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Trials Jul 2024Norepinephrine and phenylephrine are commonly used vasoactive drugs to treat hypotension during the perioperative period. The increased release of endogenous...
Effect of norepinephrine and phenylephrine on prothrombotic response in patients undergoing cesarean section under spinal anesthesia: protocol for a randomized, double-blind, controlled study.
BACKGROUND
Norepinephrine and phenylephrine are commonly used vasoactive drugs to treat hypotension during the perioperative period. The increased release of endogenous norepinephrine elicits prothrombotic changes, while parturients are generally in a hypercoagulable state. Therefore, this trial aims to investigate whether there is a disparity between equivalent doses of prophylactic norepinephrine infusion and phenylephrine infusion on prothrombotic response in patients undergoing cesarean section under spinal anesthesia.
METHODS
Sixty-six eligible parturients will be recruited for this trial and randomly assigned to the norepinephrine or phenylephrine group. The "study drug" will be administered at a rate of 15 ml/h starting from the intrathecal injection. The primary outcome are plasma coagulation factor VIII activity (FVIII: C), fibrinogen, and D-dimer levels. The secondary outcomes include hemodynamic variables and umbilical artery blood pH value.
DISCUSSION
Our study is the first trial comparing the effect of norepinephrine and phenylephrine on prothrombotic response in patients undergoing cesarean section under spinal anesthesia. Positive or negative results will all help us better understand the impact of vasoactive drugs on patients. If there are any differences, this trial will provide new evidence for maternal choice of vasoactive medications in the perioperative period.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR2300077164. Registered on 1 November 2023. https://www.chictr.org.cn/ .
Topics: Humans; Cesarean Section; Anesthesia, Spinal; Female; Norepinephrine; Double-Blind Method; Pregnancy; Phenylephrine; Vasoconstrictor Agents; Randomized Controlled Trials as Topic; Anesthesia, Obstetrical; Adult; Fibrin Fibrinogen Degradation Products; Factor VIII; Treatment Outcome; Blood Coagulation; Hemodynamics
PubMed: 38956697
DOI: 10.1186/s13063-024-08255-x -
The Journal of Organic Chemistry Jul 2024The stereoselective synthesis of -diaminopimelic acid (-DAP), the key cross-linking amino acid of the peptidoglycan cell wall layer in Gram-negative bacteria, and its...
The stereoselective synthesis of -diaminopimelic acid (-DAP), the key cross-linking amino acid of the peptidoglycan cell wall layer in Gram-negative bacteria, and its biological precursor, l,l-DAP, is described. The key step involved stereoselective reduction of a common enone-derived amino acid by substrate- or reagent-based control. Overman rearrangement of the resulting allylic alcohols, concurrent alkene hydrogenation and trichloroacetamide reduction, and subsequent ruthenium-catalyzed arene oxidation completed the synthesis of each stereoisomer. The synthetic utility of this approach was demonstrated with the efficient preparation of an l,l-DAP-derived dipeptide.
PubMed: 38955772
DOI: 10.1021/acs.joc.4c00916 -
Chemistry, An Asian Journal Jul 2024Asymmetric synthesis of chiral chemicals in high enantiomeric excess (ee) is pivotal to the pharmaceutical industry, but classic chemistry usually requires multi-step...
Asymmetric synthesis of chiral chemicals in high enantiomeric excess (ee) is pivotal to the pharmaceutical industry, but classic chemistry usually requires multi-step reactions, harsh conditions, and expensive chiral ligands, and sometimes suffers from unsatisfactory enantioselectivity. Enzymatic catalysis is a much greener and more enantioselective alternative, and cascade biotransformations with multi-step reactions can be performed in one pot to avoid costly intermediate isolation and minimise waste generation. One of the most attractive applications of enzymatic cascade transformations is to convert easily available simple racemic substrates into valuable functionalised chiral chemicals in high yields and ee. Here, we review the three general strategies to build up such cascade biotransformations, including enantioconvergent reaction, dynamic kinetic resolution, and destruction-and-reinstallation of chirality. Examples of cascade transformations using racemic substrates such as racemic epoxides, alcohols, hydroxy acids, etc. to produce the chiral amino alcohols, hydroxy acids, amines and amino acids are given. The product concentration, ee, and yield, scalability, and substrate scope of these enzymatic cascades are critically reviewed. To further improve the efficiency and practical applicability of the cascades, enzyme engineering to enhance catalytic activities of the key enzymes using the latest microfluidics-based ultrahigh-throughput screening and artificial intelligence-guided directed evolution could be useful approaches.
PubMed: 38954385
DOI: 10.1002/asia.202400565 -
Indian Journal of Ophthalmology Jul 2024
Topics: Humans; Intravitreal Injections; Administration, Oral; Central Serous Chorioretinopathy; Rifampin; Vascular Endothelial Growth Factor A; Propranolol; Angiogenesis Inhibitors; Adrenergic beta-Antagonists
PubMed: 38953136
DOI: 10.4103/IJO.IJO_3022_23 -
Communications Biology Jun 2024Acute immune responses with excess production of cytokines, lipid/chemical mediators, or coagulation factors, often result in lethal damage. In addition, the innate...
Acute immune responses with excess production of cytokines, lipid/chemical mediators, or coagulation factors, often result in lethal damage. In addition, the innate immune system utilizes multiple types of receptors that recognize neurotransmitters as well as pathogen-associated molecular patterns, making immune responses complex and clinically unpredictable. We here report an innate immune and adrenergic link inducing lethal levels of platelet-activating factor. Injecting mice with toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS), cell wall N-glycans of Candida albicans, and the α-adrenergic receptor (α-AR) agonist medetomidine induces lethal damage. Knocking out the C-type lectin Dectin-2 prevents the lethal damage. In spleen, large amounts of platelet-activating factor (PAF) are detected, and knocking out lysophospholipid acyltransferase 9 (LPLAT9/LPCAT2), which encodes an enzyme that converts inactive lyso-PAF to active PAF, protects mice from the lethal damage. These results reveal a linkage/crosstalk between the nervous and the immune system, possibly inducing lethal levels of PAF.
Topics: Animals; Platelet Activating Factor; Mice; Mice, Knockout; Mice, Inbred C57BL; Lipopolysaccharides; Candida albicans; Immunity, Innate; Male; 1-Acylglycerophosphocholine O-Acyltransferase; Toll-Like Receptor 4; Adrenergic alpha-2 Receptor Agonists
PubMed: 38951147
DOI: 10.1038/s42003-024-06498-7 -
Obstetrics and Gynecology Jul 2024To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
OBJECTIVE
To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial.
METHODS
We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding.
RESULTS
Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine.
CONCLUSION
No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT02299414.
Topics: Humans; Pregnancy; Female; Labetalol; Nifedipine; Antihypertensive Agents; Adult; Pregnancy Outcome; Hypertension; Infant, Newborn; Pregnancy Complications, Cardiovascular; Hypertension, Pregnancy-Induced; Administration, Oral; Infant, Small for Gestational Age; Pre-Eclampsia; Chronic Disease
PubMed: 38949541
DOI: 10.1097/AOG.0000000000005613 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To explore the effect and safety of calcium dibutyryl adenosine cyclophosphate (dbcAMP-Ca) combined with metoprolol in the treatment of older adults with heart failure... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To explore the effect and safety of calcium dibutyryl adenosine cyclophosphate (dbcAMP-Ca) combined with metoprolol in the treatment of older adults with heart failure combined with arrhythmia.
METHODS
A total of 102 elderly patients with heart failure combined with arrhythmia were enrolled in our hospital between February 2021 and April 2023. The list of patients enrolled was entered into a random database by independent staffs not involved in the study and random assignment sequences were generated by the SAS9.4 software. Then, the 102 elderly patients were divided into a control group ( =51) and an experimental group ( =51). Patients in the control group were given metoprolol at an initial dose of 6.25 mg/d, which was gradually increased to the target dose of 25 mg/d. Patients in the experimental group were given 40 mg of dbcAMP-Ca once a day via intravenous drip in addition to the treatment given to the control group. Both groups were treated for 4 weeks. The rate of effective response to clinical treatment (the number of cases achieving significant effects and those achieving some effects divided by the total number of cases in the group) was defined as the main outcome index. Secondary indexes included cardiac function, heart rate variability, exercise ability, hemorheology, myocardial injury indexes, inflammatory indexes, and the occurrence of adverse reactions.
RESULTS
The rate of effective response to clinical treatment was higher in the experimental group than that in the control group (94.12% [48/51] vs. 78.43% [40/51], <0.05). After treatment, the left ventricular end-diastolic and end-systolic dimensions (LVEDD and LVESD) and the interventricular septal thickness (IVS) were lower in the experimental group than those in the control group, while the left ventricular ejection fraction (LVEF) and the stroke volume (SV) were higher in the experimental group than those in the control group ( <0.05). In terms of heart rate variability after treatment, the standard deviation of all the normal-to-normal intervals/the average of all the normal-to-normal intervals (SDNN/SDANN), the percentage of NN50 in the total number of normal-to-normal intervals (PNN50%), and the root mean square of the differences between adjacent normal-to-normal intervals/root mean square differences of successive R-R intervals (RMSSD) were higher in the experimental group than those in the control group ( <0.05). In terms of exercise capacity after treatment, the subjects in the experimental group covered more distance in the 6-min walk test than those in the control group did ( <0.05). In terms of the hemorheology indexes after treatment, the levels of platelet aggregation rate (PAgT), fibrinogen (FIB), erythrocyte sedimentation rate (ESR), and whole blood viscosity (ηb) were lower in the experimental group than those in the control group ( <0.05). In terms of the myocardial injury indexes after treatment, the levels of serum N-terminal pro-brain natriuretic peptide (NT-pro BNP) and cardiac troponin I (cTnI) were lower in the experimental group than those in the control group, while the levels of insulin-like growth factor 1 (IGF-1) and cardiotrophin 1 (CT-1) were higher in the experimental group than those in the control group ( <0.05). In terms of the inflammatory indexes after treatment, the levels of interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP), and tumor necrosis factor-α (TNF-α) were lower in the experimental group than those in the control group ( <0.05). The incidence of adverse reactions in the experimental group (9.80%) and that in the control group (7.84%) were comparable ( >0.05).
CONCLUSION
The use of dbcAMP-Ca in addition to metoprolol can effectively improve cardiac function, heart rate variability, and exercise tolerance, while inhibiting inflammatory response in elderly patients with heart failure combined with arrhythmia, with high medication safety. The combination medication shows better safety and therapeutic effects than those of metoprolol used alone.
Topics: Humans; Aged; Heart Failure; Male; Female; Arrhythmias, Cardiac; Metoprolol; Drug Therapy, Combination; Adenosine; Heart Rate
PubMed: 38948272
DOI: 10.12182/20240560209 -
Drug Design, Development and Therapy 2024Fluid loading improves hemodynamic stability and reduces the incidence rate of post-spinal anesthesia hypotension when prophylactic vasopressors are administered. We... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
Up-and-Down Determination of Different Crystalloid Coload Volumes on the ED 90 of Prophylactic Norepinephrine Infusion for Preventing Postspinal Anesthesia Hypotension During Cesarean Section.
BACKGROUND
Fluid loading improves hemodynamic stability and reduces the incidence rate of post-spinal anesthesia hypotension when prophylactic vasopressors are administered. We investigated the impact of different crystalloid coload volumes on the 90% effective dose (ED) of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension in non-hypertensive patients undergoing cesarean section.
METHODS
Patients were randomly allocated to receive one of the different crystalloid coload volumes (0mL/kg [0mL/kg Group], 5mL kg [5mL/kg Group], and 10mL kg [10mL/kg Group]) in combination with prophylactic norepinephrine infusion immediately after the induction of spinal anesthesia. The prophylactic norepinephrine infusion doses were determined using the up-and-down sequential allocation methodology, with an initial dose of 0.025 μg/kg/min and a gradient of 0.005 μg/kg/min. The primary endpoint was the effective dose at which 90% (ED 90) of patients responded to prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension.
RESULTS
The estimated effective dose of norepinephrine infusion, at which 90% (ED 90) of patients responded, was found to be 0.084 (95% CI, 0.070 to 0.86), 0.074 (95% CI, 0.059 to 0.077), and 0.063 (95% CI, 0.053 to 0.064) μg/kg/min in the three groups, respectively.
CONCLUSION
A crystalloid coload of 5 mL/kg or 10 mL/kg, as opposed to the groups receiving 0 mL/kg crystalloid coloads, resulted in a reduction of approximately 11.9% and 25.0%, respectively, in the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean section.
Topics: Humans; Cesarean Section; Hypotension; Norepinephrine; Female; Adult; Crystalloid Solutions; Anesthesia, Spinal; Pregnancy; Infusions, Intravenous; Dose-Response Relationship, Drug
PubMed: 38947222
DOI: 10.2147/DDDT.S460436 -
Physiological Reports Jul 2024To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography...
To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists. Vessels were pre-contracted with 1 × 10 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT, 5-HT, 5-HT, and 5-HT. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. At 1 × 10 M 5-HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10 M 5-HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5-HT, 5-HT, or 5-HT resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5-HT receptor agonists, the selective 5-HT receptor agonist resulted in the greatest potency (-log EC) value (6.30) compared with 5-HT and 5-HT receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5-HT antagonist (1 × 10 M) for 5-min prior to the phenylephrine pre-contraction and 5-HT additions. Antagonism of the 5-HT receptor attenuated the vasorelaxation caused by 5-HT. Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT activation in bovine peripheral vasculature.
Topics: Animals; Cattle; Vasodilation; Saphenous Vein; Serotonin; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Phenylephrine; Serotonin Receptor Agonists; Male
PubMed: 38946059
DOI: 10.14814/phy2.16128 -
Journal of Nutritional Science and... 2024Oleuropein aglycone (OA), which is the absorbed form of oleuropein, is a major phenolic compound in extra virgin olive oil. We analyzed the anti-obesity effect of OA...
Oleuropein aglycone (OA), which is the absorbed form of oleuropein, is a major phenolic compound in extra virgin olive oil. We analyzed the anti-obesity effect of OA intake combined with mild treadmill walking (MTW, 4 m/min for 20 min/d, 5-6 d/wk, without electric shocks and slope) in rats under a high-fat diet (HF). Four-week-old male Sprague-Dawley rats (n=28) were equally divided into four groups: control (HF), 0.08% oleuropein-supplemented HF (HFO), HF with MTW (HF+W), and HFO with MTW (HFO+W) groups. After 28 d, the inguinal subcutaneous fat content and weight gain were significantly lower in the HFO+W group than in the control group. The HFO+W group also had significantly higher levels of urinary noradrenaline secretion, interscapular brown adipose tissue, uncoupling protein 1, brain transient receptor potential ankyrin subtype 1 (TRPA1), vanilloid subtype 1 (TRPV1), and brain-derived neurotrophic factor (BDNF) than the control group. Especially, the HFO+W group showed a synergistic effect on noradrenaline secretion. Therefore, OA combined with MTW may accelerate the enhancement of UCP1 and BDNF levels in rats with HF-induced obesity by increasing noradrenaline secretion after TRPA1 and TRPV1 activation.
Topics: Animals; Male; Uncoupling Protein 1; Iridoid Glucosides; Rats, Sprague-Dawley; Obesity; Adipose Tissue, Brown; Iridoids; Norepinephrine; Diet, High-Fat; TRPA1 Cation Channel; Brain-Derived Neurotrophic Factor; Rats; Anti-Obesity Agents; Walking; Weight Gain; Physical Conditioning, Animal; TRPV Cation Channels
PubMed: 38945884
DOI: 10.3177/jnsv.70.193