• Title/Summary/Keyword: Drug Toxicity

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Effects of Monascus-fermented Angelica gigas Nakai on the Contents of Serum Lipid and Tissue Lipid Peroxidation in Alcohol Feeding Rats (알코올성 간독성 흰쥐의 혈청 지질 및 조직 과산화지질 농도에 미치는 발효당귀의 영향)

  • Ahn, Hee-Young;Park, Kyu-Rim;Kim, Yu-Ra;Yoon, Kyoung-Hoon;Kim, Jung-Wook;Cho, Young-Su
    • Journal of Life Science
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    • v.23 no.11
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    • pp.1371-1380
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    • 2013
  • The effect of Monascus-fermented Angelica gigas Nakai (AFAG) on the contents of serum lipids and tissue lipid peroxidation was investigated in alcohol feeding rats (Alc group). The serum contents of total lipid and free fatty acid in the alcohol feeding rats were significantly increased, but these increases tended to decrease in the AFAG group. The content of serum triglyceride was also significantly decreased in the AFAG group compared to the other groups. The serum content of total-cholesterol was not significantly different between the normal group and the AFAG group. The content of HDL-cholesterol in serum was slightly increased in the AFAG group compared to the Alc group. The content of thiobarbituric acid reactive substances (TBARS) in the liver, heart, spleen, and testis were significantly increased in the Alc group compared to the normal group, but these increases were significantly decreased in the AFAG group. The content of liver zinc was decreased in the Alc group and it was significantly increased in the AFAG group, which suggested that the lipid peroxidation contents are inversely correlated with the liver zinc content. The hepatic glutathione concentration was significantly decreased in the Alc group, but this content was significantly increased in the AFAG group, and it showed the antioxidant ability of glutathione. These activities were also compared to the standard silymarin drug treatment. Thus, the findings of the present study indicated the significant antioxidant and antihyperlipidemic activity of Monascus-fermented Angelica gigas Nakai against ethanol-induced toxicity.

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

  • Kim, Andrew HyoungJin;Yoon, Sumin;Lee, Yujin;Lee, Jieon;Bae, Eunjin;Lee, Hajeong;Kim, Dong Ki;Lee, SeungHwan;Yu, Kyung-sang;Jang, In-Jin;Cho, Joo-Youn
    • Journal of Korean Medical Science
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    • v.33 no.53
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    • pp.298.1-298.10
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    • 2018
  • Background: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of $4{\beta}$-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. Methods: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers ($6{\beta}$-OH-cortisol/cortisol, $6{\beta}$-OH-cortisone/cortisone, $4{\beta}$-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the $4{\beta}$-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. Results: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary $6{\beta}$-OH-cortisol/cortisol and $6{\beta}$-OH-cortisone/cortisone as well as plasma $4{\beta}$-OH-cholesterol and $4{\beta}$-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. Conclusion: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.

Effects of Tiamulin on Starry Flounder, Platichthys stellatus Infected with Streptococcus parauberis HFTC0083 (Tiamulin이 Streptococcus parauberis HFTC0083에 감염된 강도다리(Platichthys stellatus)에 미치는 영향)

  • Joo, Min-Soo;Kim, Boseong;Kim, Do-Hyung;Seo, Jung-Soo;Kwon, Mun-Gyeong;Jee, Bo-Young;Park, Chan-Il
    • Journal of Marine Life Science
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    • v.4 no.1
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    • pp.29-37
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    • 2019
  • In order to control disease caused by multi-drug resistant bacteria in the aquaculture, the use of veterinary antibiotics, which are prohibited to fish, is increasing, instead of the existing fisheries antibiotics. Among them, tiamulin is illegally used in some cultured fish because it exhibits effective antibacterial activity against Gram-positive bacteria. To prevent unauthorized use, treatment of fish should be accompanied by a prescription from veterinarians or fisheries disease managers through research on fish of tiamulin. Tiamulin was injected intramuscularly at 5, 10 and 15 mg kg-1 for the streptococcus-infected starry flounder, but did not show any therapeutic effect. Oral administration at a concentration of 15 and 30 mg kg-1 was similarly ineffective. The concentrations of 30 and 60 mg kg-1 resulted in death due to toxicity of antibiotics. Therefore, it is inappropriate to treat antibiotics with streptococcus-infected starry flounder.

Antidotes Stocking and Delivery for Acute Poisoning Patients at 20 Emergency Departments in Korea 2015-2017 (2015-17년 전국 20개 거점병원 응급해독제 비축 및 제공 결과)

  • Lee, Seungmin;Youn, Han Deok;Chang, Hanseok;Won, Sinae;Kim, Kyung Hwan;Oh, Bum Jin
    • Journal of The Korean Society of Clinical Toxicology
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    • v.16 no.2
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    • pp.131-140
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    • 2018
  • Purpose: The National Emergency Medical Center has been running a project for the storage and delivery of antidotes for acute poisoning patients of the Department of Health and Welfare, Korea. This study analyzed the results of this project over the past two years. Methods: The requests received by the National Emergency Medical Center and the data on the delivery process were analyzed. Results: This study analyzed a total of 121 patients with acute poisoning, who were requested to receive an antidote reserved at 20 key hospitals in 2015-2017, and whose age was $52.3{\pm}23.5\;years$; old; 54 were women. Intentional poisoning were 58.7%, and the home was the most common place of exposure (66.9%). The toxic substances were chemicals (32.2%), pesticides (27.3%), medicines (24.8%), and snake venom (4.1%). The patient's poison severity score was $2.4{\pm}0.7$ (median 3) indicating moderate-to-severe toxicity. Antidote administration was the cases treated in key hospitals 67.8% (82/121), in which transferred patients accounted for 57.3% (47/82). After receiving an antidote request from a hospital other than the key hospitals, the median was 75.5 minutes (range 10 to 242 minutes) until the antidote reached the patient, and an average of 81.5 minutes was required. The results of emergency care were intensive care unit (70.3%), general wards (13.2%), death (10.7%), and discharge from emergency department (5.0%). Conclusion: This study showed that the characteristics of acute poisoning patients treated with an antidote were different from previous reports of poisoned patients in the emergency department, and basic data on the time required for delivery from key hospitals was different.

Predicting the Fetotoxicity of Drugs Using Machine Learning (기계학습 기반 약물의 태아 독성 예측 연구)

  • Myeonghyeon Jeong;Sunyong Yoo
    • Journal of Life Science
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    • v.33 no.6
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    • pp.490-497
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    • 2023
  • Pregnant women may need to take medications to treat preexisting diseases or diseases that develop during pregnancy. However, some drugs may be fetotoxic and lead to, for example, teratogenicity and growth retardation. Predicting the fetotoxicity of drugs is thus important for the health of the mother and fetus. The fetotoxicity of many drugs has not been established because various challenges hinder the ability of researchers to determine their fetotoxicity. The need exists for in silico-based fetotoxicity assessment models, as they can modernize the testing paradigm, improve predictability, and reduce the use of animals and the costs of fetotoxicity testing. In this study, we collected data on the fetotoxicity of drugs and constructed fetotoxicity prediction models based on various machine learning algorithms. We optimized the models for more precise predictions by tuning the hyperparameters. We then performed quantitative performance evaluations. The results indicated that the constructed machine learning-based models had high performance (AUROC >0.85, AUPR >0.9) in fetotoxicity prediction. We also analyzed the feature importance of our model's predictions, which could be leveraged to identify the specific features of drugs that are strongly associated with fetotoxicity. The proposed model can be used to prescreen drugs and drug candidates at a lower cost and in less time. It provides a predictive score for fetotoxicity risk, which may be beneficial in the design of studies on fetotoxicity in human pregnancy.

Contents of Mercury, Methylmercury, and Selenium in Deep-Sea Fishes (심해성 어류의 수은, 메틸수은 및 셀레늄 함량)

  • Yun-Sik Cho;Seon-Il Hwang;Sang-Woon Shin;Hyun-Ju Kim;Ji-Yeon Lee;Ji-Won Song;Jeong-Eun Kim;Byoung-Hoon Lee;A-Ra Mo;Myeong-Ki Park
    • Journal of Food Hygiene and Safety
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    • v.38 no.3
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    • pp.158-163
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    • 2023
  • This study aimed to determine mercury (Hg), methylmercury (MeHg), and selenium (Se) levels in deep-sea fishes distributed in Gyeonggi-do, South Korea. Concentrations of Hg, MeHg, and Se were measured by using a mercury analyzer and Inductively Coupled Plasma - Mass Spectrometry (ICP-MS). The average content (mg/kg) in the seafood samples was as follows: Hg, 0.7647 (0.0182-5.3620), MeHg, 0.0764 (0.0096-0.8750), and Se, 0.4728 (0.1075-3.5100). All the levels of MeHg were below the recommended standards of the Ministry of Food and Drug Safety i.e., <1.0 mg/kg. Recent studies have shown that Se prevents Hg toxicity. The average daily intake in humans was 3.3 ㎍/kg, which was lower than the recommended amount (50-200 ㎍/person/day). The weekly intake of Hg and MeHg was calculated to be 6.07% and 1.90%, respectively, of the provisional tolerable weekly intake (PTWI). This study showed that the weekly intake of Hg and MeHg from abyssal fish was less than the PTWI recommended by the Joint FAO/WHO expert committee on food additives. Therefore, the levels reported in this study are presumed to be adequately safe.

Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice

  • Hyelee Hong;Kwonmo Moon;Thuy-Tien Thi Trinh;Tae-Hui Eom;Hyun Park;Hak Sung Kim;Seon-Ju Yeo
    • Parasites, Hosts and Diseases
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    • v.62 no.1
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    • pp.42-52
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    • 2024
  • Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity of the 9 antimalarial compounds chemically synthesized using SKM13-2HCl. Except for SKM13-2HCl, the 5 newly synthesized compounds had a 50% cytotoxic concentration (CC50) >100 μM, indicating that they would be less cytotoxic than SKM13-2HCl. Among the 5 compounds, only SAM13-2HCl outperformed SKM13-2HCl for antimalarial activity, showing a 3- and 1.3-fold greater selective index (SI) (CC50/IC50) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) Plasmodium falciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lower polarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was more toxic in the rodent model. Consequently, SAM13-2HCl containing morpholine was selected from screening a combination of pharmacologically significant structures as being the most effective in vitro against human-infectious P. falciparum but was less efficient in vivo in a P. berghei-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant P. falciparum infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.

Comparison of Paraquat Actions on Oxygen Radical Generation and Lipid Peroxidation between Submitochondrial Particle and Microsome of Mouse Liver (Paraquat에 의한 산소 Radical 생성 및 지질과산화 작용의 Mouse 간 Submitochondria Particle과 Microsome에서의 비교)

  • Choi, Jung-Hwan;Kim, Yong-Sik;Park, Jong-Hwan;Chung, Myung-Hee;Yunn, Chong-Ku
    • The Korean Journal of Pharmacology
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    • v.27 no.2
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    • pp.155-166
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    • 1991
  • In order to evaluate a potential role of mitochondria in the mediation of toxicity of paraquat (PQ), submitochondrial particle and microsome of mouse liver were compared by oxygen radical generation and lipid peroxidation. With NADH in submitochondrial particle and NADPH in microsome as electron donors, PQ stimulated production of superoxide anion and $H_2O_2$ in both fractions. Under the same conditions, PQ enhanced the generation of ethylene from methional suggestiong stimulation of OH production by PQ. But these effects by PQ were somewhat lower in submitochondrial particle than in microsome. In addition, lipid peroxidation(measured as MDA production) was stimulated by PQ in both fractions. The stimulation of lipid peroxidation in both fractions seemed to occur by the same mechanism probably through perferryl ion. This was supported by the following findings: i) The lipid peroxidation in both fractions was partially inhibited by SOD and completely inhibited by DETAPAC(an iron chelator) but not by catalase or OH scavenger. ii) Addition of $ADP-Fe^{3+}$ further increased PQ-induced lipid peroxidation but decreased ethylene production from methional suggesting no correlation between OH production and lipid peroxidation. The redox-cycling of PQ in mitochondria appeared to be linked to NADH dehydrogenase, not to CoQ since all of the observed stimulations by PQ in submitochondrial particle were inhibited by p-hydroxymercuribenzoate(a NADH dehydrogenase inhibitor) but not affected by other respiratory chain blockers. The above results demonstrate that redox-cycling properties of PQ leading to oxygen radical generation and lipid peroxidation can also occur in mitochondria in the same manner as in microsome. Therefore, the observed actions of PQ in mitochondria suggest that mitochondria may also contribute to toxicity of this drug in vivo.

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Effect of N-Acetylcysteine on the Supetoxide Release, Chemotaxis from the Neutrophils and Glutathione Level of Plasma and Neutrophils (N-Acetylcysteine이 호중구의 Superoxide, Chemotaxis 및 혈장과 호중구의 Glutathione에 미치는 영향)

  • Song, Jeong-Sup;Lee, Sook-Young;Moon, Hwa-Sik;Park, Sung-Hak
    • Tuberculosis and Respiratory Diseases
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    • v.41 no.5
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    • pp.475-483
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    • 1994
  • Background: N-acetylcysteine(ACE) is used both orally and intravenously in a variety of experimental pathologies resembling human disease states which exhibit endothelial toxicity as a result of oxidative stress, including acute pulmonary oxygen toxicity, septicemia and endotoxin shock. Despite these observations in vivo, it is not certain how this thiol drug produces its protective effects. ACE is a cysteine derivative which is able to direct1y react with oxygen radicals and may also act as a cysteine and glutathione(GSH) precursor following deacetylation. In this paper, we tried to know whether the therapeutic doses of ACE can modify the inflammatory function of the neutrophils and can increase the glutathione level of plasma in chronic obstructive pulmonary disease(COPD) patients. In addition, the effect of ACE to the purified neutrophil in terms of superoxide release and glutathione synthesis were observed. Method: Firstly, we gave 600mg of ACE for seven days and compare the release of superoxide, luminol-enhanced chemiluminescence from the neutrophils, neutrophil chemotaxis, and plasma GSH levels before and after ACE treatment in COPD patients. Secondly, we observed the dose dependent effect of ACE to the purified neutrophil's superoxide release and GSH levels in vitro. Results: 1) Usual oral therapeutic doses(600mg per day) of ACE for seven days did affect neither on the neutrophil's superoxide release, chemiluminescence, chemotaxis, nor on the plasma GSH concentration in the COPD patients. 2) ACE decreases the purified neutrophil's superoxide release and increase the GSH production in dose dependent fashion in vitro. Conclusion: Despite the fact that oral ACE treatment did not affect on the neutrophil's inflammatory function and plasma GSH concentration in COPD patients in usual therapeutic doses, it decreases the superoxide release and increases the GSH production from the isolated neutrophils in high molar concentrations. These findings suggest that to obtain an antioxidative effects of ACE, it might be needed to increase the daily dosage of ACE or therapeutic duration or change the route of adminisration in COPD patients.

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APOPTOTIC EFFECT IN COMBINATION OF CYCLOSPORIN A AND TAXOL ON ORAL SQUAMOUS CELL CARCINOMA CELL LINE THROUGH THE PI-3 KINASE/AKT1 PATHWAY (구강 편평세포암종 세포주에서 Cyclosporin A와 Taxol 투여시 PI-3 kinase/Akt1 Pathway에 의한 세포사멸 병용효과)

  • Kim, Kyu-Young;Lee, Jae-Hoon
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.33 no.5
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    • pp.426-436
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    • 2007
  • Oral cancer take up 2-6% of all carcinomas and squamous cell carcinoma, which is the most common type in oral cancer, has a poor prognosis due to its high metastasis and recurrence rates. In treating oral cancer, chemotherapy to the primary, metastasized and recurrent lesion is a very important and useful treatment, even though its widespread usage is limited due to high general toxicity and local toxicity to other organs. Taxol, a microtubule stabilizing agent, is an anticancer drug that induces cell apoptosis by inhibiting depolymerization of microtubules in between the metaphase and anaphase of the cell mitosis. Recently, its effectiveness and mechanism on various tumor has been reported. However, not much research has been done on the application of Taxol to oral squamous cell carcinoma. Cyclosporin A, which is an immunosuppressant, is being used on cancers and when co-administered with Taxol, effectiveness of Taxol is enhanced by inhibition of Taxol induced multidrug resistance. In this study, Cyclosporin A with different concentration of Taxol was co-administered to HN22, the oral squamous cell carcinomacell line. To observe the cell apoptosis and the mechanisms that take part in this process, mortality evaluation of tumor cell using wortmannin, c-DNA microarray, RT-PCR analysis, cytometry analysis and western blotting were used, and based upon the observation on the effect and mechanism of the agent, the following results were obtained: 1. The HN22 cell line viability was lowest when $100{\mu}M$ of Wortmannin and $5{\mu}g/ml$ of Taxol were co-administered, showing that Taxol participates in P13K-AKT1 pathway. 2. In c-DNA microarray, where $1{\mu}g/ml$ of cyclosporine A and 3mg/ml of Taxol were co-administered, no up regulation of AKT1, PTEN and BAD c-DNA that participate in cell apoptosis was observed. 3. When $1{\mu}g/ml$ of Cyclosporin A was applied alone to HN22 cell line, no difference was found in AKT1, PTEN and BAD mRNA expression. 4. Increased AKT1, mRNA expression was observed when $3{\mu}g/ml$ of Taxol was applied alone to HN22 cell line. 5. When $1{\mu}g/ml$ of Cyclosporin A and Taxol($3{\mu}g/ml\;and\;5{\mu}g/ml$) were co-administered to HN22 cell line, PTEN mRNA expression increased, whereas AKT1 and BAD mRNA decreased. 6. As a result of cytometry analysis, in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration, increased Annxin V was observed, which shows that apoptosis occurred by deformation of plasma membrane. However, no significant difference was observed with vary ing concentration. 7. In western blot analysis, no caspase 3 was observed in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration. From the results of this study, it can be concluded that synergistic effect can be observed in combination therapy of Taxol and Cyclosporin A on oral squamous cell carcinoma cell line, where decreased activity of the cell line was observed. This resulted in decreased AKT1 and BAD mRNA and increased PTEN mRNA expression and when wortmannin and Taxol were co-administered, the viability decreased which confirms that Taxol decreases the viability of tumor cell line. Hence, when Taxol and cyclosporine A are co-administered, it can be assumed that cell apoptosis occurs through AKt1 pathway.