CN118924716B - Application of naftifine in the prevention of Mycobacterium abscessus infection - Google Patents
Application of naftifine in the prevention of Mycobacterium abscessus infection Download PDFInfo
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- CN118924716B CN118924716B CN202411250778.8A CN202411250778A CN118924716B CN 118924716 B CN118924716 B CN 118924716B CN 202411250778 A CN202411250778 A CN 202411250778A CN 118924716 B CN118924716 B CN 118924716B
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- Prior art keywords
- naftifine
- mycobacterium
- mycobacterium abscessus
- abscessus
- infection
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- 229960004313 naftifine Drugs 0.000 title claims abstract description 33
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 title claims abstract description 33
- 230000002265 prevention Effects 0.000 title description 2
- 206010064789 Mycobacterium abscessus infection Diseases 0.000 title 1
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Communicable Diseases (AREA)
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Abstract
本发明属于生物医药技术领域，具体涉及一种萘替芬在抗脓肿分枝杆菌感染中的应用。本发明发现萘替芬具有抑制脓肿分枝杆菌活性的作用。萘替芬对脓肿分枝杆菌标准菌株MIC可达1μg/mL，对脓肿分枝杆菌临床分离株MIC分布为0.125‑2μg/mL。在抗脓肿分枝杆菌感染中，萘替芬可以成为新的治疗药物。The present invention belongs to the field of biomedicine technology, and specifically relates to an application of naftifine in anti-mycobacterium abscess infection. The present invention finds that naftifine has the effect of inhibiting the activity of mycobacterium abscess. The MIC of naftifine to the standard strain of mycobacterium abscess can reach 1 μg/mL, and the MIC distribution to the clinical isolate of mycobacterium abscess is 0.125-2 μg/mL. In the anti-mycobacterium abscess infection, naftifine can become a new therapeutic drug.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of naftifine in resisting infection of mycobacterium abscessus.
Background
Mycobacterium abscessum (Mycobacterium abscessus, M.ab) infections occur mostly in patients with underlying disease, but more than 30% of patients are well-immunized, indicating that unlike other Mycobacteria, M.ab is clearly pathogenic. Can cause skin infections and a degree of pneumonia. Mycobacterium abscesses are of great concern because of their severe resistance, even if strains are not sensitive to existing antibiotics. Clinically, there is often report that skin ulcers caused by mycobacterium abscesses are not healed. The disease caused by mycobacterium abscessus seriously threatens human health.
As the prevalence of m.ab infection increases year by year, it also becomes a new health problem, and its resistance has been a long-term clinical challenge. Macrolide antibiotics including clarithromycin and azithromycin are core drugs (Marion E,Song OR,Christophe T,et al.Mycobacterial Toxin Induces Analgesia in Buruli Ulcer by Targeting the Angiotensin Pathways[J].Cell,2014,157(7):1565-1576.). for the treatment of mycobacterial abscess infections however, in recent years, mycobacteria abscesses have become increasingly resistant to clarithromycin, and the reported resistance rate is 14％～38％(Lee SH,Yoo HK,Kim SH,Koh WJ,Kim CK,Park YK,et al.The drug resistance profile ofMycobacterium abscessus group strains from Korea.Ann Lab Med.2014;34:31-7.)., the degree of resistance of mycobacteria abscesses to azithromycin is slightly lower than that of clarithromycin, and the resistance rate is about 10％(ShenY,Wang X,Jin J,Wu J,Zhang X,Chen J,et al.In Vitro Susceptibility of Mycobacterium abscessus and Mycobacterium fortuitum Isolates to 30Antibiotics.Biomed Res Int.2018;2018:4902941.).
However, there is no specially developed drug for this highly pathogenic and drug-resistant mycobacterium abscessus with high isolation rate. So its clinical treatment is usually chosen with reference to the treatment of tuberculosis. However, the side effects of antibiotics in general for the treatment of m.ab disease are common and severe. It has been found that cefoxitin is useful in the treatment of m.ab pulmonary disease patients, and that chronic treatment with the frequent occurrence of adverse effect (Jeon K,Kwon O J,Lee N Y,et al.Antibiotic treatment of Mycobacterium abscessus lung disease:a retrospective analysis of65 patients[J].American Journal ofRespiratory and Critical Care Medicine,2009,180(9):896-902.). imipenem also causes side effects (Lopeman R C,Harrison J,Desai M,et al.Mycobacterium abscessus:environmental bacterium turned clinical nightmare[J].Microorganisms,2019,7(3):90.). such as neutropenia, all of the drugs in the m.ab regimen recommended by the american chest association are currently an extended indication from marketed drugs. Because of the serious difficulty in developing the original drugs, only bedaquiline, delaimab and prim have recently been approved by the U.S. food and drug administration for more than half a century of tuberculosis. Therefore, the activity of the existing compound or antibiotics for resisting the mycobacterium abscess is fully excavated, and the method is a high-efficiency way for developing the mycobacterium abscess resisting medicine.
Naftifine is a synthetic allylamine antifungal agent, first reported in 1974 and approved by the FDA for use in the treatment of dermatophyte infections in 1988. Naftifine belongs to an acrylamide antifungal agent, and can block the synthesis of ergosterol on fungal cell membranes by inhibiting squalene epoxidase, thereby leading to fungal cell death. At present, no related report of naftifine inhibiting mycobacterium abscessus exists.
Disclosure of Invention
The present invention has been completed based on the finding that naftifine has an effect of inhibiting the activity of mycobacterium abscessus.
In a first aspect, the invention provides the use of naftifine for the preparation of a product for inhibiting mycobacterium abscessus.
Further, the mycobacterium abscessus includes a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus, or a mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
Further, the mycobacteria-inhibiting products include medical products or non-medical products.
Further, the medical product refers to a medical drug, and the non-medical product refers to an experimental reagent or a bacteriostatic agent.
Further, one or more pharmaceutically acceptable carriers or excipients may be added to the product.
Still further, the carrier material includes, but is not limited to, one or more of a water-soluble carrier material, a poorly soluble carrier material, and/or an enteric carrier material.
Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and/or an organic acid.
Further, the poorly soluble carrier materials include, but are not limited to, one or more of ethylcellulose and/or cholesterol stearate.
Further, the enteric carrier material includes, but is not limited to, one or more of cellulose acetate phthalate and/or carboxymethyl ethyl cellulose.
Further, the product may be formulated into a variety of dosage forms including, but not limited to, one or more of tablets, capsules, drops, aerosols, pills, powders, solutions, suspensions, granules, liposomes, transdermal agents, buccal tablets, suppositories, and/or lyophilized powder for injection.
Further, the formulation may be one or more of a general formulation, a slow release formulation, a controlled release formulation, and/or various microparticle delivery systems.
Further, the tablet may be widely used with various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters, and/or lubricants.
Still further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and/or aluminum silicate.
Further, the humectants and binders include, but are not limited to, one or more of water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and/or polyvinylpyrrolidone.
Further, the disintegrants include, but are not limited to, one or more of dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose and/or ethylcellulose.
Further, the disintegration inhibitors include, but are not limited to, sucrose, glyceryl tristearate, cocoa butter and/or hydrogenated oils and the like.
Further, the absorption enhancer includes, but is not limited to, one or more of a quaternary ammonium salt and/or sodium dodecyl sulfate.
Further, the lubricant includes, but is not limited to, one or more of talc, silica, corn starch, stearate, boric acid, liquid paraffin, and/or polyethylene glycol.
Further, the tablets may be further formulated into coated tablets including sugar coated tablets, film coated tablets, enteric coated tablets, bilayer tablets and multilayer tablets.
Further, the pellets may be widely used with a variety of carriers known in the art, including diluents with absorbents, binders and/or disintegrants.
Still further, the diluents and absorbents include, but are not limited to, one or more of glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, gelucire, kaolin and/or talc.
Further, the binder includes, but is not limited to, one or more of acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste and/or batter.
Further, the disintegrants include, but are not limited to, one or more of agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, and/or ethylcellulose.
Further, the suppositories may be widely used with various carriers well known in the art, including but not limited to one or more of polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and/or semisynthetic glycerides.
Further, the injectable formulation includes, but is not limited to, one or more of a solution, a lyophilized powder for injection, and/or a suspension.
Still further, the injectable formulation may use all diluents commonly used in the art including, but not limited to, one or more of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxidated isostearyl alcohol and/or polyoxyethylene sorbitol fatty acid esters.
Further, in order to prepare the isotonic injection, an appropriate amount of one or more of sodium chloride, glucose, glycerin, a conventional cosolvent, a buffer, and/or a pH adjuster may be added to the injection preparation.
Further, the various formulations may also incorporate colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials into the pharmaceutical formulation as desired.
In a second aspect, the present invention provides the use of naftifine for the manufacture of a medicament for the prevention and/or treatment of a disease caused by infection with mycobacterium abscessus, said naftifine acting by inhibiting the activity of mycobacterium abscessus.
Further, the mycobacterium abscessus comprises a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus or mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
Further, one or more pharmaceutically acceptable carriers or excipients can be added into the medicine for preventing and/or treating diseases caused by the infection of the mycobacterium abscessus.
Still further, the carrier material includes, but is not limited to, one or more of a water-soluble carrier material, a poorly soluble carrier material, and/or an enteric carrier material.
Further, the medicament for preventing and/or treating diseases caused by mycobacterium tuberculosis infection can be prepared into various dosage forms, including but not limited to one or more of tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, granules, liposomes, transdermal agents, buccal tablets, suppositories and/or freeze-dried powder injection.
Still further, the formulation may be one or more of a general formulation, a slow release formulation, a controlled release formulation, and/or various microparticle delivery systems.
Further, the various formulations may also incorporate colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials into the pharmaceutical formulation as desired.
Further, the agent for preventing and/or treating a disease caused by infection with mycobacterium abscess may be administered by injection, by luminal administration, by respiratory administration or by mucosal administration.
Still further, the administration of injections includes subcutaneous injections, intravenous injections, intramuscular injections, and intra-luminal injections.
In a third aspect, the invention provides a pharmaceutical composition comprising naftifine and another drug against infection by mycobacterium abscessus,
The pharmaceutical composition has at least one of the following effects:
a) Inhibiting mycobacteria abscesses activity;
b) Anti-mycobacterial abscess infections;
c) Preventing and/or treating diseases caused by mycobacterium abscessus.
Further, the mycobacterium abscessus comprises a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus or mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
Further, the pharmaceutical composition is used at a Minimum Inhibitory Concentration (MIC) of not less than the Minimum Inhibitory Concentration (MIC) of mycobacterium abscessus that it inhibits.
Further, the other anti-mycobacterial infection agent includes one or more of an antibiotic and other agents that can facilitate inhibiting or killing mycobacteria abscess or enhancing patient resistance.
Still further, the antibiotic comprises one or more of rifampin, streptomycin, ethambutol, moxifloxacin, clarithromycin and/or amikacin, and the other drug comprises one or more of vitamins, amino acids, proteins and/or minerals.
Further, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.
Furthermore, the pharmaceutical composition can be prepared into various forms such as injection, tablet, powder, granule, capsule, oral liquid or pharmaceutical excipients, and the medicaments of the various forms can be prepared according to the conventional method in the pharmaceutical field.
Further, the pharmaceutical composition may be introduced into the body by injection, permeation, absorption, physical or chemical mediated methods, such as intramuscular, intradermal, subcutaneous, intravenous or mucosal tissue, or may be introduced into the body after being mixed or encapsulated with other substances.
Advantageous effects
The MIC of naftifine to the standard strain of the mycobacterium abscess can reach 1 mug/mL, and the MIC distribution to the clinical isolate of the mycobacterium abscess is 0.125-2 mug/mL.
Naftifine can be a new therapeutic in the treatment of mycobacterial infections.
Drawings
FIG. 1 MIC profile of naftifine for a clinical isolate of Mycobacterium abscessum.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
Description of materials
1. Ma's turbidimetric tube
The McFarland turbidimeter tube is a standard turbidimeter tube for different turbidimeters of microorganisms, and is prepared according to the proportion of sulfuric acid and barium chloride, and specifically comprises the following steps:
2. test strains and drugs
The standard strain of Mycobacterium abscessum ATCC 19977.
Naftifine has a molecular formula of C 21H21 N and a structural formula as follows:
Naftifine hydrochloride, available from MedchemExpress, CAS number 65473-14-5, molecular formula C 21H22 N & HCl, structural formula as follows:
3. Test drug conversion
4. Naftifine hydrochloride (NAFTIFINE HYDROCHLORIDE) has a molecular weight of 323.86g/mol, wherein the molecular weight of the root of hydrochloric acid (Hydrochloric acid) is 35.45g/mol, the titer of Naftifine in the compound Naftifine hydrochloride (Naftifine) is calculated to be 89% (323.86 g/mol-35.45g/mol/323.86 g/mol=89.05%), and 14.38mg of Naftifine hydrochloride (Naftifine content 12.8 mg) is weighed according to the calculated titer, 1ml of DMSO is added, and a drug stock solution with a final concentration of 12.8mg/ml is prepared. The mixture was diluted to a working solution having a concentration of 128. Mu.g/ml at a ratio of 1:100.
Example 1 detection of the bacteriostatic Activity of naftifine against Mycobacterium abscessum Standard Strain
1.1 Preparation of Mycobacterium abscessum Standard Strain suspension
Inoculating standard strain of mycobacterium abscess (ATCC 19977) into MH culture medium, culturing until the growth log phase, and diluting with 1:200 to obtain the final product.
1.2 Minimum Inhibitory Concentration (MIC)
(1) 100 Mu LMueller Hinton (MH) medium was added to 96-well plates;
(2) Adding sequentially gradient diluted medicines into 1-11 rows;
(3) Adding diluted standard bacterial suspension of mycobacterium abscessus into 1-11 columns to make the final concentration of bacterial liquid 4X 10 5 CFU/mL;
The final drug concentration in each well is specifically shown in table 1, and cultured;
(4) Adding 30 mu L of resazurin chromogenic liquid, and observing the color change of the pore plate after culturing;
(5) The lowest inhibitory concentration (Minimal inhibitory concentration, MIC) was read.
TABLE 1 drug concentration of naftifine
MIC is the concentration of drug that inhibits 90% of colony growth. The blue wells were sterile grown and the pink wells were bacterial grown, and the lowest drug concentration that prevented the color from changing from blue to pink was noted as MIC that inhibited bacterial growth.
The positive control is a fungus-containing culture medium without medicine, namely column 12, and the other 96-well plate is taken, and the culture medium without medicine and fungus liquid is added, namely the negative control. MIC data for this batch was valid when the positive control was pink and the negative control was blue.
1.3 Test results
The MIC of naftifine for the standard strain of Mycobacterium abscessum was 1 μg/mL.
Example 2 detection of bacteriostatic Activity of naftifine on clinically isolated Mycobacterium abscessum Strain
2.1 Test samples and methods
Clinical isolation Strain 39 strains isolated and cultured from sputum specimens of patients infected with mycobacterium abscessus were identified as mycobacterium abscessus by sequencing of 16SrRNA, hsp65, rpoB and 16-23S rRNA interarea.
The in vitro bacteriostatic activity of butenafine on 39 clinical isolates of mycobacterium abscessus was tested as in example 1.
2.2 Test results
MIC results of naftifine on clinical isolates of mycobacterium abscessus are shown in table 2.
Naftifine has better antibacterial activity to mycobacterium abscessus, and the MIC of naftifine can reach 0.125 mug/mL. MIC 50 and MIC 90 were 1. Mu.g/mL and 2. Mu.g/mL, respectively.
TABLE 2 MIC of naftifine for clinical isolates of Mycobacterium abscesses
Claims (5)
1. The application of naftifine in preparing a product for inhibiting mycobacterium abscess is provided, wherein the product is selected from medical products or non-medical products, the medical products refer to medical drugs, and the non-medical products refer to experimental reagents or bacteriostats.
2. Use of naftifine in the manufacture of a medicament for the treatment of a disease caused by infection with mycobacterium abscessus, said naftifine acting by inhibiting the activity of mycobacterium abscessus.
3. The use according to claim 1, wherein one or more pharmaceutically acceptable carriers or excipients may also be added to the product.
4. The use according to claim 2, wherein the medicament may further incorporate one or more pharmaceutically acceptable carriers or excipients.
5. The use of claim 1 or 2, wherein the mycobacterium abscessus is selected from the group consisting of a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus, and mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
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| CN1481797A (en) * | 2002-09-09 | 2004-03-17 | 重庆华邦制药股份有限公司 | Composition comprising ketoconazole and sultifen |
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| CN1481797A (en) * | 2002-09-09 | 2004-03-17 | 重庆华邦制药股份有限公司 | Composition comprising ketoconazole and sultifen |
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