Further development of an in vitro skin absorption method to measure compartmental disposition and kinetics for chemicals in skin

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Тamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents.

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Phytotoxicity and Other Adverse Effects on the In Vitro Shoot Cultures Caused by Virus Elimination Treatments: Reasons and Solutions

Plants ◽

10.3390/plants10040670 ◽

2021 ◽

Vol 10 (4) ◽

pp. 670

Author(s):

Katalin Magyar-Tábori ◽

Nóra Mendler-Drienyovszki ◽

Alexandra Hanász ◽

László Zsombik ◽

Judit Dobránszki

Keyword(s):

Adverse Effects ◽

Physiological Condition ◽

Harmful Effect ◽

Shoot Cultures ◽

Virus Elimination ◽

In Vitro Shoots ◽

Further Development ◽

In Vitro Shoot Cultures ◽

Harmful Effects

In general, in vitro virus elimination is based on the culture of isolated meristem, and in addition thermotherapy, chemotherapy, electrotherapy, and cryotherapy can also be applied. During these processes, plantlets suffer several stresses, which can result in low rate of survival, inhibited growth, incomplete development, or abnormal morphology. Even though the in vitro cultures survive the treatment, further development can be inhibited; thus, regeneration capacity of treated in vitro shoots or explants play also an important role in successful virus elimination. Sensitivity of genotypes to treatments is very different, and the rate of destruction largely depends on the physiological condition of plants as well. Exposure time of treatments affects the rate of damage in almost every therapy. Other factors such as temperature, illumination (thermotherapy), type and concentration of applied chemicals (chemo- and cryotherapy), and electric current intensity (electrotherapy) also may have a great impact on the rate of damage. However, there are several ways to decrease the harmful effect of treatments. This review summarizes the harmful effects of virus elimination treatments applied on tissue cultures reported in the literature. The aim of this review is to expound the solutions that can be used to mitigate phytotoxic and other adverse effects in practice.

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A Novel In Vitro Approach for Simultaneous Evaluation of CYP3A4 Inhibition and Kinetic Aqueous Solubility

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057114552796 ◽

2014 ◽

Vol 20 (2) ◽

pp. 254-264 ◽

Cited By ~ 3

Author(s):

José Pérez ◽

Caridad Díaz ◽

Francisco Asensio ◽

Alexandra Palafox ◽

Olga Genilloud ◽

...

Keyword(s):

Drug Discovery ◽

Physicochemical Properties ◽

Safety Concern ◽

Aqueous Solubility ◽

Cyp3a4 Inhibition ◽

Use Of Resources ◽

Simultaneous Evaluation ◽

New Chemical Entities ◽

Further Development

In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug–drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug–drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.

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Preclinical Pharmacokinetics of C118P, a Novel Prodrug of Microtubules Inhibitor and Its Metabolite C118 in Mice, Rats, and Dogs

Molecules ◽

10.3390/molecules23112883 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2883 ◽

Cited By ~ 3

Author(s):

Cang Zhang ◽

Xiaolan Zhang ◽

Guangji Wang ◽

Ying Peng ◽

Xueyuan Zhang ◽

...

Keyword(s):

Clinical Development ◽

High Dose ◽

Protein Inhibitor ◽

Promising Candidate ◽

Preclinical Pharmacokinetics ◽

Tumor Bearing ◽

Microtubule Protein ◽

Further Development

C118P, a phosphate prodrug of C118, which is a novel microtubule protein inhibitor, is currently under Phase I clinical development in China for treating ovarian cancer and lung cancer. The preclinical pharmacokinetics of prodrug C118P and its metabolite C118 were extensively characterized in vivo in mice, rats, and dogs and in vitro to support the further development of C118P. The preclinical tissue distribution and excretion were investigated in rats. Plasma protein binding in mice, rat, and human, and hepatic microsomal metabolic stability in mice, rat, dog, monkey, and human, were also evaluated. The (AUC0-inf) and C30s of C118P at 50 mg/kg in rats and 6 mg/kg in dogs, and the C2min of C118 at 6 mg/kg in dogs increased less than the dosage increase, suggested nonlinear pharmacokinetic occurred at high dose. As a prodrug, C118P can be quickly hydrolyzed into C118 after an intravenous administration. The unbound C118 in plasma is slightly higher than C118P. C118P can hardly penetrate the tissue, while C118 can distribute widely into tissues. In tumor-bearing nude mice, the concentration of C118 is high in lung, ovary, and tumor, with an extended half-life in tumor. C118P is a promising candidate prodrug for further clinical development.

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1360. Antimicrobial Activity of Cefepime in Combination with VNRX-5133 Against a Global Collection of Enterobacteriaceae Including Resistant Phenotypes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1191 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S416-S417 ◽

Cited By ~ 3

Author(s):

Meredith Hackel ◽

Dan Sahm

Keyword(s):

Vitro Activity ◽

In Vitro Activity ◽

First Line ◽

First Line Therapy ◽

Carbapenem Resistant ◽

Line Therapy ◽

Resistant Strains ◽

Further Development ◽

Dose Dependent

Abstract Background VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C, and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Methods MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012–2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose-dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes. Results FEP/VNRX-5133 showed potent in vitro activity against drug-resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin–tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited >93% of all resistant subsets at ≤8 µg/mL. Conclusion Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first-line therapy, further development is warranted. Disclosures M. Hackel, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee. D. Sahm, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee.

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THE CULTIVATION OF TISSUES FOR PROLONGED PERIODS IN SINGLE FLASKS

Journal of Experimental Medicine ◽

10.1084/jem.64.1.121 ◽

1936 ◽

Vol 64 (1) ◽

pp. 121-130 ◽

Cited By ~ 20

Author(s):

Raymond C. Parker

Keyword(s):

Cell Death ◽

Chick Embryo ◽

Connective Tissue ◽

Breast Muscle ◽

Cell Multiplication ◽

Tyrode Solution ◽

Low Level ◽

Further Development

1. Fragments of breast muscle from a 12 day old chick embryo have been kept alive in single flasks for an entire year without being transferred. The nutrient materials were supplied by frequent applications of adult fowl serum diluted with Tyrode solution. 2. When fragments of fixed tissues are cultivated in serum, cell multiplication and cell death are both reduced to an extremely low level. 3. The presence of a plasma coagulum is not essential to the continued survival and further development of tissues cultivated inserum. 4. The fibrinogen, prothrombin, and fibrin of coagulated plasma are not essential to the development of connective tissue fibers in vitro.

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In Vitro Activity of LK-157, a Novel Tricyclic Carbapenem As Broad-Spectrum β-Lactamase Inhibitor

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00085-08 ◽

2008 ◽

Vol 53 (2) ◽

pp. 505-511 ◽

Cited By ~ 24

Author(s):

Susanne Paukner ◽

Lars Hesse ◽

Andrej Preželj ◽

Tomaž Šolmajer ◽

Uroš Urleb

Keyword(s):

Clavulanic Acid ◽

Broad Spectrum ◽

Clinical Settings ◽

In Vitro Activity ◽

Bacterial Strains ◽

Class A ◽

Class C ◽

Further Development ◽

Lactamase Inhibitor

ABSTRACT LK-157 is a novel tricyclic carbapenem with potent activity against class A and class C β-lactamases. When tested against the purified TEM-1 and SHV-1 enzymes, LK-157 exhibited 50% inhibitory concentrations (IC50s) in the ranges of the clavulanic acid and tazobactam IC50s (55 nM and 151 nM, respectively). Moreover, LK-157 significantly inhibited AmpC β-lactamase (IC50, 62 nM), as LK-157 was >2,000-fold more potent than clavulanic acid and approximately 28-fold more active than tazobactam. The in vitro activities of LK-157 in combination with amoxicillin, piperacillin, ceftazidime, cefotaxime, ceftriaxone, cefepime, cefpirome, and aztreonam against an array of Ambler class A (TEM-, SHV-, CTX-M-, KPC-, PER-, BRO-, and PC-type)- and class C-producing bacterial strains derived from clinical settings were evaluated in synergism experiments and compared with those of clavulanic acid, tazobactam, and sulbactam. In vitro MICs against ESBL-producing strains (except CTX-M-containing strains) were reduced 2- to >256-fold, and those against AmpC-producing strains were reduced even up to >32-fold. The lowest MICs (≤0.025 to 1.6 μg/ml) were observed for the combination of cefepime and cefpirome with a constant LK-157 concentration of 4 μg/ml, thus raising an interest for further development. LK-157 proved to be a potent β-lactamase inhibitor, combining activity against class A and class C β-lactamases, which is an absolute necessity for use in the clinical setting due to the worldwide increasing prevalence of bacterial strains resistant to β-lactam antibiotics.

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Functional optical coherence tomography of retinal photoreceptors

Experimental Biology and Medicine ◽

10.1177/1535370218816517 ◽

2018 ◽

Vol 243 (17-18) ◽

pp. 1256-1264 ◽

Cited By ~ 9

Author(s):

Xincheng Yao ◽

Taeyoon Son ◽

Tae-Hoon Kim ◽

Yiming Lu

Keyword(s):

Vision Loss ◽

Objective Assessment ◽

Age Related Macular Degeneration ◽

Retinal Stimulation ◽

Age Related ◽

Retinal Photoreceptors ◽

Severe Vision Loss ◽

Further Development

Age-related macular degeneration (AMD) is the leading cause of severe vision loss and legal blindness. It is known that retinal photoreceptors are the primary target of AMD. Therefore, a reliable method for objective assessment of photoreceptor function is needed for early detection and reliable treatment evaluation of AMD and other eye diseases such as retinitis pigmentosa that are known to cause photoreceptor dysfunctions. Stimulus-evoked intrinsic optical signal (IOS) changes promise a unique opportunity for objective assessment of physiological function of retinal photoreceptor and inner neurons. Instead of a comprehensive review, this mini-review is to provide a brief summary of our recent in vitro and in vivo optical coherence tomography (OCT) studies of stimulus-evoked IOS changes in animal retinas. By providing excellent axial resolution to differentiate individual retinal layers, depth-resolved OCT revealed rapid IOS response at the photoreceptor outer segment. The fast photoreceptor-IOS occurred almost right away (∼ 2 ms) after the onset of retinal stimulation, differentiating itself from slow IOS changes correlated with inner neural and hemodynamic changes. Further development of the functional IOS instruments and retinal stimulation protocols may provide a feasible solution to pursue clinical application of functional IOS imaging for objective assessment of human photoreceptors. Impact statement Retinal photoreceptors are the primary target of age-related macular degeneration (AMD) which is the leading cause of severe vision loss and legal blindness. An objective method for functional assessment of photoreceptor physiology can benefit early detection and better treatment evaluation of AMD and other eye diseases that are known to cause photoreceptor dysfunctions. This article summarizes in vitro study of IOS mechanisms and in vivo demonstration of IOS imaging of intact animals. Further development of the functional IOS imaging may provide a revolutionary solution to achieve objective assessment of human photoreceptors.

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