The Evaluation of Prophylactic Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase in Soman‐Poisoned Mice – A Comparison with Commonly Used Pyridostigmine

Kassa, Jiřı́; Korábečný, Jan; Šepsová, Vendula; Tumova, Martina

doi:10.1111/bcpt.12269

Cited by 7 publications

(3 citation statements)

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“…The untargeted metabolomic profiling of biological substrates provides direct and simultaneous measurements of biochemical outputs that make up a given phenotype (20). Comparative metabolomics profiling of urine specimens was performed to assess soman exposure associated metabolic alterations at 72 hrs post exposure, for seizing and non-seizing animals.…”

Section: Resultsmentioning

confidence: 99%

Altered Fecal Microbiota and Urine Metabolome as Signatures of Soman Poisoning

Gautam

Getnet

Kumar

et al. 2018

Preprint

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and Proteobacteria phyla, some of which are known to hydrolyze OPs. However, analogous 31 changes were not observed in the bacterial biota of the ileum, which remained the same 32 irrespective of dose or seizing status of animals after exposure. Interestingly, when considering 33 just the seizing status of animals, we found that the urine metabolome was markedly altered. 34Leukotriene C4, kynurenic acid, 5-hydroxyindoleacetic acid, norepinephrine, and aldosterone 35 were excreted at much higher rates at 72 hrs in seizing animals, consistent with early multi-organ 36 involvement during soman poisoning. However, at 75 days post soman exposure, bacterial biota 37 stabilized and no differences were observed. These findings demonstrate the feasibility of using was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/312660 doi: bioRxiv preprint first posted online May. 2, 2018

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Section: Resultsmentioning

confidence: 99%

Altered Fecal Microbiota and Urine Metabolome as Signatures of Soman Poisoning

Gautam

Getnet

Kumar

et al. 2018

Preprint

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“…Unfortunately, the detailed pharmacokinetics of these novel ChEIs is currently being investigated and not yet known. The central inhibitory potential can be only estimated on the basis of current in vivo evaluation 29 . Nevertheless, there is an expectation that novel compounds, at least partly, penetrate the bloodbrain barrier, and this is supported by in vitro observation in similar tacrine-donepezil hybrids 46 .…”

Section: Discussionmentioning

confidence: 99%

“…The effect of these novel ChEIs was compared to that of standard tacrine (the basis of 3, 4 and 7-MEOTA -the parent compound of 1 and 2), although tacrine is no longer utilized in clinical practice -it was withdrawn due to dose-dependent hepatotoxicity and severe side effects including nausea, vomiting, diarrhoea and weight loss 28 . From this point of view, novel 7-MEOTAdonepezil like hybrids (1 and 2) are promising due to decreased acute toxicity, especially 2, which is considered to be a low toxic compound 29 . As another standard, donepezil (the parent compound of 1 and 2), approved for the treatment of mild and moderate stages of AD in 1996, was used.…”

Section: Introductionmentioning

confidence: 99%

The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test

Mišík¹,

Korábečný²,

Nepovimová³

et al. 2015

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Aims. The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil. Methods. Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method. Results. QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. Conclusion: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.

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