av cortisoner og utfolder seg i sitt felt ved kroniske, degenerative og sclerotiserende progresjoner og ikke med noen gunstig innflytelse på forverrende, oppblussende stadium av sykdommer. I lopet ^av den kliniske anvendelse ble det ikke observert vesentlig skadelige bivirkninger ved vedvarende behandling opp til 1 år. Surprising is the wide spectrum and the apparently unrelated diseases on which litoralone has had a beneficial therapeutic effect. In this context, one can refer to cortisone and its derivatives, which have shown a therapeutic effect on hundreds of diseases. The therapeutic effect of litoralone can only be compared in its scope and importance to cortisone derivatives, and opens a new chapter in therapeutic pharmacology and biochemistry. They not only differ from cortisone derivatives in the significantly different indications (indication for dosage of the drug), these are in several cases the opposite of hydrocortisone, but also in their significantly lower toxicity and mode of action. In its generality, litoralone causes a gradually developing effect in contrast to the often rapid action of cortisones and unfolds in its field in chronic, degenerative and sclerotizing progressions and not with any beneficial influence on worsening, flaring stage of diseases. In the course of clinical use, no significantly harmful side effects were observed with continued treatment up to 1 year.
Det faktum at litoralon i vesentlig grad innvirker på silicium-innholdet i blodet, og i denne regulering spiller en bestemmende rolle (blodkonsentrasjon av silicium steg under litoralonbehandling i rotter og harer med mer enn 100$ innen 30 dager), tiltrekker oppmerksomheten ettertrykkelig mot den særdeles viktige fysiologiske oppgave sili-cium har i syntesen av glyco-mucoproteiner og besorging av deres fysiologiske funksjon. The fact that litoralone significantly affects the silicon content in the blood, and in this regulation plays a decisive role (blood concentration of silicon increased during litoralone treatment in rats and hares by more than 100$ within 30 days), draws attention emphatically to the particularly silicon has an important physiological role in the synthesis of glyco-mucoproteins and ensuring their physiological function.
Som resultat av litoralonforskning heves sannsynligvis kisel-syre og komplekser av denne seg opp i en hoy rang i vår hittil for-sbmte fysiologiske innordning. (Oppbyggelse av bradytrofier: Vev med nedsatt stoffskifte, elastiske bindevev, regulering av knokkelopp-bygning osv.). As a result of litoralone research, silicic acid and its complexes are probably being raised to a high rank in our hitherto limited physiological system. (Building up of bradytrophies: Tissues with reduced metabolism, elastic connective tissues, regulation of bone formation, etc.).
Forskjellen mellom de to hormoner fra glandula parathyreoidea: mellom parathormon og litoralon forklares mest kompakt og innlysende ved at parathormon innvirker på vitamin D-karakteristika, mens litoralon virker inn på vitamin A. The difference between the two hormones from the parathyroid gland: between parathormone and litoralon is most compactly and clearly explained by the fact that parathormone affects vitamin D characteristics, while litoralon affects vitamin A.
Det virker sannsynlig at hormoner med litoraloneffekt blir produsert i de såkalte eosinofile celler i glandula parathyreoidea. It seems likely that hormones with a litoralone effect are produced in the so-called eosinophilic cells of the parathyroid gland.
Eksempel 1 Example 1
10 g lyofilisert og malt kjertelpulver ble på fblgende kjente måte avfettet: Pulveret ble blandet med 25 ml absolutt aceton ved romtemperatu og deretter filtrert på et glassfilter G^. Deretter ble det godt avsugede kjertelpulver igjen blandet med 25 ml kloroform ved romtemperatur, og filtrert på et glassfilter G^. Operasjonen ble gjentatt. Det avsugde stoff ble deretter tilslutt suspendert i 25 ml absolutt aceton ved romtemperatur og filtrert gjennom et glassfilter G^. Det erholdte kjertelpulver ble torket i vacuum ved romtemperatur. Vekten av det torre stoff varierte mellom 7 og 9 g avhengig av fettinnholdet i utgangsmaterialet. 10 g of lyophilized and ground gland powder was degreased in the following known manner: The powder was mixed with 25 ml of absolute acetone at room temperature and then filtered on a glass filter G^. Then the well-aspirated gland powder was again mixed with 25 ml of chloroform at room temperature, and filtered on a glass filter G^. The operation was repeated. The aspirated substance was then finally suspended in 25 ml of absolute acetone at room temperature and filtered through a glass filter G^. The gland powder obtained was dried in vacuum at room temperature. The weight of the dry substance varied between 7 and 9 g depending on the fat content of the starting material.
10 g av det avfettede, vannfri kjertelpulver ble deretter ekstrahert 3 ganger, hver gang med 100 ml destillert vann, ved romtemperatur og i lopet av 1 time.. Mellom ekstraksjonstrinnene ble kjertelpulveret sentrifugert på en laboratoriesentrifuge med stor omløpshastighet. Ekstraktet ble oppbevart i en nitrogenatmosfære ved 3 - 5°C for videre opparbeiding. Den vandige ekstrakt var ninhydrin-, biuret- og trikloreddiksyre-positiv. 10 g of the defatted, anhydrous gland powder was then extracted 3 times, each time with 100 ml of distilled water, at room temperature and over the course of 1 hour. Between the extraction steps, the gland powder was centrifuged on a laboratory centrifuge at high rotation speed. The extract was stored in a nitrogen atmosphere at 3 - 5°C for further processing. The aqueous extract was ninhydrin, biuret and trichloroacetic acid positive.
De vandige ekstrakter ble deretter kombinert og en 50 volum-, vandig trikloreddiksyrelosning ble deretter dråpevis tilsatt under god omroring, inntil sluttkonsentrasjonen av trikloreddiksyre var 15%. Etter 1 time's henstand ved 3 - 5°C ble trikloreddiksyrebunn-fallet sentrifugert fra. The aqueous extracts were then combined and a 50 volume, aqueous trichloroacetic acid solution was then added dropwise with good stirring, until the final concentration of trichloroacetic acid was 15%. After 1 hour's rest at 3 - 5°C, the trichloroacetic acid precipitate was centrifuged off.
Det ovre skikt var en klar, blekgul vandig lbsning som var biuret- og trikloreddiksyre-negativ, og ninhydrin-positiv. The upper layer was a clear, pale yellow aqueous solution that was biuret and trichloroacetic acid negative, and ninhydrin positive.
Overskuddet av trikloreddiksyre ble fjernet ved flere ekstraksjoner ved romtemperatur med en vandig etheropplbsning (1 - The excess of trichloroacetic acid was removed by several extractions at room temperature with an aqueous ether solution (1 -
1,2 volumdeler ether : 1 volumdel vann). Vanligvis er 17 - 18 ekstraksjoner nbdvendig for å fjerne trikloreddiksyren. I praksis foretaes 20 - 25 ekstraksjoner. 1.2 parts by volume ether : 1 part by volume water). Usually 17 - 18 extractions are necessary to remove the trichloroacetic acid. In practice, 20 - 25 extractions are carried out.
Etter den siste ekstraksjon må den vandige fase ha en pH mellom U-,5 og 5. After the last extraction, the aqueous phase must have a pH between U-.5 and 5.
Ved hjelp av en vannstrålepumpe og ved en temperatur som By means of a water jet pump and at a temperature which
ikke overskred 30°C, ble etheren skilt fra den vandige fase. did not exceed 30°C, the ether was separated from the aqueous phase.
Fjerningen av ether tok ca. 6 timer og resulterte i en yol-umforminskning. (Også endel av den vandige fase ble avdestillert). The removal of ether took approx. 6 hours and resulted in a yol umform reduction. (Part of the aqueous phase was also distilled off).
Fjerningen av ether ble kontrollert ved provelukting. The removal of ether was checked by sample smelling.
Den vandige lbsning ble deretter lyofilisert og oppbevart i et godt lukket kar. Lbsningen er hygroskopisk. Utbytte beregnet på det totale kjertelpulver (for avfetning) var 10 - \% The aqueous solution was then lyophilized and stored in a tightly closed vessel. The solution is hygroscopic. Yield calculated on the total gland powder (for degreasing) was 10 - \%
(avhengig av fettinnholdet). (depending on the fat content).
Eksempel 2 Example 2
Det ble som angitt i eksempel 1 fremstilt et ekstrakt fra As indicated in example 1, an extract was prepared from
en vandig ekstrakt fra avfettet biskjoHbruskkjertel, hvilket ekstrakt var fritt for eggehvitestoffer og utfellingsmiddel. 5 g av en trikloreddiksyre inaktiv lyofilsats ble gelfiltrert på en 'Bephadex G-l5<IL>holdig soyle. Sbylens masse var 4,3 cm ganger 144 cm. Som elueringsmiddel ble benyttet vann. Gjennomstromningshastigheten var 60 ml pr. time. Fraksjonsstorrelsen var 15 ml. an aqueous extract from defatted bisque cartilage, which extract was free of egg whites and precipitating agent. 5 g of a trichloroacetic acid inactive lyophilic batch was gel filtered on a 'Bephadex G-15<IL> containing soil. The mass of the flush was 4.3 cm by 144 cm. Water was used as eluent. The flow rate was 60 ml per hour. The fraction size was 15 ml.
Vekt av den totale og lyofiliserte prove: Weight of the total and lyophilized sample:
Hoved fraksjonen, rornummer 46 - 83 med, et innhold på 913 mg var forholdsmessig rik på litoralon og hadde en utpreget fysiologisk, henholdsvis terapeutisk virkning ved en dosering på 5 - 10 mikrogram pr. kg kroppsvekt. The main fraction, row number 46 - 83 with, a content of 913 mg was relatively rich in litoralone and had a distinct physiological, respectively therapeutic effect at a dosage of 5 - 10 micrograms per kg body weight.
Dette er det stoff som inneholdes i begge de forste topp-punkter ved gelfiltreringen. This is the substance contained in both of the first peak points during the gel filtration.
Adskillelse av fråsjonene kan hensiktsmessig utfores ved folgende metode: a) Spektrofotométrisk absorpsjonsmåling ved 280 millimikron. b) Spektrofotométrisk absorpsjonsmåling ved 234 millimikron. c) Spektrofotométrisk absorpsjonsmåling ved 36° millimikron. Separation of the fractions can conveniently be carried out by the following method: a) Spectrophotometric absorption measurement at 280 millimicrons. b) Spectrophotometric absorption measurement at 234 millimicrons. c) Spectrophotometric absorption measurement at 36° millimicron.
d) Måling av elektrisk ledningsevne. d) Measurement of electrical conductivity.
e) Kvalitativ undersøkelse, på kloridion med solvnitrat-reagens. f) pH måling av de forente fraksjoner tilhorende det enkelte topp-punkt. e) Qualitative examination, on chloride ion with solvnitrate reagent. f) pH measurement of the combined fractions belonging to the individual peak point.
g) Undersokelse med ninhydrin-reagens. g) Examination with ninhydrin reagent.
h) Undersokelse med det blotte bye med hensyn til gjennomskinne-lighet og farge (gullig). h) Examination with the bare bye with regard to translucency and color (yellowish).
Utbytte av hovedfraksjonen 46 - 83 med hensyn på torr, ikke avfettet biskjoldbruskkjertelpulver ble beregnet til ca. 2 - 2,5$. Yield of the main fraction 46 - 83 with regard to dry, non-defatted parathyroid gland powder was calculated to be approx. 2 - 2.5$.
Eksempel Example
Eksempel 2 ble gjentatt med den forandring at begge de fbrste hovedmengder ble uttatt i separate hovedfraksjoner. Således ble fra 5 g eggehvitestof f-fritt vandig ekstrakt erholdt 302 mg i hovedf raks jon nr. 1 og 555 mg i hovedfraksjon II. Example 2 was repeated with the change that both of the first main quantities were taken out in separate main fractions. Thus, 302 mg in main fraction No. 1 and 555 mg in main fraction II were obtained from 5 g of egg white substance f-free aqueous extract.
Hovedfraksjon II ble deretter underkastet en gelfiltrering. 456 mg stoff ble uttatt på sbylen, og vann ble anvendt som elueringsmiddel. Sbylemassen var 4,3 ganger 144 cm, gjennomstromningshastigheten 50 ml pr. time, og fraksjonsstorrelsen 10 ml. Fylling: "Sephadex G-15". Main fraction II was then subjected to gel filtration. 456 mg of substance was removed from the flask, and water was used as eluent. The flushing mass was 4.3 times 144 cm, the flow rate 50 ml per hour, and the fraction size 10 ml. Filling: "Sephadex G-15".
På denne måte var hovedfraksjon II oppdelbar i 3 topper. Fraksjoner tilhorende den midtre topp ble forenet. Vekt av disse In this way, main faction II was divisible into 3 peaks. Factions belonging to the middle peak were united. Weight of these
var etter lyofili sering 237,5 mg. after lyophilization was 237.5 mg.
Utbytte beregnet på basis av ikke-avfettet biskjoldbruskkjertelpulver var 0,6 - 0,8$. Yield calculated on the basis of non-defatted parathyroid powder was 0.6 - 0.8$.
Karakteristiske egenskaper: Gul hygroskopisk substans med et innhold av C H N 0 Sog/eller P. Karakteristiske grupper: -SH, -C00H, -0H. Ved en massespektrografisk undersokelse var fblgende fragmenter karakteristiske: C^H^N^S; C^H^N^O^ og C^NO. Characteristic properties: Yellow hygroscopic substance with a content of C H N 0 Sog/or P. Characteristic groups: -SH, -C00H, -0H. In a mass spectrographic examination, the following fragments were characteristic: C^H^N^S; C^H^N^O^ and C^NO.
Det er antatt at et molekyl har en sidekjede med sulfhydryl-innhold og at det er et purinderivat. It is assumed that a molecule has a side chain with sulfhydryl content and that it is a purine derivative.
Fraksjonen inneholdt ytterligere strukturer. The faction contained additional structures.
Denne fraksjon utviste en fysiologisk henholdsvis terapeutisk virkning allerede ved en dose på 1 mikrogram pr. kg kroppsvekt. This fraction showed a physiological or therapeutic effect already at a dose of 1 microgram per kg body weight.
Produktet kunne renses ytterligere ved kromatografiske eller andre metoder. The product could be further purified by chromatographic or other methods.
Ved hjelp av en cellulase- eller ionebytterkolonne kan de forurensende aminosyrer (lysin, glutaminsyre) fjernes. Således kan det med et utbytte på 0,3 - 0,<L>>$ oppnås fremdeles forurenset litoralon. hvilket imidlertid er virksomt i en konsentrasjon under 1 mikrogram pr. kg kroppsvekt. Utbytte er beregnet på tort biskjoldbruskkjertelpulver. Using a cellulase or ion exchange column, the contaminating amino acids (lysine, glutamic acid) can be removed. Thus, with a yield of 0.3 - 0.<L>>$ still contaminated litoralon can be obtained. which, however, is effective in a concentration below 1 microgram per kg body weight. Yield is calculated on tort parathyroid gland powder.
Eksempel 4 Example 4
Det i eKsempel 1 beskrevne stoff ble gelfiltrert på "Sephadex G—15" ("Pharmacia" svensk produkt, partikkelstbrrelse 90-120 mikron) med nedadgående teknologi. The substance described in Example 1 was gel filtered on "Sephadex G-15" ("Pharmacia" Swedish product, particle size 90-120 microns) with descending technology.
Elueringsdiagrammet ble målt ved 280 nm ekstinksjon. Når man bestemmer volumet av den gjennomstrømte væskemengde som funksjon av ekstinksjonen, inneholder den annen topp regnet forfra, litoralonet. The elution diagram was measured at 280 nm extinction. When determining the volume of fluid flow through as a function of extinction, the second peak counted from the front contains the litoralone.
De karakteristiske parametere ved gelfiltreringen er de fblgende: The characteristic parameters of the gel filtration are the following:
Utgangsmengde: 5,1 g stoff (eksempel 1). Starting amount: 5.1 g of substance (Example 1).
Kolonnediameter: 4,85 cm. Column diameter: 4.85 cm.
Kolonnehoyde: 149 cm. Column height: 149 cm.
Gjennomstromningshastighet: 0,78 ml/min. Flow rate: 0.78 ml/min.
Tid: 10 minutter. Time: 10 minutes.
Storrelse av fraksjonene: 7,8 ml/rbr. Size of the fractions: 7.8 ml/rbr.
Toppen B inneholder virkestoffet. Top B contains the active ingredient.
Elueringsvolumet av 104 ror utgjor 8l4 ml. The elution volume of 104 tubes amounts to 8l4 ml.
Totalvolumet av toppen B utgjor 188 ml. The total volume of top B is 188 ml.
Mellom toppene D og E er klorreaksjonen positiv. Between peaks D and E, the chlorine reaction is positive.
Tbrrvekten av den lyofiliserte topp B varierer mellom 0,43 - 0,53 g når man går ut fra 5 g stoff. The dry weight of the lyophilized top B varies between 0.43 - 0.53 g when starting from 5 g of substance.
Identifisering ved gelfiltrering Identification by gel filtration
Efter gelfiltreringen på "Sephadex G-15" viser stoffet seg i eluatet ved (0,67-0,02) x V , når bestemmelsen skjer i vandig opp-løsning ved absorbsjon ved 280 nm. VQ betyr volumet ved hvilket saltet viser seg i eluatet (positiv klorreaksjon). After the gel filtration on "Sephadex G-15", the substance appears in the eluate at (0.67-0.02) x V , when the determination takes place in aqueous solution by absorption at 280 nm. VQ means the volume at which the salt appears in the eluate (positive chlorine reaction).
Toppen B fraksjoneres på en "Dowex' 50x2" kolonne ved pH 1,8. Peak B is fractionated on a "Dowex' 50x2" column at pH 1.8.
301 mg stoff i en 30$-ig vandig opplosning påfores på en 301 mg of substance in a 30$-ig aqueous solution is applied to a
132 x 1 cm "Dowex 50x2" kolonne som på forhånd er utbalansert med en maursyre-eddiksyreblanding på pH 1,8. Gjennomstromningshastighet: 13 ml/time. Fraksjonsstorrelse: h ml. Fraksjonene bestemmes ved 280 nm. Man fikk 9 elueringstopper: 132 x 1 cm "Dowex 50x2" column pre-equilibrated with a formic acid-acetic acid mixture at pH 1.8. Flow rate: 13 ml/hour. Fraction size: h ml. The fractions are determined at 280 nm. 9 elution peaks were obtained:
Storstedelen av virkestoffet var i fraksjon E-^, men endel av virkestoffet kan også være tilstede i fraksjonene D^, D2 og E2. The majority of the active substance was in fraction E-^, but some of the active substance may also be present in fractions D^, D2 and E2.
De ovennevnte fraksjoner påfores på Whatman 3 MM papir i en bredde på 22 cm og underkastes elektroforese ved pH 1,8 med 1500 V The above fractions are applied to Whatman 3 MM paper in a width of 22 cm and subjected to electrophoresis at pH 1.8 with 1500 V
i 90 minutter. for 90 minutes.
Materialpåfbring 0,5 mg/2 cm. Sammensetning av pufferen: Material application 0.5 mg/2 cm. Composition of the puffer:
h0 ml 98%-ig maursyre og 160 ml iseddik fortynnet med destillert vann til 2 liter. h0 ml of 98% formic acid and 160 ml of glacial acetic acid diluted with distilled water to 2 litres.
Virkstoffet er ninhydrinpositivt og vandrer jevnt fra begyn-nelseslinjen mot den positive pol (5 cm/90 rnin/l^OO V). The active substance is ninhydrin-positive and migrates evenly from the starting line towards the positive pole (5 cm/90 rnin/l^OO V).
Det ved elektroforese isolerte produkt elueres med vann og proves på sin biologiske aktivitet. Utbytte av det isolerte produkt regnet på tort kjertelpulver utgjorde 0,01-0,02$. The product isolated by electrophoresis is eluted with water and tested for its biological activity. Yield of the isolated product calculated on dry glandular powder was 0.01-0.02$.
Det på denne måte erholdte litoralon kan betraktes sorn The litoralon obtained in this way can be considered sorn
kjemisk rent, og dets biologiske aktivitet ble bevist ved fblgende forsok: chemically pure, and its biological activity was proven by the following experiment:
Vekten av Harder-kjertLene hos rottene var betydelig oket ved The weight of the Harder glands in the rats was significantly increased
en dosering på 3/120 g subkutant. Ved samme dosering ble blod-sukkerinnholdet redusert betydelig. a dosage of 3/120 g subcutaneously. At the same dosage, the blood sugar content was significantly reduced.
Ved en dosering av orale tabletter på 7 mikrogram tre ganger daglig ble symptomene på Rhinolarringo-pharingitis sicca hos mennesker helbredet og AMP-raen.gd.en som ble utskilt med urinen, oket betydelig. At a dosage of oral tablets of 7 micrograms three times a day, the symptoms of Rhinolarryngopharyngitis sicca in humans were cured and the AMP-raen.gd.en excreted in the urine increased significantly.
Eksempel 5 Example 5
Det ifolge eksempol 1 erholdte og lyofiliserte sluttprodukt ble underkastet en dialyse. 700 mg suostans ble lost i 33 ml destillert vann og dialisert i en dialysemembran hh. Det ble dialysert mot 2 ganger 100 og deretter 13 ganger 1^0 ml vann på en slik måte at den ytre vandige fase ble skiftet hver 3,5 time. I hver av de 3 -mellomliggende netter var utskiftningstiden 16 timer. Dialysen ble utfort ved 5°C. The final product obtained and lyophilized according to Example 1 was subjected to dialysis. 700 mg of suostans was dissolved in 33 ml of distilled water and dialyzed in a dialysis membrane hh. It was dialyzed against 2 times 100 and then 13 times 1^0 ml of water in such a way that the outer aqueous phase was changed every 3.5 hours. In each of the 3 intervening nights, the replacement time was 16 hours. The dialysis was carried out at 5°C.
Innen membranen forble hl ml av Ibsningen (ikke dialyserende del). Within the membrane remained hl ml of the Ibsningen (non-dialysing part).
Torrvekt etter lyofili sering var 35 mg. Dry weight after lyophilization was 35 mg.
Den ytre fase ble inndampet i vacuum ved 3U°C og ga etter lyofilisering 662 mg tdrrsubstans. The outer phase was evaporated in vacuum at 3U°C and after lyophilization gave 662 mg of tdr substance.
Eksempel 6 Example 6
Man gikk ut fra 20 g kjertelpulver (lyofili sert, ikke-avfettet) og etter fremgangsmåten ifolge eksempel 1 ble den fra eggehvitestoff og ether separerte vandige lbsning inndampet til 1/3 volum, og deretter utristet 3 ganger med kloroform (1:1) hvoretter kloroformen ble fjernet i vakuum. Den kloroformfrie vandige lbsning ble inndampet videre i vakuum til 20 ml, og ved romtemperatur ble 5 volumdeler aceton tilsatt. Lbsningen fikk stå over natten på is. The starting point was 20 g of glandular powder (lyophilized, non-defatted) and following the procedure according to example 1, the aqueous solution separated from egg white and ether was evaporated to 1/3 volume, and then decanted 3 times with chloroform (1:1) after which the chloroform was removed in vacuo. The chloroform-free aqueous solution was further evaporated in vacuo to 20 ml, and at room temperature 5 parts by volume of acetone were added. The mixture was allowed to stand overnight on ice.
Fra den praktisk talt farvelbse acetonfase separerte ut en From the practically goodbye acetone phase separated out a
gul oljeaktig del. Acetonfasen ble dekantert fra, og det gule olje-aktige stoff ble tbrret i vakuum til konstant vekt. Det ble erholdt 1,1 g av et gult, harpiksaktig konsentrat A. yellow oily part. The acetone phase was decanted off, and the yellow oily substance was evaporated in vacuo to constant weight. 1.1 g of a yellow, resinous concentrate A was obtained.
Acetonldsnin<g>en ble inndampet i vakuum til tbrrhet. Det ble erholdt 1 g av et harpiksaktig konsentrat B. The acetone solution was evaporated in vacuo to dryness. 1 g of a resinous concentrate B was obtained.
Eksempel 7 Example 7
Man gikk ut fra 50 g lyofilisert kjertelpulver som ble avfettet som beskrevet i eksempel 1. 38 g av det fettfrie kjertelpulver ble blandet med 400 ml av en 10$'ig urealosning. Etter 1 times henstand ble blandingen blandet med 400 ml iseddik og 400 ml aceton. Blandingen fikk stå. i 1 time, hvoretter den ble overhelt 1200 ml aceton og 11,2 ml N natriumhydroxydlosning. blandingen ble filtrert gjennom et lag av gas,' Til det urea- og acetonholdige ekstrakt ble tilsatt 2 1 ether. blandingen fikk stå over natten og ble deretter dekantert. Suspensjonen ble sentrifugert og vasket 2 ganger med 50 ml aceton-ether (1:1). Det erholdte bunnfall ble blandet med 200 ml av en 10$'ig eddiksyrelosning, hvorved bunnfallet lostes. Fra losningen ble ved iblanding av 10 g natriumklorid utfelt et bunnfall. Bunnfallet ble opptatt i 50 ml vann. The starting point was 50 g of lyophilized gland powder which was degreased as described in example 1. 38 g of the fat-free gland powder was mixed with 400 ml of a 10% urea solution. After standing for 1 hour, the mixture was mixed with 400 ml of glacial acetic acid and 400 ml of acetone. The mixture was allowed to stand. for 1 hour, after which it was poured over with 1200 ml of acetone and 11.2 ml of N sodium hydroxide solution. the mixture was filtered through a layer of gas, to the urea- and acetone-containing extract 2 1 of ether was added. the mixture was allowed to stand overnight and then decanted. The suspension was centrifuged and washed 2 times with 50 ml of acetone-ether (1:1). The precipitate obtained was mixed with 200 ml of a 10% acetic acid solution, whereby the precipitate was dissolved. A precipitate was precipitated from the solution by mixing in 10 g of sodium chloride. The precipitate was taken up in 50 ml of water.
Man dialyserte med 6 ganger 2 1 vann, tomte ut dialysevannet og lyofiliserte det gj-enværende produkt. Det ble erholdt 732 g av et fast konsentrat. Den etter utfelling med NaCl og sentrifugering i losning tilbakeværende stoff (197 ml) ble behandlet med 40 ml 45$'ig trikloreddiksyre og deretter sentrifugert. Den torre fase ble dialysert 4 ganger, hver gang med 3 1 vann, inndampet i vakuum og lyofilisert. Det ble erholdt 86 g av et konsentrat (substans D). One dialyzed with 6 times 2 1 of water, emptied the dialysis water and lyophilized the remaining product. 732 g of a solid concentrate were obtained. After precipitation with NaCl and centrifugation in solution, the remaining substance (197 ml) was treated with 40 ml of 45% trichloroacetic acid and then centrifuged. The dry phase was dialyzed 4 times, each time with 3 1 of water, evaporated in vacuo and lyophilized. 86 g of a concentrate (substance D) were obtained.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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HUCI1146A HU169462B (en) | 1971-08-04 | 1971-08-04 |
Publications (2)
Publication Number | Publication Date |
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NO138852B true NO138852B (en) | 1977-08-14 |
NO138852C NO138852C (en) | 1978-11-22 |
Family
ID=10994410
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Application Number | Title | Priority Date | Filing Date |
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NO722758A NO138852C (en) | 1971-08-04 | 1972-08-03 | PROCEDURES FOR THE PRODUCTION OF A NEW HORMONE, LITORALON |
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JP (1) | JPS5416565B2 (en) |
AR (1) | AR199086A1 (en) |
AT (1) | AT318802B (en) |
AU (1) | AU476825B2 (en) |
BE (1) | BE786911A (en) |
CA (1) | CA996026A (en) |
CH (1) | CH609704A5 (en) |
CS (1) | CS180062B1 (en) |
DD (2) | DD99307A1 (en) |
DE (1) | DE2234832C2 (en) |
DK (1) | DK134509B (en) |
EG (1) | EG10643A (en) |
ES (1) | ES405274A1 (en) |
FI (1) | FI51429C (en) |
FR (1) | FR2150719B1 (en) |
GB (1) | GB1404225A (en) |
HU (1) | HU169462B (en) |
IL (1) | IL39924A (en) |
IN (1) | IN138815B (en) |
NL (1) | NL173357C (en) |
NO (1) | NO138852C (en) |
PL (1) | PL82013B1 (en) |
RO (1) | RO62452A (en) |
SE (1) | SE416266B (en) |
SU (1) | SU624562A3 (en) |
YU (1) | YU35450B (en) |
ZA (1) | ZA724904B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2517028A1 (en) * | 1971-08-04 | 1975-11-20 | Chinoin Gyogyszer Es Vegyeszet | METHOD OF ISOLATING GAMMA-L-GLUTAMYLTAURINE |
JPS5076516A (en) * | 1973-11-12 | 1975-06-23 | ||
JPS543205B2 (en) * | 1973-12-28 | 1979-02-20 | ||
IL47149A (en) * | 1974-04-29 | 1979-05-31 | Chinoin Gyogyszer Es Vegyeszet | Amino acid derivatives,their preparation and pharmaceutical compositions containing them |
JPS5144219A (en) * | 1974-10-14 | 1976-04-15 | Japan Servo | Musatsushidendokino kaitenseigyosochi |
JPS5750437B2 (en) * | 1974-12-28 | 1982-10-27 | ||
JPS5238315U (en) * | 1975-09-11 | 1977-03-18 |
-
1971
- 1971-08-04 HU HUCI1146A patent/HU169462B/hu unknown
-
1972
- 1972-07-15 DE DE2234832A patent/DE2234832C2/en not_active Expired
- 1972-07-17 ZA ZA724904A patent/ZA724904B/en unknown
- 1972-07-17 IL IL39924A patent/IL39924A/en unknown
- 1972-07-21 AU AU44839/72A patent/AU476825B2/en not_active Expired
- 1972-07-28 BE BE786911A patent/BE786911A/en not_active IP Right Cessation
- 1972-07-28 ES ES405274A patent/ES405274A1/en not_active Expired
- 1972-07-31 YU YU1978/72A patent/YU35450B/en unknown
- 1972-08-01 DD DD164796A patent/DD99307A1/xx unknown
- 1972-08-01 AT AT662272A patent/AT318802B/en not_active IP Right Cessation
- 1972-08-01 DD DD168077*A patent/DD101814A1/xx unknown
- 1972-08-01 SE SE7210027A patent/SE416266B/en unknown
- 1972-08-01 CA CA148,391A patent/CA996026A/en not_active Expired
- 1972-08-02 FR FR7227814A patent/FR2150719B1/fr not_active Expired
- 1972-08-02 PL PL1972157074A patent/PL82013B1/en unknown
- 1972-08-02 FI FI722154A patent/FI51429C/en active
- 1972-08-02 EG EG314/72A patent/EG10643A/en active
- 1972-08-03 CH CH1149972A patent/CH609704A5/xx not_active IP Right Cessation
- 1972-08-03 NL NLAANVRAGE7210648,A patent/NL173357C/en not_active IP Right Cessation
- 1972-08-03 NO NO722758A patent/NO138852C/en unknown
- 1972-08-03 DK DK382572AA patent/DK134509B/en not_active IP Right Cessation
- 1972-08-03 AR AR243415A patent/AR199086A1/en active
- 1972-08-03 SU SU721818168A patent/SU624562A3/en active
- 1972-08-03 JP JP7798972A patent/JPS5416565B2/ja not_active Expired
- 1972-08-04 RO RO7200071859A patent/RO62452A/en unknown
- 1972-08-04 GB GB3660872A patent/GB1404225A/en not_active Expired
- 1972-08-04 CS CS7200005460A patent/CS180062B1/en unknown
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1973
- 1973-05-22 IN IN1198/CAL/73A patent/IN138815B/en unknown
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