American association of clinical endocrinologists and american college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport.

https://www.pnas.org/content/pnas/102/23/8132.full.pdf

The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).

Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic information has been extracted from both scientific journals and the wider patent literature.

/pdf/prescribed-drugs-containing-nitrogen-heterocycles-an-31vxbjpp0q.pdf

Prescribed drugs containing nitrogen heterocycles: an overview

▪ Abstract Phytosterols are cholesterol-like molecules found in all plant foods, with the highest concentrations occurring in vegetable oils. They are absorbed only in trace amounts but inhibit the absorption of intestinal cholesterol including recirculating endogenous biliary cholesterol, a key step in cholesterol elimination. Natural dietary intake varies from about 167–437 mg/day. Attempts to measure biological effects in feeding studies have been impeded by limited solubility in both water and fat. Esterification of phytosterols with long-chain fatty acids increases fat solubility by 10-fold and allows delivery of several grams daily in fatty foods such as margarine. A dose of 2 g/day as the ester reduces low density lipoprotein cholesterol by 10%, and little difference is observed between Δ5-sterols and 5α-reduced sterols (stanols). Phytosterols can also be dispersed in water after emulsification with lecithin and reduce cholesterol absorption when added to nonfat foods. In contrast to these suppleme...

Phytosterols in human nutrition

American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice are systematically developed statements to assist health care professionals in medical decision-making for specific clinical conditions, but are in no way a substitute for a medical professional’s independent judgment and should not be considered medical advice. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with, and not as a replacement for, their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

http://www.serm.md/ghiduri/diverse/AACE_GUIDELINES_FOR_MANAGEMENT_OF_DYSLIPIDEMIA_AND.pdf

American association of clinical endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies

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Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies