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Dyslipidemia
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
PCSK9 monoclonal antibodies are formulated for subcutaneous injection, once to twice per month. They stop proprotein convertase subtilisin/kexin type 9 from attaching to LDL receptors, improving their function. The LDL is lowered by 40%–70%. Trials with alirocumab and evolocumab revealed less cardiovascular events when previous atherosclerotic cardiovascular disease was present. The cholesterol absorption inhibitors, including ezetimibe, inhibit absorption of cholesterol and phytosterol in the intestines. The LDL is usually lowered by ezetimibe by 15%–20%, with small increases in HDL and a slight decrease in total triglycerides. Ezetimibe can be used alone if the patient cannot tolerate statins, or it can be added to statins if the patient is on maximum statin dosage, with LDL remaining chronically elevated. Adverse effects of cholesterol absorption inhibitors are rare.
Trigonella foenum-graecum L.
Published in Dilip Ghosh, Prasad Thakurdesai, Fenugreek, 2022
G. Sindhu, Chithra K. Pushpan, A. Helen
Abnormal lipid levels are a cause of concern as they are an evident potential risk to various complications like heart diseases. Global Health Observatory data indicates that increased cholesterol level is attributed to one-third of ischemic heart disease. It is also mentioned that a reduction of serum cholesterol levels by 10% reduced the heart disease in men of 40 years of age and 70 years of age by 50% and 20%. Reducing the cholesterol levels has for a long time been one of the targets for prevention and cure of heart diseases. Strategies in reducing cholesterol levels in blood includes reduction in consumption of lipid-containing foods, hypolipidemic medications that include HMG CoA reductase inhibitors, bile acid binding resins, CETP inhibitors, cholesterol absorption inhibitors, fibrates, nicotinic acid, etc. (Kramer, 2015). However, there are adverse effects from the treatment with these drugs making it challenging for clinical management of hypercholesterolemia. An important strategy in the management of hypercholesterolemia is through modification of diet and also inclusion of functional foods and nutraceuticals.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Another established hypolipidemic drug is Ezetimibe; it acts as a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol (Bays et al., 2008); it is safe and well tolerated and used—in combination with or as an alternative to statins–to reduce the LDL-cholesterol level to about 30 to 50 mg/dL (O‘Keefe, et al., 2017). Ezetimibe works by inhibiting the intestinal cholesterol absorption by selectively blocking the cholesterol transport protein Niemann Pick C1 like 1 (NPC1L1) protein in the jejunal brush border (Phan et al., 2012). The molecular mechanism of sterol uptake from the lumen of the small intestine that contribute to plasma cholesterol levels was detected by Altman et al., 2004; these authors also demonstrated that Ezetimibe had no effect on NPC1L1 knockout mice concerning the observed reduction in absorbed cholesterol.
Small molecule glucagon receptor antagonists: an updated patent review (2015–2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Chen Cheng, Salman Jabri, Brandon M Taoka, Christopher J Sinz
Structurally diverse inhibitors giving rise to similar lipid elevations point to mechanism-based lipid effects. Further studies were disclosed in WO2015066252 [59] and reported in the peer-reviewed journal [86]. Because these GRAs show substantially reduced potency against mouse GCGR, the effects were studied in hGCGR and WT mice. Identical doses showed no effect in WT, but significant increase in cholesterol absorption in hGCGR mice, providing further evidence that these effects are glucagon receptor-dependent. While the molecular mechanism of action remains to be fully elucidated, treatment with GRAs leads to significant increases in both GLP-1 and GLP-2. GLP-2 has been reported to induce crypt cell proliferation and effect intestinal lipid absorption in the presence of GLP-1 [87–89]. All compounds displayed comparable potency with regard to the suppression of glucagon-induced cAMP production in primary human hepatocytes and no significant differences in effects on β-arrestin recruitment and cellular Ca2+ concentration. It remains to be seen whether biased ligand signaling could lead to an improved therapeutic index. The MSD authors suggested a potential mitigation strategy involving combination treatment with a cholesterol absorption inhibitor.
Pharmacological management of cardiovascular risk in chronic inflammatory rheumatic diseases
Published in Expert Review of Clinical Pharmacology, 2020
Vasileios Panoulas, George D. Kitas
Statins reduce the synthesis of cholesterol in the liver by competitively inhibiting the enzyme HMG-CoA reductase. A high-intensity regime is defined as the dose of statin that reduced LDL-C by ≥50% [42]. There is however considerable variation in degree of LDL-C lowering in different individuals. When targets are not achieved the guidelines recommend the addition of a cholesterol absorption inhibitor, such as ezetimibe. Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol by interacting with the Niemann-Pick C1 like protein (NPC1L1). A 10 mg daily dose reduces LDL-C by 15–22% [43]. When added to ongoing statin therapy ezetimibe can reduce LDL-C levels by an additional 21–27% compared to placebo [44] and significantly reduce future cardiovascular events in ACS patients [45].
Monocyclic beta–lactams for therapeutic uses: a patent overview (2010–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Katarina Grabrijan, Nika Strašek, Stanislav Gobec
Monocyclic beta-lactam or 2-azetidine is a unique structural motif and represents a crucial building block of different biologically active compounds. It is a four-membered cyclic amide, with an oxo group at a second position of the ring and various substitutions on the amide nitrogen (N-1), on the carbon adjacent to the carbonyl group (C-3), and on the carbon adjacent to the nitrogen (C-4) (Figure 1). Different structural modifications of the nucleus determine the chemical reactivity and target specificity of a compound. Mainly, beta-lactams act as covalent warheads, since their reactivity derives from the ring strain of the beta-lactam skeleton in fused systems, or from an electron-withdrawing substituent on the lactam nitrogen in monocyclic rings. The reactivity of monocyclic beta-lactams can be modulated by changing the character of the electron-withdrawing substituent. Most commonly, the ring is activated with sulfonic acid, resulting in monobactams. The first monocyclic beta-lactam, Nocardin A, was discovered in 1976 in the bacterium Nocardia uniformis. Five years later, sulfazecin and isosulfazecin, which also belong to the monobactam family, were isolated from Pseudomonas strains. Their unexpected antibacterial activity led to the development of the first approved monocyclic beta-lactam drug, aztreonam, in the 1980s [1]. This drug is effective against Gram-negative bacteria, including Pseudomonas aeruginosa, and is still in use today. Another approved drug in use is ezetimibe, which acts as a cholesterol absorption inhibitor and it is used for treatment of hypercholesterolemia.