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Experimental and Clinical Endocrinology... Nov 2016Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein (LDL) cholesterol.The... (Review)
Review
Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein (LDL) cholesterol.The extent of underdiagnosis and undertreatment of individuals with FH is largely unknown.The LDL-lowering capacity of statins in combination with other lipid-lowering drugs is maximally around 50-60%. FH patients have a strongly elevated LDL-C and in most cases maximal current treatment is not sufficient to reach the desired LDL targets.Therefore, FH patients have a large residual cardiovascular risk despite the use of statins and there is a medical need for new additional drugs to further lower LDL-C in patients with FH to improve their prognosis.PCSK9 inhibitors have shown great efficacy in lowering lipids with very few side effects. No synergism between statins and PCSK9 inhibition was observed in many trials, allowing clinicians to select a statin dose before considering the initiation of PCSK9-inhibitor therapy.In patients with FH, who are at risk for markedly accelerated atherosclerosis and premature cardiovascular death, also treatment with lomitapide or mipomersen has the potential to reduce the risk of atherosclerotic cardiovascular disease and premature mortality.These new drugs will be probably reserved for the most severely affected FH patients and could help clinicians to reduce their residual cardiovascular risk.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Humans; Hyperlipoproteinemia Type II; Oligonucleotides; PCSK9 Inhibitors
PubMed: 27711959
DOI: 10.1055/s-0042-109063 -
IUBMB Life Mar 2017Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects.... (Review)
Review
Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects. 2-Deoxyglucose (2-DG) is one such glycolytic inhibitor and was identified to be a competitive inhibitor of glucose. Studies from past few decades have shown that the mechanism of action of 2-DG is complex involving several metabolic and signaling pathways. Budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe are two important models for studying metabolism, cell cycle and cell signaling. These two unicellular eukaryotes are Crabtree positive yeasts exhibiting a metabolism similar to that of cancer cells. Effects of 2-DG in yeast is of interest owing to these similarities and hence yeasts have emerged as ideal model organisms to study the mode of action and resistance to 2-DG. In this review, we summarize the studies on biological effect and resistance to 2-DG in budding and fission yeasts and give an insight into its possible mechanism of action as models for understanding cancer metabolism and drugs affecting cancer progression. © 2017 IUBMB Life, 69(3):137-147, 2017.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Deoxyglucose; Drug Screening Assays, Antitumor; Energy Metabolism; Humans; Neoplasms; Schizosaccharomyces
PubMed: 28093891
DOI: 10.1002/iub.1599 -
Protein Science : a Publication of the... Feb 2016The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this... (Review)
Review
The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this essential vitamin. Approximately 13,000 putative transporters of the family have been identified. However, before our work, no structural information was available and even functional data were minimal for this family of membrane proteins. To elucidate the structure and function of the AbgT family of transporters, we recently determined the X-ray structures of the full-length Alcanivorax borkumensis YdaH and Neisseria gonorrhoeae MtrF membrane proteins. The structures reveal that these two transporters assemble as dimers with architectures distinct from all other families of transporters. Both YdaH and MtrF are bowl-shaped dimers with a solvent-filled basin extending from the cytoplasm halfway across the membrane bilayer. The protomers of YdaH and MtrF contain nine transmembrane helices and two hairpins. These structures directly suggest a plausible pathway for substrate transport. A combination of the crystal structure, genetic analysis and substrate accumulation assay indicates that both YdaH and MtrF behave as exporters, capable of removing the folate metabolite p-aminobenzoic acid from bacterial cells. Further experimental data based on drug susceptibility and radioactive transport assay suggest that both YdaH and MtrF participate as antibiotic efflux pumps, importantly mediating bacterial resistance to sulfonamide antimetabolite drugs. It is possible that many of these AbgT-family transporters act as exporters, thereby conferring bacterial resistance to sulfonamides. The AbgT-family transporters may be important targets for the rational design of novel antibiotics to combat bacterial infections.
Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antimetabolites; Bacteria; Bacterial Proteins; Biological Transport; Crystallography, X-Ray; Folic Acid; Gene Expression Regulation, Bacterial; Membrane Transport Proteins; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Alignment
PubMed: 26443496
DOI: 10.1002/pro.2820 -
Journal of Glaucoma Sep 2021Trabeculectomy can effectively lower intraocular pressure (IOP). A more junior surgeon profile is emerging. Mitomycin C (MMC) has replaced 5-fluorouracil (5-FU)...
PRECIS
Trabeculectomy can effectively lower intraocular pressure (IOP). A more junior surgeon profile is emerging. Mitomycin C (MMC) has replaced 5-fluorouracil (5-FU) intraoperatively with comparable success rates and a decrease in postoperative antimetabolite administration.
PURPOSE
We compare 2-year outcomes for primary trabeculectomy in 2 cohorts, 10 years apart, performed at a large UK teaching hospital.
METHODS
Consecutive case series of trabeculectomies at Manchester Royal Eye Hospital between 2004-2005 (Cohort 1/C1) and 2014-2015 (Cohort 2/C2). Preoperative and postoperative data was collected for IOP outcomes and complications. Success was defined as IOP ≥6 and ≤21, ≤18, ≤16, ≤14, or ≤12 mm Hg with/without a ≥20% decrease from preoperative IOP. The need for and absence of postoperative antihypertensive medication defined qualified and complete success, respectively.
RESULTS
A total of 186 cases were analyzed [52 (C1), 134 (C2)]. Mean preoperative IOP was 24±10 mm Hg (C1) and 21±7 mm Hg (C2) (P=0.01). Overall, 34 (79%), 33 (77%), 33 (77%), 29 (67%), and 25 (58%) patients in C1 and 88 (70%), 82 (65%), 73 (58%), 64 (51%), and 40 (32%) patients in C2 achieved complete success for IOP ≤21 mm Hg (P=0.33), ≤18 mm Hg (P=0.22), ≤16 mm Hg (P=0.04), ≤14 mm Hg (P=0.09), or ≤12 mm Hg (P=0.004). Similarly, 43 (93%), 40 (87%), 40 (87%), 35 (76%), and 27 (59%) in C1 and 123 (98%), 116 (92%), 106 (84%), 87 (69%), and 58 (49%) in C2 achieved qualified success (P=0.34, 0.37, 0.83, 0.48, and 0.19). In all, 32 (74%), 31 (72%),31 (72%), 28 (65%), and 24 (56%) in C1 and 64 (51%), 63 (50%), 61 (48%), 54 (43%), and 39 (31%) in C2 achieved complete success with ≥20% reduction from preoperative IOP and IOP of ≤21 mm Hg (P=0.01), ≤18 mm Hg (P=0.02), ≤16 mm Hg (P=0.01), ≤1 mm Hg (P=0.02), or ≤12 mm Hg (P=0.006). By same definition, 37 (80%), 36 (78%), 36 (78%), 33 (72%), and 26 (57%) in C1 and 94 (75%), 93 (74%), 90 (71%), 75 (60%), and 58 (46%) in C2 achieved qualified success (P=0.55, 0.69, 0.48, 0.20, and 0.30). Mean IOP at 2 years was 13±5 mm Hg (C1) and 13±4 mm Hg (C2) (P=0.35). Overall, 62% had intraoperative 5-FU in C1; only MMC was used in C2 (P<0.0001). Postoperative 5-FU was administered in 54% versus 22% in C1 and C2, respectively (P<0.0001). Needling rates were not statistically different [42% (C1), 54% (C2)] (P=0.22).
CONCLUSIONS
Trabeculectomy is effective in lowering IOP with success comparable across various definitions. MMC replaced 5-FU as intraoperative antimetabolite resulting in reduced need for postoperative antimetabolite but not increased complications.
Topics: Antimetabolites; Follow-Up Studies; Humans; Intraocular Pressure; Mitomycin; Retrospective Studies; Trabeculectomy; Treatment Outcome
PubMed: 34049346
DOI: 10.1097/IJG.0000000000001887 -
The Cochrane Database of Systematic... Jul 2014Patients having cataract surgery have often earlier undergone a trabeculectomy for glaucoma. However, cataract surgery may be associated with failure of the previous... (Review)
Review
BACKGROUND
Patients having cataract surgery have often earlier undergone a trabeculectomy for glaucoma. However, cataract surgery may be associated with failure of the previous glaucoma surgery and antimetabolites may be used with cataract surgery to prevent such failure. There is no systematic review on whether antimetabolites with cataract surgery prevent failure of a previous trabeculectomy.
OBJECTIVES
To assess the effects of antimetabolites with cataract surgery on functioning of a previous trabeculectomy.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 June 2014. We also searched the Science Citation Index database (July 2013) and reference lists of potentially relevant studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of antimetabolites with cataract surgery in people with a functioning trabeculectomy.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed the titles and abstracts from the electronic searches. Two review authors independently assessed relevant full-text articles and entered data.
MAIN RESULTS
We identified no RCTs to test the effectiveness of antimetabolites with cataract surgery in individuals with the intention of preventing failure of a previous trabeculectomy.
AUTHORS' CONCLUSIONS
There are no RCTs of antimetabolites with cataract surgery in people with a functioning trabeculectomy. Appropriately powered RCTs are needed of antimetabolites during cataract surgery in patients with a functioning trabeculectomy.
Topics: Antimetabolites; Cataract Extraction; Humans; Trabeculectomy
PubMed: 25066789
DOI: 10.1002/14651858.CD010627.pub2 -
Molecules (Basel, Switzerland) Jul 2020We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most... (Review)
Review
We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2'-deoxyuridine-5'--monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine.
Topics: Antimetabolites, Antineoplastic; Chemical Phenomena; DNA; Drug Development; Fluorine Compounds; Fluorouracil; Humans; Precision Medicine; Pyrimidines; RNA; Structure-Activity Relationship; Thymidylate Synthase
PubMed: 32751071
DOI: 10.3390/molecules25153438 -
Orvosi Hetilap Jul 2016Considerable evidence suggests that "the lower the better" is a reasonable approach for reducing cardiovascular risk by lowering LDL cholesterol levels. Despite the... (Review)
Review
Considerable evidence suggests that "the lower the better" is a reasonable approach for reducing cardiovascular risk by lowering LDL cholesterol levels. Despite the reduction in cardiovascular events and mortality achieved by statin therapy, significant residual risk remains, especially in severe hereditary hypercholesterolemia, such as familial hypercholesterolemia. Some new strategies to achieve even lower LDL levels are now available, including the addition of cholesterol absorption inhibitor ezetimibe, and the recently available Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies. In addition, new LDL drugs may be effectively administrated in those individuals who are unable to tolerate statins. The authors summarize the efficacy and clinical indications of these new agents and review the currently available guidelines. Orv. Hetil., 2016, 157(31), 1219-1223.
Topics: Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Drug Therapy, Combination; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; PCSK9 Inhibitors
PubMed: 27476517
DOI: 10.1556/650.2016.30505 -
Expert Opinion on Drug Metabolism &... Apr 2024High-dose methotrexate (HDMTX) therapy poses challenges in various neoplasms due to individualized pharmacokinetics and associated adverse effects. Our purpose is to...
INTRODUCTION
High-dose methotrexate (HDMTX) therapy poses challenges in various neoplasms due to individualized pharmacokinetics and associated adverse effects. Our purpose is to identify early risk factors associated with HDMTX-induced toxicities, paving the way for personalized treatment.
AREAS COVERED
A systematic review of PubMed and Cochrane databases was conducted for articles from inception to July 2023. Eligible studies included reviews, clinical trials, and real-world analyses. Irrelevant studies were excluded, and manual searches and citation reviews were performed. Factors such as MTX exposure, drug interactions, demographics, serum albumin, urine pH, serum calcium, and genetic polymorphisms affecting MTX transport (e.g. SLCO1B1), intracellular folate metabolism (MTHFR), cell development (ARID5B), metabolic pathways (UGT1A1, PNPLA3), as well as epigenetics were identified.
EXPERT OPINION
This comprehensive review aids researchers and clinicians in early identification of HDMTX toxicity risk factors. By understanding the multifaceted risk factors associated with hematologic malignancies, personalized treatment approaches can be tailored to optimize therapeutic outcomes.
Topics: Humans; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Drug Interactions; Hematologic Neoplasms; Methotrexate; Polymorphism, Genetic; Precision Medicine; Risk Factors
PubMed: 38501267
DOI: 10.1080/17425255.2024.2332366 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2022A new fluorescent ribonucleoside alphabet ( N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is...
A new fluorescent ribonucleoside alphabet ( N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is described. Large bathochromic shifts and high microenvironmental susceptibility of their emission relative to previous alphabets derived from thieno[3,4-d]pyrimidine ( N) and isothiazole[4,3-d]pyrimidine ( N) scaffolds are observed. Subjecting the purine analogues to adenosine deaminase, guanine deaminase and T7 RNA polymerase indicate that, while varying, all but one enzyme tolerate the corresponding N/ NTP substrates. The robust emission quantum yields, high photophysical responsiveness and enzymatic accommodation suggest that the N alphabet is a biophysically viable tool and can be used to probe the tolerance of nucleoside/tide-processing enzymes to structural perturbations of their substrates.
Topics: Antimetabolites; Coloring Agents; Nucleosides; RNA; Ribonucleosides
PubMed: 35018663
DOI: 10.1002/chem.202104472 -
Current Pharmaceutical Design 2019Coronary heart disease (CHD) remains the leading cause of disability and death in industrialized Countries. Among many conditions, which contribute to the etiology and... (Review)
Review
Coronary heart disease (CHD) remains the leading cause of disability and death in industrialized Countries. Among many conditions, which contribute to the etiology and progression of CHD, the presence of high low density lipoprotein-cholesterol (LDL-C) levels represents the major risk factor. Therefore, the reduction of LDL-C levels plays a key role in the management of patients with high or very high cardiovascular risk. Although statins represent the gold standard therapy for the reduction of cholesterol levels, these drugs do not allow to achieve target levels of LDL-C in all patients. Indeed, a significant number of patients resulted intolerants, especially when the dosage increased. The availability of new lipid-lowering drugs, such as ezetimibe and PCSK9 inhibitors, may represent an important alternative or complement to the conventional lipid-lowering therapies. However, long-term studies are still needed to define both efficacy and safety of use of these latter new drugs. Some nutraceuticals may become an adequate and effective support in the management of some patients. To date, several nutraceuticals with different mechanism of actions that provide a good tolerability are available as lipidlowering agents. In particular, the most investigated are red yeast rice, phytosterols, berberine, beta-glucans and soy. The aim of this review was to report recent data on the efficacy and safety of principle hypocholesterolemic drugs available and to evaluate the possible role of some nutraceuticals as support therapy in the management of patients with dyslipidemias.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Dietary Supplements; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors
PubMed: 30706799
DOI: 10.2174/1381612825666190130101108