Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes

Wang, Yu; Ning, Zhonghua; Tai, Hong W.; Long, Shuang; Qin, Wei C.; Su, Li Ming; Zhao, Yuan H.

doi:10.1016/j.yrtph.2014.12.019

Cited by 26 publications

(8 citation statements)

References 18 publications

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“…As reported elsewhere, the bioavailability of the drug via intravenous and intraperitoneal route is almost similar 16 . Our in vitro data is satisfactorily correlating with data obtain by i.p.…”

Section: Discussionsupporting

confidence: 74%

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Comparative Toxicity of Bis-pyridinium Acetamide Derivatives in Human Cell Lines and their Acute Toxicity in Swiss Albino Mice

et al. 2016

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Having established the antidotal efficacy of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (HNK oximes) against Diisopropylphosphorofluoridate (DFP) and sarin poisoning. Toxicity of HNK series and 2-PAM oximes on Human cell lines and Swiss male mice i.e. in vitro and in vivo to reported. Toxicity of the oximes was investigated in Hela, Hep G2 and HEK 293 cell lines and compared with most commonly used 2-PAM. Median lethal doses (LD50) of the oximes (2-PAM, HNK-102, HNK-106, and HNK-111) were also determined following intramuscular, intraperitoneal, intravenous and oral routes of administration. All tested oximes showed no cytotoxic effect on all three cell lines in concentrations up to 0.05 mg/mL. At higher dose (0.5 mg/mL), HNK-102 found to be less toxic thus safer than 2-PAM and other oximes in all the three cell lines. In corroboration with in vitro finding, HNK-102 was found to be least toxic compared to other oximes via intra-peritoneal and intravenous routes of administration. Also, HNK-102 was found to be unequivocally safer compared to that of 2-PAM through i.m. and i.p. routes. For all tested oximes, toxicity following oral route, was found to be lower compared to injections, signifying that these are safer and convenient compounds for administration. These finding also suggested that HNK-102 is safer and better lead as an antidote compared to 2-PAM, against OP intoxicants.

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Section: Discussionsupporting

confidence: 74%

“…Also, HNK-111 contains three pyridine ring compared to other oximes. The previous reports say that toxicity of alkenes, alkynes and -cyclo compounds are greater than alkanes group 16 . Hence, the presence of more alkyl and quaternary nitrogen group contributes to the higher toxicity by HNK-106 and HNK-111.…”

Section: Discussionmentioning

confidence: 95%

Comparative Toxicity of Bis-pyridinium Acetamide Derivatives in Human Cell Lines and their Acute Toxicity in Swiss Albino Mice

et al. 2016

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“…The large difference between the toxicity of each oxime via ip and im route underlays to the structural difference 38 . Then, the general toxicity of alkenes, alkynes and -cyclo compounds are greater than alkanes group 41 . Accordingly, the presence of more alkyl and quaternary nitrogen group contributes to the higher toxicity by obidoxime and K075, respectively 42 .…”

Section: Discussionmentioning

confidence: 99%

Toxic Injury to Muscle Tissue of Rats Following Acute Oximes Exposure

Jacević

Nepovimová

Kuča

2019

Sci Rep

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Therapeutic application of newly developed oximes is limited due to their adverse effects on different tissues. Within this article, it has been investigated which morphological changes could be observed in Wistar rats after the treatment with increasing doses of selected acetyl cholinesterase reactivators - asoxime, obidoxime, K027, K048, and K075. Subsequently, heart, diaphragm and musculus popliteus were obtained for pathohistological and semiquantitative analysis 24 hrs and 7 days after im administration of a single dose of 0.1 LD50, 0.5 LD50, and 1.0 LD50 of each oxime. Different muscle damage score was based on an estimation scale from 0 (no damage) to 5 (strong damage). In rats treated with 0.1 LD50 of each oxime, muscle fibres did not show any change. The intensive degeneration was found in all muscles after treatment with 0.5 LD50 of asoxime and obidoxime, respectively. Acute toxic muscle injury was developed within 7 days following treatment with 0.5 LD50 and 1.0 LD50 of each oxime, with the highest values in K048 and K075 group (P < 0.001 vs. control and asoxime), respectively. The early muscle alterations observed in our study seem to contribute to the pathogenesis of the oxime-induced toxic muscle injury, which probably manifests as necrosis and/or inflammation.

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“…Within this dose range, almost no side effects were reported, suggesting a wide therapeutic window. Yet, explanations of this striking broad dose range might be due to the differences in species and/or the route of administration [ 35 , 40 , 79 ]. According to toxicity studies (see Section 1.5 ), oral application of TQ seems to be better tolerated as signs of toxicity occurred at much higher doses than after intraperitoneal application.…”

Section: Discussionmentioning

confidence: 99%

Plants and Surgery: The Protective Effects of Thymoquinone on Hepatic Injury—A Systematic Review of In Vivo Studies

Tekbaş

Huebner

Settmacher

et al. 2018

IJMS

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Multimodal treatment concepts including liver transplantation for hepatocellular carcinoma (HCC), extended resection methods and neoadjuvant chemotherapy for colorectal liver metastasis significantly improve patients’ outcome. However, surgery-induced hepatic ischemia-reperfusion injury (IRI) and chemotherapy-associated hepatotoxicity result in hepatocellular damage and compromised liver function. Activation of common key pathways in ischemic liver and hepatotoxic injury results in oxidative stress, inflammatory responses and apoptosis causing organ damage. Controlling liver damage before and during surgery is essential for the postoperative outcome. Nigella sativa has a long tradition as a natural remedy. In the essential oil, Thymoquinone (TQ) was identified as the main component and responsible for most of the therapeutic effects. Therefore, this systematic review aimed to summarize the hepatoprotective effects of TQ and its potential suitability to improve surgical outcome by reducing surgical ischemic injury and hepatotoxicity of neoadjuvant chemotherapy. The key findings can be summarized as TQ having strong antioxidant, anti-inflammatory, antifibrotic, anti-/proapoptotic and anticarcinogenic effects. Almost no side effects were reported irrespective of a large dose range, suggesting a wide therapeutic window. These results give rise to the expectation that TQ could evolve to a novel powerful drug to reduce hepatic injury.

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Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes

Cited by 26 publications

References 18 publications

Comparative Toxicity of Bis-pyridinium Acetamide Derivatives in Human Cell Lines and their Acute Toxicity in Swiss Albino Mice

Comparative Toxicity of Bis-pyridinium Acetamide Derivatives in Human Cell Lines and their Acute Toxicity in Swiss Albino Mice

Toxic Injury to Muscle Tissue of Rats Following Acute Oximes Exposure

Plants and Surgery: The Protective Effects of Thymoquinone on Hepatic Injury—A Systematic Review of In Vivo Studies

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