• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.1971-1976
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• 2015

Background: To evaluate our results in terms of response, survival and toxicity profile of sunitinib among Egyptian patients with metastatic renal cell carcinoma. Materials and Methods: Between January 2010 and December 2013, 44 patients with metastatic renal cell carcinoma who received sunitinib at an oncology center of Cairo university hospitals were enrolled in this retrospective analysis. Results: The median age of the patients was 53 years, 22 (50%) having localized disease at presentation, while the remaining half of the patients presented with metastasis. At a median follow up of 19 months, 9 (21%) patients achieved partial remission, while disease was reported stable in 20 cases (45%) and progressive in 7 (16%), 4 (9%) being lost to follow up, and 4 (9%) had discontinued therapy due to toxicity. The median overall survival was 23 months (95%CI 15.2 - 30.9), while progression free survival was 12 months (95%CI 11.6 - 12.3). The most commonly reported non hematological grade 3 adverse events included mucositis (15.9%), hand-foot syndrome (13.6%), and fatigue (9%), while the predominant grade 3 or 4 laboratory abnormalities were neutropenia (6.8%), followed by anemia in 4.5% of patients. Conclusions: Our efficacy data were comparable to the published literature in terms of progression free survival and overall survival, while toxicity profile is different from Asian and western countries. However, sunitinib adverse events were manageable and tolerable in most of our Egyptian patients.

• Environmental Analysis Health and Toxicology
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• v.30 no.sup
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• pp.7.1-7.10
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• 2015

Objectives For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. Methods There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. Results We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. Conclusions We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used with predicted toxicity results. Furthermore, by presenting the suitability of individual predicted results, we aimed to provide a foundation that could be used in actual assessments and regulations.

• Journal of Pharmacopuncture
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• v.18 no.3
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• pp.63-67
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• 2015

Objectives: This study was performed to analyze the single-dose oral toxicity of the super key (processed sulfur). Methods: All experiments were conducted at Medvill, an institution authorized to perform non-clinical studies, under the Good Laboratory Practice (GLP) regulations. In order to investigate the oral toxicity of super key. We administered it orally to Sprague-Dawley (SD) rats. The SD rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of super key 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg were administered to the experimental groups, and a dose of normal saline solution, 10 mL/kg, was administered to the control group. We examined the survival rates, weights, clinical signs, gross findings and necropsy findings. This study was conducted under the approval of the Institutional Animal Ethics Committee. (Approval number: A01-14018). Results: No deaths or abnormalities occurred in any of the four groups. Although slight decreases in the weights of some female rats were noted, no significant changes in weights or differences in the gross findings between the control group and the experimental groups were observed. To check for abnormalities in organs, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs. Conclusion: The results of this research showed that administration of 500 - 2,000 mg/kg of super key did not cause any changes in the weights or in the results of necropsy examinations. Neither did it result in any mortalities. The above findings suggest that treatment with super key is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

• Bulletin of the Korean Chemical Society
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• v.34 no.11
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• pp.3301-3306
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• 2013

This paper aims to address the cellular toxicity of ultra-pure titanium dioxide ($TiO_2$) and zinc oxide (ZnO) nanoparticles (NPs) frequently employed in sunscreens as inorganic physical sun blockers to provide protection against adverse effects of ultraviolet (UV) radiation including UVB (290-320 nm) and UVA (320-400 nm). In consideration that the production and the use of inorganic NPs have aroused many concerns and controversies regarding their safety and toxicity and that microsized $TiO_2$ and ZnO have been increasingly replaced by $TiO_2$ and ZnO NPs (< 100 nm), it is very important to directly investigate a main problem related to the intrinsic/inherent toxicity of these NPs and/or their incompatibility with biological objects. In the present study, we took advantage of the laser-assisted method called laser ablation for generation of $TiO_2$ and ZnO NPs. NPs were prepared through a physical process of irradiating solid targets in liquid phase, enabling verification of the toxicity of ultra-pure NPs with nascent surfaces free from any contamination. Our results show that $TiO_2$ NPs are essentially non-poisonous and ZnO NPs are more toxic than $TiO_2$ NPs based on the cell viability assays.

• Journal of Pharmacopuncture
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• v.19 no.3
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• pp.213-224
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• 2016

Objectives: Ginseng Rh2+ is enzyme-treated ginseng extract containing high amounts of converted ginsenosides, such as compound k, Rh2, Rg3, which have potent anticancer activity. We conducted general and genetic toxicity tests to evaluate the safety of ginseng Rh2+. Methods: An acute oral toxicity test was performed at a high-level dose of 4,000 mg/kg/day in Sprague-Dawley (SD) rats. A 14-day range-finding study was also conducted to set dose levels for the 90-day study. A subchronic 90-day toxicity study was performed at dose levels of 1,000 and 2,000 mg/kg/day to investigate the no-observed-adverse-effect level (NOAEL) of ginseng Rh2+ and target organs. To identify the mutagenic potential of ginseng Rh2+, we conducted a bacterial reverse mutation test (Ames test) using amino-acid-requiring strains of Salmonella typhimurium and Escherichia coli (E. coli), a chromosome aberration test with Chinese hamster lung (CHL) cells, and an in vivo micronucleus test using ICR mice bone marrow as recommended by the Korean Ministry of Food and Drug Safety. Results: According to the results of the acute oral toxicity study, the approximate lethal dose (ALD) of ginseng Rh2+ was estimated to be higher than 4,000 mg/kg. For the 90-day study, no toxicological effect of ginseng Rh2+ was observed in body-weight changes, food consumption, clinical signs, organ weights, histopathology, ophthalmology, and clinical pathology. The NOAEL of ginseng Rh2+ was established to be 2,000 mg/kg/day, and no target organ was found in this test. In addition, no evidence of mutagenicity was found either on the in vitro genotoxicity tests, including the Ames test and the chromosome aberration test, or on the in vivo in mice bone marrow micronucleus test. Conclusion: On the basis of our findings, ginseng Rh2+ is a non-toxic material with no genotoxicity. We expect that ginseng Rh2+ may be used as a novel adjuvant anticancer agent that is safe for long-term administration.

• Journal of Pharmacopuncture
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• v.18 no.2
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• pp.76-85
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• 2015

Objectives: Radix Ginseng has been traditionally used as an adaptogen that acts on the adrenal cortex and stimulates or relaxes the nervous system to restore emotional and physical balance and to improve well-being in cases of degenerative disease and/or old age. Radix Ginseng has been used for a long time, but the safety of ginseng pharmacopuncture needs testing. This study was done to analyze the single-dose toxicity of water- soluble ginseng pharmacopuncture (GP) intramuscular injections in rats. Methods: All experiments were performed at Biotoxtech, an institution authorized to perform non clinical studies under the regulations of Good Laboratory Practice (GLP). Each group contained 10 Sprague-Dawley rats, 5 males and 5 females. GP was prepared in a sterile room at the Korean Pharmacopuncture Institute under regulations of Good Manufacturing Practice (GMP). GP dosages were 0.1, 0.5 and 1.0 mL for the experimental groups; normal saline was administered to the control group. The animals general condition was examined daily for 14 days, and the rats were weighed on the starting day and at 3, 7 and 14 days after administration of the pharmacopuncture. Hematological and biochemistry tests and autopsies were done to test the toxicological effect of GP after 14 days. This study was performed with approval from the Institutional Animal Ethics Committee of Biotextech. Results: No deaths were found in this single-dose toxicity test of intramuscular injections of GP, and no significant changes in the general conditions, body weights, hematological and biochemistry tests, and autopsies were observed. The local injection site showed no changes. Based on these results, the lethal dose was assumed to be over 1.0 mL/animal in both sexes. Conclusion: These results suggest that GP is relatively safe. Further studies, including a repeated toxicity test, are needed to provide more concrete evidence for the safety of GP.

• Toxicological Research
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• v.28 no.4
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• pp.263-268
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• 2012

The aim of this study was to investigate the acute oral toxicity of fermented Scutellariae Radix (JKTMHGu-100) in rats and dogs. JKTM-HGu-100 was orally administered at a dose of 2,000 mg/kg in Sprague-Dawley rats. An escalating single-dose oral toxicity test in beagle dogs was performed at doses of 500, 1000, and 2000 mg/kg with 4-day intervals. Clinical signs, changes in body weight, mortality, and necropsy findings were examined for 2 weeks following oral administration. No toxicological changes related to the test substance nor mortality was observed after administration of a single oral dose of JKTM-HGu-100 in rats or dogs. Therefore, the approximate lethal dose (LD) for oral administration of JKTMHGu-100 in rats was considered to be over 2,000 mg/kg, and the maximum tolerance doses (MTDs) in rats and dogs were also estimated to be over 2,000 mg/kg. These results indicate that JKTM-HGu-100 shows no toxicity in rodents or non-rodents at doses of 2,000 mg/kg or less.

• Molecules and Cells
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• v.46 no.8
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• pp.496-512
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• 2023

A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of fructose-induced hepatic damage remains poorly understood. This study aimed to determine whether fructose induces cell death in primary hepatocytes, and if so, to establish the underlying cellular mechanisms. Our results revealed that treatment with high fructose concentrations for 48 h induced mitochondria-mediated apoptotic death in mouse primary hepatocytes (MPHs). Endoplasmic reticulum stress responses were involved in fructose-induced death as the levels of phosho-eIF2α, phospho-C-Jun-N-terminal kinase (JNK), and C/EBP homologous protein (CHOP) increased, and a chemical chaperone tauroursodeoxycholic acid (TUDCA) prevented cell death. The impaired oxidation metabolism of fatty acids was also possibly involved in the fructose-induced toxicity as treatment with an AMP-activated kinase (AMPK) activator and a PPAR-α agonist significantly protected against fructose-induced death, while carnitine palmitoyl transferase I inhibitor exacerbated the toxicity. However, uric acid-mediated toxicity was not involved in fructose-induced death as uric acid was not toxic to MPHs, and the inhibition of xanthine oxidase (a key enzyme in uric acid synthesis) did not affect cell death. On the other hand, treatment with inhibitors of the nicotinamide adenine dinucleotide (NAD)⁺-consuming enzyme CD38 or CD38 gene knockdown significantly protected against fructose-induced toxicity in MPHs, and fructose treatment increased CD38 levels. These data suggest that CD38 upregulation plays a role in hepatic injury in the fructose-enriched diet-mediated NASH. Thus, CD38 inhibition may be a promising therapeutic strategy to prevent fructose-enriched diet-mediated NASH.

• Journal of Environmental Health Sciences
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• v.50 no.3
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• pp.201-211
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• 2024

Background: Organic ultraviolet (UV) filters are widely used in sunscreen products and have been identified as an emerging contaminant. Organic UV filters co-exist with multiple components, but their mixture toxicity remains largely unknown. Objectives: We investigated the toxicity of single and binary mixtures of commonly used UV-filters using the human adrenocarcinoma (H295R) cell line. Methods: After exposure to non-cytotoxic concentrations of avobenzone (AVO), homosalate (HS), octisalate (OS), octinoxate (OMC), and octocrylene (OC), the levels of testosterone (T) and 17β-estradiol (E2) were measured. The median effective concentration (EC₅₀) values for the E2 of the individual substances were used to determine the mixture effect of four binary combinations: OMC+AVB, OMC+HS, OMC+OS, and OMC+OC. The synergistic, additive, and antagonistic effects of the mixture were determined by calculating toxic units (TU). To examine the mechanism of mixture toxicity, eight genes involved in steroidogenesis were analyzed using the real-time polymerase chain reaction. Results: The significant increase in E2 in H295R cells exposed to AVO, HS, OS, OMC, and OC suggest an estrogenic effect of the tested UV-filters. A significant decrease in T was observed in cells exposed to HS and OS. EC₅₀ values for E2 increase were 105 nM for AVO, 110 nM for HS, 120 nM for OS, 55 nM for OMC, and 80 nM for OC. Both binary mixtures consisting of OMC+HS and OMC+OS have synergistic effects. Conclusions: Our results showed that five types of UV-filter substances increase E2 in H295R cells. We examined the mixture toxicity in terms of increased estrogenicity and confirmed that E2 significantly increased when OMC was mixed with a salicylate-based UV-filters. These findings highlight the importance of determining the impact of UV filter mixtures.

• Biomolecules & Therapeutics
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• v.5 no.2
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• pp.133-149
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• 1997

4-week repeated dose toxicity of DA-5018, a new capsaicin analogue analgesic agent, was examined in 5D rats at dosage levels of 0,0.4,2, 10 and 50 mg/kg/day. DA-5018 was administered orally to 17 males and 17 females per group at doses of 0, 10 and 50 mg/kg and to 12 males and 12 females per group at doses of 0.4 and 2 mg/kg. After the administration period, 5 males and 5 females at the 0, 10 and 50 mg/kg were placed on withdrawal for 2 weeks. Treatment-related clinical signs were observed at 10 and 50 mg/kg. Clinical signs observed immediately after the administration of DA-5018 were grooming, sedation or depression, lacrimation, atacia, reddening of extremities and ears, ventral or lateral recumvincy, respiratory distress, cyanosis and convulsion. Delayed-type clinical signs including focal scabbing and depilation around nose were also observed 1 or 2 weeks after the start of administration of DA-5018. Only at the 50 mg/kg group, corneal opacities, reduced body weight gain (male) and death (male 6/17, female 3/17) were noted. In blood biochemical analysis, serum levels of glucose and triglyceride decreased at 10 and 50 mg/kg. In hematological examination, there were increases in the number of red blood cell, hemoglobin content and percent of hematocrit at 10 and 50 mg/kg. Pulmonary enlargement and hemorrhagic spot, focal scabbing and depilation around nose and corneal opacities were seen at the necropsy of the animals died during the dosing of DA-5018 50 mg/kg. Focal scabbing and depilation around nose were observed in the animals terminally necropsied at doses of 10 and 50 mg/kg. Histopathological examination revealed pulmonary hemorrhage, focal necrosis in the scabbed area, corneal necrosis, fibrosis and neovasculization in the stroma. At 0.4 and 2 mg/kg, there were no significant toxic changes attributable to the administration of DA-5018. In conclusion, target organs following to 4-week repeated dose of DA-5018 in the rat were determined to be lung, skin and eyes. Definite toxic dose and no-observed-adverse-effect-level (NOAEL) were estimated to be 50 and 2 mg/kg/day, respectively.