Compositions and methods for treating atherosclerotic cardiovascular disease

A technology of atherosclerosis and composition, applied in the field of pharmaceutical composition for treating atherosclerotic cardiovascular disease

Pending Publication Date: 2020-05-22
GAVISH GALILEE BIO APPL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, despite a 72% increase in blood HDL cholesterol levels, a clinical trial with a cholesteryl ester transfer protein inhibitor was terminated due to excess adverse events and futility
Niacin and fabric acid derivatives increase HDL cholesterol levels, but linking these increases to clinical risk reduction is problematic

Method used

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  • Compositions and methods for treating atherosclerotic cardiovascular disease
  • Compositions and methods for treating atherosclerotic cardiovascular disease
  • Compositions and methods for treating atherosclerotic cardiovascular disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1. Effects of hemolysis-DGTS on rePON1 lactonase and esterase activities

[0138] The effect of hemo-DGTS on the lactonase and arylesterase activities of rePON1 was examined. rePON1 (5 μg / ml in Tris buffer, pH = 8.4) was incubated with different concentrations of hemo-DGTS at 37°C for 2, 4, 24 and 48 hours using the dihydrocoumarin and phenyl acetate assays The lactonase and arylesterase activities were determined respectively.

[0139] Incubation of rePON1 with hemolytic-DGTS increased the enzymatic lactonase activity in a dose-dependent manner. After 2 hours of incubation, the enzymatic activity was significantly changed from 3.00 units without hemolyzed-DGTS to 4.05, 5.73, 8.10, 11.61 and 12.7 units with 1, 5, 10, 50 and 100 μg / ml hemolyzed-DGTS, respectively ( Figure 1A ).

[0140] The lactonase activity of rePON1 decreased over time in buffer solution and disappeared after 48 hours, whereas the presence of hemo-DGTS stabilized and maintained the proteol...

Embodiment 2

[0142] Example 2. Effect of hemolysis-DGTS on human serum PON1 lactonase activity

[0143]The effect of hemolytic-DGTS on human serum PON1 lactonase activity was examined. Human serum was diluted 20-fold with PBS buffer and incubated with 1, 5, 10 and 50 μg / ml concentrations of hemolysate-DGTS and without hemolysate-DGTS at 1, 5, 10 and 50 μg / ml concentrations for 4 hours at 37°C . The lactonase activity of the enzyme was determined using the dihydrocoumarin assay. As shown in Example 1, hemolytic-DGTS increased human serum lactonase activity to 10 μg / ml in a dose-dependent manner, from 1.8 units without hemolytic-DGTS to 1, 5, 10, and 50 μg / ml hemolysis, respectively - 2.16, 2.82, 3.01 and 2.80 units at DGTS. The change at 1 μg / ml hemolytic-DGTS was not statistically significant ( figure 2 ).

Embodiment 3

[0144] Example 3. rePON1-hemolysis-DGTS interaction using tryptophan fluorescence quenching method

[0145] The effect of hemolyso-DGTS on rePON1 could result from a specific interaction between lipids and the enzyme, which was investigated using a tryptophan fluorescence quenching method. Figure 3 shows rePON1 in the presence of various concentrations of hemolytic-DGTS at 25°C ( Figure 3A ) and 37°C ( Figure 3B ) in the range of 300-450 nm with an excitation wavelength of 290 nm. Hemolytic-DGTS quenched the fluorescence of rePON1 in a dose-dependent manner at both temperatures.

[0146] The quenching path can be described by the Stern-Volmer equation (Equation 1):

[0147] Equation 1

[0148] where F0 and F are the fluorescence intensities in the absence and presence of the quencher (hemolysis-DGTS), respectively, Ksv is the Stern-Volmer quenching constant, and [Q] is the quencher concentration (μM).

[0149] The Stern-Volmer curve (F0 / F vs. [Q]) was linear at both t...

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Abstract

The present invention relates to lyso-diacylglyceryltrimethylhomoserine (lyso- DGTS) or derivatives thereof for use in the treatment of atherosclerotic cardiovascular disease, and further provides particular such lyso-DGTS derivatives.

Description

technical field [0001] The present invention provides pharmaceutical compositions and methods for treating atherosclerotic cardiovascular disease. Background technique [0002] Atherosclerosis is a multifactorial disease and a common cause of heart attack, stroke, and peripheral vascular disease, collectively referred to as "cardiovascular disease" (CVD). Atherosclerotic CVD is a pathological process characterized by the deposition of lipids and compounds within arterial walls and is considered a major cause of morbidity and mortality in the Western world. [0003] Lowering low-density lipoprotein (LDL)-cholesterol with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) has become an integral part of strategies to reduce cardiovascular risk. However, statins reduce CVD risk by no more than 40%, and they have some side effects, such as muscle pain and damage, liver problems, digestive problems, rashes or flushing, elevated blood sugar, and memory loss or confusion...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/10C07C233/20C07C233/34C07C229/30C07C233/45C07C69/52A61K31/14A61K31/164A61K31/221A61K31/23A61K31/231A61K31/232A61P9/10C07C229/12C07C211/63C07C69/22
CPCA61K31/14A61K31/164A61K31/232C07C233/20A61P9/10C07C229/22C07C233/47C07C233/49A61K36/02A61P3/06
Inventor J·瓦雅S·哈提卜E·克维特尼茨基
Owner GAVISH GALILEE BIO APPL
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