• 대한수의학회지
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• 제43권1호
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• pp.57-66
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• 2003

Single and 28-day repeated dose toxicity studies of botulimnn toxin type A were carried out in ICR mice and Sprague-Dawley rats, respectively. In the single dose toxicity study, botulinwn toxin was injected intraperitoneally to male and female mice at a single dose of 40, 59, 89 133 and 200 ng/10 ml saline/kg. All animals died from 59 ng/kg group. Some clinical signs, such as decrease in locomotor activity, dyspnea, prone position and ptosis, were observed in most of both sexes from 59 ng/kg group, but no signs were seen in all animals at 40 ng/kg group. The results showed that the median lethal dose of botulinum toxin might be in the range of 40-59 ng/kg in both sexes. In the repeated dose toxicity study, the test material was administered intradermally for 28 days at doses of 0 (vehicle-treated control), 1.25, 2.5, 5.0 and $10.0ng/head/50{\mu}{\ell}$ saline in male and female rats. No test material-related changes were noted in survivals, clinical signs, food and water consumptions and gross finding in any group. Botulinum toxin treatment significantly decreased the body weight gain rate in male of 5.0 ng/head group and over and in female of 10.0 ng/head group compared to vehicle-treated control. One or more relative organ weights (i.e., spleen, thymus, liver and kidney) were increased significantly from 5.0 ng/head group compared to vehicle-treated control in both sexes. Serum biochemistry revealed increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase, total protein and albumin in male, and increases in AST and ALT and decreases in $K^+$ and $Cl^-$ in female without dose-pendent manners. In the histopathological study, physical stimulation by needle caused slight inflammations of dennis. In addition, botulinum toxin treatment induced denervation of nerve cell and disuse of muscle, resulting in atrophy of skeletal muscle in both sexes from 2.5 ng/head group. When the antibodies to toxin were determined in all animals, a significant increase in serum antibodies was observed from 5.0 ng/head group. The results showed that the NOAEL of botulinum toxin might be 1.25 ng/head for 28-day repeated dose toxicity in rats.

• Journal of Applied Biological Chemistry
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• 제59권3호
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• pp.227-231
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• 2016

Deep sea water (DSW) is located 100 to 500 m below the sea surface. DSW is widely used in various fields, and is an important source of minerals that can be used to treat mineral deficiency. In the present study, the oral toxicity of DSW-mineral extracts was determined using single-dose and 14-day repeated dose oral toxicity tests in ICR mice. For the single-dose oral toxicity tests, mineral extracts of magnesium (Mg) and calcium (Ca) at doses of 0, 6, 270, 810, and 1,350 mg/kg, respectively, were orally administered to mice once at the beginning of the experiment, and the mice were observed for 14 days. For the 14-day repeated dose oral toxicity tests, Mg and Ca mineral extracts at doses of 0, 3, 135, 405, 675 mg/kg, respectively, were orally administered to mice daily, and the mice were observed for 14 days. Various tests were performed including visual observation; analysis of relative organ weight, food intake, and organ weight; biochemical analysis, and histopathology. The results indicated that mortality and changes in appearance were not observed among differentially administered groups of male and female ICR mice during the experimental period. Differences in body weight gain, food intake, organ weight, and histopathology parameters were not significant between the control and mineral-administered groups. Some results of the biochemical analyses were significantly different, but showed no specific tendencies. Overall, no evidence of toxicity was observed from the oral administration of DSW extracts of Ca and Mg in ICR mice.

• Radiation Oncology Journal
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• 제35권2호
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• pp.121-128
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• 2017

Purpose: To report the results of a correlation analysis of skin dose assessed by in vivo dosimetry and the incidence of acute toxicity. This is a phase 2 trial evaluating the feasibility of intraoperative radiotherapy (IORT) as a boost for breast cancer patients. Materials and Methods: Eligible patients were treated with IORT of 20 Gy followed by whole breast irradiation (WBI) of 46 Gy. A total of 55 patients with a minimum follow-up of 1 month after WBI were evaluated. Optically stimulated luminescence dosimeter (OSLD) detected radiation dose delivered to the skin during IORT. Acute toxicity was recorded according to the Common Terminology Criteria for Adverse Events v4.0. Clinical parameters were correlated with seroma formation and maximum skin dose. Results: Median follow-up after IORT was 25.9 weeks (range, 12.7 to 50.3 weeks). Prior to WBI, only one patient developed acute toxicity. Following WBI, 30 patients experienced grade 1 skin toxicity and three patients had grade 2 skin toxicity. Skin dose during IORT exceeded 5 Gy in two patients: with grade 2 complications around the surgical scar in one patient who received 8.42 Gy. Breast volume on preoperative images (p = 0.001), ratio of applicator diameter and breast volume (p = 0.002), and distance between skin and tumor (p = 0.003) showed significant correlations with maximum skin dose. Conclusions: IORT as a boost was well-tolerated among Korean women without severe acute complication. In vivo dosimetry with OSLD can help ensure safe delivery of IORT as a boost.

• Toxicological Research
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• 제35권3호
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• pp.225-232
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• 2019

Thymus vulgaris L. is widely used as an ingredient in cooking and in herbal medicine. However, there is little information about its toxicity. The present study was performed to evaluate the acute and repeated 28-day oral dose toxicity of thyme essential oil in rats. For the acute toxicity test, two groups of three rats were used. The rats received a single dose of essential oil: 300 or 2,000 mg/kg of body weight (bw). The rats were observed individually during the first four hours, and then daily until day 14. For the toxicity test with repeated doses, four groups of 10 rats were used. Doses of 100, 250, and 500 mg/kg/day were tested for 28 days. At the end of the experiment, blood was collected and the animals were sacrificed. Histopathological examination showed that in the lungs of rats given the 2,000 mg/kg bw dose, polymorph nuclear infiltrates, hemosiderin macrophages, and interstitial space thickening were present. In the repeated dose study, all rats survived the 28-day treatment period and apparently showed no signs of toxicity. The hematological and biochemical parameters were not altered. The histopathological study of the organs showed severe changes in the lung, with the dose of 500 mg/kg/day; in the other organs, no alterations were observed or the changes were slight. The body weight was only altered in male rats given the 500 mg/kg dose. The relative weight of the organs did not show any significant changes. Our studies revealed that the essential oil of Thymus vulgaris has moderate oral toxicity according to the results of the acute test, whereas the results of the 28-day oral toxicity test suggest that the no-observed-adverse effect level (NOAEL) is greater than 250 mg/kg/day.

• Toxicological Research
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• 제22권2호
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• pp.135-144
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• 2006

This study was performed to evaluate repeated-dose toxicities of STB-HO-BM in Sprague-Dawley rats. STB-HO-BM was administered orally to rats at dose levels of 0, 100, 300 and 1,000 mg/kg/day for 13 weeks. In recent study, there were no dose related changes in mortality, clinical signs, body weight changes, food and water consumption, opthalmoscopy, organ weights, urine analysis, hematological findings, and biochemical examination of all animals treated with STB-HO-BM. Gross and histopathological findings revealed no evidence of specific toxicity related to STB-HO-BM. These results suggest that the oral no observed adverse effect level (NOAEL) of STB-HO-BM may be over 1,000 mg/kg in rats.

• Radiation Oncology Journal
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• 제31권4호
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• pp.234-238
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• 2013

Purpose: Esophageal tolerance is needed to guide the safe administration of stereotactic radiosurgery (SRS). We evaluated comprehensive dose-volume parameters of acute esophageal toxicity in patients with spinal metastasis treated with SRS. Materials and Methods: From May 2008 to May 2011, 30 cases in 27 patients with spinal metastasis received single fraction SRS to targets neighboring esophagus. Endpoints evaluated include length (mm), volume (mL), maximal dose (Gy), and series of dose-volume thresholds from the dose-volume histogram (volume of the organ treated beyond a threshold dose). Results: The median time from the start of irradiation to development of esophageal toxicity was 2 weeks (range, 1 to 12 weeks). Six events of grade 1 esophageal toxicity occurred. No grade 2 or higher events were observed. $V_{15}$ of external surface of esophagus was found to predict acute esophageal toxicity revealed by multivariate analysis (odds radio = 1.272, p = 0.047). Conclusion: In patients with spinal metastasis who received SRS for palliation of symptoms, the threshold dose-volume parameter associated with acute esophageal toxicity was found to be $V_{15}$ of external surface of esophagus. Restrict $V_{15}$ to external surface of esophagus as low as possible might be safe and feasible in radiosurgery.

• Asian Pacific Journal of Cancer Prevention
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• 제15권8호
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• pp.3619-3623
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• 2014

Background: The aim of the study was to evaluate the vaginal dose and toxicity in patients of cervical cancer treated with image guided brachytherapy at our institute. Materials and Methods: Thirty-five patients treated with image based brachytherapy for cervical cancer were included. Vaginal contouring was done on MRI at brachytherapy and with CT scans of subsequent brachytherapy fractions. Dose volume parameters (DVH) were reported in accordance with the GEC-ESTRO guidelines. These were correlated with vaginal toxicity (assessed by CTCAE version 3) and quality of sexual life assessed at one year of completion of treatment. Results: Vaginal shortness was observed in 22 out of 30 (62.8%) patients, Nine (25.7%) had vaginal dryness and in 10 (28.5%) patients, there was contact bleeding. No association could be demonstrated between the dose volume parameters and vaginal toxicity in the present study. Conclusions: The lack of association between dose volume parameters of vagina with vaginal morbidity may be due to uncertainties involved in the delineation of vaginal wall and dosimetry. Future research is required to accurately define vaginal dose distribution to study its correlation with vaginal morbidity. Vaginal morbidity needs to be documented in order to improve the sexual outcome in these patients.

• 한방재활의학과학회지
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• 제25권2호
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• pp.73-80
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• 2015

Objectives To assess the safety of Shinbaro3 Pharmacopuncture by analyzing the potential single-dose intramuscular toxicity of Shinbaro3 Pharmacopuncture at various dose levels in SD (Spraque-Dawley) rats and Beagle dogs. Methods For evaluation of single-dose intramuscular toxicity of Shinbaro3 Pharmacopuncture, 40 SD rats (20 male and 20 famale) and 4 Beagle dogs (2 male and 2 female) were used. The rats were divided in four groups of 10 each, and treated intramuscularly with Shinbaro3 Pharmacopuncture at doses of 0.3, 0.6 and 1.2 mg/kg in distilled water, and distilled water as a vehicle control group, respectively. The Beagle dogs were divided into two groups of 2 each, and treated intramuscularly with Shinbaro3 Pharmacopuncture at doses of 0.15, and 0.3 mg/kg in distilled water, respectively, and signs of toxicity were observed. After a wash-out period of 3 days, the procedure was repeated with Shinbaro3 Pharmacopuncture at doses of 0.6, and 1.2 mg/kg in distilled water, respectively. Mortality, body weight changes, and necropsy findings were examined during the study period. Results There were no mortalities in either the SD rats or Beagle dogs. There were also no significant differences in adverse effects, body weight, or necropsy findings between the Shinbaro3 Pharmacopuncture and control groups. Conclusions There results suggest that the lethal dose 50 ($LD_{50}$) and approximate lethal dose (ALD) value of the test substance Shinbaro3 Pharmacopuncture are higher than 1.2 mg/kg in SD rats and Beagle dogs.

• 한국자원식물학회:학술대회논문집
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• 한국자원식물학회 2021년도 춘계학술대회
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• pp.59-59
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• 2021

Stachys sieboldii Miq. (SSM) and Acorus gramineus Soland. (AGS) have been used as traditional medicines for thousands of years in parts of Asia, including Korea, China, and Japan. Recent researches on SSM and AGS have documented a wide spectrum of therapeutic properties, including anti-inflammatory, anti-oxidative, neurodegenerative disease effects. However, the toxicity and safety of SSM and AGS, and their mixture (medicinal herber mixture, MHMIX) were not confirmed. Therefore, this study was performed to evaluate the acute toxicity and safety of SSM, AGS and MHMIX. SSM, AGS and MHMIX were orally administered at a dose of 5,000 mg/kg in ICR mice. Animals were monitored for the mortality and changes in the body weight, clinical signs and gross observation during the 14 days after dosing, upon necropsy. We also measured parameters of organ weight, clinical chemistry, and hematology. No dead and no clinical signs were found during the experiment period after administration of a single oral dose of SSM, AGS and MHMIX. There were no adverse effects on clinical signs, body weight, or organ weight and no gross pathological findings in any treatment group. Therefore, LD50 value of SSM, AGS and MHMIX may be over 5,000 mg/kg and it may have no side toxic effect to ICR mice. The results on the single-dose toxicity of SSM, AGS and MHMIX indicate that it is not possible to reach oral dose levels related to death or dose levels with any harmful side effects.

• 한국자기공명학회논문지
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• 제15권1호
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• pp.54-68
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• 2011

$^1H$ nuclear magnetic resonance (NMR) spectroscopy of biological samples has been proven to be an effective and nondestructive approach to probe drug toxicity within an organism. In this study, ketoprofen toxicity was investigated using $^1H$-NMR spectroscopy coupled with multivariate statistical analysis. Histopathologic test of ketoprofen-induced acute gastrointestinal damage in rats demonstrated a significant dose-dependent effect. Furthermore, principal component analysis (PCA) derived from $^1H$-NMR spectra of urinary samples showed clear separation between the vehicle-treated control and ketoprofen-treated groups. Moreover, PCA derived from endogenous metabolite concentrations through targeted profiling revealed a dose-dependent metabolic shift between the vehicle-treated control, low-dose ketoprofen-treated (10 mg/kg body weight), and high-dose ketoprofen-treated (50 mg/kg) groups coinciding with their gastric damage scores after ketoprofen administration. The resultant metabolic profiles demonstrated that the ketoprofen-induced gastric damage exhibited energy metabolism perturbations that increased urinary levels of citrate, cis-aconitate, succinate, and phosphocreatine. In addition, ketoprofen administration induced an enhancement of xenobiotic activity in fatty oxidation, which caused increase levels of N-isovalerylglycine, adipate, phenylacetylglycine, dimethylamine, betaine, hippurate, 3-indoxylsulfate, N,N-dimethylglycine, trimethyl-N-oxide, and glycine. These findings demonstrate that $^1H$-NMR-based urinary metabolic profiling can be used for noninvasive and rapid way to diagnose adverse drug effects and is suitable for explaining the possible biological pathways perturbed by nonsteroidal anti-inflammatory drug toxicity.