EP1294387A2 - Utilisation de constituants de phyllanthus pour traiter ou assurer la prophylaxie d'infections par flaviviridae - Google Patents

Utilisation de constituants de phyllanthus pour traiter ou assurer la prophylaxie d'infections par flaviviridae

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Publication number
EP1294387A2
EP1294387A2 EP01947381A EP01947381A EP1294387A2 EP 1294387 A2 EP1294387 A2 EP 1294387A2 EP 01947381 A EP01947381 A EP 01947381A EP 01947381 A EP01947381 A EP 01947381A EP 1294387 A2 EP1294387 A2 EP 1294387A2
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EP
European Patent Office
Prior art keywords
viruses
virus
phyllanthus
substances
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP01947381A
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German (de)
English (en)
Inventor
Christoph Von Keudell
Robert H. M. Van Der Giessen
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Phytrix AG
Original Assignee
CMI-Centers for Medical Innovation AG
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Publication of EP1294387A2 publication Critical patent/EP1294387A2/fr
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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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the invention relates to the use of one or more Phyllanthus constituent (s) or substances or mixtures of substances obtained therefrom for the prevention or treatment of infectious diseases which are caused by viruses of the Flaviviridae family or in whose development or progression viruses of the Flaviviridae family are involved. Furthermore, the invention relates to the use of one or more phyllanthus constituent (s) or substances or mixtures of substances derived therefrom for the manufacture of a medicament for the prevention or treatment of infectious diseases which are caused by viruses of the Flaviviridae family or whose development or progression are viruses of the family of Flaviviridae are involved.
  • the invention also relates to the use of one or more of the Phyllanthus constituents or substances or mixtures of substances obtained therefrom for inhibiting the multiplication of viruses of the Flaviviridae family.
  • the invention also relates to a method for the prevention or treatment of infectious diseases in a mammal which are caused by viruses of the Flaviviridae family or are involved in the development or progression of viruses of the Flaviviridae family, the mammal comprising one or more Phyllanthus component (s) or substances or mixtures of substances obtained therefrom are administered.
  • the invention also relates to a method for inhibiting the multiplication of viruses of the Flaviviridae family, wherein one or more Phyllanthus constituent (s) or substances or mixtures of substances obtained therefrom are brought into contact with the viruses.
  • a preferred virus is the hepatitis C virus.
  • the plant genus Phyllanthus belongs to the subfamily of Phyllanthoideae, which in turn belongs to the family of Euphorbiaceae.
  • the genus Phyllanthus comprises a total of approximately 700 species in the tropical and subtropical Areas in Australia, China, the Philippines, Thailand, Indonesia, Burma, India, East and West Africa as well as North America, Mexico, Cuba, the Caribbean and Venezuela. Representatives of the genus Phyllanthus are rarely found in the northern temperate zones.
  • lignans lignans such as phyllanthin and cyclolignans or tetralignans such as hypophyllanthin occurring in the herb of Phyllanthus amarus and in all parts of Phyllanthus niruri.
  • sesquiterpenes are described in Phyllanthus acuminatus, which chemically belong to the epoxides of tricyclic sesquiterpene esters with a spiran structure and some biosen bound in ester form.
  • triterpenes occur comparatively frequently in all parts of the plant.
  • Phyllanthus amarus and Phyllanthus niruri are found in folk medicine e.g. in Nigeria, Cuba or Jamaica used for fever (Unander et al. 1991 J Ethno Pharmacol 34: 97-133).
  • the herb of some Phylianthus species is used for diarrhea, to increase the amount of urine, as a laxative as well as for spasms and colic.
  • the effectiveness of phyllanthus in diabetes (Unander, op. Cit.) Is also described, although the effectiveness in these applications has not been scientifically proven.
  • hydrolyzable tannins of the genus Phyllanthus are important eukaryotic protein kinases such as the cAMP-dependent protein kinase of rat liver, the CA 2+ -dependent protein kinase of wheat embryos, the Ca 2+ and phospholipid-dependent protein kinase C (PKC) inhibit the rat brain, with the tannins amariin, geraniin and the phenazine derivative of geraniin each being the most effective.
  • HBV hepatitis B virus
  • An aqueous extract of the dried, powdered drug (40 g in 200 ml of water, extracted for two hours at 60 ° C.) inhibits the binding of HBsAg antibodies to the surface antigen of HBV (HBsAg) in vitro and inhibits the viraie DNA polymerase of HBV and the hepatitis virus of the woodchuck.
  • hepatitis A virus and the hepatitis C virus which all belong to different virus families, are also known as hepatitis-causing viruses.
  • the only commonality of these viruses is their replication in human liver cells (human hepatocytes), which are the primary target cells of these viruses.
  • HCV belongs to the family of flaviviruses, which has three genera (flavivirus, pestivirus, HCV and hepatitis G virus (HGV)).
  • the genus of flaviviruses also includes a number of human pathogens that are transmitted by insects and arachnids. Some have been correlated with febrile hemorrhagic diseases and encephalitis in tropical countries, which coincide with the distribution areas of certain mosquitoes as carriers of the virus. These include Dengue fever and, especially in Central Europe, the causative agent of early summer meningo encephaiitis (TBE), which is spread by tick bites and is endemic in certain regions.
  • the second genus includes the pestiviruses, which are serious animal diseases such as the classic swine fever caused by hog cholera -Cause virus. However, these viruses are not transmitted by insects.
  • the hepatitis C virus was assigned to the so-called non-A / non-B hepatitis viruses.
  • the genome of these viruses was not characterized until 1999.
  • Today twelve different genotypes of the HCV are known from different geographical regions.
  • HCV was classified as a separate genus in the Flaviviridae family due to its molecular biological characteristics.
  • HCV caused 80-90% of non-A / non-B hepatitis.
  • HCV occurs only in humans and was mostly transmitted through blood transfusions or blood products.
  • One in 3000-5000 blood donations is positive, which is The risk of becoming infected when receiving a positive blood supply is approximately 75%.
  • Hepatitis acquired through transfusion is often chronic.
  • liver inflammation When infected with HCV, a generally mild liver inflammation occurs after an incubation period of about 6-8 weeks. About 75% of the infections are clinically inapparent and severe courses are very rare. Chronic persistent or chronically reactive hepatitis develops in up to 80% of all infected people. Viruses can be detected in the blood of these patients. The chronic infections are due to increased transaminase levels! characterized. Cirrhosis occurs in 3-20% of chronic cases and primary liver cell carcinoma in about 4% of these patients. The liver is the target organ of HCV, whereby the virus is transported to the liver via infected macrophages, where it infects and destroys the human hepatocytes. The result is inflammation of the liver with zeline krosis.
  • Interferon oc is produced and secreted by the liver cells. Tubular structures are observed in the cytoplasm of the infected liver cells using electron microscopy. However, little is known about the details of the pathogenesis of the acute infection. In the case of chronic infection, antigen-antibody complexes are formed which can be deposited in the glomerula. You will be held responsible for membrane proliferative glomerulonephritis in these patients.
  • HCV has a high mutation rate and changes in the course of infection in the patient, which is why we speak of new quasi-species.
  • the base change occurs during replication with a probability of 2 x 10 "3. They are due to the fact that the RNA-dependent RNA polymerase of the virus, unlike cellular DNA polymerases, cannot check the reading accuracy.
  • HCV belongs to the group of flaviviruses, whose infectious particles have a diameter
  • the capsids which only consist of a viral protein (C-protein), are surrounded by an envelope membrane, in which two viral surface proteins are embedded.
  • the genome of the flaviviruses consists of single-stranded RNA and has a total length of approximately 9100-11000 bases, with HCV having approximately 9500 bases.
  • the RNA is and is in the plus-strand orientation characterized by a single large continuous open reading frame that codes for a polyprotein that is proteolytically cleaved into the various protein components This is due both to enzymes that act as part of the polyprotein and are activated as well as cellular signalases.
  • the genome of the HCV shows differences compared to the other two genera flavi and pestiviruses.
  • the untranslated region at the ⁇ 'end is significantly longer with 340 bases and has the function of an IRES (infernal ribosomal entry site), which mediates the binding of the ribosome subunits and is required for the regulated translation of the polyprotein.
  • IRES infernal ribosomal entry site
  • HCV has a high mutation rate, with hypervariable and variable regions as well as relatively conserved sequence regions being observed in the genome.
  • the hypervariable regions are in the amino terminal area of the E2 protein between amino acids 1-27 and 90-97. They are recognized by antibodies and are therefore exposed to strong immunological selection pressure. In the course of a chronic infection, the virus changes both epitopes so that human neutralizing antibodies no longer recognize them. Virus variants presumably arise here, which can cause a chronic infection.
  • the present invention is therefore based on the object of providing means and ways of preventing infections and diseases based thereon to be triggered by viruses of the Flaviviridae group, in particular HCV, and to prevent their occurrence through prevention.
  • the invention thus relates to the use of one or more Phyllanthus constituent (s) or substances or mixtures of substances derived therefrom for the prevention or treatment of infectious diseases which are caused by viruses of the Flaviviridae family or whose development or progression involves viruses of the Flaviviridae family.
  • the term “phyllanthus component (s)”, as used according to the invention includes all components of the entire plant, such as, for example, leaves, bark, flowers, seeds, fruits, stems, branches, trunk, roots and wood, and parts thereof, such as, for example, leaf These phyllanthus constituents can have the same, similar or unrelated ingredients.
  • phyllanthus constituents can be used individually or with one another and different phyllanthus constituents from different phyllanthus species can be used individually or with one another.
  • the "phyllanthus constituents” also include the entirety of the phyllanthus constituents, for example in the form of whole plants to understand the extracts from it.
  • the Phyllanthus components can be used after pretreatment or without pretreatment. Pretreatment could include processes such as drying sheets.
  • Substances or mixtures of substances which can be obtained from phyllanthus constituents are to be understood primarily as active substances. These can be used in pure form or in a form with additional constituents. These active substances can be used individually or in combination as active substances or active substances Different active ingredients in different Phyllanthus components or the same
  • Phyllanthus components are present. Mixtures of active substances can be obtained from the same Phyllanthus component or from different Phyllanthus components. Here, the active ingredients can first be obtained individually from the various Phyllanthus components, the individual active ingredients can then be combined to form an active ingredient mixture, or an active ingredient mixture can be obtained simultaneously from previously combined Phyllanthus components. Substances or mixtures of substances according to the invention can consist of the same or different representatives of a class of chemical compounds. These chemical compounds can be used in their natural form, ie unchanged by the process of extraction or modified by the process of extraction.
  • the chemical compounds can be, for example, cyclic or branched or unbranched polar or nonpolar hydrocarbons, lipids, lipid derivatives, nucleic acids, nucleotides, nucleotide derivatives, nucleosides, nucleoside derivatives, polypeptides, peptides, amino acids, modified amino acids, saturated and unsaturated fatty acids.
  • derivatives are to be understood as meaning all compounds which can be derived from the compounds mentioned and which are obtained by chemical modification. For example, such derivatives by substitution, addition, esterification, saponification or
  • Condensation reactions occur.
  • the following are particularly important as active ingredients: flavonoids, organic acids and their esters, e.g. Coffee esters, gallotanins, polysaccharides, glycoproteins, peptides and proteins (ribosome inactive proteins, so-called RIP's).
  • prevention means the use of phyllanthus constituents or substances or mixtures of substances obtained therefrom as a preventive measure for avoiding infection with flaviviruses or for reducing the virus load. Furthermore, within the meaning of this invention, prevention of the onset of the disease or the like is to be understood
  • the phyllanthus constituents or substances or mixtures derived therefrom used for prevention may differ from or be identical to the phyllanthus constituents or substances or substance mixtures obtained therefrom for treatment or the use for prevention in the treatment of different or the same dose as well as by different or the same application. Prevention can be carried out by single or repeated application (s).
  • the dose of Phyllanthus constituents or substances or mixtures of substances obtained therefrom should, however, essentially offer adequate protection against infectious diseases which are caused by viruses of the Flaviviridae family or whose development or progression involves viruses of the Flaviviridae family.
  • the dose used for prevention should not have any harmful effects on the organism.
  • phyllanthus constituents or substances or mixtures of substances obtained therefrom for the treatment of infectious diseases When one or more phyllanthus constituents or substances or mixtures of substances obtained therefrom for the treatment of infectious diseases are used according to the invention, these phyllanthus constituents or substances or substance mixtures obtained therefrom can be used in a manner similar to that described for prevention.
  • the dose used for the treatment can combat both the cause of the infectious diseases, namely the viruses or their multiplication in the organism, and the symptoms of the infectious diseases.
  • the components or substances or mixtures of substances are formulated as pharmaceuticals, medical devices or medical aids.
  • medicinal products see. the description below.
  • Infectious diseases are characterized in particular by the fact that an immune response in the organism, caused by a pathogen, is triggered.
  • the aim of this immune response is to fight the pathogen.
  • this can also cause threatening damage to the cells and tissues of the affected organism, which in this case can be caused by your own immune system.
  • infectious diseases can also result from damage by the pathogen itself, since metabolic processes or differentiation programs, for example, can be dissolved in infected cells, which have a damaging effect on the organism.
  • the cause and symptoms of infectious diseases can affect identical cells or tissues, but also different ones. For example, a changed liver metabolism could lead to a change in the composition of the proteins contained in the blood, in particular the enzymes, which in turn could damage other organs, such as the kidney.
  • the use according to the invention of phyllanthus constituents or substances or mixtures of substances obtained therefrom not only relates to the prevention or treatment of causes of infectious diseases, such as infection by viruses, but also the prevention or treatment of secondary symptoms that are due to the presence of the pathogen in the organism based.
  • Flaviviridaes of the Flaviviridae family are to be understood as "pathogens" in the sense of the invention.
  • the Flaviviridae family currently comprises three genera, flavivirus, hepatitis C-like virus, pestivirus and a number of unclassified Flaviviridae.
  • the group of Japanese encephalitis viruses in the group of dengue viruses which currently consists of dengue virus, dengue virus type 1, dengue virus type 2, dengue virus type 3 and dengue virus type 4, which currently consists of Alfuy virus, Japanese encephalitis virus, Kokoberga virus, Koutango virus, Kunjin virus, Murray Valley encephalitis virus, St.
  • Louis encephalitis virus Stratford virus, Usutu virus and West Nile virus
  • Modoc viruses currently consisting of Cowbone Ridge virus, Jutiapa virus, Modoc virus, Sal Vieja virus and San Perlita virus
  • mosquito-borne viruses currently consisting of llheus virus and Sepik virus
  • the group of Ntaya viruses currently consisting of Bagaza virus, Israel turkey meningoencephalitis virus, Ntaya virus, Tembusu virus and Yokose virus
  • the group of Rio Bravo viruses which currently consists of overlook virus, Bukalasa bat virus, Dakar bat virus, Entebbe bat virus, Rio Bravo virus and Saboya virus
  • tick -borne encephalitis virus currently from Carey island virus, deer tick virus, Karshi virus, Kumlinge virus, Kyasanur forest disease virus, Langat virus, Louping ill virus, Negishi virus, Omsk hemorrhagic fever virus, Phnom-Penh bat virus, Powass
  • hepatitis C virus hepatitis C virus (isolate 1), hepatitis C virus (isolate BK), hepatitis C virus (isolate EC1), hepatitis C virus (isolate EC10) , Hepatitis C virus (HC-J2), Hepatitis C virus (isolate HC-J5), Hepatitis C virus (isolate HC-J6), Hepatitis C virus (isolate HC-J7), Hepatitis C virus (isolate HC-J8), Hepatitis C virus (isolate HC-JT), Hepatitis C virus (isolate HCT18), Hepatitis C virus (isolate HCT27), Hepatitis C virus (isolate HCV-476), Hepatitis C virus (isolate HCV-KF), Hepatitis C virus ( isolate Hunan), Hepatitis C virus (
  • Bovine viral diarrhea virus-2 viruses which are currently derived from border disease virus strain C413, Bovine viral diarrhea virus-2 isolate 230/98-K1 (Gi-4), Bovine viral diarrhea virus-2 isolate 230/98-K2 (Gi-5), Bovine viral diarrhea virus-2 isolate 230/98-K3 (Gi-6), Bovine viral diarrhea virus-2 isolate Giessen-3 and Bovine viral diarrhea virus- 2 isolate SCP consists of the group of pestiviruses Giraffe H138 or Strain Girafe-1, the group of type 1 pestiviruses currently consisting of Bovine viral diarrhea virus (isolate NADL), Bovine viral diarrhea virus (strain SD-1), Bovine viral diarrhea virus strain 4979, Bovine viral diarrhea virus strain 5.19006, Bovine viral diarrhea virus strain 5.19516, Bovine viral diarrhea virus strain 60.875, Bovine viral diarrhea virus strain 6384, Bovine viral diarrhea virus strain 7923, Bovine viral diarrhea virus strain 97/123, Bovine diarrhea virus strain
  • the unclassified Flaviviridae currently include douroucouli hepatitis GB virus A, GBV-A-like virus, the group of GBV-C / HG viruses currently consisting of hepatitis G virus, hepatitis GB virus C, Hepatitius GB virus C-like virus and Hepatitis GB virus C / G (Hepatitis GB virus C / Hepatitis G virus), Hepatitis GB virus A, Hepatitis GB virus B, marmoset hepatitis GB virus A, Mosquito cell fusing agent and turkey meningoencephalitis virus.
  • the family of the Flaviviridae also includes all viruses discovered in the future or assigned to the family.
  • the Flaviviridae family also includes mutants of individual members. Mutants are viruses with modified genetic information.
  • the changed genetic information can, for example, create resistance to therapeutic agents. These resistances could be based, for example, on the formation of mutated proteins as a result of the changed genetic information.
  • the members of the Flaviviridae family are mainly characterized by the fact that they all cause threatening infectious diseases. Of particular importance here is the hepatitis triggered by the hepatitis C virus, which leads to life-threatening changes in the morphology of the organism and the associated liver function.
  • Phyllanthus constituents according to the invention or substances or mixtures of substances obtained therefrom can alleviate the infectious disease caused by the viruses of the Flaviviridae family, in particular by inhibiting the multiplication of the viruses in the affected cells and tissues. This can be done, for example, by inhibiting individual or different enzymes that underlie the cellular changes in connection with the infectious disease.
  • the phyllanthus constituents used according to the invention or substances or mixtures of substances obtained therefrom can additionally, for example as immune modulators, have a positive influence on the prevention or treatment of the infectious diseases which are caused by viruses of the Flaviviridae family.
  • development or progression is to be understood that the viruses of the Flaviviridae family as pathogens can either cause and thus be involved in the development either alone or in combination with other pathogens, or the progression of an existing infectious disease either alone or can promote in combination with other pathogens.
  • the use according to the invention shows surprising and unexpected positive effects in the prevention or treatment of infectious diseases, in particular those which are based on HCV infections.
  • phyllanthus constituent (s) or substances or mixtures of substances derived therefrom for the manufacture of a medicament, medical device or medical auxiliary for the prevention or treatment of infectious diseases caused by viruses of the Flaviviridae family or in their development or progression relates to viruses the Flaviviridae family are involved.
  • medicaments are defined as substances and preparations made of substances which are intended to heal, alleviate, prevent or recognize diseases, conditions, body damage or pathological ailments by application to or in the human body.
  • medical products are all substances and preparations made of substances or other objects used individually or in conjunction with one another, which are used by the manufacturer for their use by means of their functions the detection, prevention, monitoring, treatment or relief of diseases are intended and their intended main effect in or on the human body is achieved neither by pharmacologically or immunologically active agents nor by metabolism, but the mode of action can be supported by such agents.
  • medical auxiliaries are substances which are used for the production (as active ingredients) of medicaments.
  • the pharmaceutical formulation containing the phyllanthus constituents or substances or mixtures of substances obtained therefrom is optionally in combination with a pharmaceutically acceptable carrier and / or diluent.
  • Suitable pharmaceutically acceptable carriers include phosphate-buffered saline solutions, water, emulsions such as e.g. Oil / water emulsions, various types of detergents, sterile solutions, etc.
  • Drugs comprising such carriers can be formulated using known conventional methods. These drugs can be administered to an individual in an appropriate dose. Administration can be done in several ways, e.g. oral, intravenous, intraperitoneal, subcutaneous, intramuscular, local or intradermal. The treating doctor determines the type of dosage according to the clinical factors. It is known to the person skilled in the art that the type of dosage depends on various factors, e.g. the size, body surface area, age, sex or general health of the patient, but also the particular agent that is being administered, the duration and mode of administration, and other medications that may be administered in parallel.
  • the infectious disease is yellow fever, dengue fever, early summer meningo- Encephalitis (TBE), cirrhosis, liver cell carcinoma or membrane proliferative glomerulonephritis.
  • the invention also relates to the use of one or more of the Phyllanthus constituents or substances or mixtures of substances obtained therefrom for inhibiting the multiplication of viruses of the Flaviviridae family.
  • Inhibiting the multiplication of viruses of the Flaviviridae family means that the replication of the viruses in the infected host cell or the budding out of the viruses from an infected host cell or both is prevented. Furthermore, the infection of other host cells of the viruses could be prevented and a multiplication of the viruses could be achieved by blocking the target cells (host cells).
  • target cells target cells
  • enzymes which are involved in the formation of new viruses it is possible in particular to inhibit enzymes which are involved in the formation of new viruses. In particular, these are enzymes that are involved, for example, in the replication of viral nucleic acids (polymerases and helicases) or in the processing of viral proteins (proteases).
  • the inhibition of the multiplication by inhibiting the budding of viruses from an infected host cell could be brought about in particular by inhibiting the viral and / or cellular protein essential for the budding process.
  • the inhibition of the proliferation of the blockage of further host cells could be accomplished by inhibiting the mechanisms which are involved in the recognition of host cells and virus or which are involved in the uptake of the virus into the host cell or by inhibition.
  • the inhibition is ex vivo or in vitro.
  • This embodiment is particularly for the further development of active substances according to the invention, the analysis of new ones Active substances or for quality control of the same important.
  • the inhibition can also be carried out outside the organism in isolated cells or tissues, for example in cell culture.
  • in vitro systems for example in cell cultures, it can be analyzed which components of Phyllanthus have the most advantageous properties. If an optimization of substances or mixtures of substances can be carried out on the basis of in vitro test systems.
  • phyllanthus components are preferably divided into groups of active substances or into individual components by customary chemical / physical methods, and the individual components are tested in such test systems for inhibition of virus multiplication.
  • the one or more Phyllanthus components or the substances or mixtures obtained therefrom come from Phyllanthus amarus, Phyllanthus niruri, Phyllanthus emblica, Phyllanthus urinaria, Phyllanthus acidus, Phyllanthus acuminatus and Phyllanthus reticulatus or from several of these Phyllanthus species.
  • viruses of the Flaviviridae family belong to the genus Flavivirus.
  • the genus flavivirus comprises the group of dengue viruses, the Japanese encephalitis viruses, the Modoc viruses, the Mosquito borne viruses, the Ntaya viruses, the Rio Bravo viruses, the tick-borne encephalitis viruses, the Tyuleniy Viruses, the Kenya-S virus, the yellow fever virus, and the unclassified flavivirus, in particular the TBE flavivirus.
  • the viruses of the Flaviviridae family belong to the genus hepatitis C-like viruses.
  • the genus hepatitis C-like viruses comprises the hepatitis C virus.
  • viruses of the Flaviviridae family belong to the genus Pestivirus.
  • the genus pestivirus comprises the group of the bovine viral diarrhea virus-2, the pestivirus giraffe H138, the pestivirus strain giraffe-1, the pestivirus type 1, the pestivirus type 2, in particular the hog cholera virus , and pestivirus type 3.
  • viruses of the Flaviviridae family belong to the genus of the unclassified flaviviruses.
  • the unclassified flaviviruses comprise the douroucouli hepatitis GB virus A, the GBV-A-like virus, the group of GBV-C / HG viruses, in particular the hepatitis G virus, the hepatitis GB virus A, the hepatitis GB virus B, the marmoset hepatitis GB virus A, the Mosquito cell fusing agent and the Turkey meningoencephalitis virus.
  • the prevention or treatment comprises the inhibition of one or more viral enzymes.
  • the inhibition of one or more viral enzymes means that the function of these enzymes is either directly or indirectly negatively influenced.
  • the inhibition of viral enzymes such as helicases, polymerases or proteases, is to be understood here.
  • a direct inhibition of these enzymes could be based, for example, on the interaction of inhibitors contained in phyllanthus constituents or substances or mixtures of substances obtained therefrom with the catalytic center of these enzymes or with a domain which regulates the activity.
  • cellular enzymes which are involved, for example, in the expression, translation or post-translational modification of the viral enzymes and thus control their function could either be affected or additionally affected by these inhibitors.
  • the inhibition of one or more viral enzymes according to the invention alleviates the multiplication and / or the infectious disease resulting from the infection of the virus or its development or progression.
  • the inhibition comprises the inhibition of the processing of one or more viral enzymes.
  • the processing of one or more viral enzymes is in the foreground. Processing is understood to mean that an initially inactive enzyme is activated by post-translational modifications, for example proteolytic cleavage, phosphorylation or glycosylation.
  • post-translational modifications for example proteolytic cleavage, phosphorylation or glycosylation.
  • the Phyllanthus components according to the invention or substances or mixtures of substances obtained therefrom, which are used to inhibit processing can inhibit either one or more viral enzymes at the same time. This can be done either by inhibiting the same or by inhibiting different processing steps that are required for the activation of the enzyme.
  • the viral enzymes are selected from the group consisting of NS2A, NS2B, NS3, NS4A, NS5, NS5A and NS5B.
  • the enzymes NS2A, NS2B, NS3 and NS4A belong to the class of viral proteases and / or helicases.
  • the NS5, NS5A and / or NS5B enzymes belong to the family of viral polymerases.
  • the phyllanthus constituents comprise herba drug, leaves, bark, flowers, seeds, fruits, stems, branches, trunk, roots and wood.
  • the substances or mixtures of substances are selected from the group consisting of alkaloids, tanines, gallotanines, lignans, sesquiterpenes, triterpenes, proteins, peptides, polysaccharides, glycoproteins, flavonoids, sterols and caffeic acid esters.
  • Alkaloids are a group of substances which are distinguished by the fact that they contain one or more nitrogen atoms, are usually in the form of a heterocycle and are generally salt-like to a vegetable acid. Protoalkaloids, including biogenic amines as alkaloid precursors, and pseudoalkaloids can be chemically distinguished. Alkaloids in the narrower sense include descendants of certain acid families, such as To understand presekurine. Tanines are particularly characterized by phenolic hydroxyl groups. The group of lignans is characterized chemically
  • Phenylpropane condensate compounds (cyclic, open chain).
  • the group of terpenes, to which the sesquiterpenes and the triterpenes belong consist of unsaturated hydrocarbons, which are made up of basic isoprene units and are present as a polymer.
  • the substances or mixtures of substances according to the invention can be present as pure substances or have additional constituents. Mixtures of substances may also consist of different members of this group and may also contain other substances or mixtures of substances.
  • alcohols and / or a mixture thereof are used in the extraction of the substance or mixture of substances.
  • Alcohols are understood in particular to be hydrocarbons which have one or more OH groups on carbon atoms which have a detergent or amphoteric effect.
  • the extraction of the substances or mixtures of substances according to the invention mainly uses alcohols with a skeleton of 1 to 4 carbon atoms and / or mixtures thereof.
  • methanol or ethanol mixtures are of particular importance.
  • the alcohols are short-chain primary C1 to C4 alcohols and / or mixtures thereof.
  • the alcohols are methanol and / or ethanol.
  • one or more of the phyllanthus constituents or the substances or mixtures of substances obtained therefrom are used in combination with one or more other active substances.
  • the Phyllanthus constituents according to the invention or the substances or mixtures of substances obtained therefrom can also be used in combination, ie either directly as a mixture, in parallel or in succession together with one or more other active substances.
  • active ingredients are mainly those in the therapy of infectious diseases, which are members of the family of Flaviviridae are caused to understand known medicines alone or a combination thereof.
  • cytokines such as immunomodulators, e.g. Interferon ⁇ , interferon ⁇ and interferon ⁇ , or interleukins
  • nucleoside analogs such as ribavirin, adefovir dipivoxil, famciclovir or FTC, as well as antibodies, in particular monoclonal antibodies
  • the effect of interferons is based primarily on their modulating effects on the cells of the immune system, whereas ribavirin acts in particular by inhibiting enzymes.
  • Combination therapy with two or more of these active substances should have a particularly favorable effect in the prevention as well as in the treatment of the course of the disease.
  • the other active compounds are selected from the group of cytokines.
  • the group of cytokines comprises immunomodulators, in particular interferon-oc, interferon- ⁇ , interferon- ⁇ and interleukins.
  • the other active compounds are selected from the group of the nucleoside analogs.
  • the group of nucleoside analogs comprises ribavirin, adefovir dipivoxil; Famciclovir and FTC.
  • the other active substances are selected from the group of antibodies.
  • the application is in the form of an infusion solution, injection solution, oral dosage form, ointment, medicinal pack, granules, food supplements, or in the form of clysms.
  • Phyllanthus constituents or substances or mixtures derived therefrom can be used in different forms either separately or in combination.
  • the phyllanthus components according to the invention or substances or mixtures of substances obtained therefrom can be applied in the form of infusion solutions or injection solutions.
  • active ingredients isolated from phyllanthus constituents or substances or mixtures of substances obtained therefrom are admixed in pure form or in a form with additional constituents with a pharmaceutically acceptable solvent and are brought into the bloodstream of a patient suffering from an infectious disease based on infection by Flaviviridae.
  • Infusion solutions and injection solutions as an application form are therefore preferably suitable for treatment.
  • Oral dosage forms are understood to mean, for example, a powdered or granulated mixture of active ingredients and auxiliaries in the form of regular, always the same shapes (e.g. disc, cylinder, egg, ball, stick or cube shape) for uniform dosage.
  • the active compounds can be isolated in pure form or in a form with additional constituents from the phyllanthus constituents according to the invention or substances or mixtures of substances obtained therefrom.
  • the auxiliaries are used in particular for pharmaceutical compatibility and to make the active ingredients stable and storable.
  • the active ingredients are administered in an oily liquid in capsule form.
  • An ointment that is an active ingredient that can be in pure form or in the form provided with additional components and that can be produced from the phyllanthus components according to the invention or substances or mixtures of substances obtained therefrom is a plastically deformable medicinal preparation that, in addition to the active ingredient, is based on an ointment or Vehicle includes.
  • the active ingredients can be administered, for example, as emulsions. Heilpackunqen.
  • Granules are to be understood as a coarse-grained powder mixture containing granules, which contains active ingredients from the phyllanthus constituents according to the invention or substances or mixtures of substances obtained therefrom. Granules can also be in oral form.
  • the phyllanthus constituents according to the invention or substances or mixtures of substances obtained therefrom can also be used as food supplements.
  • this also includes food supplements, for example in the form of oral dosage forms, granules or as medicinal teas.
  • the application is oral, topical or parenteral.
  • the invention also relates to a method for the prevention or treatment of infectious diseases in a mammal which are caused by viruses of the Flaviviridae family or are involved in the development or progression of viruses of the Flaviviridae family, the mammal comprising one or more Phyllanthus component (s) or substances or mixtures of substances obtained therefrom are administered.
  • the method according to the invention can also comprise further steps, such as the administration of other therapeutic agents or additional therapeutic measures.
  • the methods according to the invention or in the description thereof
  • the terms used also apply to the definitions according to the uses according to the invention.
  • the methods according to the invention also include all embodiments of the uses according to the invention.
  • the mammal is a human.
  • the invention also relates to a method for inhibiting the multiplication of viruses of the Flaviviridae family, wherein one or more Phyllanthus constituent (s) or substances or mixtures of substances obtained therefrom are brought into contact with the viruses.
  • the inhibition is ex vivo or in vitro.
  • the virus is the hepatitis C virus (HCV).
  • HCV infection A 34 year old male patient presented on November 3, 1995 with a chronic HCV infection.
  • the HCV infection was diagnosed in January 1995. According to the Mori classification of HCV, the genotype 3a found. The patient suffered from tiredness, reduced appetite and reduced resilience. He also had an enlarged liver. Since it was known that the patient was dependent on drugs until January 1995, contamination of syringes and / or needles is assumed to be the route of infection.
  • the patient was treated with Herba Phyllanthus amarus (dried plant powder) in a daily dose of 2250 mg / d until May 1996 until January 29, 1997. The dose was then increased to 3000 mg / d. Therapy was also supplemented with Liv-52 from October 14, 1996 to December 1997.
  • RNA In patients chronically infected with HCV, stable and constant amounts of RNA can usually be detected over a long period of time (Gordon 1998 Hepatology 28 (6): 1702-1796). High levels of HCV RNA are seen as negative signs of successful interferon ⁇ and ribavirin Therapy viewed (Weiland 1999 J of Hepatology 31: 168-173).
  • the patient described here had high amounts of HCV RNA before treatment with Phyllanthus amarus, so that it could be shown that Phyllanthus amarus has a direct effect on the replication of HCV.
  • the body's HCV RNA load was dramatically reduced and then persisted at a low level. Furthermore, the serological reduction in viral load could be correlated with an improvement in the quality of life.
  • Example 2 In vitro detection of the effect of phyllanthus components
  • KL-2 bovine lung cells are sown in microtiter plates at a density of 1x10 5 / mL. After 24 hours, the cells are infected with BVDV in a moi of 0.01. 30 minutes after infection, the substances are added in final dilutions of, for example, 1: 100, 1: 1, 000 and 1: 10,000 (batches in triplicate). The end point is the examination of each individual culture for virus-induced cytopathic effects (CPE). A substance is considered to have an antiviral effect if neither cytotoxic effects nor virus-induced cytopatic effects are observed in the culture. Uninfected cultures serve as a negative control, a titration series from BVDV serves as a positive control.
  • CPE virus-induced cytopathic effects

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Abstract

L'invention concerne l'utilisation d'un ou de plusieurs constituant(s) de phyllanthus ou de substances ou des mélanges de substances obtenus à partir de ces constituants pour prévenir ou traiter des maladies infectieuses induites par des virus de la famille des flaviviridae ou des virus de la famille des flaviviridae qui participent à leur développement ou à leur évolution. L'invention concerne en outre l'utilisation d'un ou de plusieurs desdits constituants de phyllanthus ou de substances ou de mélanges de substances obtenus à partir desdits constituants pour inhiber la multiplication des virus de la famille des flaviviridae. L'invention concerne par ailleurs un procédé pour prévenir ou traiter des maladies infectieuses chez un mammifère, induites par des virus de la famille des flaviviridae ou de virus de la famille des flaviviridae qui participent à leur développement ou à leur évolution, selon lequel un ou plusieurs constituants ou des substances ou des mélanges de substances obtenus à partir desdits constituants sont administrés à un mammifère. L'invention concerne en outre un procédé permettant d'inhiber la multiplication des virus de la famille des flaviviridae, selon lequel un ou plusieurs constituants de phyllanthus ou des substances ou des mélanges de substances obtenus à partir desdits constituants sont mis en contact avec les virus. Un virus préféré est le virus de l'hépatite C.
EP01947381A 2000-06-20 2001-06-20 Utilisation de constituants de phyllanthus pour traiter ou assurer la prophylaxie d'infections par flaviviridae Withdrawn EP1294387A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10030139 2000-06-20
DE10030139A DE10030139A1 (de) 2000-06-20 2000-06-20 Verwendung von Phyllanthusbesandteilen zur Behandlung oder Prophylaxe von Infekten durch Flaviviridae
PCT/EP2001/006981 WO2001097824A2 (fr) 2000-06-20 2001-06-20 Utilisation de constituants de phyllanthus pour traiter ou assurer la prophylaxie d'infections par flaviviridae

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EP1294387A2 true EP1294387A2 (fr) 2003-03-26

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Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030436A1 (fr) 2000-10-06 2002-04-18 Cmi - Centers For Medical Innovation Ag Procede de production d'extraits de phyllanthus
DE10120627A1 (de) * 2001-04-26 2002-10-31 Cmi Ag Verwendung von Phyllanthusbestandteilen zur Behandlung oder Prophylaxe von Infekten durch Hepatitis B-Viren
WO2007044468A2 (fr) * 2005-10-05 2007-04-19 The Cbr Institute For Biomedical Research, Inc. Methode de traitement d'une infection par flavivirus au moyen de petit arn intereferent
US20070196381A1 (en) * 2006-02-17 2007-08-23 Natures Benefit, Inc. Herbal compositions, methods of stimulating immunomodulation and enhancement of immunomodulating agents using the herbal compositions
AU2007286754A1 (en) * 2006-08-25 2008-02-28 Viropharma Incorporated Identification and characterization of HCV replicon variants with reduced susceptibility to HCV-796, and methods related thereto
KR101105889B1 (ko) 2009-09-29 2012-01-16 주식회사 바이오엔그린텍 생약 복합 추출물을 유효성분으로 포함하는 가축의 설사 예방 및 치료용 조성물 및 이의 제조방법
US20130122119A1 (en) * 2011-11-01 2013-05-16 Natreon, Inc. Phyllanthus amarus compositions and method of extracting same
KR101537468B1 (ko) * 2014-01-16 2015-07-16 성균관대학교산학협력단 필란두스 액시더스 추출물을 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 약학적 조성물
CN111529566A (zh) * 2020-06-11 2020-08-14 广东盛普生命科技有限公司 一种抗病毒喷剂及其制备方法和应用
CN111494452A (zh) * 2020-06-11 2020-08-07 广东盛普生命科技有限公司 一种眼用药剂及其制备方法
CN111588744A (zh) * 2020-06-11 2020-08-28 广东盛普生命科技有限公司 一种抗病毒组合物与口服液及其制备方法和应用
CN111529565A (zh) * 2020-06-11 2020-08-14 广东盛普生命科技有限公司 一种抗流感病毒的制剂及其制备方法和应用
EP3954379A1 (fr) * 2020-08-12 2022-02-16 HFM - Hybrid Fusion Medicals, GmbH Compositions comprenant de l'extrait de phyllanthus destinées à être utilisées dans le traitement ou la prévention d'une infection sars-cov-2 et/ou au moins un symptôme de covid-19

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US33275A (en) * 1861-09-10 Improved pipe-joi-nt
US161477A (en) * 1875-03-30 Improvement in curtain-fixtures
US4388457A (en) * 1982-02-11 1983-06-14 University Patents, Inc. Phyllanthostatin compounds
US4937074A (en) * 1988-03-29 1990-06-26 Fox Chase Cancer Center Method of treating retrovirus infection
US5854233A (en) * 1993-09-08 1998-12-29 Pharmacy And Therapeutic Advisory Consultancy Ltd. Method of treating liver disease and like indications with vasodilating agents
US5529778A (en) * 1994-09-13 1996-06-25 Rohatgi; Surendra Ayurvedic composition for the prophylaxis and treatment of AIDS, flu, TB and other immuno-deficiencies and the process for preparing the same
US5571441A (en) * 1994-11-01 1996-11-05 The Procter & Gamble Company Nutrient supplement compositions providing physiologic feedback
US5648089A (en) * 1995-07-03 1997-07-15 Shawkat; Tarek Extract solution and herbal mixture for treatment of hepatitis
US6136316A (en) * 1996-04-17 2000-10-24 Dabur Research Foundation Hepatoprotective compositions and composition for treatment of conditions related to hepatitis B and E infection
WO2000061161A2 (fr) * 1999-04-12 2000-10-19 University Of Madras Formulation pharmaceutique utile pour le traitement de l'hepatite b, de l'hepatite c et d'autres infections virales du foie ; procede de preparation de cette formulation pharmaceutique
DE19919585A1 (de) * 1999-04-29 2000-12-07 Cmi Ag Verwendung von Phyllanthus zur Behandlung von oxidativem Streß und anderen Symptomen

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BAO-EN WANG: "Treatment of chronic liver diseases with traditional Chinese medicine", JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, vol. 15, May 2000 (2000-05-01), pages E67 - E70 *
BAO-EN WANG: "Treatment of chronic liver diseases with traditional Chinese medicine", JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, vol. 15, no. Supl, May 2000 (2000-05-01), pages E67 - E70 *
TERRAULT N A: "Treatment of chronic hepatitis B and chronic hepatitis C, XP 008001479", REVIEWS IN MEDICAL VIROLOGY, vol. 6, 1996, pages 215 - 228 *

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US20040028754A1 (en) 2004-02-12
CA2413331A1 (fr) 2001-12-27
US20020054921A1 (en) 2002-05-09
DE10030139A1 (de) 2002-01-10
WO2001097824A3 (fr) 2002-05-10
WO2001097824A2 (fr) 2001-12-27

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