Composition comprising selenazol or thiazalone derivatives and silver and method of treatment therewith
Inventors
Assignees
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Publication Number
US-11013730-B1
Publication Date
2021-05-25
Expiration Date
Abstract
A method for treating a prokaryotic infection in an animal or human by administering a pharmaceutically acceptable composition, comprising administering a source of silver ions and a benzoisoselenazol derivative, e.g., an ebselen derivative.
Core Innovation
The invention relates to inhibiting growth of a prokaryotic organism by administering, exposing, or co-administering at least one compound according to Formula I, or a pharmaceutically acceptable salt thereof, together with a source of metal ions. The Formula I compound is effective as an inhibitor of prokaryotic thioredoxin reductase having an IC50 of less than about 25 μM.
The method further includes a water soluble source of at least one metal ion in an amount effective to achieve a dose-dependent reduction of at least 33% in the inhibitory concentration (IC50) for E. coli thioredoxin reductase versus the Formula I compound in the absence of the water soluble source. The water soluble source releases the metal ions for an extended duration at a constant rate.
The described approach includes embodiments directed to selected Formula I members, including ebselen and ebsulfur-23, and metal-ion sources such as silver salt, silver colloid, organo-silver complex, silver nitrate, and other silver metal-containing materials. The disclosure associates the approach with antimicrobial formulations and bacterial growth inhibition data for E. coli and Bacillus subtilis.
Claims Coverage
The consolidated set includes three independent claims. Across the claims, the inventive core is the combination of a Formula I compound acting as a prokaryotic thioredoxin reductase inhibitor with a water-soluble metal-ion source that releases metal ions for an extended duration at a constant rate and yields a dose-dependent reduction of at least 33% in the IC50 for E. coli thioredoxin reductase versus the compound alone.
Dose-dependent ic50 reduction with extended constant-rate metal ion release
Administering or exposing a prokaryotic organism to at least one compound according to Formula I, or a pharmaceutically acceptable salt, together with a water soluble source of at least one metal ion, where the Formula I compound inhibits prokaryotic thioredoxin reductase with an IC50 of less than about 25 μM and the metal-ion source achieves a dose-dependent reduction of at least 33% in the IC50 for E. coli thioredoxin reductase versus the absence of the water soluble source, with metal ions released for an extended duration at a constant rate.
Selective thioredoxin reductase inhibition by formula I compound
Providing at least one compound according to Formula I, or a pharmaceutically acceptable salt, effective as an inhibitor of prokaryotic thioredoxin reductase having an IC50 of less than about 25 μM, with Formula I defined by X being selenium or sulfur and by specified structural substituent selections.
Co-administration in a prokaryotic environment
Co-administering to an environment of the prokaryotic organism at least one compound selected from Formula I and a pharmaceutically acceptable salt thereof as a selective prokaryotic thioredoxin reductase inhibitor, together with an effective amount of a water soluble source of at least one metal ion to achieve a dose-dependent reduction of at least 33% in IC50 for E. coli thioredoxin reductase in the absence of the water soluble source, with extended-duration constant-rate metal ion release.
All independent claims require a Formula I compound or pharmaceutically acceptable salt that inhibits prokaryotic thioredoxin reductase with IC50 less than about 25 μM, a water-soluble metal-ion source administered or used in a prokaryotic environment, and a dose-dependent reduction of at least 33% in IC50 for E. coli thioredoxin reductase versus the compound alone, with metal-ion release occurring for an extended duration at a constant rate.
Stated Advantages
Dose-dependent reduction of at least 33% in the inhibitory concentration (IC50) for E. coli thioredoxin reductase when the water soluble source of metal ions is included versus absence of the metal ion source.
Metal ions are released for an extended duration at a constant rate.
Small metal-containing particles can increase therapeutic efficacy so less metal is needed.
Steady-state metal/drug release over about 30 minutes to 48 hours and reduced toxicological burden.
Documented Applications
Inhibiting growth of a prokaryotic organism.
Treating a prokaryotic infection in an animal or human by administering a pharmaceutically acceptable unit dosage form containing a compound of Formula I, or pharmaceutically acceptable salt, and a water soluble source of silver ions.
Determining sensitivity of a prokaryotic organism from a microbiological sample from a patient to a range of pharmaceutically acceptable treatments using compounds of Formula I, or pharmaceutically acceptable salts, and a water soluble source of at least one metal ion.
Antimicrobial use in device or article formats including wound dressings, patches, and transcutaneous medical devices, and coatings or deposition on substrates.
Use of silver-containing materials for antimicrobial formulations, including Acticoat dressings.
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