scholarly journals Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

2002 ◽  
Vol 46 (8) ◽  
pp. 2373-2380 ◽  
Author(s):  
George W. Koszalka ◽  
Nelson W. Johnson ◽  
Steven S. Good ◽  
Leslie Boyd ◽  
Stanley C. Chamberlain ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Metabolic Activation ◽  
Female Rats ◽  
Primary Metabolite ◽  
Mouse Lymphoma Assay ◽  
High Level ◽  
Favorable Safety ◽  
Rat Study ◽  
Higher Doses ◽  
Mouse Lymphoma

ABSTRACT 1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ∼50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94.

scholarly journals In vitro genotoxicity evaluation and metabolic study of residual glutaraldehyde in animal-derived biomaterials

2020 ◽  
Vol 7 (6) ◽  
pp. 619-625
Author(s):  
Jianfeng Shi ◽  
Huan Lian ◽  
Yuanli Huang ◽  
Danmei Zhao ◽  
Han Wang ◽  
...  
Keyword(s):  
Metabolic Activation ◽  
Chemical Toxicity ◽  
Major Health ◽  
Mouse Lymphoma Assay ◽  
Metabolic Mechanism ◽  
Mutagenic Effects ◽  
Mouse Lymphoma ◽  
General Balance ◽  
In Vitro Genotoxicity

Abstract Glutaraldehyde (GA) is an important additive that is mainly used in animal-derived biomaterials to improve their mechanical and antimicrobial capacities. However, GA chemical toxicity and the metabolic mechanism remain relatively unknown. Therefore, residual GA has always been a major health risk consideration for animal-derived medical devices. In this study, extracts of three bio-patches were tested via the GA determination test and mouse lymphoma assay (MLA). The results showed that dissolved GA was a potential mutagen, which could induce significant cytotoxic and mutagenic effects in mouse lymphoma cells. These toxic reactions were relieved by the S9 metabolic activation (MA) system. Furthermore, we confirmed that GA concentration decreased and glutaric acid was generated during the catalytic process. We revealed GA could be oxidized via cytochrome P450 which was the main metabolic factor of S9. We found that even though GA was possibly responsible for positive reactions of animal-derived biomaterials’ biocompatibility evaluation, it may not represent the real situation occurring in human bodies, owing to the presence of various detoxification mechanisms including the S9 system. Overall, in order to achieve a general balance between risk management and practical application, rational decisions based on comprehensive analyses must be considered.

Induced hepatocytes as a metabolic activation system for the mouse-lymphoma assay

1989 ◽  
Vol 223 (3) ◽  
pp. 295-302 ◽  
Author(s):  
Linda A. Oglesby ◽  
Karen Harrington Brock ◽  
Martha M. Moore
Keyword(s):  
Metabolic Activation ◽  
Mouse Lymphoma Assay ◽  
Activation System ◽  
Mouse Lymphoma

Final Report on the Safety Assessment of Oxyquinoline and Oxyquinoline Sulfate

1992 ◽  
Vol 11 (4) ◽  
pp. 497-507 ◽  
Keyword(s):  
Test Data ◽  
Mutagenic Activity ◽  
Metabolic Activation ◽  
Female Rats ◽  
Final Report ◽  
Cosmetic Products ◽  
Male And Female ◽  
Male And Female Rats ◽  
Cosmetic Ingredients ◽  
Mouse Lymphoma Assay

Oxyquinoline is a heterocyclic phenol which is used as a fungicide and bactericide in cosmetic formulations at concentrations at, or less than 1.0%. Oxyquinoline is metabolized and excreted in the urine as glucuronides. The acute oral LD50 toxicity in rats was 1.2 g/kg. In subchronic studies, no deaths occurred in male and female rats at 5 doses up to 12,000 ppm or in male and female mice up to doses of 6000 ppm. Solid 100% Oxyquinoline was mildly irritating to rabbit skin and a 100 mg dose of Oxyquinoline was only slightly irritating to the eye. No sensitization test data were available for either of these cosmetic ingredients. Oxyquinoline and Oxyquinoline Sulfate were mutagenic when assayed using the Ames procedure with metabolic activation. Mutagenic activity was also demonstrated in the mouse lymphoma assay. Oxyquinoline was noncarcinogenic in several oral rodent feeding studies. The data from this negative oral carcinogenic assay were judged to be insufficient to evaluate the safety of use of Oxyquinoline and Oxyquinoline Sulfate when cosmetic products containing these ingredients are applied to the skin. It is concluded that the available carcinogenicity and sensitization test data are insufficient to support a conclusion on the safety of Oxyquinoline and Oxyquinoline Sulfate as used in cosmetic products.

Genotoxicity studies of a desealant solvent mixture, SR-51®

2009 ◽  
Vol 25 (1) ◽  
pp. 5-13
Author(s):  
DJ Oakes ◽  
HE Ritchie ◽  
PDC Woodman ◽  
E Narup ◽  
M Moscova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Comet Assay ◽  
Ames Test ◽  
Micronucleus Test ◽  
Metabolic Activation ◽  
Lymphoma Cells ◽  
Mouse Lymphoma Assay ◽  
Mouse Lymphoma Cells ◽  
Presence And Absence ◽  
Mouse Lymphoma

The Royal Australian Air Force (RAAF) has reported that personnel involved in F-111 fuel tank maintenance were concerned that exposure to a range of chemicals during the period 1977 to mid-1990s was the cause of health problems, including cancer. Particular concern was directed at SR-51®, a desealant chemical mixture containing the following four solvents: aromatic 150 solvent (Aro150), dimethylacetamide, thiophenol (TP), and triethylphosphate. The present study examined the mutagenic potential of SR-51® using a range of well-known mutagen and genotoxin assays. The tests used were i) a modified version of the Ames test, ii) the mouse lymphoma assay, iii) the comet assay (a single-cell gel electrophoresis assay), and iv) a mouse micronucleus test. The modified Ames test used mixed bacterial strains in liquid suspension media. The Ames test results showed that SR-51® (tested up to the cytotoxic concentration of 36 μg/ml, 30 min incubation) in the presence and absence of S9 metabolic activation was not mutagenic. The mouse lymphoma assay used cultured mouse lymphoma cells in a microwell suspension method. The mouse lymphoma assay was also negative with SR-51® (tested up to the cytotoxic concentration of 22.5 μg/ml, 3 h incubation) in the presence and absence of S9 metabolic activation. The Comet assay, using cultured mouse lymphoma cells, showed no evidence of DNA damage in cells exposed up to the cytotoxic concentration of SR-51® at 11.25 μg/ml. The in-vivo mouse micronucleus test was undertaken in wild-type C57Bl6J male mice dosed orally with SR-51® for 14 days with a single daily dose up to 360 mg/kg/day (the maximum-tolerated dose). No increases were observed in micronuclei (MN) frequency in bone marrow collected (24 h after final dose) from SR-51®-treated mice compared to the number of MN observed in bone marrow collected from untreated mice. Tissues collected from treated mice at necropsy demonstrated a significant increase in spleen weights in the high dose mice. Gas chromatography analysis of SR-51® identified more than 40 individual components and an oxidation product, diphenyldisulfide derived from TP under conditions of mild heating. In conclusion, there was no evidence that SR-51® is mutagenic.

Prepubertal exposure to T-2 toxin advances pubertal onset and development in female rats via promoting the onset of hypothalamic–pituitary–gonadal axis function

2016 ◽  
Vol 35 (12) ◽  
pp. 1276-1285 ◽  
Author(s):  
R Yang ◽  
Y-M Wang ◽  
L Zhang ◽  
Z-M Zhao ◽  
J Zhao ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Female Rats ◽  
Intragastric Administration ◽  
Corpora Lutea ◽  
Sprague Dawley ◽  
Trichothecene Mycotoxin ◽  
Pubertal Onset ◽  
Serum Hormone ◽  
Puberty Onset ◽  
High Level

T-2 toxin, a naturally produced Type A trichothecene mycotoxin, has been shown to damage the reproductive and developmental functions in livestocks. However, whether T-2 toxin can disturb the pubertal onset and development following prepubertal exposure remains unclear. To clarify this point, infantile female Sprague–Dawley rats were given a daily intragastric administration of vehicle or T-2 toxin at a dose of 375 μg/kg body weight for 5 consecutive days from postnatal day (PND) 15–19 (PND15–PND19). The days of vaginal opening, first diestrus, and first estrus in regular estrous cycle were advanced following T-2 toxin treatment, indicating prepubertal exposure to T-2 toxin induced the advancement of puberty onset. The relative weights of uterus and ovaries and the incidence of corpora lutea were all increased in T-2 toxin-treated rats; serum hormone levels of luteinizing hormone and estradiol and the messenger RNA expressions of gonadotropin-releasing hormone (GnRH) and GnRH receptor also displayed marked increases following exposure to T-2 toxin, all of which were well consistent with the manifestations of the advanced puberty onset. In conclusion, the present study reveals that prepubertal exposure to a high level of T-2 toxin promotes puberty onset in infantile female rats by advancing the initiation of hypothalamic–pituitary–gonadal axis function in female rats.

ANALYSIS OF MT2A AND MT3 GENE EXPRESSION IN RAT'S LIVER AND KIDNEY IN RESPONSE TO CADMIUM CHLORIDE POISONING

2021 ◽  
pp. 38-42
Author(s):  
M. M. Ziatdinova ◽  
T. G. Yakupova ◽  
Ya. V. Valova ◽  
G. F. Mukhammadieva ◽  
D. O. Karimov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Liver ◽  
Cadmium Chloride ◽  
Transcriptional Activity ◽  
Female Rats ◽  
Expression Level ◽  
Cadmium Poisoning ◽  
Liver And Kidney ◽  
Dose Dependent ◽  
Higher Doses

The aim of this study was to investigate the expression of metallothionein genes in the liver and kidneys of rats with acute cadmium poisoning.Simulation of poisoning with cadmium chloride was carried out on white outbred female rats, divided into 4 groups depending on the dose of the injected toxicant. RNA samples isolated from rat liver and kidneys were used as research materials.The multiplicity of expression of the MT3 gene in the kidneys increased at the lowest dose of CdCl2 , which was used in this experiment (0.029 mg / kg); with increasing dosage, the expression level decreased, but not lower than the control values. Analysis of the expression of the same gene in the liver showed a tendency towards a decrease in the content of transcripts with increasing dose. The frequency of expression of the MT2A gene at higher doses of CdCl2 increased both in the liver and in the kidneys.In the present work, statistically significant dose-dependent changes in the expression multiplicity of metallothionein genes were detected 24 hours after CdCl2 administration. The revealed differences in the level of transcriptional activity of metallothionein genes require further investigation, since there are probably differences in the level of gene expression at earlier and later periods of toxicant action.

scholarly journals The dilemma of using physical restraint in delirium tremens: a case report

2019 ◽  
Vol 7 (8) ◽  
pp. 3172
Author(s):  
Yogender Kumar Malik ◽  
Debasish Basu ◽  
Chandrima Naskar
Keyword(s):  
Case Report ◽  
Clinical Setting ◽  
Tertiary Care ◽  
Delirium Tremens ◽  
Physical Restraint ◽  
Common Presentation ◽  
Usual Dose ◽  
High Level ◽  
Tertiary Care Hospitals ◽  
Higher Doses

Delirium tremens (DT) is a common presentation in tertiary care hospitals. Refractory DT, though not very common, is a dreaded presentation in any clinical setting. Usually, patients with DT respond to standard doses of benzodiazepines, but sometimes we encounter patients requiring higher than the usual dose. Also, due to the high level of agitation, confusion and hallucinatory behaviour, physical restraint is frequently used in these patients. We hereby report a case of refractory DT in whom the dilemma of using physical restraint and need for higher doses of Benzodiazepine has been highlighted.

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