EP1051184A1 - Vanadium und/oder deren salze enthaltende pharmazeutische zusammensetzung zur behandlung von verbrennungen - Google Patents

Vanadium und/oder deren salze enthaltende pharmazeutische zusammensetzung zur behandlung von verbrennungen

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Publication number
EP1051184A1
EP1051184A1 EP99907421A EP99907421A EP1051184A1 EP 1051184 A1 EP1051184 A1 EP 1051184A1 EP 99907421 A EP99907421 A EP 99907421A EP 99907421 A EP99907421 A EP 99907421A EP 1051184 A1 EP1051184 A1 EP 1051184A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
vanadium
composition according
aeruginosa
iron
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Withdrawn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
EP99907421A
Other languages
English (en)
French (fr)
Inventor
Pierre Cornelis
Daniel De Vos
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.)
Vlaams Instituut voor Biotechnologie VIB
Original Assignee
Vlaams Instituut voor Biotechnologie VIB
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 Vlaams Instituut voor Biotechnologie VIB filed Critical Vlaams Instituut voor Biotechnologie VIB
Priority to EP99907421A priority Critical patent/EP1051184A1/de
Publication of EP1051184A1 publication Critical patent/EP1051184A1/de
Withdrawn legal-status Critical Current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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • 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

  • composition comprising vanadium and/or salts thereof and its use to treat burns.
  • the invention relates to the use of multivalent transition elements and/or salts thereof to inhibit bacterial or yeast growth. Especially bacterial Pseudomonas growth is inhibited by using vanadium and/or a salt thereof.
  • vanadium or a vanadium salt is incorporated in a pharmaceutical composition as an essential ingredient whereupon this pharmaceutical is applied to burns.
  • Said pharmaceutical composition is also used to treat opportunistic infections.
  • Pseudomonas aeruginosa (P.aeruginosa) emerged during the last decades, following the introduction of antibiotic therapy, as one of the most problematic gram-negative bacterium in our modern hospital settings; this organism is increasingly isolated as a nosocomial pathogen resulting in high morbidity and mortality rates.
  • Burn wound patients and cystic fibrosis patients are very susceptible to the latter micro-organism which is inherently resistant to common antibiotics and even survives in antiseptics. Early diagnosis of P.aeruginosa infection is a key feature in the management of those patients.
  • the source of a contamination can be endogenous, exogenous or both. It is known by several epidemiological studies that several exogenous infections are nosocomial in origin and that specific installations such as water distillation systems, hydrotherapy facilities and humidifiers can be potential reservoirs of bacteria, specifically of pseudomonads. The need actually exists for the development of alternative clinical strategies to combat and/or prevent P.aeruginosa infections. Pseudomonas aeruginosa is, as mentioned above, an opportunistic gram-negative human pathogenic bacterium which causes severe and often fatal infections particularly affecting immuno-compromised patients with severe burns.
  • pathogenic bacteria have usually developed specialized take-up systems for directly using these iron sources, as Haemophillus sp. or Neisseria sp., or have developed powerful siderophores which could successfully compete for iron with the host iron proteins, e.g., aerobactin, vibriobactin or amonabactin.
  • P.aeruginosa produces two types of siderophores: pyochelin and pyoverdine, the latter being the typical fluorescent peptidic siderophore produced by most of fluorescent pseudomonads.
  • Siderophores are low molecular weight molecules (800-1500 Da) with variable chemical structure which possess specific ligands essential for the sequestration of iron. The most commonly involved ligands are the hydroxamate and cathecholate groups. Alpha-hydroxy and oxaziline groups on the other hand are rarely involved ligands.
  • Some siderophores have three hydroxamate groups (ferrioxamine), whereas others bear only 3 catecholates (enterobactin) or are not uniform and have a mixed composition.
  • the known P.aeruginosa strains produce three different types of pyoverdines. The complete structures of these latter types were also recently elucidated. All contain the rare amino acid ⁇ -N-hydroxyomithine but differ in the amino acid composition of the peptidic part of the molecule which is linked to a quinolinic (chromophore) moiety. In contrast to pyoverdine, which is a high-affinity iron chelator, pyochelin is a thiazoline derivative and a low affinity iron scavenger.
  • the three structurally different pyoverdines have been identified from several P.aeruginosa strains: from P.aeruginosa ATCC 15692 (Briskot et al., 1989, Liebigs Ann Chem, p.375-384), from P.aeruginosa ATCC 27853 (Tappe et al., 1993, J.Prakt-Chem., 335, p.83-87) and from a natural isolate, P.aeruginosa R (Gipp et al., 1991 , Z. Naturforsch, 46c, p.534-541 ).
  • Pyoverdines are the main siderophores of pseudomonads such as P.aeruginosa.
  • P.aeruginosa pseudomonads
  • USP 5,079,010 to S.Natterer discloses a pharmaceutical preparation which is a solution containing water and metallic trace elements to treat wounds, burns or other inflammatory changes.
  • a pharmaceutical composition has among others an anti-bacterial action.
  • metallic trace elements can be used iron, zinc, manganese,chromium,copper,cobalt, molybdenum, tin, vanadium, nickel and selenium.
  • An essential factor for the efficacy of the preparation is its pH which ranges between 4.0 and 1.0 and which is preferably less than 3.5. It is further disclosed that the trace elements are completely dissolved in the acid solution in order to enter into action.
  • Fukuda and Yamase discloses the in- vitro antibacterial activity of vanadate and specific vanadyl compounds against gram-positive bacteria such as Streptococcus pneumoniae.
  • the activity of the tested compounds against pathogenic bacteria such as the gram-negative bacteria Escherichia Coli and Pseudomonas aeruginosa, was estimated to be negligible.
  • the present invention aims to use a multivalent transition element and/or a salt thereof such as vanadium or a vanadium salt which interferes with bacterial iron uptake and inhibits bacterial growth, especially the growth of Pseudomonas aeruginosa, under iron limiting conditions.
  • multivalent transition elements which can be used for this purpose are chromium or titanium and their respective salts.
  • vanadium salts can be used vanadium carbonyl, vanadium pentafluohde, vanadium pentoxide, vanadium tetrafluoride, vanadium trifluoride, vanadium trioxide, vanadium trisulfate, vanadium trisuifide, vanadyl dichloride, vanadyl sulfate or vanadyl trichloride.
  • bacterial strains in this respect susceptible for vanadium, chromium or titanium and their respective salts are Escherichia coli, Klebsiella oxytoca, Staphylococcus aureus, Stenotrophomonas maltophilia and the like.
  • a chelator agent such as EDDHA (ethylenediaminedihydroxyphenylacetic acid) was added to the CAA- medium, optionally supplemented with vanadium or a vanadium salt.
  • EDDHA ethylenediaminedihydroxyphenylacetic acid
  • the preferred concentration and chelator used in this respect is EDDHA in a concentration of 0.2 mg/ml.
  • a primary aspect of the current invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one transition element and/or salt thereof which interferes with a bacterial and/or fungal/yeast iron-uptake mechanism.
  • the interference occurs through a high affinity siderophore mediated iron-uptake system present in bacteria and/or fungi/yeast. Preferably it occurs at the level of the pyoverdine-mediated iron transport pathway.
  • the transition elements in the pharmaceutical composition are selected from the group comprising vanadium, chromium or titanium and/or salts thereof.
  • vanadium and/or salts thereof can be used in a pharmaceutical composition to prevent infection in burns. It is known that in bum-wound victims opportunistic P.aeruginosa infections frequently occur; furthermore P.aeruginosa is also the main lung pathogen in cystic fibrosis patients. In patients having ulcers, like diabetic patients having foot ulcers, for instance a topical application of a pharmaceutical composition according to the invention is beneficial for said patient in order to help curing the infection as such.
  • the pharmaceutical composition according to the invention comprising vanadium or a salt thereof may be supplemented with other metal trace elements such as zinc, silver or a salt thereof and the like.
  • vanadium on pyoverdine production, excretion or uptake, when applied in a pharmaceutical composition, is a helpful tool in the fight against said P.aeruginosa infections. Consequently application of said pharmaceutical composition to burn wound patients in order to prevent the bacterial infection is another important feature of the present invention.
  • vanadium or salts thereof can unexpectedly be used to inhibit the growth of yeast or fungi, especially Candida albicans.
  • the pharmaceutical composition according to the invention comprising at least one of the above indicated-transition elements interfering with the fungal/yeast iron-uptake mechanism, is effective against the fungi/yeasts selected from the group comprising Candida, Histoplasma, Cryptococcus or Rhodotorula, more specifically Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans or Rhodotorula piiimanae.
  • Another aspect of the present invention is a pharmaceutical composition to treat burns, Candida infection or any opportunistic infection in order to prevent a further spread of the pathogenic organisms.
  • the amount/dosage of a transition element in said pharmaceutical composition varies within the limits of pharmaceutically acceptable activity (i.e. suitably prepared and approved for use in the desired application) depending on the infection/contamination to combat.
  • the dosage needed to provide an effective amount of the composition will vary depending upon factors such as the recipient's age, condition, extent of disease, body weight of the patient and other variables which can be adjusted by one of ordinary skill in the art.
  • the dosage of the transition element can vary from about 0.01 ⁇ g/kg to about 1 mg/kg body weight of a patient, preferably from about 0.05 ⁇ g/kg to about 0.5 mg/kg body weight of a patient depending upon the type of formulation and the condition of the patient to be treated. It is well-known in the medical field that in order for a pharmaceutical composition to be effective against a certain infection/contamination, 18-24 hours after the first application an extra dosage of said pharmaceutical composition is needed.
  • compositions comprising vanadium or salts thereof according to the invention can be formulated in any acceptable manner.
  • “Dermatological Formulations” Percutaneous Absorption, by Brian W.Barry, (1983), Ed. Marcel Dekker.lnc. and to " Encyclopedia of pharmaceutical technology", by J.Swarbrick and J.C.Boylan,(1996/1997),Vol.14, Ed. Marcel Dekker, Inc.
  • Some non-limitative examples are formulations as hydrogel, (dry)-sprays, tablets, injection preparations, suntan composition such as suntan lotion, cream, balm or salve, as impregnating agent in (sticking) plasters and the like.
  • a pharmaceutical composition according to the invention is to impregnate, or an uptake of, vanadium or salts thereof into preferably proliferating skin cells of a burn-wound victim in order to prevent that a Pseudomonas infection occurs.
  • Said proliferating skin cells preferably from the patient concerned, can be applied for instance as a layer of cells to the area of the burn in order to cure the burned area by a skin-grafting technique known to a skilled person.
  • Transition element refers to the position of the chemical elements concerned as mentioned in the "Periodic Chart of Elements" known to a skilled person.
  • a transition element e.g. vanadium or a salt thereof
  • a transition element e.g. vanadium or a salt thereof
  • to treat burns also means the prevention of infection upon a contamination by, for instance, P.aeruginosa in the burns.
  • Opportunistic infection means an infection caused by a microorganism, e.g. bacteria, yeast or fungi, which will develop to a disease or infectious pathogenic status in a patient, if in said patient already a predetermined situation has been developed like a trauma or immune deficiency.
  • P.aeruginosa strains are used : P.aeruginosa ATCC 15692 (Briskot et al., 1989, Liebigs Ann Chem, p.375-384), P.aeruginosa ATCC 27853 (Tappe et al., 1993, J.Prakt-Chem., 335, p.83-87) and from a natural isolate, P.aeruginosa R (Gipp et al., 1991 , Z. Naturforsch, 46c, p.534-541 ).
  • Casaminoacids medium (CAA), a liquid medium with low iron content, was used for the experiments (Hofte et al., 1993). Its composition is 5 g.l "1 CAA, 1.3 g.l “1 K 2 HP0 4 .3H 2 0 and 0.25 g.l “1 MgS0 4 .7H 2 0.
  • the pH value of this medium is above 4, preferably between 4.5 and 10 and has more preferably a pH value of about 7.
  • V0S0 4 .5H 2 0 was purchased from Merck and a 100 mM stock solution was prepared.
  • the metal solution of vanadate was filter sterilized using a bacterial filter (0.2 ⁇ m pore size) and added after autoclaving to avoid metal precipitation.
  • Bacteria were grown in a New Brunswick Innova shaker at 200 rpm at 28° C.
  • the production of pyoverdine was determined by 400 nm absorption of culture supernatant (figures 1 d, e, f and 2 b) as well as by visual inspection using UV- fluorescence (table 1).
  • the growth inhibition by vanadium clearly corresponds to an inhibition or shortage of pyoverdine production.
  • Table 1 Colour and fluorescence of P.aeruginosa culture (supernatant) after 24 hours of growth.
  • vanadium When vanadium is added directly to this supernatant prior to IEF, the 2 pyoverdine bands can still be detected, although at a slightly different level than in the absence of vanadium. In contrast, when supernatant from P.aeruginosa cells which were grown in vanadium-containing CAA-medium was analysed through IEF, no bands at all could be detected under UV. Thus, vanadium binds to pyoverdine (resulting in a band-shift) but this complex is not the same as the yellow-brown colour that appears when P.aeruginosa cells are grown in the presence of vanadium.
  • Pvd type I. II and III P.aeruginosa strains. From P.aeruginosa strains three structurally different pyoverdines have been identified: Pvd type I, II and III respectively (see text above). These three types have been tested for growth / inhibition under several conditions. Clinical isolates comprising the three types (I, II and III), have been tested as well and demonstrate the same growth / inhibition characteristics as given hereunder. Growth / inhibition was measured at OD 600nm and is depicted in tables A and B.
  • CAA medium only CAA medium+ CAA medium+ 2mM Vanadium 3 mM Vanadium

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP99907421A 1998-01-27 1999-01-26 Vanadium und/oder deren salze enthaltende pharmazeutische zusammensetzung zur behandlung von verbrennungen Withdrawn EP1051184A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP99907421A EP1051184A1 (de) 1998-01-27 1999-01-26 Vanadium und/oder deren salze enthaltende pharmazeutische zusammensetzung zur behandlung von verbrennungen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP98200223 1998-01-27
EP98200223 1998-01-27
PCT/EP1999/000483 WO1999037312A1 (en) 1998-01-27 1999-01-26 Pharmaceutical composition comprising vanadium and/or salts thereof and its use to treat burns
EP99907421A EP1051184A1 (de) 1998-01-27 1999-01-26 Vanadium und/oder deren salze enthaltende pharmazeutische zusammensetzung zur behandlung von verbrennungen

Publications (1)

Publication Number Publication Date
EP1051184A1 true EP1051184A1 (de) 2000-11-15

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EP99907421A Withdrawn EP1051184A1 (de) 1998-01-27 1999-01-26 Vanadium und/oder deren salze enthaltende pharmazeutische zusammensetzung zur behandlung von verbrennungen

Country Status (4)

Country Link
EP (1) EP1051184A1 (de)
AU (1) AU2719299A (de)
CA (1) CA2318902A1 (de)
WO (1) WO1999037312A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20040943A1 (it) * 2004-05-11 2004-08-11 Icim Internat S R L Composizione farmaceutica cicatrizzante
WO2011160443A1 (zh) * 2010-06-24 2011-12-29 攀枝花东方微元科技有限公司 一种含钒的药物组合物及其用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3929411A1 (de) * 1988-09-22 1990-03-29 Siegfried Natterer Pharmazeutische zubereitung sowie verfahren zu ihrer herstellung
RU2078570C1 (ru) * 1993-01-11 1997-05-10 Галина Юрьевна Рыльникова Средство для энтеросорбции при термических ожогах

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9937312A1 *

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AU2719299A (en) 1999-08-09
CA2318902A1 (en) 1999-07-29
WO1999037312A1 (en) 1999-07-29

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