EP0765161A2 - Compositions antibiotiques synergique contenant une porphyrine et un antibiotique - Google Patents

Compositions antibiotiques synergique contenant une porphyrine et un antibiotique

Info

Publication number
EP0765161A2
EP0765161A2 EP95923690A EP95923690A EP0765161A2 EP 0765161 A2 EP0765161 A2 EP 0765161A2 EP 95923690 A EP95923690 A EP 95923690A EP 95923690 A EP95923690 A EP 95923690A EP 0765161 A2 EP0765161 A2 EP 0765161A2
Authority
EP
European Patent Office
Prior art keywords
antibiotic
composition according
porphyrin
dab
composition
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Withdrawn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
EP95923690A
Other languages
German (de)
English (en)
Inventor
Zvi Malik
Yeshayahu Nitzan
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.)
Lichtenstein Joseph
Bar Ilan University
Original Assignee
Lichtenstein Joseph
Bar Ilan University
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
Priority claimed from IL10987494A external-priority patent/IL109874A0/xx
Priority claimed from IL10987694A external-priority patent/IL109876A0/xx
Priority claimed from IL10987594A external-priority patent/IL109875A0/xx
Application filed by Lichtenstein Joseph, Bar Ilan University filed Critical Lichtenstein Joseph
Publication of EP0765161A2 publication Critical patent/EP0765161A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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 present invention relates to antimicrobial and to pharmaceutical preparations. More particularly, the invention relates to the use of porphyrins to increase antibiotic efficacy, to antimicrobial liquid compositions useful for hygienic and medical uses, and to antimicrobial cream compositions.
  • antibiotic materials are widely used in today's medicine, both for the treatment and for the prevention of infections.
  • Antibiotics are administered mostly systemically, orally or intravenously, but for a number of uses, such as for superficial cuts and skin wounds, antibiotic ointments are also available.
  • antibiotic ointments are ineffective or cannot be used.
  • One such case is the treatment of severe injuries, which are prone to become seriously infected by gram-positive bacteria.
  • sterilization of surfaces is also an important task, particularly for medical applications.
  • One of the problems encountered is that of sterilizing the hands of surgeons and of medical staff involved in surgery. This problem is particularly severe, because gram-positive bacterial nest in the various irregularities of the skin, whence they are very difficultly removed.
  • Porphyrins have been known for some time to be efficient in the treatment of infections by photodynamic therapy (PDT) [Malik et al, in "Photo dynamic Therapy, Basic Principles and Clinical Applications", B. W. Henderson and T.J. Dougherty, Eds., Rosewell Park center Institute, Buffalo, New York].
  • PDT photodynamic therapy
  • the antibacterial properties of hemin have also been described [Ladan et al., FEMS Microbiology letters, 112(1993), 173-178].
  • Porphyrins are known to be effective antimicrobial agents. However, the art has so far not addressed the use of porphyrins and components of sterilizing •solutions for sterilizing hands or other surfaces which come into contact with exposed wounds.
  • the invention is directed to a synergistic antibiotic composition, comprising as an antibiotic active ingredient a mixture of one or more porphyrins and at least one antibiotic compound.
  • the invention is directed to a method of treating bacterial infections using reduced amounts of antibiotic materials.
  • the invention is directed to an antimicrobial composition, comprising as an active ingredient a porphyrin or a mixture of one or more porphyrins, alone or in admixture with conventional antibiotic materials and/ or pharmaceutically acceptable or beneficial agents or additives, in a water-based cream composition, as well as to the use of porphyrins for the treatment and the prevention of bacterial infections, and to the method of treatment which utilizes such compositions.
  • Preferred porphyrins include deuteroporphyrin and hemin.
  • the invention has as another objective a sterilizing liquid composition, comprising as an active ingredient a porphyrin or a mixture of one or more porphyrins, in an aqueous solution, together with a surface-active agent.
  • a sterilizing liquid composition comprising as an active ingredient a porphyrin or a mixture of one or more porphyrins, in an aqueous solution, together with a surface-active agent.
  • the combined action of the porphyrin and the surface-active agent is effective to reduce the concentration of bacteria on a surface, even when deeply nested, and to maintain it at a low value for a long period of time.
  • Fig. 1 shows the effect of the combined treatment of tetracycline and hemin on the growth of S. aurens
  • Fig. 2 illustrates the effect of the combined treatment of methicillin and hemin on cell growth of S. aureus
  • Fig. 3 illustrates the effect of methicillin, ampicillin, hemin and their combinations, on the viability of S. aureus
  • Fig. 4 shows the effect of the combined treatment of tetracycline and photoactivated deuteroporphyrin on cell growth of S. aureus
  • Fig. 5 shows the effect of the combined treatment of tetracycline and photoactivated deuteroporphyrin on the viability of S. aureus
  • Fig. 6 shows the synergistic effect of a combination of an irradiated composition comprising deuteroporphyrin and polymyxin B nonapeptide, with tetracycline, on the gram negative bacteria E. coli;
  • Fig. 7 illustrates the effect of deuteroporphyrin, alone and with hemin, in a specific base cream (Merck);
  • Fig. 8 illustrates the effect of tetracycline, and of deuteroporphyrin, alone and with hemin, in another specific base cream (Johnson's);
  • Fig. 9 illustrates the effect of tetracycline, and of deuteroporphyrin, alone and with hemin, in yet another specific base cream (Carbopol);
  • Fig. 10 illustrates the effect of tetracycline and of hemin, alone and in combination, in the Merck base cream;
  • Fig. 11 illustrates the activity of different sterilizing liquid compositions on S. aureus.
  • the synergistic antibiotic composition of the invention comprises as an antibiotic active ingredient a mixture of one or more porphyrins and at least one antibiotic compound.
  • antibiotics can be conveniently exploited with a variety of antibiotics.
  • suitable antibiotic materials are those which owe their activity to their ability to inhibit the synthesis of bacterial cell walls by blocking the te ⁇ ninal cross-linking of linear glycopeptides into the complex peptidoglycan, and which activate autolytic enzymes in the cell walls.
  • antibiotic materials are the penicillins and the cephalosporins.
  • Other antibiotic materials which can be used according to the invention are those which are active because they inhibit protein synthesis.
  • antibiotic materials are, e.g., the tetracyclines, which act by inhibiting the binding of aminoacyl-tRNA to the 30S unit of bacterial ribisomes, chloroamphenicol, which blocks the attachment of amino acids to the nascent peptide chain on the 50S unit of ribosomes by interfering with the action of peptidyl transferase, and the macrolide antibiotics, which attach to a receptor on the 50S subunit of the bacterial ribosome.
  • the antibiotic materials useful in conjunction with the invention are many and of many different types. Accordingly, while the following description will be limited to specific materials, for the sake of brevity, it is not to be construed as intending to limit the invention to any particular antibiotic material.
  • antibiotic materials which can be conveniently used in the context of the invention are penicillin (G and V), ampicillin, methicillin, oxacillin, amoxicillin, cephalexin, cephradine, tetracycline, erythromycin and chloroamphenicol, and mixtures of two or more of such compounds with or without additional antibiotic and/ or antibiotic synergistic materials.
  • the porphyrin is selected from the group consisting essentially of deuteroporphyrin, hemin, hematoporphyrin, protoporphyrin, and eta-, para- or orto-hydroxy phenylporphyrin.
  • composition of the invention can further comprise a peptide of the formula:
  • DAB* is a 2,4-diaminobutyric acid residue
  • DAB is a 2,4- diaminobutyric acid residue containing a free 4-amino group.
  • This compound is a known material, which is useful to disorganize the bacterial membrane of gram-negative bacteria.
  • a specific peptide is polymyxin B nonapeptide. Therefore, it can be conveniently used when the invention is exploited to combat infections generated by gram-negative bacteria.
  • alternative additives can of course be used for this purpose, and the invention is not limited to the use of any particular additive. It should be understood that the compositions of the invention can be used together with any useful and pharmaceutically-acceptable additive, carrier and adjuvant, which are not listed nor discussed in detail herein, for the sake of brevity, since they are readily apparent to the skilled person.
  • the invention is directed to the use of a composition comprising one or more porphyrins and one or more antibiotic materials, for the manufacture of a pharmaceutical preparation for the treatment of infections caused by gram-positive bacteria.
  • the invention is directed to the use of a composition comprising one or more porphyrins and one or more antibiotic materials, for the manufacture of a pharmaceutical preparation for the treatment of infections caused by gram-negative bacteria.
  • the synergistic composition of the invention is useful, inter alia, in a method of treating an infection in an animal, including humans, which infection is susceptible of treatment by a given antibiotic material or mixture of antibiotic materials, comprising administering to the animal in need thereof an amount lower than the effective amount of the said antibiotic material or mixture of antibiotic materials, together with one or more porphyrins.
  • the compositions of the invention can be used effectively to treat infections which, for practical purposes, cannot be treated by the antibiotic material or by the combination of antibiotic materials contained therein alone, because the dosage required to affect the bacteria exceeds acceptable boundaries.
  • the synergistic compositions of the invention not only substantially reduce the amount of antibiotic material needed for a given treatment, which is an extremely important result by itself, but also permits to use antibiotic materials which are essentially ineffective as such, for the treatment of infections so far untr eatable or only difficulty treatable by the same antibiotics.
  • the invention is directed to an antimicrobial composition, comprising as an active ingredient a porphyrin or a mixture of one or more porphyrins, alone or in admixture with conventional antibiotic materials and/ or pharmaceutically acceptable or beneficial agents or additives, in a water-based cream composition.
  • the porphyrin is deuteroporphyrin or hemin.
  • One preferred composition of the invention comprises a mixture of deuteroporphyrin and hemin.
  • Another preferred embodiment of the invention comprises a mixture of hemin and tetracycline.
  • cream is meant to indicate all water-based compositions which are creamy in consistence, and which can be easily applied in thin layer to a surface.
  • Water-based compositions may, of course, contain small amounts of materials which may be considered water-unmiscible solvents, such as for the purpose of creating emulsions, or as jellyfying agents, or for any other purpose, as long as such materials do not substantially dissolve the porphyrin therein.
  • An illustrative and non-limitative antimicrobial cream composition according to the invention may comprise, along with other components, the following major components: paraffin, propylenglycol, polysorbat 40, cetylstearyl alcohol, Vaseline and water.
  • Another illustrative and non-limitative antimicrobial cream composition according to the invention may comprise, along with other components, the following major components: synthetic beeswax, glyceryl stearate, stearic acid, propylene glycol, alkylparaben(s), preservatives, and water.
  • the invention is also directed to the use of a cream composition according to the invention, for the treatment of infections caused by gram-positive bacteria.
  • infections may comprise, inter alia, infections caused by flesh wounds, surgical cuts, or exposed bone injuries.
  • the cream composition according to the invention can be conveniently employed for the sterilization of bones.
  • a particularly important use, which addresses a need so far unsolved, is the sterilization of chest bones exposed during chest surgery, to prevent the occurrence of post-surgical infection.
  • the treatment when a photoporphyrin is employed, the treatment may further be rendered more effective by irradiating the treated area with light. Such irradiation procedure is within the scope of the routineer, and is therefore not described herein in detail, for the sake of brevity.
  • the invention therefore provides a method of treating or preventing the occurrence of an infection caused by Gram-positive bacteria, comprising applying to the area to be treated a cream composition as described above.
  • the amount of active material used in a given composition depends on the type or porphyrin, or porphyrin combination or antibiotic used, as well as on additional additives that may be employed for a specific purpose.
  • the skilled person will easily determine the amount of each active material which it is desirable to employ in a given composition, by simple experiments of the kind described in the examples given below.
  • an average composition may comprise each of the porphyrin(s) and of the antibiotic material(s) in an amount comprised between 5 and 100 ⁇ g/ml.
  • the synergistic antibiotic compositions described above which comprise, as an antibiotic active ingredient, a mixture of one or more porphyrins and at least one antibiotic compound, can of course be employed also in conjunction with the antibiotic creams of the invention.
  • the creams of the invention are not limited to those which comprise synergistic compositions, and are intended to encompass all the antibiotic combinations described or referred to herein, which can be incorporated in water-based creams, whether they exhibit svnergistically improved activity or not.
  • all the antibiotic materials described above, as well as many others can be used in conjunction with the creams of the invention.
  • compositions of the invention can of course be used together with any useful and pharmaceutically-acceptable additive, carrier and adjuvant, which are not listed nor discussed in detail herein, for the sake of brevity, since they are readily apparent to the skilled person.
  • the invention has as a further objective a sterilizing liquid composition, comprising as an active ingredient a porphyrin or a mixture of one or more porphyrins, in an aqueous solution, together with a surface- active agent.
  • disinfectizing composition is meant to indicate a composition that, when applied to a surface infected with bacteria, is capable of reducing the concentration of the bacteria to a non-dangerous level, preferably to a non- detectable level. However, in some instances a reduction of several orders of magnitude will be considered a disinfection, when appropriate according to the case, even if the bacteria are still detectable on the sterilized surface.
  • porphyrin is deuteroporphyrin or hemin, or a mixture thereof. These porphyrins are preferred because they are widely used and mostly do not present regulatory problems, but as stated, other porphyrins are also useful. Other porphyrins include, e.g Berry hematoporphyrin, protoporphyrin, and meta-, para- or orto- hydroxy phenylporphyrin.
  • the surface-active agent appears to be instrumental in allowing a better contact between the bacteria and the porphyrin, although the actual mechanism through which it acts has not been fully elucidated.
  • the art is crowded with many surface-active agents, some of which may be unsuitable for the purposes of the invention because the may be hazardous to health.
  • the surface-active agent is a detergent, preferably a detergent which is in use and is recognized as being non-hazardous to health.
  • Triton X-100 which is iso-octylphenoxypolyethoxyethanol, containing approximately 5 moles/ lit of ethyl ene oxide, manufactured by BDH Chemicals Ltd., England
  • sodium dodecyl sulphate and sodium lauryl sulphate or a mixture of two or more of such agents.
  • the concentration of the porphyrin in the sterilizing solution may vary, according to the porphyrin or mixture of porphyrins employed, the surface- active agent used, and the purpose for which it is desired to employ it.
  • the skilled person will be able to tailor specific sterilizing solutions for specific uses, which is within the scope of the routineer.
  • the porphyrin may be present in a concentration of 1 to 100 ⁇ g/ml of sterilizing solution.
  • the concentration of the surface-active agent may vary over a wide range, depending on the surface-active agent employed, the porphyrin used and the purpose for which the solution is intended. Illustrative concentrations of the surface-active agent in the solution are 0.5 - 5 wt%.
  • the invention also encompasses the use of a liquid composition according to the invention, for the sterilization of surfaces.
  • the surfaces to be sterilized can be of many types, e.g. the human hand or a bone.
  • a particularly important case of bone sterilization is when the bones are chest bones exposed during chest surgery.
  • the invention therefore provides a method of preventing the occurrence of an infection caused by Gram-positive bacteria, comprising applying to the area to be treated a liquid sterilizing composition as described above.
  • the synergistic antibiotic compositions described above which comprise, as an antibiotic active ingredient, a mixture of one or more porphyrins and at least one antibiotic compound, can be employed also in conjunction with the sterilizing compositions of the invention.
  • conventional antibiotics are not required in the liquid compositions of the invention. Nevertheless, the addition of amounts of conventional antibiotics to the sterilizing liquid compositions does not exceed the scope of the invention.
  • compositions of the invention can of course be used together with any useful and pharmaceutically-acceptable additive, carrier and adjuvant, which are not listed nor discussed in detail herein, for the sake of brevity, since they are readily apparent to the skilled person.
  • any useful and pharmaceutically-acceptable additive, carrier and adjuvant which are not listed nor discussed in detail herein, for the sake of brevity, since they are readily apparent to the skilled person.
  • conventional dermatologically-acceptable additives e.g., perfumes, can of course be employed.
  • Illustrative Gram-positive bacteria are the coagulase and DN Ase positive Staphylococcus aureus which belong to phage type 0[88/89/95] and resistant to the majority of the common antibiotics such as Methicillin, Ampicillin, Chloramphenicol, Tetracycline, Ofloxacin, Imipinen, Ciprofloxacin, Gentamicin, and Erythromycin.
  • Illustrative Gram- negative bacteria are Esche ⁇ chia coli of serotype 0111/ B4, resistant to Ampicillin, Chloramphenicol, Tetracycline and Sulfamethoxazol trimethoprin. All of these strains were recovered from clinical material submitted to the Bacteriological Laboratory of the Meir Hospital, Kfar-Saba, Israel.
  • Bacterial growth was determined by the increase of the optical density as a function of time at 660 ran with a Novaspec Biochrom LKB spectrophotometer. Viable bacteria were monitored by counting the number of colony-forming units on nutrient agar plates.
  • the indicated antibiotics were added, as described specifically in each example, at the indicated concentrations, to the cultures at the time of porphyrin addition, not prior to that, and the experiment was continued as described above.
  • the relevant base cream were mixed with pre-dissolved deuteroporphyrin or hemin, from a stock solution.
  • the stock solution was prepared by dissolving 5 mg of porphyrin in 2 drops of 0.1 N NaOH, and then diluting in phosphate buffer to pH 6.8, to a concentration of 1 mg/ml.
  • the diluted solution was mixed with a base cream, to a final concentration of porphyrin of 100 ⁇ g/ml and, when used, 100 ⁇ g/ml concentration of antibiotic was added.
  • the sterilizing solutions were prepared by adding pre-dissolved deuteroporphyrin or hemin, from a stock solution.
  • the stock solution was prepared by dissolving 5 mg of porphyrin in 2 drops of 0.1 N NaOH, and then diluting in phosphate buffer to pH 6.8, to a concentration of 1 mg/ml.
  • the diluted solution was mixed with phosphate buffer saline (PBS) 0.15 M, pH 7, to a final concentration of porphyrin of 10 ⁇ g/ml.
  • PBS phosphate buffer saline
  • concentrations given in ⁇ g/ml refer to ml of nutrient broth, or culture broth, or buffer, as appropriate.
  • the optical density of the nutrient broth containing the calls was measured at 660 ran, as detailed above, as a function of time. The results are shown in Fig. 1, from which it can be seen that a combination of 10 ⁇ g/ml hemin + 10 ⁇ g/ml tetracycline was the most effective, and was substantially more effective than 30 ⁇ g/ml tetracycline alone.
  • hemin alone inhibits the growth of S. aureus for only 5 hours, while the combined effect of hemin and methycillin (in amounts in which methicillin alone does not show any effect) inhibit the growth for 7-8 hours, which represents a striking synergistic effect.
  • test compositions are identified as follows: control - no active materials added; AMP - ampicillin, 10 ⁇ g/ml; MET - methicillin, 10 ⁇ g/ml; HM - hemin, 10 ⁇ g/ml;
  • Penicillase activity in S. aureus was measured by the phenol red test. In the test there were used 10 ⁇ cells induced by methicillin, 50 ⁇ g/ml penicillin (in the mother liquor), and 0.5% phenol red. The experiment was carried out according to the method described by Escamilla J., [Susceptibility of Haemophilus influenzae to ampicillin as determined by use of a modified, one-minute beta-lactamase test", Antimicrob. Agents Chemoter., 9, 196-198 (1976)].
  • Example 7 The effect of the synergistic combination of the tetracycline and photoactivated deuteroporphyrin was tested using S. aureus. Viable counts were taken at the beginning of the experiment, and after one and two hours. The results are shown in Fig. 5. The tested compositions are identified as in Example 5.
  • Example 7 The tested compositions are identified as in Example 5.
  • Fig. 6A shows the optical density that was measured to determine total biomass
  • Fig. 6B represents the same results, given in terms of colony forming units. The following materials were used:
  • Tc lO ⁇ g/ml of tetracycline
  • NP 650 ⁇ g/ml of polymyxin B nonapeptide.
  • the E. coli cells were essentially insensitive to the polymyxin B nonapeptide alone, to its combination with tetracycline, and to tetracycline alone.
  • the cells treated with these compositions behaved essentially as the untreated control cells (Cont).
  • the combination of the invention comprising polymyxin B nonapeptide, deuteroporphyrin and tetracycline shows a surprising activity against E. coli.
  • control base cream only
  • deuteroporphyrin 100 ⁇ g/ml - in the dark
  • deuteroporphyrin 100 ⁇ g/ml - with a light irradiation of 10 J/ cm 2
  • deuteroporphyrin 100 ⁇ g/ml + hemin, 100 ⁇ g/ml - in the dark.
  • Staphylococcus aureus bacteria grown in nutrient broth media to their log phase were spinned and bacterial concentrate containing 10 8 - 10 9 bacteria were added to the various cream compositions.
  • Creams tested in the dark were kept at 37°C, while irradiated creams were ill__minated as described above.
  • 100 ⁇ g samples of the cream were diluted in PBS and plated on nutrient agar plates to determine the colony forming units / ml sample. Incubation intervals of 30 minutes and 180 minutes were employed.
  • the base cream was a commercially available cream, the so-called Johnson's baby moisturizer cream (manufactured by Johnson & Johnson Ltd., U.K.), containing: dimethicone; isopropyl palmitate; polysorbate 61; sorbitan stearate; myristyl myristate; cetyl alcohol; stearyl alcohol; synthetic beeswax; glyceryl stearate; stearic acid; oleic acid; propylene glycol; carbomer 941; methylparaben; propylparaben; butylparaben;
  • BHT stearoxytrimethylsilane
  • stearyl alcohol stearyl alcohol
  • benzyl alcohol sodium hydroxide
  • essence water.
  • Example 10 was repeated, but instead of the Johnson & Johnson base cream, Carbopol 940 was used.
  • Carbopol 940 is a commercially available acrylic copolymer (produced by B. F. Goodrich Company, U.S.A.).
  • Examples 9 - 12 were repeated, but instead of adding the bacterial concentrate directly to the cream, it was smeared on a bovine bone, and left to incubate at 37°C on the bone before a thin layer of cream was applied thereto. At the end of the incubation periods, the bone was washed with equal volumes of PBS, and the washings were plated on nutrient agar plates to determine the CFU.
  • Example 17 Example 16 was repeated, using S. epi ⁇ ermidis instead of S. aureus, and allowing incubation times of up to 6 hours. The results obtained were comparable to those obtained with S. aureus.
  • Examples 9 - 12 were tested in mice, to treat surgical cuts infected with S. aureus concentrate.
  • the cuts were of identical lengths, and the bacterial concentrate was taken from the same stock solution.
  • the cuts were tested periodically for bacterial presence. The results were essentially the same as those obtained in Examples 9 - 12.
  • Triton X- 100 Triton X- 100
  • sodium dodecyl sulphate sodium dodecyl sulphate
  • sodium lauryl sulphate Triton X- 100
  • Staphylococcus aureus bacteria grown in nutrient broth media to their log phase were spinned and bacterial concentrate containing 10 8 - 10 9 bacteria were added to the various sterilizing compositions.
  • the solutions were kept at 37°C.
  • 10 ml samples of the solution were plated on nutrient agar plates to determine the colony forrning units / ml sample. Incubation intervals of 1, 2 and 3 hours were employed.
  • Example 19 was repeated, with the exception that the bacterial concentrate was smeared on a human hand, which was allowed to incubate for 10 minutes and was then washed with one of the solutions of Example 19.
  • the washing liquid was then plated on an agar plate and tested for bacterial growth.
  • the control solution showed substantial bacterial concentration
  • the deuteroporphyrin and the hemin solution showed traces of bacteria, which the bacteria were non-detectable in the washings containing both a porphyrin and a detergent.
  • Example 20 was repeated, but this time the hands which had previously been washed with one of the solutions were immersed in PBS for 2 minutes, and the PBS was then analyzed for bacterial growth. The results obtained were consistent with those of Example 20.
  • Example 22
  • Example 21 was repeated, but instead of smearing the bacterial concentrate onto a human hand, it was smeared on a bovine bone, and left to incubate at 37°C on the bone before the bone was washed with one of the solutions of Example 19. At the end of the incubation periods, the bone was washed with equal volumes of PBS, and the washings were plated on nutrient agar plates to determine the CFU.
  • Example 22 was repeated, using S. epi ⁇ ermi ⁇ is instead of S. aureus. The results obtained were comparable to those obtained with S. aureus.
  • Example 24 The solutions of Example 19 were tested in mice, to treat surgical cuts • infected with S. aureus concentrate.
  • the cuts were of identical lengths, and the bacterial concentrate was taken from the same stock solution.
  • the cuts were tested periodically for bacterial presence. The results were essentially the same as those obtained in Example 19 - 23.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

On utilise des porphyrines en tant qu'agents antimicrobiens dans une composition antibiotique synergique comprenant en tant que principe actif antibiotique un mélange d'une ou de plusieurs porphyrines ainsi qu'au moins un composé antibiotique. On décrit une composition antimicrobienne comprenant en tant que principe actif une porphyrine ou un mélange d'une ou plusieurs porphyrines, seule(s) ou mélangée(s) à des agents antibiotiques classiques, et/ou des agents ou additifs acceptables ou bénéfiques sur le plan pharmacologique, dans une composition de crème à base d'eau. On décrit également une composition liquide de stérilisation comprenant en tant que principe actif une porphyrine ou un mélange d'une ou de plusieurs porphyrines, dans une solution aqueuse, ainsi qu'un tensioactif.
EP95923690A 1994-06-02 1995-05-30 Compositions antibiotiques synergique contenant une porphyrine et un antibiotique Withdrawn EP0765161A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
IL10987494A IL109874A0 (en) 1994-06-02 1994-06-02 Synergistic antimicrobial compositions
IL10987694A IL109876A0 (en) 1994-06-02 1994-06-02 Antimicrobial liquid compositions
IL10987594A IL109875A0 (en) 1994-06-02 1994-06-02 Antimicrobial cream compositions
IL10987694 1994-06-02
IL10987494 1994-06-02
IL10987594 1994-06-02
PCT/US1995/006998 WO1995033463A2 (fr) 1994-06-02 1995-05-30 Compositions antibiotiques synergique contenant une porphyrine et un antibiotique

Publications (1)

Publication Number Publication Date
EP0765161A2 true EP0765161A2 (fr) 1997-04-02

Family

ID=27271659

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95923690A Withdrawn EP0765161A2 (fr) 1994-06-02 1995-05-30 Compositions antibiotiques synergique contenant une porphyrine et un antibiotique

Country Status (5)

Country Link
EP (1) EP0765161A2 (fr)
AU (1) AU2816195A (fr)
CA (1) CA2191627A1 (fr)
NO (1) NO965109D0 (fr)
WO (1) WO1995033463A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6620805B1 (en) 1996-03-14 2003-09-16 Yale University Delivery of nucleic acids by porphyrins
NL1020336C2 (nl) * 2002-04-09 2003-10-13 Photobiochem Leiden N V Toepassing van een verbinding voor de bereiding van een farmaceutisch preparaat voor het behandelen van brandwonden, en een werkwijze voor het behandelen van brandwonden.
GB2397067B (en) 2002-12-23 2005-05-11 Destiny Pharma Ltd Porphin & azaporphin derivatives with at least one cationic-nitrogen-containing meso-substituent for use in photodynamic therapy & in vitro sterilisation
US12570665B2 (en) 2019-06-10 2026-03-10 University Of Massachusetts Compositions comprising fullerenyl mesochlorin nano-photosensitizers with covalently bound antibiotics and their uses in combination therapy
CN113425850B (zh) * 2021-06-04 2022-10-11 江南大学 光敏抗菌的改性卟啉金属有机骨架材料及其制备方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU721442A1 (ru) * 1977-09-12 1980-03-15 Московский Ордена Трудового Красного Знамени Институт Тонкой Химической Технологии Им. М.В. Ломоносова Способ получени -незамещенных порфиринов
JPS58981A (ja) * 1981-06-26 1983-01-06 Tama Seikagaku Kk 水溶性ポルフイリン誘導体
US4753958A (en) * 1985-02-07 1988-06-28 University Of Cal Photochemotherapy of epithelial diseases with derivatives of hematoporphyrins
JPS61189284A (ja) * 1985-02-18 1986-08-22 Tama Seikagaku Kk 水溶性ポルフイリン誘導体金属キレ−ト化合物
US4782049A (en) * 1986-12-08 1988-11-01 The Rockefeller University Tin protoporphyrin and tin mesoporphyrin in the treatment of psoriasis
US5109016A (en) * 1988-05-23 1992-04-28 Georgia State University Foundation, Inc. Method for inhibiting infection or replication of human immunodeficiency virus with porphyrin and phthalocyanine antiviral compositions
US4925736A (en) * 1988-07-06 1990-05-15 Long Island Jewish Medical Center Topical hematoporphyrin
FR2683724A1 (fr) * 1991-11-15 1993-05-21 Agronomique Inst Nat Rech Produit bactericide, composition pharmaceutique le contenant et additif alimentaire.
ATE159661T1 (de) * 1992-04-30 1997-11-15 Eastman Dental Inst Medikament zur desinfektion der mundhöhle
WO1995017893A1 (fr) * 1993-12-28 1995-07-06 New York Blood Center Methodes destinees a prevenir ou a traiter l'infection a vih-1 ou vih-2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9533463A2 *

Also Published As

Publication number Publication date
AU2816195A (en) 1996-01-04
WO1995033463A2 (fr) 1995-12-14
NO965109D0 (no) 1996-11-29
WO1995033463A3 (fr) 1996-05-17
CA2191627A1 (fr) 1995-12-14

Similar Documents

Publication Publication Date Title
Casewell et al. In-vitro activity of mupirocin (‘pseudomonic acid’) against clinical isolates of Staphylococcus aureus
AU2011373911B2 (en) Pharmaceutical compositions comprising sulbactam and beta-lactamase inhibitor
KR101738210B1 (ko) 베타-락탐계 항생제, 술박탐 및 베타―락타마아제 저해제를 포함하는 약학 조성물
Chin et al. Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection
KR20150089086A (ko) 박테리아 감염을 치료하기 위한 조성물 및 방법
Figueredo et al. Synergy of ciprofloxacin with fosfomycin in vitro against Pseudomonas isolates from patients with cystic fibrosis
WO1995033463A2 (fr) Compositions antibiotiques synergique contenant une porphyrine et un antibiotique
EP3412289A1 (fr) Compositions antibactériennes
Johnson et al. Comparative efficacy of ciprofloxacin, azlocillin, and tobramycin alone and in combination in experimental Pseudomonas sepsis
JP6525999B2 (ja) 抗菌性組成物
KR102620652B1 (ko) 미생물 콜로니화의 조절을 위한 치환된 톨란
KR20160126004A (ko) 항세균제를 포함하는 제약학적 조성물
Babalola Anti‐bacterial activity of synthetic N‐heterocyclic oxidizing compounds
EP0621783A1 (fr) Formulations pharmaceutiques comprenant un sel d'acide clavulanique et un derive d'erythromycine
Slack et al. Cefsulodin, a cephalosporin with specific antipseudomonal activity; in vitro studies of the drug alone and in combination
US7169792B2 (en) Method of treating bacterial infections using gemifloxacin or a salt thereof and a β-lactam antibiotic
KR20160138304A (ko) 항균 물질들을 포함하는 약학 조성물
JP4542644B2 (ja) 抗菌作用の増強方法
Shanson et al. Susceptibility of Salmonella typhi to rifamycins and novobiocin
Beale et al. Inactivation of cefuroxime and cefotaxime by Bacteroides fragilis in vitro, and its influence on the treatment of an experimental Escherichia coli/Bacteroides fragilis mixed infection
Fu et al. Synergistic activity of apalcillin and gentamicin in a combination therapy in experimental Pseudomonas bacteraemia of neutropenic mice
Pusztai-Markos et al. In vitro activity of N-formimidoyl-thienamycin in comparison to that of moxalactam and cefotaxime against gentamicin-resistant gram-negative bacteria
EP1458390A1 (fr) Procede de traitement d'infections bacteriennes au moyen de gemifloxacine ou d'un sel de ce compose et d'un agent antibacterien carbapeneme
JPH02250829A (ja) 抗菌剤
KR20160072262A (ko) 항균제를 포함하는 제약학적 조성물

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19961203

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19991201