EP0689446A1 - Drugs for the treatment of retrovirus infections - Google Patents

Drugs for the treatment of retrovirus infections

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Publication number
EP0689446A1
EP0689446A1 EP94910387A EP94910387A EP0689446A1 EP 0689446 A1 EP0689446 A1 EP 0689446A1 EP 94910387 A EP94910387 A EP 94910387A EP 94910387 A EP94910387 A EP 94910387A EP 0689446 A1 EP0689446 A1 EP 0689446A1
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Prior art keywords
extracts
extract
medicament according
ginkgo
retrovirus infections
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German (de)
French (fr)
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Hans-Georg Laves
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LAVES HANS GEORG
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LAVES HANS GEORG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to medicaments for the treatment of retrovirus infections.
  • Retroviruses are spherical enveloped RNA viruses, of which two subfamilies are pathogenic for humans and animals. Retroviruses are characterized by reverse transcriptase, an RNA-dependent DNA polymerase. During replication, the single-stranded virus RNA is transcribed from the reverse transcriptase into a double-stranded DNA intermediate and this is incorporated into the genome of the host cell as a provirus. From the provirus, regular transcription initiates the formation of RNA-containing virus particles which leave the host cell after budding. Retroviruses cause leukaemias, autoimmune diseases and immune depressions, in people in particular AIDS and ARS, namely AIDS-related syndromes, the preliminary stage for the full clinical picture of AIDS.
  • Extracts from the leaves of Ginkgo biloba have been used for some time for the therapy of peripheral and cerebral arterial circulatory disorders.
  • Processes for producing ginkgo extracts from green leaves are described, for example, in DE-PS 17 67 098, DE-PS 21 17 429 and in EP-A 0 324 197, from EP-A 0 330 567 and from DE-OS 39 40 091 known.
  • Another method for extracting yellow autumn leaves from Ginkgo biloba is described in EP-B 0 352 146.
  • the leaves of Ginkgo biloba contain a number of different compounds in which the so-called ginkgo flavone glycosides predominate.
  • a typical representative of this class of substances is 5, 7, 3 * 4 'tetrahydroxy-flavono-3-O- ⁇ - rhamnopyranosyl-4-O- ⁇ -D- (6' '' -transcoumaroyl) glycopyranoside.
  • Terpene lactones are contained in smaller amounts, for example the ginkgolides which have been described, for example, by Okabe et al., J. Chem. SOC (1967), 2201-2206.
  • Bilobalide the use of which for the treatment of neuropathies and similar diseases is known from US Pat. No. 4,571,407, is also closely related to the terpene lactones.
  • Leaves of Ginkgo biloba also contain the so-called ginkgol acids, which are 6-alkyl
  • REPLACEMENT BLA ⁇ (RULE 26) salicylic acids, which have alkyl radicals with 13 - 19 carbon atoms and 0 - 3 double bonds.
  • These ginkgolic acids can be used to produce the correspondingly substituted phenol, which is known to be allergic, biogenetically or when working up the leaves.
  • the production processes for the extracts therefore differ essentially in that an attempt is made to eliminate the undesired ingredients or accompanying substances as far as possible, in particular if the extracts are later to be used in injectable form.
  • a number of methods are available to the person skilled in the art from the known literature in order to separate undesired ingredients.
  • the ginkgo extracts commercially available today are therefore generally well tolerated even in injectable form; such products are for example from the company Dr. Wilmar Schwabe GmbH & Co. in D-7500 Düsseldorf marketed under the "Tebonin" brand.
  • EP-B-0 352 146 already mentions that extracts from the yellow leaves of Ginkgo biloba would be able to reduce an increased level of gamma globulins in mammals, as can also be observed, for example, in AIDS patients. This publication does not provide any further details as to whether and with what success this extract can actually be used in AIDS.
  • the bacterial and protein-free extracts from Escherichia coli contain relatively short-chain oligopeptides and, as can be seen from the studies in Drug Res. 23, 829-830 (1973), a polysaccharide component consisting predominantly of glucose, galactose and xylose and a small proportion of fatty acids. However, nucleic acids could not be detected. It is striking that the quantitative studies on these peptides to date have confirmed the absence of aromatic amino acids with the exception of histidine.
  • Such cell and protein-free extracts from Escherichia coli cultures can be administered orally or as an injection.
  • Corresponding preparations are, for example, from Laves Arzneistoff GmbH, Barbarastr. 14, 3003 Ronnenberg under the "Colibiogen" brand.
  • the medicaments according to the invention can be administered orally, but preferably as an injection. It has been found that coli and ginkgo extracts can be given together with the nucleoside therapeutics, but on the other hand it also has advantages if the coli or ginkgo extract is used before the nucleoside therapeutic is administered, this time shift can range from a few hours to 1-2 days.
  • the invention therefore also relates to a so-called kit which contains the individual active ingredients for oral or parenteral administration in spatially separated form.
  • the dosage for the dose unit for the coli extract is protein- and cell-free metabolites from about 4 - 9 x germs, while for the ginkgo extract the dose unit contains about 50 - 200 mg dry extract.
  • the daily dose must be set individually for each patient. No side effects have been identified, even with long-term treatment. The invention is explained in more detail below with the aid of the examples:
  • the coli extract was prepared according to the method described in DE-PS 38 16 298 by inoculating bouillon cultures with a strain of the desired E. coli serotype and incubating at 37 ° C. for at least 5 days.
  • the serotype 02: K1: K6 is preferably used.
  • the extracts can be freed of water by gentle vacuum drying and processed into capsules or tablets in a manner known per se.
  • green or yellow leaves of Ginkgo biloba are finely chopped and mixed in a known manner with aqueous acetone or ethanol, in particular a mixture of water with acetone or ethanol in a ratio of 50:50 for several hours at temperatures between about 40- 60 ° extracted.
  • aqueous acetone or ethanol in particular a mixture of water with acetone or ethanol in a ratio of 50:50 for several hours at temperatures between about 40- 60 ° extracted.
  • liquid is pressed from the leaves, which can be subjected to a further extraction.
  • the aqueous extract obtained is extracted in a first purification stage with a water-immiscible solvent, preferably cyclohexane.
  • the aqueous ketonic phase is then processed further, the non-polar phase is discarded.
  • the aqueous ketonic phase is then concentrated to approximately half its volume and the precipitate which has separated out is filtered off.
  • the filtered Solution is mixed with ammonium sulfate in a known manner and extracted with butanol. After drying over sodium sulfate, the extract obtained is concentrated under reduced pressure and finally extracted exhaustively with ethanol. This residue is then concentrated under vacuum to dry.
  • This extract which can now be made up in the usual way, contains on average, depending on the origin and age of the leaves, about 10% up or down, about 25% ginkgo flavone glycosides and about 5% terpene lactones.

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  • Immunology (AREA)
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Abstract

The invention concerns drugs for the treatment of retrovirus infections, the drugs containing bacteria-free and protein-free extracts of Escherichia coli, optionally with the addition of extracts of green or yellow leaves of Ginkgo biloba.

Description

Arzneimittel zur Behandlung von RetrovirusinfektionenMedicines used to treat retrovirus infections
Die Erfindung betrifft Arzneimittel zur Behandlung von Retro¬ virusinfektionen.The invention relates to medicaments for the treatment of retrovirus infections.
Retroviren sind kugelförmige umhüllte RNA-Viren, von denen zwei Subfamilien human- und tierpathogen sind. Kennzeichen der Retroviren ist die reverse Transkriptase, eine RNA-ab- hängige DNA-Poly erase. Bei der Replikation wird die ein- strängige Virus-RNA von der reversen Transkriptase in eine doppelsträngige DNA-Zwischenstufe transkribiert und- diese wird als Provirus in das Genom der Wirtszelle eingebaut. Vom Provirus aus wird durch eine reguläre Transkription die Bildung RNA-haltiger Viruspartikel eingeleitet, die die Wirts¬ zelle nach Knospung verlassen. Retroviren verursachen Leukämien, Autoimmunkrankheiten sowie Immundepressionen, und zwar bei Menschen insbesondere Aids und ARS, nämlich Aids Related Syndrome , die Vorstufe zum vollen Krankheitsbild von Aids. Eine Heilung von Retrovirusinfektionen bei Menschen ist bis heutehin nicht möglich, da bisher alle Versuche, einen Impf¬ stoff gegen das Virus zu entwickeln, wegen dessen sehr hoher Mutationsgeschwindigkeit gescheitert sind. Therapeutisch werden Medikamente bisher verwendet, die die reverse Trans¬ kriptase hemmen, hierbei handelt es sich meist um substitu¬ ierte Desoxynucleoside von Guanosin, Cytitin und Thymidin. Bisher bekanntester Wirkstoff ist das AZT, das allerdings auch nur in der Lage ist, die Symptome einer Retrovirusin- fektion deutlich zu verzögern, nicht aber die Krankheit zu heilen.Retroviruses are spherical enveloped RNA viruses, of which two subfamilies are pathogenic for humans and animals. Retroviruses are characterized by reverse transcriptase, an RNA-dependent DNA polymerase. During replication, the single-stranded virus RNA is transcribed from the reverse transcriptase into a double-stranded DNA intermediate and this is incorporated into the genome of the host cell as a provirus. From the provirus, regular transcription initiates the formation of RNA-containing virus particles which leave the host cell after budding. Retroviruses cause leukaemias, autoimmune diseases and immune depressions, in people in particular AIDS and ARS, namely AIDS-related syndromes, the preliminary stage for the full clinical picture of AIDS. A cure for retrovirus infections in humans has not been possible until now, since all attempts to develop a vaccine against the virus have failed because of its very high mutation rate. Medicaments which inhibit reverse transcriptase have hitherto been used therapeutically; these are mostly substituted deoxynucleosides of guanosine, cytinine and thymidine. The best known active ingredient to date is AZT, which, however, is only able to significantly delay the symptoms of a retrovirus infection, but not to cure the disease.
Völlig überraschend wurde jetzt festgestellt, daß an sich bekannte bakterien- und eiweißfreie Extrakte aus Escherichia coli, ggf. in Kombination mit Extrakten aus Ginkgo biloba in der Lage sind, die Entwicklung von Retrovirusinfektionen deutlich zu verlangsamen, ohne die bisher von den Nukleosid- therapeutika bekannten Nebenwirkungen aufzuweisen. Die Coli- Extrakte können zusammen mit den Ginkgo-Extrakten als solche eingesetzt werden, es ist aber auch möglich, die Extrakte mit einer Therapie mit Nukleosidtherapeutika zu kombinieren, wobei eine Verringerung der Dosis der Nukleoside und damit auch der zu erwartenden Nebenwirkungen möglich ist.It has now been found, completely surprisingly, that known bacterial and protein-free extracts from Escherichia coli, possibly in combination with extracts from Ginkgo biloba, are capable of significantly slowing down the development of retrovirus infections without exhibiting the side effects known to date from nucleoside therapeutics. The coli extracts can be used as such together with the ginkgo extracts, but it is also possible to combine the extracts with therapy with nucleoside therapeutics, whereby a reduction in the dose of the nucleosides and thus also the expected side effects is possible.
Extrakte aus den Blättern von Ginkgo biloba werden bereits seit geraumer Zeit für die Therapie von peripheren und zere¬ bralen arteriellen Durchblutungsstörungen eingesetzt. Verfahren zur Herstellung von Ginkgo-Extrakten aus grünen Blä/ttern sind beispielsweise aus der DE-PS 17 67 098, DE-PS 21 17 429 sowie in der EP-A 0 324 197, aus der EP-A 0 330 567 und aus der DE-OS 39 40 091 bekannt. Ein weiteres Verfahren zur Ex-trahierung von gelben Herbstblättern von Ginkgo biloba ist in der EP-B 0 352 146 beschrieben.Extracts from the leaves of Ginkgo biloba have been used for some time for the therapy of peripheral and cerebral arterial circulatory disorders. Processes for producing ginkgo extracts from green leaves are described, for example, in DE-PS 17 67 098, DE-PS 21 17 429 and in EP-A 0 324 197, from EP-A 0 330 567 and from DE-OS 39 40 091 known. Another method for extracting yellow autumn leaves from Ginkgo biloba is described in EP-B 0 352 146.
Die Blätter von Ginkgo biloba enthalten eine Reihe von unter¬ schiedlichen Verbindungen, bei denen die sogenannten Ginkgo- flavonglykoside überwiegen. Ein typischer Verteter dieser Substanzklasse ist das 5 ,7 ,3 * 4 ' -Tetrahydroxy-Flavono-3-O-^ - rhamnopyranosyl-4-O- Λ -D- (6 ' ' ' -transcumaroyl) -glycopyranosid. In geringeren Mengen sind Terpenlactone enthalten wie bei¬ spielsweise die Ginkgolide, die beispielsweise von Okabe et al., J. Chem. SOC (1967) , 2201-2206 näher beschrieben wurden. Eng verwandt mit den Terpenlactonen ist auch das Bilobalid, dessen Verwendung zur Behandlung von Neuropathien und ähnlichen Erkrankungen aus der US-PS 4571407 bekannt ist.The leaves of Ginkgo biloba contain a number of different compounds in which the so-called ginkgo flavone glycosides predominate. A typical representative of this class of substances is 5, 7, 3 * 4 'tetrahydroxy-flavono-3-O- ^ - rhamnopyranosyl-4-O- Λ -D- (6' '' -transcoumaroyl) glycopyranoside. Terpene lactones are contained in smaller amounts, for example the ginkgolides which have been described, for example, by Okabe et al., J. Chem. SOC (1967), 2201-2206. Bilobalide, the use of which for the treatment of neuropathies and similar diseases is known from US Pat. No. 4,571,407, is also closely related to the terpene lactones.
Des weiteren enthalten Blätter von Ginkgo biloba noch die sogenannten Ginkgol-Säuren, bei denen es sich um 6-Alkyl-Leaves of Ginkgo biloba also contain the so-called ginkgol acids, which are 6-alkyl
ERSATZBLAπ(REGEL26) salicylsäuren handelt, die über Alkylreste mit 13 - 19 C- Atomen und 0 - 3 Doppelbindungen verfügen. Aus diesen Ginkgol- säuren kann biogenetisch oder bei der Aufarbeitung der Blät¬ ter das jeweils entsprechend substituierte Phenol entste¬ hen, das als allergisierend bekannt ist. Die Herstellungs¬ verfahren für die Extrakte unterscheiden sich daher im we¬ sentlichen dadurch, daß versucht wird, die unerwünschten Inhalts- oder Begleitstoffe soweit wie möglich zu eliminie¬ ren, insbesondere, wenn die Extrakte später in injizierbarer Form angewendet werden sollen. Dem Fachmann stehen aber aus der bekannten Literatur eine Reihe von Verfahren zur Verfü¬ gung, um unerwünschte Inhaltsstoffe abzutrennen. Die heute im Handel erhältlichen Ginkgo-Extrakte sind daher in der Regel auch in injizierbarer Form gut verträglich; solche Produkte werden beispielsweise von der Firma Dr. Wilmar Schwa¬ be GmbH & Co. in D-7500 Karlsruhe unter der Marke "Tebonin" in den Handel gebracht.REPLACEMENT BLAπ (RULE 26) salicylic acids, which have alkyl radicals with 13 - 19 carbon atoms and 0 - 3 double bonds. These ginkgolic acids can be used to produce the correspondingly substituted phenol, which is known to be allergic, biogenetically or when working up the leaves. The production processes for the extracts therefore differ essentially in that an attempt is made to eliminate the undesired ingredients or accompanying substances as far as possible, in particular if the extracts are later to be used in injectable form. However, a number of methods are available to the person skilled in the art from the known literature in order to separate undesired ingredients. The ginkgo extracts commercially available today are therefore generally well tolerated even in injectable form; such products are for example from the company Dr. Wilmar Schwabe GmbH & Co. in D-7500 Karlsruhe marketed under the "Tebonin" brand.
Die EP-B-0 352 146 erwähnt bereits, daß Extrakte aus den gelben Blättern von Ginkgo biloba in der Lage wären, einen erhöhten Spiegel an Gammaglobulinen bei Säugetieren zu redu¬ zieren, wie er beispielsweise auch bei Aidskranken zu beobach¬ ten ist. Nähere Einzelheiten darüber, ob und mit welchem Erfolg dieser Extrakt tatsächlich bei Aids eingesetzt wer¬ den kann, ergeben sich aber nicht aus dieser Veröffentlichung.EP-B-0 352 146 already mentions that extracts from the yellow leaves of Ginkgo biloba would be able to reduce an increased level of gamma globulins in mammals, as can also be observed, for example, in AIDS patients. This publication does not provide any further details as to whether and with what success this extract can actually be used in AIDS.
Bakterien- und eiweißfreie Filtrate aus Escherichia coli Kulturen werden schon seit langem therapeutische verwendet, und zwar einerseits bei Motilitäts- oder Permeabilitätsstörungen der Darmschleimhaut, aber auch bei Entzündungen wie Morbus Crohn oder nach Antibiotika-, Chemo- oder Strahlentherapie. Ein anderes Anwendungsgebiet der Coli-Extrakte sind Allergien wie Heuschnupfen, Urtikaria, Ekzem, Nahrungsmittelallergien und Asthma. Schließlich hat sich auch ein weiteres therapeu¬ tisches Anwendungsgebiet bei Akne und Migräne ergeben und darüber hinaus sind diese Extrakte, wie in der DE-PS 38 16 298 beschrieben, anabol wirksam und führen zu einer Stimula¬ tion der nicht erregerspezifischen Immunabwehr. Herstellungs¬ verfahren sind unter anderen auch in der DE-PS 38 16 298 beschrieben. Die bakterien- und eiweißfreien Extrakte aus Escherichia coli enthalten relativ kurzkettige Oligopeptide und, wie sich aus den Untersuchungen in Drug Res. 23, 829- 830 (1973) ergibt, einen Polysacharidanteil aus überwiegend Glukose, Galaktose und Xylose sowie einen geringen Anteil an Fettsäuren. Nucleinsäuren konnten jedoch nicht nachgewie¬ sen werden. Auffallend ist, daß die bisherigen quantitativen Untersuchungen an diesen Peptiden das Fehlen von aromatischen Aminosäuren mit Ausnahme von Histidin bestätigt haben.Bacteria and protein-free filtrates from Escherichia coli cultures have long been used therapeutically, on the one hand for motility or permeability disorders of the intestinal mucosa, but also for inflammations such as Crohn's disease or after antibiotic, chemotherapy or radiation therapy. Another area of application for coli extracts is allergies such as hay fever, urticaria, eczema, food allergies and asthma. Finally, a further therapeutic area of application for acne and migraines has emerged and moreover, these extracts, as described in DE-PS 38 16 298, are anabolically active and lead to a stimulation of the non-pathogen-specific immune defense. Manufacturing processes are also described in DE-PS 38 16 298, among others. The bacterial and protein-free extracts from Escherichia coli contain relatively short-chain oligopeptides and, as can be seen from the studies in Drug Res. 23, 829-830 (1973), a polysaccharide component consisting predominantly of glucose, galactose and xylose and a small proportion of fatty acids. However, nucleic acids could not be detected. It is striking that the quantitative studies on these peptides to date have confirmed the absence of aromatic amino acids with the exception of histidine.
Derartige zell- und eiweißfreie Extrakte aus Escherichia coli Kulturen können peroral oder auch als Injektion verab¬ reicht werden. Entsprechende Präparate sind beispielsweise von der Fa. Laves Arzneimittel GmbH, Barbarastr. 14, 3003 Ronnenberg unter der Marke "Colibiogen" im Handel.Such cell and protein-free extracts from Escherichia coli cultures can be administered orally or as an injection. Corresponding preparations are, for example, from Laves Arzneimittel GmbH, Barbarastr. 14, 3003 Ronnenberg under the "Colibiogen" brand.
Die Wirkung von Coli-Extrakten, insbesondere in Kombination mit Ginkgo-Extrakten bei Retrovirusinfektionen läßt sich zur Zeit wissenschaftlich noch nicht eindeutig erklären. Klinische Versuche haben allerdings deutlich gezeigt, daß sich unter dieser Medikation der Allgemeinzustand der Patienten verbessert und daß sich der Anteil an T^Lymphozyten erhält oder sogar meist eindeutig erhöht. Nach einer vor kurzem entwickelten Arbeitshypothese beruht der zu beobachtende Ausfall der spezifischen Immunabwehr vermutlich darauf, daß die Infektionen mit Retroviren zu einer Abnahme der T4-Lympho- zyten und später auch zu einer Abnahme der Tg-Lymphozyten führt. Eine hierauf beruhende Überproduktion von "ungerichteten" Immunglobulinen durch B-Lymphyzyten soll dann zu einer Schwächung der spezifischen Immunabwehr und zu deren Zusam¬ menbruch beitragen. Es gibt aus den klinischen Beobachtungen Gründe für die Annahme, daß die Wirkstoffe im Coli- und Ginkgo- Extrakt die zunehmende Produktion von "ungerichteten" Immun- globulinen reduzieren bzw. verhindern.The effect of coli extracts, especially in combination with ginkgo extracts in retrovirus infections, cannot yet be clearly explained scientifically. Clinical trials, however, have clearly shown that the general condition of the patients improves with this medication and that the proportion of T ^ lymphocytes is maintained or even significantly increased in most cases. According to a recently developed working hypothesis, the observed failure of the specific immune defense is probably due to the fact that the infections with retroviruses lead to a decrease in the T 4 lymphocytes and later also to a decrease in the Tg lymphocytes. An overproduction of "undirected" immunoglobulins based on this by B-lymphycytes should then contribute to a weakening of the specific immune defense and its breakdown. There are clinical observations Reasons for the assumption that the active ingredients in the coli and ginkgo extract reduce or prevent the increasing production of "undirected" immunoglobulins.
Außerdem hat sich herausgestellt, daß bei Gabe von Coli- und Ginkgo-Extrakten eine Reduzierung der Dosis von retroviren- spezifischen Arzneimitteln erfolgen kann, womit die Gefahr von Nebenwirkungen, insbesondere sekundären Anämien wesent¬ lich verkleinert wird. Die Dosisreduzierung scheint nur zum Teil mit einer besseren Ansprechbarkeit auf Nukleosidtherapeu- tika begründet zu sein. In wieweit durch die Kombination auch andere biochemische Mechanismen angesprochen werden, ist noch ungeklärt.In addition, it has been found that when coli and ginkgo extracts are administered, the dose of retrovirus-specific medicaments can be reduced, which significantly reduces the risk of side effects, in particular secondary anemias. The dose reduction appears to be only partly due to better responsiveness to nucleoside therapeutics. The extent to which other biochemical mechanisms are addressed by the combination is still unclear.
Die erfindungsgemäßen Arzneimittel können peroral, vorzugswei¬ se aber als Injektion verabreicht werden. Es hat sich herausge¬ stellt, daß Coli- und Ginkgo-Extrakte zusammen mit dem Nukleosid- therapeutika gegeben werden können, daß es aber andererseits auch Vorzüge aufweist, wenn der Coli- bzw. Ginkgo-Extrakt zeitlich vor der Gabe des Nukleosidtherapeutikums eingesetzt wird, wobei diese zeitliche Verschiebung einige Stunden bis 1-2 Tage betragen kann. Die Erfindung betrifft daher auch einen sogenannten Kit, der die einzelnen Wirkstoffe für die perorale oder parenterale Gabe in räumlich getrennter Form enthält.The medicaments according to the invention can be administered orally, but preferably as an injection. It has been found that coli and ginkgo extracts can be given together with the nucleoside therapeutics, but on the other hand it also has advantages if the coli or ginkgo extract is used before the nucleoside therapeutic is administered, this time shift can range from a few hours to 1-2 days. The invention therefore also relates to a so-called kit which contains the individual active ingredients for oral or parenteral administration in spatially separated form.
Die Dosierung beträgt für die Dosiseinheit beim Coli-Extrakt eiweiß- und zellfreie Stoffwechselprodukte aus etwa 4 - 9 x Keimen, während beim Ginkgo-Extrakt die Dosiseinheit etwa 50 - 200 mg Trockenextrakt enthält. Die Tagesdosis muß für jeden Patienten individuell eingestellt werden. Auch bei Langzeitbehandlung sind bisher keine Nebenwirkungen festgestellt worden. Die Erfindung wird im folgenden anhand der Beispiele näher erläutert:The dosage for the dose unit for the coli extract is protein- and cell-free metabolites from about 4 - 9 x germs, while for the ginkgo extract the dose unit contains about 50 - 200 mg dry extract. The daily dose must be set individually for each patient. No side effects have been identified, even with long-term treatment. The invention is explained in more detail below with the aid of the examples:
Beispiel 1example 1
Die Herstellung des Coli-Extraktes erfolgte nach dem in der DE-PS 38 16 298 näher beschriebenen Verfahren, indem Bouil¬ lonkulturen mit einem Stamm der gewünschten E. coli-Serotype beimpft und mindestens 5 Tage bei 37°C bebrütet werden. Vorzugs¬ weise wird der Serotyp 02:K1:K6 eingesetzt. Aus dieser Bouil¬ lonkultur mit etwa 4 bis 9 x lO^2 koloniebildenden Einheiten/ml werden dann in an sich bekannter Weise unter sterilen Bedingungen bakterien- und eiweißfreie Filtrate hergestellt, die entweder in an sich bekannter Weise zu Injektionslösungen wei,terverarbei¬ tet oder als solche zur peroralen Medikation eingesetzt werden können. Außerdem können die Extrakte durch schonende Vakuumtrock¬ nung vom Wasser befreit und in an sich bekannter Weise zu Kapseln oder Tabletten verarbeitet werden.The coli extract was prepared according to the method described in DE-PS 38 16 298 by inoculating bouillon cultures with a strain of the desired E. coli serotype and incubating at 37 ° C. for at least 5 days. The serotype 02: K1: K6 is preferably used. From this broth culture with about 4 to 9 × 10 ^ 2 colony-forming units / ml, bacteria and protein-free filtrates are then produced in a manner known per se under sterile conditions, which filtrates are either further processed in a manner known per se to form injection solutions or as such can be used for oral medication. In addition, the extracts can be freed of water by gentle vacuum drying and processed into capsules or tablets in a manner known per se.
Beispiel 2Example 2
11
Zur Herstellung des Ginkgo-Extraktes werden grüne oder gelbe Blätter von Ginkgo biloba fein zerkleinert und in an sich bekannter Weise mit wäßrigem Azeton oder Ethanol, insbesondere eine Mischung von Wasser mit Azeton oder Ethanol im Verhältnis 50:50 mehrere Stunden bei Temperaturen zwischen etwa 40 - 60° extrahiert. Nach der Extraktion wird Flüssigkeit von den Blättern abgepreßt, die nochmals einer weiteren Extraktion unterzogen werden können. Der erhaltene wäßrige Extrakt wird in einer ersten Reinigungsstufe mit einem mit Wasser nicht mischbaren Lösungsmittel, vorzugsweise Cyclohexan, extrahiert. Die wäßrig-ketoniεche Phase wird dann weiterverarbeitet, die unpolare Phase wird verworfen. Die wäßrig-ketonische Phase wird dann auf etwa die Hälfte ihres Volumens eingeengt und der ausgefallene Niederschlag abfiltriert. Die filtrierte Lösung wird in bekannter Weise mit Ammonsulfat versetzt und mit Butanol extrahiert. Der erhaltene Extrakt wird nach dem Trocknen über Natriumsulfat unter verminderten Druck einge¬ engt und abschliessend mit Ethanol erschöpfend extrahiert. Dieser Rückstand wird dann unter Vakuum zur Trocknung einge¬ engt.To produce the ginkgo extract, green or yellow leaves of Ginkgo biloba are finely chopped and mixed in a known manner with aqueous acetone or ethanol, in particular a mixture of water with acetone or ethanol in a ratio of 50:50 for several hours at temperatures between about 40- 60 ° extracted. After the extraction, liquid is pressed from the leaves, which can be subjected to a further extraction. The aqueous extract obtained is extracted in a first purification stage with a water-immiscible solvent, preferably cyclohexane. The aqueous ketonic phase is then processed further, the non-polar phase is discarded. The aqueous ketonic phase is then concentrated to approximately half its volume and the precipitate which has separated out is filtered off. The filtered Solution is mixed with ammonium sulfate in a known manner and extracted with butanol. After drying over sodium sulfate, the extract obtained is concentrated under reduced pressure and finally extracted exhaustively with ethanol. This residue is then concentrated under vacuum to dry.
Dieser Extrakt, der nunmehr in üblicher Weise konfektioniert werden kann, enthält im Mittel, das je nach Herkunft und Alter der Blätter um etwa 10% nach oben oder nach unten schwanken kann, etwa 25% Ginkgoflavonglykoside und etwa 5% Terpenlactone.This extract, which can now be made up in the usual way, contains on average, depending on the origin and age of the leaves, about 10% up or down, about 25% ginkgo flavone glycosides and about 5% terpene lactones.
Beispiel 3Example 3
Die bisherigen klinischen Versuche zeigen, daß Patienten mit ARS bei täglich oraler Gabe von einem Teelöffel Coli- Extrakt peroral oder von einer Injektion Coli-Extrakt in 2 Tagen bereits eine deutliche Besserung des Allgemenbefin- dens und ein Anstieg der T^-Lymphozyten-Population zeigten. Wenn zusätzlich zu dem Coli-Extrakt jeweils eine Ampulle des Ginkgo-Extraktes mit einem Trockenextraktgehalt von 50 mg gegeben wurde, konnte selbst in schwereren Fällen ein Anstieg der T^Lymphozytenzahl auf über 400/μl erreicht werden. Bei zusätzlicher Gabe von Coli- und Ginkgo-Extrakten unter der Therapie mit Nukleosidtherapeutika wurden deutlich weniger subjektive und objektive Nebenwirkungen beobachtet, so daß bei einer Dauertherapie jetzt erstmals eine Dosisreduzierung vorgenommen werden konnte. The clinical trials to date have shown that patients with ARS who received oral oral doses of one teaspoon of coli extract or one injection of coli extract showed a clear improvement in general condition and an increase in the T ^ lymphocyte population within 2 days . If, in addition to the coli extract, an ampoule of the ginkgo extract with a dry extract content of 50 mg was given, an increase in the T ^ lymphocyte count to over 400 / μl could be achieved even in more severe cases. With additional administration of coli and ginkgo extracts under therapy with nucleoside therapeutics, significantly fewer subjective and objective side effects were observed, so that a dose reduction could now be carried out for the first time in continuous therapy.

Claims

Patentansprüche Claims
1. Arzneimittel zur Behandlung von Retrovirusinfektionen, dadurch gekennzeichnet, daß es an sich bekannte bakterien- und eiweißfreie Extrakte aus Escherichia coli enthält.1. Medicament for the treatment of retrovirus infections, characterized in that it contains known bacterial and protein-free extracts from Escherichia coli.
2. Arzneimittel nach Anspruch 1, dadurch gekennzeichnet, daß es zusätzlich ebenfalls an sich bekannte Extrakte aus den grünen oder gelben Blättern von Ginkgo biloba enthält.2. Medicament according to claim 1, characterized in that it additionally contains known extracts from the green or yellow leaves of Ginkgo biloba.
3. Arzneimittel nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Dosiseinheit des Coliextraktes Stoffwechselprodukte aus etwa 4 - 9 x lO^-2 Keimen enthält.3. Medicament according to claim 1 or 2, characterized in that the dose unit of the colie extract contains metabolic products from about 4 - 9 x 10 ^ - 2 germs.
4. Arzneimittel nach Anspruch 2 oder 3, dadurch gekennzeichnet, daß die Dosiseinheit des Ginkgo-Extraktes etwa 50 - 200 mg eines Extraktes aus trockenen Blättern enthält.4. Medicament according to claim 2 or 3, characterized in that the dose unit of the ginkgo extract contains about 50 - 200 mg of an extract from dry leaves.
5. Arzneimittel nach Anspruch 2 bis 4, dadurch gekennzeichnet, daß im Trockenextrakt das Verhältnis von Ginkgoflavonglykosiden zu Terpenlactonen etwa 5:1 beträgt.5. Medicament according to claim 2 to 4, characterized in that the ratio of ginkgoflavone glycosides to terpene lactones in the dry extract is about 5: 1.
6. Arzneimittel nach Anspruch 2 bis 5, dadurch gekennzeichnet, daß die Extrakte in räumlich getrennter Form enthalten sind.6. Medicament according to claim 2 to 5, characterized in that the extracts are contained in spatially separate form.
7. Arzneimittel nach Anspruch 1 bis 6, dadurch gekennzeichnet, daß es zusätzlich ein Chemotherapeutikum gegen Retrovirusinfek¬ tionen enthält.7. Medicament according to claim 1 to 6, characterized in that it additionally contains a chemotherapeutic agent against retrovirus infections.
8. Arzneimittel nach Anspruch 1 bis 7, dadurch gekennzeichnet, daß es in injizierbarer Form vorliegt. 8. Medicament according to claim 1 to 7, characterized in that it is in injectable form.
EP94910387A 1993-03-17 1994-03-08 Drugs for the treatment of retrovirus infections Withdrawn EP0689446A1 (en)

Applications Claiming Priority (3)

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DE4308443 1993-03-17
DE4308443A DE4308443C2 (en) 1993-03-17 1993-03-17 Medicines used to treat retrovirus infections
PCT/EP1994/000687 WO1994021269A1 (en) 1993-03-17 1994-03-08 Drugs for the treatment of retrovirus infections

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Publication number Priority date Publication date Assignee Title
FR2523154A1 (en) * 1982-03-09 1983-09-16 Fabre Sa Pierre PROCESS FOR THE PREPARATION OF INTERFERON-INDUCING IMMUNOSTIMULATING PROTEOGLYCANS, PROTEOGLYCANS OBTAINED AND MEDICAMENTS CONTAINING THEM
FR2634380B1 (en) * 1988-07-19 1990-10-12 Beljanski Mirko BIOLOGICAL REGULATOR, ACTIVE IN VARIOUS PATHOLOGIES
DE3832056A1 (en) * 1988-09-21 1990-03-22 Scholle Helmut Dr Med USE OF A GINKGO EXTRACT
FR2639830B1 (en) * 1988-12-02 1991-03-22 Beljanski Mirko ANTIVIRAL COMPOSITION AND ITS APPLICATIONS
DE4105570A1 (en) * 1991-02-22 1992-08-27 Helmut Dr Med Scholle USE OF A BACTERIA- AND PROTEIN-FREE FILTRATE

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Title
See references of WO9421269A1 *

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SK115495A3 (en) 1996-11-06
AU684755B2 (en) 1998-01-08
AU6283494A (en) 1994-10-11
DE4308443A1 (en) 1994-09-22
CZ238795A3 (en) 1996-02-14
PL310659A1 (en) 1995-12-27
RU2104023C1 (en) 1998-02-10
CA2158551A1 (en) 1994-09-29
HUT73382A (en) 1996-07-29
JP2735386B2 (en) 1998-04-02
HU9502697D0 (en) 1995-11-28
WO1994021269A1 (en) 1994-09-29
BR9405887A (en) 1995-12-12
DE4308443C2 (en) 1996-09-19

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