• Biomolecules & Therapeutics
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• v.6 no.1
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• pp.95-110
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• 1998

A 13-week dermal toxicity test was conducted to assess the toxicity of DA-5018, a capsaicin derivative. Three groups of Sprague-Dawley rats (10-15 males and 10-15 females) were treated with DA-5018 cream daily by dermal application at concentrations of 0.1%, 0.3% or 0.9% as 500 mg/kg for 13 weeks. One further group of rats (15 males and 15 females) received cream base at 500 mg/kg/day and acted as controls. One male receiving 0.3% DA-5018 cream died during the treatment period. But the animal did not show any signs of treatment-related toxicity until death. There were no local skin reaction of application site and systemic reaction to the treatment of DA-5018 creams in all experimental groups throughout treatment and recovery period. Weight gain and food consumption in animals that received DA-5018 creams appeared to be comparable to that of the controls. Laboratory analyses (hematology, urinalysis and opthalmoscopic examination) did not revealed pathological values. In biochemical investigations, an increase of glucose level associated with increased food consumption and some other significant changes were noted in the animals of both sexes received DA-5018 creams. But these changes were not considered to be of toxicological importance. Postmortem examination did not show macroscopic or histological alterations attributable to the DA-5018 treatments. Based on these results, NOAEL(no-observable-adverse-effect level) of DA-5018 cream if estimated to be over 500 mg/tg/day as 0.9% cream.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4567-4570
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• 2014

Background: This systemic analysis was conducted to evaluate the efficacy and safety of pemetrexed based chemotherapy in treating patients with metastatic breast cancer as first or second line chemotherapy. Methods: Clinical studies evaluating the efficacy and safety of pemetrexed based regimens on response and safety for patients with breast cancer were identified using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. Results: In first line pemetrexed based regimens, 10 clinical studies which including 513 patients with advanced breast cancer were considered eligible for inclusion. For second line pemetrexed based chemotherapy, 5 clinical studies which including 281 patients with advanced breast cancer were considered eligible. Systemic analysis suggested that, in all patients, pooled RR was 32.6% (167/513) in pemetrexed based first line regimens, and 13.9 % (39/281) in pemetrexed based second line regimens. Major adverse effects were neutropenia, leukopenia, fatigue, and anemia in pemetrexed based first line treatment; and lymphopenia, neutropenia, leukopenia, as well as anemia in second line chemotherapy. One treatment related death occurred with pemetrexed based second line treatment. Conclusion: This systemic analysis suggests that pemetrexed based first line regimens are associated with a reasonable response rate and acceptable toxicity, however with low response rate for treating patients with metastatic breast cancer when is used in the second line.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.407-411
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• 2014

Objective: To observe local and systemic toxicity after sustained-release 5-fluorouracil (5-Fu) implantation in canine peritoneum and para-aortic abdominalis and the changes of drug concentration in the local implanted tissue with time. Methods: 300 mg sustained-release 5-Fu was implanted into canine peritoneum and para-aorta abdominalis. Samples were taken 3, 5, 7 and 10 days after implantation for assessment of changes and systemic reactions. High performance liquid chromatography was applied to detect the drug concentrations of peritoneal tissue at different distances from the implanted site, lymphatic tissue of para-aortic abdominalis, peripheral blood and portal venous blood. Results: 10 days after implantation, the drug concentrations in the peritoneum, lymphatic tissue and portal vein remained relatively high within 5 cm of the implanted site. There appeared inflammatory reaction in the local implanted tissue, but no visible pathological changes such as cell degeneration and necrosis, and systemic reaction like anorexia, nausea, vomiting and fever. Conclusions: Sustained-release 5-Fu implantation in canine peritoneum and para-aortic abdominalis can maintain a relatively high tumour-inhibiting concentration for a longer time in the local implanted area and portal vein, and has mild local and systemic reactions. Besides, it is safe and effective to prevent or treat recurrence of gastrointestinal tumours and liver metastasis.

• Toxicological Research
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• v.31 no.1
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• pp.49-59
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• 2015

Eye is a highly vascularised organ. There are chances that a foreign substance can enter the systemic circulation through the eye and cause oxidative stress and evoke immune response. Here the eyes of rabbits were exposed, for a period of 7 days, to 5 known ocular irritants: Cetyl pyridinium chloride (CPC), sodium salicylate (SS), imidazole (IMI), acetaminophen (ACT) and nicotinamide (NIC). The eyes were scored according to the draize scoring. Blood collected from the treated rabbit were analyzed for haematological and biochemical parameters. After sacrifice, histological analysis of the eye and analysis of pro-inflammatory biomarkers ($IL-1{\alpha}$, $IL-1{\beta}$, IL-8 and $TNF-{\alpha}$) in the cornea using ELISA was carried out. Spleen was collected and the proliferation capacities of spleenocytes were analyzed. Liver and brain were collected and assessed for oxidative stress. The eye irritation potential of the chemicals was evident from the redness and swelling of the conjunctiva and cornea. Histopathological analysis and ELISA assay showed signs of inflammation in the eye. However, the haematological and biochemical parameters showed no change. Spleenocyte proliferations showed only slight alterations which were not significant. Also oxidative stress in the brain and liver were negligible. In conclusion, chemicals which cause ocular irritation and inflammation did not show any systemic side-effects in the present scenario.

• YAKHAK HOEJI
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• v.39 no.4
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• pp.417-426
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• 1995

6-[(N-4-Chlorophenyl)amino]-7-chloro-5,8-quinolinedione (RCK20) was tested for antifungal activities, in vivo, against Candida albicans. RCK20 was compared vath ketoconazole and fluconazole in the treatment of systemic infection with Candida albicans in normal rats. The therapeutic potential of RCK20 had been assessed by evaluating their activities (survival rate) against systemic infections with in normal mice with Candida albicans. RCK20 improved survival rates as well as ketokonazole. RCK20 had ED$_{50}$. 0.25$\pm$0.18 mg/kg but ketoeonazole and fluconazole had ED$_{50}$, 8.00$\pm$0.73, 10$\pm$0.43 mg/kg respectively. Activities of RCK20 showed superior to that of ketoconazole and fluconazole. Intraperitoneauy administered RCK20 at the ED$_{50}$, 0.25 mg/kg for 7days and 14days reduced Candida albicans colony count in the kidneys and livers as well as ketoconazole and fluconazole at these ED$_{50}$, 8.00 and 10 mg/kg. Acute oral toxicity studies of RCK20 were carried out in ICR mice of both sexes. These acute oral toxicities of RCK20 were low and LD$_{50}$ values were over 2.850 mg/kg in ICR mice. The Genotoxicities of RCK20 had been evaluated. RCK20 was negative in Ames test with Salmonella typhimurium (TA98 and TA100). The clastogenicity was tested on the RCK20 with in vivo mouse micronucleus assay. RCK20 did not show any clastogenic effect in mouse peripheral blood and was negative in mouse micronucleus assay. These results indicate that RCK20 has no genotoxic potential under these experimental condition.

• Journal of Environmental Health Sciences
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• v.46 no.6
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• pp.667-675
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• 2020

Objectives: Exposure to fine dust (PM10) could contribute to the occurrence of cardiovascular disease or respiratory abnormalities. Since garlic is known to possess an anti-oxidative stress effect, the present study was performed to evaluate the effect of garlic intake on fine dust-mediated pulmonary toxicity. Methods: Rats were intratracheally instilled with fine dust at 15 mg/kg body weight (BW)/day for five days following five-day intragastric intubation of garlic at 0.7 or 1.4 g/kgBW/day, or 13.1 mg/kgBW/day S-allyl-cysteine (SAC) as a reference component in garlic. Blood and bronchoalveolar lavage fluid (BALF) were collected. Results: Deposit of fine dust was visually and histopathologically observed in the lungs. Body weight gain during the instillation period was significantly lowered in all the groups instilled with fine dust. Neutrophil numbers in blood were significantly elevated in the fine dust alone group, but this alteration was diminished in the groups administered with garlic. Levels of serum glutathione were lower in the rats instilled with fine dust alone, and this decrease in the glutathione level seems dose-dependently compensated among the groups administered with garlic. Similar findings were observed in the BALF with statistical significance. Typical pulmonary histopathological observation related with inflammation was demonstrated in the lungs of the rats exposed to fine dust alone, whereas such histopathologic findings were not improved in the groups administered with garlic. Conclusion: The present study suggests that garlic intake could alleviate fine dust-mediated pulmonary or systemic toxicities. Further investigation is necessary to delineate the mechanism of garlic-mediated effects on pulmonary function.

• Journal of Pharmaceutical Investigation
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• v.31 no.1
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• pp.7-12
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• 2001

Amphotericin B (AmB) is a drug of choice for the treatment of systemic fungal diseases, but its use is considerably limited due to a high incidence of toxicity, particularly nephrotoxicity. It has been demonstrated that the toxicity of AmB is caused by self-aggregated species of the drug and that unaggregated (monomeric) drug is nontoxic but still expresses antifungal activity. Poly (ethylene oxide) (PEO) is a water-soluble polymer, which may impact the aggregation state of AmB. We have studied the aggregation state of AmB as a function of PEO molecular weight and concentration. At 3,000 and 8,000 g/mole, there was minimal or no change of critical aggregation concentration (CAC) of AmB regardless of the concentration of polymer. By contrast at 20,000 g/mole, the CAC of AmB strikingly increased to 24.3 and $37.5\;{\mu}M$ at 5.0% and 10 % w/v of polymer, respectively. The critical overlap concentration (COC) of PEO 20,000 g/mole was 5.5%. It appears that an interaction between monomeric AmB and polymer coil increases above the COC, competing with self-aggregation of the drug. Accordingly, the degree of aggregation of AmB stayed low and the toxicity became less. There was no such effect at 3,000 and 8,000 g/mole of PEO, owing perhaps to small dimensions in comparison to AmB. Based upon these findings, less toxic AmB formulation may be developed by a pharmaceutical technique such as solid dispersion system containing both AmB and PEO 20,000 g/mole.

• Toxicological Research
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• v.20 no.2
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• pp.143-151
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• 2004

This study was to investigate single and repeated-dose toxicities of CJ-11555, an anticirrhotic agent, in Sprague-Dawley (SO) rats. In single-dose oral toxicity study, the test article were administered once by gavage to males and females at dose levels of 0 and 2,000 mg/kg. No dead animals and abnormal necropsy findings were found in control and CJ-11555 treated group. Therefore, the approximate lethal dose of CJ-11555 was considered to be higher than 2,000 mg/kg in rats. In the 4-week repeated oral toxicity study, the test article was administered once daily by gavage to male and female rats at dose levels of 0, 10, 50 and 200 mg/kg/day for 4-weeks. In clinical signs, yellow-colored urine and yellow hair coat were observed in the 50 and 200 mg/kg male and female groups. In hematology, erythrocyte count and hemoglobin were significantly decreased in the 200mg/kg male and female groups. In serum biochemistry, total cholesterol was significantly increased and aspartate aminotransferase (AST) was significantly decreased in the 50 or 200 mg/kg male and female groups. In histopathological examinations, centrilobular hepatocellular hypertrophy in the liver, congestion and pigmentation in the spleen, hyaline droplets in the kidney were observed in the 50 and 200 mg/kg male and female groups. In toxicokinetic study, CJ-11555 was dose-dependent in systemic exposure and showed better absorption in female with minimum accumulation after multidosing. Based on these results, it was concluded that the 4-week repeated oral dose of CJ-11555 resulted in the suppression of AST activity and centrilobular hepatocellular hypertrophy in both sexes at a dose level of 50 or 200 mg/kg/day. The target organ was estimated to be liver, spleen and male's kidney. The no-observed-adverse-effect level (NOAEL) for CJ-11555 in rats following gavage for at least 4-week is 10 mg/kg/day.

• Journal of Ginseng Research
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• v.43 no.4
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• pp.562-571
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• 2019

Background: Ginsenosides have been widely used clinically for many years and were regarded as very safe. However, a few researches on the toxicities of these kinds of agents showed that some ginsenosides may have side-effect on the rats or dogs. So it is extremely necessary to further clarify the potential toxicity of ginsenosides. This study was carried out to investigate long-term toxicity and genotoxicity of 25-methoxydammarane-3, 12, 20-triol ($25-OCH_3-PPD$), a new derivative of ginsenoside, in beagle dogs. Methods: Twenty-four beagle dogs were divided randomly into four treatment groups and repeatedly orally administered with $25-OCH_3-PPD$ capsule at 60, 120, and 240 mg/kg/day for 91 consecutive days. Ames, micronucleus, and chromosomal aberration tests were established to analyze the possible genotoxicity of $25-OCH_3-PPD$. Results: There was no $25-OCH_3-PPD$einduced systemic toxicity in beagle dogs at any doses. The level of $25-OCH_3-PPD$ at which no adverse effects were observed was found to be 240 mg/kg/day. The result of Ames test showed that there was no significant increase in the number of revertant colonies of $25-OCH_3-PPD$ administrated groups compared to the vehicle control group. There were also no significant differences between $25-OCH_3-PPD$ administrated groups at all dose levels and negative group in the micronucleus test and chromosomal aberration assay. Conclusion: The highest dose level of $25-OCH_3-PPD$ at which no adverse effects were observed was found to be 240 mg/kg per day, and it is not a genotoxic agent either in somatic cells or germs cells. $25-OCH_3-PPD$ is an extremely safe candidate compound for antitumor treatment.

• Journal of Yeungnam Medical Science
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• v.37 no.3
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• pp.230-235
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• 2020

Systemic therapy for metastatic triple-negative breast cancer (TNBC) still remains challenging because there are no targeted agents or endocrine therapies currently available. The present case report documents the successful use of cisplatin monotherapy to manage a heavily pretreated TNBC patient showing poor response to therapy. The patient was a 51-year-old woman who had already undergone several lines of systemic chemotherapy for widespread TNBC. Although the mutation analysis performed on DNA isolated from blood cells and progressed lesion samples confirmed the tumor to be germline BRCA wild-type, cisplatin monotherapy was administered based on the increasing evidence of safety and efficacy of platinum for breast cancer. After three cycles of cisplatin treatment, the patient's metastatic lesions dramatically improved without any major toxicity, and she completed 17 cycles with good response. This case study indicates that patients with heavily pretreated TNBC can potentially achieve a good response to cisplatin monotherapy.