Pressure Dependence of the Crystallization Rate for the S-Enantiomer and a Racemic Mixture of Ibuprofen.
Ontology highlight
ABSTRACT:
SUBMITTER: Koperwas K
PROVIDER: S-EPMC8641391 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:AimsRacemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model.MethodsWe prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24-30] weeks, median body weight 0.83 [0.45-1.59] kg, median postnatal age [PNA] 3 [1-12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen.ResultsWe found that S-ibuprofen clearance (CLS , 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen.ConclusionS-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CLS during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.
| S-EPMC7495289 | biostudies-literature
Project description:Three-phase crystallization (TPC) was introduced in this study to purify L-menthol from menthol enantiomer mixtures in consideration of the formation of solid solutions. TPC is a new separation technology, which combines melt crystallization and vaporization to result in the desired crystalline product from a liquid mixture along with the unwanted components vaporized via the three-phase transformation by reducing temperature and pressure. The three-phase transformation conditions for the liquid menthol enantiomer mixtures were determined based on the thermodynamic calculations to direct the TPC experiments. A new model was proposed based on the mass and energy balances in consideration of the formation of the solid solutions to predict the yield and purity of the final L-menthol product during TPC. The yield and purity obtained from the TPC experiments were compared with those predicted by the model.
| S-EPMC10573351 | biostudies-literature
Project description:It is qualitatively well known that kinetics related to nucleation and growth can shift apparent phase boundaries from their equilibrium value. In this work, we have measured this effect in Bi using time-resolved X-ray diffraction with unprecedented 0.25 ms time resolution, accurately determining phase transition pressures at compression rates spanning five orders of magnitude (10-2-103 GPa/s) using the dynamic diamond anvil cell. An over-pressurization of the Bi-III/Bi-V phase boundary is observed at fast compression rates for different sample types and stress states, and the largest over-pressurization that is observed is ΔP = 2.5 GPa. The work presented here paves the way for future studies of transition kinetics at previously inaccessible compression rates.
| S-EPMC8295338 | biostudies-literature
Project description:ImportanceChiral switching, a strategy in which drug manufacturers develop a single-enantiomer formulation of a drug to be substituted for a racemic formulation, allows manufacturers to maintain market exclusivity for drugs losing patent protection, even without demonstrating superior efficacy or safety.ObjectiveTo identify and characterize all randomized clinical trials (RCTs) directly comparing a Food and Drug Administration (FDA)-approved single-enantiomer drug against a previously approved racemic drug for 1 or more efficacy or safety end points.Evidence reviewDrugs were identified using the Drugs@FDA database. Randomized clinical trials were identified using Ovid MEDLINE (1949 to October 22, 2019), Ovid Embase (1974 to October 22, 2019), Web of Science Core Collection (all years), ClinicalTrials.gov, and Cochrane Central Registry of Controlled Trials (CENTRAL, Wiley, Issue 8 of 12, October 22, 2019). Trials were characterized as favoring the single-enantiomer or racemic drugs based on whether the primary efficacy, secondary efficacy, and safety end points achieved each study's defined significance level (eg, P < .05). Trials were characterized as favoring neither drug if no statistically significant differences were reported for any end point or if both drugs were found to be superior for 1 or more separate end points.FindingsFifteen FDA-approved single-enantiomer drugs were identified with racemic precursors approved in the US or Europe. For 3 single-enantiomer racemic drug pairs, no RCTs directly comparing the drugs were identified. For the remaining 12 pairs, 185 RCTs comparing efficacy or safety of the drug pairs were identified, 124 (67.0%) of which studied 1 pair (levobupivacaine/bupivacaine). There were 179 RCTs directly comparing drug pairs using efficacy end points, of which 23 (12.8%) favored the single enantiomer based on primary efficacy end point results. There were 124 RCTs directly comparing drug pairs using safety end points, of which 17 (13.7%) favored the single-enantiomer drug. For 9 of the 15 single-enantiomer drugs (60.0%), no RCTs were identified providing evidence of improved efficacy, based on primary end point results, or safety as compared with their racemic precursors.Conclusions and relevanceThe results of this systematic review suggest that most newly marketed FDA-approved single-enantiomer drugs are infrequently directly compared with their racemic precursors, and when compared, they are uncommonly found to provide improved efficacy or safety, despite their greater costs.
| S-EPMC8103227 | biostudies-literature
Project description:Chirality has risen as an attractive topic in materials research in recent years, but the attainment of enantiopure materials remains a major challenge. Herein, we obtained homochiral nanoclusters by a recrystallization strategy, without any chiral factors (i.e., chiral ligands, counterions, etc.). Through the rapid flipping of configuration of silver nanoclusters in solution, the initial racemic Ag40 (triclinic) nanoclusters are converted to homochiral (orthorhombic) as revealed by X-ray crystallography. In the seeded crystallization, one homochiral Ag40 crystal is used as a seed to direct the growth of crystals with specific chirality. Furthermore, enantiopure Ag40 nanoclusters can be used as amplifiers for the detection of chiral carboxylic drugs. This work not only provides chiral conversion and amplification strategies to obtain homochiral nanoclusters but also explains the chirality origin of nanoclusters at the molecular level.
| S-EPMC10258841 | biostudies-literature
Project description:Carvedilol is the current ?-blocker of choice for suppressing ventricular tachyarrhythmia (VT). However, carvedilol's benefits are dose-limited, attributable to its potent ?-blocking activity that can lead to bradycardia and hypotension. The clinically used carvedilol is a racemic mixture of ?-blocking S-carvedilol and non-?-blocking R-carvedilol. We recently reported that novel non-?-blocking carvedilol analogues are effective in suppressing arrhythmogenic Ca(2+) waves and stress-induced VT without causing bradycardia. Thus, the non-?-blocking R-carvedilol enantiomer may also possess this favourable anti-arrhythmic property. To test this possibility, we synthesized R-carvedilol and assessed its effect on Ca(2+) release and VT. Like racemic carvedilol, R-carvedilol directly reduces the open duration of the cardiac ryanodine receptor (RyR2), suppresses spontaneous Ca(2+) oscillations in human embryonic kidney (HEK) 293 cells, Ca(2+) waves in cardiomyocytes in intact hearts and stress-induced VT in mice harbouring a catecholaminergic polymorphic ventricular tachycardia (CPVT)-causing RyR2 mutation. Importantly, R-carvedilol did not significantly alter heart rate or blood pressure. Therefore, the non-?-blocking R-carvedilol enantiomer represents a very promising prophylactic treatment for Ca(2+)- triggered arrhythmia without the bradycardia and hypotension often associated with racemic carvedilol. Systematic clinical assessments of R-carvedilol as a new anti-arrhythmic agent may be warranted.
| S-EPMC4902270 | biostudies-literature
Project description:The value of time-dependent toxicity (TDT) data in predicting mixture toxicity was examined. Single chemical (A and B) and mixture (A+B) toxicity tests using Microtox(®) were conducted with inhibition of bioluminescence (Vibrio fischeri) being quantified after 15, 30 and 45-min of exposure. Single chemical and mixture tests for 25 sham (A1:A2) and 125 true (A:B) combinations had a minimum of seven duplicated concentrations with a duplicated control treatment for each test. Concentration/response (x/y) data were fitted to sigmoid curves using the five-parameter logistic minus one parameter (5PL-1P) function, from which slope, EC25, EC50, EC75, asymmetry, maximum effect, and r(2) values were obtained for each chemical and mixture at each exposure duration. Toxicity data were used to calculate percentage-based TDT values for each individual chemical and mixture of each combination. Predicted TDT values for each mixture were calculated by averaging the TDT values of the individual components and regressed against the observed TDT values obtained in testing, resulting in strong correlations for both sham (r(2)=0.989, n=25) and true mixtures (r(2)=0.944, n=125). Additionally, regression analyses confirmed that observed mixture TDT values calculated for the 50% effect level were somewhat better correlated with predicted mixture TDT values than at the 25 and 75% effect levels. Single chemical and mixture TDT values were classified into five levels in order to discern trends. The results suggested that the ability to predict mixture TDT by averaging the TDT of the single agents was modestly reduced when one agent of the combination had a positive TDT value and the other had a minimal or negative TDT value.
| S-EPMC4280022 | biostudies-literature
Project description:In this paper, preferential enrichment (PE) is described for three pairs of novel amino acid Schiff base Cu(II)/Cu(I) complexes. Single crystal X-ray diffraction indicated that 1-S/R are one-dimensional coordination polymers (CPs) with helical structures, and 2-S/R and 3-S/R are one-dimensional CPs with auxiliary ligands. By tuning the pH, the solvent and second ligands, the 1-S/R, 3-S/R underwent polymorphic transitions, resulting in enantioselective liberation of excess enantiomers into solution, until the deposited crystals were slightly enriched with the opposite enantiomer, thereby successfully exhibiting PE. However, under the effects of Cu(II), the solvent and low pH, 2-S/R did not exhibit PE and resulted in enrichment of racemic compounds, which was attributed to amino acid Schiff base chiral complex mechanisms of PE. The three pairs of Cu complex structures were characterized by UV-vis, MS and X-ray photoelectron spectroscopy (XPS). All chiral properties were studied by circular dichroism (CD) in the solid and liquid.
| S-EPMC9861923 | biostudies-literature
Project description:In an ex vivo rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABAA receptors and autophagy. We now examine whether its enantiomer (ent-AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in ex vivo and in vivo rat OHT models. Ex vivo rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An in vivo ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, ent-AlloP, picrotoxin (a GABAA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and ent-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABAA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). ent-AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and ent-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by ent-AlloP. In an rat in vivo OHT model, single intravitreal ent-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, ent-AlloP was more effective in activating autophagy than AlloP. We conclude that ent-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.
| S-EPMC8966700 | biostudies-literature
Project description:Since Pasteur first successfully separated right-handed and left-handed tartrate crystals in 1848, the understanding of how homochirality is achieved from enantiomeric mixtures has long been incomplete. Here, we report on a chirality dominance effect where organized, three-dimensional homochiral suprastructures of the biomineral calcium carbonate (vaterite) can be induced from a mixed nonracemic amino acid system. Right-handed (counterclockwise) homochiral vaterite helicoids are induced when the amino acid L-Asp is in the majority, whereas left-handed (clockwise) homochiral morphology is induced when D-Asp is in the majority. Unexpectedly, the Asp that incorporates into the homochiral vaterite helicoids maintains the same enantiomer ratio as that of the initial growth solution, thus showing chirality transfer without chirality amplification. Changes in the degree of chirality of the vaterite helicoids are postulated to result from the extent of majority enantiomer assembly on the mineral surface. These mechanistic insights potentially have major implications for high-level advanced materials synthesis.
| S-EPMC6534569 | biostudies-literature