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Cell Chemical Biology Sep 2017Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism... (Review)
Review
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.
Topics: Antimetabolites; Argininosuccinate Synthase; Carbohydrate Metabolism; Fatty Acids; Glutamine; Glycolysis; Humans; Isocitrate Dehydrogenase; Metabolic Engineering; NAD; Neoplasms
PubMed: 28938091
DOI: 10.1016/j.chembiol.2017.08.028 -
American Journal of Cardiovascular... Sep 2023Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular... (Review)
Review
Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Secondary Prevention; Hypolipidemic Agents; Ezetimibe; Cardiovascular Diseases; Hypertriglyceridemia; Pharmaceutical Preparations; Angiopoietin-Like Protein 3
PubMed: 37486464
DOI: 10.1007/s40256-023-00594-5 -
Current Atherosclerosis Reports Jul 2022Despite the elevation of lipid values during pregnancy is mostly physiological, evidence suggest that it may be associated with adverse events. This article reviews the... (Review)
Review
PURPOSE OF REVIEW
Despite the elevation of lipid values during pregnancy is mostly physiological, evidence suggest that it may be associated with adverse events. This article reviews the characteristics of lipid disorders and the possible management with dyslipidemia in pregnant women.
RECENT FINDINGS
Among many available groups of lipid-lowering drugs, only bile acid sequestrants are approved for the treatment of dyslipidemia during pregnancy. Ezetimibe and fenofibrate might be considered if benefits outweigh the potential risk. Statins are still contraindicated due to the results mainly from animal studies and series of human cases. However, recent systematic reviews and meta-analyses showed that their use may not be detrimental, and in some selected cases may be beneficial. Especially, in some groups of pregnant patients with very high cardiovascular risk-those already after an event, or with established cardiovascular disease, with homozygous familial hypercholesterolemia; in such cases the final decision should weight the potential risk of discontinuation of therapy. Finally, we need to wait for the data with new drugs, including PCSK9 inhibitors and especially inclisiran, which (still hypothetically) might be a very interesting option as it may be used just before the pregnancy and immediately after with the duration of about 9 months between injections. The decisions on lipid-lowering therapy in pregnant patients should be individualized. Despite design and ethical difficulties with such studies, further investigations on dyslipidemia treatment during pregnancy are highly awaited.
Topics: Animals; Anticholesteremic Agents; Cholesterol, LDL; Dyslipidemias; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Proprotein Convertase 9
PubMed: 35499807
DOI: 10.1007/s11883-022-01030-w -
Clinica E Investigacion En... May 2021Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors...
Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors and increasing low-density lipoproteins (LDL-C) plasma clearence. It is a prodrug for oral administration with intracellular activation. It is activatedin liver cells and to a lesser extent in kidney cells, being absent in adipose tissue and muscle cells. Therefore, unlike statins, its potential myotoxic effect is very limited. It has recently been approved as a lipid-lowering drug in combination with diet, with statins, or with other lipid-lowering drugs in patients with hypercholesterolaemia, mixed dyslipidaemia, statin intolerance, or when these are contraindicated. The marketing of bempedoic acid implies, in clinical practice, having a new family of lipid-lowering drugs.
Topics: Dicarboxylic Acids; Drug Therapy, Combination; Dyslipidemias; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents
PubMed: 33966814
DOI: 10.1016/j.arteri.2021.02.012 -
Current Atherosclerosis Reports Oct 2023It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid... (Review)
Review
PURPOSE OF REVIEW
It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals.
RECENT FINDINGS
The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Ezetimibe; Dyslipidemias; Drug Therapy, Combination; Atherosclerosis; Anticholesteremic Agents; Treatment Outcome
PubMed: 37715044
DOI: 10.1007/s11883-023-01142-x -
Vnitrni Lekarstvi 2020PCSK9 inhibitors (inhibitors of proprotein convertase subtilisin/kexin type 9) offer a promising treatment strategy decreasing the concentrations of both atherogenic low...
PCSK9 inhibitors (inhibitors of proprotein convertase subtilisin/kexin type 9) offer a promising treatment strategy decreasing the concentrations of both atherogenic low density lipoprotein (LDL) and cholesterol contained within LDL. Alirocumab is one of two PCSK9 inhibitors that entered clinical practice so far. Alirocumab is a specific antibody against PCSK9, manufactured using recombinant technique. When the antibody binds to the PCSK9 isoenzyme, no complex encompassing PCSK9 and LDL receptor can be formed, thus enabling further recirculation of the LDL receptor. Increasing the amount of LDL receptors available on the cell membranes leads to higher internalization of LDL within cells and to lowering of LDL cholesterol concentration. It has been shown that alirocumab exerts favorable effect on atherogenic lipoproteins (i.e. decrease of concentrations of LDL cholesterol by more than 50%) both in monotherapy and in combination with statins or other hypolipidemics. Odyssey Outcomes study brought new information into light and changed the guidelines of treating the patients with cardivascular diseases. Alirokumab added to intensive statin therapy reduced significantly the risk of cardiovascular diseases and the post hoc analysis confirmed also the reduction of total death rate. The positive effect of alirocumab is higher in patients with higher initial LDL-C. The therapy with alirokumab is safe, with minimum adverse events.
Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Proprotein Convertase 9
PubMed: 32942879
DOI: No ID Found -
International Journal of Molecular... Dec 2023Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as spp., spp.,... (Review)
Review
Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as spp., spp., , and have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects.
Topics: Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacy; Fungi; Lovastatin
PubMed: 38203637
DOI: 10.3390/ijms25010466 -
Vnitrni Lekarstvi 2019Dyslipidemia belongs to the main risk factors for atherosclerosis. To achieve current blood lipid targets, it is often necessary to use intensive hypolipidemic therapy... (Review)
Review
Dyslipidemia belongs to the main risk factors for atherosclerosis. To achieve current blood lipid targets, it is often necessary to use intensive hypolipidemic therapy including a combination of individual hypolipidemic drugs. In terms of cardiovascular risk reduction, it is important that the patient is treated with the highest tolerated dose of statin. In the next step, we decide to co-administer ezetimibe and/or fibrate, and for high-risk patients an additional treatment with proprotein convertase subtilisin kexin 9 inhibitors should be considered. The manuscript provides an overview of the individual combinations effectiveness to influence lipid spectrum and the incidence of cardiovascular diseases. Key words: cardiovascular disease - dyslipidemia - ezetimibe - fibrates - PCSK9 inhibitors - statins.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Drug Therapy, Combination; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; PCSK9 Inhibitors
PubMed: 30704254
DOI: No ID Found -
Journal of the American College of... Oct 2021
Topics: Anticholesteremic Agents; Ezetimibe; Humans
PubMed: 34620407
DOI: 10.1016/j.jacc.2021.08.029 -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2020The recently delineated structure- and reactivity-based concept of antivitamins B has begun to bear fruit by the generation, and study, of a range of such B -dummies,... (Review)
Review
The recently delineated structure- and reactivity-based concept of antivitamins B has begun to bear fruit by the generation, and study, of a range of such B -dummies, either vitamin B -derived, or transition metal analogues that also represent potential antivitamins B or specific B -antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B -chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B -deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B to induce functional B -deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells.
Topics: Animals; Antimetabolites; Humans; Neoplasms; Vitamin B 12; Vitamins
PubMed: 32956545
DOI: 10.1002/chem.202003788