• Archives of Pharmacal Research
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• v.27 no.2
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• pp.127-135
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• 2004

Multiple drug administration is common in elderly, HIV, and cancer patients. Such treatments may result in drug-drug interactions due to interference at the metabolic enzyme level, and due to modulation of transporter protein functions. Both kinds of interference may result in altered drug distribution and toxicity in the human body. In this review, we have dealt with drug-drug interactions related to the most studied human transporter, P-glycoprotein. This transporter is constitutively expressed in several sites in the human body. Its function can be studied in vitro with different cell lines expressing P-glycoprotein in experiments using methods and equipment such as flow cytometry, cell proliferation, cell-free ATP as activity determination and Transwell culture equipment. In vivo experiments can be carried out by mdr1a(-/-) animals and by noninvasive methods such as NMR spectrometry. Some examples are also given for determination of possible drug-drug interactions using the above-mentioned cell lines and methods. Such preclinical studies may influence decisions concerning the fate of new drug candidates and their possible dosages. Some examples of toxicities obtained in clinics and summarized in this review indicate careful consideration in cases of polypharmacy and the requirement of preclinical studies in drug development activities.

• Journal of The Korean Society of Clinical Toxicology
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• v.10 no.2
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• pp.111-117
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• 2012

Purpose: In Korea, few studies have examined the acute toxicity of anti-obesity drugs. The purpose of this study is to analyze the general characteristics and clinical aspect of acute anti-obesity drug intoxication. Methods: We retrospectively investigated patients admitted to the emergency department after anti-obesity drug intoxication between March, 2004 and February, 2012. The medical records of these patients were reviewed for demographic data, toxicologic history, time elapsed to presentation, clinical symptoms and signs, treatment, and outcome. Results: There were a total of 18 anti-obesity intoxication cases during the study period; of 16 which were included in our study. The purchasing route of the anti-obesity drug was mainly through a doctor's prescription (68.8%), however, some were obtained through the internet and the pharmacies. The mean time to The most commonly ingested antiobesity drug was sibutramine (31.3%) and many of the cases (62.5%) were multi-drug ingestions. The most common clinical manifestations were gastrointestinal symptoms (94%), but, CNS symptoms (75%) and cardiovascular symptoms (75%) were almost equally present. 13 patients (81%) were discharged after clearance of toxic symptoms and signs with a mean observational period of 7.0 hours. 3 patients were admitted for observation and treatment; of which 1 patient died due to fatal complications. Conclusion: Most anti-obesity intoxications show mild toxicity and a nonfatal clinical course. However, the recent trend toward prescribing psychostimulant anti-obesity medication, which can be fatal after an acute overdose, calls physicians' attention to treating of anti-obesity intoxications.

• Bulletin of the Korean Chemical Society
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• v.32 no.12
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• pp.4309-4315
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• 2011

For synthesis of benzastatin E, F and G analogues, the indole-2-carbaldehydes with or without substituents at C-5 position were prepared as key intermediates. Several synthetic attempts to achieve benzastatin E-G analogues were suggested using the indole-2-carbaldehyde intermediates.

• Interdisciplinary Bio Central
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• v.2 no.4
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• pp.9.1-9.5
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• 2010

Many neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are devastating disorders that affect millions of people worldwide. However, the number of therapeutic options remains severely limited with only symptomatic management therapies available. With the better understanding of the pathogenesis of neurodegenerative diseases, discovery efforts for disease-modifying drugs have increased dramatically in recent years. However, the process of translating basic science discovery into novel therapies is still lagging behind for various reasons. The task of finding new effective drugs targeting central nervous system (CNS) has unique challenges due to blood-brain barrier (BBB). Furthermore, the relatively slow progress of neurodegenerative disorders create another level of difficulty, as clinical trials must be carried out for an extended period of time. This review is intended to provide molecular and cell biologists with working knowledge and resources on CNS drug discovery and development.

• Toxicological Research
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• v.29 no.1
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• pp.1-6
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• 2013

The process of drug discovery and development requires substantial resources and time. The drug industry has tried to reduce costs by conducting appropriate animal studies together with molecular biological and genetic analyses. Basic science research has been limited to in vitro studies of cellular processes and ex vivo tissue examination using suitable animal models of disease. However, in the past two decades new technologies have been developed that permit the imaging of live animals using radiotracer emission, X-rays, magnetic resonance signals, fluorescence, and bioluminescence. The main objective of this review is to provide an overview of small animal molecular imaging, with a focus on nuclear imaging (single photon emission computed tomography and positron emission tomography). These technologies permit visualization of toxicodynamics as well as toxicity to specific organs by directly monitoring drug accumulation and assessing physiological and/or molecular alterations. Nuclear imaging technology has great potential for improving the efficiency of the drug development process.

• Communications for Statistical Applications and Methods
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• v.29 no.4
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• pp.421-439
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• 2022

Phase I dose-finding trials are essential in drug development. By finding the maximum tolerated dose (MTD) of a new drug or treatment, a Phase I trial establishes the recommended doses for later-phase testing. The primary toxicity endpoint of interest is often a binary variable, which describes an event of a patient who experiences dose-limiting toxicity. However, there is a growing interest in dose-finding studies regarding non-binary outcomes, defined by either the weighted sum of rates of various toxicity grades or a continuous outcome. Although several novel methods have been proposed in the literature, accessible software is still lacking to implement these methods. This study introduces a newly developed R package, UnifiedDoseFinding, which implements three phase I dose-finding methods with non-binary outcomes (Quasi- and Robust Quasi-CRM designs by Yuan et al. (2007) and Pan et al. (2014), gBOIN design by Mu et al. (2019), and by a method by Ivanova and Kim (2009)). For each of the methods, UnifiedDoseFinding provides corresponding functions that begin with next that determines the dose for the next cohort of patients, select, which selects the MTD defined by the non-binary toxicity endpoint when the trial is completed, and get oc, which obtains the operating characteristics. Three real examples are provided to help practitioners use these methods. The R package UnifiedDoseFinding, which is accessible in R CRAN, provides a user-friendly tool to facilitate the implementation of innovative dose-finding studies with nonbinary outcomes.

• Environmental Analysis Health and Toxicology
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• v.13 no.3_4
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• pp.87-94
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• 1998

The use of cisplatin is limited by severe side effects such as renal toxicity. Our platinum-base drug discovery is aimed at developing drugs capable of diminishing toxicity and improving antitumor activity. We synthesized new Pt (II) complex analogue [Pt (cis-DACH)(DPPP)]. 2NO$_3$ (PC) containing cis-1,2-diaminocyclohexane as a carrier ligand and 1,3-bis(diphenylphosphino) propane as a leaving group. Furthermore, nitrate was added to improved the solubility. In this study, its structure was determined and its antitumor activity against SKOV-3 and NIH-OVCAR-3 human ovarian adenocarcinoma, and in vitro cytotoxicity was determined against primary cultured rabbit kidney proximal tubular and renal cortical cells of human kidney using colorimetric MTT assay. PC demonstrated acceptable antitumor activity against SKOV-3 and NIH-OVCAR-3 human ovarian adenocarcinoma and significant activity as compared with that of cisplatin. The toxicity of PC was found quite less than that of cisplatin using MTT and $^3$H-thymidine uptake tests in rabbit proximal tubular cells and human kidney cortical cells. PC was used for human cortical tissue in 7 weeks hitoculture by the glucose-consumption tests. We determined that the new platinum drug has lower nephrotoxicity than cisplatin. Based on these results, this novel platinum (II) complex compound (PC) represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low nephrotoxicity.

• Journal of Food Hygiene and Safety
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• v.24 no.4
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• pp.352-356
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• 2009

The purpose of this study was to introduce the toxicological study review to evaluate the safety of PDMS on the 69th JECFA meeting. Polydimethylsiloxane is a polymer and its ADI was established at 23rd JECFA meeting in 1979. The ADI was maintained although the specification was expanded at its 26th, 29 th, 37 th meetings. Recently, it was reported that PDMS with low molecular weight and viscosity has high absorption rate and different toxicity, so it was submitted at 69th meeting. Toxicological studies of PDMS were submitted from the sponsor and additional information is collected from a document searching. The toxicological studies were reviewed in accordance with the 'Guidelines for the preparation of toxicological working papers for the Joint FAO/WHO Expert Committee on Food Additives'. In the available acute, sub-chronic and chronic toxicity studies on PDMS, dose-related increases in incidence and severity of ocular lesions(corneal crystal, inflammation of the corneal epithelium etc.) were consistently observed after oral dosing. It seems to be a local irritant effect, but the mechanism by which the ocular lesions arose is unclear, although the lack of absorption of PDMS indicates that it is unlikely to be a direct systemic effect. Consequently, the relevance of the ocular lesions for food use of PDMS could not be determined. The ADI of PDMS was re-established from 0-1.5 mg/kg bw/day to 0-0.8 mg/kg bw/day by applying additional safety factor 2 based on its ocular toxicity. The result of 0-0.8 mg/kg bw/day is a temporary ADI until further data are provided to 2010.

• BMB Reports
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• v.50 no.11
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• pp.535-536
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• 2017

A novel approach has been used to identify functional interactions relevant to human disease. Using high-throughput human-yeast genetic interaction screens, a first draft of disease interactome was obtained. This was achieved by first searching for candidate human disease genes that confer toxicity in yeast, and second, identifying modulators of toxicity. This study found potentially disease-relevant interactions by analyzing the network of functional interactions and focusing on genes implicated in amyotrophic lateral sclerosis (ALS), for example. In the subsequent proof-of-concept study focused on ALS, similar functional relationships between a specific kinase and ALS-associated genes were observed in mammalian cells and zebrafish, supporting findings in human-yeast genetic interaction screens. Results of combined analyses highlighted MAP2K5 kinase as a potential therapeutic target in ALS.

• Toxicological Research
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• v.13 no.3
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• pp.183-186
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• 1997

Acute toxicity of pectenotoxin 2 (PTX2) was examined in mice. Treatment of mice with a toxic dose of PTX2 resulted in clinical signs such as ataxia, cyanosis and an abrupt decrease in body temperature. Histopathological studies revealed that the liver is the major target organ for PTX2. Activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SDH) were significantly elevated by PTX2 administration. Glucose-6-phosphatase activities were not changed by the treatment. The PTX2 treatment decreased relative liver weight without changing the body weight. The effect of PTX2 on hepatic drug metabolizing enzyme system was determined. An ip dose of PTX2 (200 $\mu$g/kg) induced a significant decrease in the hepatic microsomal protein content. Cytochrome P-450 content, cytochrome b$_5$ content, NADPH cytochrome c reductase, aminopyrine N-demethylase activities, or hepatic glutathione content were not altered by PTX2 treatment.