Treatment and prevention of cardiovascular disease and thrombosis

Patent metadata

Field	Value
Publication number	US-2016101062-A1
Application number	US-201514922380-A
Country	US
Kind code	A1
Filing date	Oct 26, 2015
Priority date	Jun 11, 2012
Publication date	Apr 14, 2016
Grant date	—

Abstract

Provided herein are compositions for the treatment and/or prevention of cardiovascular disease (CVD), and methods of application and use thereof. In particular, the present invention provides treatment and/or prevention of cardiovascular disease with compounds that inhibit the production of TMA in the gut, such as 3,3-dimethyl-1-butanol (DMB) or other compounds represented by Formula I or as shown in FIGS. 20 - 23.

First claim

We claim:

1 . A method for the treatment and/or prevention of cardiovascular disease and/or thrombosis comprising:
a) identifying a subject as having increased platelet aggregation and/or elevated TMAO levels, and b) administering to said subject: i) a composition comprising a compound selected from the group consisting of: N,N-dimethylethanolamine (DMEA), N-methylethanolamine (MEA), ethanolamine (EA), trimethylsilyl ethanol, and P,P,P-trimethyl ethanolphosphine; and/or ii) a composition comprising a compound represented by Formula I:

wherein n is an integer, or n is 0, indicating that CH 2 is not present;
wherein Y is C, Si, P, S, Ge, Sn, Pb, P, As, Sb, or Bi;
wherein X is O or S and the corresponding bond is either present or absent or double, wherein R is H, an alkyl group, alkenyl group, alkynyl group, phenyl group, or a benzyl group;
wherein Z is C, CH 2 , CH, O or S,
wherein XR is an ester, thioester, or thionester; glycerol, or one of the following three formulas:

wherein R′ is H, an alkyl group, alkenyl group, alkynyl group, phenyl group, or a benzyl group; and
wherein X′ is O, or S.

2 . The method of claim 1 , further comprising administering a prebiotic, probiotic, and/or fiber to said subject.

3 . The method of claim 1 , wherein said identifying comprises viewing results of a platelet aggregation assay performed on a sample from said subject which shows increased platelet aggregation.

4 . The method of claim 1 , wherein said identifying comprises viewing results of a TMA or TMAO assay performed on a sample or exhaled breath from said subject which show elevated TMA or TMAO levels.

5 . The method of claim 1 , wherein said Formula I has a formula selected from the group consisting of:

6 . The method of claim 1 , wherein said Formula I has a formula selected from the group consisting of:

7 . The method of claim 1 , wherein said Formula I has a formula selected from the group consisting of:

8 . The method of claim 1 , wherein said Formula I induces one or more of the following when administered to a subject: reduced trimethyl amine level, reduced TMAO level, reduced total cholesterol level, reduced LDL level, increased HDL level, reduced triglyceride level, reduced glucose level, and reduced hemoglobin A1C level.

9 . The method of claim 1 , wherein said dimethylbutanol, and/or derivatives thereof reduce the risk of cardiovascular disease and/or thrombosis when administered to a subject.

10 . The method of claim 1 , wherein said Formula I has a formula selected from the group consisting of:

11 . The method of claim 1 , wherein said Formula I has a formula selected from the group consisting of:

12 . A method of treating and/or preventing cardiovascular disease and/or thrombosis comprising administering to a subject: i) a composition comprising a compound selected from the group consisting of: N,N-dimethylethanolamine (DMEA), N-methylethanolamine (MEA), ethanolamine (EA), trimethylsilyl ethanol, and P,P,P-trimethyl ethanolphosphine; and/or ii) a composition comprising a compound represented by Formula I:

wherein n is an integer, or n is 0, indicating that CH 2 is not present;
wherein Y is C, Si, P, S, Ge, Sn, Pb, P, As, Sb, or Bi;
wherein X is O or S and the corresponding bond is either present or absent or double, wherein R is H, an alkyl group, alkenyl group, alkynyl group, phenyl group, or a benzyl group;
wherein Z is C, CH 2 , CH, O or S,
wherein XR is an ester, thioester, or thionester; glycerol, or one of the following three formulas:

wherein R′ is H, an alkyl group, alkenyl group, alkynyl group, phenyl group, or a benzyl group; and
wherein X′ is O, or S.

13 . The method of claim 11 , wherein said subject has been determined to have increased platelet aggregation.

14 . The method of claim 11 , wherein said subject has been determined to have an elevated TMAO level or an elevated TMA level as indicated by a breath test.

15 . The method of claim 13 , wherein said administering is under such conditions that at least one symptom of said cardiovascular disease and/or said thrombosis is reduced or eliminated.

16 . The method of claim 11 , further comprising administering a probiotic, a prebiotic, and/or fiber to said subject.

17 . The method of claim 11 , wherein said composition comprises dimethylbutanol.

18 . The method of claim 11 , wherein said composition is co-administered with one or more agents which provide therapy for cardiovascular disease.

19 . The method of claim 17 , wherein said one or more agents comprises one or more antibiotics that target gut flora.

20 . A food or beverage comprising: i) a compound selected from the group consisting of: N,N-dimethylethanolamine (DMEA), N-methylethanolamine (MEA), ethanolamine (EA), trimethylsilyl ethanol, and P,P,P-trimethyl ethanolphosphine; and/or ii) a compound represented by Formula I:

wherein n is an integer, or n is 0, indicating that CH 2 is not present;
wherein Y is C, Si, P, S, Ge, Sn, Pb, P, As, Sb, or Bi;
wherein X is O or S and the corresponding bond is either present or absent or double, wherein R is H, an alkyl group, alkenyl group, alkynyl group, phenyl group, or a benzyl group;
wherein Z is C, CH 2 , CH, O or S,
wherein XR is an ester, thioester, or thionester; glycerol, or one of the following three formulas:

wherein R′ is H, an alkyl group, alkenyl group, alkynyl group, phenyl group, or a benzyl group; and
wherein X′ is O, or S.

Assignees

• Cleveland Clinic Foundation

Inventors

• Hazen Stanley L
• Levison Bruce
• Wang Zeneng

Classifications

• A61K31/695

  Silicon compounds · CPC title

• A61K31/22

  of acyclic acids, e.g. pravastatin · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A23V2002/00

  Food compositions, function of food ingredients or processes for food or foodstuffs · CPC title

• A61K31/045 Primary

  Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates · CPC title