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WO2013055674A1 - Méthode de traitement d'infections - Google Patents

Méthode de traitement d'infections Download PDF

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Publication number
WO2013055674A1
WO2013055674A1 PCT/US2012/059333 US2012059333W WO2013055674A1 WO 2013055674 A1 WO2013055674 A1 WO 2013055674A1 US 2012059333 W US2012059333 W US 2012059333W WO 2013055674 A1 WO2013055674 A1 WO 2013055674A1
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WIPO (PCT)
Prior art keywords
corynebacterium
indol
methoxy
benzyl
sulfonylaminocarbonyl
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Ceased
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PCT/US2012/059333
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English (en)
Inventor
Donald Ronning
Jimmy FRANCO
Choong-Min Kang
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University of Toledo
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University of Toledo
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Publication date
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Publication of WO2013055674A1 publication Critical patent/WO2013055674A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to methods and compositions for treating, controlling, reducing or inhibiting a bacterial infection in a subject in need thereof.
  • the method includes: administering to the subject an effective amount of a composition comprising a leukotriene receptor antagonist compound or a pharmaceutically acceptable salt thereof.
  • TB tuberculosis
  • the typical treatment for TB comes in the form of antibiotics, however, due to the nature and structure of the cell effective TB treatment is difficult. Additionally, drug resistant strains are increasingly common.
  • the standard treatment for tuberculosis is a six-month regimen consisting of four drugs given for two months, followed by two drugs given for four months. Two drugs, given throughout the six-month course of therapy, are isoniazid and rifampin.
  • mycobacteria there are a number of other human and animal diseases caused by mycobacteria, including for example leprosy (Hansen's disease), lymphadenitis, a variety of pulmonary and skin diseases, and wound infection. Although less prevalent, each of these diseases is associated with morbidity, mortality and economic costs such as lost production time and the cost of medical treatment. Resistance to drugs used heretofore to control and treat such diseases is also a current problem, thus raising a further need in this art for more effective drugs against many different Mycobacterium species.
  • leprosy Haansen's disease
  • lymphadenitis a variety of pulmonary and skin diseases
  • wound infection a variety of pulmonary and skin diseases
  • a method for treating, controlling, reducing or inhibiting a bacterial infection in a subject in need thereof includes: administering to the subject an effective amount of a composition comprising a leukotriene receptor antagonist compound or a pharmaceutically acceptable salt thereof.
  • the leukotriene receptor antagonist compound comprises one or more of:
  • the leukotriene receptor antagonist compound comprises zafirlukast or a pharmacologically active derivative thereof.
  • the leukotriene receptor antagonist compound comprises a metabolite of zafirlukast, or a pharmacologically active derivative thereof.
  • Non-limiting examples include:
  • Zafirlukast [3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl)benzyl]-l-methyl-lH- indol-5-yl]carbamic acid cyclopentyl ester.
  • the infection is a chronic bacterial infection.
  • the chronic bacterial infection is a mycobacterial infection.
  • the mycobacterial infection is caused by M. tuberculosis, M. avium-intracellulare, M. kansasii, M. fortuitum, M. chelonae, M. leprae, M. africanum, M. bovis, M. avium, M. microti, M. avium paratuberculosis, M. intracellulare, M. scrofulaceum, M.
  • the infection is caused Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis as well as other Corynebacterium sp, including, but not limited to: species Corynebacterium diphtheriae and the nondiphtherial corynebacteria, collectively referred to as diphtheroids; Corynebacterium haemolyticum (Arcanobacterium haemolyticum); Corynebacterium jeikeium; Corynebacterium glutamicun; Corynebacterium pseudodiphtheriticum.
  • Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis as well as other Corynebacterium sp, including, but not limited to: species Corynebacterium diphtheriae and the nondiphtherial corynebacteria, collectively referred to as diphtheroids; Corynebacterium haemolyticum (Arcanobacter
  • the present invention contemplates treatment instead of and/or in addition to the Current treatment of an infected individual who had not been previously immunized for Corynebacterium infection, which includes treatment with antitoxin produced against the diptheria toxin plus penicillin or erythromycin.
  • the subject is a mammal. And, in certain embodiments, the mammal is a human.
  • the subject is a member selected from a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.
  • the effective amount is administered topically, orally, peritoneally, subcutaneously, intramuscularly, intraocularly, intraarterially, intravenously, or locally using an implantable dosage unit.
  • the compound is administered as a solid, liquid or aerosol.
  • the solid is a pill or an implantable dosage unit.
  • the aerosol comprises an inhaler formulation.
  • the solid, liquid or aerosol comprises a sustained release matrix.
  • the effective amount of the compound comprises from 100 to 0.1 mg per kg of body weight. In certain embodiments, the effective amount of the compound comprises from 50 to 0.2 mg per kg of body weight. In certain embodiments, the effective amount of the compound comprises from 25 to 0.5 mg per kg of body weight. In certain embodiments, the effective amount of the compound comprises from 1 to 1000 mg.
  • a method of inhibiting growth of bacteria comprising: exposing bacteria to an agent that disrupts inhibits binding of Lsr2 protein to DNA under conditions effective to inhibit growth of the bacteria.
  • a method of treating a bacterial infection in a subject generally comprises: administering to the subject an agent that inhibits binding of Lsr2 protein to DNA under conditions effective to treat the bacterial infection.
  • the method can comprise selecting a subject having a bacterial infection prior to said administering.
  • the agent is administered in combination with one or more antibacterial agents.
  • the one or more antibacterial agents are selected from the group consisting of isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, ethambutol, kanamycin, erythromycin or other aminoglycoside antibiotics.
  • a method of identifying a compound that inhibits binding of Lsr2 protein to DNA of a pathogen generally comprises: providing one or more candidate compounds;
  • the pathogen comprises a detectable indicator of binding of Lsr2 protein to DNA
  • detecting a change in the binding of Lsr2 protein to DNA in the presence of a candidate compound identifies a compound that interferes with the binding of Lsr2 protein to DNA of the pathogen.
  • the pathogen is bacterium. Further, in certain embodiments, the bacterium is Mycobacterium. And, in certain embodiments, the Mycobacterium is
  • a method of killing a tuberculosis- causing microorganism infecting a mammalian cell generally comprises: contacting said cell with a composition comprising a leukotriene receptor antagonist compound or a pharmaceutically acceptable salt thereof.
  • a method of treating an infection in an animal generally comprises: administering to the animal a therapeutically effective amount of a leukotriene receptor antagonist compound, or a pharmaceutically acceptable salt thereof, sufficient to treat said infection.
  • a method of treating an animal infected with a disease-causing microorganism of a Mycobacterium species generally comprises: administering to the animal a therapeutically effective amount of a pharmaceutical composition comprising a leukotriene receptor antagonist compound or a pharmaceutically acceptable salt thereof.
  • the method generally comprises: contacting said cell with the composition comprising a leukotriene receptor antagonist compound or a pharmaceutically acceptable salt thereof.
  • Figure 2 Kirby-Bauer disk diffusion assay showing growth inhibition of M.
  • smegmatis Increasing amounts of Zafirlukast were impregnated onto wafers and applied to an agar plate inoculated with M. smegmatis. The sizes of the zones of inhibition are directly proportional to the amount of Zafirlukast in the disk.
  • the sigA gene is a housekeeping gene
  • sodA is a virulence factor
  • otsA and fpbC are important for bacterial metabolism and division
  • the lsr2 gene that encodes the Lsr2 protein. The only gene whose expression does not increase as a result of administering
  • Zafirlukast was sigA.
  • the expression of the lsr2 gene has increased 8.8 fold; to compensate for the decreased ability of the Lsr2 protein to bind DNA in the presence of the drug.
  • Figure 5 A plot of polarization versus concentration of Lsr2 demonstrating an increase in polarization corresponding to the Lsr2/DNA complex formation. The concentration of Lsr2 was increased until saturation was reached. From fitting of the normalized data, the K d for the Lsr2-DNA complexation was determined to be 0.87 ⁇ ⁇ 0.09 (R 2 0.961).
  • Figure 7 Spectra from the Intensity Fading experiment comparing the relative ion intensities of Zafirlukast and Ritonavir. As the concentration of Lsr2 is increased from top to bottom, the relative intensity of Zafirlukast diminishes as compared to the internal standard (Ritonavir). The decrease in relative intensity is attributed to complexation between Lsr2 and Zafirlukast.
  • Figure 8 Plot of the intensity ratio of Zafirlukast (Z) over Ritonavir (R) versus the concentration of Lsr2. As the concentration of Lsr2 is increased a larger portion of the
  • Zafirlukast is bound to the protein decreasing the amount of free ion to be ionized, thus decreasing the intensity of the Zafirlukast signal.
  • the term “tuberculosis” comprises disease states usually associated with infections caused by mycobacteria species comprising M. tuberculosis (M.tb.) complex.
  • the term “tuberculosis” is also associated with mycobacterial infections caused by mycobacteria other than M. tuberculosis (MOTT).
  • mycobacterial species include M. avium- intracellulare, M. kansarii, M. fortuitum, M. chelonae, M. leprae, M. africanum, and M. microti, M. avium paratuberculosis, M. intracellulare, M. scrofulaceum, M. xenopi, M. marinum, M.
  • the tuberculosis is multidrug-resistant tuberculosis (MDR tuberculosis) or extensively drug-resistant tuberculosis (XDR tuberculosis).
  • MDR tuberculosis means a form of tuberculosis that is resistant to two or more of the primary drugs (e.g., isoniazid and rifampicin) used for the treatment of tuberculosis.
  • the present invention is based, at least in part, on the discovery that Lsr2 binds more than 20% of the genes identified in the M. tb genome.
  • Lsr2 is a nucleoid-associated protein found in M. tb as well as in other actinobacteria.
  • Lsr2 appears to be functionally analogous to eukaryotic histone proteins as well as the H-NS nucleoid-associated proteins found in E. coli and related gammaproteobacteria.
  • Lsr2 binds AT-rich DNA to promote DNA condensation and structural organization of the genome. While not wishing to be bound by theory, the inventors herein now believe that a consequence of this function is that Lsr2 binds promoter regions in the GC-rich mycobacterial genome and thereby acts as a global repressor of transcription.
  • M. smegmatis a common non-pathogenic surrogate for M. tb as well inhibiting the growth of M. tb.
  • the infection is caused Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis as well as other Corynebacterium sp, including, but not limited to: species Corynebacterium diphtheriae and the nondiphtherial corynebacteria, collectively referred to as diphtheroids; Corynebacterium haemolyticum (Arcanobacterium haemolyticum); Corynebacterium jeikeium; Corynebacterium glutamicun; Corynebacterium pseudodiphtheriticum.
  • Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis as well as other Corynebacterium sp, including, but not limited to: species Corynebacterium diphtheriae and the nondiphtherial corynebacteria, collectively referred to as diphtheroids; Corynebacterium haemolyticum (Arcanobacter
  • Nondiphtherial corynebacteria also cause chronic and subclinical diseases in domestic animals and can lead to significant economic losses for farmers.
  • Examples of widespread and difficult-to-control infections include Corynebacterium pseudotuberculosis caseous lymphadenitis in sheep, goats, and alpacas; C. pseudotuberculosis ulcerative dermatitis in cattle; and urinary tract infections and mastitis (affecting milk production) in cattle due to infection with Corynebacterium renale, Corynebacterium cystidis, Corynebacterium pilosum, and Corynebacterium bovis.
  • Specific pathogenic groups or species include the following:
  • Corynebacterium ulcer ans C pseudotuberculosis (also known as Corynebacterium ovis);
  • Corynebacterium pyogenes A haemolyticum; Corynebacterium aquaticum; C
  • pseudodiphtheriticum also known as Corynebacterium hofinannii
  • Group D2 also known as Corynebacterium urealyticum
  • Group E also known as Corynebacterium urealyticum
  • Cjeikeium ie, group JK
  • the inhibitor screening methodology used a preincubated Lsr2/DNA complex where the Lsr2 concentration was chosen to be above the Kd value to ensure that the assay was both sensitive and discriminating.
  • the assay was used to screen a portion of the NIH Clinical Collection (BioFocus, Saffron Walden, UK). Of the 281 compounds tested, seven compounds were identified as potential leads based on a criterion of an FP signal decrease greater than three times the standard deviation from the mean polarization measurement. Of these indentified inhibitors, six are known DNA intercalators or groove binders so they were dismissed from further study. Although compounds with these attributes have been previously used to disrupt protein/DNA complex formation they are also known for their lack of specificity and severe side effects when used therapeutically.
  • Zafirlukast is a leukotriene receptor antagonist commonly prescribed as a prophylactic treatment for asthma.
  • a dose-dependence study using the same FP-based assay was used ( Figure 1).
  • the protein and DNA concentrations were held constant at 50 ⁇ and 10 nM, respectively, as the concentration of Zafirlukast was varied.
  • Zafirlukast inhibits complexation by binding Lsr2 and not DNA.
  • Zafirlukast is also supported by the chemical structure of Zafirlukast, in that it is not a polycyclic aromatic compound and that it is anionic at physiological pH. For example, see the structures shown in Figure 4.
  • Zafirlukast is binding Lsr2 and not DNA
  • an Intensity Fading MALDI-TOF mass spectrometry assay was performed. This methodology is advantageous when attempting to show non-covalent binding of inhibitors possessing limited solubility, like Zafirlukast, to their protein targets. Samples containing fixed concentrations of Zafirlukast and Ritonavir, as an internal standard, were titrated with increasing concentrations of Lsr2.
  • Zafirlukast does inhibit mycobacterial growth and the radius of the zone of inhibition is directly correlated to the amount of Zafirlukast on the respective discs. In contrast, the same amount of compound in a similar experiment using E. coli exhibited no growth inhibition
  • RT-PCR Real-Time PCR
  • sigA As sigA is constitutively expressed at a constant level in cultured bacteria, transcription of this gene is unlikely to respond to only a single signal.
  • the regulatory factors present in response to the stress imparted by administering Zafirlukast likely supersedes the effect of inhibiting Lsr2 function or the subsequent increase in Lsr2 concentration as a consequence of its over expression.
  • Zafirlukast specifically inhibits Lsr2 function in mycobacterial cells.
  • the present inventors herein identified compounds that inhibit the activity of the highly conserved DNA-binding protein Lsr2. Not only is Zafirlukast now identified as an inhibitor of Lsr2 function, but the application of this drug also alters gene expression levels in M. tb and leads to growth inhibition of mycobacteria presumably by profoundly dysregulating protein expression levels in the bacterial cell.
  • Zafirlukast has synergistic effects with other first-line drugs since Lsr2 expression increases during the administration of known anti-tubercular drugs presumably to help M. tb survive during pharmacologically-induced stress.
  • Lsr2 is clearly important for the mycobacterial response to environmental stress, the efficacy of Zafirlukast may be greater in the host by disrupting defenses evolved in M. tb. to evade or disrupt the human immune response. This may promote killing of M. tb by the human immune system.
  • Zafirlukast does not appear to function through the same mechanism of any current TB drugs, so it is likely to be effective against XDR-TB.
  • Zafirlukast is an approved, safe, orally available drug that is readily transported to lung tissue, repurposing it for the treatment of TB could have an immediate impact on global health.
  • Zafirlukast was purchased from Sigma-Aldrich.
  • 5'-fluoroscein labeled AT-rich stem-loop DNA with the sequence 5'- CCTAATTATAACGAAGTTATAATTAGG-3' [SEQ ID NO:l] was purchased from Integrated DNA Technologies (Coralville, IA) and dissolved in deionized water at a concentration of 100 ⁇ , heated to 95°C for 15 minutes, cooled on ice, and stored at -20°C until needed. All mass spectrometry experiments were carried out on a Bruker ultrafleXtreme MALDI TOF/TOF.
  • Lsr2 from recombinant DNA was expressed in E. coli BL21 (DE3) using Luria- Bertani (LB) media. The culture was grown at 37°C until reaching an O.D. 6 o 0 mn between 0.6 and 0.8 followed by induction with IPTG at 16°C for 36 hours. Lsr2 was purified using immobilized metal affinity chromatography followed by cation exchange chromatography.
  • the K d was obtained using a 384-well microplate format fluorescence polarization (FP) assay performed at 37°C. Each well contained 1 ⁇ ⁇ of fluorescently labeled DNA (10 nM) and concentrations of Lsr2 ranging from 0 to 200 ⁇ . Additional buffer solution (20 mM Tris pH 7.5, 50 mM NaCl) was added as needed to reach a final volume of 25 ⁇ ⁇ .
  • FP fluorescence polarization
  • the NCC was screened in a corning 384-well microplate at 37°C with an excitation of 485 nm and an emission of 528 nm.
  • each well 22.75 ⁇ ⁇ of Lsr2 (15 ⁇ ) in 20 mM Tris pH 7.5, 50 mM NaCl, 1.25 ⁇ , of fluorescently labeled DNA (5 ⁇ ) and 1 ⁇ , of compound (10 mM) in DMSO.
  • Controls were also performed by adding 1 ⁇ of DMSO lacking drug.
  • the FP signals were evaluated for each tested drug. Any compound showing a decrease in the FP signal that was greater than three times the standard deviation was considered a hit.
  • the 3 ⁇ 4 was obtained using the same FP assay format. Each well contained 1 ⁇ of fluorescently labeled DNA (10 nM), 20 ⁇ of Lsr2 (50 ⁇ ) and the concentration of Zafirlukast was varied by adding a constant volume (1 ⁇ ) with increasing concentrations, from 0 to 300 ⁇ . Kj was calculated with Prism (GraphPad software) using the equation
  • M. smegmatis with Ampicillin was grown at 37°C for 72 hours in Middlebrook 7H9 Broth.
  • a carbenicillin agar plate was inoculated with 250 ⁇ ⁇ of the M. smegmatis solution.
  • Zafirlukast 392 ⁇ g, 196 ⁇ g, 95 ⁇ g, 50 ⁇ g, 0 ⁇ g in 20 ⁇ . of DMSO
  • the agar plate was incubated for 14 hours at 37°C then the zones of inhibition were examined.
  • the analogous experiment using E. coli in LB media was performed using the same protocol.
  • the Kirby-Bauer disk diffusion assays were performed in a similar manner using M. tb. However, growth at 37°C was for 10 days because of the much longer doubling time exhibited by M. tb.
  • the nonbinding internal standard, Ritonavir was diluted to a concentration that gave a MALDI MS ion signal of intensity that resembled that of the Zafirlukast.
  • the compounds were both dissolved in DMSO, combined and diluted with a 20 mM Tris pH 8.5 solution. From this solution 2 ⁇ were added to each of the solutions containing increasing concentration of Lsr2 in 20 mM Tris pH 8.5. The solutions were then incubated at 4 °C for 12 hours. The sample was mixed using the dried droplet method with a matrix solution (1:2 v/v) of sinapinic acid
  • compositions containing the leukotriene receptor antagonist compounds can be prepared in physiologically acceptable formulations, such as in
  • the compound can be combined with a pharmaceutically acceptable excipient to form a therapeutic composition.
  • compositions may be administered in the form of a solid, liquid or aerosol.
  • solid compositions include pills, creams, soaps and implantable dosage units. Pills may be administered orally.
  • Therapeutic creams and anti-mycobacteria soaps may be administered topically.
  • Implantable dosage units may be administered locally, for example, in the lungs, or may be implanted for systematic release of the therapeutic composition, for example, subcutaneously.
  • liquid compositions include formulations adapted for injection intramuscularly, subcutaneously, intravenously, intraarterially, and formulations for topical and intraocular administration.
  • aerosol formulations include inhaler formulations for administration to the lungs.
  • a sustained release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid/base hydrolysis, or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids.
  • the sustained release matrix is chosen desirably from biocompatible materials, including, but not limited to, liposomes, polylactides, polyglycolide (polymer of glycolic acid), polylactide co-glycolide (coplymers of lactic acid and glycolic acid), poly anhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipds, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • biocompatible materials including, but not limited to, liposomes, polylactides, polyglycolide (polymer of glycolic acid), polylactide co-glycolide (coplymers of lactic acid and glycolic acid), poly anhydrides
  • Biodegradable matrix include, for example, a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide.
  • the dosage of the composition will depend on the condition being treated, the particular composition used, and other clinical factors, such as weight and condition of the patient, and the route of administration.
  • One suitable dosage may range from 100 to 0.1 mg/kg.
  • Another dosage may range from 50 to 0.2 mg/kg.
  • Still another dosage may range from 25 to 0.5 mg/kg.
  • Tablets or other forms of media may contain from 1 to 1000 mg of the leukotriene receptor antagonist. Dosage ranges and schedules of administration similar to ethambutol or other anti-tuberculosis drugs may be used.
  • compositions may be administered in combination with other compositions and procedures for the treatment of other disorders occurring in combination with mycobacterial disease.
  • tuberculosis frequently occurs as a secondary complication associated with acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • Patients undergoing AIDS treatment which includes procedures such as surgery, radiation or chemotherapy, may benefit from the therapeutic methods and compositions described herein.
  • the amount of active ingredients in the combinations required for use in treatment will vary according to a variety of factors, including the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or health care practitioner.
  • the factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.

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Abstract

L'invention concerne des méthodes et des compositions pour la détection, le traitement, la caractérisation et le diagnostic d'infections, la composition comprenant un composé antagoniste d'un récepteur des leucotriènes ou un sel de qualité pharmaceutique de celui-ci.
PCT/US2012/059333 2011-10-10 2012-10-09 Méthode de traitement d'infections Ceased WO2013055674A1 (fr)

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Cited By (6)

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WO2015079254A1 (fr) * 2013-11-29 2015-06-04 University Of East London Antagonistes des recepteurs des leucotrienes et leurs derives pour utilisation en tant qu'agents antibacteriens
CN106361737A (zh) * 2016-09-06 2017-02-01 南京医科大学第附属医院 曲尼司特在制备治疗结核病的药物中的应用
CN107714694A (zh) * 2017-11-01 2018-02-23 天津国际生物医药联合研究院 扎鲁司特在抗结核分枝杆菌感染中的应用
WO2020092016A1 (fr) * 2018-10-31 2020-05-07 Systamedic Inc. Activateurs d'autophagie et inhibiteurs de la ferroptose pour prévenir l'insuffisance rénale aiguë et la neurotoxicité induite par certains antibiotiques
US11535592B2 (en) * 2019-06-07 2022-12-27 University Of Kentucky Research Foundation Antimicrobial compounds, compositions, and method
US11872210B2 (en) 2017-01-30 2024-01-16 Western New England University Thiol isomerases inhibitors and use thereof

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JP2016540048A (ja) * 2013-11-29 2016-12-22 ユニバーシティ オブ イースト ロンドン 抗菌物質として使用されるロイコトリエンレセプターアンタゴニストおよびそれらの誘導体
CN106361737A (zh) * 2016-09-06 2017-02-01 南京医科大学第附属医院 曲尼司特在制备治疗结核病的药物中的应用
US11872210B2 (en) 2017-01-30 2024-01-16 Western New England University Thiol isomerases inhibitors and use thereof
CN107714694A (zh) * 2017-11-01 2018-02-23 天津国际生物医药联合研究院 扎鲁司特在抗结核分枝杆菌感染中的应用
WO2020092016A1 (fr) * 2018-10-31 2020-05-07 Systamedic Inc. Activateurs d'autophagie et inhibiteurs de la ferroptose pour prévenir l'insuffisance rénale aiguë et la neurotoxicité induite par certains antibiotiques
US11535592B2 (en) * 2019-06-07 2022-12-27 University Of Kentucky Research Foundation Antimicrobial compounds, compositions, and method

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