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WO2010087260A1 - Agent antituberculeux et son utilisation - Google Patents

Agent antituberculeux et son utilisation Download PDF

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Publication number
WO2010087260A1
WO2010087260A1 PCT/JP2010/050665 JP2010050665W WO2010087260A1 WO 2010087260 A1 WO2010087260 A1 WO 2010087260A1 JP 2010050665 W JP2010050665 W JP 2010050665W WO 2010087260 A1 WO2010087260 A1 WO 2010087260A1
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WO
WIPO (PCT)
Prior art keywords
disulfiram
drug
tuberculosis
ddc
drugs
Prior art date
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Ceased
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PCT/JP2010/050665
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English (en)
Japanese (ja)
Inventor
猛将 瀧井
康弘 堀田
衣美 稲垣
菊夫 小野嵜
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Nagoya City University
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Nagoya City University
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Publication date
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Priority to JP2010548473A priority Critical patent/JPWO2010087260A1/ja
Publication of WO2010087260A1 publication Critical patent/WO2010087260A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an antituberculosis drug and its use (prevention or treatment of tuberculosis).
  • This application claims priority based on Japanese Patent Application No. 2009-21026 filed on Jan. 31, 2009, the entire contents of which are incorporated by reference.
  • tuberculosis is recognized in Japan as an infectious disease that needs to be addressed.
  • effective tuberculosis treatments such as streptomycin (SM), isoniazid (INH) and rifampicin (RFP) were developed, and the number of tuberculosis patients was steadily decreasing.
  • SM streptomycin
  • IH isoniazid
  • RFP rifampicin
  • MDR-TB multidrug-resistant tuberculosis
  • MAC avium-intracellulare complex
  • FQ fluoroquinolone
  • CPM capreomycin
  • an object of the present invention is to provide a novel antituberculosis drug and its use.
  • the present inventors paid attention to the drug disulfiram used as an anti-alcohol drug, and examined its action against Mycobacterium tuberculosis. As a result, it was revealed that disulfiram and its metabolite diethyldithiocarbamate (DDC) have a strong antibacterial activity against Mycobacterium tuberculosis H 37 Rv (MTB). The strength was intermediate between the first-line drugs and the second-line drugs, and the in vitro MIC was 0.78 to 1.56 ⁇ g / ml, which is equivalent to the existing second-line drugs for antituberculosis drugs. Disulfiram was reported as an aldehyde dehydrogenase inhibitory effect by Erik Jacobsen et al.
  • Non-patent Document 1 Methicillin resistant Staphylococcus aureus aureus aureus
  • Giardia Non-patent Document 2
  • Metronidazole-resistant Trichomonas vaginalis Meronidazole
  • fungi such as Aspergillus spp
  • An antituberculosis drug containing disulfiram or diethyldithiocarbamate or a pharmaceutically acceptable salt thereof as an active ingredient [2] an antituberculosis drug containing isoniazid, rifampicin, streptomycin, kanamycin, amikacin, ethambutol, or para-aminosalicylate as an active ingredient
  • the antituberculosis drug according to [1] which is administered in combination.
  • a method for preventing or treating tuberculosis comprising a step of administering the antituberculous drug according to [1] to a subject.
  • An antituberculosis drug containing isoniazid, ryfampicin, streptomycin, kanamycine, amikacin, ethambutol, or paraaminosalicylate (p-aminosalicylate) as an active ingredient The method for preventing or treating tuberculosis according to [3], which is administered in combination.
  • [5] Use of disulfiram or diethyldithiocarbamate or a pharmaceutically acceptable salt thereof for the manufacture of an antituberculosis drug.
  • BDT method antibacterial activity measurement method
  • the minimum inhibitory concentrations (MIC) of various antibacterial drugs are summarized in the table.
  • the minimum inhibitory concentrations (MIC) of disulfiram and DDC are summarized in the table.
  • INH isoniazid
  • RFP rifampicin
  • SM streptomycin
  • EB ethambutol
  • PAS paraaminosalicylic acid
  • AMK amikacin
  • KM kanamycin
  • GM gentamicin
  • TC tetracycline
  • DOXY doxycycline
  • CAM clarithromycin
  • CPFX cystein Profloxacin
  • VCM Vancomycin
  • PCG Benzylpenicillin
  • ABPC Ampicillin
  • C Toxicity to THP-1 cells.
  • the horizontal axis is the drug concentration (logarithm), and the vertical axis is the ratio (%) to the control.
  • INH isoniazid
  • RFP rifampicin
  • SM streptomycin
  • EB ethambutol
  • DDC diethyldithiocarbamate.
  • the graph which shows the antibacterial activity with respect to the tubercle bacillus parasitizing the host cell of disulfiram and DDC.
  • B Activity in A549 cells.
  • the horizontal axis represents the drug concentration, and the vertical axis represents the amount of decrease in the number of colonies (logarithm).
  • surface which shows the pH dependence of the antituberculous action of disulfiram and DDC.
  • CPFX Ciprofloxacin
  • DDC Diethyldithiocarbamate. Examination of the mode of action (bactericidal or bacteriostatic) of disulfiram on M. bovis BCG. The results of the drug sensitivity test are summarized in a graph. The activity of the drug was evaluated by the number of colonies of Mycobacterium bovis BCG.
  • A sensitivity to isoniazid
  • B sensitivity to ethambutol
  • C sensitivity to disulfiram
  • D sensitivity to DDC
  • E sensitivity to disulfiram
  • D sensitivity to DDC.
  • the horizontal axis is the number of days after drug addition.
  • the vertical axis of A to D is the absorbance at 530 nm.
  • the vertical axis of E and F is the number of colonies (CFU).
  • the results of the drug sensitivity test are summarized in a graph. The activity of the drug was evaluated by the number of colonies of Staphylococcus aureus.
  • the horizontal axis is the time after drug addition.
  • the vertical axis is the absorbance at 530 nm.
  • Examination of mode of action (bactericidal or bacteriostatic) of disulfiram against M. smegmatis. The results of the drug sensitivity test are summarized in a graph. The activity of the drug was evaluated by the number of colonies of Mycobacterium smegmatis.
  • the horizontal axis is the time after drug addition.
  • the vertical axis is the absorbance at 530 nm.
  • the horizontal axis of A is the drug concentration, and the vertical axis is the residual activity (%).
  • INH isoniazid
  • RFP rifampicin
  • SM streptomycin
  • EB ethambutol
  • KM kanamycin
  • PAS paraaminosalicylic acid
  • CPFX ciprofloxacin
  • DSF disulfiram
  • DDC diethyldithiocarbamate.
  • DSF Disulfiram
  • DDC Diethyldithiocarbamate. Table showing antibacterial activity of disulfiram and DDC against clinical isolates (drug-sensitive strains). Table showing antibacterial activity of disulfiram and DDC against clinical isolates (drug resistant strains).
  • INH isoniazid
  • RFP rifampicin
  • EB ethambutol
  • LVFX levofloxacin
  • SPFX spafloxacin
  • CPFX ciprofloxacin
  • KM kanamycin
  • SM streptomycin
  • PAS paraaminosalicylic acid
  • TH ethionamide
  • PZA pyrazinamide
  • DSF Disulfiram
  • DDC diethyldithiocarbamate. Table showing drug resistance frequency for disulfiram and DDC.
  • INH isoniazid
  • RFP rifampicin
  • SM streptomycin
  • EB ethambutol
  • KM kanamycin
  • CPFX ciprofloxacin
  • PAS paraaminosalicylic acid
  • DSF disulfiram
  • DDC diethyldithiocarbamate.
  • RFP rifampicin
  • DSF disulfiram
  • the graph which shows the weight change of a tuberculosis chronic infection model mouse.
  • A Rifampicillin was administered at 20 mg / kg (R20), 10 mg / kg (R10) or 5 mg / kg (R5), and changes in body weight were recorded.
  • Disulfiram was administered at 160 mg / kg (D160), 80 mg / kg (D80) or 40 mg / kg (D40), and changes in body weight were recorded.
  • the graph which shows the infection protective effect of disulfiram.
  • Disulfiram 40 mg / kg (D40), 80 mg / kg (D80) or 160 mg / kg (D160)
  • rifampicin 5 mg / kg (R5), 10 mg / kg (R10) or 20 mg / kg (R20)
  • 5% gum arabic control group
  • Disulfiram 40 mg / kg (D40), 80 mg / kg (D80) or 160 mg / kg (D160)
  • rifampicin 5 mg / kg (R5), 10 mg / kg (R10) or After administration of 20 mg / kg (R20)) or 5% gum arabic (control group), liver injury markers in the liver and serum were detected.
  • NS is not significantly different.
  • Disulfiram 40 mg / kg (D40), 80 mg / kg (D80) or 160 mg / kg (D160)
  • rifampicin 5 mg / kg (R5), 10 mg / kg (R10) or After administration of 20 mg / kg (R20)) or 5% gum arabic (control group), liver injury markers in the liver and serum were detected.
  • ALP level left
  • ChE inhibitory effect right
  • NS is not significantly different.
  • the first aspect of the present invention relates to an antituberculosis drug.
  • disulfiram (1- (diethylthiocarbamoyldisulfanyl) -N, N-diethyl-methanethioamide) or its metabolite diethyldithiocarbamate or a salt thereof is used as an active ingredient.
  • the salt here is not particularly limited as long as it is pharmaceutically acceptable, and salts (inorganic acid salts) with hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, formic acid, acetic acid, lactic acid, fumaric acid Examples thereof include salts (organic acid salts) with maleic acid, tartaric acid, citric acid and the like. These salts can be prepared by conventional means.
  • Disulfiram was reported as an aldehyde dehydrogenase inhibitory effect by Erik Jacobsen et al. In 1948 and is now widely used as a drug with indications for chronic alcoholism. The structure of disulfiram is shown below.
  • Disulfiram is known to be metabolized in vivo as follows.
  • Disulfiram is used clinically as an anti-alcohol drug and is readily available.
  • Mitsubishi Tanabe Pharma Co., Ltd., Nacalai Tesque Co., Ltd., Wako Pure Chemicals Co., Ltd., and SIGNA-ALORICHORI Group sell disulfiram. Diethyldithiocarbamate is available from Nacalai Tesque.
  • the active ingredient can be formulated according to a conventional method.
  • other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological Saline solution and the like.
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, diethylin sulfite, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • the dosage form for formulation is not particularly limited, and can be prepared, for example, as tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories.
  • the drug of the present invention thus formulated can be applied to a subject by oral administration or parenteral administration (intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal injection, etc.) depending on the form.
  • the “subject” here is not particularly limited, but preferably a human.
  • the content of the active ingredient in the antituberculosis drug of the present invention generally varies depending on the dosage form, but is, for example, about 0.001% by weight to about 90% by weight so as to achieve a desired dose.
  • anti-tuberculosis drugs including existing anti-tuberculosis drugs may be used. If drugs with different action points are combined, a multifaceted antituberculosis action can be exerted. When the same or similar drugs are combined, enhancement of antituberculous action can be expected.
  • existing anti-tuberculosis agents include Isoniazid, Rifampicin, Streptomycin, Kanamycin, Amikacin, Ethambutol, and para-aminosalicylate.
  • the treatment method of the present invention includes a step of administering the antituberculosis drug of the present invention to the living body.
  • the administration route is not particularly limited, and examples thereof include oral, intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, and transmucosal. These administration routes are not mutually exclusive, and two or more arbitrarily selected can be used in combination (for example, intravenous injection or the like is performed simultaneously with oral administration or after a predetermined time has elapsed). In addition, oral administration is preferable because administration is easy.
  • the dose of the antituberculosis drug varies depending on the symptom, age of the subject, sex, weight, etc., but a person skilled in the art can appropriately set an appropriate dose.
  • the dose can be set so that the amount of the active ingredient per day is about 100 mg to about 1000 mg, preferably about 250 mg to about 500 mg for an adult (body weight: about 60 kg).
  • the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted. In setting the administration schedule, it is possible to consider the condition of the administration subject, the duration of effect of the drug, and the like.
  • the antituberculosis drug of the present invention is administered alone or in combination with other antituberculosis drugs.
  • examples of other anti-tuberculosis drugs include Isoniazid, Rifampicin, Streptomycin, Kanamycin, Amikacin, Ethambutol, or para-aminosalicylate It is an anti-tuberculosis drug.
  • Disulfiram had a minimum inhibitory concentration of 0.78 to 1.56 ⁇ g / ml against M. tuberculosis® H37Rv. Disulfiram is metabolized to diethyldithiocarbamate (DDC) by glutathione reductase in the blood, excreted in the urine after hepatic metabolism. DDC was shown to be a narrow-spectrum compound with no antibacterial activity in M.Msmegmatis, Gram-positive bacteria S. aureus, and Gram-negative bacteria E. coli even in the same mycobacteria group . The MBC / MIC values of disulfiram and DDC were both 1, suggesting the possibility of bactericidal action (data not shown).
  • DDC diethyldithiocarbamate
  • Mycobacterium tuberculosis is one of the host body parasites. It is a latent infection in the phagosome of human M ⁇ s and relapses with aging and immunity, causing pulmonary tuberculosis. It is a fungus.
  • the phagosomes in the M ⁇ are slightly acidic (pH 6.1-6.5) and are in a restricted environment. With existing drugs, CAM, CPFX, INH, etc. have been found to decrease in activity under acidic conditions. Therefore, human M ⁇ -like cells were used to examine the intracellular migration of disulfiram, and the antibacterial activity of disulfiram under acidic conditions was examined.
  • Method THP-1 was treated with 100 ng / ml of PMA for 2 days, and spread in a 24-well plate at 1.0 ⁇ 10 6 cells / ml. After incubation for 1 day and infection with 5.0 ⁇ 10 7 cfu / ml of H37Rv for 4 hours, the cells were washed twice with HBSS and treated with SM for 20 hours. After washing twice with HBSS, a drug dilution series was made and added and treated for 4 hours. After washing twice with HBSS and lysing the cells with 0.1% SDS solution, a colony assay was performed. The cells were cultured for 14 days and evaluated by the number of colonies. The experiment was performed three times independently, and the average value was calculated.
  • Drug sensitivity test (1) Method (M. bovis BCG) The bacterial solution cultured in 7H9 liquid medium until the early log phase was dispensed in 3.6 ml aliquots. The drug was prepared so that the concentrations were 1 MIC, 10 MIC, and 50 MIC, 400 ⁇ l was added to a test tube containing the bacterial solution, and cultured at 37 ° C. Absorbance measurement and colony assay were performed on days 2, 4, 7, 10, 14, and 21 with day 0 as the day when the drug was added. The number of colonies after 14 days of culture was evaluated.
  • DTNB method To a 96-well plate, 150 ⁇ l of 0.01% DTNB (5,5′-dithiobis-2-nitrobenzoic acid) solution was sprinkled, and 5 ⁇ l of 5% acetylthiocholine iodide was added. A dilution series of each drug was prepared in advance using FBS (non-immobilized) as a solvent. 2 ⁇ l of this solution was added to the plate, cultured at 37 ° C., and after 10 minutes, the wavelength at an absorbance of 405 nm was measured. The cholinesterase inhibitory effect was evaluated by IC 50 . Neostigmine bromide was used as a positive control.
  • Dialkyldithiocarbamates have been reported to exhibit antibacterial activity against some acid-fast bacteria such as M. leprae (Vadim, 2006 J Antimicrob Chemother. 2006 Jun; 57 (6): 1134-8. Epub 2006 Apr 4. Synthesis and antileprosy activity of some dialkyldithiocarbamates.).
  • the MIC of disulfiram was 0.78 to 1.56 ⁇ g / ml, and the MIC of DDC was 1.56 to 3.13 ⁇ g / ml (FIG. 14).
  • the MIC of disulfiram for the drug-resistant strain (22 strains) was 0.78 to 1.56 ⁇ g / ml, and the MIC of DDC was 1.56 to 3.13 ⁇ g / ml (FIG. 15).
  • the MIC for drug-sensitive strains and the MIC for drug-resistant strains were equivalent, suggesting that disulfiram and DDC do not have cross-resistance with existing drugs. It was also shown that disulfiram and DDC have antibacterial activity against quinolone (MXFX, FXGFLX, LVFX) resistant strains, which are new drug candidate compounds.
  • a dilution series of 1.8 ⁇ 10 8 CFU / ml bacterial solution was prepared and 100 ⁇ l was added to each drug plate.
  • the resistance frequency was determined from the number of colonies after 2 weeks of culture. The experiment was performed twice in duplicate. Further, the obtained resistant bacteria were subcultured 3 times (6 weeks), and 10 strains were stored.
  • Tuberculosis is a chronic respiratory infection, and new anti-tuberculosis drugs are required to be orally administrable and cross-resistant with existing drugs, and have excellent pharmacokinetics in cells and lungs. Furthermore, it has a narrow spectrum that shows bactericidal activity against M. tuberculosis in both the logarithmic growth phase and the mitotic resting phase. The results indicate that disulfiram and DDC meet these conditions. Moreover, since it was effective also against drug resistant M. smegmatis (FIG. 11), it was suggested that an action point differs from the existing drug (data not shown). It was also found to have a lytic action specific to human and bovine tuberculosis.
  • disulfiram (antabuse) has been used as a treatment for chronic alcoholism.
  • antibacterial activity against pathogenic bacteria, parasitic protists, and fungi has been reported. It has also been proven effective in vivo against Trichomonas muris and Candida albicans.
  • disulfiram is effective against Mycobacterium tuberculosis.
  • the anti-tuberculosis drug of the present invention comprises a compound having characteristics such as (1) high selectivity for M. tuberculosis and (2) bactericidal action, and is extremely useful for the treatment or prevention of tuberculosis. It is.
  • the compound of the active ingredient showed antibacterial activity against drug-resistant bacteria, it can be highly expected to be effective against drug-resistant tuberculosis bacteria. It is also possible to use the antituberculous drug of the present invention in combination with other antituberculous drugs.

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Abstract

La présente invention concerne un nouvel agent antituberculeux et son utilisation. L'agent antituberculeux comprend du disulfiram, du dithiocarbamate de diéthyle, ou un sel pharmaceutiquement acceptable de disulfiram ou de dithiocarbamate de diéthyle en tant que principe actif.
PCT/JP2010/050665 2009-01-31 2010-01-21 Agent antituberculeux et son utilisation Ceased WO2010087260A1 (fr)

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JP2010548473A JPWO2010087260A1 (ja) 2009-01-31 2010-01-21 抗結核薬及びその用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105853461A (zh) * 2016-06-14 2016-08-17 黄峰 一种治疗肺结核的药物组合

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHONG, C. ET AL.: "Pyrrolidine dithiocarbamate and diethyldithiocarbamate are active against growing and nongrowing persister mycobacterium tuberculosis", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 51, no. 12, 2007, pages 4495 - 4497, XP002688075, DOI: doi:10.1128/AAC.00753-07 *
EMI INAGAKI ET AL.: "Ko Shuhekiyaku Disulfiram no Kekkakukin Tokuiteki na Sayo ni Kansuru Kenkyu", NIPPON KAGAKU RYOHO GAKKAI SOKAI PROGRAM KOEN SHOROKU, vol. 57, no. 127, 30 April 2009 (2009-04-30), pages 227 *
EMI INAGAKI ET AL.: "Ko Shuhekiyaku Disuliram no Kekkakukin Tokuiteki na Sayo ni Kansuru Kenkyu", ABSTRACTS OF ANNUAL MEETING OF PHARMACEUTICAL SOCIETY OF JAPAN, vol. 129, no. 27P, 5 March 2009 (2009-03-05), pages 171 *
HUEBNER, L. ET AL.: "Enhancement of monocyte antimycobacterial activity by diethyldithiocarbamate (DTC).", INT J IMMUNOPHARAMACOL, vol. 13, no. 8, 1991, pages 1067 - 1072 *
YASUHIRO HORITA ET AL.: "Ko Shuhekiyaku Disulfiram no Kekkakukin Tokuiteki na Sayo ni Kansuru Kenkyu", KEKKAKU, vol. 84, no. 5, 15 May 2009 (2009-05-15), pages 406 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105853461A (zh) * 2016-06-14 2016-08-17 黄峰 一种治疗肺结核的药物组合

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