In Vitro Activities of the Ketolides Telithromycin (HMR 3647) and HMR 3004 Compared to Those of Clarithromycin against Slowly Growing Mycobacteria at pHs 6.8 and 7.4

ABSTRACT The in vitro activities of HMR 3647 (telithromycin) and HMR 3004, two novel semisynthetic ketolides, were investigated and compared with that of the reference macrolide drug, clarithromycin, against 34 strains of slowly growing mycobacteria at pHs 6.8 and 7.4, as determined radiometrically. The MICs at pH 7.4 were about 1 to 2 dilutions lower than those observed at pH 6.8. In terms of the highest to the lowest activity, the three antibiotics could be classified as follows: clarithromycin > HMR 3004 > HMR 3647. Among the species tested, Mycobacterium bovis BCG, M. ulcerans, M. avium, and M. paratuberculosis were moderately susceptible to HMR 3004 and HMR 3647 (MICs at pH 7.4, ≤5.0 and ≤20.0 μg/ml, respectively, versus ≤1.25 μg/ml for clarithromycin), whereas M. tuberculosis, M. africanum, M. bovis, andM. simiae were resistant (MICs, ≥10.0 and ≥40.0 μg/ml, respectively, at pH 7.4). Although not more active than clarithromycin in vitro, the high level of intracellular accumulation of the two ketolides inside phagocytes warrants further screening in experimental animal models.

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Development of Animal Models, Presenting Appropriate Analogues to Respective Human Systems

Journal of Immunology and Allergy ◽

10.37191/mapsci-2582-4333-3(1)-055 ◽

2021 ◽

Author(s):

Iskra V Sainova

Keyword(s):

Animal Models ◽

Experimental Animal ◽

Normal Mouse ◽

Recombinant Dna ◽

Embryonic Stem ◽

Human Origin ◽

Experimental Animal Models ◽

Cellular Types

The main idea of the current study was directed to developed appropriate experimental animal models, imitating respective systems with the human origin, and giving a possibility when the last is not available, experiments about necessary applications to humans to be performed. So, an additional copy of oncogene Dcn1 in normal mouse embryonic stem cells (mESCs), was inserted, by appropriate recombinant DNA-constructs, based on the AAV DNA-genome. All derived genetically-manipulated cellular types were co-cultivated with early myeloid and lymphoid progenitors, derived from non-transfected mESCs in the presence of GM-CSF (for induction of initial stages of both myeloid and lymphoid differentiation), and subsequently, malignant antigens were added (about further phagocyte and plasmatic cell differentiation, respectively). The derived and selected mESCs, containing an additionally-inserted copy of oncogene Dcn1, which indicated preserved normal/non-malignant characteristics both in vitro and in vivo, presented appropriate experimental normal mouse cellular analog of the cited in the scientific literature human embryonic trophoblasts, immortalized by infection with virus SV40. Additionally, the results obtained showed a possibility about the expression of membrane receptor glycoproteins by non-lymphoid and non-myeloid cellular types inappropriate conditions. Also, the presented study demonstrated the importance of the blood-testes barrier (BTB) for the prevention of malignancy development in the experimental hamster Graffi tumor model. The role of bio-molecules, as well as of intra- and extra-cellular inter-molecular interactions in cascade regulatory mechanisms, inactivation of the differentiation of embryonic and adult stem/progenitor cells in normal types, as well as for suppression of malignant transformation, was suggested. The established analogy of the developed and investigated in the current study experimental animal models gives a possibility for their application about performing of specific experiments when the respective systems with human origin are not available.

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Gonadotrophic Hormones – An Overview of their Involvement in Gonadal and Extragonadal Tumours

European Endocrinology ◽

10.17925/ee.2011.07.01.8 ◽

2010 ◽

Vol 7 (1) ◽

pp. 8 ◽

Cited By ~ 1

Author(s):

Ilpo Huhtaniemi ◽

Maria Alevizaki ◽

◽

Keyword(s):

Animal Models ◽

Experimental Animal ◽

Clinical Evidence ◽

Critical Evaluation ◽

Regulatory Action ◽

Experimental Animal Models ◽

Direct Involvement ◽

Long Time

The concept of the direct involvement of gonadotrophins in tumorigenesis has been around for a long time. First, because the gonads are direct targets of gonadotrophin action, their tumours have been proposed to be gonadotrophin-dependent. Second, the recent findings of gonadotrophin receptors in extragonadal tissues has prompted the hypothesis that some extragonadal tumours (e.g. breast, uterus, prostate, pituitary and adrenal) could also be under the direct regulatory action of gonadotrophins. However, although supported by numerousin vitroexperiments and experimental animal models, the clinical evidence for a direct tumorigenic role of gonadotrophins remains weak. The purpose of this brief review is to present a critical evaluation of current information, both clinical and experimental, about the involvement of gonadotrophins in the induction and growth of gonadal and extragonadal tumours.

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Translating Neurobehavioral Toxicity Across Species From Zebrafish to Rats to Humans: Implications for Risk Assessment

Frontiers in Toxicology ◽

10.3389/ftox.2021.629229 ◽

2021 ◽

Vol 3 ◽

Author(s):

Charles V. Vorhees ◽

Michael T. Williams ◽

Andrew B. Hawkey ◽

Edward D. Levin

Keyword(s):

Risk Assessment ◽

Animal Models ◽

Experimental Animal ◽

High Throughput ◽

Clinical Studies ◽

Drugs Of Abuse ◽

Toxicant Exposure ◽

Essential Information ◽

Experimental Animal Models

There is a spectrum of approaches to neurotoxicological science from high-throughput in vitro cell-based assays, through a variety of experimental animal models to human epidemiological and clinical studies. Each level of analysis has its own advantages and limitations. Experimental animal models give essential information for neurobehavioral toxicology, providing cause-and-effect information regarding risks of neurobehavioral dysfunction caused by toxicant exposure. Human epidemiological and clinical studies give the closest information to characterizing human risk, but without randomized treatment of subjects to different toxicant doses can only give information about association between toxicant exposure and neurobehavioral impairment. In vitro methods give much needed high throughput for many chemicals and mixtures but cannot provide information about toxicant impacts on behavioral function. Crucial to the utility of experimental animal model studies is cross-species translation. This is vital for both risk assessment and mechanistic determination. Interspecies extrapolation is important to characterize from experimental animal models to humans and between different experimental animal models. This article reviews the literature concerning extrapolation of neurobehavioral toxicology from established rat models to humans and from zebrafish a newer experimental model to rats. The functions covered include locomotor activity, emotion, and cognition and the neurotoxicants covered include pesticides, metals, drugs of abuse, flame retardants and polycyclic aromatic hydrocarbons. With more complete understanding of the strengths and limitations of interspecies translation, we can better use animal models to protect humans from neurobehavioral toxicity.

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