scholarly journals Can an Intermediate Rate of Nitrogen Inversion Affect Drug Efficacy?

Symmetry ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1753
Author(s):  
Raphael R. Steimbach ◽  
Gergely Tihanyi ◽  
Magalie N. E. Géraldy ◽  
Alicja Wzorek ◽  
Aubry K. Miller ◽  
...  

Nitrogen-inversion rates and diffusion coefficients were measured using 1H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availability, hence efficacy, of these compounds if they were utilized as drugs. The postulated intermediate range is based on a capture-volume concept, whereby the nitrogen inversion during the time a ligand takes to pass through a volume surrounding the protein binding site, as calculated by the diffusion rate, determines if it will influence ligand binding to the protein. In the systems examined here, the measured nitrogen-inversion rates and the times required to traverse the capture volume differed by a few orders of magnitude. Potentially more consequential are intermediate nitrogen-inversion rates in epimeric cases—since the energies of the interconverting species are unequal, a heavy bias against the eutomer might occur. The implications of an intermediate nitrogen-inversion rate are significant for in silico drug design, drug efficacy, molecular modeling of drug–protein binding, pharmacokinetics, drug enantiomer evaluation, etc. Due consideration of the process should thus be taken into account for drug development directions and in vitro evaluation.

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S223-S246 ◽  
Author(s):  
C. R. Wira ◽  
H. Rochefort ◽  
E. E. Baulieu

ABSTRACT The definition of a RECEPTOR* in terms of a receptive site, an executive site and a coupling mechanism, is followed by a general consideration of four binding criteria, which include hormone specificity, tissue specificity, high affinity and saturation, essential for distinguishing between specific and nonspecific binding. Experimental approaches are proposed for choosing an experimental system (either organized or soluble) and detecting the presence of protein binding sites. Techniques are then presented for evaluating the specific protein binding sites (receptors) in terms of the four criteria. This is followed by a brief consideration of how receptors may be located in cells and characterized when extracted. Finally various examples of oestrogen, androgen, progestagen, glucocorticoid and mineralocorticoid binding to their respective target tissues are presented, to illustrate how researchers have identified specific corticoid and mineralocorticoid binding in their respective target tissue receptors.


1974 ◽  
Vol 77 (1_Suppl) ◽  
pp. S86
Author(s):  
D. Egert ◽  
W. Jonat ◽  
H. Maass

2014 ◽  
Vol 11 (6) ◽  
pp. 770-777
Author(s):  
Yewei Sun ◽  
Kaiyi Liao ◽  
Sai Li ◽  
Zaijun Zhang ◽  
Pei Yu ◽  
...  

1956 ◽  
Vol 222 (1) ◽  
pp. 373-386
Author(s):  
Helmut R. Gutmann ◽  
John H. Peters ◽  
Jerome G. Burtle
Keyword(s):  

1989 ◽  
Vol 264 (31) ◽  
pp. 18707-18713 ◽  
Author(s):  
K Matsuno ◽  
C C Hui ◽  
S Takiya ◽  
T Suzuki ◽  
K Ueno ◽  
...  

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 401
Author(s):  
Pauline Nogaret ◽  
Fatima El El Garah ◽  
Anne-Béatrice Blanc-Potard

The opportunistic human pathogen Pseudomonas aeruginosa is responsible for a variety of acute infections and is a major cause of mortality in chronically infected cystic fibrosis patients. Due to increased resistance to antibiotics, new therapeutic strategies against P. aeruginosa are urgently needed. In this context, we aimed to develop a simple vertebrate animal model to rapidly assess in vivo drug efficacy against P. aeruginosa. Zebrafish are increasingly considered for modeling human infections caused by bacterial pathogens, which are commonly microinjected in embryos. In the present study, we established a novel protocol for zebrafish infection by P. aeruginosa based on bath immersion in 96-well plates of tail-injured embryos. The immersion method, followed by a 48-hour survey of embryo viability, was first validated to assess the virulence of P. aeruginosa wild-type PAO1 and a known attenuated mutant. We then validated its relevance for antipseudomonal drug testing by first using a clinically used antibiotic, ciprofloxacin. Secondly, we used a novel quorum sensing (QS) inhibitory molecule, N-(2-pyrimidyl)butanamide (C11), the activity of which had been validated in vitro but not previously tested in any animal model. A significant protective effect of C11 was observed on infected embryos, supporting the ability of C11 to attenuate in vivo P. aeruginosa pathogenicity. In conclusion, we present here a new and reliable method to compare the virulence of P. aeruginosa strains in vivo and to rapidly assess the efficacy of clinically relevant drugs against P. aeruginosa, including new antivirulence compounds.


1993 ◽  
Vol 28 (3) ◽  
pp. 259-264 ◽  
Author(s):  
R. Zordan ◽  
R. Padrini ◽  
V. Bernini ◽  
D. Piovan ◽  
M. Ferrari

1989 ◽  
Vol 120 (2) ◽  
pp. 175-179 ◽  
Author(s):  
C. Street ◽  
R. J. S. Howell ◽  
L. Perry ◽  
S. Al-Othman ◽  
T. Chard

Abstract. The effect of non-esterified fatty acids (NEFA) on the in vitro binding of testosterone, 5-alpha dihydrotestosterone and estradiol E2 to sex hormone binding globulin (SHBG) was examined using pooled normal female serum, and SHBG and albumin fractions obtained from the partial purification of late pregnancy serum. A range of saturated and unsaturated fatty acids were examined for their effect on steroid-protein binding. In normal female serum, NEFA added at physiological concentrations disrupted steroid-protein binding. The shorter chain (C8–C12) saturated acids and the poly-unsaturated acids proved to be more effective inhibitors than the longer chain saturated or mono-unsaturated acids. The greatest inhibition was obtained with E2 whereas the binding of dihydrotestosterone was least affected. With partially purified SHBG, the same concentrations of NEFA were less effective at inhibiting the binding of dihydrotestosterone and testosterone but elicited the same effect with E2. The binding of steroids to albumin appeared to be unaffected by these concentrations of NEFA.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lauren Andrews ◽  
Scott Benken ◽  
Xing Tan ◽  
Eric Wenzler

Abstract Background To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. Methods Apixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was utilized to provide dosing estimations for flow rates from 0.5–5 L/h. Results Mean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81 ± 0.01%. Effect of CVVH point of dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 2.5–7.5 mg twice daily (BID) may be needed for flow rates ranging from 0.5–5 L/h, respectively. Conclusion For CRRT flow rates most commonly employed in clinical practice, the standard labeled 5 mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.


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