scholarly journals Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in in vitro and in vivo test systems

2021 ◽  
Vol 98 (5) ◽  
pp. 548-557
Author(s):  
E. A. Jain ◽  
D. Pleimes ◽  
A. A. Globenko
Keyword(s):  
Oral Administration ◽  
Chromosomal Aberrations ◽  
Ames Test ◽  
Chronic Toxicity ◽  
Micronucleus Test ◽  
Human Lymphocytes ◽  
Antiviral Drug ◽  
Systemic Exposure

Introduction. The antiviral properties of imidazolyl ethanamide pentandioic acid (IPA), the active compound of the drug product, has been proven in various experimental models. However, the literature data on the toxicological properties of IPA are limited.Purpose. To evaluate mutagenic and genotoxic properties in in vitro and in vivo models, as well as to study the toxicity of IPA following chronic oral administration to rats and dogs.Materials and methods. Mutagenic and genotoxic properties of IPA were assessed using the Ames test, the test of chromosomal aberrations in human lymphocytes, and the micronucleus test in rats. The chronic toxicity of IPA was studied in Sprague Dawley rats and beagle dogs of both sexes, to which IPA was administered orally at doses of 30-300 mg/kg/day for 26 and 39 weeks, respectively.Results and discussion. In the Ames test, the addition of IPA up to the maximum dose (5000 mcg/plate) did not result in the increase in the number of revertant colonies. At a concentration of up to 5000 mcg/ml, IPA did not cause chromosomal aberrations in human leukocytes. At doses doses ≤ 2000 mg/kg, IPA did not increase the amount of micronuclei in the bone marrow of rats. In chronic experiments, animals tolerated the administration of IPA well: the dose without an observed effect (NOEL) for rats and dogs was 300 mg/kg/day.Conclusion. IPA did not show mutagenic and genotoxic properties in standard in vitro and in vivo tests. With chronic oral administration to rats and dogs, NOEL IPA equal to 300 mg/kg/day provided a systemic exposure that was 8-10 and 41-65 times higher than that in humans, respectively. The results obtained allow us to consider the safety profile of the prolonged use in humans as favorable.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals In Vitro Genotoxicity Assessment from the Glycyrrhiza New Variety Extract

2021 ◽  
Vol 11 (21) ◽  
pp. 10257
Author(s):  
Young-Jae Song ◽  
Dong-Gu Kim ◽  
Jeonghoon Lee ◽  
Wonnam Kim ◽  
Hyo-Jin An ◽  
...  
Keyword(s):  
Ames Test ◽  
Micronucleus Test ◽  
Herbal Medicines ◽  
Mouse Bone Marrow ◽  
New Variety ◽  
Polychromatic Erythrocytes ◽  
Chromosome Aberration Test ◽  
In Vitro Genotoxicity

The various species that comprise the genus Glycyrrhiza (Licorice) have long been used as oriental herbal medicines in Asian countries. Wongam (WG), which is a new variety of Glycyrrhiza, was developed in Korea to overcome the limitations of low productivity, environmental restrictions, and an insufficient presence of glycyrrhizic acid and liquiritigenin. In this study, we evaluated WG extract’s genotoxicity through an in vitro bacterial reverse mutation (AMES) test, an in vitro chromosome aberration test, and an in vivo mouse bone marrow micronucleus test. In the AMES test, WG extract at concentrations of up to 5000 µg/plate showed no genotoxicity regardless of S9 mix. No chromosome aberrations appeared after 6 h in 1400 µg/mL WG extract regardless of S9 mix or in 1100 µg/mL WG extract after 24 h without S9 mix. Nor was there a significant increase in the number of micronucleated polychromatic erythrocytes to total erythrocytes up to 5000 mg/kg/day for 2 days detected in the micronucleus test. These results confirm that WG extract is safe for use as an herbal medicine, as it precipitates no detectable genotoxic effects.

scholarly journals Genotoxic and Antigenotoxic Assessment of Chios Mastic Oil by the In Vitro Micronucleus Test on Human Lymphocytes and the In Vivo Wing Somatic Test on Drosophila

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0130498 ◽  
Author(s):  
Dimitris Vlastos ◽  
Elena Drosopoulou ◽  
Ioanna Efthimiou ◽  
Maximos Gavriilidis ◽  
Dimitra Panagaki ◽  
...  
Keyword(s):  
Micronucleus Test ◽  
Human Lymphocytes

scholarly journals Antimutagenic Effects of Polymethoxy Flavonoids of Citrus unshiu

2017 ◽  
Vol 12 (1) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Takahiro Matsumoto ◽  
Taisuke Nishikawa ◽  
Ayano Furukawa ◽  
Saki Itano ◽  
Yuka Tamura ◽  
...  
Keyword(s):  
Salmonella Typhimurium ◽  
Traditional Medicine ◽  
Ames Test ◽  
Micronucleus Test ◽  
Ethanolic Extract ◽  
Citrus Unshiu ◽  
Citrus Fruits ◽  
Edible Fruit

Citrus fruits have been used as edible fruit and traditional medicine for various diseases such as cancer. In the courses of our study to find antimutagens, we have found that the ethanolic extract of the peel of Citrus unshiu Marc showed antimutagenic effects against several mutagens in the Ames test using Salmonella typhimurium TA98 strain. Three polymethoxy flavonoids, nobiletin, 3,5,6,7,8,3′,4′-heptamethoxyflavone, and tangeretin, were identified in the extract as major constituents. These three polymethoxy flavonoids showed antimutagenic effects in the Ames test in vitro and in the micronucleus test in vivo.

scholarly journals Monitoring the Fate of Orally Administered PLGA Nanoformulation for Local Delivery of Therapeutic Drugs

Pharmaceutics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 658 ◽  
Author(s):  
Lucia Morelli ◽  
Sara Gimondi ◽  
Marta Sevieri ◽  
Lucia Salvioni ◽  
Maria Guizzetti ◽  
...  
Keyword(s):  
Oral Administration ◽  
Systemic Exposure ◽  
Plga Nanoparticles ◽  
In Vivo Studies ◽  
Cancer Drug ◽  
Therapeutic Drugs ◽  
Human Disorders ◽  
Carcinoma Colon

One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract; (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells; (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure; (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders.

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