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Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility.

ABSTRACT: A great need exists to develop tocolytic and uterotonic drugs that combat poor, labor-related maternal and fetal outcomes. A widely utilized method to assess novel compounds for their tocolytic and uterotonic efficacy is the isometric organ bath contractility assay. Unfortunately, water-insoluble compounds can be difficult to test using the physiological, buffer-based, organ bath assay. Common methods for overcoming solubility issues include solvent variation, cosolvency, surfactant or complexion use, and emulsification. However, these options for drug delivery or formulation can impact tissue function. Therefore, the goal of this study was to evaluate the ability of common solvents, surfactants, cosolvents, and emulsions to adequately solubilize compounds in the organ bath assay without affecting mouse myometrial contractility. We found that acetone, acetonitrile, and ethanol had the least effect, while dimethylacetamide, ethyl acetate, and isopropanol displayed the greatest inhibition of myometrial contractility based on area under the contractile curve analyses. The minimum concentration of surfactants, cosolvents, and human serum albumin required to solubilize nifedipine, a current tocolytic drug, resulted in extensive bubbling in the organ bath assay, precluding their use. Finally, we report that an oil-in-water base emulsion containing no drug has no statistical effect beyond the control (water), while the drug emulsion yielded the same potency and efficacy as the freely solubilized drug.

SUBMITTER: Hansen CJ

PROVIDER: S-EPMC8782813 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility.

Hansen Christopher J CJ Siricilla Shajila S Boatwright Naoko N Rogers Jackson H JH Kumi Melissa E ME Herington Jennifer J

Reproductive sciences (Thousand Oaks, Calif.) 20210414 2

A great need exists to develop tocolytic and uterotonic drugs that combat poor, labor-related maternal and fetal outcomes. A widely utilized method to assess novel compounds for their tocolytic and uterotonic efficacy is the isometric organ bath contractility assay. Unfortunately, water-insoluble compounds can be difficult to test using the physiological, buffer-based, organ bath assay. Common methods for overcoming solubility issues include solvent variation, cosolvency, surfactant or complexio ...[more]

PMID: 33852137

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Project description:BACKGROUND:In a previous study we found a significant correlation between dystocia and hyponatraemia that developed during labour. The present study examined a possible causal relationship. In vitro studies often use area under the curve (AUC) determined by frequency and force of contractions as a measure of myometrial contractility. However, a phase portrait plot of isometric contraction, obtained by plotting the first derivate of contraction against force of contraction, could indicate that bi-or multiphasic contractions might be less effective compared to the smooth contractions. MATERIAL AND METHODS:Myometrial biopsies were obtained from 17 women undergoing elective caesarean section at term. Each biopsy was divided into 8 strips and mounted isometrically in a force transducer. Seven biopsies were used in the first part of the study when half of the strips were immersed in the hyponatraemic study solution S containing Na+ 120 mmol/L and observed for 1 hour, followed by 1 hour in normonatraemic control solution C containing Na+ 136 mmol/L, then again in S for 1 hour, and finally 1 hour in C. The other half of the strips were studied in reverse order, C-S-C-S. The remaining ten biopsies were included in the second part of the study. Response to increasing doses of oxytocin (OT) in solutions S and C was studied. In the first part of the study we calculated AUC, and created phase portrait plots of two different contractions from the same strip, one smooth and one biphasic. In both parts of the study we registered frequency and force of contractions, and described appearance of the contractions. RESULTS:First part of the study: Mean (median) contractions per hour in C: 8.7 (7.6), in S 14,3 (13). Mean (SD) difference between groups 5.6 (4.2), p = 0.018. Force of contractions in C: 11.8 (10.2) mN, in S: 10.8 (9.2) mN, p = 0.09, AUC increased in S; p = 0.018. Bi-/multiphasic contractions increased from 8% in C to 18% in S, p = 0.001. All changes were reversible in C. Second part of the study: Frequency after OT 1.65 x 10-9 M in C:3.4 (2.9), in S: 3.8 (3.2), difference between groups: p = 0.48. After OT 1.65 x 10-7 M in C: 7.8 (8.9), increase from previous OT administration: p = 0.09, in S: 8.7 (9.0), p = 0.04, difference between groups, p = 0.32. Only at the highest dose of OT dose was there an increase in force of contraction in S, p = 0.05, difference between groups, p = 0.33. Initial response to OT was more frequently bi/multiphasic in S, reaching significance at the highest dose of OT(1.65 x 10-7 M), p = 0.015. when almost all contractions were bi/multiphasic. CONCLUSION:Hyponatraemia reversibly increased frequency of contractions and appearance of bi-or multiphasic contractions, that could reduce myometrial contractility. This could explain the correlation of hyponatraemia and instrumental delivery previously observed. Contractions in the hyponatraemic solution more frequently showed initial multiphasic contractions when OT was added in increasing doses. Longer lasting labours carry the risk both of hyponatraemia and OT administration, and their negative interaction could be significant. Further studies should address this possibility.

Project description:BackgroundDonation after circulatory death (DCD) hearts have to withstand ischemia/reperfusion injury that is partially driven by proinflammatory cytokines and decreases ventricular contractility. We hypothesize that cytokine adsorption during normothermic ex vivo blood perfusion of DCD hearts reduces the cytokine levels and improves ventricular contractility.Methods and resultsPorcine DCD hearts were maintained 4 hours by ex vivo blood perfusion with (DCD-BPCytoS, all groups: N=8) or without (DCD-BP) CytoSorb, followed by 2 hours reperfusion with fresh blood, including left ventricular functional analysis using a balloon catheter. In a control and a DCD group, hearts were evaluated after procurement. We determined lactate and cytokines after ex vivo blood perfusion and the myocardial and left anterior descending artery transcriptome using microarrays after reperfusion. In DCD-BPCytoS, the developed pressure (control: 124±7 mm Hg/s, DCD: 86±4 mm Hg/s, DCD-BP: 69±11 mm Hg/s, DCD-BPCytoS: 112±9 mm Hg/s; P<0.05) and maximal slope of pressure increment (control: 2010±39 mm Hg/s, DCD: 1219±164 mm Hg/s, DCD-BP: 964±163 mm Hg/s, DCD-BPCytoS: 1794±205 mm Hg/s; P<0.05) were higher compared with DCD-BP and DCD hearts. However, contractility decreased later during reperfusion without CytoSorb. After 4 hours, troponin, lactate (45±5% versus 69±9%, P<0.05), IL (interleukin)-1β, -1ra, and -8 were lower in DCD-BPCytoS hearts. In the myocardium of DCD-BPCytoS compared with DCD-BP hearts, inflammatory mediator receptor activity/binding pathways were enriched, and pathways for collagen-containing extracellular matrix and contractile fiber were underrepresented. In the left anterior descending artery of DCD-BPCytoS hearts, serine/threonine/tyrosine kinase activity and wound-healing pathways were enriched, and mitochondrial protein-containing complex and respiratome-associated pathways were underrepresented.ConclusionsCytoSorb during ex vivo blood perfusion enhances the maintenance of DCD hearts and is likely to improve graft function after transplantation.

Dataset Information

Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility.

Publications

Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility.

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