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Cell Feb 2021Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney...
Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
Topics: Allosteric Regulation; Allosteric Site; Amino Acid Motifs; Amino Acid Sequence; Binding Sites; Catechols; Cryoelectron Microscopy; Fenoldopam; GTP-Binding Protein alpha Subunits, Gs; HEK293 Cells; Humans; Ligands; Models, Molecular; Protein Multimerization; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Structural Homology, Protein
PubMed: 33571432
DOI: 10.1016/j.cell.2021.01.028 -
Journal of Vascular Surgery Aug 2011Contrast-induced nephropathy (CIN) has been extensively studied since the 1950s due, in part, to its devastating adverse events. The intellectual push for additional... (Review)
Review
Contrast-induced nephropathy (CIN) has been extensively studied since the 1950s due, in part, to its devastating adverse events. The intellectual push for additional investigation into pathogenesis and prevention has heightened in recent years due to increased utilization of contrast enhanced imaging studies. Lack of a universal CIN definition and varied glomerular filtration rate markers have resulted in a varied reported incidence. Risk assessment and risk reduction strategies have evolved over the past several years. Current evidence supports volume supplementation before the administration of intravascular contrast to reduce the hazard of CIN. Other strategies to reduce the risk of CIN, including low osmolar contrast media, N-acetylcysteine, and intrarenal fenoldopam therapy, have variable levels of evidence, and further randomized trials are necessary.
Topics: Acetylcysteine; Antioxidants; Contrast Media; Evidence-Based Medicine; Fenoldopam; Fluid Therapy; Humans; Kidney Diseases; Risk Assessment; Risk Factors; Treatment Outcome; Vasodilator Agents
PubMed: 21741789
DOI: 10.1016/j.jvs.2011.04.047 -
Journal of Geriatric Cardiology : JGC Jul 2018Hypertensive crises are elevations of blood pressure higher than 180/120 mmHg. These can be urgent or emergent, depending on the presence of end organ damage. The... (Review)
Review
Hypertensive crises are elevations of blood pressure higher than 180/120 mmHg. These can be urgent or emergent, depending on the presence of end organ damage. The clinical presentation of hypertensive crises is quite variable in elderly patients, and clinicians must be suspicious of non-specific symptoms. Managing hypertensive crises in elderly patients needs meticulous knowledge of the pathophysiological changes in them, pharmacological options, pharmacokinetics of the medications used, their side effects, and their interactions with other medications. Clevidipine, nicardipine, labetalol, esmolol, and fenoldopam are among the preferred choices in the elderly due to their efficacy and tolerability. Nitroprusside, hydralazine, and nifedipine should be avoided, unless there are no other options available, due to the high risk of complications and unpredictable responses.
PubMed: 30364798
DOI: 10.11909/j.issn.1671-5411.2018.07.007 -
BMJ Clinical Evidence Mar 2011Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate, which leads to accumulation of urea and other chemicals in the blood.... (Review)
Review
INTRODUCTION
Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate, which leads to accumulation of urea and other chemicals in the blood. The term acute kidney injury has been introduced to encompass a wide spectrum of acute alterations in kidney function from mild to severe. Acute kidney injury is classified according to the RIFLE criteria, in which a change from baseline serum creatinine or urine output determines the level of renal dysfunction.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent acute kidney injury in people at high risk? What are the effects of treatments for critically ill people with acute kidney injury? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 82 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: albumin supplementation plus loop diuretics (intravenous), aminoglycosides, aminophylline, amphotericin B, calcium channel blockers, contrast media, dialysis membranes, dopamine, early versus late dialysis, extended daily dialysis, fenoldopam, loop diuretics, mannitol, N-acetylcysteine, natriuretic peptides, renal replacement therapy, sodium bicarbonate-based fluids, sodium chloride-based fluids, and theophylline.
Topics: Acetylcysteine; Acute Kidney Injury; Contrast Media; Creatinine; Glomerular Filtration Rate; Humans; Renal Dialysis
PubMed: 21443811
DOI: No ID Found -
Medicina (Kaunas, Lithuania) Jul 2023Adipocytes accumulate triacylglycerols as an energy store, thereby causing an increase in the adipose tissue volume. Weight gain can be prevented through damage to the...
Adipocytes accumulate triacylglycerols as an energy store, thereby causing an increase in the adipose tissue volume. Weight gain can be prevented through damage to the adipocyte structure or an increase in the body's metabolic rate. Commonly used methods to disintegrate the cell membrane of adipocytes include injection lipolysis, cryolipolysis, ultrasonic lipolysis, radiofrequency lipolysis, laser lipolysis, carboxytherapy, and lipolysis using an electromagnetic field. The names of these methods suggest which substances are being used, and their main advantages are a very low invasiveness, as well as effectiveness. However, new discoveries in medicine, along with individuals' desire to improve their appearance, have resulted in numerous studies on more ways of reducing body fat. Great potential is seen in beige adipocytes, which can be transformed, i.e., "recruited" from white adipocytes, or synthesized de novo; they also show thermogenic properties. One of the stimuli inducing the formation of beige adipocytes is cold and B3-adrenergic stimulation. Based on these findings, the researchers created, for example, cooling clothing. Additionally, curcumin and natural anthocyanins have proven to be helpful in the treatment of obesity and diabetes, by stimulating the secretion of glucagon-like peptide-1, and inducing the formation of beige adipocytes. Another study showed that the conversion of white adipose tissue is indirectly influenced by interleukin-6 secreted by the muscles, the expression of which is increased in people actively exercising. Moreover, there is potential in adenosine analogs, fenoldopam, rhubarb, the herbal extract Stapf, electroacupuncture simulation, and the drug CBL-514. Despite knowledge and experience, the ideal method for a quick and noticeable, but safe and non-invasive reduction of body fat has not been found yet. The research conducted nowadays may bring us closer to the development of a universal method, and turn out to be a breakthrough in the fight against overweight and obesity.
Topics: Humans; Adipocytes; Adipose Tissue; Anthocyanins; Obesity; Cosmetic Techniques
PubMed: 37629668
DOI: 10.3390/medicina59081378 -
Journal of Pediatric Intensive Care Jun 2014Contrast-induced nephropathy (CIN) remains a common and potentially serious complication in at risk patients after exposure to contrast agents. Risk factors for CIN... (Review)
Review
Contrast-induced nephropathy (CIN) remains a common and potentially serious complication in at risk patients after exposure to contrast agents. Risk factors for CIN include chronic kidney disease, hypotension, diabetes mellitus, recent previous exposure to contrast and all of these are potentially additive. Therefore, careful pre-procedural risk stratification is important. In high-risk patients, contrast should be avoided if possible. If avoidance is not possible, the volume of contrast should be minimized and the type of contrast used should if possible be non-ionic iso-osmolar contrast. In view of the clinical importance of CIN, numerous potential risk-reduction strategies have been evaluated. Adequate intravenous volume expansion with isotonic crystalloid (1.0-1.5 mL/kg per hr) for 3-12 hr before the procedure and continued for 6-24 hr afterward can lessen the probability of CIN in patients at risk. But there are insufficient data on oral fluids as a preventive strategy. Nephrotoxic drugs should be withdrawn before contrast administration in patients at risk for CIN. No adjunctive medical or mechanical treatment has been proved to be efficacious in reducing risk for CIN including prophylactic hemodialysis and hemofiltration, N-acetylcysteine, fenoldopam, dopamine, calcium channel blockers, atrial natriuretic peptide, and L-arginine. The CIN Consensus Working Panel considered that, of the pharmacologic agents that have been evaluated, theophylline, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), ascorbic acid, and prostaglandin E deserve further evaluation.
PubMed: 31214451
DOI: 10.3233/PIC-14090 -
Clinical Journal of the American... Oct 2021AKI is a common complication after pediatric cardiac surgery and has been associated with higher morbidity and mortality. We aimed to compare the efficacy of available... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
AKI is a common complication after pediatric cardiac surgery and has been associated with higher morbidity and mortality. We aimed to compare the efficacy of available pharmacologic and nonpharmacologic strategies to prevent AKI after pediatric cardiac surgery.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
PubMed/MEDLINE, Embase, Cochrane Controlled Trials Register, and reference lists of relevant articles were searched for randomized controlled trials from inception until August 2020. Random effects traditional pairwise, Bayesian network meta-analyses, and trial sequential analyses were performed.
RESULTS
Twenty randomized controlled trials including 2339 patients and 11 preventive strategies met the eligibility criteria. No overall significant differences were observed compared with control for corticosteroids, fenoldopam, hydroxyethyl starch, or remote ischemic preconditioning in traditional pairwise meta-analysis. In contrast, trial sequential analysis suggested a 80% relative risk reduction with dexmedetomidine and evidence of <57% relative risk reduction with remote ischemic preconditioning. Nonetheless, the network meta-analysis was unable to demonstrate any significant differences among the examined treatments, including also acetaminophen, aminophylline, levosimendan, milrinone, and normothermic cardiopulmonary bypass. Surface under the cumulative ranking curve probabilities showed that milrinone (76%) was most likely to result in the lowest risk of AKI, followed by dexmedetomidine (70%), levosimendan (70%), aminophylline (59%), normothermic cardiopulmonary bypass (57%), and remote ischemic preconditioning (55%), although all showing important overlap.
CONCLUSIONS
Current evidence from randomized controlled trials does not support the efficacy of most strategies to prevent AKI in the pediatric population, apart from limited evidence for dexmedetomidine and remote ischemic preconditioning.
Topics: Acute Kidney Injury; Adrenergic alpha-2 Receptor Agonists; Age Factors; Bayes Theorem; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child, Preschool; Dexmedetomidine; Female; Humans; Infant; Infant, Newborn; Ischemic Preconditioning; Male; Network Meta-Analysis; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome
PubMed: 34620647
DOI: 10.2215/CJN.05800421 -
Journal of Chromatography. B,... Aug 2021Fenoldopam is an approved drug used to treat hypotension. The purpose of this study is to develop and validate an LC-MS method to quantify fenoldopam and its major...
Fenoldopam is an approved drug used to treat hypotension. The purpose of this study is to develop and validate an LC-MS method to quantify fenoldopam and its major metabolites fenoldopam-glucuronide and fenoldopam-sulfate in plasma and apply the method to a pharmacokinetic study in rats. A Waters C column was used with 0.1% formic acid in acetonitrile and 0.1% formic acid in water as the mobile phases to elute the analytes. A positive-negative switching method was performed in a triple quadrupole mass spectrometer using Multiple Reaction Monitoring (MRM) mode. A one-step protein precipitation using methanol and ethyl acetate was successfully applied for plasma sample preparation. The method was validated following the FDA guidance. The results show that the LLOQ of fenoldopam, fenoldopam-glucuronide and fenoldopam-sulfate is 0.98, 9.75 and 0.98 nM, respectively. The intraday and interday variance is less than 8.4% and the accuracy is between 82.5 and 116.0 %. The extraction recovery for these three analytes ranged from 81.3 ± 4.1% to 113.9 ± 13.2%. There was no significant matrix effect and no significant degradation under the experimental conditions. PK studies showed that fenoldopam was rapidly eliminated (t = 0.63 ± 0.24 h) from the plasma and glucuronide is the major metabolite. This method was suitably selective and sensitive for pharmacokinetic and phase II metabolism studies.
Topics: Animals; Chromatography, Liquid; Female; Fenoldopam; Glucuronides; Limit of Detection; Linear Models; Male; Mice, Inbred C57BL; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Reproducibility of Results; Sulfates; Tandem Mass Spectrometry; Mice
PubMed: 34242859
DOI: 10.1016/j.jchromb.2021.122854