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Gaceta Medica de Mexico 2021Estrogens that are used as contraceptives or in replacement therapy are associated with an increase in the risk for developing thrombosis, mainly during the first year...
BACKGROUND
Estrogens that are used as contraceptives or in replacement therapy are associated with an increase in the risk for developing thrombosis, mainly during the first year of treatment and in women with associated risk factors.
OBJECTIVE
To synthesize, characterize and identify the anticoagulant, antiplatelet aggregation and microvesicle-reducing effect of the new aminoestrogen Tyrame.
MATERIAL AND METHODS
CD1 strain mice were used, which had Tyrame (0, 1 and 2 mg/100 g) subcutaneously administered. At 24 h, a blood sample was obtained to determine whole-blood clotting time, microvesicles concentration and inhibitory effect on platelet aggregation.
RESULTS
Blood clotting time increased up to 1.5 times in comparison with the control. Platelet aggregation inhibition had different magnitude depending on the agonist agent employed, and was complete with collagen. Both effects had a dose-dependent relationship. The microvesicles decreased up to six times with respect to the control.
CONCLUSIONS
Tyrame reduces platelet aggregation and microvesicle formation, which emphasizes its potential therapeutic utility as an estrogen free of thrombotic effects.
Topics: Animals; Anticoagulants; Fibrinolytic Agents; Mice; Phenethylamines; Platelet Aggregation; Thrombosis
PubMed: 35108248
DOI: 10.24875/GMM.M21000621 -
JACC. Clinical Electrophysiology May 2021The study's goal was to compare the efficacy and safety of dofetilide (DOF) versus amiodarone (AMIO) in patients with atrial fibrillation (AF).
OBJECTIVES
The study's goal was to compare the efficacy and safety of dofetilide (DOF) versus amiodarone (AMIO) in patients with atrial fibrillation (AF).
BACKGROUND
Comparative efficacy of DOF versus AMIO in patients with AF has not been well established. In addition, proarrhythmia has been a concern with DOF therapy.
METHODS
Rhythm control was attempted by using DOF in 657 consecutive patients (mean age 72 ± 9 years; 35% women) with AF (n = 528) or atrial flutter and AF (n = 129) between January 2014 and December 2018.
RESULTS
DOF was successfully initiated in 573 (87%) of 657 patients, including 510 (89%) with persistent AF and 63 (11%) with paroxysmal AF. During a mean follow-up of 19 ± 7 months, sinus rhythm was maintained in 361 (63%) of the 573 DOF-treated patients. At 12 months, patients on DOF had a similar likelihood of experiencing recurrent atrial arrhythmias compared with the 2,476 consecutive patients treated with AMIO for rhythm control during the study period (37% vs. 39%; p = 0.56). The efficacy of DOF and AMIO was also similar in specific subgroups of patients, including patients >75 years of age, with a low left ventricular ejection fraction, obesity, renal insufficiency, and prior catheter ablation for AF. Among patients with atypical atrial flutter, likelihood of recurrent atrial flutter was similar between the DOF (43 of 108 [40%]) and AMIO (211 of 555 [38%]; p = 0.69) groups.
CONCLUSIONS
When properly initiated and monitored, DOF has efficacy comparable to that of amiodarone for rhythm control in patients with AF.
Topics: Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Phenethylamines; Stroke Volume; Sulfonamides; Ventricular Function, Left
PubMed: 33812835
DOI: 10.1016/j.jacep.2020.11.027 -
Journal of Animal Science Aug 2022Beta-adrenergic agonists (β-AAs) are widely used supplements in beef and pork production to improve feed efficiency and increase lean muscle mass, yet little is known...
Beta-adrenergic agonists (β-AAs) are widely used supplements in beef and pork production to improve feed efficiency and increase lean muscle mass, yet little is known about the molecular mechanism by which β-AAs achieve this outcome. Our objective was to identify the influence of ractopamine HCl and zilpaterol HCl on mitochondrial respiratory activity in muscle satellite cells isolated from crossbred beef steers (N = 5), crossbred barrows (N = 2), Yorkshire-cross gilts (N = 3), and commercial weather lambs (N = 5). Real-time measurements of oxygen consumption rates (OCRs) were recorded using extracellular flux analyses with a Seahorse XFe24 analyzer. After basal OCR measurements were recorded, zilpaterol HCl, ractopamine HCl, or no β-AA was injected into the assay plate in three technical replicates for each cell isolate. Then, oligomycin, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, and rotenone were injected into the assay plate sequentially, each inducing a different cellular state. This allowed for the measurement of OCR at these states and for the calculation of the following measures of mitochondrial function: basal respiration, non-mitochondrial respiration, maximal respiration, proton leak, adenosine triphosphate (ATP)-linked respiration, and spare respiratory capacity. Incubation of bovine cells with either zilpaterol HCl or ractopamine HCl increased maximal respiration (P = 0.046) and spare respiratory capacity (P = 0.035) compared with non-supplemented counterparts. No difference (P > 0.05) was observed between zilpaterol HCl and ractopamine HCl for maximal respiration and spare respiratory capacity in bovine cell isolates. No measures of mitochondrial function (basal respiration, non-mitochondrial respiration, maximal respiration, proton leak, ATP-linked respiration, and spare respiratory capacity) were altered by β-AA treatment in ovine or porcine cells. These findings indicate that β-AAs in cattle may improve the efficiency of oxidative metabolism in muscle satellite cells by modifying mitochondrial respiratory activity. The lack of response by ovine and porcine cells to β-AA incubation also demonstrates differing physiological responses to β-AA across species, which helps to explain the variation in its effectiveness as a growth supplement.
Topics: Adenosine Triphosphate; Adrenergic beta-Agonists; Animals; Cattle; Female; Myoblasts; Oxidative Phosphorylation; Phenethylamines; Protons; Sheep; Sheep, Domestic; Swine
PubMed: 35908785
DOI: 10.1093/jas/skac208 -
Epilepsy & Behavior : E&B Jan 2023To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome... (Randomized Controlled Trial)
Randomized Controlled Trial
Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (<5 years) with Dravet syndrome: A critical period for early neurodevelopment.
OBJECTIVE
To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome (DS).
METHODS
Children with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive Function®-Preschool (BRIEF®-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI ≥ 90% and RCI ≥ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEF®-P indexes/composite T-scores were evaluated using Somers'd; pairwise comparisons were calculated by 2-sided Fisher's Exact tests (p ≤ 0.05) and Cramér's V.
RESULTS
Data were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T ≥ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in ∼33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI ≥ 90% certainty) in at least one BRIEF®-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (≥50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEF®-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05).
SIGNIFICANCE
In this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14-15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment.
Topics: Child; Child, Preschool; Humans; Epilepsies, Myoclonic; Executive Function; Fenfluramine; Parents; Seizures
PubMed: 36463826
DOI: 10.1016/j.yebeh.2022.108994 -
Human Psychopharmacology Jan 2020The number of novel psychedelic phenethylamines and tryptamines has continued to increase, but little academic research has focused on the effects of these substances....
OBJECTIVE
The number of novel psychedelic phenethylamines and tryptamines has continued to increase, but little academic research has focused on the effects of these substances. We sought to determine and compare the subjective effects of various substances.
METHODS
We conducted in-depth interviews with 39 adults (75.4% male and 87.2% White) who reported experience using psychedelic phenethylamines and/or tryptamines. Participants described the effects of compounds they have used. We examined the subjective drug effects in a qualitative descriptive manner.
RESULTS
Participants reported on the use of 36 compounds. The majority (64.1%) reported the use of 2C series drugs, with 2C-B use being most prevalent; 38.5% reported the use of NBOMe, and 25.6% reported the use of DOx. With regard to tryptamines, 46.2% reported use, and 4-AcO-DMT was the most prevalent drug used in this class. 2C-B was often described as being more favorable than other 2C series compounds with the effects described as being comparable with MDMA and LSD. NBOMe effects were generally described in an unfavorable manner, and the effects of DOx were often described as lasting too long (12-36 hr). The effects of 4-AcO-DMT were often described as mimicking psilocybin.
CONCLUSION
Knowing the effects of various compounds can inform education, prevention, and harm reduction efforts regarding the use of these drugs.
Topics: Adolescent; Adult; Drug Users; Female; Hallucinogens; Humans; Male; Phenethylamines; Qualitative Research; Self Report; Tryptamines; Young Adult
PubMed: 31909513
DOI: 10.1002/hup.2719 -
Journal of Neurovirology Feb 2022Macrophages are key elements of the innate immune system. Their HIV-1 infection is a complex process that involves multiple interacting factors and various steps and is...
Macrophages are key elements of the innate immune system. Their HIV-1 infection is a complex process that involves multiple interacting factors and various steps and is further altered by exposure of infected cells to methamphetamine (Meth), a common drug of abuse in people living with HIV. This is reflected by dynamic changes in the intracellular and secreted proteomes of these cells. Quantification of these changes poses a challenge for experimental design and associated analytics. In this study, we measured the effect of Meth on expression of intracellular and secreted galectins-1, -3, and -9 in HIV-1 infected human monocyte-derived macrophages (hMDM) using SWATH-MS, which was further followed by MRM targeted mass spectrometry validation. Cells were exposed to Meth either prior to or after infection. Our results are the first to perform comprehensive quantifications of galectins in primary hMDM cells during HIV-1 infection and Meth exposure a building foundation for future studies on the molecular mechanisms underlying cellular pathology of hMDM resulting from viral infection and a drug of abuse-Meth.
Topics: HIV Infections; HIV Seropositivity; HIV-1; Humans; Macrophages; Methamphetamine
PubMed: 35175539
DOI: 10.1007/s13365-021-01025-4 -
Molecules (Basel, Switzerland) Oct 2020New developments in the synthesis, resolution, and synthetic applications of chiral 1-phenylethylamine (α-PEA) reported in the last decade have been reviewed. In... (Review)
Review
New developments in the synthesis, resolution, and synthetic applications of chiral 1-phenylethylamine (α-PEA) reported in the last decade have been reviewed. In particular, improvements in the synthesis of α-PEA and its derivatives and chiral resolution, as well as their applications in the resolution of other compounds, were discussed. α-PEA was used as a chiral auxiliary in the diastereoselective synthesis of medicinal substances and natural products. Chiral ligands with α-PEA moieties were applied in asymmetric reactions, and effective modular chiral organocatalysts were constructed with α-PEA fragments and used in important synthetic reactions.
Topics: Chemistry Techniques, Synthetic; Phenethylamines; Stereoisomerism
PubMed: 33114098
DOI: 10.3390/molecules25214907 -
Biological Psychiatry. Cognitive... Sep 2022Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity as measured by resting-state functional magnetic resonance...
BACKGROUND
Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity as measured by resting-state functional magnetic resonance imaging. Specifically, thalamic intrinsic functional connectivity is increased with sensorimotor cortices (hyperconnectivity) and decreased with prefrontal limbic cortices (hypoconnectivity). Psychedelics such as lysergic acid diethlyamide (LSD) elicit similar thalamocortical hyperconnectivity with sensorimotor areas in healthy volunteers. It is unclear whether LSD also induces thalamocortical hypoconnectivity with prefrontal limbic cortices, because current findings are equivocal. Thalamocortical hyperconnectivity was associated with psychotic symptoms in patients and substance-induced altered states of consciousness in healthy volunteers. Thalamocortical dysconnectivity is likely evoked by altered neurotransmission, e.g., via dopaminergic excess in psychotic disorders and serotonergic agonism in psychedelic-induced states. It is unclear whether thalamocortical dysconnectivity is also elicited by amphetamine-type substances, broadly releasing monoamines (i.e., dopamine, norepinephrine) but producing fewer perceptual effects than psychedelics.
METHODS
We administrated LSD, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers and investigated their effects on thalamic intrinsic functional connectivity with 2 brain networks (auditory-sensorimotor and salience networks, corresponding to sensorimotor and prefrontal limbic cortices, respectively), using a double-blind, placebo-controlled, crossover design.
RESULTS
All active substances elicited auditory-sensorimotor-thalamic hyperconnectivity compared with placebo, despite predominantly distinct pharmacological actions and subjective effects. LSD-induced effects correlated with subjective changes in perception, indicating a link between hyperconnectivity and psychedelic-type perceptual alterations. Unlike d-amphetamine and MDMA, which induced hypoconnectivity with the salience network, LSD elicited hyperconnectivity. D-amphetamine and MDMA evoked similar thalamocortical dysconnectivity patterns.
CONCLUSIONS
Psychedelics, empathogens, and psychostimulants evoke thalamocortical hyperconnectivity with sensorimotor areas, akin to findings in patients with psychotic disorders.
Topics: Cross-Over Studies; Dextroamphetamine; Double-Blind Method; Hallucinogens; Humans; Lysergic Acid; Lysergic Acid Diethylamide; N-Methyl-3,4-methylenedioxyamphetamine
PubMed: 35500840
DOI: 10.1016/j.bpsc.2022.04.003 -
Molecules (Basel, Switzerland) Oct 2023The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human...
Development of an HPLC-MS/MS Method for Chiral Separation and Quantitation of ()- and ()-Salbutamol and Their Sulfoconjugated Metabolites in Urine to Investigate Stereoselective Sulfonation.
The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human urine to allow for bioanalytical quantitation of the targeted analytes and investigations of stereoselectivity in the sulfonation pathway of human phase Ⅱ metabolism. For analytical method development, a systematic screening of columns and mobile phases to develop a separation via enantiomerically selective high performance liquid chromatography was performed. Electrospray ionization settings were optimized via multiple-step screening and a full factorial design-of-experiment. Both approaches were performed matrix-assisted and the predicted values were compared. The full factorial design was superior in terms of prediction power and knowledge generation. Performing a longitudinal excretion study in one healthy volunteer allowed for the calculation of excretion rates for all four targeted analytes. For this proof-of-concept, either racemic salbutamol or enantiopure levosalbutamol was administered perorally or via inhalation, respectively. A strong preference for sulfonation of ()-salbutamol for inhalation and peroral application was found in experiments. In previous studies phenol sulfotransferase 1A3 was described to be mainly responsible for salbutamol sulfonation in humans. Thus, in vitro and in silico investigations of the stereoselectivity of sulfotransferase 1A3 complemented the study and confirmed these findings.
Topics: Humans; Albuterol; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Levalbuterol; Administration, Inhalation; Stereoisomerism
PubMed: 37894685
DOI: 10.3390/molecules28207206 -
Journal of the American Chemical Society May 2017The rate of hydrogen-deuterium exchange (HDX) in aqueous droplets of phenethylamine has been determined with submillisecond temporal resolution by mass spectrometry...
The rate of hydrogen-deuterium exchange (HDX) in aqueous droplets of phenethylamine has been determined with submillisecond temporal resolution by mass spectrometry using nanoelectrospray ionization with a theta-capillary. The average speed of the microdroplets is measured using microparticle image velocimetry. The droplet travel time is varied from 20 to 320 μs by changing the distance between the emitter and the heated inlet to the mass spectrometer and the voltage applied to the emitter source. The droplets were found to accelerate by ∼30% during their observable travel time. Our droplet imaging shows that the theta-capillary produces two Taylor cone-jets (one per channel), causing mixing to take place from droplet fusion in the Taylor spray zone. Phenethylamine (ϕCHCHNH) was chosen to study because it has only one functional group (-NH) that undergoes rapid HDX. We model the HDX with a system of ordinary differential equations. The rate constant for the formation of -NHD from -NH is 3660 ± 290 s, and the rate constant for the formation of -NHD from -NHD is 3330 ± 270 s. The observed rates are about 3 times faster than what has been reported for rapidly exchangeable peptide side-chain groups in bulk measurements using stopped-flow kinetics and NMR spectroscopy. We also applied this technique to determine the HDX rates for a small 10-residue peptide, angiotensin I, in aqueous droplets, from which we found a 7-fold acceleration of HDX in the droplet compared to that in bulk solution.
Topics: Deuterium Exchange Measurement; Nanotechnology; Particle Size; Phenethylamines; Spectrometry, Mass, Electrospray Ionization; Water
PubMed: 28481522
DOI: 10.1021/jacs.7b03541