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Investigative Ophthalmology & Visual... Sep 2022To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
PURPOSE
To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
METHODS
Rabbits received subconjunctival injections of trypan blue or fixable fluorescent dextrans. Bleb-related outflow pathways were quantified. Immunofluorescence for vessel-specific markers (lymphatics [podoplanin and LYVE-1] and blood vessels [CD31]) were performed in native rabbit conjunctiva and after fixable fluorescent dextran injection. Vascular endothelial cell growth factor-C (VEGFC) was injected subconjunctivally in rabbits. mRNA and protein were assessed for the above markers using RT-PCR and Western blot. Alternatively, mouse studies used Prox1-tdTomato transgenic reporter mice. Subconjunctival injection conditions included: no injection, balanced salt solution (BSS), VEGFC, 5-fluorouracil (5FU) and two concentrations of mitomycin-C (MMC). Two mouse injection protocols (short and long) with different follow-up times and number of injections were performed. Mouse eyes were enucleated, flat mounts created, and subconjunctival branching and length assessed.
RESULTS
Rabbit eyes demonstrated clear bleb-related subconjunctival outflow pathways that were distinct from blood vessels and were without nasal/temporal predilection. Immunofluorescence against vessel-specific markers showed lymphatics and blood vessels in rabbit conjunctiva, and these lymphatics overlapped with bleb-related subconjunctival outflow pathways. Subconjunctival VEGFC increased lymphatic (P = 0.004-0.04) but not blood vessel (P = 0.77-0.84) mRNA or protein in rabbits. Prox1-tdTomato transgenic reporter mice demonstrated natively fluorescent lymphatics. Subconjunctival VEGFC increased murine lymphatic branching and length (P ≤ 0.001-0.004) while antimetabolites (P ≤ 0.001-0.043) did the opposite for the long protocol.
DISCUSSION
Subconjunctival lymphatics are pharmacologically responsive to both VEGFC and antimetabolites in two animal models studied using different methodologies. These results may be important for bleb-forming glaucoma surgeries or ocular drug delivery.
Topics: Animals; Mice; Rabbits; Antimetabolites; Conjunctiva; Dextrans; Fluorouracil; Glaucoma; Intraocular Pressure; Mitomycin; RNA, Messenger; Trypan Blue
PubMed: 36166215
DOI: 10.1167/iovs.63.10.16 -
Journal of Cardiology Aug 2017The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients... (Review)
Review
The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients who have experienced myocardial infarction (MI) are at high risk of recurrence of cardiovascular events compared with those who are healthy or have stable coronary artery disease. Acute coronary events induce further inflammatory responses and plaque vulnerability in either a coronary culprit or whole vessels. The majority of data have supported the importance of coronary risk management to prevent secondary events. Dyslipidemia is common and one of the therapeutic targets in patients with ACS. Statins can reduce coronary plaque burden and lower the risk of cardiovascular death, recurrent MI, stroke, and coronary revascularization in patients with ACS. Growing evidence from clinical trials and meta-analyses supports early, intensive, and continuous therapy with statins in patients with ACS. Statins are accepted worldwide as the first-line lipid-lowering therapy as guidelines recommend. However, some patients do not reach the target level of low-density lipoprotein cholesterol by statins alone or are contra-indicated for statins. Recently, several clinical trials showed the further benefit of ezetimibe combined with statins on cardiovascular outcomes and coronary plaque regression in patients with ACS. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, novel and powerful lipid-lowering agents, have been developed and used in clinical settings. In this review, we summarize the present statin therapy, and refer to ezetimibe and PCSK9 as novel or additional non-statin strategies in the management of ACS.
Topics: Acute Coronary Syndrome; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipid Metabolism; PCSK9 Inhibitors; Plaque, Atherosclerotic
PubMed: 28325524
DOI: 10.1016/j.jjcc.2017.02.004 -
Giornale Italiano Di Cardiologia (2006) Dec 2015
Topics: Acute Coronary Syndrome; Anticholesteremic Agents; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Randomized Controlled Trials as Topic; Simvastatin; Treatment Outcome
PubMed: 26667942
DOI: 10.1714/2088.22578 -
Pharmacological Research Nov 2015For decades, metformin has been the first-line drug for the treatment of type II diabetes mellitus, and it thus is the most widely prescribed antihyperglycemic drug.... (Review)
Review
For decades, metformin has been the first-line drug for the treatment of type II diabetes mellitus, and it thus is the most widely prescribed antihyperglycemic drug. Retrospective studies associate the use of metformin with a reduction in cancer incidence and cancer-related death. However, despite extensive research about the molecular effects of metformin in cancer cells, its mode of action remains controversial. In this review, we summarize the current molecular evidence in an effort to elucidate metformin's mode of action against cancer cells. Some authors describe that metformin acts directly on mitochondria, inhibiting complex I and restricting the cell's ability to cope with energetic stress. Furthermore, as the drug interrupts the tricarboxylic acid cycle, metformin-induced alteration of mitochondrial function leads to a compensatory increase in lactate and glycolytic ATP. It has also been reported that cell cycle arrest, autophagy, apoptosis and cell death induction is mediated by the activation of AMPK and Redd1 proteins, thus inhibiting the mTOR pathway. Additionally, unbiased metabolomics studies have provided strong evidence to support that metformin alters the methionine and folate cycles, with a concomitant decrease in nucleotide synthesis. Indeed, purines such as thymidine or hypoxanthine restore the proliferation of tumor cells treated with metformin in vitro. Consequently, some authors prefer to refer to metformin as an "antimetabolite drug" rather than a "mitochondrial toxin". Finally, we also review the current controversy concerning the relationship between the experimental conditions of in vitro-reported effects and the plasma concentrations achieved by chronic treatment with metformin.
Topics: Animals; Antimetabolites; Energy Metabolism; Folic Acid Antagonists; Humans; Hypoglycemic Agents; In Vitro Techniques; Metformin; Models, Biological; Neoplasms
PubMed: 26277279
DOI: 10.1016/j.phrs.2015.06.014 -
Progress in Cardiovascular Diseases 2023Statins are first-line therapy for treating dyslipidemia because of their low-density lipoprotein cholesterol (LDL-C) lowering efficacy, superior event-reduction data... (Review)
Review
Statins are first-line therapy for treating dyslipidemia because of their low-density lipoprotein cholesterol (LDL-C) lowering efficacy, superior event-reduction data and unrivaled cost-effectiveness. Yet, many people are intolerant of statins, whether due to true adverse events or the nocebo effect, so within one year about two-thirds of primary prevention patients and one-third of secondary prevention patients are no longer taking their prescription. Statins still dominate this landscape, but other agents, often used in combination, potently reduce LDL-C levels, regress atherosclerosis and lower risk of major adverse cardiovascular events (MACE). Ezetimibe lowers LDL-C by reducing intestinal absorption of cholesterol. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower LDL-C by increasing the number and durability of hepatic LDL receptors. Bempedoic acid reduces hepatic cholesterol synthesis. Ezetimibe, PCSK9i and bempedoic are evidence-based, non-statin therapies that synergistically lower LDL-C and reduce risk of MACE; they also have benign side-effect profiles and are generally well tolerated.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ezetimibe; PCSK9 Inhibitors; Cholesterol, LDL; Proprotein Convertase 9; Anticholesteremic Agents; Cholesterol
PubMed: 36871887
DOI: 10.1016/j.pcad.2023.02.007 -
The Journal of Family Practice Jun 2023YES. In patients with known cardiovascular disease (CVD), ezetimibe with a statin decreases major adverse cardiovascular events (MACE) but has no effect on all-cause and... (Meta-Analysis)
Meta-Analysis
YES. In patients with known cardiovascular disease (CVD), ezetimibe with a statin decreases major adverse cardiovascular events (MACE) but has no effect on all-cause and cardiovascular mortality, compared to a statin alone (strength of recommendation [SOR], A; meta-analysis of randomized controlled trials [RCTs] including 1 large RCT). In adults with atherosclerotic CVD (ASCVD), the combination of ezetimibe and a moderate-intensity statin (rosuvastatin 10 mg) was noninferior at decreasing cardiovascular death, major cardiovascular events, and nonfatal stroke, but was more tolerable, compared to a high-intensity statin (rosuvastatin 20 mg) alone (SOR, B; 1 RCT).
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ezetimibe; Cardiovascular Diseases; Anticholesteremic Agents; Rosuvastatin Calcium; Secondary Prevention
PubMed: 37339492
DOI: 10.12788/jfp.0610 -
The American Journal of Medicine Dec 2022Lipid-lowering guidelines emphasize shared decision-making between clinicians and patients, resulting in patients anticipating the degree of response from diet or drug... (Review)
Review
Lipid-lowering guidelines emphasize shared decision-making between clinicians and patients, resulting in patients anticipating the degree of response from diet or drug therapy. Challenging for physicians is understanding the sources of variability complicating their management decisions, which include non-adherence, genetic considerations, additional lipid parameters including lipoprotein (a) levels, and rare systemic responses limiting benefits that result in non-responsiveness to monoclonal antibody injection. In this narrative review, we focus on the variability of low-density lipoprotein cholesterol (LDL-C) response to guideline-directed interventions such as statins, ezetimibe, bile acid sequestrants, fibrates, proprotein/convertase subtilisin-kexin type 9 inhibitors, and LDL-C-lowering diets. We hypothesize that the variability in individual lipid responses is multifactorial. We provide an illustrative model with a check list that can be used to identify factors that may be present in the individual patient.
Topics: Humans; Cholesterol, LDL; Anticholesteremic Agents; Ezetimibe; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Proprotein Convertase 9
PubMed: 35878687
DOI: 10.1016/j.amjmed.2022.06.018 -
Annals of Transplantation Jan 2018Infections account for 15-20% of deaths in transplant recipients, requiring rapid and appropriate therapeutic interventions. Many anti-infective agents interact with... (Review)
Review
Infections account for 15-20% of deaths in transplant recipients, requiring rapid and appropriate therapeutic interventions. Many anti-infective agents interact with immunosuppressive regimens used in transplantation, placing patients at increased risk for adverse drug reactions and prolonged hospitalizations. There is established data regarding the level of evidence and magnitude of interactions between calcineurin inhibitors and mammalian target of rapamycin inhibitors with anti-infective agents. Less is known about the interactions with anti-proliferative agents and corticosteroids, with gaps in knowledge on the appropriate management of these interactions. The objective of this review was to highlight the pharmacokinetic drug-drug interactions between antimetabolites and corticosteroids with commonly used anti-infective agents.
Topics: Adrenal Cortex Hormones; Anti-Infective Agents; Antimetabolites; Drug Interactions; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Organ Transplantation
PubMed: 29358572
DOI: 10.12659/aot.906164 -
Future Cardiology Jul 2017Dr Derek Connolly speaks to Adam Price-Evans, Commissioning Editor of Future Cardiology: Derek Leslie Connolly is a Consultant Interventional Cardiologist at Birmingham...
Dr Derek Connolly speaks to Adam Price-Evans, Commissioning Editor of Future Cardiology: Derek Leslie Connolly is a Consultant Interventional Cardiologist at Birmingham City Hospital (UK). He qualified from the University of Edinburgh (UK) summa cum laude in Pharmacology in 1985 and in Medicine in 1988 where he was the Brunton Medalist. As a Carnegie scholar at the University of California, San Diego (CA, USA) he saw the early promise of angioplasty and changed his career plan from cardiac surgery to coronary intervention. He then spent a decade training in Cardiology in Cambridge (UK) where he held a British Heart Foundation PhD Fellowship at the University of Cambridge. His main clinical and research interest is the detection and treatment of atherosclerosis. He was appointed to his current role in 2000 and has been integral to the early development of both primary angioplasty and cardiac CT programs. He was UK Chief Investigator for the FOURIER trial.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cardiology; Clinical Trials, Phase III as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors
PubMed: 28621180
DOI: 10.2217/fca-2017-0052 -
Current Drug Targets 2019Quinolizidine alkaloids, a main form of alkaloids found in the genus Sophora, have been shown to have many pharmacological effects. This review aims to summarize the... (Review)
Review
Quinolizidine alkaloids, a main form of alkaloids found in the genus Sophora, have been shown to have many pharmacological effects. This review aims to summarize the photochemical reports and biological activities of quinolizidine alkaloids in Sophora. The collected information suggested that a total of 99 quinolizidine alkaloids were isolated and detected from different parts of Sophora plants, represented by lupinine-type, cytisine-type, sparteine-type, and matrine-type. However, quality control needs to be monitored because it could provide basic information for the reasonable and efficient use of quinolizidine alkaloids as medicines and raw materials. The nonmedicinal parts may be promising to be used as a source of quinolizidine alkaloid raw materials and to reduce the waste of resources and environmental pollution. In addition, the diversity of chemical compounds based on the alkaloid scaffold to make a biological compound library needs to be extended, which may reduce toxicity and find new bioactivities of quinolizidine alkaloids. The bioactivities most reported are in the fields of antitumor activity along with the effects on the cardiovascular system. However, those studies rely on theoretical research, and novel drugs based on quinolizidine alkaloids are expected.
Topics: Alkaloids; Analgesics; Anti-Infective Agents; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Cardiovascular Agents; Drug Development; Drug Discovery; Humans; Insecticides; Plant Extracts; Quality Control; Quinolizidines; Sophora
PubMed: 31215388
DOI: 10.2174/1389450120666190618125816