EP1523324A1 - Traitement d'infections severes et de choc septique - Google Patents

Traitement d'infections severes et de choc septique

Info

Publication number
EP1523324A1
EP1523324A1 EP03735502A EP03735502A EP1523324A1 EP 1523324 A1 EP1523324 A1 EP 1523324A1 EP 03735502 A EP03735502 A EP 03735502A EP 03735502 A EP03735502 A EP 03735502A EP 1523324 A1 EP1523324 A1 EP 1523324A1
Authority
EP
European Patent Office
Prior art keywords
rtd
bacteria
therapy
gram
lps
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.)
Withdrawn
Application number
EP03735502A
Other languages
German (de)
English (en)
Inventor
Christoph Ladel
Ben Newton
Harald Labischinski
Nina Brunner
Christoph Gerdes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California
Original Assignee
Prof Dr Harald Labischinski
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Prof Dr Harald Labischinski filed Critical Prof Dr Harald Labischinski
Publication of EP1523324A1 publication Critical patent/EP1523324A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—Antimycotics

Definitions

  • the invention relates to the use of Rhesus-Theta-Defensin 1 (RTD-1) for the manufacture of a medicament for the treatment and / or prophylaxis of patients with severe infections (bacteria) including septic shock.
  • RTD-1 Rhesus-Theta-Defensin 1
  • Sepsis is a severe, life-threatening clinical picture resulting from an infection with bacteria on a systemic level (bacteremia) and other clinical findings according to the internationally valid definition (Madot, I. and
  • Sepsis is characterized by fever, hypotension and so-called shock symptoms (e.g. shock lung, shock kidney, gastrointestinal bleeding; generally referred to as multi-organ failure).
  • shock symptoms e.g. shock lung, shock kidney, gastrointestinal bleeding; generally referred to as multi-organ failure.
  • shock symptoms e.g. shock lung, shock kidney, gastrointestinal bleeding; generally referred to as multi-organ failure.
  • These different symptoms are the clinical signs of pathophysiological processes caused by the germs themselves or their products, eg endotoxins, hemolysins or pyrogens.
  • Pathological conditions such as severe nervous disorders can also be Burns, trauma or acute lung changes with subsequent or simultaneous colonization with bacteria, fungi or niren occur. In these cases, too, symptoms of shock are found, with only partial direct diagnosis of the bacteria or other pathogens being possible.
  • the patient's own factors of the immune system are both protective and harmful, depending on concentration, place of action and the like.
  • the trigger for these events is by definition the presence of bacteria and / or the presence of bacterial products such as LPS / LTA and others. This leads to the release of e.g. Tumor ⁇ ecrosis factor- ⁇ , interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as factors that influence coagulation (e.g.
  • PAF platelet activating factor
  • factors that intervene in a regulatory manner on the resulting inflammatory process such as prostaglandins, leukotrienes, interleukin-10.
  • PAF platelet activating factor
  • factors that intervene in a regulatory manner on the resulting inflammatory process such as prostaglandins, leukotrienes, interleukin-10.
  • Another approach is to influence the clinical picture with immunomodulatory treatments in order to prevent or at least alleviate an excessive response of the organism to bacteria or bacterial products and thus to avoid organ failure (Zanotti, S. et al. (2002), Expert Opin. Investig. Drugs 11, 1061-1075).
  • Soluble immune system mediators which are administered as therapy, are of particular interest. These mediators include the so-called defensins, molecules with anti-bacterial, anti-fungal or even anti-viral properties (Kagan, B.L. et al. (1994), Toxicology 87, 131-149;
  • RTD-1 A defensin from immune cells of the rhesus monkey (Rhesus-Theta-Defensin 1; RTD-1) was isolated and its properties, its broad antibacterial activity, also against non-growing bacteria, and its antifungal activity have been described in detail (Tang et al. (1999) , Science 286, 498-502; Tran et al. (2002), J. Biol.
  • RTD-1 is characterized by some characteristic and determining properties against other defensins or cationic peptides. On the one hand, RTD-1 is a small circular peptide and, in contrast to other defensins, is therefore stable against degradation and degradation. RTD-1 shows no dependence on the effect of salts in the
  • RTD-1 a further effect of the RTD-1 is surprisingly found in states of bacteremia with subsequent sepsis and septic shock, as well as such disease states after exposure to bacterial products such as LPS.
  • RTD-1 intervenes in the disease process by 1. showing anti-microbial activity against various pathogens, 2. neutralizing effect on bacterial products such as LPS or LTA (effect on products of gram-positive and gram-negative bacteria) , which also allows prophylactic therapy, 3. has an immunomodulatory effect in the sense of mediator modulation, and 4. has a regulated anticoagulant effect.
  • the combined effect on various disease-relevant parameters results in a clearly improved therapeutic success with simplified therapy.
  • therapy with RTD-1 closes the current standard therapies (e.g. antibiotics, circulatory stabilizers
  • RTD-1 Treatment with RTD-1 leads to increased survival of mice with severe bacteremia after application of living bacteria, both after infection with gram-positive and gram-negative bacteria. Surprisingly, there is no dependency on the minimum inhibitory concentration of RTD-1 on the bacterium used.
  • mice with symptoms of septic shock after administration of LPS or SEB also shows a significantly increased survival under therapy with
  • RTD first Cytokine analyzes in the serum or plasma of the animals show a regulation of the release of soluble mediators.
  • a decrease in pro-inflammatory cytokines such as TNF-, IL-6, MIF
  • regulatory factors such as IFN- ⁇ , IL-10
  • Comparable results are found in whole human blood, and the values for pro-inflammatory cytokines and chemokines are lowered.
  • RTD-1 Under the influence of RTD-1, there is a dose-dependent increase in the clotting time of human plasma and human whole blood. RTD-1 therefore shows an influence on the coagulation parameters in human blood without additionally influencing the coagulation by bacterial products such as LPS or LTA.
  • the present invention therefore relates to the use of theta-defensin from the rhesus monkey for the production of a medicament for the treatment and / or prophylaxis of bacteria and / or sepsis.
  • the disease triggers can be gram-positive bacteria, gram-negative bacteria, bacterial products, viruses or yeasts.
  • the invention further relates to the use of RTD-1 for the production of a medicament for binding bacterial products such as LPS and / or LTA.
  • the invention further relates to the use of RTD-1 for the manufacture of a medicament for the treatment of disease states which are characterized by changes in blood coagulation.
  • Table 1 Minimum inhibitory concentrations of RTD-1, vancomycin and ampicillin on various bacterial species determined by the NCCLS method. The table shows the concentration of the respective compounds which showed a clear inhibition of the growth of the bacteria.
  • Bacterial suspensions are administered intraperitoneally (i.p.) in CFW-1 mice.
  • the mice are obtained from Harlan. After 30 min. the animals are then treated intravenously (IV) with RTD-1 in various doses. The survival of the animals with and without therapy results in the success of the therapy.
  • mice survival of mice after ip infection with S. aureus in the bacteremia model and therapy with 0.1, 1 and 10 mg / kg RTD-1 IV.
  • the mice are infected with 1.68 x 10 7 colonies of S. aureus ATCC Smith ip and treated iv after 30 min with the indicated doses.
  • mice survival of mice after ip infection with S. pneumoniae in the bacteremia model and therapy with 0.1, 1 and 10 mg / kg RTD-1 i. ..
  • the mice are infected with 3 ⁇ 10 3 colonies of S. pneumoniae L3TV ip and treated iv after 30 min with the indicated doses.
  • mice survival of mice after ip infection with E. coli in the bacteremia model and therapy with 0.1, 1 and 10 mg / kg RTD-1 IV.
  • the mice are infected with 1.68 x 10 7 colonies of E. coli Neumann ip and treated iv after 30 min with the indicated doses.
  • LPS is injected ip into mice and at different times before and after the LPS administration, RTD-1 is administered iv in various doses to simulate septic shock.
  • the survival of the animals is the measure of the therapeutic success in the model for septic shock.
  • a relevant affinity of the RTD-1 for binding bacterial products can be calculated from the inhibition.
  • Table 6 LPS and LTA binding by RTD-1 and Polymyxin B after 4 hours of incubation. The concentration at which the fluorescence of dansyl polymyxin is reduced by 50% is indicated.
  • the membrane permeability of bacteria under the influence of RTD-1 is investigated using a fluorescence method (Silvestro et al. (2000), Antimicrob. Agents Chemotherap. 44, 602-607). This allows an evaluation of the potential of the RTD-1 with regard to damage to the cell membrane of bacteria and thus on the release of bacterial products.
  • Table 7 Membrane potential change under the influence of RTD-1 and polymyxin B after 10 minutes exposure to S. aureus bacteria. It shows the concentration that leads to a 50% change in the fluorescence signal.
  • Table 7 Membrane potential change under the influence of RTD-1 and polymyxin B.
  • RTD-1 becomes a membrane fraction from E. coli (as an example for gram-negative bacteria) or from Bacillus megaterium (as an example for gram-positive bacteria) and the necessary substrates and the inhibitory activity is determined (Chandrakala, B. et al. (2001) Antimicrob. Agents Chemother. 45, 768-775). This approach determines the incorporation of radioactive precursors into high-molecular peptidoglycan via binding to wheat germ agglutinin.
  • An influence of RTD-1 on the cell wall synthesis in bacteria provides essential information on an effect on the bacterium (e.g. lysis) and in particular in connection with the release of bacterial products, which is an essential prerequisite for assessing the therapeutic potential of RTD-1 in severe Infections including septic shock.
  • Table 8 Inhibition of cell wall synthesis by RTD-1, ampicillin (Sigma), a lactam antibiotic, chloramphenicol (Sigma), a protein biosynthesis inhibitor and vancomycin (Sigma), a glycopeptide antibiotic.
  • ampicillin Sigma
  • a lactam antibiotic a lactam antibiotic
  • chloramphenicol Sigma
  • a protein biosynthesis inhibitor a protein biosynthesis inhibitor
  • vancomycin Sigma
  • glycopeptide antibiotic The inhibition of binding to wheat germ agglutinin from radioactive precursors in high-molecular peptidoglycan is shown. Only substances that influence cell wall biosynthesis, but not protein biosynthesis inhibitors, show inhibition in this approach.
  • This parameter is used to determine faults in the exogenous system of
  • Blood coagulation used.
  • the thromboplastin time is determined in the citrate plasma after adding calcium and tissue factor.
  • blood is taken from healthy people of both sexes in collecting vessels with citrate (Monovetten, Sarstedt, Nümbrecht, Germany) and the plasma is obtained after centrifugation. Samples of this plasma are incubated with various concentrations of the test compounds for 10 minutes at 37 ° C. Thereafter, thromplastin (Recombiplastin, OrthoDiagnostic Systems, Neckargemünd, Germany) is added to start the exogenous path of blood clotting. In a device for determining coagulation (coagulometer, Amelung, KC 4A micro), this approach is mixed and the coagulation time is determined.
  • This parameter is used to determine disorders in the endogenous blood coagulation system.
  • the thromboplastin time is determined in the citrate
  • Plasma after adding an activator and phospholipid Plasma after adding an activator and phospholipid.
  • blood is taken from healthy people of both sexes in collecting vessels with citrate (Monovetten, Sarstedt, Nürnbrecht, Germany) and the plasma is obtained after centrifugation. Samples of this plasma are incubated with various concentrations of the test compounds for 10 minutes at 37 ° C. Then the activator
  • Kaolin and phospholipid (aPTT reagent, Diagnostica Stago, Asnieres, France) added.
  • the coagulation is started by adding 0.025 M calcium chloride to this mixture.
  • a device for determining coagulation coagulometer, Amelung, KC 4A micro
  • this approach is mixed and the coagulation time is determined.
  • Table 10 Influencing of the coagulation parameters aPTT, PT, and the clotting time of whole human blood under the influence of RTD-1. Measured clotting time is shown in seconds after adding RTD-1.
  • Table 10 Influencing of the coagulation parameters aPTT, PT, and the clotting time of whole human blood under the influence of RTD-1.
  • Plasma samples are obtained by bleeding the animals at various times after LPS or SEB administration in mice. Plasma samples are taken from these blood samples and subjected to a cytokine analysis. The amount of cytokine in the
  • Plasma is determined quantitatively using the CBA methods (CBA system, BectonDickinson, Heidelberg, Germany).
  • Table 11 Cytokine modulation after therapy with RTD-1 in the mouse model of septic shock after administration of LPS. The maximum percentage change compared to the untreated LPS control is given. negative Values indicate a decrease, positive values indicate an increase in the amount of cytokine in the plasma.
  • Table 11 Cytokine modulation after therapy with RTD-1 in the mouse model of septic shock after administration of LPS.
  • Table 12 Cytokine modulation after therapy with RTD-1 in the mouse model of septic shock after administration of SEB. The maximum percentage change compared to the untreated SEB control is given. negative
  • Values indicate a decrease, positive values indicate an increase in the amount of cytokine in the plasma.
  • Blood is drawn from healthy donors and infected with bacteria in vitro. Both gram-positive pathogens (S. aureus) and gram-negative pathogens (E. coli) are used. After the pathogens have been added, samples of the infected and infected and treated blood are taken at defined times and the plasma is obtained by centrifugation. The amount of cytokine in the plasma is determined quantitatively using the CBA methods (CBA system, BectonDickinson, Heidelberg, Germany). In addition, the analysis for MIF is carried out by ELISA technology (human MIF ELISA system, R&D Systems Inc., Minneapolis, USA).
  • Table 13 Cytokine modulation after therapy with RTD-1 in the infection model with whole human blood after administration of S. aureus. The maximum percentage change in pro-inflammatory mediators compared to the untreated infection control is given. Negative values indicate a decrease, positive values indicate an increase in the amount of cytokine in the blood culture.
  • Table 13 Cytokine modulation after therapy with RTD-1 in the infection model with whole human blood after administration of S. aureus.
  • Table 14 Cytokine modulation after therapy with RTD-1 in the infection model with whole human blood after administration of E. coli The maximum percentage change compared to the untreated infection control is given. Negative values indicate a decrease, positive values indicate an increase in the amount of cytokine in the blood culture.
  • RTD-1 can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.
  • the application is carried out in the usual way, preferably intravenously, transdermally, orally or parenterally, in particular orally or intravenously. However, it can also be done by inhalation via the mouth or nose, for example with the aid of a spray, or topically via the skin.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne l'utilisation de rhésus-théta-défensine 1 (RTD-1) pour préparer un médicament pour assurer le traitement et/ou la prophylaxie de patients atteints d'affections sévères (bactériémies), choc septique compris.
EP03735502A 2002-06-13 2003-05-30 Traitement d'infections severes et de choc septique Withdrawn EP1523324A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10226216A DE10226216A1 (de) 2002-06-13 2002-06-13 Behandlung von schweren Infektionen und septischem Schock
DE10226216 2002-06-13
PCT/EP2003/005694 WO2003105883A1 (fr) 2002-06-13 2003-05-30 Traitement d'infections severes et de choc septique

Publications (1)

Publication Number Publication Date
EP1523324A1 true EP1523324A1 (fr) 2005-04-20

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ID=29594458

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03735502A Withdrawn EP1523324A1 (fr) 2002-06-13 2003-05-30 Traitement d'infections severes et de choc septique

Country Status (5)

Country Link
EP (1) EP1523324A1 (fr)
AU (1) AU2003238175A1 (fr)
CA (1) CA2489244A1 (fr)
DE (1) DE10226216A1 (fr)
WO (1) WO2003105883A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7119070B2 (en) 2002-04-30 2006-10-10 The Regents Of The University Of California Antimicrobial theta defensins, analogs thereof, and methods of use
EP1850861A1 (fr) * 2005-02-08 2007-11-07 Novozymes A/S Traitement par voie generale des infections a l'aide de defensines
EP2714064B1 (fr) * 2011-06-02 2019-05-15 The Regents of The University of California Blocage de protéases inflammatoires par des thêta-défensines
US20170035845A1 (en) * 2015-08-07 2017-02-09 The Regents Of The University Of California Compositions and Methods for Inhibiting Pro-Inflammatory Cytokine Gene Expression
BR112021026216A8 (pt) 2019-06-26 2022-12-13 Tran Dat Composições e métodos para o tratamento de infecções fúngicas

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6335318B1 (en) * 1999-05-10 2002-01-01 The Regents Of The University Of California Antimicrobial theta defensins and methods of using same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03105883A1 *

Also Published As

Publication number Publication date
DE10226216A1 (de) 2003-12-24
WO2003105883A1 (fr) 2003-12-24
CA2489244A1 (fr) 2003-12-24
AU2003238175A1 (en) 2003-12-31

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