• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2002년도 창립10주년기념 및 국립독성연구원 의약품동등성평가부서 신설기념 국재학술대회:생물학적 동등성과 의약품 개발 전략을 위한 국제심포지움
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• pp.219-219
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• 2002

The SPP003 is a mixture of water extract from Schizandrae Fructus, Poligoni multiflori Radix, Ginseng Radix Akba and Hoelen. The aim of this study was to investigate the anti-hyperglycemic effect of SPP003 in normal and streptozotocin (STZ)-induced diabetic rats, and to monitor the toxicity of SPP003. Oral glucose tolerance test (OGTT) was performed after oral administration of SPP003 100, 300, 600 and 900 mg/kg in normal rats. Blood glucese concentration was measured at -30 min (vehicle, SPP003 or tolbutamide 60 mg/kg, 0 min (glucose treatment), 60, 120 and 180 min. Rats were administerd STZ 65mg/kg (0.1M citrate buffer, pH 4.5) intraperitoneally to induce diabetes and administered vehicle, Spp003 (100, 300 and 600 mg/kg) or tolbutamide (60 mg/kg) orally once a day for 4 weeks. Blood glucose level was measured a 0, 4, 7, 14, 21 and 29 day after initial drug administration. A single oral toxicity of SPP003 was studied in Sprague-Dawley rats of both sexes. In this study, rats were administered with doses of 1, 2 and 5 g/kg of SPP003. In glucose tolerance test, SPP003 900 mg/kg markedly decreased glucose concentration at 1 hr after glucose treatment. Blood glucose levels were much higher in STZ-diabetic rats. These increases were significantly attenuated by SPP003 600 mg/kg. SPP003 did not show any signigicant toxicity. These findings suggest that SPP003 has hypoglycemic properties in STZ-diabetic rats.

• 대한약침학회지
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• 제22권3호
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• pp.147-153
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• 2019

Objectives: Many studies have been reported the efficacy of intravenous lipid emulsion (ILE) as an antidote on acute lipophilic drug toxicity. Clozapine, highly lipophilic dibenzodiazepine neuroleptics, is an important medication in the schizophrenia therapy regimen. Acute intoxication with antipsychotics is one of the main reasons for the referral of poisoned patients to the hospital. We expected that ILE could be used for the therapy of acute clozapine intoxicated patients. Methods: We used two groups of consisting of six male rats. Both groups received a toxic dose of clozapine (40 mg/kg) intravenously, via the tail vein. After 15 minutes, they were treated with intravenous infusion of 18.6 mg/kg normal saline (NS group), or 18.6 mg/kg ILE 20% (ILE group). We evaluated blood pressure (BP) and heart rate by power lab apparatus through the tail artery, ataxia by a rat rotary circle, seizure scores and death in multiple times after starting clozapine administration. For biochemical and pathological evaluations the samples of tissue and blood were taken. Results: Our results demonstrated that ILE 20% could return hypotension-induced clozapine better than normal saline. Furthermore, ataxia and seizure have rectified more rapidly and deaths reduced. Clozapine administration causes pancreatitis and lung injury but fat emulsion did not show an optimal effect on tissue damages caused by clozapine toxicity. Conclusion: In conclusion, ILE can remove toxic signs of clozapine same as other lipophilic medicines, however, clinical uses of ILE for this intention requires more appraisement to determine the precise implication and safety.

• Journal of Ginseng Research
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• 제35권3호
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• pp.294-300
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• 2011

Zearalenone (ZEA) is a phenolic resorcylic acid lactone compound produced by several species of Fusarium. ZEA has toxic effects in the testes of domestic and laboratory animals. Korean red ginseng (KRG), the steamed root of Panax ginseng Meyer, has multiple pharmacological effects such as vasorelaxation, anti-thrombosis, anti-hypertension, etc. In this study, we investigated the effects of KRG extract on testicular toxicity induced by ZEA. Rats were treated with 300 mg/kg oral doses of KRG for 4 weeks every other day. The rats were then treated with a single dose of 5 mg/kg ZEA delivered intraperitoneally, whereas control rats received only doses of the vehicle. As a result, germ cell apoptosis induced by ZEA was decreased by KRG pre-treatment. In addition, Fas and Fas-L expression was reduced in rats that received KRG pre-treatment compared to ones treated with ZEA alone. In conclusion, impaired spermatogenesis resulting from ZEA treatment was prevented by KRG through Fas-Fas L modulating.

• Journal of Oral Medicine and Pain
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• 제40권2호
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• pp.82-87
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• 2015

Methotrexate (MTX) is a chemotherapeutic agent that is used to treat a host of malignancies. But recently, MTX has also been used as a therapeutic agent for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus. However, MTX is an antimetabolite that affects rapidly dividing normal cells such as oral mucosal epithelial cells, gastrointestinal epithelial cells, and bone marrow cells-which explains why oral mucositis is often an initial manifestation of MTX toxicity. Because oral lesions are frequently initially presented in dental clinics, dentists should consider the possibility of adverse drug reactions in the differential diagnoses of oral lesions through a meticulous collection of patients' medical histories. In this report, we examine patients who suffered from oral ulcerative lesions upon diagnosis of MTX-induced oral mucositis. Then, we suggest approaches for the diagnosis and treatment of MTX-induced oral mucositis through a review of literature.

• 한국진공학회:학술대회논문집
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• 한국진공학회 2013년도 제44회 동계 정기학술대회 초록집
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• pp.108-109
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• 2013

Mitochondria play key roles in the production of cell's energy. Their dominant function is the synthesis of adenosine 5'-triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (Pi) through the oxidative phosphorylation. Evaluation of drug-induced mitochondrial toxicity has become increasingly important since mitochondrial dysfunction has recently been implicated in numerous diseases including cancer and diabetes mellitus. Mitochondrial functions have been monitored via oxygen consumption, mitochondrial membrane potential, and more importantly via ATP synthesis since ATP synthesis is the most essential function of mitochondria. Various analytical methods have been employed to investigate ATP synthesis in mitochondria, including high performance liquid chromatography (HPLC), bioluminescence technique, and pH measurement. However, most of these methods are based on destructive analysis or indirect monitoring through the enzymatic reaction. Infrared absorption spectroscopy (IRAS) is one of the useful techniques for real-time, label-free, and direct monitoring of biological reactions [1,2]. However, the strong water absorption requires very short path length in the order of several micrometers. Transmission measurements with thin path length are not suitable for mitochondrial assays because solution handlings necessary for evaluating mitochondrial toxicity, such as rapid mixing of drugs and oxygen supply, are difficult in such a narrow space. On the other hand, IRAS in the multiple internal reflection (MIR) geometry provides an ideal optical configuration to combine solution handling and aqueous-phase measurement. We have recently reportedon a real-time monitoring of drug-induced necrotic and apoptotic cell death using MIR-IRAS [3,4]. Clear discrimination between viable and damaged cells has been demonstrated, showing a promise as a label-free and real-time detection for cell-based assays. In the present study, we have applied our MIR-IRAS system to mitochondria-based assays by monitoring ATP synthesis in isolated mitochondria from rat livers. Mitochondrial ATP synthesis and hydrolysis were in situ monitored with MIR-IRAS, while dissolved oxygen level and solution pH were simultaneously monitored with O2 and pH electrodes, respectively. It is demonstrated that ATP synthesis and hydrolysis can be monitored by the IR spectral changes in phosphate groups in adenine nucleotides and MIR-IRAS is useful for evaluating time-dependent drug effects of mitochondrial toxicants.

• Genomics & Informatics
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• 제4권1호
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• pp.16-22
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• 2006

The KFDA (Korea Food & Drug Administration) has performed a collaborative toxicogenomics project since 2003. Its aim is to construct a toxicology database of 12 compounds administered to mice at initial phase. We chose 6-MP (6-mercaptopurine) which has been used in the treatment of childhood leukemia. It was administered at low (0.224 mg/kg) and at high (2.24 mg/kg) dose (5 mice per group) intraperitonealy to the postnatal 6 weeks mice, then the serum and liver were collected at the indicated time (6, 24 and 72 h) after scarification. Serum biochemical markers for liver toxicity were measured and histopathologic studies also were carried out. The gene expression profiling was carried out by using Applied Biosystems 1700 Full Genome Expression Mouse. By self-organization maps (SOM), we identified groups with unique gene expression patterns, some of them are supposed to be related to 6-MP induced toxicity, including lipid metabolism abnormality, inflammatory response, oxidative stress, ATP depletion and cell death. The potential toxic effects appearing as gene expression changes are dependent of the time of 6-MP but independent of the dosage of it. This study would contribute to establishment of international database as well as national one about hepatotoxicity.

• Journal of Pharmaceutical Investigation
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• 제32권2호
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• pp.113-117
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• 2002

Cyto-toxic effect of silver sulfadiazine (Ag-SD) on keratinocytes and its implication on wound healing process were investigated in $2^{nd}$ degree bum hairless mouse model. As a dermal model, HaCat (immortalized keratinocytes) monolayer culture in DMEM with 10% FBS was used. Cyto-toxicity of Ag-SD was estimated by measuring the cell viability using neutral red assay after adding the drug. The $2^{nd}$ degree bum was prepared on hairless mouse back skin (1 cm diameter) and dressings with Ag-SD were applied for 96 hr. The process of re-epithelialization and the presence of inflammatory cells were investigated and histology with Hematoxylin-Eosin staining was performed. Ag-SD displayed highly cyto-toxic effect on cultured HaCat cells in a concentration dependent manner $(1-100\;{\mu}g/mL)$. Topical application of Ag-SD (2%) could control the infection: no inflammatory cells were observed in histology. However the cyto-toxic effect of Ag-SD on skin cells induced the impairment in epidermal regeneration.

• 대한약리학회지
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• 제32권2호
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• pp.211-219
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• 1996

The inhibitory effect of cyclosporin A (CsA) on nitric oxide production is not related to the immunosuppressive action of the drug, but to the renal toxicity and arterial hyper-tension. In this study the experimental interventions to reverse the inhibition of nitric oxide production by cyclosporin A in rat aortic smooth muscle cells were examined. CsA inhibited the accumulation of nitrite, the stable end product of nitric oxide, in culture media in a concentration $(0.1{\sim}100{\mu}g/ml)-dependent$ manner. The inhibitory effect of CsA on nitrite accumulation were not antagonized by arginine (10 mM), a substrate of nitric oxide synthase, nor by calcium ionophore A23187 $(7{\mu}M)$. Forskolin, an activator of adenylate cyclase, which enhanced iNOS induction at transcriptional level, completely reversed the inhibitory action of CsA on nitrite accumulation. However, PMA (2 nM) and PDB (50 nM), PKC activators, increased the inhibitory action of CsA on nitrite accumulalion. From these results, it is suggested that cyclic AMP-elevating agents may be candidates of therapeutic agents in prevention and treatment of renal toxicity and arterial hypertension induced by CsA. Among conventional antihypertensive drugs, calcium channel blockers and ${\alpha}-blockers$ are preferred to ${\beta}-blockers$.

• Archives of Pharmacal Research
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• 제24권2호
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• pp.119-125
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• 2001

We have reported that kalopanaxsaponin A (KPS-A) Isolated from Kalopanax pictus have anti-rheumatoidal activity in the rat treated with Freunds complete adjuvant (FCA) reagent. In addition, it has been also reported that KPS-A is a potent antioxidant in the rheumatoidal rat. This research was undertaken to examine whether the saponins of KPS-A and -1 could adjust the abnormal lipid metabolisms and hematological changes in immunological diseases. KPS-A significantly inhibited the increases in both triglycerides and total proteins in addition to the decrease in total cholesterol induced by FCA reagent treatment. KPS-A treatment decreased the number of leucocytes elevated by FCA reagent treatment. Excess dose of the methanol extract produced no severe toxicity on the body weight, wet organ weights and hepatic functions. Since $LD_50$ value of K. pictus methanol extract was shown to be 4,033 ${mg/kg}$, it could be estimated to be a safe agent for anti-rheumatoidal herbal medicines.

• Archives of Pharmacal Research
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• 제22권6호
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• pp.565-570
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• 1999

DW2282,(S)-(+)-4-phenyl-1-[1-(4-aminobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-2-imidazolone hydrochloride, is a new anticancer agent which is thought to exhibit a characteristic mechanism of action in the inhibition of tumor growth. In this study, we estimated the toxicities of DW2282 in mice. When mice were orally dosed for five consecutive days at the dosages of 50, 100 and 150 mg/kg, DW2282 did not induced methemoglobinemia and hypoglycemia at any of these doses. However, increased ALT and AST values were observed in the 150 mg/kg dosing group, and white blood cells (WBC) were significantly decreased at all doses. However, the changes in WBC count, ALT and AST immediately reversed after the cessation of drug administration. In addition, we found that DW2282 did not cause an increase in hemolysis in human blood. Taken together, these data suggested that DW2282 may have a relatively low level of toxicity, and that there may be a quick recovery from any toxicity it dose produce.