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JAMA Nov 2019
Topics: Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 31714973
DOI: 10.1001/jama.2019.16598 -
CMAJ : Canadian Medical Association... Dec 2016
Topics: Acne Vulgaris; Age of Onset; Anti-Bacterial Agents; Benzoyl Peroxide; Dermatologic Agents; Dicarboxylic Acids; Humans; Infant; Male; Retinoids
PubMed: 27873756
DOI: 10.1503/cmaj.160139 -
Drug Design, Development and Therapy 2021Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD)... (Review)
Review
Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.
Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Drug Design; Drug Development; Fatty Acids; Humans; Hyperlipoproteinemia Type II
PubMed: 34007155
DOI: 10.2147/DDDT.S251865 -
Scientific Reports Jul 2022Dicarboxylic acids are one of the important water-soluble organic compounds in atmospheric aerosols, causing adverse effects to both climate and human health. More...
Dicarboxylic acids are one of the important water-soluble organic compounds in atmospheric aerosols, causing adverse effects to both climate and human health. More attention has therefore been paid to organic acids in aerosols. In this study, the molecular distribution and diurnal variations of wintertime dicarboxylic acids in a rural site of Guanzhong Plain, Northwest China, were explored. Oxalic acid (C, day: 438.9 ± 346.8 ng m, night: 398.8 ± 392.3 ng m) is the most abundant compound followed by methylglyoxal (mGly, day: 207.8 ± 281.1 ng m, night: 222.9 ± 231.0 ng m) and azelaic (C, day: 212.8 ± 269.1 ng m, night: 211.4 ± 136.7 ng m) acid. The ratios of C/C and C/Ph indicating that atmospheric dicarboxylic acids in winter in the region mainly come from biomass burning. Furthermore, secondary inorganic ions (NO, SO, and NH), relative humidity, liquid water content, and in-situ pH of aerosols are highly linearly correlated with C, suggesting that liquid phase oxidation is an important pathway for the formation of dicarboxylic acids. The δC analysis of C suggested that lighter carbon isotope compositions tend to be oxidized to form aqueous-phase secondary organic aerosols (aqSOA), leading to the decay of C in aqSOA products rather than aerosol aging. This study provides a theoretical basis for the mechanism of formation of dicarboxylic acid.
Topics: Aerosols; Carbon; Carbon Isotopes; China; Dicarboxylic Acids; Humans; Oxalic Acid; Water
PubMed: 35789176
DOI: 10.1038/s41598-022-15222-6 -
Chemical & Pharmaceutical Bulletin 2018Axially chiral binaphthothiophene dicarboxylic acid was prepared as a novel functionalized chiral dicarboxylic acid. The crystal structures of both the racemic form and...
Axially chiral binaphthothiophene dicarboxylic acid was prepared as a novel functionalized chiral dicarboxylic acid. The crystal structures of both the racemic form and its salt with chiral diamine revealed the intramolecular S···O interactions (chalcogen bonds) between the sulfur in the naphthothiophene rings and the oxygen of the carboxy groups. The negative-positive and the positive-negative Cotton effects from longer to shorter wavelengths were observed for (R)- and (S)-enantiomers, respectively, in the circular dichroism (CD) spectra.
Topics: Dicarboxylic Acids; Models, Molecular; Molecular Structure; Stereoisomerism; Thiophenes
PubMed: 30504635
DOI: 10.1248/cpb.c18-00668 -
Molecular Pharmaceutics Aug 2022Acid-base multicomponent systems have become a popular choice as a strategy to fine-tune the physicochemical properties of active pharmaceutical ingredients. Current...
Acid-base multicomponent systems have become a popular choice as a strategy to fine-tune the physicochemical properties of active pharmaceutical ingredients. Current prediction tools based on the principles of anticrystal engineering cannot always accurately predict the nature of intermolecular interactions within a multicomponent system. Even small changes in the physicochemical parameters of parent components can result in unexpected outcomes, and many salt, cocrystal, and ionic liquid forms are still being discovered empirically. In this work, we aimed to establish structural consistency in a series of mixtures comprising lidocaine (LID) with decanedioic, undecanedioic, dodecanedioic, and tridecanedioic acids and to explore how length and flexibility of the acid carbon backbone affect the molecular recognition, crystallization, and thermal behavior of the expected binary systems. We found that neat grinding of LID with dicarboxylic acids results in the formation of eutectic phases. The observed eutectic melting points deviated from the ideal eutectic temperatures predicted by the Schroeder van Laar model because of hydrogen bonding between the reacting components within the mixtures. Furthermore, thermal and infrared analysis provided evidence for the possible formation of new phases stemming from partial ionization of the counterions. Besides, the structure of a previously undetermined form I of the tridecanedioic acid was solved by single crystal X-ray diffraction.
Topics: Crystallization; Dicarboxylic Acids; Hydrogen Bonding; Ionic Liquids; Lidocaine
PubMed: 35850530
DOI: 10.1021/acs.molpharmaceut.2c00381 -
The Journal of Biological Chemistry Jun 1989The fate of the acetyl-CoA units released during peroxisomal fatty acid oxidation was studied in isolated hepatocytes from normal and peroxisome-proliferated rats....
The fate of the acetyl-CoA units released during peroxisomal fatty acid oxidation was studied in isolated hepatocytes from normal and peroxisome-proliferated rats. Ketogenesis and hydrogen peroxide generation were employed as indicators of mitochondrial and peroxisomal fatty acid oxidation, respectively. Butyric and hexanoic acids were employed as mitochondrial substrates, 1, omega-dicarboxylic acids as predominantly peroxisomal substrates, and lauric acid as a substrate for both mitochondria and peroxisomes. Ketogenesis from dicarboxylic acids was either absent or very low in normal and peroxisome-proliferated hepatocytes, but free acetate release was detected at rates that could account for all the acetyl-CoA produced in peroxisomes by dicarboxylic and also by monocarboxylic acids. Mitochondrial fatty acid oxidation also led to free acetate generation but at low rates relative to ketogenesis. The origin of the acetate released was confirmed employing [1-14C]dodecanedioic acid. Thus, the activity of peroxisomes might contribute significantly to the free acetate generation known to occur during fatty acid oxidation in rats and possibly also in humans.
Topics: Acetates; Animals; Bezafibrate; Cells, Cultured; Dicarboxylic Acids; Fatty Acids; Hydrogen Peroxide; Ketone Bodies; Kinetics; Liver; Male; Microbodies; Oxidation-Reduction; Rats; Rats, Inbred Strains
PubMed: 2732225
DOI: No ID Found -
Clinica E Investigacion En... May 2021We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in... (Review)
Review
We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.
Topics: Cholesterol, LDL; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dicarboxylic Acids; Drug Development; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Inflammation
PubMed: 33966815
DOI: 10.1016/j.arteri.2021.02.005 -
The Journal of Biological Chemistry 2021Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. Capitalizing on this therapeutically, however, has been only moderately...
Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. Capitalizing on this therapeutically, however, has been only moderately successful because of the relatively small magnitude of these differences and because cancers may further adapt their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bifunctional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate the toxic metabolite dodecanedioic acid (DDDA), which causes acute hepatocyte necrosis and liver failure. We noted that, in a murine model of pediatric hepatoblastoma (HB) and in primary human HBs, downregulation of Ehhadh occurs in association with the suppression of mitochondrial β- and endosomal/peroxisomal ω-fatty acid oxidation pathways. This suggested that HBs might be more susceptible than normal liver tissue to C12 dietary intervention. Indeed, HB-bearing mice provided with C12- and/or DDDA-supplemented diets survived significantly longer than those on standard diets. In addition, larger tumors developed massive necrosis following short-term DDDA administration. In some HBs, the eventual development of DDDA resistance was associated with 129 transcript differences, ∼90% of which were downregulated, and approximately two-thirds of which correlated with survival in numerous human cancers. These transcripts often encoded extracellular matrix components, suggesting that DDDA resistance arises from reduced Ehhadh uptake. Lower Ehhadh expression was also noted in murine hepatocellular carcinomas and in subsets of certain human cancers, supporting the likely generality of these results. Our results demonstrate the feasibility of C12 or DDDA dietary supplementation that is nontoxic, inexpensive, and likely compatible with more standard chemotherapies.
Topics: Animals; Dicarboxylic Acids; Fatty Acids; Hepatoblastoma; Humans; Liver; Liver Neoplasms; Metabolism; Mice; Mice, Knockout; Mitochondria; Oxidation-Reduction; Peroxisomal Bifunctional Enzyme; Peroxisomes
PubMed: 33450224
DOI: 10.1016/j.jbc.2021.100283 -
Journal of the American Chemical Society Aug 2020The intriguing structure of tagetitoxin (), a long-standing challenge in natural product synthesis, has been the subject of multiple revisions and has been confirmed...
The intriguing structure of tagetitoxin (), a long-standing challenge in natural product synthesis, has been the subject of multiple revisions and has been confirmed through total synthesis. The route commences from a renewable furan starting material and features a number of unusual transformations (such as rearrangements, bromocyclization, and P(V)-based phosphate installation) to arrive at the target in 15 steps. As the route was designed to enable access to both enantiomers, the absolute configuration of the natural product could be assigned using a bioassay on (+)- and (-)-.
Topics: Dicarboxylic Acids; Molecular Structure; Organophosphorus Compounds; Stereoisomerism
PubMed: 32687336
DOI: 10.1021/jacs.0c06641