STEREOSPECIFICITY OF METHYLSULFINYL REDUCTION
This disclosure relates to compositions and methods of use involving compounds (e.g., drugs) containing methylsulfinyl moieties. For example, a compound may be administered in an excess of either the R- or S-epimer of the methylsulfinyl moiety based on whether the compound exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form or the methylsulfide-reduced form.
1 . A method for treating a subject with a drug comprising a methylsulfinyl moiety comprising:
a) determining whether the drug comprising the methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form or the methylsulfide-reduced form; and
b) administering, to the subject, a composition comprising the drug in an excess amount of the R-epimer relative to the S-epimer if the methylsulfinyl-oxidized form exhibits higher biological activity, or a composition comprising the drug in an excess amount of the S-epimer relative to the R-epimer if the methylsulfide-reduced form exhibits higher biological activity.
2 . The method of claim 1 , wherein the drug is chosen from: enoximone; pergolide; lincomycin; thiethylperazine; fensulfothion; nifuratel; albendazole; modafinil; captodiame; sulfinpyrazone; clindamycin; thiocolchicoside; omeprazole; flosequinan; dimethylsulfoxide; sulmazole; triclabendazole; mesoridazine; oxisuran; and sulindac.
3 . The method of claim 1 , wherein the amount of the drug in the R-epimer form is at least 75% by weight compared to the S-epimer.
4 . The method of claim 1 , wherein the amount of the drug in the R-epimer form is at least 90% by weight compared to the S-epimer.
5 . The method of claim 1 , wherein the amount of the drug in the S-epimer form is at least 75% by weight compared to the R-epimer.
6 . The method of claim 1 , wherein the amount of the drug in the S-epimer form is at least 90% by weight compared to the R-epimer.
7 . The method of claim 1 , wherein the drug is administered with a pharmaceutically acceptable carrier or diluent.
8 . The method of claim 7 , wherein the pharmaceutically acceptable carrier or diluent has a methylsulfinyl moiety if the methylsulfinyl-oxidized form exhibits higher biological activity.
9 . The method of claim 7 , wherein the pharmaceutically acceptable carrier or diluent does not have a methylsulfinyl moiety if the methylsulfide-reduced form exhibits higher biological activity.
10 . A method for increasing the shelf-stability of a drug comprising a methylsulfinyl moiety comprising:
a) determining whether the drug comprising the methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form or the methylsulfide-reduced form; and
b) formulating
(i) a composition comprising the drug in an excess amount of the R-epimer relative to the S-epimer if the methylsulfinyl-oxidized form exhibits higher biological activity and an oxidant, or
(ii) a composition comprising the drug in an excess amount of the S-epimer relative to the R-epimer if the methylsulfide-reduced form exhibits higher biological activity and a reductant.
11 . The method of claim 10 , wherein the oxidant is chosen from hydrogen peroxide, hypochlorous acid, urea peroxide, sodium perborate tetrahydrate, sodium percarbonate, sodium perborate, sodium peroxide, sodium periodate, calcium peroxide, and mixtures thereof.
12 . The method of claim 10 , wherein the reductant is chosen from dithiothreitol (DTT), a thioredoxin, sodium dithionite, sodium bisulphite, ascorbic acid, sodium ascorbate, calcium ascorbate, palmityl-DL-ascorbic acid, propyl gallate, octyl gallate, dodecyl gallate, butylhydroxyanisole gallate and butylhydroxytoluene gallate, formamidine sulphinic acid, stannous ion, Fe(II), Cu(I), erythrobate, α-tocopherol, γ-tocopherol, δ-tocopherol, oxalic acid, formic acid, and mixtures thereof.
13 . A method for increasing the in vivo activity of a drug comprising a methylsulfinyl moiety in a subject comprising:
a) determining whether the drug comprising the methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form or the methylsulfide-reduced form; and
b) administering, to the subject,
(i) an oxidant and a composition comprising the drug in an excess amount of the R-epimer relative to the S-epimer if the oxidized form exhibits higher biological activity; or
(ii) a reductant and a composition comprising an excess amount of the S-epimer relative to the R-epimer if the reduced form exhibits higher biological activity.
14 . The method of claim 13 wherein the oxidant or the reductant is administered before or after the drug.
15 . The method of claim 13 , wherein the oxidant or the reductant and the drug are administered together.
16 . The method of claim 13 , wherein the oxidant or reductant is formulated into the composition comprising the drug.
17 . The method of claim 13 , wherein the oxidant is chosen from hydrogen peroxide, hypochlorous acid, urea peroxide, sodium perborate tetrahydrate, sodium percarbonate, sodium perborate, sodium peroxide, sodium periodate, calcium peroxide, and mixtures thereof.
18 . The method of claim 13 , wherein the reductant is chosen from dithiothreitol (DTT), a thioredoxin, sodium dithionite, sodium bisulphite, ascorbic acid, sodium ascorbate, calcium ascorbate, palmityl-DL-ascorbic acid, propyl gallate, octyl gallate, dodecyl gallate, butylhydroxyanisole gallate and butylhydroxytoluene gallate, formamidine sulphinic acid, stannous ion, Fe(II), Cu(I), erythrobate, α-tocopherol, γ-tocopherol, δ-tocopherol, oxalic acid, formic acid, and mixtures thereof.
19 . A composition wherein a drug comprising a methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form comprising:
a) the drug in an excess amount of the R-epimer relative to the S-epimer; and
b) an oxidant.
20 . The method of claim 19 , wherein the oxidant is chosen from hydrogen peroxide, hypochlorous acid, urea peroxide, sodium perborate tetrahydrate, sodium percarbonate, sodium perborate, sodium peroxide, sodium periodate, calcium peroxide, and mixtures thereof.
21 . A composition wherein a drug comprising a methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfide-reduced form comprising:
c) the drug in an excess amount of the S-epimer relative to the R-epimer; and
d) a reductant.
22 . The method of claim 21 , wherein the reductant is chosen from dithiothreitol (DTT), a thioredoxin, sodium dithionite, sodium bisulphite, ascorbic acid, sodium ascorbate, calcium ascorbate, palmityl-DL-ascorbic acid, propyl gallate, octyl gallate, dodecyl gallate, butylhydroxyanisole gallate and butylhydroxytoluene gallate, formamidine sulphinic acid, stannous ion, Fe(II), Cu(I), erythrobate, α-tocopherol, γ-tocopherol, δ-tocopherol, oxalic acid, formic acid, and mixtures thereof.
23 . A method of treating a subject with a drug comprising a methylsulfinyl moiety comprising:
e) determining whether the drug comprising the methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form or the methylsulfide-reduced form; and
f) administering, to the subject, a composition comprising the drug and a pharmaceutically acceptable carrier or diluent having a methylsulfinyl moiety, if the methylsulfinyl-oxidized form exhibits higher biological activity, or a composition comprising the drug and a pharmaceutically acceptable carrier or diluent lacking a methylsulfinyl moiety, if the methylsulfide-reduced form exhibits higher biological activity.
24 . A method of treating a subject with a compound comprising a methylsulfinyl moiety comprising:
g) determining whether the compound comprising the methylsulfinyl moiety exhibits higher biological activity when the methylsulfinyl moiety is present in the methylsulfinyl-oxidized form or the methylsulfide-reduced form; and
h) contacting the subject with a composition comprising the compound in an excess amount of the R-epimer relative to the S-epimer if the methylsulfinyl-oxidized form exhibits higher biological activity, or a composition comprising the compound in an excess amount of the S-epimer relative to the R-epimer if the methylsulfide-reduced form exhibits higher biological activity.