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Sample records for drug toxicity

  1. Investigation of toxic metabolites during drug development

    International Nuclear Information System (INIS)

    Park, Kevin; Williams, Dominic P.; Naisbitt, Dean J.; Kitteringham, Neil R.; Pirmohamed, Munir

    2005-01-01

    Adverse drug reactions (ADRs) are a significant human health problem. Any organ system can be affected, including the liver, skin and kidney. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. The clinical picture is often diverse, even for the same drug. Mild, asymptomatic effects occur at a relatively high frequency with a number of drugs. Idiosyncratic toxicity is rare but potentially life-threatening. Many serious ADRs that occur in man are unpredictable from routine pathology and clinical chemistry in laboratory animals and are therefore poorly understood. The drug metabolist can determine the propensity of a novel chemical entity to either accumulate in the hepatocyte or undergo bioactivation in numerous model systems, from expressed enzymes, genetically engineered cells to whole animals. Bioactivation can be measured using trapping experiments with model nucleophiles or by measurement of non-specific covalent binding. The chemistry of the process is defined and the medicinal chemist can address the issue by seeking a metabolically stable pharmacophore to replace the potential toxicophore. However, we require a more fundamental understanding of the role of drug chemistry and biochemistry in ADRs. This requires knowledge of the ultimate toxin, signalling in cell defense and the sequence of molecular events, which ultimately lead to cell and tissue damage. It is imperative that such studies have a clinical level, but then translated into laboratory-based molecular studies. This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines

  2. Mechanisms of reduction of antitumor drug toxicity by liposome encapsulation

    Energy Technology Data Exchange (ETDEWEB)

    Rahman, Y. E.; Hanson, W. R.; Bharucha, J.; Ainsworth, E. J.; Jaroslow, B.

    1977-01-01

    The antitumor drug Actinomycin D is effective against the growth of some human solid tumors but its use is limited by its extreme toxicity. The development of a method of administering Act. D to reduce its systemic toxicity by incorporating the drug within liposomes reduced its toxicity but its tumoricidal activity was retained.

  3. Toxicity studies of drugs and chemicals in animals: An overview

    OpenAIRE

    S. Saganuwan

    2017-01-01

    Toxicity study is the investigation of either short or long-term toxic effects of a drug or chemical on animals. The toxicity is dose-dependent as asserted by Paracelsus over 500 years ago. However, short-term toxic effect is determined using median lethal dose (LD50) first introduced by Trevan in 1927 and revised many times. Presently there is a growing preponderance of rejection of scientific papers on acute toxicity study, simply because of the belief that in the current hazard and safety ...

  4. Toxicity studies of drugs and chemicals in animals: An overview

    Directory of Open Access Journals (Sweden)

    S. Saganuwan

    2017-12-01

    Full Text Available Toxicity study is the investigation of either short or long-term toxic effects of a drug or chemical on animals. The toxicity is dose-dependent as asserted by Paracelsus over 500 years ago. However, short-term toxic effect is determined using median lethal dose (LD50 first introduced by Trevan in 1927 and revised many times. Presently there is a growing preponderance of rejection of scientific papers on acute toxicity study, simply because of the belief that in the current hazard and safety as-sessment of drugs and chemicals, LD50 values are no longer used. In view of this, literature search was carried out with a view to investigating the relevance of LD50 in development and assessment of drugs and chemicals. The findings revealed that in the past, many animals had been used for LD50 determination. OECD has reduced the number of test animals to 5–15 and presently it is further re-duced to 2–6. Acute toxicity study is being carried out in medicinal plants research and in the study of patent medicine. Although the application of LD50 has been drastically reduced, it is still applied and accepted in some parts of the world. Moreover, animals on which LD50 tests are conducted, should be allowed to die to see the end effect of the test drug or chemical because euthanisia of test animals may mask some toxicity signs of the test agents. Therefore, toxicity study of drugs and chemicals is a sci-entific process necessary for discovery and development of drugs as well as identification of potential toxicants.

  5. Toxic keratopathy due to abuse of topical anesthetic drugs.

    Science.gov (United States)

    Yeniad, Baris; Canturk, Serife; Esin Ozdemir, Fatma; Alparslan, Nilufer; Akarcay, Koray

    2010-06-01

    To describe 8 cases of toxic keratopathy due to abuse of topical anesthetic drugs. Clinical findings from patients with toxic keratopathy were investigated retrospectively. Two patients had toxic keratopathy bilaterally. Five of 8 patients had an ocular history of a corneal foreign body, 1 had basal membrane dystrophy, 1 had ultraviolet radiation, and 1 had chemical burn. All patients had undergone psychiatric consultation. Four patients had anxiety disorder and 1 had bipolar disease. Clinical signs were improved in all patients with discontinuation of topical anesthetic drug use along with adjunctive psychiatric treatment. Penetrating keratoplasty was performed in 2 patients. Toxic keratopathy due to topical anesthetic abuse is a curable disease. Early diagnosis and prevention of topical anesthetic drug use are the most important steps in the treatment of this condition. As these patients commonly exhibit psychiatric disorders, adjunctive psychiatric treatment may help to break the chemical addiction.

  6. Pulmonary toxicity of cytostatic drugs: cell kinetics

    International Nuclear Information System (INIS)

    Witschi, H.; Godfrey, G.; Frome, E.; Lindenschmidt, R.C.

    1987-01-01

    Mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3 H-labeled thymidine and autoradiography. In cyclophosphamide-treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2-3 weeks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature whereas in animals treated with oleic acid there was an initial burst of type II cell proliferation. It is concluded that the patterns of pulmonary repair vary between chemicals designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid

  7. The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity.

    Science.gov (United States)

    Morén, Constanza; Juárez-Flores, Diana Luz; Cardellach, Francesc; Garrabou, Glòria

    2016-01-01

    Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient. The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide. We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs. One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.

  8. Understanding mechanisms of toxicity: Insights from drug discovery research

    International Nuclear Information System (INIS)

    Houck, Keith A.; Kavlock, Robert J.

    2008-01-01

    Toxicology continues to rely heavily on use of animal testing for prediction of potential for toxicity in humans. Where mechanisms of toxicity have been elucidated, for example endocrine disruption by xenoestrogens binding to the estrogen receptor, in vitro assays have been developed as surrogate assays for toxicity prediction. This mechanistic information can be combined with other data such as exposure levels to inform a risk assessment for the chemical. However, there remains a paucity of such mechanistic assays due at least in part to lack of methods to determine specific mechanisms of toxicity for many toxicants. A means to address this deficiency lies in utilization of a vast repertoire of tools developed by the drug discovery industry for interrogating the bioactivity of chemicals. This review describes the application of high-throughput screening assays as experimental tools for profiling chemicals for potential for toxicity and understanding underlying mechanisms. The accessibility of broad panels of assays covering an array of protein families permits evaluation of chemicals for their ability to directly modulate many potential targets of toxicity. In addition, advances in cell-based screening have yielded tools capable of reporting the effects of chemicals on numerous critical cell signaling pathways and cell health parameters. Novel, more complex cellular systems are being used to model mammalian tissues and the consequences of compound treatment. Finally, high-throughput technology is being applied to model organism screens to understand mechanisms of toxicity. However, a number of formidable challenges to these methods remain to be overcome before they are widely applicable. Integration of successful approaches will contribute towards building a systems approach to toxicology that will provide mechanistic understanding of the effects of chemicals on biological systems and aid in rationale risk assessments

  9. In vitro pyrogen test for toxic or immunomodulatory drugs

    OpenAIRE

    Daneshian, Mardas; Guenther, Armin; Wendel, Albrecht; Hartung, Thomas; Aulock, Sonja von

    2006-01-01

    Pyrogenic contaminations of some classes of injectable drugs, e.g. toxic or immunomodulatory as well as false-positive drugs, represent a major risk which cannot yet be excluded due to the limitations of current tests. Here we describe a modification of the In vitro Pyrogen Test termed AWIPT (Adsorb, Wash, In vitro Pyrogen Test), which addresses this problem by introducing a pre-incubation step in which pyrogenic contaminations in the test sample are adsorbed to albumin-coated beads. After ri...

  10. Psychosis associated with acute recreational drug toxicity: a European case series

    OpenAIRE

    Vallersnes, Odd Martin; Dines, Alison M.; Wood, David M.; Yates, Christopher; Heyerdahl, Fridtjof; Hovda, Knut Erik; Giraudon, Isabelle; Dargan, Paul I.

    2016-01-01

    Background Psychosis can be associated with acute recreational drug and novel psychoactive substance (NPS) toxicity. However, there is limited data available on how common this is and which drugs are most frequently implicated. We describe a European case series of psychosis associated with acute recreational drug toxicity, and estimate the frequency of psychosis for different recreational drugs. Methods ...

  11. In vitro pyrogen test for toxic or immunomodulatory drugs.

    Science.gov (United States)

    Daneshian, Mardas; Guenther, Armin; Wendel, Albrecht; Hartung, Thomas; von Aulock, Sonja

    2006-06-30

    Pyrogenic contaminations of some classes of injectable drugs, e.g. toxic or immunomodulatory as well as false-positive drugs, represent a major risk which cannot yet be excluded due to the limitations of current tests. Here we describe a modification of the In vitro Pyrogen Test termed AWIPT (Adsorb, Wash, In vitro Pyrogen Test), which addresses this problem by introducing a pre-incubation step in which pyrogenic contaminations in the test sample are adsorbed to albumin-coated beads. After rinsing, the beads are incubated with human whole blood and the release of the endogenous pyrogen interleukin-1beta is measured as a marker of pyrogenic activity. Intentional contaminations with lipopolysaccharide were retrieved from the chemotherapeutic agents paclitaxel, cisplatin and liposomal daunorubicin, the antibiotic gentamicin, the antifungal agent liposomal amphotericin B, and the corticosteroid prednisolone at lower dilutions than in the standard in vitro pyrogen test. This represents a promising new approach for the detection of pyrogenic contamination in drugs or in drugs containing interfering additives and should lead to improved safety levels.

  12. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

    Directory of Open Access Journals (Sweden)

    Kanika Madaan

    2014-01-01

    Full Text Available Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity.

  13. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

    Science.gov (United States)

    Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

    2014-01-01

    Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633

  14. Drug metabolizing enzyme systems and their relationship to toxic mechanisms

    International Nuclear Information System (INIS)

    Boyd, M.R.; Ravindranath, V.; Burka, L.T.

    1983-01-01

    The metabolism and toxicity of 3-methylfuran (3-MF) are described. The major product of metabolic activation of 3-MF appears to be disemicarbazones. Cursory description of toxic effects of 3-MF on lung and kidneys are provided. 18 refs

  15. Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

    Science.gov (United States)

    Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

    2018-02-01

    More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  16. Neurological manifestation of phenytoin toxicity, resulting from drug ...

    African Journals Online (AJOL)

    Phenytoin toxicity masquerading as deterioration of neurological symptoms caused by interaction with chloramphenicol is a very rare but real risk. To the authors' knowledge only one such case occurring in humans has been reported in the English literature. No case of clinical phenytoin toxicity occurring at less than ...

  17. Generation of human pluripotent stem cell-derived hepatocyte-like cells for drug toxicity screening.

    Science.gov (United States)

    Takayama, Kazuo; Mizuguchi, Hiroyuki

    2017-02-01

    Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes are limited, making it difficult to supply the abundant quantities required for large-scale drug toxicity screening. Therefore, there is an urgent need for a novel unlimited, efficient, inexpensive, and predictive model which can be applied for large-scale drug toxicity screening. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are able to replicate indefinitely and differentiate into most of the body's cell types, including hepatocytes. It is expected that hepatocyte-like cells generated from human ES/iPS cells (human ES/iPS-HLCs) will be a useful tool for drug toxicity screening. To apply human ES/iPS-HLCs to various applications including drug toxicity screening, homogenous and functional HLCs must be differentiated from human ES/iPS cells. In this review, we will introduce the current status of hepatocyte differentiation technology from human ES/iPS cells and a novel method to predict drug-induced liver injury using human ES/iPS-HLCs. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  18. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    Full Text Available Objectives: Advancements in nanotechnology have led to nanoparticle (NP use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos (Danio rerio. Methods: Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED. For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. Results: The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Conclusion: Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and

  19. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs: - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model.

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty; Thakur, Mansee

    2016-12-01

    Advancements in nanotechnology have led to nanoparticle (NP) use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos ( Danio rerio ). Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED). For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH) during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and exposure times used in this study. The embryonic zebrafish

  20. Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

    Science.gov (United States)

    2013-03-01

    Neratinib Versus Lapatinib Plus Capecitabine For ErbB2 Positive Advanced Breast Cancer Active, not recruiting No Results Available YES neratinib -9...Drug: Neratinib |Drug: Lapatinib|Drug: Capecitabine Efficacy and Safety of BMS-690514 in Combination With Letrozole to Treat Metastatic Breast Cancer

  1. A simple approach discriminating cardio­safe drugs from toxic ones

    Science.gov (United States)

    Falah, Mizied; Nassar, Taher; Rayan, Anwar

    2009-01-01

    More than 130 FDA-approved drugs have been identified for now to prolong the QT interval and possibly lead to sudden cardiac death. Due to their toxic effect, some of these drugs have been withdrawn from the pharmaceutical market. In this study, we have formulated few rules to assess the ability to prolong QT interval and thereby discriminate between cardiotoxic and -safe drugs. These rules have clearly determined that cardio-toxic drugs are more likely to obey Lipinski rule of 5 and Oprea lead-like rule. Moreover, the cardio-toxic drugs have been found to have in common values of -0.5 to 6.5 log P, 1-5 nitrogen atoms, up to 4 oxygen atoms, 5-27 hydrophobic atoms, and 15-53 single bonds. Matthews Correlation Coefficient with the value of 0.6 was also attained and nearly 96% of the cardio-toxic drugs were successfully covered. Thus, despite the simplicity of this methodology, we have obtained interesting and informative results. The proposed set of these simple rules could be employed to infer cardio-toxicity or -safety for current and potential drugs. The present study will have important impact on decision making in the fields of drug development, molecule screening in biological assays, and other applications as well. PMID:19759813

  2. Safety studies of homoeopathic drugs in acute, sub-acute and chronic toxicity in rats

    Directory of Open Access Journals (Sweden)

    Surender Singh

    2017-01-01

    Full Text Available Background: Homoeopathic drugs are frequently recommended in day to day life as therapeutic agents by homoeopathic practitioners. However, safety of homoeopathic drugs remains a challenge because of the high variability of chemical components involved. Aim: The objective of the present study was to investigate the acute, subacute, and chronic oral toxicity of different homoeopathic drugs (Ferrum phosphoricum 3X, Ferrum phosphoricum 6X, Calcarea phosphoricum 6X, and Magnesium phosphoricum 6X in experimental models. Materials and Methods: In acute oral toxicity study, homoeopathic drugs were administered orally at 2000mg/kg body weight, and animals were observed for toxic symptoms till 10 days as per the OECD guidelines. For subacute and chronic toxicity study, homoeopathic drugs were administered for 28 and 180 days, respectively, as per the OECD guidelines. At the end of 28 and 180 days, the animals were sacrificed and toxicity parameters were assessed. Histopathological evaluation of different organs was also performed to assess any toxicity. Results: In acute toxicity study, no mortality was found at a dose of 2000 mg/kg which indicates that oral LD50of homoeopathic drugs were more than 2000 mg/kg. The administration of drugs at a dose of 70 mg/kg body weight for 28 and 180 days did not produce any significant change in haematological and biochemical parameters of male and female rats as compared to normal control group. No pathological changes were observed in histology of various organs of treated rats as compared to normal control animals. Conclusion: These homoeopathic drugs are safe & produce no toxicity when administered for longer duration.

  3. In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts

    Science.gov (United States)

    Yang, Hongbin; Sun, Lixia; Li, Weihua; Liu, Guixia; Tang, Yun

    2018-02-01

    For a drug, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future.

  4. In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts

    Directory of Open Access Journals (Sweden)

    Hongbin Yang

    2018-02-01

    Full Text Available During drug development, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future.

  5. In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts.

    Science.gov (United States)

    Yang, Hongbin; Sun, Lixia; Li, Weihua; Liu, Guixia; Tang, Yun

    2018-01-01

    During drug development, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future.

  6. Ex vivo preparations of human tissue for drug metabolism, toxicity and transport

    NARCIS (Netherlands)

    Groothuis, Genoveva

    2012-01-01

    Before new drugs are allowed on the market, their safety and metabolite profile should be extensively tested, as often reactive metabolites are the ultimate toxicant. The exposure of the target cell to the drug and its metabolites is determined by the expression levels of the transporters and the

  7. Radiology of adverse reactions to drugs and toxic hazards

    International Nuclear Information System (INIS)

    Ansell, G.

    1989-01-01

    The book reviews the contribution offered by radiological methods to detection of lesions, confirmation of tentative diagnoses, and differentiation of lesions. The radiological methods discussed cover the conventional roentgenology as well as computed tomography, ultrasonography, scintiscanning, and NMR tomography, which are the useful tools for the very important task, to detect and define the manifestations of adverse reactions and toxic hazards, in order to commence treatment in time. (orig.) With 154 figs [de

  8. Lead Toxicity: A Probable Cause of Abdominal Pain in Drug Abusers

    Directory of Open Access Journals (Sweden)

    Hossein Froutan

    2011-05-01

    Full Text Available Background: Lead toxicity is caused by ingestion, inhalation, or contact with particles or vapors containing lead. It can present with nonspecific signs and symptoms such as abdominal pain, constipation, irritability, difficulty concentrating, and anemia. In this study, we have tried to find a relationship between lead poisoning and drug abuse.Methods: In a cross sectional study, drug addicts presenting with abdominal pain referring to GI center ofImam Khomeini hospital in 2008 were observed. Patients having occupational contact with lead were excluded from the study. Required data included age, sex, clinical findings, Para clinic results and blood lead level. Results were analyzed through SPSS-15 software.Results: 42 patients (all male with average age of 46.9 ± 10.1 years were included in the study. Averageblood lead level was 51.17±27.96µg/dl. 22 patients (52.6% had lead toxicity. A significant relation was found between lead toxicity and mode of opium drug use; however relation between lead toxicity and duration of addiction was not significant. Similarly, a meaningful relation was found between lead toxicity and abnormal liver function test, urine tests, ECG, presence of basophilic stippling and hyperuricemia.Conclusion: There seems to be a significant relation between opium drug abuse and lead toxicity. Further studies with more cases and ethnicities are needed.

  9. Gamma irradiation reduces the immunological toxicity of doxorubicin, anticancer drug

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae-Hun; Sung, Nak-Yun; Raghavendran, H. Balaji; Yoon, Yohan; Song, Beom-Seok; Choi, Jong-il [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Yoo, Young-Choon [Department of Microbiology, College of Medicine, Konyang University, Daejeon 302-718 (Korea, Republic of); Byun, Myung-Woo [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Hwang, Young-Jeong [Division of Food Science, International University of Korea, Jinju 660-759 (Korea, Republic of); Lee, Ju-Woon [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of)], E-mail: sjwlee@kaeri.re.kr

    2009-07-15

    Doxorubicin (DOX) is a widely used anticancer agent, but exhibits some immunological toxicity to patients during chemotherapy. The present study was conducted to evaluate the effect of gamma irradiation on the immunological response and the inhibition activity on in vivo tumor mass of DOX. The results showed that DOX irradiated at 10 and 20 kGy reduce the inhibition of mouse peritoneal macrophage proliferation and induce the release of cytokines (TNF-{alpha} and IL-6) when compared with non-irradiated DOX. The cytotoxicity against human breast (MCF-7), murine colon adenocarcinoma (Colon 26) and human monocytic (THP-1) tumor cell were not significantly different between non-irradiated and irradiated DOX (P<0.05). In vivo study on the tumor mass inhibition, gamma-irradiated DOX showed a considerable inhibition of tumor mass and this effect was statistically non-significant as compared with non-irradiated DOX. In conclusion, gamma irradiation could be regarded as a potential method for reducing the immunological toxicity of DOX. Further researches is needed to reveal the formation and activity of radiolysis products by gamma irradiation.

  10. Gamma irradiation reduces the immunological toxicity of doxorubicin, anticancer drug

    International Nuclear Information System (INIS)

    Kim, Jae-Hun; Sung, Nak-Yun; Raghavendran, H. Balaji; Yoon, Yohan; Song, Beom-Seok; Choi, Jong-il; Yoo, Young-Choon; Byun, Myung-Woo; Hwang, Young-Jeong; Lee, Ju-Woon

    2009-01-01

    Doxorubicin (DOX) is a widely used anticancer agent, but exhibits some immunological toxicity to patients during chemotherapy. The present study was conducted to evaluate the effect of gamma irradiation on the immunological response and the inhibition activity on in vivo tumor mass of DOX. The results showed that DOX irradiated at 10 and 20 kGy reduce the inhibition of mouse peritoneal macrophage proliferation and induce the release of cytokines (TNF-α and IL-6) when compared with non-irradiated DOX. The cytotoxicity against human breast (MCF-7), murine colon adenocarcinoma (Colon 26) and human monocytic (THP-1) tumor cell were not significantly different between non-irradiated and irradiated DOX (P<0.05). In vivo study on the tumor mass inhibition, gamma-irradiated DOX showed a considerable inhibition of tumor mass and this effect was statistically non-significant as compared with non-irradiated DOX. In conclusion, gamma irradiation could be regarded as a potential method for reducing the immunological toxicity of DOX. Further researches is needed to reveal the formation and activity of radiolysis products by gamma irradiation.

  11. Spirulina maxima Protects Liver From Isoniazid and Rifampicin Drug Toxicity.

    Science.gov (United States)

    Jatav, Santosh Kumar; Kulshrestha, Archana; Zacharia, Anish; Singh, Nita; Tejovathi, G; Bisen, P S; Prasad, G B K S

    2014-07-01

    Hepatotoxicity associated with isoniazid and rifampicin is one of the major impediments in antituberculosis therapy. The present study explored the prophylactic and therapeutic efficacies of Spirulina maxima in isoniazid and rifampicin induced hepatic damage in a rat model. Hepatic damage induced in Wistar rats by isoniazid and rifampicin resulted in significant alterations in biomarkers of liver function, namely, bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and oxidative stress markers such as superoxide dismutase, catalase, glutathione, and thiobarbituric acid reactive substances. Co-administration of Spirulina maxima along with antituberculosis drugs protected liver from hepatotoxicity due to isoniazid and rifampicin. Administration of Spirulina maxima consecutively for 2 weeks to hepatodamaged animals resulted in restoration of hepatic function as evident from normalization of serum markers of liver function. Thus, the present study revealed remarkable prophylactic and therapeutic potential of Spirulina maxima. Co-administration of Spirulina maxima and antituberculosis drugs is advantageous as it provides extra nutritional benefit. © The Author(s) 2014.

  12. Pulmonary drug toxicity. FDG-PET findings in patients with lymphoma

    International Nuclear Information System (INIS)

    Kazama, Toshiki; Faria, S.C.; Macapinlac, H.A.; Uchida, Yoshitaka; Ito, Hisao

    2008-01-01

    The objective of this study was to evaluate the prevalence and positron emission tomography (PET) imaging features of pulmonary drug toxicity in patients with lymphoma during or just following chemotherapy. A total of 677 PET scans on 460 patients with lymphoma (351 non-Hodgkin's lymphoma, 92 Hodgkin's disease, and 17 both Hodgkin's and non-Hodgkin's lymphoma) were performed for the evaluation of chemotherapy response. In 51 patients, abnormal accumulation on both sides of the chest was reported. A review of medical records, 18 fluorodeoxyglucose ( 18 FDG)-PET scans, and chest computed tomography (CT) was performed, and cases with probable drug toxicity were identified. Inclusion criteria of probable drug toxicity were abnormal but symmetrical FDG accumulation in both lungs seen during or just following the completion of chemotherapy, the abnormal accumulation or corresponding abnormal CT findings resolved on subsequent studies, exclusion of clinical diagnosis of pneumonia, radiation pneumonitis, or lymphoma involvement. In 10 patients (six men and four women, average age 47.3), 2.2% of cases, probable drug toxicity was identified. In all 10 cases, diffuse and subpleural-dominant FDG accumulation was seen on FDG-PET scans, and scattered or diffuse ground-glass opacities were observed on chest CT. Four patients reported symptoms, and six patients did not report any symptoms. Diffuse and peripheral-dominant FDG accumulation in the lung, which may represent pulmonary drug toxicity, was not uncommon in patients with lymphoma who underwent chemotherapy. FDG-PET scan might be able to detect pulmonary drug toxicity in asymptomatic patients. (author)

  13. Toxicity Evaluation of Through Fish Bioassay Raw Bulk Drug Industry Wastewater After Electrochemical Treatment

    Directory of Open Access Journals (Sweden)

    S Satyanarayan

    2011-10-01

    Full Text Available Considering the high pollution potential that the synthetic Bulk Drug industry Wastewater (BDW possesses due to the presence of variety of refractory organics, toxicity evaluation is of prime importance in assessing the efficiency of the applied wastewater treatment system and in establishing the discharge standards. Therefore, in this study the toxic effects of high strength bulk drug industry wastewater before and after electrochemical treatment on common fish Lebistes reticulatus-(peter were studied under laboratory conditions. Results indicated that wastewater being very strong in terms of color, COD and BOD is found to be very toxic to the studied fish. The LC50 values for raw wastewater and after electrochemical treatment with carbon and aluminium electrodes for 24, 48, 72 and 96 hours ranged between, 2.5-3.6%, 6.8-8.0%, 5.0-5.8% respectively. Carbon electrode showed marginally better removals for toxicity than aluminium electrode. It was evident from the studies that electrochemical treatment reduces toxicity in proportion to the removal efficiency shown by both the electrodes. The reduction in toxicity after treatment indicates the intermediates generated are not toxic than the parent compounds. Furthermore, as the electrochemical treatment did not result in achieving disposal standards it could be used only as a pre-treatment and the wastewater needs further secondary treatment before final disposal.

  14. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty

    2016-01-01

    Objectives: Advancements in nanotechnology have led to nanoparticle (NP) use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos (Danio rerio). Methods: Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED). For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. Results: The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH) during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Conclusion: Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and exposure times used

  15. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

    Directory of Open Access Journals (Sweden)

    Divya eSingh

    2016-01-01

    Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

  16. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  17. A categorical structure-activity relationship analysis of the developmental toxicity of antithyroid drugs.

    Science.gov (United States)

    Cunningham, Albert R; Carrasquer, C Alex; Mattison, Donald R

    2009-01-01

    The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

  18. A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

    Directory of Open Access Journals (Sweden)

    Cunningham AlbertR

    2009-11-01

    Full Text Available The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

  19. A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

    Directory of Open Access Journals (Sweden)

    Albert R. Cunningham

    2009-01-01

    Full Text Available The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

  20. Psychosis associated with acute recreational drug toxicity: a European case series.

    Science.gov (United States)

    Vallersnes, Odd Martin; Dines, Alison M; Wood, David M; Yates, Christopher; Heyerdahl, Fridtjof; Hovda, Knut Erik; Giraudon, Isabelle; Dargan, Paul I

    2016-08-18

    Psychosis can be associated with acute recreational drug and novel psychoactive substance (NPS) toxicity. However, there is limited data available on how common this is and which drugs are most frequently implicated. We describe a European case series of psychosis associated with acute recreational drug toxicity, and estimate the frequency of psychosis for different recreational drugs. The European Drug Emergencies Network (Euro-DEN) collects data on presentations to Emergency Departments (EDs) with acute recreational drug and NPS toxicity at 16 centres in ten countries. Euro-DEN data from October 2013 through September 2014 was retrospectively searched, and cases with psychosis were included. The proportion of cases with psychosis per drug was calculated in the searched Euro-DEN dataset. Psychosis was present in 348 (6.3 %) of 5529 cases. The median (interquartile range) age was 29 (24-38) years, 276 (79.3 %) were male and 114 (32.8 %) were admitted to psychiatric ward. The drugs most commonly reported were cannabis in 90 (25.9 %) cases, amphetamine in 87 (25.0 %) and cocaine in 56 (16.1 %). More than one drug was taken in 189 (54.3 %) cases. Psychosis was frequent in those ED presentations involving tryptamines (4/7; 57.1 %), methylenedioxypyrovalerone (MDPV) (6/22; 27.3 %), methylphenidate (6/26; 23.1 %), lysergic acid diethylamide (LSD) (18/86; 20.9 %), psilocybe mushrooms (3/16; 18.8 %), synthetic cannabinoid receptor agonists (4/26; 15.4 %) and amphetamine (87/593; 14.7 %), but less common in those involving mephedrone (14/245; 5.7 %), methylenedioxymethamphetamine (MDMA) (20/461; 4.3 %) and methedrone (3/92; 3.3 %). Amphetamine was the most frequent drug associated with psychosis when only one agent was reported, with psychosis occurring in 32.4 % of these presentations. The frequency of psychosis in acute recreational drug toxicity varies considerably between drugs, but is a major problem in amphetamine poisoning. In rapidly changing drug markets and

  1. Toxicity of anthelmintic drugs (fenbendazole and flubendazole) to aquatic organisms.

    Science.gov (United States)

    Wagil, Marta; Białk-Bielińska, Anna; Puckowski, Alan; Wychodnik, Katarzyna; Maszkowska, Joanna; Mulkiewicz, Ewa; Kumirska, Jolanta; Stepnowski, Piotr; Stolte, Stefan

    2015-02-01

    Flubendazole (FLU) and fenbendazole (FEN) belong to benzimidazoles-pharmaceuticals widely used in veterinary and human medicine for the treatment of intestinal parasites as well as for the treatment of systemic worm infections. In recent years, usage of these drugs increased, which resulted in a larger contamination of the environment and possible negative effects on biota. Hence, in our research, we investigated an aquatic ecotoxicity of these pharmaceuticals towards: marine bacteria (Vibrio fischeri), green algae (Scenedesmus vacuolatus), duckweed (Lemna minor) and crustacean (Daphnia magna). Ecotoxicity tests were combined with chemical analysis in order to investigate the actual exposure concentration of the compounds used in the experiment as well as to stability and adsorption studies. As a result, study evaluating sensitivity of different aquatic organisms to these compounds and new ecotoxicological data is presented. The strongest negative impact of FLU and FEN was observed to D. magna.

  2. Human skeletal muscle drug transporters determine local exposure and toxicity of statins.

    Science.gov (United States)

    Knauer, Michael J; Urquhart, Bradley L; Meyer zu Schwabedissen, Henriette E; Schwarz, Ute I; Lemke, Christopher J; Leake, Brenda F; Kim, Richard B; Tirona, Rommel G

    2010-02-05

    The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity. We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro. We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1. These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.

  3. A Relational Learning Approach to Structure-Activity Relationships in Drug Design Toxicity Studies

    Directory of Open Access Journals (Sweden)

    Camacho Rui

    2011-12-01

    Full Text Available It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current “target-rich, lead-poor” scenario.

  4. Cutaneous drug toxicity from 2,4-dinitrophenol (DNP): Case report and histological description.

    Science.gov (United States)

    Le, Patricia; Wood, Benjamin; Kumarasinghe, Sujith Prasad

    2015-11-01

    The use of 2,4-dinitrophenol (DNP) has regained popularity as a weight loss aid in the last two decades due to increased marketing to bodybuilders and the increasing availability of this banned substance via the Internet. 2,4-DNP is a drug of narrow therapeutic index and toxicity results in hyperthermia, diaphoresis, tachycardia, tachypnoea and possible cardiac arrest and death. Skin toxicity from 2,4-DNP has not been reported since the 1930s. We report a case of a 21-year-old bodybuilding enthusiast who presented with a toxic exanthem after taking 2,4-DNP, and describe the first skin biopsy findings in a case of 2,4-DNP toxicity. © 2014 The Australasian College of Dermatologists.

  5. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

    Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

  6. Algorithm of Molecular and Biological Assessment of the Mechanisms of Sensitivity to Drug Toxicity by the Example of Cyclophosphamide.

    Science.gov (United States)

    Telegin, L Yu; Sarmanaev, S Kh; Devichenskii, V M; Tutelyan, V A

    2018-01-01

    Comparative study of the liver, blood, and spleen of DBA/2JSto and BALB/cJLacSto mice sensitive and resistant to acute toxicity of the cyclophosphamide allowed us to reveal basic toxicity biomarkers of this antitumor and immunosuppressive agent. Obtained results can be used for the development of an algorithm for evaluation of toxic effects of drugs and food components.

  7. Phototransformation of Amlodipine in Aqueous Solution: Toxicity of the Drug and Its Photoproduct on Aquatic Organisms

    Directory of Open Access Journals (Sweden)

    Marina DellaGreca

    2007-01-01

    Full Text Available The phototransformation of amlodipine in water was investigated under various conditions. A quantum yield ΦS2.2×10−4 and a half-life time t1/2 0.419 days were calculated when the drug in water (10−4 M was exposed to sunlight. The only photoproduct found was its pyridine derivative. Formation of this product was explained on the basis of a radical cation intermediate. The acute and chronic toxicity of the drug and its photoproduct were evaluated on different organisms of the freshwater chain (Brachionus calyciflorus, Thamnocephalus platyurus, Daphnia magna, Ceriodaphnia dubia. The photoproduct exhibited a stronger toxic potential than the parent drug on the long time for C. dubia.

  8. Computational chemistry approach for the early detection of drug-induced idiosyncratic liver toxicity.

    Science.gov (United States)

    Cruz-Monteagudo, Maykel; Cordeiro, M Natália D S; Borges, Fernanda

    2008-03-01

    Idiosyncratic drug toxicity (IDT), considered as a toxic host-dependent event, with an apparent lack of dose response relationship, is usually not predictable from early phases of clinical trials, representing a particularly confounding complication in drug development. Albeit a rare event (usually approach proposed in the present study, can play an important role in addressing IDT in early drug discovery. We report for the first time a systematic evaluation of classification models to predict idiosyncratic hepatotoxicity based on linear discriminant analysis (LDA), artificial neural networks (ANN), and machine learning algorithms (OneR) in conjunction with a 3D molecular structure representation and feature selection methods. These modeling techniques (LDA, feature selection to prevent over-fitting and multicollinearity, ANN to capture nonlinear relationships in the data, as well as the simple OneR classifier) were found to produce QSTR models with satisfactory internal cross-validation statistics and predictivity on an external subset of chemicals. More specifically, the models reached values of accuracy/sensitivity/specificity over 84%/78%/90%, respectively in the training series along with predictivity values ranging from ca. 78 to 86% of correctly classified drugs. An LDA-based desirability analysis was carried out in order to select the levels of the predictor variables needed to trigger the more desirable drug, i.e. the drug with lower potential for idiosyncratic hepatotoxicity. Finally, two external test sets were used to evaluate the ability of the models in discriminating toxic from nontoxic structurally and pharmacologically related drugs and the ability of the best model (LDA) in detecting potential idiosyncratic hepatotoxic drugs, respectively. The computational approach proposed here can be considered as a useful tool in early IDT prognosis.

  9. Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging.

    Science.gov (United States)

    Mititelu, Mihai; Wong, Brandon J; Brenner, Marie; Bryar, Paul J; Jampol, Lee M; Fawzi, Amani A

    2013-09-01

    Given the infrequent occurrence of hydroxychloroquine toxic effects, few data are available about the presenting features and long-term follow-up of patients with hydroxychloroquine retinopathy, making it difficult to surmise the clinical course of patients after cessation of drug treatment. To report functional and structural findings of hydroxychloroquine retinal toxic effects after drug therapy discontinuation. A retrospective medical record review was performed to identify patients taking hydroxychloroquine who were screened for toxic effects from January 1, 2009, through August 31, 2012, in the eye centers of Northwestern University and the University of Southern California. Northwestern University Sorrel Rosin Eye Center, Chicago, Illinois, and the Doheny Eye Institute at the University of Southern California, Los Angeles. Seven consecutive patients diagnosed as having hydroxychloroquine retinal toxic effects. Retinal toxic effects. Seven patients (1 man and 6 women) with a mean age of 55.9 years (age range, 25-74 years) developed retinal toxic effects after using hydroxychloroquine for a mean of 10.4 years (range, 3-19 years). Fundus examination revealed macular pigmentary changes in all 7 patients, corresponding to abnormal fundus autofluorescence (FAF). On spectral domain optical coherence tomography, there was outer retinal foveal resistance (preservation of the external limiting membrane and the photoreceptor layer) in 6 patients. After drug therapy discontinuation, 5 patients experienced outer retinal regeneration (3 subfoveally and 2 parafoveally), with associated functional visual improvement on static perimetry in 2 patients. Over time, FAF remained stable in 3 patients, whereas the remaining patients had a pattern of hypoautofluorescence that replaced areas of initial hyperautofluorescence (2 patients) and enlargement of the total area of abnormal FAF (2 patients). Preservation of the external limiting membrane carries a positive prognostic value in

  10. Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.

    Science.gov (United States)

    Jabir, Rafid Salim; Naidu, Rakesh; Annuar, Muhammad Azrif Bin Ahmad; Ho, Gwo Fuang; Munisamy, Murali; Stanslas, Johnson

    2012-12-01

    Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

  11. Chinese proprietary medicine in Singapore: regulatory control of toxic heavy metals and undeclared drugs.

    Science.gov (United States)

    Koh, H L; Woo, S O

    2000-11-01

    Traditional Chinese medicine (TCM) is gaining popularity as a form of complementary and alternative medicine. Reports of efficacy of TCM are increasing in numbers. TCM includes both crude Chinese medicinal materials (plants, animal parts and minerals) and Chinese proprietary medicine (CPM) [final dosage forms]. Despite the belief that CPM and herbal remedies are of natural origin, unlike Western medicine, and are hence safe and without many adverse effects, there have been numerous reports of adverse effects associated with herbal remedies. Factors affecting the safety of herbal medicines include intrinsic toxicity, adulteration, substitution, contamination, misidentification, lack of standardisation, incorrect preparation and/or dosage and inappropriate labelling and/or advertising. Hence, new regulations on the control of CPM were enforced in Singapore with effect from 1 September 1999. These include licensing and labelling requirements, as well as control of microbial contamination. This article also reviews reports of excessive toxic heavy metals and undeclared drugs in CPM in Singapore between 1990 and 1997. The names, uses, toxic heavy metal or drug detected and the year of detection are tabulated. Information on the brand or manufacturer's name are provided whenever available. The public and healthcare professionals should be better informed of the basic concept of TCM and its usefulness, as well as the potential adverse effects associated with its use. Greater control over the safety and quality of CPM could be achieved through good manufacturing practice, regulatory control, research, education, reporting usage of Chinese medicine (as in drug history) as well as reporting of adverse events.

  12. Mixture toxicity of the antiviral drug Tamiflu (oseltamivir ethylester) and its active metabolite oseltamivir acid

    Energy Technology Data Exchange (ETDEWEB)

    Escher, Beate I., E-mail: b.escher@uq.edu.au [University of Queensland, National Research Centre for Environmental Toxicology (Entox), 39 Kessels Rd, Brisbane, Qld 4108 (Australia); Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Duebendorf (Switzerland); Bramaz, Nadine; Lienert, Judit; Neuwoehner, Judith [Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Duebendorf (Switzerland); Straub, Juerg Oliver [F.Hoffmann-La Roche Ltd, Corporate Safety, Health and Environmental Protection, 4070 Basel (Switzerland)

    2010-02-18

    Tamiflu (oseltamivir ethylester) is an antiviral agent for the treatment of influenza A and B. The pro-drug Tamiflu is converted in the human body to the pharmacologically active metabolite, oseltamivir acid, with a yield of 75%. Oseltamivir acid is indirectly photodegradable and slowly biodegradable in sewage works and sediment/water systems. A previous environmental risk assessment has concluded that there is no bioaccumulation potential of either of the compounds. However, little was known about the ecotoxicity of the metabolite. Ester hydrolysis typically reduces the hydrophobicity and thus the toxicity of a compound. In this case, a zwitterionic, but overall neutral species is formed from the charged parent compound. If the speciation and predicted partitioning into biological membranes is considered, the metabolite may have a relevant contribution to the overall toxicity. These theoretical considerations triggered a study to investigate the toxicity of oseltamivir acid (OA), alone and in binary mixtures with its parent compound oseltamivir ethylester (OE). OE and OA were found to be baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri. Their mixture effect lay between predictions for concentration addition and independent action for the mixture ratio excreted in urine and nine additional mixture ratios of OE and OA. In contrast, OE was an order of magnitude more toxic than OA towards algae, with a more pronounced effect when the direct inhibition of photosystem II was used as toxicity endpoint opposed to the 24 h growth rate endpoint. The binary mixtures in this assay yielded experimental mixture effects that agreed with predictions for independent action. This is consistent with the finding that OE exhibits slightly enhanced toxicity, while OA acts as baseline toxicant. Therefore, with respect to mixture classification, the two compounds can be considered as acting according to different modes of toxic action, although there are

  13. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Wenhu, E-mail: wenhu.huang@pfizer.com; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A.; Sacaan, Aida

    2015-12-15

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.

  14. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

    International Nuclear Information System (INIS)

    Huang, Wenhu; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A.; Sacaan, Aida

    2015-01-01

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.

  15. Underestimated impact of novel psychoactive substances: laboratory confirmation of recreational drug toxicity in Oslo, Norway.

    Science.gov (United States)

    Vallersnes, Odd Martin; Persett, Per Sverre; Øiestad, Elisabeth Leere; Karinen, Ritva; Heyerdahl, Fridtjof; Hovda, Knut Erik

    2017-08-01

    Recreational drug toxicity is frequent. Availability of new psychoactive substances is steadily increasing. However, data with verified analyses from clinical settings are limited. To evaluate the impact of novel psychoactive substances (NPS) on recreational drug toxicity in Oslo, Norway, we analysed samples from a selection of patients. All the patients presenting with recreational drug toxicity at the Oslo Accident and Emergency Outpatient Clinic (OAEOC) and at the Oslo University Hospital (OUH) were registered from April through September 2014. Oral fluid samples were collected at the OAEOC. Blood samples were collected at the OUH. The samples were screened using ultra-high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS). Nine hundred and sixty-four cases were included, 841 (87.2%) at the OAEOC and 123 (12.8%) at the OUH. A total of 55 oral fluid samples (OAEOC) and 103 blood samples (OUH) could be analysed. NPS were not clinically suspected in any of the screened cases. At the outpatient clinic, the most commonly found substances were clonazepam in 42/55 (76.4%) cases, amfetamines in 40/55 (72.7%) and heroin in 39/55 (70.9%). In seven (12.7%) cases NPS were detected: 4-methylamfetamine in three cases, dimethyltryptamine in two, methylone in one, and N,N-dimethyl-3,4-methylenedioxyamfetamine in one. Among the hospital patients, the most commonly found substances were clonazepam in 51/103 (49.5%) cases, amfetamines in 48/103 (46.6%), heroin in 31/103 (30.1%), and diazepam in 30/103 (29.1%). In five (4.9%) cases NPS were detected: JWH-210 in two cases, AM-2201 in two, and 5-EAPB in one. NPS were clinically not suspected, though found in eight percent of cases. Still, the vast majority of patients treated for recreational drug toxicity in Oslo have taken classical drugs. Management of these patients should be based on their clinical condition. However, it is highly important to be alert to atypical presentations possibly resulting from

  16. Simultaneous treatment of toxic diffuse goiter with I-131 and antithyroid drugs: a prospective study

    International Nuclear Information System (INIS)

    Steinbach, J.J.; Donoghue, G.D.; Goldman, J.K.

    1979-01-01

    We report a prospective study to evaluate the effect of antithyroid drugs containing the sulfhydryl radical on the outcome of I-131 (RAI) therapy. Twenty-four male patients with toxic diffuse goiter were assigned randomly into two treatment groups: Group A received RAI treatment while on antithyroid drugs after attainment of euthyroidism; Group B received no antithyroid drugs before, or when, RAI was given. Patients in each group received a dose of RAI calculated to deliver approximately 5000 rads per treatment. The incidence of hypothyroidism at 12 mo was 8% for Group A and 36% for Group B (p 0.45). The improved therapeutic outcome of patients in Group A suggests that further validation of the method in a larger patient population, including females, is warranted

  17. Adverse drug reaction and toxicity caused by commonly used antimicrobials in canine practice

    Directory of Open Access Journals (Sweden)

    K. Arunvikram

    2014-05-01

    Full Text Available An adverse drug reaction (ADR is a serious concern for practicing veterinarians and other health professionals, and refers to an unintended, undesired and unexpected response to a drug that negatively affects the patient's health. It may be iatrogenic or genetically induced, and may result in death of the affected animal. The ADRs are often complicated and unexpected due to myriad clinical symptoms and multiple mechanisms of drug-host interaction. Toxicity due to commonly used drugs is not uncommon when they are used injudiciously or for a prolonged period. Licosamides, exclusively prescribed against anaerobic pyoderma, often ends with diarrhoea and vomiting in canines. Treatment with Penicillin and β-lactam antibiotics induces onset of pemphigious vulgare, drug allergy or hypersensitivity. Chloroamphenicol and aminoglycosides causes Gray's baby syndrome and ototoxicity in puppies, respectively. Aminoglycosides are very often associated with nephrotoxicity, ototoxicity and neuromuscular blockage. Injudicious use of fluroquinones induces the onset of arthropathy in pups at the weight bearing joints. The most effective therapeutic measure in managing ADR is to treat the causative mediators, followed by supportive and symptomatic treatment. So, in this prospective review, we attempt to bring forth the commonly occurring adverse drug reactions, their classification, underlying mechanism, epidemiology, treatment and management as gleaned from the literature available till date and the different clinical cases observed by the authors.

  18. Critical analysis of 3-D organoid in vitro cell culture models for high-throughput drug candidate toxicity assessments.

    Science.gov (United States)

    Astashkina, Anna; Grainger, David W

    2014-04-01

    Drug failure due to toxicity indicators remains among the primary reasons for staggering drug attrition rates during clinical studies and post-marketing surveillance. Broader validation and use of next-generation 3-D improved cell culture models are expected to improve predictive power and effectiveness of drug toxicological predictions. However, after decades of promising research significant gaps remain in our collective ability to extract quality human toxicity information from in vitro data using 3-D cell and tissue models. Issues, challenges and future directions for the field to improve drug assay predictive power and reliability of 3-D models are reviewed. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, Bret D.; Roberts, Adam B.; Pollet, Rebecca M.; Ingle, James D.; Biernat, Kristen A.; Pellock, Samuel J.; Venkatesh, Madhu Kumar; Guthrie, Leah; O’Neal, Sara K.; Robinson, Sara J.; Dollinger, Makani; Figueroa, Esteban; McShane, Sarah R.; Cohen, Rachel D.; Jin, Jian; Frye, Stephen V.; Zamboni, William C.; Pepe-Ranney, Charles; Mani, Sridhar; Kelly, Libusha; Redinbo, Matthew (Einstein); (UNC); (Cornell)

    2015-09-01

    The selective inhibition of bacterial β-glucuronidases was recently shown to alleviate drug-induced gastrointestinal toxicity in mice, including the damage caused by the widely used anticancer drug irinotecan. Here, we report crystal structures of representative β-glucuronidases from the Firmicutes Streptococcus agalactiae and Clostridium perfringens and the Proteobacterium Escherichia coli, and the characterization of a β-glucuronidase from the Bacteroidetes Bacteroides fragilis. While largely similar in structure, these enzymes exhibit marked differences in catalytic properties and propensities for inhibition, indicating that the microbiome maintains functional diversity in orthologous enzymes. Small changes in the structure of designed inhibitors can induce significant conformational changes in the β-glucuronidase active site. Finally, we establish that β-glucuronidase inhibition does not alter the serum pharmacokinetics of irinotecan or its metabolites in mice. Together, the data presented advance our in vitro and in vivo understanding of the microbial β-glucuronidases, a promising new set of targets for controlling drug-induced gastrointestinal toxicity.

  20. Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery.

    Science.gov (United States)

    Sadekar, S; Ghandehari, H

    2012-05-01

    This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer-drug conjugates, as a function of physicochemical properties will further need to be assessed. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Indefinite antithyroid drug therapy in toxic Graves′ disease: What are the cons

    Directory of Open Access Journals (Sweden)

    Rajesh Rajput

    2013-01-01

    Full Text Available Existing treatment modalities for Graves′ disease includes antithyroid drugs (ATDs, radioactive iodine, and surgery. There has been a lack of general agreement as to which therapy is the best as none is ideal since all effectively restore euthyroidism, but with some limitations. Previously, therapies were selected with the goal of achieving euthyroidism. Instead, hypothyroidism is now the goal of treatment, to ensure that hyperthyroidism does not recur. Current evidences suggest that high relapse rate and not so rare fatal side effects seen with ATD therapy compel one to consider other definite modes of treatment like radiotherapy and surgery for toxic Graves′ disease after discussing this with the patient.

  2. Indefinite antithyroid drug therapy in toxic Graves’ disease: What are the cons

    Science.gov (United States)

    Rajput, Rajesh; Goel, Vasudha

    2013-01-01

    Existing treatment modalities for Graves’ disease includes antithyroid drugs (ATDs), radioactive iodine, and surgery. There has been a lack of general agreement as to which therapy is the best as none is ideal since all effectively restore euthyroidism, but with some limitations. Previously, therapies were selected with the goal of achieving euthyroidism. Instead, hypothyroidism is now the goal of treatment, to ensure that hyperthyroidism does not recur. Current evidences suggest that high relapse rate and not so rare fatal side effects seen with ATD therapy compel one to consider other definite modes of treatment like radiotherapy and surgery for toxic Graves’ disease after discussing this with the patient. PMID:24251229

  3. Possible inclinations for psychostimulant, toxic agent and drug abuse among youths and students

    Directory of Open Access Journals (Sweden)

    V. G. Ginzburg

    2012-03-01

    Full Text Available Taking into account modern achievements in medicine, psychology and sociology, the attempt at complex research of possible inclinations for psychostimulant, toxic agent and drug abuse among youths and students was made with the subsequent determination of the possible alternates of primary prevention. It is analysed the basic and additional risk factors promoting smoking, drinking, psychostimulant abuse, toxicomania and narcomania among young people. The dynamics of possible influences of medical, psychological and social factors is studied. The attempt of short-term prognostication and ranking was made.

  4. Non-steroidal anti-inflammatory drugs vs. paracetamol: drug availability, patient's preference and knowledge of toxicity

    International Nuclear Information System (INIS)

    Zamir, Q.; Nadeem, A.

    2017-01-01

    Self-medication is a common practice which is influenced by level of education, society factors and health care facilities availability. In our region, Pakistan, it is very common and awareness regarding prescription implementation needs to be ensured. Hence the current study highlights the preference, availability and knowledge of toxicity of non-steroidal anti-inflammatory medications and paracetamol in Pakistan. Method: It was a Descriptive, cross sectional, conducted in Rawalpindi and Islamabad, Pakistan from May to august 2012. A total of 1000 questionnaires comprising of 21 questions were distributed to the persons with age groups from 18 years to 40 years. Non-probability convenience sampling technique was used for results deduction. Data was analysed using descriptive statistics. Results: The most commonly used medicine was Mefenamic acid (n=191, 40.8 percent). Paracetamol was second on the priority list (n=146, 31.3 percent). About 178 out of 467(38.1 percent) used these medications for headache. Very few responders knew about the toxic doses of the medicines they used. Only 52 (11 percent) were aware of the raised bleeding tendency being the most common side effect of acetylsalicylic acid and 129 (28 percent) were aware of liver damage by paracetamol toxicity. Conclusion: In Pakistan, common people take NSAIDs and Paracetamol without prescription and majority of them are unaware of the side effects of these medicines. This is the reason it is important to make the general public aware of the problems they may face if they misuse or over use the drugs without the prescription. (author)

  5. Modulation of the toxicity of photons by non-conventional drugs

    International Nuclear Information System (INIS)

    Bohm, L.; Theron, T.; Serafin, A.; Verheye, F.

    1997-01-01

    The 3 drugs under investigation Pentoxifylline, Ouabain and Thalidomide are non-conventional in the sense that they have a low toxicity and do not damage DNA. Pentoxifylline reduces blood viscosity ad enhances peripheral blood flow. When combined with irradiation in a mouse rhabdomyosarcoma model we found markedly enhanced tumour growth delay and in cultured cells dose modifying factors for SF2 and alpha in the region of 1.2-1.7 (Strahlentherapie 1995;170:595-01). The drug also alters cell regulation by inhibiting the radiation induced G2/M block and suppressing control of DNA synthesis (Theron and Boehm, unpubl.). When Thalidomide was added in the absence of irradiation to the myelo-blastic cell line K-562 we found characteristic changes of cell morphology and cell surface markers suggesting differentiation and expression of a megacaryocytic lineage (Leukemia Research 1991;15:129-136). A summary of the current state of research is given. (authors)

  6. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

    International Nuclear Information System (INIS)

    Noor, Fozia; Niklas, Jens; Mueller-Vieira, Ursula; Heinzle, Elmar

    2009-01-01

    Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC 50 values 100 μM or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

  7. Toxicoproteomics: serum proteomic pattern diagnostics for early detection of drug induced cardiac toxicities and cardioprotection.

    Science.gov (United States)

    Petricoin, Emanuel F; Rajapaske, Vinodh; Herman, Eugene H; Arekani, Ali M; Ross, Sally; Johann, Donald; Knapton, Alan; Zhang, J; Hitt, Ben A; Conrads, Thomas P; Veenstra, Timothy D; Liotta, Lance A; Sistare, Frank D

    2004-01-01

    Proteomics is more than just generating lists of proteins that increase or decrease in expression as a cause or consequence of pathology. The goal should be to characterize the information flow through the intercellular protein circuitry which communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. The nature of this information can be a cause, or a consequence, of disease and toxicity based processes as cascades of reinforcing information percolate through the system and become reflected in changing proteomic information content of the circulation. Serum Proteomic Pattern Diagnostics is a new type of proteomic platform in which patterns of proteomic signatures from high dimensional mass spectrometry data are used as a diagnostic classifier. While this approach has shown tremendous promise in early detection of cancers, detection of drug-induced toxicity may also be possible with this same technology. Analysis of serum from rat models of anthracycline and anthracenedione induced cardiotoxicity indicate the potential clinical utility of diagnostic proteomic patterns where low molecular weight peptides and protein fragments may have higher accuracy than traditional biomarkers of cardiotoxicity such as troponins. These fragments may one day be harvested by circulating nanoparticles designed to absorb, enrich and amplify the diagnostic biomarker repertoire generated even at the critical initial stages of toxicity.

  8. Increased Toxicity of Chemotherapeutic Drugs by All-Trans Retinoic Acid in Cd44 Cells

    Directory of Open Access Journals (Sweden)

    A Abbasi

    2016-03-01

    Full Text Available BACKGROUND AND OBJECTIVE: In recent studies, undifferentiated CD44 cells have been introduced as the major cause of chemotherapeutic drug resistance in esophageal cancer. In this study, we aimed to evaluate the effects of all-trans retinoic acid on reducing chemotherapeutic drug resistance and improving the associated toxic effects. METHODS: In this clinical study, CD44+ and CD44- cells were separated from KYSE-30 cell line, using magnetic-activated cell sorting (MACS method. The cytotoxic effects of retinoic acid treatment, combined with cisplatin and 5-fluorouracil, were separately evaluated in two cell groups, i.e., CD44+ and CD44-. Cytotoxicity was determined by identifying cellular metabolic activity, acridine orange/ethidium bromide staining, and flow cytometry. FINDINGS: In this study, CD44 marker was expressed in 6.25% of the cell population in KYSE-30 cell line. The results of flow cytometry revealed that treatment with a combination of retinoic acid and chemotherapeutic drugs could improve cell cycle arrest in CD44+ cells (p<0.05, unlike CD44- cells. Determination of cellular metabolic activity, increased cell apoptosis along with decreased half maximal inhibitory concentration (IC50, and acridine orange/ethidium bromide staining were indicative of the increased percentage of primary and secondary apoptotic CD44+ cells. However, in CD44- cells, these effects were only observed by using a combination of retinoic acid and cisplatin (p<0.05. CONCLUSION: The present results showed that all-trans retinoic acid could increase the toxicity of cisplatin and 5-fluorouracil in CD44+ cells.

  9. Financial Toxicity of Cancer Drugs: Possible Remedies from an Ethical Perspective.

    Science.gov (United States)

    Marckmann, Georg; In der Schmitten, Jürgen

    2017-05-01

    Spiraling costs of cancer treatments have become a major concern for the payers in the health care system and for individual patients suffering from the cancer drugs' financial toxicity. This article discusses possible solutions from an ethical perspective. First, it gives some orientation about what constitutes a fair price for innovative anticancer agents. While a definitive answer remains difficult, there are good reasons to enter into price negotiations with the pharmaceutical companies to align the price with the R&D costs and the added value of the product. Information about the drug's cost-effectiveness should be available, a fixed threshold, however, seems ethically problematic. Rather, a 'signal cost-effectiveness threshold' should indicate when the drug price requires special justification. Further strategies include an improved benefit assessment after market authorization by independent publicly financed studies, which will provide a valid basis for price negotiations and clinical decision-making at the micro level. Last but not least, cancer treatments should be tailored not only to the biology of the tumor but also to the preferences of the patient. Primarily mandated by the respect for autonomy, promoting patient-centered care has the potential to improve quality of care and enable a wise use of scarce health care resources.

  10. Impact of Drug Therapy, Radiation Dose, and Dose Rate on Renal Toxicity Following Bone Marrow Transplantation

    International Nuclear Information System (INIS)

    Cheng, Jonathan C.; Schultheiss, Timothy E.; Wong, Jeffrey Y.C.

    2008-01-01

    Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age ≥18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function

  11. Stress-related behavioral alterations accompanying cocaine toxicity: the effects of mixed opioid drugs.

    Science.gov (United States)

    Hayase, T; Yamamoto, Y; Yamamoto, K

    2000-12-01

    The present study evaluated the effects of mixed opioid drugs on the severity of cocaine (COCA) toxicity by examining stress-related behavioral alterations in mice. In order to ascertain the strength of the stress, the continuous observation of the behavioral symptoms in the cage and the forced swimming test (Porsolt test) were performed in the COCA (75 mg/kg, i.p.)-treated groups, with or without the mixed mu-kappa receptor-related opioid drugs, buprenorphine (BUP) and pentazocine (PEN). Using the high-sensitivity activity measuring instrument Supermex, both the spontaneous behaviors in the cage and the forced swimming behaviors in the water were assessed as activity counts. The behavioral alterations in the COCA-treated groups were compared with a group of mice given a 10 min immobilization stress (IM group). In the COCA-only group, a prolonged increase in the spontaneous behaviors accompanied by convulsive seizures was observed even in the surviving mice, unlike in the IM group. However, an acceleration of behavioral despair in the Porsolt test similar to that observed in the IM group was observed in the COCA group after the disappearance of the acute toxic symptoms (5 hours after the COCA treatment). Among the opioid-treated groups, the mortality rate was attenuated only in the COCA-BUP (0.25 mg/kg, i.p.) group. In the COCA-BUP group, a prolonged suppression of the morbid hyperactivity in the cage except for the convulsive seizures, and a normalization of the swimming behavior in the Porsolt test were observed in the survivors. On the other hand, in the COCA-PEN (5 mg/kg, i.p.) group, the swimming behavior in the Porsolt test was abnormally increased in addition to the prolonged morbid hyperactivity in the cage. Therefore, the COCA-induced stress-related behaviors were normalized in the group of mice treated with BUP, a group with a good prognosis.

  12. Stevens Johnson syndrome, toxic epidermal necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome

    Directory of Open Access Journals (Sweden)

    Sharma Vinod

    2008-01-01

    Full Text Available Background and Aims: Stevens Johnson syndrome (SJS, toxic epidermal necrolysis (TEN and SJS-TEN overlap are serious adverse cutaneous drug reactions. Drugs are often implicated in these reactions. Methods: A retrospective analysis of inpatients′ data with these dermatological diagnoses were carried out for three years, to study the causative drugs, clinical outcome, and mortality in these conditions. Results: Thirty patients (15 TEN, nine SJS-TEN overlap, and six SJS were admitted. In 21 cases, multiple drugs were implicated whereas single drugs were responsible in nine. Anticonvulsants (35.08% were the most commonly implicated drugs followed by antibiotics (33.33% and NSAIDS (24.56%. Twenty-five patients recovered whereas five died (four TEN, one SJS-TEN overlap. Conclusion: Anticonvulsants, antibiotics and NSAIDs were the most frequently implicated drugs. TEN causes higher mortality than both SJS and SJS-TEN overlap.

  13. Stevens-Johnson syndrome and toxic epidermal necrolysis: an update on pharmacogenetics studies in drug-induced severe skin reaction.

    Science.gov (United States)

    Rufini, Sara; Ciccacci, Cinzia; Politi, Cristina; Giardina, Emiliano; Novelli, Giuseppe; Borgiani, Paola

    2015-11-01

    Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening drug reactions involving skin and membranes mucous, which are associated with significant morbidity and mortality and triggered, especially by drug exposure. Different studies have demonstrated that drug response is a multifactorial character and that the interindividual variability in this response depends on both environmental and genetic factors. The last ones have a relevant significance. In fact, the identification of new specific genetic markers involved in the response to drugs, will be of great utility to establish a more personalized therapeutic approach and to prevent the appearance of these adverse reactions. In this review, we summarize recent progresses in the Pharmacogenetics studies related to Stevens-Johnson syndrome/toxic epidermal necrolysis reporting the major genetic factors identified in the last years as associated with the disease and highlighting the use of some of these genomic variants in the clinical practice.

  14. Fatal toxic leukoencephalopathy secondary to overdose of a new psychoactive designer drug 2C-E (“Europa”)

    OpenAIRE

    Sacks, Justin; Ray, M. Jordan; Williams, Sue; Opatowsky, Michael J.

    2012-01-01

    We present a case of a fatal toxic leukoencephalopathy following ingestion of a new psychoactive designer drug known as 2C-E or “Europa.” Recreational drugs, particularly hallucinogenic substances, appear to be growing in popularity, with increasing amounts of information available via the Internet to entice potential users. In addition, some newer “designer” psychoactive substances are available for purchase online without adverse legal consequences, therefore adding to their popularity. We ...

  15. Zebrafish on a chip: a novel platform for real-time monitoring of drug-induced developmental toxicity.

    Directory of Open Access Journals (Sweden)

    Yinbao Li

    Full Text Available Pharmaceutical safety testing requires a cheap, fast and highly efficient platform for real-time evaluation of drug toxicity and secondary effects. In this study, we have developed a microfluidic system for phenotype-based evaluation of toxic and teratogenic effects of drugs using zebrafish (Danio rerio embryos and larvae as the model organism. The microfluidic chip is composed of two independent functional units, enabling the assessment of zebrafish embryos and larvae. Each unit consists of a fluidic concentration gradient generator and a row of seven culture chambers to accommodate zebrafish. To test the accuracy of this new chip platform, we examined the toxicity and teratogenicity of an anti-asthmatic agent-aminophylline (Apl on 210 embryos and 210 larvae (10 individuals per chamber. The effect of Apl on zebrafish embryonic development was quantitatively assessed by recording a series of physiological indicators such as heart rate, survival rate, body length and hatch rate. Most importantly, a new index called clonic convulsion rate, combined with mortality was used to evaluate the toxicities of Apl on zebrafish larvae. We found that Apl can induce deformity and cardiovascular toxicity in both zebrafish embryos and larvae. This microdevice is a multiplexed testing apparatus that allows for the examination of indexes beyond toxicity and teratogenicity at the sub-organ and cellular levels and provides a potentially cost-effective and rapid pharmaceutical safety assessment tool.

  16. Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

    International Nuclear Information System (INIS)

    Boelsterli, Urs A.

    2003-01-01

    The nonsteroidal antiinflammatory drug diclofenac causes rare but significant cases of serious hepatotoxicity, typically with a delayed onset (>1-3 months). Because there is no simple dose relationship and because liver injury cannot be reproduced in current animal models, individual patient-specific susceptibility factors have been evoked to account for the increased risk. While these patient factors have remained undefined, a number of molecular hazards have been characterized. Among these are metabolic factors (bioactivation by hCYP2C9 or hCYP3A4 to thiol-reactive quinone imines, activation by hUGT2B7 to protein-reactive acyl glucuronides and iso-glucuronides, and 4'-hydroxylation secondary to diclofenac glucuronidation), as well as kinetic factors (Mrp2-mediated concentrative transport of diclofenac metabolites into bile). From the toxicodynamic view, both oxidative stress (caused by putative diclofenac cation radicals or nitroxide and quinone imine-related redox cycling) and mitochondrial injury (protonophoretic activity and opening of the permeability transition pore) alone or in combination have been implicated in diclofenac toxicity. In some cases, immune-mediated liver injury is involved, inferred from inadvertent rechallenge data and from a number of experiments demonstrating T cell sensitization. Why certain underlying diseases (e.g., osteoarthritis) also increase the susceptibility to diclofenac hepatotoxicity is not clear. To date, cumulative damage to mitochondrial targets seems a plausible putative mechanism to explain the delayed onset of liver failure, perhaps even superimposed on an underlying silent mitochondrial abnormality. Increased efforts to identify both patient-specific risk factors and disease-related factors will help to define patient subsets at risk as well as increase the predictability of unexpected hepatotoxicity in drug development

  17. The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity

    International Nuclear Information System (INIS)

    Amacher, David E.

    2010-01-01

    Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in

  18. Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human?Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

    OpenAIRE

    Goda, Keisuke; Kobayashi, Akio; Takahashi, Akemi; Takahashi, Tadakazu; Saito, Kosuke; Maekawa, Keiko; Saito, Yoshiro; Sugai, Shoichiro

    2017-01-01

    In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury...

  19. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  20. Green tea, red wine and lemon extracts reduce experimental tumor growth and cancer drug toxicity.

    Science.gov (United States)

    Zaletok, S P; Gulua, L; Wicker, L; Shlyakhovenko, V A; Gogol, S; Orlovsky, O; Karnaushenko, O V; Verbinenko, A; Milinevska, V; Samoylenko, O; Todor, I; Turmanidze, T

    2015-12-01

    To evaluate antitumor effect of plant polyphenol extracts from green tea, red wine lees and/or lemon peel alone and in combination with antitumor drugs on the growth of different transplanted tumors in experimental animals. Green tea extract (GTE) was prepared from green tea infusion. GTE-based composites of red wine (GTRW), lemon peel (GTRWL) and/or NanoGTE as well as corresponding nanocomposites were prepared. The total polyphenolics of the different GTE-based extracts ranged from 18.0% to 21.3%. The effects of GTE-based extracts were studied in sarcoma 180, Ehrlich carcinoma, B16 melanoma, Ca755 mammary carcinoma, P388 leukemia, L1210 leukemia, and Guerin carcinoma (original, cisplatin-resistant and doxorubicin-resistant variants). The extracts were administered as 0.1% solution in drinking water (0.6-1.0 mg by total polyphenolics per mouse per day and 4.0-6.3 mg per rat per day). Tumor growth inhibition (TGI) in mice treated with NanoGTE, cisplatin or cisplatin + NanoGTE was 27%, 55% and 78%, respectively, in Sarcoma 180%, 21%, 45% and 59%, respectively, in Ehrlich carcinoma; and 8%, 13% and 38%, respectively in B16 melanoma. Composites of NanoGTE, red wine, and lemon peel (NanoGTRWL) enhanced the antitumor effects of cyclophosphamide in mice with Ca755 mammary carcinoma. The treatment with combination of NanoGTE and inhibitors of polyamines (PA) synthesis (DFMO + MGBG) resulted in significant TGI of P388 leukemia (up to 71%) and L1210 leukemia. In rats transplanted with Guerin carcinoma (parental strain), treatment with GTRW or GTE alone resulted in 25-28% TGI vs. 55-68% TGI in cisplatin-treated animals. The inhibition observed in the case of combination of GTE or GTRW with cisplatin was additive giving 81-88% TGI. Similar effects were observed when combinations of the cytostatics with GTE (or NanoGTE) were tested against cisplatin- or doxorubicin-resistant Guerin carcinoma. Moreover, the plant extracts lowered side toxicity of the drugs. Treatment with GTE

  1. Fatal toxic leukoencephalopathy secondary to overdose of a new psychoactive designer drug 2C-E ("Europa").

    Science.gov (United States)

    Sacks, Justin; Ray, M Jordan; Williams, Sue; Opatowsky, Michael J

    2012-10-01

    We present a case of a fatal toxic leukoencephalopathy following ingestion of a new psychoactive designer drug known as 2C-E or "Europa." Recreational drugs, particularly hallucinogenic substances, appear to be growing in popularity, with increasing amounts of information available via the Internet to entice potential users. In addition, some newer "designer" psychoactive substances are available for purchase online without adverse legal consequences, therefore adding to their popularity. We describe magnetic resonance imaging (MRI) findings to include selective diffuse toxic injury of the cerebral white matter with sparing of the cortex and most of the deep gray nuclei. To our knowledge, this is the first reported description of cerebral findings on MRI that are likely related to a lethal ingestion of 2C-E.

  2. Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

    Energy Technology Data Exchange (ETDEWEB)

    Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

    2016-12-01

    Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

  3. Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric Acute Lymphocytic Leukemia (ALL): Review from an International Consensus Conference

    NARCIS (Netherlands)

    T.M. Horton (Terzah); R. Sposto (Richard); P. Brown (Patrick); C.P. Reynolds (Patrick); S.P. Hunger (Stephen); N.J. Winick (Naomi); E.A. Raetz (Elizabeth); W.L. Carroll (William); R.J. Arceci (Robert); M.J. Borowitz (Michael); P.S. Gaynon (Paul); L. Gore (Lia); S. Jeha (Sima); B.J. Maurer (Barry); S.E. Siegel (Stuart); A. Biondi (Andrea); P. Kearns (Pamela); A. Narendran (Aru); L.B. Silverman (Lewis); M.A. Smith (Malcolm); C.M. Zwaan (Christian Michel); J.A. Whitlock (James)

    2010-01-01

    textabstractOne of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute

  4. Acute and subchronic toxicity studies of the original drug FS-1

    Directory of Open Access Journals (Sweden)

    Assem Kalykova

    2016-01-01

    Full Text Available Interest in iodine complexes has increased significantly in recent years because of their wide spectrum of biological activity. The FS-1 is an ion nanostructured complex formed by proteins and/or polypeptides, carbohydrates, salts of alkali and alkaline earth metals with intercalated iodine. Patented in 2014, it is intended for the treatment of infectious diseases of bacterial origin including nosocomial infections and multidrug resistant tuberculosis. The aim of the study was to determine its acute and subchronic toxicity. The study of acute and subchronic toxicity was performed on adult Wistar rats according to OECD guidelines. The data on acute toxicity showed LD50 > 2,000 mg/kg after a single intragastric administration. Twenty-eight days of FS-1 administration at a dose of 500 mg/kg resulted in toxic effects. At a dose of 250 mg/kg, the toxic effects were temporary and a return to normal followed after the recovery period. Doses of 100 mg/kg had no adverse effects on the rats.

  5. VirtualToxLab — A platform for estimating the toxic potential of drugs, chemicals and natural products

    Energy Technology Data Exchange (ETDEWEB)

    Vedani, Angelo, E-mail: angelo.vedani@unibas.ch [Biographics Laboratory 3R, Klingelbergstrasse 50, 4056 Basel (Switzerland); Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland); Dobler, Max [Biographics Laboratory 3R, Klingelbergstrasse 50, 4056 Basel (Switzerland); Smieško, Martin [Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland)

    2012-06-01

    The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, and thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on (http://www.virtualtoxlab.org). The free platform — the OpenVirtualToxLab — is accessible (in client–server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. -- Highlights: ► In silico technology for estimating the toxic potential of drugs and chemicals. ► Simulation of binding towards 16 proteins suspected to trigger adverse effects. ► Mechanistic interpretation and real-time 3D visualization. ► Accessible over the Internet. ► Free of charge for universities, governmental agencies, regulatory bodies and NPOs.

  6. VirtualToxLab — A platform for estimating the toxic potential of drugs, chemicals and natural products

    International Nuclear Information System (INIS)

    Vedani, Angelo; Dobler, Max; Smieško, Martin

    2012-01-01

    The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, and thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on (http://www.virtualtoxlab.org). The free platform — the OpenVirtualToxLab — is accessible (in client–server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. -- Highlights: ► In silico technology for estimating the toxic potential of drugs and chemicals. ► Simulation of binding towards 16 proteins suspected to trigger adverse effects. ► Mechanistic interpretation and real-time 3D visualization. ► Accessible over the Internet. ► Free of charge for universities, governmental agencies, regulatory bodies and NPOs.

  7. In Silico Systems Pharmacology to Assess Drug's Therapeutic and Toxic Effects

    DEFF Research Database (Denmark)

    Orozco, Alejandro Aguayo; Audouze, Karine; Brunak, Soren

    2016-01-01

    For many years, the "one target, one drug" paradigm has been the driving force behind developments in pharmaceutical research. With the recent advances in molecular biology and genomics technologies, the focus is shifting toward "drug-holistic" systems based approaches (i.e. systems pharmacology......). The integration of large and diverse amount of data from chemistry and biology coupled with the development and the application of network-based approaches to cope with these data is the next paradigm of drug discovery. Systems pharmacology offers a novel way of approaching drug discovery by developing models...

  8. Nanomedicine for therapeutic drug therapy: Approaches to increase the efficacy of drug therapy with nanoemulsion delivery and reduce the toxicity of quantum dots

    Science.gov (United States)

    Kambalapally, Swetha Reddy

    The advancement of nanotechnology has paved the way for novel nanoscale materials for use in a wide range of applications. The use of these nanomaterials in biomedicine facilitates the improvement of existing technologies for disease prevention and treatment through diagnostics, tumor detection, drug delivery, medical imaging and vaccine development. Nanotechnology delivery systems for therapeutic uses includes the formulation of nanoparticles in emulsions. These novel delivery systems can improve drug efficacy by their ability to enhance bioavailability, minimize drug side effects, decrease drug toxicity, provide targeted site delivery and increase circulation of the drug in the blood. Additionally, these delivery systems also improve the drug stability and encapsulation efficiency. In the Introduction, this thesis will describe a novel technique for the preparation of nanoemulsions which was utilized in drug delivery and diagnostic applications. This novel Phase Inversion Temperature (PIT) method is a solvent and polymer-free and low energy requiring emulsification method, typically utilizing oils stabilized by nonionic surfactants to prepare water in oil (W/O) emulsions. The correlation between the particle size, zeta potential and the emulsion stability is described. The use of this nanoemulsion delivery system for pharmaceuticals and nutraceuticals by utilizing in vitro systems was investigated. Using the PIT method, a self assembling nanoemulsion (SANE) of gamma Tocotrienols (gammaT3), a component of Vitamin E family has been demonstrated to reduce cholesterol accumulation in HepG-2 cells. The nanoemulsion is stable and the particle size is around 20 nm with a polydispersity index (PDI) of 0.065. The effect of the nano gammaT3 on the metabolism of cholesterol, HMG-CoA activity and Apo-B levels were evaluated in an in vitro system utilizing HepG2 cells. A new class of nanoparticles, Quantum dots (QDs) has shown immense potential as novel nanomaterials used as

  9. Effectiveness of combinations of Ayurvedic drugs in alleviating drug toxicity and improving quality of life of cancer patients treated with chemotherapy.

    Science.gov (United States)

    Deshmukh, Vineeta; Kulkarni, Arvind; Bhargava, Sudhir; Patil, Tushar; Ramdasi, Vijay; Gangal, Sudha; Godse, Vasanti; Datar, Shrinivas; Gujar, Shweta; Sardeshmukh, Sadanand

    2014-11-01

    This study was conducted to assess the effectiveness of combinations of Ayurvedic drugs in alleviating the toxicity of chemotherapy and improving the quality of life of cancer patients. The following was the research question: Can Ayurvedic drugs be used to alleviate the side effects of chemotherapy and improve the quality of life of cancer patients? Random patients with malignancies of different tissues, grades, and stages were divided into two groups according to their treatment modality. Group 1 consisted of 15 patients treated with six cycles of chemotherapy alone and who did not receive any Ayurvedic drugs (control group). Group 2 consisted of patients (divided into three arms) who received Ayurvedic drugs during chemotherapy and after chemotherapy. Nineteen patients in arm 1 received the Ayurvedic drugs Mauktikyukta Kamdudha (MKD) and Mauktikyukta Praval Panchamruta (MPP) along with a full course of chemotherapy. Fifteen patients in arm 2 received the same Ayurvedic treatment, but the treatment was started after completing the sixth cycle of chemotherapy. Eighteen patients in arm 3 received the Suvarnabhasmadi formulation (SBD) in addition to MKD and MPP after completing the sixth cycle of chemotherapy. Treatment was given for 16 weeks in all three arms. Patients from both groups were observed for a period of 6 months. The assessment criteria depended on Common Toxicity Criteria (CTC designed by NIH and NCI): haemogram; weight; physical examination including Quality of Life Questionnaire (QLQ designed by the European Organization of Research and Treatment of Cancer (EORTC)) for functional, symptom and global scores; and Karnofsky score for assessment of general well-being and activities of daily life. ECOG (Eastern Cooperation Oncology Group) score was also additionally included for assessment of symptoms. From amongst the symptomatic criteria, there was significant improvement in all the three arms compared with the control group in nausea, loss of appetite

  10. Modulation of the toxicity and antitumour activity of alkylating drugs by steroids.

    OpenAIRE

    Shepherd, R.; Harrap, K. R.

    1982-01-01

    The steroids prednisolone and progesterone significantly altered the therapeutic indices of the alkylating agents, nitrogen mustard, melphalan, cyclophosphamide, phenyl acetic mustard and chlorambucil. For nitrogen mustard, chlorambucil and phenyl acetic mustard, prednisolone reduced host toxicity in the rat and enhanced the antitumour effectiveness against alkylating-agent-resistant strains of the Yoshida sarcoma and Walker carcinosarcoma. Progesterone also increased the therapeutic index of...

  11. An overview of data mining algorithms in drug induced toxicity prediction.

    Science.gov (United States)

    Omer, Ankur; Singh, Poonam; Yadav, N K; Singh, R K

    2014-04-01

    The growth in chemical diversity has increased the need to adjudicate the toxicity of different chemical compounds raising the burden on the demand of animal testing. The toxicity evaluation requires time consuming and expensive undertaking, leading to the deprivation of the methods employed for screening chemicals pointing towards the need to develop more efficient toxicity assessment systems. Computational approaches have reduced the time as well as the cost for evaluating the toxicity and kinetic behavior of any chemical. The accessibility of a large amount of data and the intense need of turning this data into useful information have attracted the attention towards data mining. Machine Learning, one of the powerful data mining techniques has evolved as the most effective and potent tool for exploring new insights on combinatorial relationships among various experimental data generated. The article accounts on some sophisticated machine learning algorithms like Artificial Neural Networks (ANN), Support Vector Machine (SVM), k-mean clustering and Self Organizing Maps (SOM) with some of the available tools used for classification, sorting and toxicological evaluation of data, clarifying, how data mining and machine learning interact cooperatively to facilitate knowledge discovery. Addressing the association of some commonly used expert systems, we briefly outline some real world applications to consider the crucial role of data set partitioning.

  12. Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.

    Directory of Open Access Journals (Sweden)

    Pascaline Boudou-Rouquette

    Full Text Available BACKGROUND: Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. METHODS: Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. RESULTS: Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008. Multivariate analysis showed that increased cumulated sorafenib (AUC(cum was independently associated with any grade ≥ 3 toxicity (p = 0.037; UGT1A9 polymorphism (rs17868320 with grade ≥ 2 diarrhea (p = 0.015 and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018. Using ROC curve, the threshold AUC(cum value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018. CONCLUSION: In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320 identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.

  13. Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer's Disease

    Science.gov (United States)

    Downey, Matthew A.; Giammona, Maxwell J.; Lang, Christian A.; Buratto, Steven K.; Singh, Ambuj; Bowers, Michael T.

    2018-04-01

    Alzheimer's disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule's efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aβ42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aβ42, destabilizes preformed fibrils, and reverses Aβ42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development.

  14. The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo.

    Science.gov (United States)

    Pereira, Claudia V; Nadanaciva, Sashi; Oliveira, Paulo J; Will, Yvonne

    2012-02-01

    Nowadays the 'redox hypothesis' is based on the fact that thiol/disulfide couples such as glutathione (GSH/GSSG), cysteine (Cys/CySS) and thioredoxin ((Trx-(SH)2/Trx-SS)) are functionally organized in redox circuits controlled by glutathione pools, thioredoxins and other control nodes, and they are not in equilibrium relative to each other. Although ROS can be important intermediates of cellular signaling pathways, disturbances in the normal cellular redox can result in widespread damage to several cell components. Moreover, oxidative stress has been linked to a variety of age-related diseases. In recent years, oxidative stress has also been identified to contribute to drug-induced liver, heart, renal and brain toxicity. This review provides an overview of current in vitro and in vivo methods that can be deployed throughout the drug discovery process. In addition, animal models and noninvasive biomarkers are described. Reducing post-market drug withdrawals is essential for all pharmaceutical companies in a time of increased patient welfare and tight budgets. Predictive screens positioned early in the drug discovery process will help to reduce such liabilities. Although new and more efficient assays and models are being developed, the hunt for biomarkers and noninvasive techniques is still in progress.

  15. Ischemic or toxic injury: A challenging diagnosis and treatment of drug-induced stenosis of the sigmoid colon.

    Science.gov (United States)

    Zhang, Zong-Ming; Lin, Xiang-Chun; Ma, Li; Jin, An-Qin; Lin, Fang-Cai; Liu, Zhuo; Liu, Li-Min; Zhang, Chong; Zhang, Na; Huo, Li-Juan; Jiang, Xue-Liang; Kang, Feng; Qin, Hong-Jun; Li, Qiu-Yang; Yu, Hong-Wei; Deng, Hai; Zhu, Ming-Wen; Liu, Zi-Xu; Wan, Bai-Jiang; Yang, Hai-Yan; Liao, Jia-Hong; Luo, Xu; Li, You-Wei; Wei, Wen-Ping; Song, Meng-Meng; Zhao, Yue; Shi, Xue-Ying; Lu, Zhao-Hui

    2017-06-07

    A 48-year-old woman was admitted with 15-mo history of abdominal pain, diarrhea and hematochezia, and 5-mo history of defecation difficulty. She had been successively admitted to nine hospitals, with an initial diagnosis of inflammatory bowel disease with stenotic sigmoid colon. Findings from computed tomography virtual colonoscopy, radiography with meglumine diatrizoate, endoscopic balloon dilatation, metallic stent implantation and later overall colonoscopy, coupled with the newfound knowledge of compound Qingdai pill-taking, led to a subsequent diagnosis of ischemic or toxic bowel disease with sigmoid colon stenosis. The patient was successfully treated by laparoscopic sigmoid colectomy, and postoperative pathological examination revealed ischemic or toxic injury of the sigmoid colon, providing a final diagnosis of drug-induced sigmoid colon stenosis. This case highlights that adequate awareness of drug-induced colon stenosis has a decisive role in avoiding misdiagnosis and mistreatment. The diagnostic and therapeutic experiences learnt from this case suggest that endoscopic balloon expansion and colonic metallic stent implantation as bridge treatments were demonstrated as crucial for the differential diagnosis of benign colonic stenosis. Skillful surgical technique and appropriate perioperative management helped to ensure the safety of our patient in subsequent surgery after long-term use of glucocorticoids.

  16. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity.

    Science.gov (United States)

    Murphy, Cormac D; Sandford, Graham

    2015-04-01

    Fluorine's unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the physicochemical characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biological systems for fluorinated drug production is discussed. The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technology for the manufacturing scale and new reagents and methods are required to meet the demands for the preparation of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to determine the nature of transformation products that may cause ecological damage.

  17. From actually toxic to highly specific – novel drugs against poxviruses

    Directory of Open Access Journals (Sweden)

    Schnierle Barbara

    2007-01-01

    Full Text Available Abstract The potential use of variola virus, the causative agent of smallpox, as a bioweapon and the endemic presence of monkeypox virus in Africa demonstrate the need for better therapies for orthopoxvirus infections. Chemotherapeutic approaches to control viral infections have been less successful than those targeting bacterial infections. While bacteria commonly reproduce themselves outside of cells and have metabolic functions against which antibiotics can be directed, viruses replicate in the host cells using the cells' metabolic pathways. This makes it very difficult to selectively target the virus without damaging the host. Therefore, the development of antiviral drugs against poxviruses has initially focused on unique properties of the viral replication cycle or of viral proteins that can be selectively targeted. However, recent advances in molecular biology have provided insights into host factors that represent novel drug targets. The latest anti-poxvirus drugs are kinase inhibitors, which were originally developed to treat cancer progression but in addition block egress of poxviruses from infected cells. This review will summarize the current understanding of anti-poxvirus drugs and will give an overview of the development of the latest second generation poxvirus drugs.

  18. Ameliorating effect of microdoses of a potentized homeopathic drug, Arsenicum Album, on arsenic-induced toxicity in mice

    Directory of Open Access Journals (Sweden)

    Guha B

    2003-10-01

    Full Text Available Abstract Background Arsenic in groundwater and its accumulation in plants and animals have assumed a menacing proportion in a large part of West Bengal, India and adjoining areas of Bangladesh. Because of the tremendous magnitude of the problem, there seems to be no way to tackle the problem overnight. Efforts to provide arsenic free water to the millions of people living in these dreaded zones are being made, but are awfully inadequate. In our quest for finding out an easy, safe and affordable means to combat this problem, a homeopathic drug, Arsenicum Album-30, appears to yield promising results in mice. The relative efficacies of two micro doses of this drug, namely, Arsenicum Album-30 and Arsenicum Album-200, in combating arsenic toxicity have been determined in the present study on the basis of some accepted biochemical protocols. Methods Mice were divided into different sets of control (both positive and negative and treated series (As-intoxicated, As-intoxicated plus drug-fed. Alanine amino transferase (ALT and aspartate amino transferase (AST activities and reduced glutathione (GSH level in liver and blood were analyzed in the different series of mice at six different fixation intervals. Results Both Arsenicum Album-30 and Arsenicum Album-200 ameliorated arsenic-induced toxicity to a considerable extent as compared to various controls. Conclusions The results lend further support to our earlier views that microdoses of potentized Arsenicum Album are capable of combating arsenic intoxication in mice, and thus are strong candidates for possible use in human subjects in arsenic contaminated areas under medical supervision.

  19. Impedimetric toxicity assay in microfluidics using free and liposome-encapsulated anticancer drugs

    DEFF Research Database (Denmark)

    Caviglia, Claudia; Zor, Kinga; Montini, Lucia

    2015-01-01

    In this work, we have developed a microfluidic cytotoxicity assay for a cell culture and detection platform, which enables both fluid handling and electrochemical/optical detection. The cytotoxic effect of anticancer drugs doxorubicin (DOX), oxaliplatin (OX) as well as OX-loaded liposomes, develo...

  20. Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference.

    Science.gov (United States)

    Horton, Terzah M; Sposto, Richard; Brown, Patrick; Reynolds, C Patrick; Hunger, Stephen P; Winick, Naomi J; Raetz, Elizabeth A; Carroll, William L; Arceci, Robert J; Borowitz, Michael J; Gaynon, Paul S; Gore, Lia; Jeha, Sima; Maurer, Barry J; Siegel, Stuart E; Biondi, Andrea; Kearns, Pamela R; Narendran, Aru; Silverman, Lewis B; Smith, Malcolm A; Zwaan, C Michel; Whitlock, James A

    2010-07-01

    One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials. Copyright 2010 Wiley-Liss, Inc.

  1. Determination of Drug Toxicity Using 3D Spheroids Constructed From an Immortal Human Hepatocyte Cell Line

    DEFF Research Database (Denmark)

    Fey, S. J.; Wrzesinski, Krzysztof

    2012-01-01

    that a precise dose can be provided in a manner similar to in vivo studies. This avoided correction of the actual dose given based on a protein determination after treatment (when some cells may have lysed). Conversion of published in vitro LC50 data (mM) for six common drugs (acetaminophen, amiodarone...... different from 2D cultures and are more representative of the liver in vivo....

  2. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity

    OpenAIRE

    Murphy, Cormac D.; Sandford, Graham

    2015-01-01

    Introduction: Fluorine’s unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the p...

  3. Effect of piroxicam on lipid membranes: Drug encapsulation and gastric toxicity aspects.

    Science.gov (United States)

    Wilkosz, Natalia; Rissanen, Sami; Cyza, Małgorzata; Szybka, Renata; Nowakowska, Maria; Bunker, Alex; Róg, Tomasz; Kepczynski, Mariusz

    2017-03-30

    Uptake of piroxicam, a non-steroidal anti-inflammatory drug, from the intestines after oral intake is limited due to its low solubility and its wide use is associated with several side effects related to the gastrointestinal tract. In this study, all-atom molecular dynamics (MD) simulations and fluorescent spectroscopy were employed to investigate the interaction of piroxicam in neutral, zwitterionic, and cationic forms with lipid bilayers composed of phosphatidylcholine, cholesterol, and PEGylated lipids. Our study was aimed to assess the potential for encapsulation of piroxicam in liposomal carriers and to shed more light on the process of gastrointestinal tract injury by the drug. Through both the MD simulations and laser scanning confocal microscopy, we have demonstrated that all forms of piroxicam can associate with the lipid bilayers and locate close to the water-membrane interface. Conventional liposomes used in drug delivery are usually stabilized by the addition of cholesterol and have their bloodstream lifetime extended through the inclusion of PEGylated lipids in the formulation to create a protective polymer corona. For this reason, we tested the effect of these two modifications on the behavior of piroxicam in the membrane. When the bilayer was PEGylated, piroxicam localize to the PEG layer and within the lipid headgroup region. This suggests that PEGylated liposomes are capable of carrying a larger quantity of piroxicam than the conventional ones. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. [Extrapyramidal toxicity caused by metoclopramide and clebopride: study of voluntary notifications of adverse effects to the Spanish Drug Surveillance System].

    Science.gov (United States)

    Cuena Boy, R; Maciá Martínez, M A

    1998-03-31

    To clarify if there is any basis for the hypothesis that Clebopride leads to more extrapyramidal reactions than Metoclopramide. Observational, longitudinal, retrospective and comparative study of two series of cases. The entire Spanish healthcare system. Those notified to the Spanish Drug watch system as possibly having suffered an adverse reaction to Metoclopramide (n = 98) or Clebopride (n = 123) between 1/1/1990 and 10/6/1997. None. 84.3% of suspected adverse reactions to Clebopride and 51.6% of those to Metoclopramide had a non-hospital precedence (P Clebopride, there was extrapyramidal toxicity (P = 0.021). There is a basis for the hypothesis that Clebopride causes more extrapyramidal reactions than Metoclopramide. It was reasonable to realize a study based on this hypothesis.

  5. Screening tests in toxicity or drug effect studies with use of centrifichem general-purpose spectrophotometeric analyzer

    International Nuclear Information System (INIS)

    Nagy, B.; Bercz, J.P.

    1986-01-01

    CentrifiChem System 400 general-purpose spectrophotometric analyzer which can process simultaneously 30 samples and reads the reactions within milliseconds was used for toxicity studies. Organic and inorganic chemicals were screened for inhibitory action of the hydrolytic activity of sarcoplasmic reticulum (SR) Ca,Mg-ATPase and that of the sacrolemmal (SL) Na,K-ATPase, or mitochondrial ATPase (M). SR and SL were prepared from rabbit muscles, Na,K-ATPase from pig kidneys, M from pig hearts. Pseudosubstrates of paranitrophenyl phosphate and 2,4-dinitrophenyl phosphate, both proven high energy phosphate substitutes for ATPase coupled ion transfer were used. The reaction rates were followed spectrophotometrically at 405 nm measuring the accumulation of yellow nitrophenolate ions. The reported calcium transfer coupling ratio to hydrolysis of 2:1 was ascertained with use of 45 Ca in case of SR. Inhibition constants (pI) on SR, SL, and M for the pseudosubstrate hydrolysis will be given for over 20 chemicals tested. The applicability of the system to general toxicity testing and to general cardio-effective drug screening will be presented

  6. Antithyroid drugs as a factor influencing the outcome of radioiodine therapy in Graves' disease and toxic nodular goitre?

    International Nuclear Information System (INIS)

    Koerber, C.; Schneider, P.; Koerber-Hafner, N.; Haenscheid, H.; Reiners, C.

    2001-01-01

    There is controversy over the factors that may influence the outcome of radioiodine therapy for benign thyroid diseases. Antithyroid medication has been claimed to negatively influence the effectiveness of radioiodine therapy in Graves' disease. In a longitudinal study, we assessed the influence of sex, age, antithyroid drugs, target radiation dose, target mass, applied activity, delivered dose, interval between last meal and application, and TSH, FT 3 and FT 4 levels on the outcome of radioiodine therapy. One hundred and forty-four patients (111 female, 33 male) suffering from Graves' disease (GD) and 563 patients (434 female, 129 male) with toxic nodular goitre (TNG) were entered in the study and followed up until 8 months after therapy. Treatment was defined as successful when the TSH level was found to be normal or elevated. Ninety-eight GD patients and 418 TNG patients were successfully treated. Forward stepwise multiple regression analysis models retained only the target mass in GD and the applied activity in TNG as significantly associated with the outcome of therapy. The predictive value of all variables involved was extremely low in both disease groups. Whereas concomitant antithyroid medication had no influence in GD, it adversely influenced radioiodine therapy of TNG. This effect may be attributed to a radioiodine ''steal phenomenon'' induced by TSH-stimulated normal thyroid tissue, which causes overestimation of the uptake in toxic nodules. (orig.)

  7. Antithyroid drugs as a factor influencing the outcome of radioiodine therapy in Graves' disease and toxic nodular goitre?

    Energy Technology Data Exchange (ETDEWEB)

    Koerber, C.; Schneider, P.; Koerber-Hafner, N.; Haenscheid, H.; Reiners, C. [Wuerzburg Univ. (Germany). Abt. fuer Nuklearmedizin

    2001-09-01

    There is controversy over the factors that may influence the outcome of radioiodine therapy for benign thyroid diseases. Antithyroid medication has been claimed to negatively influence the effectiveness of radioiodine therapy in Graves' disease. In a longitudinal study, we assessed the influence of sex, age, antithyroid drugs, target radiation dose, target mass, applied activity, delivered dose, interval between last meal and application, and TSH, FT{sub 3} and FT{sub 4} levels on the outcome of radioiodine therapy. One hundred and forty-four patients (111 female, 33 male) suffering from Graves' disease (GD) and 563 patients (434 female, 129 male) with toxic nodular goitre (TNG) were entered in the study and followed up until 8 months after therapy. Treatment was defined as successful when the TSH level was found to be normal or elevated. Ninety-eight GD patients and 418 TNG patients were successfully treated. Forward stepwise multiple regression analysis models retained only the target mass in GD and the applied activity in TNG as significantly associated with the outcome of therapy. The predictive value of all variables involved was extremely low in both disease groups. Whereas concomitant antithyroid medication had no influence in GD, it adversely influenced radioiodine therapy of TNG. This effect may be attributed to a radioiodine ''steal phenomenon'' induced by TSH-stimulated normal thyroid tissue, which causes overestimation of the uptake in toxic nodules. (orig.)

  8. Effects of lemongrass oil and citral on hepatic drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in rats

    Directory of Open Access Journals (Sweden)

    Chien-Chun Li

    2018-01-01

    Full Text Available The essential oil from a lemongrass variety of Cymbopogon flexuosus [lemongrass oil (LO] is used in various food and aroma industry products and exhibits biological activities, such as anticancer and antimicrobial activities. To investigate the effects of 200 LO (200 mg/kg and 400 LO (400 mg/kg and its major component, citral (240 mg/kg, on drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in the liver, male Sprague-Dawley rats were fed a pelleted diet and administered LO or citral by gavage for 2 weeks. After 2 weeks of feeding, the effects of LO and citral on the metabolism and toxicity of acetaminophen were determined. The results showed that rats treated with 400 LO or citral had significantly reduced hepatic testosterone 6β-hydroxylation and ethoxyresorufin O-deethylation activities. In addition, NAD(PH:quinone oxidoreductase 1 activity was significantly increased by citral, and Uridine 5′-diphospho (UDP glucurosyltransferase activity was significantly increased by 400 LO in the rat liver. Treatment with 400 LO or citral reduced lipid peroxidation and reactive oxygen species levels in the liver. After acetaminophen treatment, however, LO and citral treatment resulted in little or no change in plasma alanine aminotransferase activity and acetaminophen-protein adducts content in the liver. Our results indicate that LO and citral may change the activities of drug-metabolizing enzymes and reduce oxidative stress in the liver. However, LO and citral may not affect the detoxification of acetaminophen.

  9. Effects of lemongrass oil and citral on hepatic drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in rats.

    Science.gov (United States)

    Li, Chien-Chun; Yu, Hsiang-Fu; Chang, Chun-Hua; Liu, Yun-Ta; Yao, Hsien-Tsung

    2018-01-01

    The essential oil from a lemongrass variety of Cymbopogon flexuosus [lemongrass oil (LO)] is used in various food and aroma industry products and exhibits biological activities, such as anticancer and antimicrobial activities. To investigate the effects of 200 LO (200 mg/kg) and 400 LO (400 mg/kg) and its major component, citral (240 mg/kg), on drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in the liver, male Sprague-Dawley rats were fed a pelleted diet and administered LO or citral by gavage for 2 weeks. After 2 weeks of feeding, the effects of LO and citral on the metabolism and toxicity of acetaminophen were determined. The results showed that rats treated with 400 LO or citral had significantly reduced hepatic testosterone 6β-hydroxylation and ethoxyresorufin O-deethylation activities. In addition, NAD(P)H:quinone oxidoreductase 1 activity was significantly increased by citral, and Uridine 5'-diphospho (UDP) glucurosyltransferase activity was significantly increased by 400 LO in the rat liver. Treatment with 400 LO or citral reduced lipid peroxidation and reactive oxygen species levels in the liver. After acetaminophen treatment, however, LO and citral treatment resulted in little or no change in plasma alanine aminotransferase activity and acetaminophen-protein adducts content in the liver. Our results indicate that LO and citral may change the activities of drug-metabolizing enzymes and reduce oxidative stress in the liver. However, LO and citral may not affect the detoxification of acetaminophen. Copyright © 2017. Published by Elsevier B.V.

  10. Application of metabolomics to toxicology of drugs of abuse: A mini review of metabolomics approach to acute and chronic toxicity studies.

    Science.gov (United States)

    Zaitsu, Kei; Hayashi, Yumi; Kusano, Maiko; Tsuchihashi, Hitoshi; Ishii, Akira

    2016-02-01

    Metabolomics has been widely applied to toxicological fields, especially to elucidate the mechanism of action of toxicity. In this review, metabolomics application with focus on the studies of chronic and acute toxicities of drugs of abuse like stimulants, opioids and the recently-distributed designer drugs will be presented in addition to an outline of basic analytical techniques used in metabolomics. Limitation of metabolomics studies and future perspectives will be also provided. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  11. Synthesis, characterization, release kinetics and toxicity profile of drug-loaded starch nanoparticles.

    Science.gov (United States)

    El-Naggar, Mehrez E; El-Rafie, M H; El-sheikh, M A; El-Feky, Gina S; Hebeish, A

    2015-11-01

    The current research work focuses on the medical application of the cost-effective cross-linked starch nanoparticles, for the transdermal delivery using Diclofenac sodium (DS) as a model drug. The prepared DS-cross-linked starch nanoparticles were synthesized using nanoprecipitation technique at different concentrations of sodium tripolyphosphate (STPP) in the presence of Tween 80 as a surfactant. The resultant cross-linked starch nanoparticles loaded with DS were characterized using world-class facilities such as TEM, DLS, FT-IR, XRD, and DSc. The efficiency of DS loading was also evaluated via entrapment efficiency as well as in vitro release and histopathological study on rat skin. The optimum nanoparticles formulation selected by the JMP(®) software was the formula that composed of 5% maize starch, 57.7mg DS and 0.5% STPP and 0.4% Tween 80, with particle diameter of about 21.04nm, polydispersity index of 0.2 and zeta potential of -35.3mV. It is also worth noting that this selected formula shows an average entrapment efficiency of 95.01 and sustained DS release up to 6h. The histophathological studies using the best formula on rat skin advocate the use of designed transdermal DS loaded cross-linked starch nanoparticles as it is safe and non-irritant to rat skin. The overall results indicate that, the starch nanoparticles could be considered as a good carrier for DS drug regarding the enhancement in its controlled release and successful permeation, thus, offering a promising nanoparticulate system for the transdermal delivery non-steroidal anti-inflammatory drug (NSAID). Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Update on the renal toxicity of iodinated contrast drugs used in clinical medicine

    Directory of Open Access Journals (Sweden)

    Andreucci M

    2017-05-01

    Full Text Available Michele Andreucci,1 Teresa Faga,1 Raffaele Serra,2 Giovambattista De Sarro,3 Ashour Michael1 1Renal Unit, Department of Health Sciences, 2Interuniversity Center of Phlebolymphology (CIFL, International Research and Educational Program in Clinical and Experimental Biotechnology, Department of Medical and Surgical Sciences, 3Pharmacology Unit, Department of Health Sciences, Magna Graecia University, Catanzaro, Italy Abstract: An important side effect of diagnostic contrast drugs is contrast-induced acute kidney injury (CI-AKI; a sudden decrease in renal function occurring 48–72 hours after injection of a contrast drug that cannot be attributed to other causes. Its existence has recently been challenged, because of some retrospective studies in which the incidence of AKI was not different between subjects who received a contrast drug and those who did not, even using propensity score matching to prevent selection bias. For some authors, only patients with estimated glomerular filtration rate <30 mL/min/1.73 m2 are at significant risk of CI-AKI. Most agree that when renal function is normal, there is no CI-AKI risk. Many experimental studies, however, are in favor of the existence of CI-AKI. Contrast drugs have been shown to cause the following changes: renal vasoconstriction, resulting in a rise in intrarenal resistance (decrease in renal blood flow and glomerular filtration rate and medullary hypoxia; epithelial vacuolization and dilatation and necrosis of proximal tubules; potentiation of angiotensin II effects, reducing nitric oxide (NO and causing direct constriction of descending vasa recta, leading to formation of reactive oxygen species in isolated descending vasa recta of rats microperfused with a solution of iodixanol; increasing active sodium reabsorption in the thick ascending limbs of Henle’s loop (increasing O2 demand and consequently medullary hypoxia; direct cytotoxic effects on endothelial and tubular epithelial cells (decrease

  13. MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.

    Science.gov (United States)

    Layer, R T; Bland, L R; Skolnick, P

    1993-10-15

    Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

  14. Five years audit for presence of toxic agents/drug of abuse at autopsy

    International Nuclear Information System (INIS)

    Ali, S.M.A.; Khalil, I.R.; Saeed, A.; Hussain, Z.

    2003-01-01

    Objective: To know the frequency of fatal poisoning in Peshawar regarding the toxic agents mostly involved and year wise percentage. To know the age group and the gender that is most vulnerable to fatal poisoning. Results: Poisoning was the cause of death in 1.48% of the total autopsies conducted during the five years. Males were more involved than the females, 90.38%. Suicidal poisoning was present in 17.30% of the total cases and accidental poisoning was found in 80.72% cases, while homicidal cases were 1.29% only. Diacetylmorphine (heroin) was the most commonly involved agent, 65.38%, of the total cases. The incidence of poisoning was more during the third and fourth decades of life. Conclusion: Diacetylmorphine (heroin) was the main causative agent involved in young males due to accidental over-dosage. Accidental and suicidal deaths should not be considered as inevitable. More elaborative studies are required in this area of recent research to adopt appropriate and adequate measures to save precious lives.(author)

  15. Evolution of camel CYP2E1 and its associated power of binding toxic industrial chemicals and drugs.

    Science.gov (United States)

    Kandeel, Mahmoud; Altaher, Abdullah; Kitade, Yukio; Abdelaziz, Magdi; Alnazawi, Mohamed; Elshazli, Kamal

    2016-10-01

    Camels are raised in harsh desert environment for hundreds of years ago. By modernization of live and the growing industrial revolution in camels rearing areas, camels are exposed to considerable amount of chemicals, industrial waste, environmental pollutions and drugs. Furthermore, camels have unique gene evolution of some genes to withstand living in harsh environments. In this work, the camel cytochrome P450 2E1 (CYP2E1) is compromised to detect its evolution rate and its power to bind with various chemicals, protoxins, procarcinogens, industrial toxins and drugs. In comparison with human CYP2E1, camel CYP2E1 more efficiently binds to small toxins as aniline, benzene, catechol, amides, butadiene, toluene and acrylamide. Larger compounds were more preferentially bound to the human CYP2E1 in comparison with camel CYP2E1. The binding of inhalant anesthetics was almost similar in both camel and human CYP2E1 coinciding with similar anesthetic effect as well as toxicity profiles. Furthermore, evolutionary analysis indicated the high evolution rate of camel CYP2E1 in comparison with human, farm and companion animals. The evolution rate of camel CYP2E1 was among the highest evolution rate in a subset of 57 different organisms. These results indicate rapid evolution and potent toxin binding power of camel CYP2E1. Copyright © 2016. Published by Elsevier Ltd.

  16. New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.

    Science.gov (United States)

    Kroschinsky, Frank; Stölzel, Friedrich; von Bonin, Simone; Beutel, Gernot; Kochanek, Matthias; Kiehl, Michael; Schellongowski, Peter

    2017-04-14

    Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation

  17. Utilization of carbon 13-labelled stable isotopes for studying drug toxicity on cellular metabolism

    International Nuclear Information System (INIS)

    Herve, M.; Wietzerbin, J.; Tran-Dinh, S.

    1994-01-01

    A new approach for studying the effects of two drugs, amphotericine B (AMB), an anti-fungal antibiotic, and 2-deoxy-D-glucose (DG), on the glucose metabolism in brewer yeast cells (Saccharomyces cerevisiae), is presented; AMB interacts with the membrane sterols, inducing formation of pores through which ions and small molecules can pass. DG may enter in the cytosol, where it is phosphoryled by hexokinase into deoxy-D-glucose 6-phosphate (DG6P) which disappears very slowly. DG slows down the glycolysis process and induces the formation of new substances. This paper shows the advantages of utilizing carbon 13-labelled substrates combined to the NMR-13C and NMR-1H techniques. 6 figs., 5 refs

  18. The eTOX Data-Sharing Project to Advance in Silico Drug-Induced Toxicity Prediction

    Directory of Open Access Journals (Sweden)

    Montserrat Cases

    2014-11-01

    Full Text Available The high-quality in vivo preclinical safety data produced by the pharmaceutical industry during drug development, which follows numerous strict guidelines, are mostly not available in the public domain. These safety data are sometimes published as a condensed summary for the few compounds that reach the market, but the majority of studies are never made public and are often difficult to access in an automated way, even sometimes within the owning company itself. It is evident from many academic and industrial examples, that useful data mining and model development requires large and representative data sets and careful curation of the collected data. In 2010, under the auspices of the Innovative Medicines Initiative, the eTOX project started with the objective of extracting and sharing preclinical study data from paper or pdf archives of toxicology departments of the 13 participating pharmaceutical companies and using such data for establishing a detailed, well-curated database, which could then serve as source for read-across approaches (early assessment of the potential toxicity of a drug candidate by comparison of similar structure and/or effects and training of predictive models. The paper describes the efforts undertaken to allow effective data sharing intellectual property (IP protection and set up of adequate controlled vocabularies and to establish the database (currently with over 4000 studies contributed by the pharma companies corresponding to more than 1400 compounds. In addition, the status of predictive models building and some specific features of the eTOX predictive system (eTOXsys are presented as decision support knowledge-based tools for drug development process at an early stage.

  19. Hydroxychloroquine binding to cytoplasmic domain of Band 3 in human erythrocytes: Novel mechanistic insights into drug structure, efficacy and toxicity.

    Science.gov (United States)

    Nakagawa, Mizuki; Sugawara, Kotomi; Goto, Tatsufumi; Wakui, Hideki; Nunomura, Wataru

    2016-05-13

    Hydroxychloroquine (HCQ) is a widely used drug in the treatment of autoimmune diseases, such as arthritis and systemic lupus erythematosus. It has also been prescribed for the treatment of malaria owing to its lower toxicity compared to its closely related compound chloroquine (CQ). However, the mechanisms of action of HCQ in erythrocytes (which bind preferentially this drug) have not been documented and the reasons underlying the lower side effects of HCQ compared to CQ remain unclear. Here we show that, although the activity of erythrocyte lactate dehydrogenase (LDH), but not GAPDH, was inhibited by both HCQ and CQ in vitro, LDH activity in erythrocytes incubated with 20 mM HCQ was not significantly reduced within 5 h in contrast to CQ did. Using HCQ coupled Sepharose chromatography (HCQ-Sepharose), we identified Band 3, spectrin, ankyrin, protein 4.1R and protein 4.2 as HCQ binding proteins in human erythrocyte plasma membrane. Recombinant cytoplasmic N-terminal 43 kDa domain of Band 3 bound to HCQ-Sepharose and was eluted with 40 mM (but not 20 mM) HCQ. Band 3 transport activity was reduced by only 23% in the presence of 20 mM HCQ. Taken together, these data demonstrate that HCQ binds to the cytoplasmic N-terminal domain of Band 3 in human erythrocytes but does not inhibit dramatically its transport activity. We hypothesize that the trapping of HCQ on Band 3 contributes to the lower side effects of the drug on energy production in erythrocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Authorization and Toxicity of Veterinary Drugs and Plant Protection Products: Residues of the Active Ingredients in Food and Feed and Toxicity Problems Related to Adjuvants.

    Science.gov (United States)

    Klátyik, Szandra; Bohus, Péter; Darvas, Béla; Székács, András

    2017-01-01

    Chemical substances applied in animal husbandry or veterinary medicine and in crop protection represent substantial environmental loads, and their residues occur in food and feed products. Product approval is governed differently in these two sectors in the European Union (EU), and the occurrence of veterinary drug (VD) and pesticide residues indicated by contamination notification cases in the Rapid Alert System for Food and Feed of the EU also show characteristic differences. While the initial high numbers of VD residues reported in 2002 were successfully suppressed to less than 100 cases annually by 2006 and on, the number of notification cases for pesticide residues showed a gradual increase from a low (approximately 50 cases annually) initial level until 2005 to more than 250 cases annually after 2009, with a halt occurring only in 2016. Main notifiers of VD residues include Germany, Belgium, the UK, and Italy (63, 59, 42, and 31 notifications announced, respectively), and main consigning countries of non-compliances are Vietnam, India, China, and Brazil (88, 50, 34, and 23 notifications, respectively). Thus, countries of South and Southeast Asia are considered a vulnerable point with regard to VD residues entering the EU market. Unintended side effects of VDs and plant protection products may be caused not only by the active ingredients but also by various additives in these preparations. Adjuvants (e.g., surfactants) and other co-formulants used in therapeutic agents and feed additives, as well as in pesticide formulations have long been considered as inactive ingredients in the aspects of the required main biological effect of the pharmaceutical or pesticide, and in turn, legal regulations of the approval and marketing of these additives specified significantly less stringent risk assessment requirements, than those specified for the active ingredients. However, numerous studies have shown additive, synergistic, or antagonistic side effects between the

  1. Authorization and Toxicity of Veterinary Drugs and Plant Protection Products: Residues of the Active Ingredients in Food and Feed and Toxicity Problems Related to Adjuvants

    Directory of Open Access Journals (Sweden)

    Szandra Klátyik

    2017-09-01

    Full Text Available Chemical substances applied in animal husbandry or veterinary medicine and in crop protection represent substantial environmental loads, and their residues occur in food and feed products. Product approval is governed differently in these two sectors in the European Union (EU, and the occurrence of veterinary drug (VD and pesticide residues indicated by contamination notification cases in the Rapid Alert System for Food and Feed of the EU also show characteristic differences. While the initial high numbers of VD residues reported in 2002 were successfully suppressed to less than 100 cases annually by 2006 and on, the number of notification cases for pesticide residues showed a gradual increase from a low (approximately 50 cases annually initial level until 2005 to more than 250 cases annually after 2009, with a halt occurring only in 2016. Main notifiers of VD residues include Germany, Belgium, the UK, and Italy (63, 59, 42, and 31 notifications announced, respectively, and main consigning countries of non-compliances are Vietnam, India, China, and Brazil (88, 50, 34, and 23 notifications, respectively. Thus, countries of South and Southeast Asia are considered a vulnerable point with regard to VD residues entering the EU market. Unintended side effects of VDs and plant protection products may be caused not only by the active ingredients but also by various additives in these preparations. Adjuvants (e.g., surfactants and other co-formulants used in therapeutic agents and feed additives, as well as in pesticide formulations have long been considered as inactive ingredients in the aspects of the required main biological effect of the pharmaceutical or pesticide, and in turn, legal regulations of the approval and marketing of these additives specified significantly less stringent risk assessment requirements, than those specified for the active ingredients. However, numerous studies have shown additive, synergistic, or antagonistic side effects

  2. Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

    Science.gov (United States)

    Goda, Keisuke; Kobayashi, Akio; Takahashi, Akemi; Takahashi, Tadakazu; Saito, Kosuke; Maekawa, Keiko; Saito, Yoshiro; Sugai, Shoichiro

    2017-01-01

    In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans. We conducted in vivo and in vitro exploratory studies for this purpose. In vivo lipidomics analysis was conducted to investigate the relationships between alteration of the hepatic lipids and mitochondrial dysfunction. In the liver of rats treated with compound X, triglycerides containing long-chain fatty acids, which are the main energy source of the mitochondria, accumulated. Accumulation of these triglycerides was considered to be related to the inhibition of mitochondrial respiration based on the results of in vitro mitochondria toxicity studies. In conclusion, fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction. PMID:28417920

  3. Zebrafish embryotoxicity test for developmental (neuro)toxicity : Demo case of an integrated screening approach system using anti-epileptic drugs

    NARCIS (Netherlands)

    Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; De Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

    2014-01-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid

  4. Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs

    NARCIS (Netherlands)

    Beker van Woudenberg, A.; Snel, C.; Rijkmans, E.; Groot, D. de; Bouma, M.; Hermsen, S.; Piersma, A.; Menke, A.; Wolterbeek, A.

    2014-01-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid

  5. Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO

    Directory of Open Access Journals (Sweden)

    Ai-Ming Yu

    2017-03-01

    Full Text Available Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21st International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2–6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.

  6. Cytotoxicity and Acute Gastrointestinal Toxicity of Bacterial Cellulose-Poly (acrylamide-sodium acrylate Hydrogel: A Carrier for Oral Drug Delivery

    Directory of Open Access Journals (Sweden)

    Manisha Pandey 1,2 * , Hira Choudhury 1, Mohd Cairul Iqbal Mohd Amin 2

    2016-12-01

    Full Text Available Background: Preliminary safety evaluation of polymer intended to use as drug delivery carrier is essential. Methods: In this study polyacrylamide grafted bacterial cellulose (BC/AM hydrogel was prepared by microwave irradiation initiated free radical polymerization. The synthesized hydrogel was subjected to in vitro cytotoxicity and acute gastrointestinal toxicity studies to evaluate its biological safety as potential oral drug delivery carrier. Results: The results indicate that hydrogel was non cytotoxic and did not show any histopathological changes in GI tract after a high dose of oral administration. Conclusion: The results revealed that hydrogel composed of bacterial cellulose and polyacrylamide is safe as oral drug delivery carrier.

  7. Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

    Science.gov (United States)

    Whitehurst, V E; Vick, J A; Alleva, F R; Zhang, J; Joseph, X; Balazs, T

    1999-09-01

    An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.

  8. Determination of Drug Toxicity Using 3D Spheroids Constructed From an Immortal Human Hepatocyte Cell Line

    Science.gov (United States)

    Fey, Stephen J.; Wrzesinski, Krzysztof

    2012-01-01

    Numerous publications have documented that the immortal cells grown in three-dimensional (3D) cultures possess physiological behavior, which is more reminiscent of their parental organ than when the same cells are cultivated using classical two-dimensional (2D) culture techniques. The goal of this study was to investigate whether this observation could be extended to the determination of LD50 values and whether 3D data could be correlated to in vivo observations. We developed a noninvasive means to estimate the amount of protein present in a 3D spheroid from it is planar area (± 21%) so that a precise dose can be provided in a manner similar to in vivo studies. This avoided correction of the actual dose given based on a protein determination after treatment (when some cells may have lysed). Conversion of published in vitro LC50 data (mM) for six common drugs (acetaminophen, amiodarone, diclofenac, metformin, phenformin, and valproic acid) to LD50 data (mg compound/mg cellular protein) showed that the variation in LD50 values was generally less than that suggested by the original LC50 data. Toxicological analysis of these six compounds in 3D spheroid culture (either published or presented here) demonstrated similar LD50 values. Although in vitro 2D HepG2 data showed a poor correlation, the primary hepatocyte and 3D spheroid data resulted in a much higher degree of correlation with in vivo lethal blood plasma levels. These results corroborate that 3D hepatocyte cultures are significantly different from 2D cultures and are more representative of the liver in vivo. PMID:22454432

  9. Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity.

    Science.gov (United States)

    Kim, Jeong Ho; Park, Soo-Heon; Cho, Chul-Soo; Lee, Soo Teik; Yoo, Wan-Hee; Kim, Sung Kook; Kang, Young Mo; Rew, Jong Sun; Park, Yong-Wook; Lee, Soo Kon; Lee, Yong Chan; Park, Won; Lee, Don-Haeng

    2014-07-01

    The use of proton pump inhibitors or misoprostol is known to prevent the gastrointestinal complications of nonsteroidal anti-inflammatory drugs (NSAIDs). Rebamipide is known to increase the mucosal generation of prostaglandins and to eliminate free oxygen radicals, thus enhancing the protective function of the gastric mucosa. However, it is unknown whether rebamipide plays a role in preventing NSAID-induced gastropathy. The aim of this study was to determine the effectiveness of rebamipide compared to misoprostol in preventing NSAID-induced gastrointestinal complications in patients requiring continuous NSAID treatment. We studied 479 patients who required continuous NSAID treatment. The patients were randomly assigned to groups that received 100 mg of rebamipide three times per day or 200 μg of misoprostol three times per day for 12 weeks. The primary endpoint of the analysis was the occurrence rate of gastric ulcers, as determined by endoscopy after 12 weeks of therapy. Of the 479 patients in the study, 242 received rebamipide, and 237 received misoprostol. Ultimately, 44 patients (18.6%) withdrew from the misoprostol group and 25 patients (10.3%) withdrew from the rebamipide group. There was a significant difference in withdrawal rate between the two groups (p=0.0103). The per protocol analysis set was not valid because of the dropout rate of the misoprostol group; thus, the intention to treat (ITT) analysis set is the main set for the efficacy analysis in this study. After 12 weeks, the occurrence rate of gastric ulcers was similar in the rebamipide and misoprostol groups (20.3% vs 21.9%, p=0.6497) according to ITT analysis. In addition, the therapeutic failure rate was similar in the rebamipide and misoprostol groups (13.6% vs 13.1%, p=0.8580). The total severity score of the gastrointestinal symptoms was significantly lower in the rebamipide group than in the misoprostol group (p=0.0002). The amount of antacid used was significantly lower in the rebamipide

  10. 25C-NBOMe: Preliminary Data on Pharmacology, Psychoactive Effects, and Toxicity of a New Potent and Dangerous Hallucinogenic Drug

    Directory of Open Access Journals (Sweden)

    Francesco Saverio Bersani

    2014-01-01

    Full Text Available Introduction. The use of novel psychoactive substances (NPSs has rapidly increased as well as their online availability. The aim of this paper is to provide a comprehensive review of the nature and the risks associated with 25C-NBOMe, which has recently appeared in the drug market. Methods. A systematic analysis of the scientific literature and a qualitative assessment of online and media resources (e.g., e-newsgroups, chat-rooms, and e-newsletters in 10 languages were carried out. Results. 25C-NBOMe is sold online as legal LSD or as research chemical with different designations such as “Boom,” “Pandora,” “Holland film,” or “N-bomb.” It is a partial agonist of 5-HT2A receptors. It is usually ingested orally/sublingually and, less commonly, nasally, through injection, vaginally, rectally, and smoked. Its effects include sublingual numbing, stimulation, “body high,” hallucinations, dissociation, and anxiety. 25C-NBOMe presents high risk of overdoses; acute toxicity and fatalities have been reported. Conclusions. 25C-NBOMe consumption represents an emerging phenomenon with potential harmful effects. Its use is increased by its online availability at low costs. Health and other professionals should be informed about this new trend of substance use.

  11. Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes

    International Nuclear Information System (INIS)

    Nadanaciva, Sashi; Aleo, Michael D.; Strock, Christopher J.; Stedman, Donald B.; Wang, Huijun; Will, Yvonne

    2013-01-01

    To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify “toxic” and “non-toxic” drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. - Highlights: • NSAIDS cause liver and GI toxicity. • Mitochondrial uncoupling contributes to NSAID liver toxicity. • ER stress is a mechanism that contributes to liver toxicity. • Zebrafish and cell based assays are complimentary

  12. Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes

    Energy Technology Data Exchange (ETDEWEB)

    Nadanaciva, Sashi [Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer, Inc., Groton, CT 06340 (United States); Aleo, Michael D. [Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340 (United States); Strock, Christopher J. [Cyprotex US, Watertown, MA 02472 (United States); Stedman, Donald B. [Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340 (United States); Wang, Huijun [Computational Sciences, Pfizer Inc., Groton, CT 06340 (United States); Will, Yvonne, E-mail: yvonne.will@pfizer.com [Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer, Inc., Groton, CT 06340 (United States)

    2013-10-15

    To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify “toxic” and “non-toxic” drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. - Highlights: • NSAIDS cause liver and GI toxicity. • Mitochondrial uncoupling contributes to NSAID liver toxicity. • ER stress is a mechanism that contributes to liver toxicity. • Zebrafish and cell based assays are complimentary.

  13. Histological vis-a-vis biochemical assessment on the toxic level and antineoplastic efficacy of a synthetic drug Pt-ATP on experimental animal models.

    Science.gov (United States)

    Pal, Shipra; Sadhu, Arpita Sengupta; Patra, Swarup; Mukherjea, Kalyan K

    2008-11-12

    Cisplatin, a platinum based anticancer drug has played a vital role in the treatment of cancers by chemical agents, but in view of the serious toxicity including nephrotoxicity of cisplatin, various other platinum based drugs have been synthesized and screened to overcome its toxicity. A Pt-ATP compound was prepared in our laboratory hoping to have reduced or no toxicity along with the potentiality of reducing neoplasm growth. A Pt-ATP compound was prepared. It was first screened for its antineoplastic efficacy. Confirming that, subsequent experiments were carried on to test its toxicity on animals, viz. Albino Swiss mice. The animals were randomly divided into four sets--Set I: Erhlich Ascites Carcinoma (EAC) challenged mice; Set II: Normal mice; Set III: Drug treated mice, Set IVA Cisplatin (CDDP) treated mice, Set IV B EAC challenged Cisplatin treated mice. Set I was used to test antineoplasticity of the drug, Set II and Set III for studying drug toxicity and Set IV was treated with CDDP. Set II was used as a control. Animals were sacrificed after 5 days, 10 days 15 days and 20 days of drug administration on the 6th, 11th, 16th and 21st days respectively for Set I, II and III. Set IVA was sacrificed only on the 16th day and Set IV B on 6th and 11th days. For Set I only tumor cell count and packed cell volume (PCV) of tumor cells were recorded. For Set II and III, aspartate aminotransferase (AST), alanine aminotransferase (ALT) assays were done using serum while blood creatinine and creatine were assayed from blood filtrate. For cytotoxicity assessment liver, spleen and kidney tissues were collected and subjected to scanning electron microscopy (SEM) after extensive treatment. Set IV A was only studied for the biochemical parameters viz. aspartate aminotransferase (AST), alanine aminotransferase (ALT) assays were done using serum while blood creatinine and creatine were assayed from blood filtrate. Set IV B was studied for tumor cell count after treatment with

  14. A methylcellulose microculture assay for the in vitro assessment of drug toxicity on granulocyte/macrophage progenitors (CFU-GM).

    Science.gov (United States)

    Pessina, Augusto; Croera, Cristina; Bayo, Maria; Malerba, Ilaria; Passardi, Laura; Cavicchini, Loredana; Neri, Maria G; Gribaldo, Laura

    2004-03-01

    reduction of the amount of drug needed for testing, which is crucial for screening new molecules, when many different toxicological tests have to be carried out. The microassay is therefore a useful and reproducible tool for screening compounds (chemicals, drugs and xenobiotics) for potential haematotoxicity directly on human myeloid progenitors, and could contribute significantly to reducing the use of animals in toxicity testing.

  15. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    International Nuclear Information System (INIS)

    Chintamani; Singhal, Vinay; Singh, JP; Lyall, Ashima; Saxena, Sunita; Bansal, Anju

    2004-01-01

    Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins) brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio). Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide) were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was assessed using chi-square test and coefficient

  16. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    Directory of Open Access Journals (Sweden)

    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  17. HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent manner leading to neuronal toxicity.

    Science.gov (United States)

    Yu, Chunjiang; Narasipura, Srinivas D; Richards, Maureen H; Hu, Xiu-Ti; Yamamoto, Bryan; Al-Harthi, Lena

    2017-10-01

    Emerging evidence suggests that cell senescence plays an important role in aging-associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV-associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (β-galactosidase and p16 INK 4A ), senescence-associated morphologic changes, and cell cycle arrest. HIV- and meth-mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG-huPBMCs, HIV-transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that β-catenin, a pro-survival/proliferation transcriptional co-activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of β-catenin blocks HIV- and meth-mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the β-catenin pathway as potential therapeutic target to overcome astrocyte senescence. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  18. Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.

    Science.gov (United States)

    Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung; Park, Yumi; Dodd, Lori E; Dartois, Véronique; Follman, Dean; Wang, Jing; Cai, Ying; Goldfeder, Lisa C; Olivier, Kenneth N; Xie, Yingda; Via, Laura E; Cho, Sang Nae; Barry, Clifton E; Chen, Ray Y

    2015-11-01

    Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23-7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ = - 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

  19. Acute and Subchronic Toxicity of Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from Chloroform Bay Leaf Extract (Eugenia Polyantha W.) with Palm Kernel Oil as A Carrier

    Science.gov (United States)

    Prihapsara, F.; Mufidah; Artanti, A. N.; Harini, M.

    2018-03-01

    The present study was aimed to study the acute and subchronic toxicity of Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from chloroform bay leaf extract with Palm Kernel Oil as carrier. In acute toxicity test, five groups of rat (n=5/groups) were orally treated with Self Nanoemulsifying Drug Delivery Systems (SNEDDS) from chloroform bay leaf extract with doses at 48, 240, 1200 and 6000 mg/kg/day respectively, then the median lethal dose LD50, advers effect and mortality were recorded up to 14 days. Meanwhile, in subchronic toxicity study, 4 groups of rats (n=6/group) received by orally treatment of SNEDDS from chloroform bay leaf extract with doses at 91.75; 183.5; 367 mg/kg/day respectively for 28 days, and biochemical, hematological and histopatological change in tissue such as liver, kidney, and pancreatic were determined. The result show that LD50 is 1045.44 mg/kg. Although histopathological examination of most of the organs exhibited no structural changes, some moderate damage was observed in high‑ dose group animals (367 mg/kg/day). The high dose of SNEDDS extract has shown mild signs of toxicity on organ function test.

  20. Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

    Science.gov (United States)

    Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

    2016-01-01

    Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

  1. Acute toxicity evaluation of in situ gel-forming controlled drug delivery system based on biodegradable poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) copolymer

    International Nuclear Information System (INIS)

    Fang Fang; Gong Changyang; Dong Pengwei; Fu Shaozhi; Gu Yingchun; Guo Gang; Zhao Xia; Wei Yuquan; Qian Zhiyong

    2009-01-01

    In this paper, biodegradable poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) triblock copolymer was synthesized, and was characterized by FTIR, 1 H-NMR and GPC. The PCL-PEG-PCL/dimethyl sulfoxide (DMSO) solution displayed in situ gelling behavior when subcutaneously injected into the body. Toxicity tests and a histopathological study were performed in BALB/c mice. We focused mainly on acute organ toxicity of BALB/c mice by subcutaneous injection. In the acute toxicity test, the dose of subcutaneous injection was 5 g/kg body weight (b.w.), and the mice were observed continuously for 14 days. For the histopathological study, samples including heart, lung, liver, kidneys, spleen, stomach and intestine were histochemically prepared and stained with hematoxylin-eosin for histopathological examination. No mortality or significant signs of toxicity were observed during the whole observation period, and there is no significant lesion to be shown in histopathological study of major organs in the mice. Therefore, the maximal tolerance dose of dimethyl sulfoxide (DMSO) solution of PCL-PEG-PCL copolymer by subcutaneous injection was calculated to be higher than 5 g/kg b.w. Therefore, the PCL-PEG-PCL/DMSO system was thought to be non-toxic after subcutaneous injection, and it might be a candidate for an in situ gelling controlled drug delivery system.

  2. Antimony Toxicity

    Directory of Open Access Journals (Sweden)

    Shyam Sundar

    2010-12-01

    Full Text Available Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The major toxic side-effects of antimonials as a result of therapy are cardiotoxicity (~9% of patients and pancreatitis, which is seen commonly in HIV and visceral leishmaniasis co-infections. Quality control of each batch of drugs produced and regular monitoring for toxicity is required when antimonials are used therapeutically.

  3. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  4. An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.

    Science.gov (United States)

    Habchi, Johnny; Arosio, Paolo; Perni, Michele; Costa, Ana Rita; Yagi-Utsumi, Maho; Joshi, Priyanka; Chia, Sean; Cohen, Samuel I A; Müller, Martin B D; Linse, Sara; Nollen, Ellen A A; Dobson, Christopher M; Knowles, Tuomas P J; Vendruscolo, Michele

    2016-02-01

    The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer's disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer's disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.

  5. Acute And Subchronic Toxicity Studies Of SNEDDS (Self Nanoemulsifying Drug Delivery Systems) From Ethyl Acetate Extract Of Bay Leaf (Eugenia polyantha W.) with Virgin Coconut Oil As Oil Phase

    Science.gov (United States)

    Prihapsara, F.; Alamsyah, R. I.; Widiyani, T.; Artanti, A. N.

    2018-03-01

    Bay leaf (Eugenia polyantha) is widely used as an alternative therapy for diabetic and hypercholesterol. However, the administration of the extract has a low oral bioavailability, therefore it is prepared by Self Nanoemulsifying Drug Delivery Systems (SNEDDS) ethyl acetate extract of bay leaf. Therefore, acute and subchronic toxicity test is required. The toxicity test performed was an experimental study, including acute and subchronic toxicity tests. Animal experiments were used using Wistar strain rats. Acute toxicity test using 5 groups (n=5) consisted of 1 control group and 4 groups of SNEDDS dose with 48 mg/kgBW 240 mg/kg, 1200 mg/kg, and 6000 mg/kg, while for subchronic toxicity test with 1 group control and 3 groups of doses of SNEDDS with dose group variation 91.75 mg/kgBW, 183.5 mg/kg, and 367 mg/kg. Duration of observation at acute toxicity test for 14 days while for subcronic toxicity test for 28 days with continuous SNEDDS dosage. The results of the acute toxicity test showed toxic symptoms and obtained median lethal dose (LD50) values from SNEDDS from ethyl acetate extract of bay leaf 1409.30 mg/kgBW belonging to slightly toxic category. Subchronic toxicity studies show that the test drug has minor damage in liver and kidneys and moderate damage in pancreas.

  6. High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment.

    Science.gov (United States)

    Sivadasan, Ajith; Abraham, O C; Rupali, Priscilla; Pulimood, Susanne A; Rajan, Joyce; Rajkumar, S; Zachariah, Anand; Kannangai, Rajesh; Kandathil, Abraham Joseph; Sridharan, G; Mathai, Dilip

    2009-05-01

    To determine the rates, reasons and predictors of treatment change of the initial antiretroviral treatment (ART) regimen in HIV-infected south Indian adults. In this prospective cohort study, ART-naive adults initiated on generic, fixed dose combination ART as per the National AIDS Control Organization guidelines were followed up at an academic medical center. Treatment change was defined as any event which necessitated a change in or discontinuation of the initial ART regimen. Two hundred and thirty persons with HIV infection (males 74.8% and median age 37 years) were followed up for median duration of 48 weeks. The majority (98.7%) had acquired HIV infection through the heterosexual route. Most (70.4%) had advanced IV infection (WHO clinical stage 3 or 4) and 78% had CD4+ T-lymphocyte counts below 200 cells/microL. The initial ART regimens used were: Lamivudine (3TC) with Stavudine (d4T) (in 76%) or Azidothymidine (AZT) and Nevirapine (NVP) (in 86%) or Efavirenz (EFV). The cumulative incidence of treatment change was 39.6% (91 patients). Drug toxicity (WHO grade 3 or 4) was the reason for treatment change among 62 (27%) (incidence rate 35.9/100 person-years). The most common toxicities were attributable to the thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs), d4T and AZT [lactic acidosis (8.7%), anemia (7%) and peripheral neuropathy (5.2%)]. The other toxicities were rash (3.9%) and hepatitis (1.3%) due to NVP. The mortality (4.6/100 person-years) and disease progression rates (4.1/100 person-years) were low. The ART regimens used in this study were effective in decreasing disease progression and death. However, they were associated with high rates of drug toxicities, particularly those attributable to thymidine analogue NRTI. As efforts are made to improve access to ART, treatment regimens chosen should not only be potent, but also safe.

  7. Studies on the toxic effects of periodontal sustained release drug containing ornidazole and pefloxacin mesylate on early embryonic development of SD rat

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    Zheng-mou DONG

    2011-01-01

    Full Text Available Objective To evaluate the toxic effects of periodontal sustained release drug containing ornidazole and pefloxacin mesylate on early embryonic development of SD rats.Methods A total of 100female SD rats were randomly divided into negative control,low-,medium-,high-dose group and intervention group(20each.Rats in low-,medium-and high-dose group were fed daily with the sustained release drug at 1,4,and 8g/kg respectively;those in negative control group were fed daily with distilled water from the 14th day before mating to the 7th day of pregnancy continuously,and those in intervention group received cyclophosphamide(40mg/kgby intraperitoneal injection for 5successive days.During this period,the general status,mating,pregnancy,coefficient of ovary and uterus,the numbers of corpus luteum,nidation,live births,stillbirths,absorbed embryo,prenidatory and postnidatory mortality,serum testosterone(Tand estradiol(E2were determined respectively.Histopathologic examination of the ovary and uterus,immunohistochemical observation of ovaries for proliferating cell nuclear antigen(PCNAand Bcl-2associated X protein(Baxwere also performed respectively.Results The general status of those rats was good except one in the low-dose group and one in the intervention group died on the 14th day of administration,and one in negative control and one in high dose group died on the 5th day of pregnancy,respectively.The body weight of animals decreased significantly(P 0.05.The serum T level in medium-and high-dose group and the E2level in high-dose group declined compared to that in negative control group(P < 0.05.Conclusions Although the periodontal sustained release drug containing ornidazole and pefloxacin mesylate shows no toxicity to the early embryonic development of SD rats,the high dose drug has certain toxicity to ovary.Declined serum concentrations of T and E2,reduced expression of PCNA,and increased Bax may be the causes of the toxicity.

  8. Effects of MHRA drug safety advice on time trends in prescribing volume and indices of clinical toxicity for quinine

    Science.gov (United States)

    Acheampong, Paul; Cooper, Gill; Khazaeli, Behshad; Lupton, David J; White, Sue; May, Margaret T; Thomas, Simon H L

    2013-01-01

    Aims To ascertain the effects of the Medicines and Healthcare products Regulatory Agency's (MHRA) safety update in June 2010 on the volume of prescribing of quinine and on indices of quinine toxicity. Methods We analysed quarterly primary care total and quinine prescribing data for England and quinine prescribing volume for individual Primary Care Trusts in the North East of England from 2007/8 to 2011/12 obtained from the ePACT.net database. We also analysed quinine toxicity enquiries to the National Poisons Information Service (NPIS) via Toxbase® and by telephone between 2004/5 and 2011/12. Joinpoint regression and Pearson's correlation tests were used to ascertain changes in trends in prescribing and indices of toxicity and associations between prescribing and indices of toxicity, respectively. Results Total prescribing continued to increase, but annual growth in quinine prescribing in England declined from 6.0 to −0.6% following the MHRA update [difference −0.04 (95% confidence interval −0.07 to −0.01) quinine prescriptions per 100 patients per quarter, P = 0.0111]. Much larger reductions were observed in Primary Care Trusts that introduced comprehensive prescribing reviews. The previously increasing trend in Toxbase® quinine searches was reversed [difference −19.76 (95% confidence interval −39.28 to −9.20) user sessions per quarter, P = 0.0575]. Telephone enquiries to NPIS for quinine have declined, with stabilization of the proportion of moderate to severe cases of quinine poisoning since the update. Conclusions The MHRA advice was followed by limited reductions in the growth in quinine prescribing and in indicators of quinine overdose and toxicity. Quinine prescribing, however, remains common, and further efforts are needed to reduce availability and use. PMID:23594200

  9. Incidence and risk factors of major toxicity associated to first-line antituberculosis drugs for latent and active tuberculosis during a period of 10 years

    Directory of Open Access Journals (Sweden)

    Ana Tavares e Castro

    2015-05-01

    Full Text Available Introduction: Adverse drug reactions (ADR to first-line antituberculosis drugs are frequent and have important implications that may affect the effectiveness of treatment and course of tuberculosis (TB. Material and methods: Retrospective data analysis of clinical records and national registration forms from patients with ADR to first line antituberculosis that occurred between 2004 and 2013 at a Portuguese Pulmonology Diagnostic Centre, and from a case–control population matched by sex, age and year of initiation of treatment. Results: Of the 764 patients treated with antituberculosis drugs, 55 (52.7% male, 92.7% European, mean age 50.8 ± 19.5 years had at least one severe ADR and six had a second ADR, for a total of 61 events. The most frequent ADR were hepatotoxicity (86.9%, rash (8.2% and others, such as ocular toxicity, gastrointestinal intolerance and angioedema (4.9%. Isoniazid, alone or in combination, was the antituberculosis drug most associated to toxicity. Due to ADR, treatment time changed an average of 1.0 ± 2.6 months (range −3.4 to 10.6. There was no correlation between age or gender and the overall incidence of ADR although we found a significant association between younger age and an increased risk of hepatotoxicity (P = 0.035. There was also a statistically significant relationship between ADR and diabetes mellitus (P = 0.042 but not for other comorbidities or multi-resistant TB risk factors. Conclusions: This study found a high frequency of ADR with strong impact on subsequent therapeutic orientation. What seems to be of particular interest is the relationship between ADR and diabetes mellitus and the increased frequency of hepatotoxicity in younger patients. Keywords: Tuberculosis, Adverse reaction, Antituberculosis, Treatment

  10. Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.

    Science.gov (United States)

    Kitamura, Shigeyuki; Sugihara, Kazumi

    2014-01-01

    1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

  11. Comparing probabilistic and descriptive analyses of time–dose–toxicity relationship for determining no-observed-adverse-effect level in drug development

    International Nuclear Information System (INIS)

    Glatard, Anaïs; Berges, Aliénor; Sahota, Tarjinder; Ambery, Claire; Osborne, Jan; Smith, Randall; Hénin, Emilie; Chen, Chao

    2015-01-01

    The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; and then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. - Highlights: • Simulations revealed issues with NOAEL concept, determination and application. • Probabilistic modelling was used to address these issues. • The model integrated time-dose-toxicity data from multiple studies. • The approach uses data efficiently and may allow more meaningful human translation.

  12. Comparing probabilistic and descriptive analyses of time–dose–toxicity relationship for determining no-observed-adverse-effect level in drug development

    Energy Technology Data Exchange (ETDEWEB)

    Glatard, Anaïs; Berges, Aliénor; Sahota, Tarjinder; Ambery, Claire [Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1 Iron Bridge Road, Uxbridge, UB11 1BT London (United Kingdom); Osborne, Jan [Non-Clinical Safety Projects, GlaxoSmithKline, Ware (United Kingdom); Smith, Randall [Computational Toxicology, GlaxoSmithKline, Upper Merion (United States); Hénin, Emilie [UMR 5558 Laboratoire Biométrie et de Biologie Evolutive, Equipe EMET (Evaluation et Modélisation des Effets Thérapeutiques), Université Claude Bernard Lyon1, Service de Pharmacologie Clinique et Essais Thérapeutiques, Hospices Civils de Lyon, Lyon (France); Chen, Chao, E-mail: chao.c.chen@gsk.com [Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1 Iron Bridge Road, Uxbridge, UB11 1BT London (United Kingdom)

    2015-10-15

    The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; and then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. - Highlights: • Simulations revealed issues with NOAEL concept, determination and application. • Probabilistic modelling was used to address these issues. • The model integrated time-dose-toxicity data from multiple studies. • The approach uses data efficiently and may allow more meaningful human translation.

  13. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

    Directory of Open Access Journals (Sweden)

    Dan Xu

    2014-04-01

    Full Text Available Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU] developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology

  14. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

    Science.gov (United States)

    Xu, Dan; Nishimura, Toshi; Nishimura, Sachiko; Zhang, Haili; Zheng, Ming; Guo, Ying-Ying; Masek, Marylin; Michie, Sara A; Glenn, Jeffrey; Peltz, Gary

    2014-04-01

    Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve

  15. Prediction of drug-related cardiac adverse effects in humans--B: use of QSAR programs for early detection of drug-induced cardiac toxicities.

    Science.gov (United States)

    Frid, Anna A; Matthews, Edwin J

    2010-04-01

    This report describes the use of three quantitative structure-activity relationship (QSAR) programs to predict drug-related cardiac adverse effects (AEs), BioEpisteme, MC4PC, and Leadscope Predictive Data Miner. QSAR models were constructed for 9 cardiac AE clusters affecting Purkinje nerve fibers (arrhythmia, bradycardia, conduction disorder, electrocardiogram, palpitations, QT prolongation, rate rhythm composite, tachycardia, and Torsades de pointes) and 5 clusters affecting the heart muscle (coronary artery disorders, heart failure, myocardial disorders, myocardial infarction, and valve disorders). The models were based on a database of post-marketing AEs linked to 1632 chemical structures, and identical training data sets were configured for three QSAR programs. Model performance was optimized and shown to be affected by the ratio of the number of active to inactive drugs. Results revealed that the three programs were complementary and predictive performances using any single positive, consensus two positives, or consensus three positives were as follows, respectively: 70.7%, 91.7%, and 98.0% specificity; 74.7%, 47.2%, and 21.0% sensitivity; and 138.2, 206.3, and 144.2 chi(2). In addition, a prospective study using AE data from the U.S. Food and Drug Administration's (FDA's) MedWatch Program showed 82.4% specificity and 94.3% sensitivity. Furthermore, an external validation study of 18 drugs with serious cardiotoxicity not considered in the models had 88.9% sensitivity. Published by Elsevier Inc.

  16. Capture compound mass spectrometry sheds light on the molecular mechanisms of liver toxicity of two Parkinson drugs.

    Science.gov (United States)

    Fischer, Jenny J; Michaelis, Simon; Schrey, Anna K; Graebner, Olivia Graebner nee; Glinski, Mirko; Dreger, Mathias; Kroll, Friedrich; Koester, Hubert

    2010-01-01

    Capture compound mass spectrometry (CCMS) is a novel technology that helps understand the molecular mechanism of the mode of action of small molecules. The Capture Compounds are trifunctional probes: A selectivity function (the drug) interacts with the proteins in a biological sample, a reactivity function (phenylazide) irreversibly forms a covalent bond, and a sorting function (biotin) allows the captured protein(s) to be isolated for mass spectrometric analysis. Tolcapone and entacapone are potent inhibitors of catechol-O-methyltransferase (COMT) for the treatment of Parkinson's disease. We aimed to understand the molecular basis of the difference of both drugs with respect to side effects. Using Capture Compounds with these drugs as selectivity functions, we were able to unambiguously and reproducibly isolate and identify their known target COMT. Tolcapone Capture Compounds captured five times more proteins than entacapone Capture Compounds. Moreover, tolcapone Capture Compounds isolated mitochondrial and peroxisomal proteins. The major tolcapone-protein interactions occurred with components of the respiratory chain and of the fatty acid beta-oxidation. Previously reported symptoms in tolcapone-treated rats suggested that tolcapone might act as decoupling reagent of the respiratory chain (Haasio et al., 2002b). Our results demonstrate that CCMS is an effective tool for the identification of a drug's potential off targets. It fills a gap in currently used in vitro screens for drug profiling that do not contain all the toxicologically relevant proteins. Thereby, CCMS has the potential to fill a technological need in drug safety assessment and helps reengineer or to reject drugs at an early preclinical stage.

  17. Molecular and cellular determinants of the cyto-toxicity in combined ionizing radiations and anti-tumoral drugs exposure

    International Nuclear Information System (INIS)

    Hennequin, Ch.

    1998-01-01

    The radio-chemo-therapy combinations represent a major research way in oncology. The knowledge of the interaction mechanisms can contribute to an improvement of the clinical protocols and to a knowledge of the action processes of drugs and radiations. Three different drugs have been studied - etoposide, camptothecine and taxoids (paclitaxel, docetaxel) - on different in vitro cell descendants (V79, HeLa and SQ-20B). For etoposide, the isobolic analysis shows an additive interaction in slightly deferred exposure but a strong supra-additive interaction in concomitant exposure. A sensitization to the drug effect inside the radio-induced G2 block is also noticed. The supra-additivity in concomitant exposure is linked with the alteration of the sub-lethal lesions repair. For camptothecine, the analysis of survival curves shows a strictly additive interaction (mode II) in concomitant exposure. However, the association becomes additive at low radiation dose rates (1 Gy/h). This synergy is the result of a cyto-kinetic effect corresponding to the radio-induced accumulation of cells inside the most drug sensible compartment. With taxoids, it is shown that all kinds of interactions are possible, from a pronounced antagonism to a significant synergy. The effect depends on drugs and radiation doses and on the cells descendants. Paclitaxel and docetaxel present major differences of phase specificity: the first one targets the mitosis transition, while the second one targets the S phase. These results have permitted to precise some of the mechanisms involved in drugs and radiations synergy. In particular, it is shown that two major mechanisms, the cyto-kinetic cooperation and the alteration of DNA lesions repair, determine the effect of combined treatments on proliferating cells. (J.S.)

  18. Methods of acute biological assays in guinea-pigs for the study of toxicity and innocuity of drugs and chemicals

    Directory of Open Access Journals (Sweden)

    Gui Mi Ko

    2010-06-01

    Full Text Available In this study, 602 samples were tested by the following assays performed at the animal facilities (Cedeme of the Federal University of São Paulo (UNIFESP: 385 for dermal irritability, 90 for ocular irritability (discontinued in 1995, 31 for systemic toxicity by injection, 26 for oral acute toxicity, 15 for toxicity by intracutaneous injection, 15 for skin sensitization, 15 for toxicity of serum and vaccines for human use, 14 for toxicity by intramuscular implantation, 7 for pyrogens, 2 for acute dermal toxicity, and 2 for irritation of mucous membrane. The following agents were tested: cosmetics and related substances (42.0%, chemicals used in industry (32.9%, plastics, rubber, and other polymers (15.9%, agrotoxics (4.0%, medicines (2.7%, and vaccines (2.5%. In the present description, emphasis was given to tests of dermal irritability and sensitization. This work was conducted entirely in animal facilities, according to our general belief that animal facilities at universities, while considering ethic principles and sanitary, genetic, nutritional, and pathophysiological controls, also require laboratories specialized in areas such as transgenics, cryopreservation, ambiental physiology, functional genomics, alternative models, and mainly activities and research on methods in toxicology, as focused in this study.Descrevemos os testes usados em ensaios biológicos de curta duração para estudo de toxicidade e inocuidade de cosméticos, fármacos e outras substâncias químicas, feitos no Biotério Central/Cedeme da Unifesp, de 1986 a 2000. Testamos 602 amostras nos seguintes ensaios: 385 de irritação cutânea, 90 de irritação ocular (até 1995, 31 de toxicidade sistêmica por injeção, 26 de toxicidade oral aguda, 15 de toxicidade por aplicação intracutânea, 15 de sensibilização da pele, 15 de toxicidade de soros e vacinas de uso humano, 14 de toxicidade por implantação intramuscular, 7 de pirogênio, 2 de toxicidade dérmica aguda e

  19. LimTox: a web tool for applied text mining of adverse event and toxicity associations of compounds, drugs and genes.

    Science.gov (United States)

    Cañada, Andres; Capella-Gutierrez, Salvador; Rabal, Obdulia; Oyarzabal, Julen; Valencia, Alfonso; Krallinger, Martin

    2017-07-03

    A considerable effort has been devoted to retrieve systematically information for genes and proteins as well as relationships between them. Despite the importance of chemical compounds and drugs as a central bio-entity in pharmacological and biological research, only a limited number of freely available chemical text-mining/search engine technologies are currently accessible. Here we present LimTox (Literature Mining for Toxicology), a web-based online biomedical search tool with special focus on adverse hepatobiliary reactions. It integrates a range of text mining, named entity recognition and information extraction components. LimTox relies on machine-learning, rule-based, pattern-based and term lookup strategies. This system processes scientific abstracts, a set of full text articles and medical agency assessment reports. Although the main focus of LimTox is on adverse liver events, it enables also basic searches for other organ level toxicity associations (nephrotoxicity, cardiotoxicity, thyrotoxicity and phospholipidosis). This tool supports specialized search queries for: chemical compounds/drugs, genes (with additional emphasis on key enzymes in drug metabolism, namely P450 cytochromes-CYPs) and biochemical liver markers. The LimTox website is free and open to all users and there is no login requirement. LimTox can be accessed at: http://limtox.bioinfo.cnio.es. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. Synthesis and toxicity test of magnetic nanoparticle via biocompatible microemulsion system as template for application in targeted drug delivery

    Science.gov (United States)

    Kader, Razinah Abdul; Rose, Laili Che; Suhaimi, Hamdan; Manickam, Mariessa Soosai

    2017-09-01

    This work reports the preparation of magnetic nanoparticles (FeNPs) using biocompatible W/O microemulsion for biomedical applications. W/O microemulsion was formed using decane as oil phase, water, tween 80 as non-ionic surfactant and hexanol as organic solvent. The synthesized FeNPs were characterised by using Fourier Transform Infrared Resonance Spectroscopy (FTIR), Scanning Electron Microscopy (SEM) and X-Ray Diffraction (XRD). The FTIR showed that Fe-O bond exist on 581cm-1 having strong magnetic strength whereas SEM showed the morphology surface of magnetic nanoparticles (FeNPs). Furthermore, analysis of XRD pattern magnetic nanoparticles (FeNPs) reveals a cubic iron oxide phase with good crystallize structure. Furthermore, toxicity test on human liver cells proved that it is 70% safe on human and proved to be a safety nanomedicine.

  1. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity

    International Nuclear Information System (INIS)

    Okawa, Hiromi; Motohashi, Hozumi; Kobayashi, Akira; Aburatani, Hiroyuki; Kensler, Thomas W.; Yamamoto, Masayuki

    2006-01-01

    Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions. Germ line deletion of the keap1 gene results in constitutive activation of Nrf2, but the pups unexpectedly died before weaning. To investigate how constitutive activation of Nrf2 influences the detoxification system in adult mice, we generated mice bearing a hepatocyte-specific disruption of the keap1 gene. Homozygous mice were viable and their livers displayed no apparent abnormalities, but nuclear accumulation of Nrf2 is elevated. Microarray analysis revealed that, while many detoxifying enzyme genes are highly expressed, some of the typical Nrf2-dependent genes are only marginally increased in the Keap1-deficient liver. The mutant mice were significantly more resistant to toxic doses of acetaminophen than control animals. These results demonstrate that chronic activation of Nrf2 confers animals with resistance to xenobiotics without affecting the morphological and physiological integrity of hepatocytes

  2. Beyond platinum: synthesis, characterization, and in vitro toxicity of Cu(II-releasing polymer nanoparticles for potential use as a drug delivery vector

    Directory of Open Access Journals (Sweden)

    Harris Alesha

    2011-01-01

    Full Text Available Abstract The field of drug delivery focuses primarily on delivering small organic molecules or DNA/RNA as therapeutics and has largely ignored the potential for delivering catalytically active transition metal ions and complexes. The delivery of a variety of transition metals has potential for inducing apoptosis in targeted cells. The chief aims of this work were the development of a suitable delivery vector for a prototypical transition metal, Cu2+, and demonstration of the ability to impact cancer cell viability via exposure to such a Cu-loaded vector. Carboxylate-functionalized nanoparticles were synthesized by free radical polymerization and were subsequently loaded with Cu2+ via binding to particle-bound carboxylate functional groups. Cu loading and release were characterized via ICP MS, EDX, XPS, and elemental analysis. Results demonstrated that Cu could be loaded in high weight percent (up to 16 wt.% and that Cu was released from the particles in a pH-dependent manner. Metal release was a function of both pH and the presence of competing ligands. The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading. The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.

  3. Influence of drugs with antioxidant properties on the state of the sperm antioxidant system in men with excretory-toxic forms of infertility

    Directory of Open Access Journals (Sweden)

    O.K. Onufrovych

    2013-10-01

    Full Text Available Since the development of many disorders of the reproductive function in men involves processes of free radical oxidation, the purpose of this study was to form an evaluation of the pro- and antioxidant status of sperm and to restore its biological usefulness in men with excretory-toxic forms of infertility by using drugs with antioxidant properties. It is shown that excretory-toxic forms of infertility in men are mostly caused by such infectious agents as Chlamydia (22%, Chlamydia + Ureaplasma (16%, Chlamydia + Trichomonas (13%, Ureaplasma (10%. This reduces the total number of sperm in the ejaculate by 2.7 times, and motility by 1.8 times. The number of abnormal forms increases by 1.75 times. With the development of chronic inflammation of the male sex organs sperm lipid peroxidation increases by 1.3 times while the activity of glutathione peroxidase decreases (by 2.3 times and that of glutathione reductase (by 1.7 times. We observed a close correlation between the low biological quality of sperm (low concentration, low number and motility of sperm in the ejaculate with activation of lipid peroxidation and inhibition of activity of the glutathione antioxidant system. In the case of superoxide dismutase, the negative impact of reactive oxygen species on this enzyme was not observed. A course of drugs with antioxidant properties – vitamin E, vitamin C and zinc sulfate leads to improvement in the indicators on the spermagram (mostly sperm mobility and morphology, to reduction of the number of peroxide compounds and activation of the glutathione antioxidant system. In this case, the activity of glutathione peroxidase is increased by 1.5 times and the activity of glutathione reductase by 1.3 times. The activity of superoxide dismutase at the same time approaches the norm for zoospermia. The data obtained show that one of the pathogenic factors of the chronic inflammation of male sex organs, considered as a main developmental reason for infertility

  4. Influence of chemotherapeutic drug-related gene polymorphisms on toxicity and survival of early breast cancer patients receiving adjuvant chemotherapy.

    Science.gov (United States)

    Ludovini, Vienna; Antognelli, Cinzia; Rulli, Antonio; Foglietta, Jennifer; Pistola, Lorenza; Eliana, Rulli; Floriani, Irene; Nocentini, Giuseppe; Tofanetti, Francesca Romana; Piattoni, Simonetta; Minenza, Elisa; Talesa, Vincenzo Nicola; Sidoni, Angelo; Tonato, Maurizio; Crinò, Lucio; Gori, Stefania

    2017-07-26

    We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.

  5. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.

    Science.gov (United States)

    Al-Bari, Md Abdul Alim

    2015-01-01

    Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine.

    Science.gov (United States)

    Ghare, Smita S; Donde, Hridgandh; Chen, Wei-Yang; Barker, David F; Gobejishvilli, Leila; McClain, Craig J; Barve, Shirish S; Joshi-Barve, Swati

    2016-09-01

    Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Evaluation of the toxic effects of four anti-cancer drugs in plant bioassays and its potency for screening in the context of waste water reuse for irrigation.

    Science.gov (United States)

    Lutterbeck, Carlos Alexandre; Kern, Deivid Ismael; Machado, Ênio Leandro; Kümmerer, Klaus

    2015-09-01

    Anti-cancer drugs are compounds that are of high environmental relevance because of their lack of specific mode of action. They can be extremely harmful to living organisms even at low concentrations. The present study evaluated the toxic effects of four frequently used anti-cancer drugs against plant seedlings, namely Cyclophosphamide (CP), Methotrexate (MTX), 5-Fluorouracil (5-FU) and Imatinib (IM). The phytotoxicity experiments were performed with Lactuca sativa seedlings whereas cytotoxicity, genotoxicity and mutagenicity investigations were performed with the well-established Allium cepa assays. MTX was the most phytotoxic compound, followed by 5-FU, CP and IM. Significant differences in the Mitotic Indexes (MI) were observed in three of the studied compounds (MTX, 5-FU and CP), indicating potential cytotoxic activity of these substances. Chromosome aberrations were registered in cells that were exposed to 5-FU, CP and IM. All the four compounds caused the formation of micronucleated cells indicating mutagenic potential. Besides, the assays performed with MTX samples presented a high number of cell apoptosis (cell death). Although it is unlikely that the pharmaceuticals concentrations measured in the environment could cause lethal effects in plants, the obtained results indicate that these compounds may affect the growth and normal development of these plants. So, both tests can constitute important tools for a fast screening of environmental contamination e.g. in the context of the reuse of treated wastewater and biosolids of agricultural purpose. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. A six-month prospective study to find out the treatment outcome, prognosis and offending drugs in toxic epidermal necrolysis from an urban institution in Kolkata

    Directory of Open Access Journals (Sweden)

    Sudip Das

    2013-01-01

    Full Text Available Toxic epidermal necrolysis is the life-threatening dermatological emergency, most often an adverse cutaneous drug reaction with high mortality. A 6-month prospective study was conducted in our institution to find out the offending drugs, to assess the prognosis on admission using SCORTEN: Severity of illness score and to find out the treatment outcome. Anticonvulsants, NSAIDs and sulphonamides are the common offending agents; but in our study, 2 were due to homeopathic medicines. Out of 20 patients, on the date of admission SCORTEN prognostic score was 2 in 11 patients, 3 in 8 patients and 4 in 1 patient. Eighteen patients were treated with dexamethasone intramuscular injection and 2 patients got intravenous immunoglobulin (IVIG. All patients survived without any mortality. Though improvement was slightly faster with IVIG, early administration of corticosteroids was also of encouraging efficacy and should be considered in developing countries due to low cost. No mortality in our study suggests need to validate the SCORTEN index in our country in a large number of patients.

  9. Elimination of Endogenous Toxin, Creatinine from Blood Plasma Depends on Albumin Conformation: Site Specific Uremic Toxicity & Impaired Drug Binding

    Science.gov (United States)

    Varshney, Ankita; Rehan, Mohd; Subbarao, Naidu; Rabbani, Gulam; Khan, Rizwan Hasan

    2011-01-01

    Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state. PMID:21386972

  10. Targeting property and toxicity of a novel ultrasound contrast agent microbubble carrying the targeting and drug-loaded complex FA-CNTs-PTX on MCF7 cells.

    Science.gov (United States)

    Zhang, Jie; Zhang, Yu; Liu, Junxi; Li, Guozhong; Wen, Zhaohui; Zhao, Yue; Zhang, Xiangyu; Liu, Fenghua

    2017-10-01

    The application of ultrasound contrast agents not only is confined to the enhancement of ultrasound imaging but also has started to be used as a drug system for diagnosis and treatment. In this paper, Span60 and PEG1500 were used as membrane materials, and a new targeting and drug-loading multifunctional ultrasound contrast agent microbubble enveloping the FA-CNTs-PTX complex was successfully prepared by acoustic cavitation. With the breast cancer cell line MCF7 as the research target, the effects of the microbubble with FA-CNTs-PTX on the proliferation and toxicity of MCF7 cells were studied using a CCK-8 and AO/EB double-staining method. The influences of the microbubbles with FA-CNTs-PTX on the cellular morphology and apoptosis period of the MCF7 cells were detected using an inverted fluorescence microscope. The apoptosis of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was investigated with flow cytometry and an annexin and PI double staining fluorescence quantitative analysis. The results indicated that the ultrasound contrast agent microbubble with FA-CNTs-PTX remarkably inhibited the proliferation of MCF7 cells, which was mainly controlled by the drug loading rate and the nanometer size of the microbubbles. Moreover, the proliferative inhibition rate of the microbubbles with FA-CNTs-PTX was related to the cell apoptosis period of MCF7 cells. Its inhibition degree on the proliferation of MCF7 cells was higher than that of the hepatoma HepG2 cells. The apoptosis rate of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was higher than that of normal human umbilical vein endothelial cells (HUVECs), and the microbubbles with FA-CNTs-PTX could target the MCF7 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. PRX1 knockdown potentiates vitamin K3 toxicity in cancer cells: a potential new therapeutic perspective for an old drug.

    Science.gov (United States)

    He, Tiantian; Hatem, Elie; Vernis, Laurence; Lei, Ming; Huang, Meng-Er

    2015-12-21

    significantly up-regulated mRNA and protein levels of NRH:quinone oxidoreductase 2, which was partially responsible for vitK3-induced ROS accumulation and consequent cell death. Our data suggest that PRX1 inactivation could represent an interesting strategy to enhance cancer cell sensitivity to vitK3, providing a potential new therapeutic perspective for this old molecule. Conceptually, a combination of drugs that modulate intracellular redox states and drugs that operate through the generation of ROS could be a new therapeutic strategy for cancer treatment.

  12. Toxicity of Xanthene Food Dyes by Inhibition of Human Drug-Metabolizing Enzymes in a Noncompetitive Manner

    International Nuclear Information System (INIS)

    Mizutani, T.

    2010-01-01

    The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC50 values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC50 values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the non inhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of O 12 originating on xanthene dyes by light irradiation, because inhibition was prevented by O 12 quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin.

  13. Toxicity of xanthene food dyes by inhibition of human drug-metabolizing enzymes in a noncompetitive manner.

    Science.gov (United States)

    Mizutani, Takaharu

    2009-01-01

    The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC(50) values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC(50) values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of (1)O(2) originating on xanthene dyes by light irradiation, because inhibition was prevented by (1)O(2) quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin.

  14. Toxicity of Xanthene Food Dyes by Inhibition of Human Drug-Metabolizing Enzymes in a Noncompetitive Manner

    Science.gov (United States)

    Mizutani, Takaharu

    2009-01-01

    The synthetic food dyes studied were rose bengal (RB), phroxine (PL), amaranth, erythrosine B (ET), allura red, new coccine, acid red (AR), tartrazine, sunset yellow FCF, brilliant blue FCF, and indigo carmine. First, data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. ET inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). We showed the inhibitory effect of xanthene dye on human UGT1A6 activity. Basic ET, PL, and RB in those food dyes strongly inhibited UGT1A6 activity, with IC50 values = 0.05, 0.04, and 0.015 mM, respectively. Meanwhile, AR of an acidic xanthene food dye showed no inhibition. Next, we studied the inhibition of CYP3A4 of a major phase I drug-metabolizing enzyme and P-glycoprotein of a major transporter by synthetic food dyes. Human CYP3A4 and P-glycoprotein were also inhibited by basic xanthene food dyes. The IC50 values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the inhibition level of UGT1A6 by three halogenated xanthene food dyes (ET, PL, and RB) described above, except AR, like the results with UGT1A6 and UGT2B7. We also confirmed the noninhibition of CYP3A4 and P-gp by other synthetic food dyes. Part of this inhibition depended upon the reaction of 1O2 originating on xanthene dyes by light irradiation, because inhibition was prevented by 1O2 quenchers. We studied the influence of superoxide dismutase and catalase on this inhibition by dyes and we found prevention of inhibition by superoxide dismutase but not catalase. This result suggests that superoxide anions, originating on dyes by light irradiation, must attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins on skin under lighting and may lead to rough skin. PMID:20041016

  15. Effectiveness of Action in India to Reduce Exposure of Gyps Vultures to the Toxic Veterinary Drug Diclofenac

    Science.gov (United States)

    Cuthbert, Richard; Taggart, Mark A.; Prakash, Vibhu; Saini, Mohini; Swarup, Devendra; Upreti, Suchitra; Mateo, Rafael; Chakraborty, Soumya Sunder; Deori, Parag; Green, Rhys E.

    2011-01-01

    Contamination of their carrion food supply with the non-steroidal anti-inflammatory drug diclofenac has caused rapid population declines across the Indian subcontinent of three species of Gyps vultures endemic to South Asia. The governments of India, Pakistan and Nepal took action in 2006 to prevent the veterinary use of diclofenac on domesticated livestock, the route by which contamination occurs. We analyse data from three surveys of the prevalence and concentration of diclofenac residues in carcasses of domesticated ungulates in India, carried out before and after the implementation of a ban on veterinary use. There was little change in the prevalence and concentration of diclofenac between a survey before the ban and one conducted soon after its implementation, with the percentage of carcasses containing diclofenac in these surveys estimated at 10.8 and 10.7%, respectively. However, both the prevalence and concentration of diclofenac had fallen markedly 7–31 months after the implementation of the ban, with the true prevalence in this third survey estimated at 6.5%. Modelling of the impact of this reduction in diclofenac on the expected rate of decline of the oriental white-backed vulture (Gyps bengalensis) in India indicates that the decline rate has decreased to 40% of the rate before the ban, but is still likely to be rapid (about 18% year−1). Hence, further efforts to remove diclofenac from vulture food are still needed if the future recovery or successful reintroduction of vultures is to be feasible. PMID:21589920

  16. Effects of the antituberculous drug ethambutol on zinc balance, distribution, and turnover: short-term studies modeling chronic toxicity

    International Nuclear Information System (INIS)

    King, A.B.

    1987-01-01

    Alterations in Zn metabolism have been reported in both tuberculous patients and experimental animals receiving ethambutol (d-2-2'-ethylenediimino-di-1-butanol dihydrochloride) (EMB), and these changes have been associated with ocular side effects of EMB. EMB has chelating properties but is not likely to chelate Zn at physiologic pH. However, its acid metabolite is a stronger chelator. This research addressed whether EMB affects the absorption and disposition of dietary Zn, and whether effects of EMB on Zn are modified by (a) marginal Zn intake of (b) drugs that may induce metabolism of EMB. Weanling male Sprague-Dawley rats fed an AIN-76A diet received daily by gavage either deionized water or EMB doses of 400-1600 mg/kg bw. in a preliminary, 15-day dose-response study and 400-600 mg/kg in three subsequent 15- to 30-day studies. Apparent absorption and biological turnover of Zn were measured by 65 Zn balance and retention in rats fed adequate (49 ppm) or marginal (11 ppm) Zn. Effects of EMB were similar in both dietary groups. EMB treatment produced alopecia and reduced feed intake, feed efficiency, weight gain, and serum Zn, but showed no effect on hepatic, renal, or femoral Zn concentrations. Absorption, turnover, and urinary excretion of Zn were increased in rats fed EMB

  17. Effects of the antituberculous drug ethambutol on zinc balance, distribution, and turnover: short-term studies modeling chronic toxicity

    Energy Technology Data Exchange (ETDEWEB)

    King, A.B.

    1987-01-01

    Alterations in Zn metabolism have been reported in both tuberculous patients and experimental animals receiving ethambutol (d-2-2'-ethylenediimino-di-1-butanol dihydrochloride) (EMB), and these changes have been associated with ocular side effects of EMB. EMB has chelating properties but is not likely to chelate Zn at physiologic pH. However, its acid metabolite is a stronger chelator. This research addressed whether EMB affects the absorption and disposition of dietary Zn, and whether effects of EMB on Zn are modified by (a) marginal Zn intake of (b) drugs that may induce metabolism of EMB. Weanling male Sprague-Dawley rats fed an AIN-76A diet received daily by gavage either deionized water or EMB doses of 400-1600 mg/kg bw. in a preliminary, 15-day dose-response study and 400-600 mg/kg in three subsequent 15- to 30-day studies. Apparent absorption and biological turnover of Zn were measured by /sup 65/Zn balance and retention in rats fed adequate (49 ppm) or marginal (11 ppm) Zn. Effects of EMB were similar in both dietary groups. EMB treatment produced alopecia and reduced feed intake, feed efficiency, weight gain, and serum Zn, but showed no effect on hepatic, renal, or femoral Zn concentrations. Absorption, turnover, and urinary excretion of Zn were increased in rats fed EMB.

  18. Utilization of bio-degradable fermented tapioca to synthesized low toxicity of carbon nanotubes for drug delivery applications

    International Nuclear Information System (INIS)

    Nurulhuda, I.; Poh, R.; Mazatulikhma, M. Z.; Rusop, M.; Salman, A. H. A.; Haseeb, A. K.

    2016-01-01

    Carbon nanotubes (CNT) have potential biomedical applications, and investigations are shifting towards the production of such nanotubes using renewable natural sources. CNTs were synthesized at various temperatures of 700, 750, 800, 850 and 900 °C, respectively, using a local fermented food known as “tapai ubi” or fermented tapioca as a precursor. The liquid part of this fermented food was heated separately at 80°C and channeled directly into the furnace system that employs the thermal chemical vapor deposition (CVD) method. Ferrocene, which was the catalyst was placed in furnace 1 in the thermal CVD process. The resulting CNTs produced from the process were studied using field emission scanning electron microscopy (FESEM) and Raman spectroscopy. The FESEM images showed the growth morphology of the CNTs at the different temperatures employed. It was observed that the higher the synthesis temperature up to a point, the diameter of CNTs produced, after which the diameter increased. CNTs with helical structures were observed at 700 °C with a diameter range of 111 - 143 nm. A more straightened structure was observed at 750 °C with a diameter range of 59 - 121 nm. From 800 °C onwards, the diameters of the CNTs were less than 60 nm. Raman analysis revealed the present of D, G and G’ peak were observed at 1227-1358, 1565-1582, and 2678-2695 cm −1 , respectively. The highest degree of crystallity of the carbon nanotubes synthesized were obtained at 800 °C. The radial breathing mode (RBM) were in range between 212-220 and 279-292 cm −1 . Carbon nanotubes also being functionalized with Polyethylene bis(amine) Mw2000 (PEG 2000-NH2) and showed highly cells viability compared to non-functionalized CNT. The nanotubes synthesized will be applied as drug delivery in future study.

  19. Utilization of bio-degradable fermented tapioca to synthesized low toxicity of carbon nanotubes for drug delivery applications

    Energy Technology Data Exchange (ETDEWEB)

    Nurulhuda, I., E-mail: nurulnye@gmail.com [NANO-SciTech Centre, Institute of Science, Universiti Teknologi MARA, 40450 Shah Alam, Selangor (Malaysia); Poh, R. [Department of Molecular Medicine, University of Malaya, 50603 Kuala Lumpur (Malaysia); Mazatulikhma, M. Z. [Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor (Malaysia); Rusop, M., E-mail: nanouitm@gmail.com [NANO-Electronic Centre, Faculty of Electrical Engineering, Universiti Teknologi MARA, 40450 Shah Alam, Selangor (Malaysia); Salman, A. H. A.; Haseeb, A. K.

    2016-07-06

    Carbon nanotubes (CNT) have potential biomedical applications, and investigations are shifting towards the production of such nanotubes using renewable natural sources. CNTs were synthesized at various temperatures of 700, 750, 800, 850 and 900 °C, respectively, using a local fermented food known as “tapai ubi” or fermented tapioca as a precursor. The liquid part of this fermented food was heated separately at 80°C and channeled directly into the furnace system that employs the thermal chemical vapor deposition (CVD) method. Ferrocene, which was the catalyst was placed in furnace 1 in the thermal CVD process. The resulting CNTs produced from the process were studied using field emission scanning electron microscopy (FESEM) and Raman spectroscopy. The FESEM images showed the growth morphology of the CNTs at the different temperatures employed. It was observed that the higher the synthesis temperature up to a point, the diameter of CNTs produced, after which the diameter increased. CNTs with helical structures were observed at 700 °C with a diameter range of 111 - 143 nm. A more straightened structure was observed at 750 °C with a diameter range of 59 - 121 nm. From 800 °C onwards, the diameters of the CNTs were less than 60 nm. Raman analysis revealed the present of D, G and G’ peak were observed at 1227-1358, 1565-1582, and 2678-2695 cm{sup −1}, respectively. The highest degree of crystallity of the carbon nanotubes synthesized were obtained at 800 °C. The radial breathing mode (RBM) were in range between 212-220 and 279-292 cm{sup −1}. Carbon nanotubes also being functionalized with Polyethylene bis(amine) Mw2000 (PEG 2000-NH2) and showed highly cells viability compared to non-functionalized CNT. The nanotubes synthesized will be applied as drug delivery in future study.

  20. Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations.

    Science.gov (United States)

    Teraki, Y; Shibuya, M; Izaki, S

    2010-10-01

    Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant-related DIHS (n = 6). Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV-6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS. © 2009 The Author(s). Journal compilation © 2009 British Association of Dermatologists.

  1. Racial disparities in the risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States.

    Science.gov (United States)

    Lu, Na; Rai, Sharan K; Terkeltaub, Robert; Kim, Seoyoung C; Menendez, Mariano E; Choi, Hyon K

    2016-10-01

    HLA-B*5801 allele carriage (a strong determinant of allopurinol hypersensitivity syndrome) varies substantially among races, which may lead to racial disparities in the risk of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in the context of urate-lowering drug adverse events (ULDAEs). We examined this hypothesis in a large, racially diverse, and generalizable setting. Using a database representative of US hospitalizations (2009-2013), we investigated the racial distribution of hospitalized SJS/TEN (principal discharge diagnosis) as ULDAEs (ICD-9-CM Classification of External Causes). Our reference groups included the US Census population, US allopurinol users, and ULDAE hospitalizations without SJS/TEN. We identified 606 cases hospitalized for SJS/TEN as ULDAEs (mean age = 68 years; 44% male), among which there was an overrepresentation of Asians (27%) and Blacks (26%), and an underrepresentation of Whites (29%) and Hispanics (% too-low-to-report), compared with the US Census population (5%, 12%, 67%, and 15%, respectively). The hospitalization rate ratios for SJS/TEN among Asians, Blacks, and Whites were 11.9, 5.0, and 1.0 (referent), respectively. These associations persisted using other national referents. According to the NHANES 2009-2012, allopurinol constituted 96.8% of urate-lowering drug use, followed by probenecid (2.1%). These national data indicate that Asians and Blacks have a substantially higher risk of SJS/TEN as ULDAEs than Whites (or Hispanics), correlating well with corresponding frequencies of HLA-B*5801 in the US population (i.e., 7.4%, 4%, 1%, and 1%, respectively). Given its market dominance and established association with SJS/TEN, our findings support the use of vigilance in these minorities when considering allopurinol. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. The pharmacokinetic study on the mechanism of toxicity attenuation of rhubarb total free anthraquinone oral colon-specific drug delivery system.

    Science.gov (United States)

    Zhang, Lin; Chang, Jin-hua; Zhang, Bao-qi; Liu, Xi-gang; Liu, Pei; Xue, He-fei; Liu, Li-yan; Fu, Qiang; Zhu, Meng; Liu, Cui-zhe

    2015-07-01

    Rhubarb is commonly used as laxatives in Asian countries, of which anthraquinones are the major active ingredients, but there are an increased number of concerns regarding the nephrotoxicity of anthraquinones. In this study, we compared the pharmacokinetic characteristics of rhubarb anthraquinones in rats after orally administered with rhubarb and rhubarb total free anthraquinone oral colon-specific drug delivery granules (RTFA-OCDD-GN), and then explained why these granules could reduce the nephrotoxicity of anthraquinones when they produced purgative efficacy. A sensitive and reliable high performance liquid chromatography (HPLC) method has been fully validated for simultaneous determination of the five active components of rhubarb, and successfully applied to investigate and compare the remarkable differences in pharmacokinetic study of rhubarb anthraquinones after orally administered with rhubarb and RTFA-OCDD-GN. The results showed that, compared with rhubarb group, the AUC, Cmax, t1/2z and Vz/F of aloe-emodin, rhein, emodin and chrysophanol in rats receiving the RTFA-OCDD-GN were significantly decreased, and the Tmax of the four analytes was prolonged. Moreover, the Tmax of rhein, the Cmax of chrysophanol and emodin all have significant differences (Panthraquinone prototype excretion rates in urine and feces of aloe-emodin, rhein, emodin, chrysophanol and physcion were all increased. These findings suggested that oral colon-specific drug delivery technology made anthraquinone aglycone to colon-specific release after oral administration. This allowed anthraquinones to not only play the corresponding purgative effect but also avoid intestinal absorption and promote excretion. And thereby greatly reduced the nephrotoxicity of rhubarb. The result is a new breakthrough in rhubarb toxicity attenuated research. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: Possible role in drug induced liver injury (DILI).

    Science.gov (United States)

    Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honoré

    2016-03-01

    Diclofenac is a widely prescribed NSAID, which by itself and its reactive metabolites (Phase-I and Phase-II) may be involved in serious idiosyncratic hepatotoxicity. Mitochondrial injury is one of the mechanisms of drug induced liver injury (DILI). In the present work, an investigation of the inhibitory effects of diclofenac (Dic) and its phase I [4-hydroxy diclofenac (4'-OH-Dic) and 5-hydroxy diclofenac (5-OH-dic)] and Phase-II [diclofenac acyl glucuronide (DicGluA) and diclofenac glutathione thioester (DicSG)] metabolites, on ATP synthesis in rat liver mitochondria was carried out. A mechanism based inhibition of ATP synthesis is exerted by diclofenac and its metabolites. Phase-I metabolite (4'-OH-Dic) and Phase-II metabolites (DicGluA and DicSG) showed potent inhibition (2-5 fold) of ATP synthesis, where as 5-OH-Dic, one of the Phase-I metabolite, was a less potent inhibitor as compared to Dic. The calculated kinetic constants of mechanism based inhibition of ATP synthesis by Dic showed maximal rate of inactivation (Kinact) of 2.64 ± 0.15 min(-1) and half maximal rate of inactivation (KI) of 7.69 ± 2.48 μM with Kinact/KI ratio of 0.343 min(-1) μM(-1). Co-incubation of mitochondria with Dic and reduced GSH exhibited a protective effect on Dic mediated inhibition of ATP synthesis. Our data from this study strongly indicate that Dic as well as its metabolites could be involved in the hepato-toxic action through inhibition of ATP synthesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Electronic Cigarette Toxicity.

    Science.gov (United States)

    Payne, J Drew; Michaels, David; Orellana-Barrios, Menfil; Nugent, Kenneth

    2017-04-01

    Electronic cigarettes (e-cigarettes) are often advertised as a healthier product when compared with traditional cigarettes. Currently, there are limited data to support this and only a threat of federal regulation from the US Food and Drug Administration. Calls to poison control centers about e-cigarette toxicity, especially in children, and case reports of toxic exposures have increased over the past 3 years. This research letter reports the frequency of hazardous exposures to e-cigarettes and characterizes the reported adverse health effects associated with e-cigarette toxicity.

  5. Kombucha--toxicity alert.

    Science.gov (United States)

    The Kombucha mushroom, also known as Manchurian mushroom, is a mail-order product touted to lower blood pressure and raise T-cell counts. No controlled trials have been conducted to test these claims. Aspergillus, a mold that may grow on the Kombucha mushroom, attacks the brain and may be fatal to persons with weakened immune systems. Reported toxicity reactions have included stomach problems and yeast infections. Taking Kombucha in combination with other drugs may affect the drugs potency.

  6. Introducing Toxics

    OpenAIRE

    David C. Bellinger

    2013-01-01

    With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present ...

  7. Local anaesthetic toxicity

    African Journals Online (AJOL)

    Local anaesthetic toxicity has been known since the introduction of local anaesthetic drugs into anaesthetic practice more than a hundred ... was the first to think of cocaine as a narcotic. ..... anaesthetics act as Na+ channel-blocking agents, they slow down .... all neurons, leading to global CNS depression, slowing and.

  8. How toxic is ibogaine?

    NARCIS (Netherlands)

    Litjens, Ruud P. W.; Brunt, Tibor M.

    2016-01-01

    Ibogaine is a psychoactive indole alkaloid found in the African rainforest shrub Tabernanthe Iboga. It is unlicensed but used in the treatment of drug and alcohol addiction. However, reports of ibogaine's toxicity are cause for concern. To review ibogaine's pharmacokinetics and pharmacodynamics,

  9. Hydroxycut-induced Liver Toxicity

    African Journals Online (AJOL)

    hanumantp

    Annals of Medical and Health Sciences Research | Jan-Feb 2014 | Vol 4 ... supplements can be responsible for documented or undocumented adverse drug effects. The ... Keywords: Hydroxycut, Liver toxicity, Nutritional supplements ... Caffeine anhydrous: 200 mg* ... series and review of liver toxicity from herbal weight loss.

  10. Effect of some drugs on radioprotective effectiveness, toxicity and distribution of 35S-Aminopropyl-aminoethyl-thiophosphate orally administered to mice

    International Nuclear Information System (INIS)

    Grechka, I.I.; Belavina, L.P.; Kalistpatov, G.V.; Zherebchenko, P.G.

    1979-01-01

    Studied was the influence of adreno- adn cholinolytics and cholinomimetic substances on radioprotective effectiveness and toxicity of aminopropyl-aminoehtyl-thiophosphate (APAETP) and distribution thereof among organs after oral and intraperitoneal administration. Atropine and INPEA decrease the toxicity and radioprotectiVe efficiency of APAETP when administered orally and do not influence these properties after intraperitoneal in ection. Deposition of the labelled radioprotector within the organs after oral administration is also indicative that atropine and INPEA can delay the transfer of APAETP from the stomach to the intenstine

  11. HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer

    Science.gov (United States)

    Garziera, Marica; Virdone, Saverio; De Mattia, Elena; Scarabel, Lucia; Cecchin, Erika; Polesel, Jerry; D’Andrea, Mario; Pella, Nicoletta; Buonadonna, Angela; Favaretto, Adolfo; Toffoli, Giuseppe

    2017-01-01

    Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC. PMID:28653974

  12. HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4 Chemotherapy in Non-Metastatic Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Marica Garziera

    2017-06-01

    Full Text Available Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4. Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G, a non-classical major histocompatibility complex (MHC class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4 toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015 and neurotoxicity (OR = 8.78, p = 0.016; rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027. HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017 and neurotoxicity (OR = 11.29, p = 0.009. A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.

  13. Eventos toxicológicos relacionados a medicamentos no Estado de São Paulo Drug-related toxic events in the state of São Paulo, Brazil

    Directory of Open Access Journals (Sweden)

    Eliane Gandolfi

    2006-12-01

    Full Text Available OBJETIVO: Analisar as características epidemiológicas dos eventos toxicológicos relacionados a medicamentos. MÉTODOS: Realizou-se um estudo epidemiológico descritivo de série de casos. Utilizando a categoria "evento toxicológico relacionado a medicamentos", analisaram-se 6.673 casos registrados em centros de assistência toxicológica do Estado de São Paulo, no ano de 1998. As variáveis estudadas compreenderam características dos eventos, das pessoas afetadas, dos agentes tóxicos e das circunstâncias envolvidas. A análise dos agentes tóxicos considerou três níveis de desagregação: grupos terapêuticos, princípios ativos e nomes comerciais. RESULTADOS: Os medicamentos ocuparam o primeiro lugar entre todos os tipos de agentes tóxicos registrados pelos centros. Os eventos toxicológicos relacionados a medicamentos caracterizaram-se por serem registrados por telefone (78,5%, a partir de hospitais (86,6%; originaram-se de exposições agudas, pela via oral (90,2%, ocorridas em residência (85,7% de área urbana (95%. Houve predomínio do sexo feminino (59% e maior concentração na primeira década de vida (49,4%, sobretudo aos dois e três anos de idade. Os princípios ativos mais freqüentemente encontrados foram: fenobarbital, diazepam, haloperidol, carbamazepina e bromazepam. As principais circunstâncias foram as acidentais (38,8% e tentativas de suicídio (36,5%. Entre os princípios ativos relacionados predominaram os dos grupos terapêuticos psiquiatria, analgesia/anestesia e respiratório. CONCLUSÕES: Aponta-se a necessidade de cumprimento da legislação quanto à venda de medicamentos sob receituário médico e de construção da toxicovigilância conforme diretrizes do Sistema Único de Saúde.OBJECTIVE: To assess the epidemiological characteristics of drug-related toxic events in the State of São Paulo, Brazil. METHODS: A descriptive epidemiological case series study was conducted. Using the category "drug

  14. Cyclophosphamide-induced pulmonary toxicity

    International Nuclear Information System (INIS)

    Siemann, D.W.; Macler, L.; Penney, D.P.

    1986-01-01

    Unlike radiation effects, pulmonary toxicity following drug treatments may develop soon after exposure. The dose-response relationship between Cyclophosphamide and lung toxicity was investigated using increased breathing frequency assays used successfully for radiation induced injury. The data indicate that release of protein into the alveolus may play a significant role in Cy induced pulmonary toxicity. Although the mechanism responsible for the increased alveolar protein is as yet not identified, the present findings suggest that therapeutic intervention to inhibit protein release may be an approach to protect the lungs from toxic effects. (UK)

  15. Toxic Elements

    DEFF Research Database (Denmark)

    Hajeb, Parvaneh; Shakibazadeh, Shahram; Sloth, Jens Jørgen

    2016-01-01

    Food is considered the main source of toxic element (arsenic, cadmium, lead, and mercury) exposure to humans, and they can cause major public health effects. In this chapter, we discuss the most important sources for toxic element in food and the foodstuffs which are significant contributors to h...

  16. Capping Drugs

    Indian Academy of Sciences (India)

    preventing disease in human beings or in animals. In the process ... of requirement. In the process, they may cause toxic side effects. .... the liver to release the physiologically active drug. Similarly ... patients addicted to alcohol. However, it is a ...

  17. Clopidogrel in a combined therapy with anticancer drugs-effect on tumor growth, metastasis, and treatment toxicity: Studies in animal models.

    Directory of Open Access Journals (Sweden)

    Agnieszka Denslow

    Full Text Available Clopidogrel, a thienopyridine derivative with antiplatelet activity, is widely prescribed for patients with cardiovascular diseases. In addition to antiplatelet activity, antiplatelet agents possess anticancer and antimetastatic properties. Contrary to this, results of some studies have suggested that the use of clopidogrel and other thienopyridines accelerates the progression of breast, colorectal, and prostate cancer. Therefore, in this study, we aimed to evaluate the efficacy of clopidogrel and various anticancer agents as a combined treatment using mouse models of breast, colorectal, and prostate cancer. Metastatic dissemination, selected parameters of platelet morphology and biochemistry, as well as angiogenesis were assessed. In addition, body weight, blood morphology, and biochemistry were evaluated to test toxicity of the studied compounds. According to the results, clopidogrel increased antitumor and/or antimetastatic activity of chemotherapeutics such as 5-fluorouracil, cyclophosphamide, and mitoxantrone, whereas it decreased the anticancer activity of doxorubicin, cisplatin, and tamoxifen. The mechanisms of such divergent activities may be based on the modulation of tumor vasculature via factors, such as transforming growth factor β1 released from platelets. Moreover, clopidogrel increased the toxicity of docetaxel and protected against mitoxantrone-induced toxicity, which may be due to the modulation of hepatic enzymes and protection of the vasculature, respectively. These results demonstrate that antiplatelet agents can be useful but also dangerous in anticancer treatment and therefore use of thienopyridines in patients undergoing chemotherapy should be carefully evaluated.

  18. The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro-to-In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research.

    Science.gov (United States)

    Poulin, Patrick; Burczynski, Frank J; Haddad, Sami

    2016-02-01

    (IVIVEs) of toxicity (efficacy) at the cellular level from data generated in cell assays. Overall, this present study may help to optimize the human dose prediction in preclinical and clinical studies, while prescribing drugs with narrow therapeutic windows that are highly bound to extracellular proteins and/or highly ionized at the physiological pH. This may facilitate building a more accurate safety (efficacy) profile for such drugs. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  19. Introducing Toxics

    Directory of Open Access Journals (Sweden)

    David C. Bellinger

    2013-04-01

    Full Text Available With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present their work in as much detail as they wish. Toxics will publish original research papers, conventional reviews, meta-analyses, short communications, theoretical papers, case reports, commentaries and policy perspectives, and book reviews (Book reviews will be solicited and should not be submitted without invitation. Toxins and toxicants concern individuals from a wide range of disciplines, and Toxics is interested in receiving papers that represent the full range of approaches applied to their study, including in vitro studies, studies that use experimental animal or non-animal models, studies of humans or other biological populations, and mathematical modeling. We are excited to get underway and look forward to working with authors in the scientific and medical communities and providing them with a novel venue for sharing their work. [...

  20. A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development

    Directory of Open Access Journals (Sweden)

    Woollett Laura A

    2008-08-01

    Full Text Available Abstract Background The alarming rise in the obesity epidemic and growing concern for the pathologic consequences of the metabolic syndrome warrant great need for development of obesity-related pharmacotherapeutics. The search for such therapeutics is severely limited by the slow throughput of animal models of obesity. Amenable to placement into a 96 well plate, zebrafish larvae have emerged as one of the highest throughput vertebrate model organisms for performing small molecule screens. A method for visually identifying non-toxic molecular effectors of fat metabolism using a live transparent vertebrate was developed. Given that increased levels of nicotinamide adenine dinucleotide (NAD via deletion of CD38 have been shown to prevent high fat diet induced obesity in mice in a SIRT-1 dependent fashion we explored the possibility of directly applying NAD to zebrafish. Methods Zebrafish larvae were incubated with daily refreshing of nile red containing media starting from a developmental stage of equivalent fat content among siblings (3 days post-fertilization, dpf and continuing with daily refreshing until 7 dpf. Results PPAR activators, beta-adrenergic agonists, SIRT-1 activators, and nicotinic acid treatment all caused predicted changes in fat, cholesterol, and gene expression consistent with a high degree of evolutionary conservation of fat metabolism signal transduction extending from man to zebrafish larvae. All changes in fat content were visually quantifiable in a relative fashion using live zebrafish larvae nile red fluorescence microscopy. Resveratrol treatment caused the greatest and most consistent loss of fat content. The resveratrol tetramer Vaticanol B caused loss of fat equivalent in potency to resveratrol alone. Significantly, the direct administration of NAD decreased fat content in zebrafish. Results from knockdown of a zebrafish G-PCR ortholog previously determined to decrease fat content in C. elegans support that future GPR

  1. Antimony Toxicity

    OpenAIRE

    Sundar, Shyam; Chakravarty, Jaya

    2010-01-01

    Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The...

  2. Oxygen toxicity

    Directory of Open Access Journals (Sweden)

    C. A. van der Westhuizen

    1990-07-01

    Full Text Available Oxygen has been discovered about 200 years ago. Since then the vital physiological involvement of oxygen in various biologi­cal processes, mainly energy production, has been established. However, in the body molecular oxygen can be converted to toxic oxygen metabolites such as superoxide anion, hydrogen peroxide, the hydroxyl radical and singlet oxygen. These toxic metabolites are produced mainly in the mitochondria, plasma membranes and endoplasmic reticulum.

  3. Biomarkers of Treatment Toxicity in Combined-Modality Cancer Therapies with Radiation and Systemic Drugs: Study Design, Multiplex Methods, Molecular Networks

    Directory of Open Access Journals (Sweden)

    Anne Hansen Ree

    2014-12-01

    Full Text Available Organ toxicity in cancer therapy is likely caused by an underlying disposition for given pathophysiological mechanisms in the individual patient. Mechanistic data on treatment toxicity at the patient level are scarce; hence, probabilistic and translational linkages among different layers of data information, all the way from cellular targets of the therapeutic exposure to tissues and ultimately the patient’s organ systems, are required. Throughout all of these layers, untoward treatment effects may be viewed as perturbations that propagate within a hierarchically structured network from one functional level to the next, at each level causing disturbances that reach a critical threshold, which ultimately are manifested as clinical adverse reactions. Advances in bioinformatics permit compilation of information across the various levels of data organization, presumably enabling integrated systems biology-based prediction of treatment safety. In view of the complexity of biological responses to cancer therapy, this communication reports on a “top-down” strategy, starting with the systematic assessment of adverse effects within a defined therapeutic context and proceeding to transcriptomic and proteomic analysis of relevant patient tissue samples and computational exploration of the resulting data, with the ultimate aim of utilizing information from functional connectivity networks in evaluation of patient safety in multimodal cancer therapy.

  4. Detection and identification of drugs and toxicants in human body fluids by liquid chromatography-tandem mass spectrometry under data-dependent acquisition control and automated database search.

    Science.gov (United States)

    Oberacher, Herbert; Schubert, Birthe; Libiseller, Kathrin; Schweissgut, Anna

    2013-04-03

    Systematic toxicological analysis (STA) is aimed at detecting and identifying all substances of toxicological relevance (i.e. drugs, drugs of abuse, poisons and/or their metabolites) in biological material. Particularly, gas chromatography-mass spectrometry (GC/MS) represents a competent and commonly applied screening and confirmation tool. Herein, we present an untargeted liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay aimed to complement existing GC/MS screening for the detection and identification of drugs in blood, plasma and urine samples. Solid-phase extraction was accomplished on mixed-mode cartridges. LC was based on gradient elution in a miniaturized C18 column. High resolution electrospray ionization-MS/MS in positive ion mode with data-dependent acquisition control was used to generate tandem mass spectral information that enabled compound identification via automated library search in the "Wiley Registry of Tandem Mass Spectral Data, MSforID". Fitness of the developed LC/MS/MS method for application in STA in terms of selectivity, detection capability and reliability of identification (sensitivity/specificity) was demonstrated with blank samples, certified reference materials, proficiency test samples, and authentic casework samples. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Radionuclide toxicity

    International Nuclear Information System (INIS)

    Galle, P.

    1982-01-01

    The aim of this symposium was to review the radionuclide toxicity problems. Five topics were discussed: (1) natural and artificial radionuclides (origin, presence or emission in the environment, human irradiation); (2) environmental behaviour of radionuclides and transfer to man; (3) metabolism and toxicity of radionuclides (radioiodine, strontium, rare gas released from nuclear power plants, ruthenium-activation metals, rare earths, tritium, carbon 14, plutonium, americium, curium and einsteinium, neptunium, californium, uranium) cancerogenous effects of radon 222 and of its danghter products; (4) comparison of the hazards of various types of energy; (5) human epidemiology of radionuclide toxicity (bone cancer induction by radium, lung cancer induction by radon daughter products, liver cancer and leukaemia following the use of Thorotrast, thyroid cancer; other site of cancer induction by radionuclides) [fr

  6. Identification of clinically significant drug-drug interactions in cardiac ...

    African Journals Online (AJOL)

    Purpose: To identify clinically significant potential drug-drug interactions in cardiac intensive care units of two tertiary care ... hypertension, hyperlipidemia, diabetes or other diseases .... May result in digoxin toxicity (nausea, vomiting, cardiac.

  7. Is LSD toxic?

    Science.gov (United States)

    Nichols, David E; Grob, Charles S

    2018-03-01

    LSD (lysergic acid diethylamide) was discovered almost 75 years ago, and has been the object of episodic controversy since then. While initially explored as an adjunctive psychiatric treatment, its recreational use by the general public has persisted and on occasion has been associated with adverse outcomes, particularly when the drug is taken under suboptimal conditions. LSD's potential to cause psychological disturbance (bad trips) has been long understood, and has rarely been associated with accidental deaths and suicide. From a physiological perspective, however, LSD is known to be non-toxic and medically safe when taken at standard dosages (50-200μg). The scientific literature, along with recent media reports, have unfortunately implicated "LSD toxicity" in five cases of sudden death. On close examination, however, two of these fatalities were associated with ingestion of massive overdoses, two were evidently in individuals with psychological agitation after taking standard doses of LSD who were then placed in maximal physical restraint positions (hogtied) by police, following which they suffered fatal cardiovascular collapse, and one case of extreme hyperthermia leading to death that was likely caused by a drug substituted for LSD with strong effects on central nervous system temperature regulation (e.g. 25i-NBOMe). Given the renewed interest in the therapeutic potential of LSD and other psychedelic drugs, it is important that an accurate understanding be established of the true causes of such fatalities that had been erroneously attributed to LSD toxicity, including massive overdoses, excessive physical restraints, and psychoactive drugs other than LSD. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

  9. Immunological effects of iron oxide nanoparticles and iron-based complex drug formulations: Therapeutic benefits, toxicity, mechanistic insights, and translational considerations.

    Science.gov (United States)

    Shah, Ankit; Dobrovolskaia, Marina A

    2018-04-01

    Nanotechnology offers several advantages for drug delivery. However, there is the need for addressing potential safety concerns regarding the adverse health effects of these unique materials. Some such effects may occur due to undesirable interactions between nanoparticles and the immune system, and they may include hypersensitivity reactions, immunosuppression, and immunostimulation. While strategies, models, and approaches for studying the immunological safety of various engineered nanoparticles, including metal oxides, have been covered in the current literature, little attention has been given to the interactions between iron oxide-based nanomaterials and various components of the immune system. Here we provide a comprehensive review of studies investigating the effects of iron oxides and iron-based nanoparticles on various types of immune cells, highlight current gaps in the understanding of the structure-activity relationships of these materials, and propose a framework for capturing their immunotoxicity to streamline comparative studies between various types of iron-based formulations. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Toxic clinical hypoxic radiation sensitizers plus radiation-induced toxicity

    International Nuclear Information System (INIS)

    Richmond, R.C.

    1984-01-01

    The operational definition espoused twelve years ago that clinical hypoxic radiation sensitizers should be nontoxic interferes with the recognition and research of useful radiation sensitizers. Eight years ago the toxic antitumor drug cis-dichlorodiammineplatinum(II) was reported to be a hypoxic radiation sensitizer and the selective antitumor action of this drug was stressed as potentially creating tumor-targeted radiation sensitization. This rationale of oxidative antitumor drugs as toxic and targeted clinical sensitizers is useful, and has led to the study reported here. The antitumor drug cis-(1,1-cyclobutane-dicarboxylato)diammineplatinum(II), or JM-8, is being tested in clinical trials. Cells of S. typhimurium in PBS in the presence of 0.2mM JM-8 are found to be sensitized to irradiation under hypoxic, but not oxic, conditions. JM-8 is nontoxic to bacteria at this concentration, but upon irradiation the JM-8 solution becomes highly toxic. This radiation induced toxicity of JM-8 preferentially develops from hypoxic solution, and thus contributes to the rationale of hypoxic tumor cell destruction

  11. Nanotechnology and Drug Delivery Part 2: Nanostructures for Drug ...

    African Journals Online (AJOL)

    Some challenges associated with the technology as it relates to drug effectiveness, toxicity, stability, pharmacokinetics and drug regulatory control are discussed in this review. Clearly, nanotechnology is a welcome development that is set to transform drug delivery and drug supply chain management, if optimally developed ...

  12. Update on ocular toxicity of ethambutol

    Directory of Open Access Journals (Sweden)

    Priscilla Makunyane

    2016-08-01

    Full Text Available The purpose of this review is to update clinicians on available literature on the ocular toxicity of ethambutol and the type of eye care to be provided to patients treated with these medications. Ethambutol is a commonly used first-line anti-tuberculosis drug. Since its first use in the 1960s, ocular toxicity is described as related to dose and duration, and it is reversible on therapy discontinuation. However, the reversibility of the toxic optic neuropathy remains controversial. The mechanism of ocular toxicity owing to ethambutol is still under investigation. Other than discontinuing the drug, no specific treatment is available for the optic neuropathy caused by ethambutol. Doctors prescribing ethambutol should be aware of the ocular toxicity, and the drug should be used with proper patient education and ophthalmic monitoring.

  13. [Club drugs].

    Science.gov (United States)

    Guerreiro, Diogo Frasquilho; Carmo, Ana Lisa; da Silva, Joaquim Alves; Navarro, Rita; Góis, Carlos

    2011-01-01

    Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma-hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse.

  14. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ..., both under drug pressure and during inhibition. Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. The book concludes with the role of drug metabolism in the commercial development of therapeutic agents as well as the pharmacology of some illicit drugs.

  15. Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-¹⁰Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model.

    Science.gov (United States)

    Roda, E; Nion, S; Bernocchi, G; Coccini, T

    2014-10-02

    Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood-brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-(10)Boronophenyl)alanine, L-(10)BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-(10)BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-(10)BPA toxicity at 80 µg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-(10)BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39 ± 0.01 × 10(-3)cm min(-1)), corroborating the scarce probability that L-(10)BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. ORIGINAL ARTICLES Nevirapine toxicity- implications for ...

    African Journals Online (AJOL)

    Nevirapine was the first non-nucleoside drug (NNRTI) to be approved by the ... related toxicities in pregnancy were highlighted by a study published in 2004 ..... health, of consumption of scarce financial resources, of concern about doctors ...

  17. Evaluation of patterns of liver toxicity in patients on antiretroviral and anti-tuberculosis drugs: a prospective four arm observational study in ethiopian patients.

    Directory of Open Access Journals (Sweden)

    Getnet Yimer

    Full Text Available OBJECTIVES: To evaluate the incidence, type, severity and predictors of antiretroviral and/or anti-tuberculosis drugs induced liver injury (DILI. METHODS: A total of 1,060 treatment naive patients were prospectively enrolled into four treatment groups: HIV patients receiving efavirenz based HAART alone (Arm-1; TB-HIV co-infected patients with CD4≤200 cells/μL, receiving concomitant rifampicin based anti-TB and efavirenz based HAART (Arm-2; TB-HIV co-infected patients with CD4>200 cells/μL, receiving anti-TB alone (Arm-3; TB patients taking rifampicin based anti-TB alone (Arm-4. Liver enzyme levels were monitored at baseline, 1st, 2nd, 4th, 8th, 12th and 24th weeks during treatment. CD4 and HIV viral load was measured at baseline, 24th and 48th weeks. Data were analyzed using multivariate Cox Proportional Hazards Model. RESULTS: A total of 159 patients (15% developed DILI with severity grades 1, 2, 3 and 4 of 53.5%, 32.7%, 11.3% and 2.5% respectively. The incidence of cholestatic, hepatocellular or mixed pattern was 61%, 15% and 24%, respectively. Incidence of DILI was highest in Arm-2 (24.2%>Arm-3 (10.8%>Arm-1 (8.8%>Arm-4 (2.9%. Concomitant anti-TB-HIV therapy increased the risk of DILI by 10-fold than anti-TB alone (p<0.0001. HIV co-infection increased the risk of anti-TB DILI by 4-fold (p = 0.004. HAART associated DILI was 3-fold higher than anti-TB alone, (p = 0.02. HAART was associated with cholestatic and grade 1 DILI whereas anti-TB therapy was associated with hepatocellular and grade ≥ 2. Treatment type, lower CD4, platelet, hemoglobin, higher serum AST and direct bilirubin levels at baseline were significant DILI predictors. There was no effect of DILI on immunologic recovery or virologic suppression rate of HAART. CONCLUSION: HAART associated DILI is mainly cholestatic and mild whereas hepatocellular or mixed pattern with high severity grade is more common in anti-tuberculosis DILI. TB-HIV co-infection, disease severity

  18. Toxic shock syndrome

    Science.gov (United States)

    Staphylococcal toxic shock syndrome; Toxic shock-like syndrome; TSLS ... Toxic shock syndrome is caused by a toxin produced by some types of staphylococcus bacteria. A similar problem, called toxic shock- ...

  19. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    all chemicals and impact pathways characterizes the contribution of each factor to the total variation of 10–12 orders of magnitude in impacts per kg across all chemicals. This large variation between characterisation factors for different chemicals as well as the 3 orders of magnitude uncertainty....... As a whole, the assessment of toxicity in LCA has progressed on a very sharp learning curve during the past 20 years. This rapid progression is expected to continue in the coming years, focusing more on direct exposure of workers to chemicals during manufacturing and of consumers during product use...

  20. Genomics and the prediction of xenobiotic toxicity

    International Nuclear Information System (INIS)

    Meyer, Urs-A.; Gut, Josef

    2002-01-01

    The systematic identification and functional analysis of human genes is revolutionizing the study of disease processes and the development and rational use of drugs. It increasingly enables medicine to make reliable assessments of the individual risk to acquire a particular disease, raises the number and specificity of drug targets and explains interindividual variation of the effectiveness and toxicity of drugs. Mutant alleles at a single gene locus for more than 20 drug metabolizing enzymes are some of the best studied individual risk factors for adverse drug reactions and xenobiotic toxicity. Increasingly, genetic polymorphisms of transporter and receptor systems are also recognized as causing interindividual variation in drug response and drug toxicity. However, pharmacogenetic and toxicogenetic factors rarely act alone; they produce a phenotype in concert with other variant genes and with environmental factors. Environmental factors may affect gene expression in many ways. For instance, numerous drugs induce their own and the metabolism of other xenobiotics by interacting with nuclear receptors such as AhR, PPAR, PXR and CAR. Genomics is providing the information and technology to analyze these complex situations to obtain individual genotypic and gene expression information to assess the risk of toxicity

  1. Hazards and Benefits of Drug Interaction

    Science.gov (United States)

    Labianca, Dominick A.

    1978-01-01

    Most cases of drug toxicity are direct consequences of drug misuse--either intentional or inadvertent. Discusses two types of drug interaction--synergistic and antagonistic. The former produces a combined effect greater than the sum of the effects of the individual drugs concerned; the latter is produced when the desired action of one drug is…

  2. Modern toxic antipersonnel projectiles.

    Science.gov (United States)

    Gaillard, Yvan; Regenstreif, Philippe; Fanton, Laurent

    2014-12-01

    In the spring of 1944, Kurt von Gottberg, the SS police chief in Minsk, was shot and injured by 2 Soviet agents. Although he was only slightly injured, he died 6 hours later. The bullets were hollow and contained a crystalline white powder. They were 4-g bullets, semi-jacketed in cupronickel, containing 28 mg of aconitine. They were later known as akonitinnitratgeschosse. The Sipo (the Nazi security police) then ordered a trial with a 9-mm Parabellum cartridge containing Ditran, an anticholinergic drug with hallucinogenic properties causing intense mental confusion. In later years, QNB was used and given the NATO code BZ (3-quinuclidinyl-benzylate). It was proven that Saddam Hussein had this weapon (agent 15) manufactured and used it against the Kurds. Serbian forces used the same type of weapon in the Bosnian conflict, particularly in Srebrenica.The authors go on to list the Cold War toxic weapons developed by the KGB and the Warsaw pact countries for the discreet elimination of dissidents and proindependence leaders who had taken refuge in the West. These weapons include PSZh-13 launchers, the Troika electronic sequential pistol, and the ingenious 4-S110T captive piston system designed by the engineer Stechkin. Disguised as a cigarette case, it could fire a silent charge of potassium cyanide. This rogues gallery also includes the umbrella rigged to inject a pellet of ricin (or another phytalbumin of similar toxicity, such as abrin or crotin) that was used to assassinate the Bulgarian writer and journalist Georgi Markov on September 7, 1978, in London.During the autopsy, the discovery of a bullet burst into 4 or 5 parts has to make at once suspecting the use of a toxic substance. Toxicological analysis has to look for first and foremost aconitine, cyanide, suxamethonium, Ditran, BZ, or one of the toxic phytalbumins. The use of such complex weapons has to make suspect a powerful organization: army, secret service, terrorism. The existence of the Russian UDAR spray

  3. Titanium pigment in tissues of drug addicts: report of 5 necropsied cases Pigmento de titânio em tecidos de toxicômanos: relatos de cinco casos necropsiados

    Directory of Open Access Journals (Sweden)

    Marcus Aurelho de Lima

    2004-01-01

    Full Text Available The aim of this report is to describe the anatomic-pathologic findings from necropsies of 5 drug addicts with titanium pigment in several organs after chronic intravenous injection of crushed propoxyphene hydrochloride tablets. Samples from liver, spleen, lungs, lymph nodes, and bone marrow were obtained, and after being grossly studied, they were submitted to evaluation using common light and polarized microscopy. In all 5 cases, a pigment with characteristics of titanium dioxide was found within tissue samples of the organs studied. Our findings suggest that research concerning titanium pigment within body tissues should be enhanced, considering the potential contribution of this morphologic data to forensic pathology.O objetivo deste relato é descrever os achados anatomopatológicos de cinco casos de toxicômanos com pigmento de titânio em vários órgãos, após injeção de comprimidos esmagados de cloridrato de propoxifeno. Foram obtidos fragmentos do fígado, baço, pulmões, linfonodos e medula óssea e, após a avaliação macroscópica, amostras foram submetidas à microscopia de luz comum e de luz polarizada. Em todos os cinco casos, foi encontrado um pigmento com características de dióxido de titânio nas amostras dos órgãos estudados. Nossos achados sugerem que a pesquisa sobre pigmento de titânio em tecidos corporais deva ser complementada, considerando-se a contribuição de dados morfológicos em Patologia Forense.

  4. Adverse ocular reactions to drugs.

    OpenAIRE

    Spiteri, M. A.; James, D. G.

    1983-01-01

    Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration.

  5. Salicylate toxicity model of tinnitus

    Directory of Open Access Journals (Sweden)

    Daniel eStolzberg

    2012-04-01

    Full Text Available Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs or aging which affects ~14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed.

  6. Nail toxicity induced by cancer chemotherapy.

    Science.gov (United States)

    Gilbar, Peter; Hain, Alice; Peereboom, Veta-Marie

    2009-09-01

    To provide a comprehensive literature review of chemotherapy-induced nail toxicity, including clinical presentation, implicated drugs and approaches for prevention and management. A search of MEDLINE and EMBASE (1966-2008) databases was conducted using the terms (and variations of the terms) antineoplastic agents, nails, nail toxicity, onycholysis, and paronychia. Bibliographies from selected articles were reviewed for appropriate references. The retrieved literature was reviewed to include all articles relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of chemotherapy-induced nail toxicity. Nail toxicity is a relatively uncommon adverse effect linked to a number of chemotherapeutic agents. Clinical presentation varies, depending on which nail structure is affected and the severity of the insult. Nail changes may involve all or some nails. Toxicity may be asymptomatic and limited to cosmetic concerns, however, more severe effects, involving pain and discomfort can occur. Taxanes and anthracyclines are the antineoplastic drug groups most commonly implicated. It is suggested that the administration schedule may influence the incidence of nail abnormalities, for example reported cases linked to the weekly administration of paclitaxel.Before instituting chemotherapy, patients should be educated regarding potential nail toxicities and strategies for prevention implemented. Management includes appropriate nail cutting, avoiding potential irritants, topical, or oral antimicrobials, and possibly cessation or dose reduction of the offending agent. Cryotherapy, through the application of frozen gloves or socks, has been beneficial in reducing docetaxel-induced nail toxicity and may be effective for other drugs.

  7. Distributed Structure Searchable Toxicity

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Distributed Structure Searchable Toxicity (DSSTox) online resource provides high quality chemical structures and annotations in association with toxicity data....

  8. Therapeutic drug monitoring of aminoglycosides in neonates

    NARCIS (Netherlands)

    Touw, Daniël J; Westerman, Elsbeth M; Sprij, Arwen J

    2009-01-01

    The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to

  9. Drug Facts

    Medline Plus

    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug ... Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug ...

  10. Toxic epidermal necrolysis.

    Science.gov (United States)

    Pereira, Frederick A; Mudgil, Adarsh Vijay; Rosmarin, David M

    2007-02-01

    Toxic epidermal necrolysis (TEN) is an unpredictable, life-threatening drug reaction associated with a 30% mortality. Massive keratinocyte apoptosis is the hallmark of TEN. Cytotoxic T lymphocytes appear to be the main effector cells and there is experimental evidence for involvement of both the Fas-Fas ligand and perforin/granzyme pathways. Optimal treatment for these patients remains to be clarified. Discontinuation of the offending drug and prompt referral to a burn unit are generally agreed upon steps. Beyond that, however, considerable controversy exists. Evidence both pro and con exists for the use of IVIG, systemic corticosteroid, and other measures. There is also evidence suggesting that combination therapies may be of value. All the clinical data, however, is anecdotal or based on observational or retrospective studies. Definitive answers are not yet available. Given the rarity of TEN and the large number of patients required for a study to be statistically meaningful, placebo controlled trials are logistically difficult to accomplish. The absence of an animal model further hampers research into this condition. This article reviews recent data concerning clinical presentation, pathogenesis and treatment of TEN. At the conclusion of this learning activity, participants should have acquired a more comprehensive knowledge of our current understanding of the classification, clinical presentation, etiology, pathophysiology, prognosis, and treatment of TEN.

  11. Therapeutic Drug Monitoring in Rheumatic Diseases

    Directory of Open Access Journals (Sweden)

    NG Hoi-Yan Alexandra

    2016-12-01

    Full Text Available The ultimate goal of treating rheumatic disease is to achieve rapid suppression of inflammation, while at the same time minimizing the toxicities from rheumatic drugs. Different patients have different individual pharmacokinetics that can affect the drug level. Moreover, different factors, such as renal function, age or even different underlying diseases, can affect the drug level. Therefore, giving the same dosage of drugs to different patients may result in different drug levels. This article will review the usefulness of therapeutic drug monitoring in maximizing drug efficacy, while reducing the risk of toxicities in Hydroxychloroquine, Mycophenolate Mofetil, Tacrolimus and Tumor Necrosis Factor inhibitors (TNF Inhibitors.

  12. Electrochemical studies of ropinirole, an anti-Parkinson's disease drug

    Indian Academy of Sciences (India)

    trochemical techniques have application to drug-protein. ∗. For correspondence ... drug bioavailability and toxicity tests. ... analysis ranging from the assay of drugs in bulk form, ... stability-indicating assays.13,14 Separation and quantifi-.

  13. DRUG INTERACTIONS WITH TUBERCULOSIS THERAPY

    African Journals Online (AJOL)

    Kurt

    ous toxicity and a low therapeutic index, where relatively small changes in drug level can have ... Paracetamol. Increased clearance of paracetamol ... Rifampicin reduces ritonavir levels by Monitoring of liver function advised ritonavir enzyme ...

  14. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  15. Drug Facts

    Medline Plus

    Full Text Available ... Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, ... Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug Use and Kids ...

  16. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Use and Families Drug Use and Kids Drug Use and Unborn Children Drug Use and ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used ...

  17. Drugs in breast milk.

    Science.gov (United States)

    Hervada, A R; Feit, E; Sagraves, R

    1978-09-01

    The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

  18. Recreational drugs of abuse.

    Science.gov (United States)

    Albertson, Timothy E

    2014-02-01

    The use of recreational drugs of abuse continues to expand without limitations to national boundaries, social status, race, or education. Beyond the prevalence of illicit drug use and dependence, their contribution to the global burden of disease and death are large and troubling. All medical providers should be aware of the evolving drugs of abuse and their medical and social consequences. In addition to heroin and stimulants such as cocaine and methamphetamine, new designer stimulants called "bath salts" and cannabinoids called "spice," along with the abuse of prescription drugs and volatile substances, are now widely recognized problems in many societies. The wide variety and continuingly expanding clinical manifestations of toxicity of recreational drugs of abuse is not widely appreciated by clinicians. This edition attempts to summarize six major classes of drugs of abuse and their clinical effects with special emphasis on their immunological and respiratory effects.

  19. Toxicity alarm: Case history

    International Nuclear Information System (INIS)

    Hogan, D.; Retallack, J.

    1993-01-01

    In late fall 1991, the Novacor petrochemical plant near Joffre, Alberta experienced a toxicity alarm, the first since its startup 14 years ago. Fish exposed to a normal toxicity test were stressed within 2 h and showed 100% mortality after 24 h. A history of the events leading up to, during, and after the toxicity alarm is presented. The major effluent sources were three cooling water systems. Although these sources are well characterized, the event causes were not immediately clear. Initial toxic screening indicated that one was very toxic, another moderately toxic, and the third not toxic at all. All three systems utilized the same chemical treatment program to avoid fouling: stabilized phosphates with minor variants. The most toxic of the cooling systems operated at 10-12 cycles, had three chemicals for biocide control, and had three makeup streams. Toxic and nontoxic system characteristics were compared. An in-depth modified toxicity identification and evaluation program was then performed to identify and evaluate the cause of the toxicity alarm for future prevention. The most probable causes of toxicity were identified by elimination. The combination of high numbers of cycles, hydrocarbons in the makeup water, and bromine added as an antifoulant resulted in formation of aromatic bromamines which are capable of causing the toxic condition experienced. 2 tabs

  20. Toxic substances handbook

    Science.gov (United States)

    Junod, T. L.

    1979-01-01

    Handbook, published in conjunction with Toxic Substances Alert Program at NASA Lewis Research Center, profiles 187 toxic chemicals in their relatively pure states and include 27 known or suspected carcinogens.

  1. Thermal Stress and Toxicity | Science Inventory | US EPA

    Science.gov (United States)

    Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at subthermoneutral temperatures of —22 °C. When exposed to chemical toxicants under these relatively cool conditions, rodents typically undergo a regulated hypothermic response, characterized by preference for cooler ambient temperatures and controlled reduction in core temperature. Reducing core temperature delays the clearance of most toxicants from the body; however, a mild hypothermia also improves recovery and survival from the toxicant. Raising ambient temperature to thermoneutrality and above increases the rate of clearance of the toxicant but also exacerbates toxicity. Furthermore, heat stress combined with work or exercise is likely to worsen toxicity. Body temperature of large mammals, including humans, does not decrease as much in response to exposure to a toxicant. However, heat stress tan nonetheless worsen toxic outcome in humans through a variety of mechanisms. For example, heat-induced sweating and elevation in skin blood flow accelerates uptake of some insecticides. Epidemiological studies suggest that thermal stress may exacerbate the toxicity of airborne pollutants such as ozone and particulate matter. Overall, translating results of studies in rodents to that of humans is a formidable

  2. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention.

    NARCIS (Netherlands)

    Vonkeman, Harald Erwin; van de Laar, Mart A F J

    2010-01-01

    Objectives: To discuss nonsteroidal anti-inflammatory drugs (NSAIDs), their history, development, mode of action, toxicities, strategies for the prevention of toxicity, and future developments. - Methods: Medline search for articles published up to 2007, using the keywords acetylsalicylic acid,

  3. Toxicity Studies of the Crude Aqueous Root Extract of Albizzia ...

    African Journals Online (AJOL)

    acer

    drugs commonly used today are of herbal origin. Higher ... stored in small, capped plastic container at ... Acute Toxicity Studies: The limit test dose, ..... may be due to factors other than kidney problem ... Protein (total protein) in serum, urine.

  4. Assessment of the Developmental Toxicity of Epidermal Growth ...

    African Journals Online (AJOL)

    developmental toxicity, using the embryonic stem cell test (EST), as well as ascertain how EGF ... differentiation of embryonic stem cells, EST was used to assess changes in different blastodermic ..... However, as an extraneous drug, it is worth.

  5. Evaluation of toxic effects of metformin hydrochloride and ...

    African Journals Online (AJOL)

    olayemitoyin

    Drug Metabolism and Toxicology Research Laboratories, Department of ... This study was designed to investigate the toxic effect of MET and GB in the Liver, kidney and testis of rats. Twenty one ..... glibenclamide on male reproductive system,.

  6. Drug Facts

    Medline Plus

    Full Text Available ... Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used Drugs in the Past Drug Use ... Videos Information About Drugs Alcohol ...

  7. Drug Allergy

    Science.gov (United States)

    ... Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days or ... you take the drug. Drugs commonly linked to allergies Although any drug can cause an allergic reaction, ...

  8. Metabolism related toxicity of diclofenac in yeast as model system

    NARCIS (Netherlands)

    van Leeuwen, J.S.; Vredenburg, G.; Dragovic, S.; Tjong, T.F.; Vos, J.C.; Vermeulen, N.P.E.

    2010-01-01

    Diclofenac is a widely used drug that can cause serious hepatotoxicity, which has been linked to metabolism by cytochrome P450s (P450). To investigate the role of oxidative metabolites in diclofenac toxicity, a model for P450-related toxicity was set up in Saccharomyces cerevisiae. We expressed a

  9. Toxic agents causing cerebellar ataxias.

    Science.gov (United States)

    Manto, Mario

    2012-01-01

    The cerebellum is particularly vulnerable to intoxication and poisoning, especially so the cerebellar cortex and Purkinje neurons. In humans, the most common cause of a toxic lesion to the cerebellar circuitry is alcohol related, but the cerebellum is also a main target of drug exposure (such as anticonvulsants, antineoplastics, lithium salts, calcineurin inhibitors), drug abuse and addiction (such as cocaine, heroin, phencyclidine), and environmental toxins (such as mercury, lead, manganese, toluene/benzene derivatives). Although data for the prevalence and incidence of cerebellar lesions related to intoxication and poisoning are still unknown in many cases, clinicians should keep in mind the list of agents that may cause cerebellar deficits, since toxin-induced cerebellar ataxias are not rare in daily practice. Moreover, the patient's status may require immediate therapies when the intoxication is life-threatening. 2012 Elsevier B.V. All rights reserved.

  10. Metabonomics and drug development.

    Science.gov (United States)

    Ramana, Pranov; Adams, Erwin; Augustijns, Patrick; Van Schepdael, Ann

    2015-01-01

    Metabolites as an end product of metabolism possess a wealth of information about altered metabolic control and homeostasis that is dependent on numerous variables including age, sex, and environment. Studying significant changes in the metabolite patterns has been recognized as a tool to understand crucial aspects in drug development like drug efficacy and toxicity. The inclusion of metabonomics into the OMICS study platform brings us closer to define the phenotype and allows us to look at alternatives to improve the diagnosis of diseases. Advancements in the analytical strategies and statistical tools used to study metabonomics allow us to prevent drug failures at early stages of drug development and reduce financial losses during expensive phase II and III clinical trials. This chapter introduces metabonomics along with the instruments used in the study; in addition relevant examples of the usage of metabonomics in the drug development process are discussed along with an emphasis on future directions and the challenges it faces.

  11. Thrombotic microangiopathy associated with Valproic acid toxicity.

    Science.gov (United States)

    Hebert, Sean A; Bohan, Timothy P; Erikson, Christian L; Swinford, Rita D

    2017-08-03

    Thrombotic microangiopathy (TMA) is a serious, sometimes life-threatening disorder marked by the presence of endothelial injury and microvascular thrombi. Drug-induced thrombotic microangiopathy (DI-TMA) is one specific TMA syndrome that occurs following drug exposure via drug-dependent antibodies or direct tissue toxicity. Common examples include calcineurin inhibitors Tacrolimus and Cyclosporine and antineoplastics Gemcitabine and Mitomycin. Valproic acid has not been implicated in DI-TMA. We present the first case of a patient meeting clinical criteria for DI-TMA following admission for valproic acid toxicity. An adolescent male with difficult to control epilepsy was admitted for impaired hepatic function while on valproic acid therapy. On the third hospital day, he developed severe metabolic lactic acidosis and multiorgan failure, prompting transfer to the pediatric intensive care unit. Progressive anemia and thrombocytopenia instigated an evaluation for thrombotic microangiopathy, where confirmed by concomitant hemolysis, elevated lactate dehydrogenase (LDH), low haptoglobin, and concurrent oliguric acute kidney injury. Thrombotic thrombocytopenic purpura was less likely with adequate ADAMTS13. Discontinuing valproic acid reversed the anemia, thrombocytopenia, and normalized the LDH and haptoglobin, supporting a drug-induced cause for the TMA. To the best of our knowledge, this is the first report of drug-induced TMA from valproic acid toxicity.

  12. Pharmacokinetic drug interactions of antimicrobial drugs : a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams

    NARCIS (Netherlands)

    Bolhuis, Mathieu S; Panday, Prashant N; Pranger, Arianna D; Kosterink, Jos G W; Alffenaar, Jan-Willem C

    2011-01-01

    Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug

  13. Toxic substances alert program

    Science.gov (United States)

    Junod, T. L.

    1978-01-01

    A toxicity profile is provided, of 187 toxic substances procured by NASA Lewis Research Center during a 3 1/2 year period, including 27 known or suspected carcinogens. The goal of the program is to assure that the center's health and safety personnel are aware of the procurement and use of toxic substances and to alert and inform the users of these materials as to the toxic characteristics and the control measures needed to ensure their safe use. The program also provides a continuing record of the toxic substances procured, who procured them, what other toxic substances the user has obtained in the past, and where similar materials have been used elsewhere at the center.

  14. Systemic toxicity of ropivacaine during ovine pregnancy.

    Science.gov (United States)

    Santos, A C; Arthur, G R; Pedersen, H; Morishima, H O; Finster, M; Covino, B G

    1991-07-01

    Ropivacaine is a new amide local anesthetic structurally related to bupivacaine and mepivacaine. Its potency and duration of action are similar to those of bupivacaine but its therapeutic index may be greater. Since pregnancy enhances the cardiotoxicity of bupivacaine, the current study was devised to compare the toxicity of ropivacaine in chronically instrumented nonpregnant and pregnant ewes during continuous intravenous infusion of the drug at the rate of 0.5 mg.kg-1.min-1. In all animals, symptoms of local anesthetic toxicity occurred in the usual order--convulsions, hypotension, apnea, and circulatory collapse. There were no significant differences between the two groups of animals in the doses and plasma concentrations of ropivacaine associated with each toxic manifestations. For example, circulatory collapse occurred at a mean dose of 11.3 +/- 1.1 mg.kg-1 in nonpregnant and 12.4 +/- 0.9 mg.kg-1 in pregnant animals, with corresponding plasma concentrations of 7.3 +/- 0.3 and 9.6 +/- 2.1 micrograms.ml-1 (P = not significant). Protein binding of ropivacaine in the concentration range associated with toxic manifestations was similar in sera obtained from nonpregnant and pregnant ewes. In conclusion, ovine pregnancy does not enhance the systemic toxicity of ropivacaine, possibly because of an absence of gestation-related increase in the availability of free drug.

  15. Potential enzyme toxicity of oxytetracycline to catalase

    International Nuclear Information System (INIS)

    Chi Zhenxing; Liu Rutao; Zhang Hao

    2010-01-01

    Oxytetracycline (OTC) is a kind of widely used veterinary drugs. The residue of OTC in the environment is potentially harmful. In the present work, the non-covalent toxic interaction of OTC with catalase was investigated by the fluorescence spectroscopy, UV-vis absorption and circular dichroism (CD) spectroscopy at physiological pH 7.4. OTC can interact with catalase to form a complex mainly by van der Waals' interactions and hydrogen bonds with one binding site. The association constants K were determined to be K 293K = 7.09 x 10 4 L mol -1 and K 311K = 3.31 x 10 4 L mol -1 . The thermodynamic parameters (ΔH o , ΔG o and ΔS o ) of the interaction were calculated. Based on the Foerster theory of non-radiative energy transfer, the distance between bound OTC and the tryptophan residues of catalase was determined to be 6.48 nm. The binding of OTC can result in change of the micro-environment of the tryptophan residues and the secondary structure of catalase. The activity of catalase was also inhibited for the bound OTC. This work establishes a new strategy to probe the enzyme toxicity of veterinary drug residues and is helpful for clarifying the molecular toxic mechanism of OTC in vivo. The established strategy can be used to investigate the potential enzyme toxicity of other small organic pollutants and drugs.

  16. VORICONAZOLE TOXICITY IN MULTIPLE PENGUIN SPECIES.

    Science.gov (United States)

    Hyatt, Michael W; Georoff, Timothy A; Nollens, Hendrik H; Wells, Rebecca L; Clauss, Tonya M; Ialeggio, Donna M; Harms, Craig A; Wack, Allison N

    2015-12-01

    Aspergillosis is a common respiratory fungal disease in penguins managed under human care. Triazole antifungal drugs, including itraconazole, are most commonly used for treatment; however, itraconazole treatment failures from drug resistance are becoming more common, requiring newer treatment options. Voriconazole, a newer triazole, is being used more often. Until recently, no voriconazole pharmacokinetic studies had been performed in penguins, leading to empiric dosing based on other avian studies. This has led to increased anecdotal reporting of apparent voriconazole toxicity in penguins. This report describes 18 probable and 6 suspected cases of voriconazole toxicity in six penguin species from nine institutions: 12 African penguins (Spheniscus demersus), 5 Humboldt penguins (Spheniscus humboldti), 3 Magellanic penguins (Spheniscus magellanicus), 2 gentoo penguins (Pygoscelis papua papua), 1 macaroni penguin (Eudyptes chrysolophus), and 1 emperor penguin (Aptenodytes forsteri). Observed clinical signs of toxicity included anorexia, lethargy, weakness, ataxia, paresis, apparent vision changes, seizure-like activity, and generalized seizures. Similar signs of toxicity have also been reported in humans, in whom voriconazole therapeutic plasma concentration for Aspergillus spp. infections is 2-6 μg/ml. Plasma voriconazole concentrations were measured in 18 samples from penguins showing clinical signs suggestive of voriconazole toxicity. The concentrations ranged from 8.12 to 64.17 μg/ml, with penguins having plasma concentrations above 30 μg/ml exhibiting moderate to severe neurologic signs, including ataxia, paresis, and seizures. These concentrations were well above those known to result in central nervous system toxicity, including encephalopathy, in humans. This case series highlights the importance of species-specific dosing of voriconazole in penguins and plasma therapeutic drug monitoring. Further investigation, including pharmacokinetic studies, is

  17. Therapeutic drug monitoring of atypical antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Grundmann Milan

    2014-12-01

    Full Text Available Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

  18. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  19. Drug Abuse

    Science.gov (United States)

    ... Cocaine Heroin Inhalants Marijuana Prescription drugs, including opioids Drug abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to ...

  20. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Kids Drug Use and Unborn Children Drug Use and Your Health Other Effects on ... Someone Find Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids ...

  2. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  3. Reverse Phase Protein Arrays for High-throughput Toxicity Screening

    DEFF Research Database (Denmark)

    Pedersen, Marlene Lemvig; Block, Ines; List, Markus

    High-throughput screening is extensively applied for identification of drug targets and drug discovery and recently it found entry into toxicity testing. Reverse phase protein arrays (RPPAs) are used widespread for quantification of protein markers. We reasoned that RPPAs also can be utilized...... beneficially in automated high-throughput toxicity testing. An advantage of using RPPAs is that, in addition to the baseline toxicity readout, they allow testing of multiple markers of toxicity, such as inflammatory responses, which do not necessarily cumulate in cell death. We used transfection of si......RNAs with known killing effects as a model system to demonstrate that RPPA-based protein quantification can serve as substitute readout of cell viability, hereby reliably reflecting toxicity. In terms of automation, cell exposure, protein harvest, serial dilution and sample reformatting were performed using...

  4. Toxicity of carbon nanotubes: A review.

    Science.gov (United States)

    Francis, Arul Prakash; Devasena, Thiyagarajan

    2018-03-01

    Carbon nanotubes (CNTs) are widely used in the aerospace, automotive, and electronics industries because of their stability, enhanced metallic, and electrical properties. CNTs are also being investigated for biomedical applications such as drug delivery systems and biosensors. However, the toxic potential of CNTs was reported in various cell lines and animal models. The toxicity depends on diverse properties of the CNTs, such as length, aspect ratio, surface area, degree of aggregation, purity, concentration, and dose. In addition, CNTs and/or associated contaminants were well known for oxidative stress, inflammation, apoptosis, pulmonary inflammation, fibrosis, and granuloma in lungs. The increased production of CNTs likely enhanced the possibility of its exposure in people. Studies on the toxicity of CNTs are mainly focused on the pulmonary effects after intratracheal administration, and only a few studies are reported about the toxicity of CNTs via other routes of exposure. So, it is essential to consider the chronic toxicity of CNTs before using them for various biomedical applications. This review focuses on the potential toxicities of CNTs.

  5. Drug interactions in primary health care in the George subdistrict ...

    African Journals Online (AJOL)

    2012-02-15

    Feb 15, 2012 ... Drug-drug interactions are a recognised cause of morbidity and mortality ..... or fatal if the interaction increases toxicity or reduces the intended effect of the ... antihypertensive effect of angiotensin-converting enzyme inhibitors ...

  6. Females and Toxic Leadership

    Science.gov (United States)

    2012-12-14

    labeled as toxic, can he or she be rehabilitated?; Are there leadership styles that can be promoted to combat toxic leadership?; and Are the senior...examines leadership styles that are favorable for female leaders, and offers Transformational/Adaptive leadership as a style promising rehabilitative tools

  7. A study on the toxicity of three radiosensitizers on retinoblastoma cells by MTT assay

    International Nuclear Information System (INIS)

    Yi Xianjin; Jin Yizun; Ding Li; Ni Zhou; Wang Wenji

    1994-01-01

    The toxicity of three radiosensitizers BSO, CM and RSU-1069 on retinoblastoma cells was determined and the efficiency of in vitro MTT assay on drug-screening for retinoblastoma was also evaluated. The results showed that the MTT assay is very useful. The toxicity of radiosensitizers on retinoblastoma cells is dependent on cell line characteristics, drug concentration and time of exposure to it

  8. Mechanisms of Phosphine Toxicity

    Directory of Open Access Journals (Sweden)

    Nisa S. Nath

    2011-01-01

    Full Text Available Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH3, the chemistry of phosphorus is central to its toxicity. The elements above and below phosphorus in the periodic table are nitrogen (N and arsenic (As, which also produce toxic hydrides, namely, NH3 and AsH3. The three hydrides cause related symptoms and similar changes to cellular and organismal physiology, including disruption of the sympathetic nervous system, suppressed energy metabolism and toxic changes to the redox state of the cell. We propose that these three effects are interdependent contributors to phosphine toxicity.

  9. Antiretroviral therapy: current drugs.

    Science.gov (United States)

    Pau, Alice K; George, Jomy M

    2014-09-01

    The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date. Published by Elsevier Inc.

  10. Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems.

    Science.gov (United States)

    Kumar, Santosh; Rao, P S S; Earla, Ravindra; Kumar, Anil

    2015-03-01

    Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse.

  11. Gut microbiota modulation of chemotherapy efficacy and toxicity

    OpenAIRE

    Alexander, James L.; Wilson, Ian D.; Teare, Julian; Marchesi, Julian Roberto; Nicholson, Jeremy K.; Kinross, James M.

    2017-01-01

    Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidenc...

  12. Electrosynthesis methods and approaches for the preparative production of metabolites from parent drugs

    NARCIS (Netherlands)

    Gül, Turan; Bischoff, Rainer; Permentier, Hjalmar

    2015-01-01

    Identification of potentially toxic metabolites is important for drug discovery and development. Synthesis of drug metabolites is typically performed by organic synthesis or enzymatic methods, but is not always straightforward. Electrochemical (EC) methods are increasingly used to study drug

  13. Soluble polymer conjugates for drug delivery.

    Science.gov (United States)

    Minko, Tamara

    2005-01-01

    The use of water-soluble polymeric conjugates as drug carriers offers several possible advantages. These advantages include: (1) improved drug pharmacokinetics; (2) decreased toxicity to healthy organs; (3) possible facilitation of accumulation and preferential uptake by targeted cells; (4) programmed profile of drug release. In this review, we will consider the main types of useful polymeric conjugates and their role and effectiveness as carriers in drug delivery systems.: © 2005 Elsevier Ltd . All rights reserved.

  14. Pediatric Toxic Shock Syndrome

    Directory of Open Access Journals (Sweden)

    Jennifer Yee

    2017-09-01

    Full Text Available Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of a pediatric patient with toxic shock syndrome. The case is also appropriate for teaching of medical students and advanced practice providers, as well as a review of the principles of crisis resource management, teamwork, and communication. Introduction: Toxic shock syndrome is a low-frequency, high-acuity scenario requiring timely identification and aggressive management. If patients suffering from this condition are managed incorrectly, they may progress into multi-organ dysfunction and potentially death. Toxic shock syndrome has been associated with Streptococcus and Staphylococcus aureus (Staph. Approximately half of Staph cases are associated with menstruation, which was first described in the 1970s-1980s and was associated with the use of absorbent tampons.1 Group A Streptococcus may cause complications such as necrotizing fasciitis and gangrenous myositis.2 Pediatric patients may present critically ill from toxic shock syndrome. Providers need to perform a thorough history and physical exam to discern the source of infection. Management requires aggressive care with antibiotics and IV fluids. Objectives: By the end of this simulation session, the learner will be able to: 1 Recognize toxic shock syndrome. 2 Review the importance of a thorough physical exam. 3 Discuss management of toxic shock syndrome, including supportive care and the difference in antibiotic choices for streptococcal and staphylococcal toxic shock syndrome. 4 Appropriately disposition a patient suffering from toxic shock syndrome. 5 Communicate effectively with team members and nursing staff during a resuscitation of a critically ill patient. Method: This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on toxic shock syndrome.

  15. Toxicity Estimation Software Tool (TEST)

    Science.gov (United States)

    The Toxicity Estimation Software Tool (TEST) was developed to allow users to easily estimate the toxicity of chemicals using Quantitative Structure Activity Relationships (QSARs) methodologies. QSARs are mathematical models used to predict measures of toxicity from the physical c...

  16. Toxic Amblyopia (Nutritional Amblyopia)

    Science.gov (United States)

    ... Generic and Brand Natural Products, Search Drug Interactions Pill Identifier Commonly searched drugs Aspirin Metformin Warfarin Tramadol Lactulose Ranitidine News & Commentary Recent News Strict Gun Laws Spare Young Lives: Study 'Smart Dresser' Might Help Alzheimer's Patients Clothe Themselves AHA: ...

  17. Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.

    Science.gov (United States)

    Yasinzai, Masoom; Khan, Momin; Nadhman, Akhtar; Shahnaz, Gul

    2013-10-01

    Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered.

  18. Alimentary, metabolic and toxic osteopathies in adults

    Energy Technology Data Exchange (ETDEWEB)

    Ellegast, H.H.

    1986-12-01

    Skeletal changes in deficient or badly balanced nutrition (alimentary osteopathies) and osseous changes accompanying chronic desease of internal organs and metabolic disorders (metabolic osteopathies) are discussed. Basically, the classical generalised skeletal changes such as osteoporosis, osteomalacia, fibroosteoclacia and sklerosis of the bone can occur in their pure form or as a combination of two or more of these disorders. Finally the exogenic toxic osteopathies are discussed, nowadays fluorosis being the most important. Other external factors may be drugs like methotrexate and antiepileptic medications.

  19. Novel Molecular Strategies Against Sulfur Mustard Toxicity

    Directory of Open Access Journals (Sweden)

    Zeki Ilker Kunak

    2012-04-01

    Full Text Available Among the available chemical warfare agents, sulfur mustard (SM, also known as mustard gas, has been widely used chemical weapon. In our laboratory, we have shown that, acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose polymerase activation and energy depletion within the affected cell. In spite of the knowledge about acute SM-induced cellular toxicity, unfortunately, it is not clear how mustard gas causes severe multi-organ damage years after even a single exposure. A variety of treatment modalities including antioxidants, anti-inflammatory drugs and others have resulted no promising results. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. The term epigenetic describes the study of inheritable alterations in gene expression that occur in the absence of changes in genome sequence. Therefore, epigenetic gene regulation requires molecular mechanisms that encode information in addition to the DNA base sequence and can be propagated through mitosis and meiosis. Our current understanding of epigenetic regulation of gene expression involves basically two classes of molecular mechanisms: histone modifications and DNA methylation. Preliminary evidence obtained from our laboratory reveals that exposure to mustards may not only cause nitro-oxidative stress and DNA (genetic damage, but epigenetic perturbations as well. Epigenetic therapy is a new and rapidly developing field in pharmacology. Epigenetic drugs alone or in combination with conventional drugs may prove to be a significant advance over the conventional drugs used to treat both acute and delayed SM toxicity. Future studies are urgently needed to clarify the mechanism of delayed SM-induced toxicity and novel treatment modalities. [TAF Prev Med Bull 2012; 11(2.000: 231-236

  20. Molecular basis of cadmium toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Nath, R; Prasad, R; Palinal, V K; Chopra, R K

    1984-01-01

    Cadmium has been shown to manifest its toxicity in human and animals by mainly accumulating in almost all of the organs. The kidney is the main target organ where it is concentrated mainly in the cortex. Environmental exposure of cadmium occurs via food, occupational industries, terrestrial and aquatic ecosystem. At molecular level, cadmium interferes with the utilization of essential metals e.g. Ca, Zn, Se, Cr and Fe and deficiencies of these essential metals including protein and vitamins, exaggerate cadmium toxicity, due to its increased absorption through the gut and greater retention in different organs as metallothionein (Cd-Mt). Cadmium transport, across the intestinal and renal brush border membrane vesicles, is carrier mediated and it competes with zinc and calcium. It has been postulated that cadmium shares the same transport system. Cadmium inhibits protein synthesis, carbohydrate metabolism and drug metabolizing enzymes in liver of animals. Chronic environmental exposure of cadmium produces hypertension in experimental animals. Functional changes accompanying cadmium nephropathy include low molecular weight proteinuria which is of tubular origin associated with excess excretion of proteins such as beta 2 microglobulin, metallothionein and high molecular weight proteinuria of glomerular origin (excretion of proteins such as albumin IgG, transferrin etc.). Recent data has shown that metallothionein is more nephrotoxic to animals. Cadmium is also toxic to central nervous system. It causes an alterations of cellular functions in lungs. Cadmium affects both humoral and cell mediated immune response in animals. Cadmium induces metallothionein in liver and kidney but under certain nutritional deficiencies like protein-calorie malnutrition and calcium deficiency, enhanced induction and greater accumulation of cadmium metallothionein has been observed.

  1. Amiodarone pulmonary toxicity: Case report

    Directory of Open Access Journals (Sweden)

    Vasić Nada

    2014-01-01

    Full Text Available Introduction. Amiodarone, an antiarrhythmic drug, which contains iodine compound, has a tendency to accumulate in some organs including the lungs. This is age, drug dosage and therapy duration dependent. Case Outline. We present a case of a 73-year-old man, a smoker, who was admitted as emergency case due to severe dyspnea, tachypnea with signs of cyanosis and respiratory insufficiency. Chest x-ray revealed bilateral diffuse pulmonary shadows in the middle and upper parts of the lungs, similar to those in tuberculosis. His illness history showed chronic obstructive pulmonary disease, arterial hypertension, and atrial fibrillation which has been treated with amiodarone for six years. Sputum smears were negative for mycobacteria, and by the diagnostic elimination method for specific, non-specific and malignant disease the diagnosis of amiodarone pulmonary toxicity was made. Fiberoptic bronchoscopy and pathohistological findings of bronchiolitis obliterans organizing pneumonia confirmed the diagnosis. As the first therapeutic approach, amiodarone therapy was stopped. Then, systemic therapy with methylprednisolone 21 (sodium succinate 40 mg i.v. daily during the first two weeks was initiated and continued with daily dose of methylprednisolone 30 mg orally during the next three months. The patient showed a marked subjective improvement during the first week, which was followed by the improvement of respiratory function and withdrawal of pulmonary changes with complete radiographic and CT resolution after eight months. Conclusion. Amiodarone pulmonary toxicity should be taken into consideration, especially in elderly patients with respiratory symptoms and pulmonary changes, even if only a low dose of amiodarone is administred over a longer time period.

  2. In silico assessment of the acute toxicity of chemicals: recent advances and new model for multitasking prediction of toxic effect.

    Science.gov (United States)

    Kleandrova, Valeria V; Luan, Feng; Speck-Planche, Alejandro; Cordeiro, M Natália D S

    2015-01-01

    The assessment of acute toxicity is one of the most important stages to ensure the safety of chemicals with potential applications in pharmaceutical sciences, biomedical research, or any other industrial branch. A huge and indiscriminate number of toxicity assays have been carried out on laboratory animals. In this sense, computational approaches involving models based on quantitative-structure activity/toxicity relationships (QSAR/QSTR) can help to rationalize time and financial costs. Here, we discuss the most significant advances in the last 6 years focused on the use of QSAR/QSTR models to predict acute toxicity of drugs/chemicals in laboratory animals, employing large and heterogeneous datasets. The advantages and drawbacks of the different QSAR/QSTR models are analyzed. As a contribution to the field, we introduce the first multitasking (mtk) QSTR model for simultaneous prediction of acute toxicity of compounds by considering different routes of administration, diverse breeds of laboratory animals, and the reliability of the experimental conditions. The mtk-QSTR model was based on artificial neural networks (ANN), allowing the classification of compounds as toxic or non-toxic. This model correctly classified more than 94% of the 1646 cases present in the whole dataset, and its applicability was demonstrated by performing predictions of different chemicals such as drugs, dietary supplements, and molecules which could serve as nanocarriers for drug delivery. The predictions given by the mtk-QSTR model are in very good agreement with the experimental results.

  3. Toxicity Reference Database

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Toxicity Reference Database (ToxRefDB) contains approximately 30 years and $2 billion worth of animal studies. ToxRefDB allows scientists and the interested...

  4. Toxics Release Inventory (TRI)

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Toxics Release Inventory (TRI) is a dataset compiled by the U.S. Environmental Protection Agency (EPA). It contains information on the release and waste...

  5. The classification and application of toxic Chinese materia medica.

    Science.gov (United States)

    Liu, Xinmin; Wang, Qiong; Song, Guangqing; Zhang, Guangping; Ye, Zuguang; Williamson, Elizabeth M

    2014-03-01

    Many important drugs in the Chinese materia medica (CMM) are known to be toxic, and it has long been recognized in classical Chinese medical theory that toxicity can arise directly from the components of a single CMM or may be induced by an interaction between combined CMM. Traditional Chinese Medicine presents a unique set of pharmaceutical theories that include particular methods for processing, combining and decocting, and these techniques contribute to reducing toxicity as well as enhancing efficacy. The current classification of toxic CMM drugs, traditional methods for processing toxic CMM and the prohibited use of certain combinations, is based on traditional experience and ancient texts and monographs, but accumulating evidence increasingly supports their use to eliminate or reduce toxicity. Modern methods are now being used to evaluate the safety of CMM; however, a new system for describing the toxicity of Chinese herbal medicines may need to be established to take into account those herbs whose toxicity is delayed or otherwise hidden, and which have not been incorporated into the traditional classification. This review explains the existing classification and justifies it where appropriate, using experimental results often originally published in Chinese and previously not available outside China. Copyright © 2013 John Wiley & Sons, Ltd.

  6. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The first time ...

  7. Study Drugs

    Science.gov (United States)

    ... to quit, they may have withdrawal symptoms like depression, thoughts of suicide, intense drug cravings, sleep problems, and fatigue. The health risks aren't the only downside to study drugs. Students caught with illegal prescription drugs may get suspended ...

  8. Drug Facts

    Medline Plus

    Full Text Available ... symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen ... to prescription drugs. The addiction slowly took over his life. I need different people around me. To ...

  10. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  11. Drug Facts

    Science.gov (United States)

    ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  12. Ecotoxicogenomic assessment of diclofenac toxicity in soil

    International Nuclear Information System (INIS)

    Chen, Guangquan; Braver, Michiel W. den; Gestel, Cornelis A.M. van; Straalen, Nico M. van; Roelofs, Dick

    2015-01-01

    Diclofenac is widely used as nonsteroidal anti-inflammatory drug leaving residues in the environment. To investigate effects on terrestrial ecosystems, we measured dissipation rate in soil and investigated ecotoxicological and transcriptome-wide responses in Folsomia candida. Exposure for 4 weeks to diclofenac reduced both survival and reproduction of F. candida in a dose-dependent manner. At concentrations ≥200 mg/kg soil diclofenac remained stable in the soil during a 21-day incubation period. Microarrays examined transcriptional changes at low and high diclofenac exposure concentrations. The results indicated that development and growth were severely hampered and immunity-related genes, mainly directed against bacteria and fungi, were significantly up-regulated. Furthermore, neural metabolic processes were significantly affected only at the high concentration. We conclude that diclofenac is toxic to non-target soil invertebrates, although its mode of action is different from the mammalian toxicity. The genetic markers proposed in this study may be promising early markers for diclofenac ecotoxicity. - Highlights: • Diclofenac is toxic to the non-target soil invertebrate Folsomia candida. • Diclofenac mainly caused mortality and thus only indirectly affected reproduction. • Diclofenac mode of action in F. candida was checked with gene expression profiling. • Diclofenac significantly affected development, growth and immune related processes. • Diclofenac nervous system activity in F. candida was different from that in mammals. - Diclofenac is toxic to non-target soil invertebrates with a mode of action clearly different from mammalian toxicity

  13. Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

    International Nuclear Information System (INIS)

    Diaz, Dolores; Ford, Kevin A.; Hartley, Dylan P.; Harstad, Eric B.; Cain, Gary R.; Achilles-Poon, Kirsten; Nguyen, Trung; Peng, Jing; Zheng, Zhong; Merchant, Mark; Sutherlin, Daniel P.; Gaudino, John J.; Kaus, Robert; Lewin-Koh, Sock C.; Choo, Edna F.; Liederer, Bianca M.; Dambach, Donna M.

    2013-01-01

    Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstrated by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.

  14. Identification of Chemical Toxicity Using Ontology Information of Chemicals

    Directory of Open Access Journals (Sweden)

    Zhanpeng Jiang

    2015-01-01

    Full Text Available With the advance of the combinatorial chemistry, a large number of synthetic compounds have surged. However, we have limited knowledge about them. On the other hand, the speed of designing new drugs is very slow. One of the key causes is the unacceptable toxicities of chemicals. If one can correctly identify the toxicity of chemicals, the unsuitable chemicals can be discarded in early stage, thereby accelerating the study of new drugs and reducing the R&D costs. In this study, a new prediction method was built for identification of chemical toxicities, which was based on ontology information of chemicals. By comparing to a previous method, our method is quite effective. We hope that the proposed method may give new insights to study chemical toxicity and other attributes of chemicals.

  15. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  16. Aptamers as Both Drugs and Drug-Carriers

    Directory of Open Access Journals (Sweden)

    Md. Ashrafuzzaman

    2014-01-01

    Full Text Available Aptamers are short nucleic acid oligos. They may serve as both drugs and drug-carriers. Their use as diagnostic tools is also evident. They can be generated using various experimental, theoretical, and computational techniques. The systematic evolution of ligands by exponential enrichment which uses iterative screening of nucleic acid libraries is a popular experimental technique. Theory inspired methodology entropy-based seed-and-grow strategy that designs aptamer templates to bind specifically to targets is another one. Aptamers are predicted to be highly useful in producing general drugs and theranostic drugs occasionally for certain diseases like cancer, Alzheimer’s disease, and so on. They bind to various targets like lipids, nucleic acids, proteins, small organic compounds, and even entire organisms. Aptamers may also serve as drug-carriers or nanoparticles helping drugs to get released in specific target regions. Due to better target specific physical binding properties aptamers cause less off-target toxicity effects. Therefore, search for aptamer based drugs, drug-carriers, and even diagnostic tools is expanding fast. The biophysical properties in relation to the target specific binding phenomena of aptamers, energetics behind the aptamer transport of drugs, and the consequent biological implications will be discussed. This review will open up avenues leading to novel drug discovery and drug delivery.

  17. Acute and subacute toxicity of 18F-FDG

    International Nuclear Information System (INIS)

    Dantas, Danielle Maia

    2013-01-01

    Before starting clinical trials of a new drug, it is necessary to perform a battery of safety tests for assessing human risk. Radiopharmaceuticals like any new drug must be tested taking into account its specificity, duration of treatment and especially the toxicity of both parties, the unlabeled molecule and its radionuclide, apart from impurities emanating from radiolysis. Regulatory agencies like the Food and Drug Administration - USA (FDA) and the European Medicine Agency (EMEA), establish guidelines for the regulation of production and research of radiopharmaceuticals. In Brazil the production of radiopharmaceuticals was not regulated until the end of 2009, when were established by the National Agency for Sanitary Surveillance (ANVISA) resolutions No. 63, which refers to the Good Manufacturing Practices of Radiopharmaceuticals and No. 64 which seeks the registration of record radiopharmaceuticals. To obtain registration of radiopharmaceuticals are necessary to prove the quality, safety, efficacy and specificity of the drug . For the safety of radiopharmaceuticals must be presented studies of acute toxicity, subacute and chronic toxicity as well as reproductive, mutagenic and carcinogenic. Nowadays IPEN-CNEN/SP produces one of the most important radiopharmaceutical of nuclear medicine, the 18 F-FDG, which is used in many clinical applications, particularly in the diagnosis and staging of tumors. The objective of this study was to evaluate the systemic toxicity (acute/ subacute) radiopharmaceutical 18 F-FDG in an in vivo test system, as recommended by the RDC No. 64, which will serve as a model for protocols toxicity of radiopharmaceuticals produced at IPEN. The following tests were performed: tests of acute and subacute toxicity, biodistribution studies of 18 F-FDG, comet assay and reproductive toxicity. In acute toxicity, healthy rats were injected . (author)

  18. Microfluidics for Antibiotic Susceptibility and Toxicity Testing

    Directory of Open Access Journals (Sweden)

    Jing Dai

    2016-10-01

    Full Text Available The recent emergence of antimicrobial resistance has become a major concern for worldwide policy makers as very few new antibiotics have been developed in the last twenty-five years. To prevent the death of millions of people worldwide, there is an urgent need for a cheap, fast and accurate set of tools and techniques that can help to discover and develop new antimicrobial drugs. In the past decade, microfluidic platforms have emerged as potential systems for conducting pharmacological studies. Recent studies have demonstrated that microfluidic platforms can perform rapid antibiotic susceptibility tests to evaluate antimicrobial drugs’ efficacy. In addition, the development of cell-on-a-chip and organ-on-a-chip platforms have enabled the early drug testing, providing more accurate insights into conventional cell cultures on the drug pharmacokinetics and toxicity, at the early and cheaper stage of drug development, i.e., prior to animal and human testing. In this review, we focus on the recent developments of microfluidic platforms for rapid antibiotics susceptibility testing, investigating bacterial persistence and non-growing but metabolically active (NGMA bacteria, evaluating antibiotic effectiveness on biofilms and combinatorial effect of antibiotics, as well as microfluidic platforms that can be used for in vitro antibiotic toxicity testing.

  19. Haloacetonitriles: metabolism and toxicity.

    Science.gov (United States)

    Lipscomb, John C; El-Demerdash, Ebtehal; Ahmed, Ahmed E

    2009-01-01

    The haloacetonitriles (HANs) exist in drinking water exclusively as byproducts of disinfection. HANs are found in drinking water more often, and in higher concentrations, when surface water is treated by chloramination. Human exposure occurs through consumption of finished drinking water; oral and dermal contact also occurs, and results from showering, swimming and other activities. HANs are reactive and are toxic to gastrointestinal tissues following oral administration. Such toxicity is characterized by GSH depletion, increased lipid peroxidation, and covalent binding of HAN-associated radioactivity to gut tissues. The presence of GSH in cells is an important protective mechanism against HAN toxicity; depletion of cellular GSH results in increased toxicity. Some studies have demonstrated an apparently synergistic effect between ROS and HAN administration, that may help explain effects observed in GI tissues. ROS are produced in gut tissues, and in vitro evidence indicates that ROS may contribute to the degradation and formation of reactive intermediates from HANs. The rationale for ROS involvement may involve HAN-induced depletion of GSH and the role of GSH in scavenging ROS. In addition to effects on GI tissues, studies show that HAN-derived radiolabel is found covalently bound to proteins and DNA in several organs and tissues. The addition of antioxidants to biologic systems protects against HAN-induced DNA damage. The protection offered by antioxidants supports the role of oxidative stress and the potential for a threshold in han-induced toxicity. However, additional data are needed to substantiate evidence for such a threshold. HANs are readily absorbed from the GI tract and are extensively metabolized. Elimination occurs primarily in urine, as unconjugated one-carbon metabolites. Evidence supports the involvement of mixed function oxidases, the cytochrome P450 enzyme family and GST, in HAN metabolism. Metabolism represents either a detoxification or

  20. Emerging drugs of abuse.

    Science.gov (United States)

    Nelson, Michael E; Bryant, Sean M; Aks, Steven E

    2014-02-01

    Many new emerging drugs of abuse are marketed as legal highs despite being labeled "not for human consumption" to avoid regulation. The availability of these substances over the Internet and in "head shops" has lead to a multitude of emergency department visits with severe complications including deaths worldwide. Despite recent media attention, many of the newer drugs of abuse are still largely unknown by health care providers. Slight alterations of the basic chemical structure of substances create an entirely new drug no longer regulated by current laws and an ever-changing landscape of clinical effects. The purity of each substance with exact pharmacokinetic and toxicity profiles is largely unknown. Many of these substances can be grouped by the class of drug and includes synthetic cannabinoids, synthetic cathinones, phenethylamines, as well as piperazine derivatives. Resultant effects generally include psychoactive and sympathomimetic-like symptoms. Additionally, prescription medications, performance enhancing medications, and herbal supplements are also becoming more commonly abused. Most new drugs of abuse have no specific antidote and management largely involves symptom based goal directed supportive care with benzodiazepines as a useful adjunct. This paper will focus on the history, epidemiology, clinical effects, laboratory analysis, and management strategy for many of these emerging drugs of abuse. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  2. Drug Facts

    Medline Plus

    Full Text Available ... 4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from drugs. But she's afraid ...

  3. Medical Applications and Toxicities of Gallium Compounds

    Directory of Open Access Journals (Sweden)

    Christopher R. Chitambar

    2010-05-01

    Full Text Available Over the past two to three decades, gallium compounds have gained importance in the fields of medicine and electronics. In clinical medicine, radioactive gallium and stable gallium nitrate are used as diagnostic and therapeutic agents in cancer and disorders of calcium and bone metabolism. In addition, gallium compounds have displayed anti-inflammatory and immunosuppressive activity in animal models of human disease while more recent studies have shown that gallium compounds may function as antimicrobial agents against certain pathogens. In a totally different realm, the chemical properties of gallium arsenide have led to its use in the semiconductor industry. Gallium compounds, whether used medically or in the electronics field, have toxicities. Patients receiving gallium nitrate for the treatment of various diseases may benefit from such therapy, but knowledge of the therapeutic index of this drug is necessary to avoid clinical toxicities. Animals exposed to gallium arsenide display toxicities in certain organ systems suggesting that environmental risks may exist for individuals exposed to this compound in the workplace. Although the arsenic moiety of gallium arsenide appears to be mainly responsible for its pulmonary toxicity, gallium may contribute to some of the detrimental effects in other organs. The use of older and newer gallium compounds in clinical medicine may be advanced by a better understanding of their mechanisms of action, drug resistance, pharmacology, and side-effects. This review will discuss the medical applications of gallium and its mechanisms of action, the newer gallium compounds and future directions for development, and the toxicities of gallium compounds in current use.

  4. Antibacterial properties and toxicity from metallic nanomaterials

    Directory of Open Access Journals (Sweden)

    Vimbela GV

    2017-05-01

    Full Text Available Gina V Vimbela,1,* Sang M Ngo,2,* Carolyn Fraze,3 Lei Yang,4,5 David A Stout5–7 1Department of Chemical Engineering, 2Department of Electrical Engineering, California State University, Long Beach, CA, 3Brigham Young University Idaho, Rexburg, ID, USA; 4Department of Orthopaedics, Orthopaedic Institute, The First Affiliated Hospital, 5International Research Center for Translational Orthopaedics (IRCTO, Soochow University, Suzhou, Jiangsu, People’s Republic of China; 6Department of Mechanical and Aerospace Engineering, 7Department of Biomedical Engineering, California State University, Long Beach, CA, USA *These authors contributed equally to this work Abstract: The era of antibiotic resistance is a cause of increasing concern as bacteria continue to develop adaptive countermeasures against current antibiotics at an alarming rate. In recent years, studies have reported nanoparticles as a promising alternative to antibacterial reagents because of their exhibited antibacterial activity in several biomedical applications, including drug and gene delivery, tissue engineering, and imaging. Moreover, nanomaterial research has led to reports of a possible relationship between the morphological characteristics of a nanomaterial and the magnitude of its delivered toxicity. However, conventional synthesis of nanoparticles requires harsh chemicals and costly energy consumption. Additionally, the exact relationship between toxicity and morphology of nanomaterials has not been well established. Here, we review the recent advancements in synthesis techniques for silver, gold, copper, titanium, zinc oxide, and magnesium oxide nanomaterials and composites, with a focus on the toxicity exhibited by nanomaterials of multidimensions. This article highlights the benefits of selecting each material or metal-based composite for certain applications while also addressing possible setbacks and the toxic effects of the nanomaterials on the environment. Keywords

  5. Potential enzyme toxicity of oxytetracycline to catalase

    Energy Technology Data Exchange (ETDEWEB)

    Zhenxing, Chi; Rutao, Liu; Zhang Hao, E-mail: Trutaoliu@sdu.edu.cn [School of Environmental Science and Engineering, Shandong University, China-America CRC for Environment and Health, Shandong Province, 27 Shanda South Road, Jinan 250100 (China)

    2010-10-15

    Oxytetracycline (OTC) is a kind of widely used veterinary drugs. The residue of OTC in the environment is potentially harmful. In the present work, the non-covalent toxic interaction of OTC with catalase was investigated by the fluorescence spectroscopy, UV-vis absorption and circular dichroism (CD) spectroscopy at physiological pH 7.4. OTC can interact with catalase to form a complex mainly by van der Waals' interactions and hydrogen bonds with one binding site. The association constants K were determined to be K{sub 293K} = 7.09 x 10{sup 4} L mol{sup -1} and K{sub 311K} = 3.31 x 10{sup 4} L mol{sup -1}. The thermodynamic parameters ({Delta}H{sup o}, {Delta}G{sup o} and {Delta}S{sup o}) of the interaction were calculated. Based on the Foerster theory of non-radiative energy transfer, the distance between bound OTC and the tryptophan residues of catalase was determined to be 6.48 nm. The binding of OTC can result in change of the micro-environment of the tryptophan residues and the secondary structure of catalase. The activity of catalase was also inhibited for the bound OTC. This work establishes a new strategy to probe the enzyme toxicity of veterinary drug residues and is helpful for clarifying the molecular toxic mechanism of OTC in vivo. The established strategy can be used to investigate the potential enzyme toxicity of other small organic pollutants and drugs.

  6. Emerging Frontiers in Drug Delivery.

    Science.gov (United States)

    Tibbitt, Mark W; Dahlman, James E; Langer, Robert

    2016-01-27

    Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.

  7. The toxicity of plutonium

    International Nuclear Information System (INIS)

    Crouse, P.L.

    1994-01-01

    Shipments of plutonium occasionally pass around the Cape coastal waters on its way to Japan from Europe. This invariably leads to a great deal of speculation of the dangers involved and of the extreme toxicity of plutonium, with the media and environmental groups claiming that (a) plutonium is the most toxic substance known to man, and that (b) a few kilograms of plutonium ground finely and dispersed in the atmosphere could kill every human being on earth. Comparisons with other poisons are drawn, e.g. common inorganic chemicals and biological agents. The original scare around the extraordinary toxicity of Pu seems to have started in 1974 with the claims of Tamplin and Cochran's hot particle theory about plutonium lodging in the sensitive portions of the lungs in small concentrated aggregates where they are much more effective in producing cancers. This theory, however, is regarded as thoroughly discredited by the experts in the field of radiotoxicity. 8 refs

  8. Iron metabolism and toxicity

    International Nuclear Information System (INIS)

    Papanikolaou, G.; Pantopoulos, K.

    2005-01-01

    Iron is an essential nutrient with limited bioavailability. When present in excess, iron poses a threat to cells and tissues, and therefore iron homeostasis has to be tightly controlled. Iron's toxicity is largely based on its ability to catalyze the generation of radicals, which attack and damage cellular macromolecules and promote cell death and tissue injury. This is lucidly illustrated in diseases of iron overload, such as hereditary hemochromatosis or transfusional siderosis, where excessive iron accumulation results in tissue damage and organ failure. Pathological iron accumulation in the liver has also been linked to the development of hepatocellular cancer. Here we provide a background on the biology and toxicity of iron and the basic concepts of iron homeostasis at the cellular and systemic level. In addition, we provide an overview of the various disorders of iron overload, which are directly linked to iron's toxicity. Finally, we discuss the potential role of iron in malignant transformation and cancer

  9. Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

    Science.gov (United States)

    Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

    2017-01-01

    Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.

  10. Addressing the selectivity and toxicity of antiviral nucleosides.

    Science.gov (United States)

    Feng, Joy Y

    2018-01-01

    Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies.

  11. How Many Drugs Are Catecholics

    Directory of Open Access Journals (Sweden)

    Da-Peng Yang

    2007-04-01

    Full Text Available By examination of the 8659 drugs recorded in the Comprehensive Medicinal Chemistry (CMC database, 78 catecholics (including five pyrogallolics were identified, of which 17 are currently prescribed by FDA. Through analyzing the substitutent patterns, ClogPs and O-H bond dissociation enthalpies(BDEs of the catecholic drugs, some molecular features that may benefit circumventing the toxicity of catecholics were revealed: i strong electron-donating substituents are excluded; ii ClogP 3; iii an energy penalty exists for quinone formation. Besides, the present analyses also suggest that the clinical usage and dosage of currently prescribed catecholic drugs are of importance in designing or screening catecholic antioxidants.

  12. Drug interactions between common illicit drugs and prescription therapies.

    Science.gov (United States)

    Lindsey, Wesley T; Stewart, David; Childress, Darrell

    2012-07-01

    The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug-drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

  13. The use of antimicrobial drugs in agriculture.

    Science.gov (United States)

    Black, W D

    1984-08-01

    Antibacterial drugs have been used widely in animal production for treatment and prevention of disease and for growth promotion. Concern has been expressed about possible harm to humans, through the use of drugs, in the following ways: increased microbial drug resistance; drug residues in food; allergic reactions and sensitization to antimicrobials; and drug toxicity. Research has shown that microbial resistance in people can develop from drugs used in animals. Farmers, butchers, etc., have been shown to have an increased incidence of drug-resistant organisms. Resistance to antibiotics can develop in two ways; genetic mutation and natural selection, and through R-factor plasmid transfer. Allergic reactions have been reported following the ingestion of penicillin-containing milk; however, residues in other foods have not caused allergic reactions. Sensitization of humans to antimicrobials through the consumption of drug residues in foods has never been documented. Evidence suggests that the residue levels in food are too low to cause sensitization. Drug toxicity, other than allergic reactions, appears not to result from residues of antimicrobial drugs in food. While it has been studied many times, monitoring programs have failed to find any evidence of a problem. This appears to reflect the low toxicity of these agents and the small amounts obtained in the food, however, it could also reflect failure of the monitoring systems.

  14. Indolealkylamines: biotransformations and potential drug-drug interactions.

    Science.gov (United States)

    Yu, Ai-Ming

    2008-06-01

    Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug-drug interactions (DDIs). A stable, principal metabolite of an IAA drug of abuse could serve as a useful biomarker in assessing intoxication of the IAA substance. Studies on the metabolism of IAA drugs of abuse including lysergic acid amides, tryptamine derivatives and beta-carbolines are therefore emerging. An important role for polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of IAA drugs of abuse has been revealed by recent studies, suggesting that variations in IAA metabolism, pharmaco- or toxicokinetics and dynamics can arise from distinct CYP2D6 status, and CYP2D6 polymorphism may represent an additional risk factor in the use of these IAA drugs. Furthermore, DDIs with IAA agents could occur additively at the pharmaco/toxicokinetic and dynamic levels, leading to severe or even fatal serotonin toxicity. In this review, the metabolism and potential DDIs of these therapeutic and abused IAA drugs are described.

  15. Test systems to identify reproductive toxicants.

    Science.gov (United States)

    Riecke, K; Stahlmann, R

    2000-09-01

    Experience with drugs and other xenobiotics indicates that both animal testing and epidemiological studies are necessary to provide adequate data for an estimation of risks that might be associated with exposure to a chemical substance. In this review, the pros and cons of test systems for reproductive toxicity are discussed. Usually, several studies are performed to cover the different phases of the reproductive cycle. In the preclinical development of drugs, the three so-called 'segment testing protocols' have been used for several decades now. More recently, new testing concepts have been accepted internationally which include more flexibility in implementation. Several examples of compounds with the potential for reproductive toxicity are presented in more detail in a discussion of some pitfalls of the tests for fertility (phthalates and fluoroquinolones), teratogenicity (acyclovir and protease inhibitors) and postnatal developmental toxicity (fluoroquinolones). In addition, important aspects of kinetics and metabolism as a prerequisite for a rational interpretation of results from toxicological studies are briefly discussed. In vitro assays are useful for supplementing the routinely used in vivo approaches or for studying an expected or defined effect, but they are not suitable for revealing an unknown effect of a chemical on the complex reproductive process.

  16. Radiation and platinum drug interaction

    International Nuclear Information System (INIS)

    Nias, A.H.W.

    1985-01-01

    The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. Electron-affinic agents are employed with this aim, but the commoner platinum drugs are only weakly electron-affinic. They do have a quasi-alkylating action however, and this DNA targeting may account for the radiosensitizing effect which occurs with both pre- and post-radiation treatments. Because toxic drug dosage is usually required for this, the evidence of the biological responses to the drug and to the radiation, as well as to the combination, requires critical analysis before any claim of true enhancement, rather than simple additivity, can be accepted. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships. (author)

  17. Substance use - prescription drugs

    Science.gov (United States)

    Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance ...

  18. Classification and occurrence of clinically significant drug interactions with irinotecan and oxaliplatin in patients with metastatic colorectal cancer

    NARCIS (Netherlands)

    Jansman, FGA; Idzinga, FSF; Smit, WM; de Graaf, JC; Coenen, JLLM; Sleijfer, DT; Brouwers, JRBJ

    Background: Pharmacokinetic and pharmacodynamic drug interactions with cytotoxic drugs may significantly influence the efficacy and toxicity of chemotherapy. Objective: The purpose of this study was to identify drug interactions with irinotecan and oxaliplatin reported in the literature, to assess

  19. External radiation toxicity

    International Nuclear Information System (INIS)

    Fritz, T.E.

    1979-01-01

    The section contains summaries of research on neutron and gamma-ray toxicity in rodents, late effects of low-dose rate, whole-body, protracted exposure to 60 Co gamma rays on young adult beagles, and the effects of protracted, low-dose rate exposure to 60 Co gamma rays on preclinical leukemic phase-related changes in the granulopoietic system of beagles

  20. Toxicity of lunar dust

    NARCIS (Netherlands)

    Linnarsson, D.; Carpenter, J.; Fubini, B.; Gerde, P.; Loftus, D.; Prisk, K.; Staufer, U.; Tranfield, E.; van Westrenen, W.

    2012-01-01

    The formation, composition and physical properties of lunar dust are incompletely characterised with regard to human health. While the physical and chemical determinants of dust toxicity for materials such as asbestos, quartz, volcanic ashes and urban particulate matter have been the focus of

  1. Uranium: biokinetics and toxicity

    International Nuclear Information System (INIS)

    Menetrier, F.; Renaud-Salis, V.; Flury-Herard, A.

    2000-01-01

    This report was achieved as a part of a collaboration with the Fuel Cycle Direction. Its aim was to give the state of the art about: the behaviour of uranium in the human organism (biokinetics) after ingestion, its toxicity (mainly renal) and the current regulation about its incorporation. Both in the upstream and in the downstream of the fuel cycle, uranium remains, quantitatively, the first element in the cycle which is, at the present time, temporarily disposed or recycled. Such a considerable quantity of uranium sets the problem of its risk on the health. In the long term, the biosphere may be affected and consequently the public may ingest water or food contaminated with uranium. In this way, radiological and chemical toxicity risk may be activated. This report emphasizes: the necessity of confirming some experimental and epidemiological biokinetic data used or not in the ICRP models. Unsolved questions remain about the gastrointestinal absorption according to chemical form (valency state, mixtures...), mass and individual variations (age, disease) further a chronic ingestion of uranium. It is well established that uranium is mainly deposited in the skeleton and the kidney. But the skeleton kinetics following a chronic ingestion and especially in some diseases has to be more elucidated; the necessity of taking into account uranium at first as a chemical toxic, essentially in the kidney and determining the threshold of functional lesion. In this way, it is important to look for some specific markers; the problem of not considering chemical toxicity of uranium in the texts regulating its incorporation

  2. Monosodium Glutamate Toxicity

    African Journals Online (AJOL)

    Dr Olaleye

    The brain is reportedly sensitive to monosodium glutamate (MSG) toxicity via oxidative stress. Sida acuta leaf ethanolic .... wherein the right hemisphere, was preserved for histology and fixed in 10% ... Biochemical Assays: The left hemisphere of the brain samples was ...... development in male and female rats. Exp Physiol.

  3. Nanomaterials and Retinal Toxicity

    Science.gov (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  4. Toxic Hazards in Aviation.

    Science.gov (United States)

    1981-04-01

    Pasteur, Lillm,FRANCE. (2) CONISH H.H., EARTH M.L.& IANNi F.L, "Comparative Toxicology of Platics during Thar-modecoqiorition Intsw-re8posium on...Pyrolysnis and Combustion of Materials" Firm and Materials (1976).1, 29-35 (8) ALAAIE Y."Toxicity of Platic dacomposition ProductsŖd Annu~al Progress

  5. Emerging technologies and challenges for better and safer drugs.

    Science.gov (United States)

    Theodosiou, Maria; Amir-Aslani, Arsia; Mégarbane, Bruno

    2014-04-01

    Regardless of stringent safety regulations and increased compound selectivity by pharmaceutical companies, prediction of toxicity in humans is still far from perfect and adverse drug reactions are still detected after drug marketing. High costs of failures due to toxicity has led pharmaceutical companies to search for screening methods that would allow detection of toxicity issues at an early stage and improve their preclinical and clinical toxicology. Thanks to the last decade's biotechnology revolution, new technologies like toxicogenomics have demonstrated the capacity to improve toxicity assessment. However, our understanding of toxicological mechanisms is still incomplete and a wide range of approaches must be used to gain insight into toxicity issues. Consequently, an array of in silico, in vitro and in vivo methods is utilized to predict toxicity and its causative mechanisms, improving drug development processes and minimizing costs of failure.

  6. Nanosuspension Technology for Solubilizing Poorly Soluble Drugs

    OpenAIRE

    Deoli Mukesh

    2012-01-01

    Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. It is estimated that around 40% of drugs in the pipeline cannot be delivered through the preferred route or in some cases, at all owing to poor water solubility. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor1 EL). To date, nanoscale systems f...

  7. Ultrasound-guided drug delivery in cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chowdhury, Sayan Mullick; Lee, Tae Hwa; Willmann, Jugen K. [Dept. of Radiology, Stanford University School of Medicine, Stanford (United States)

    2017-07-15

    Recent advancements in ultrasound and microbubble (USMB) mediated drug delivery technology has shown that this approach can improve spatially confined delivery of drugs and genes to target tissues while reducing systemic dose and toxicity. The mechanism behind enhanced delivery of therapeutics is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. In this review, progress and challenges of USMB mediated drug delivery are summarized, with special focus on cancer therapy.

  8. Ultrasound-guided drug delivery in cancer

    Directory of Open Access Journals (Sweden)

    Sayan Mullick Chowdhury

    2017-07-01

    Full Text Available Recent advancements in ultrasound and microbubble (USMB mediated drug delivery technology has shown that this approach can improve spatially confined delivery of drugs and genes to target tissues while reducing systemic dose and toxicity. The mechanism behind enhanced delivery of therapeutics is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. In this review, progress and challenges of USMB mediated drug delivery are summarized, with special focus on cancer therapy.

  9. Estimation of toxicity using the Toxicity Estimation Software Tool (TEST)

    Science.gov (United States)

    Tens of thousands of chemicals are currently in commerce, and hundreds more are introduced every year. Since experimental measurements of toxicity are extremely time consuming and expensive, it is imperative that alternative methods to estimate toxicity are developed.

  10. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can ...

  11. Prescription Drugs

    Science.gov (United States)

    ... different competition is going on: the National Football League (NFL) vs. drug use. Read More » 92 Comments ... Future survey highlights drug use trends among the Nation’s youth for marijuana, alcohol, cigarettes, e-cigarettes (e- ...

  12. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  13. Drug Facts

    Medline Plus

    Full Text Available ... form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts ... addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain ...

  14. Drug Facts

    Medline Plus

    Full Text Available ... Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of ... Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1- ...

  15. Drug Control

    Science.gov (United States)

    Leviton, Harvey S.

    1975-01-01

    This article attempts to assemble pertinent information about the drug problem, particularily marihuana. It also focuses on the need for an educational program for drug control with the public schools as the main arena. (Author/HMV)

  16. Drug Facts

    Medline Plus

    Full Text Available ... Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs ... Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call ...

  17. Drug Facts

    Medline Plus

    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of someone ... use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted ...

  18. Drug Facts

    Medline Plus

    Full Text Available ... Numbers and Websites Search Share Listen English Español Information about this page Click on the button that ... about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana ...

  19. Drug Facts

    Medline Plus

    Full Text Available ... Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) ... treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice ( ...

  20. Drug Facts

    Medline Plus

    Full Text Available ... call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I ... The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , the ...

  1. Orphan drugs

    OpenAIRE

    Goločorbin-Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojša; Mikov, Momir

    2013-01-01

    Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ”adopting” them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of ...

  2. Toxic spongiform leucoencephalopathy after inhaling heroin vapour

    Energy Technology Data Exchange (ETDEWEB)

    Weber, W.; Henkes, H.; Kuehne, D. [Klinik fuer Allgemeine Roentgendiagnostik und Neuroradiologie, Alfried-Krupp-Krankenhaus, Alfried Krupp Strasse 21, D-45117, Essen (Germany); Moeller, P.; Bade, K. [Neurologische Klinik, Knappschafts-Krankenhaus, D-45657 Recklinghausen (Germany)

    1998-06-02

    This is a report of clinical, CT and MRI findings in a patient with toxic spongiform leucoencephalopathy after heroin ingestion. The disease is observed in drug addicts who inhale pre-heated heroin. The clinical onset, which usually occurs some days or even longer after the last heroin consumption, is characterized by a cerebellar syndrome. The cerebellar hemispheres, the cerebellar and cerebral peduncles and the pyramidal tract may be affected. Spongiform demyelination is the morphological substrate of the lesions, which are not contrast enhancing, hypodense on CT and hyperintense on T2-weighted MRI. The frequently perfect symmetry of the affection of functional systems points to a toxic and/or metabolic pathophysiological mechanism. (orig.) With 2 figs., 2 tabs., 26 refs.

  3. Toxic spongiform leucoencephalopathy after inhaling heroin vapour

    International Nuclear Information System (INIS)

    Weber, W.; Henkes, H.; Kuehne, D.; Moeller, P.; Bade, K.

    1998-01-01

    This is a report of clinical, CT and MRI findings in a patient with toxic spongiform leucoencephalopathy after heroin ingestion. The disease is observed in drug addicts who inhale pre-heated heroin. The clinical onset, which usually occurs some days or even longer after the last heroin consumption, is characterized by a cerebellar syndrome. The cerebellar hemispheres, the cerebellar and cerebral peduncles and the pyramidal tract may be affected. Spongiform demyelination is the morphological substrate of the lesions, which are not contrast enhancing, hypodense on CT and hyperintense on T2-weighted MRI. The frequently perfect symmetry of the affection of functional systems points to a toxic and/or metabolic pathophysiological mechanism. (orig.)

  4. Acute Liver Failure Secondary to Niacin Toxicity

    Directory of Open Access Journals (Sweden)

    Marc A. Ellsworth

    2014-01-01

    Full Text Available A 17-year-old male was transferred to the pediatric intensive care unit for evaluation of acute liver failure. He was recently released from an alcohol treatment center with acute onset of chest pain. Cardiac workup was negative but he was found to have abnormal coagulation studies and elevated liver transaminases. Other evaluations included a normal toxicology screen and negative acetaminophen level. Autoimmune and infectious workups were normal providing no identifiable cause of his acute liver failure. He initially denied any ingestions or illicit drug use but on further query he admitted taking niacin in an attempt to obscure the results of an upcoming drug test. Niacin has been touted on the Internet as an aid to help pass urine drug tests though there is no evidence to support this practice. Niacin toxicity has been associated with serious multisystem organ failure and fulminant hepatic failure requiring liver transplantation. Pediatric providers should be aware of the risks associated with niacin toxicity and other experimental medical therapies that may be described on the Internet or other nonreputable sources.

  5. Drug Testing

    Science.gov (United States)

    ... testing, substance abuse testing, toxicology screen, tox screen, sports doping tests What is it used for? Drug screening is used to find out whether or not a person has taken a certain drug or drugs. It ... Sports organizations. Professional and collegiate athletes usually need to ...

  6. Drug Facts

    Medline Plus

    Full Text Available ... to main content Easy-to-Read Drug Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts ... Past Drug Use Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page ...

  7. Drug Facts

    Medline Plus

    Full Text Available ... can call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from ...

  8. Drug Facts

    Medline Plus

    Full Text Available ... the computer will read the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos ... I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs ... adicción. English Español About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | Contact ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  11. Drug Facts

    Medline Plus

    Full Text Available ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  12. Differential toxicity and influence of salinity on acute toxicity of ...

    African Journals Online (AJOL)

    Differential toxicity and influence of salinity on acute toxicity of copper sulphate and lead nitrate against Oreochromis niloticus. KA Bawa-Allah, F Osuala, J Effiong. Abstract. This study investigated the salinity-tolerance of Oreochromis niloticus and the influence of salinity changes on the acute toxicities of copper sulphate ...

  13. Toxicity and toxicokinetics of metformin in rats

    International Nuclear Information System (INIS)

    Quaile, Michael P.; Melich, David H.; Jordan, Holly L.; Nold, James B.; Chism, Jack P.; Polli, Joseph W.; Smith, Glenn A.; Rhodes, Melissa C.

    2010-01-01

    Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of ≥ 900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given ≥ 600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses ≥ 600 mg/kg/day. There were no significant sex differences in mean AUC 0-24 or C max nor were there significant differences in mean AUC 0-24 or C max following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC 0-24 = 41.1 μg h/mL; mean C max = 10.3 μg/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.

  14. Rational drug design paradigms: the odyssey for designing better drugs.

    Science.gov (United States)

    Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

    2015-01-01

    Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.

  15. Toxic Shock Syndrome

    Science.gov (United States)

    ... Kids and Teens Pregnancy and Childbirth Women Men Seniors Your Health Resources Healthcare Management End-of-Life Issues Insurance & Bills Self Care Working With Your Doctor Drugs, Procedures & Devices Over-the- ...

  16. Biological control of toxic cyanobacteri

    CSIR Research Space (South Africa)

    Ndlela, Luyanda L

    2017-05-01

    Full Text Available . Ecotoxicity studies: is toxicity reduced? (Testing on daphnids, fish and human cell lines) Resulting impacts on cyanotoxins (Toxin conformation changes, ELISA detection) Competition assays against toxic cyanobacteria (Can Bacillus etc. outcompete...

  17. Allegheny County Toxics Release Inventory

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — The Toxics Release Inventory (TRI) data provides information about toxic substances released into the environment or managed through recycling, energy recovery, and...

  18. Screening of Compounds Toxicity against Human Monocytic cell line-THP-1 by Flow Cytometry

    Directory of Open Access Journals (Sweden)

    Pick Neora

    2004-01-01

    Full Text Available The worldwide rapid increase in bacterial resistance to numerous antibiotics requires on-going development of new drugs to enter the market. As the development of new antibiotics is lengthy and costly, early monitoring of compound's toxicity is essential in the development of novel agents. Our interest is in a rapid, simple, high throughput screening method to assess cytotoxicity induced by potential agents. Some intracellular pathogens, such as Mycobacterium tuberculosis primary site of infection is human alveolar macrophages. Thus, evaluation of candidate drugs for macrophage toxicity is crucial. Protocols for high throughput drug toxicity screening of macrophages using flow cytometry are lacking in the literature. For this application we modified a preexisting technique, propidium iodide (PI exclusion staining and utilized it for rapid toxicity tests. Samples were prepared in 96 well plates and analyzed by flow cytometry, which allowed for rapid, inexpensive and precise assessment of compound's toxicity associated with cell death.

  19. WAr on DrugS

    African Journals Online (AJOL)

    2009-04-12

    Apr 12, 2009 ... ABStrAct. Since drugs became both a public and social issue in Nigeria, fear about both the real and .... drugs as being morally reprehensible, and ..... tice system (see for instance, Shaw, 1995; ..... A cut throat business:.

  20. Toxic waste liquor disposal

    International Nuclear Information System (INIS)

    Burton, W.R.

    1985-01-01

    Toxic waste liquors, especially radio active liquors, are disposed in a sub-zone by feeding down a bore hole a first liquid, then a buffer liquid (e.g. water), then the toxic liquors. Pressure variations are applied to the sub-zone to mix the first liquid and liquors to form gels or solids which inhibit further mixing and form a barrier between the sub-zone and the natural waters in the environment of the sub-zone. In another example the location of the sub-zone is selected so that the environement reacts with the liquors to produce a barrier around the zone. Blind bore holes are used to monitor the sub-zone profile. Materials may be added to the liquor to enhance barrier formation. (author)

  1. Drug induced rhabdomyolysis

    Science.gov (United States)

    Hohenegger, Martin

    2012-01-01

    Rhabdomyolysis is a clinical condition of potential life threatening destruction of skeletal muscle caused by diverse mechanisms including drugs and toxins. Given the fact that structurally not related compounds cause an identical phenotype pinpoints to common targets or pathways, responsible for executing rhabdomyolysis. A drop in myoplasmic ATP paralleled with sustained elevations in cytosolic Ca2+ concentration represents a common signature of rhabdomyolysis. Interestingly, cardiac tissue is hardly affected or only secondary, as a consequence of imbalance in electrolytes or acid–base equilibrium. This dogma is now impaired by compounds, which show up with combined toxicity in heart and skeletal muscle. In this review, cases of rhabdomyolysis with novel recently approved drugs will be explored for new target mechanisms in the light of previously described pathomechanisms. PMID:22560920

  2. Portable, accurate toxicity testing

    International Nuclear Information System (INIS)

    Sabate, R.W.; Stiffey, A.V.; Dewailly, E.L.; Hinds, A.A.; Vieaux, G.J.

    1994-01-01

    Ever tightening environmental regulations, severe penalties for non-compliance, and expensive remediation costs have stimulated development of methods to detect and measure toxins. Most of these methods are bioassays that must be performed in the laboratory; none previously devised has been truly portable. The US Army, through the Small Business Innovative Research program, has developed a hand-held, field deployable unit for testing toxicity of battlefield water supplies. This patented system employs the measurable quenching, in the presence of toxins, of the natural bioluminescence produced by the marine dinoflagellate alga Pyrocystis lunula. The procedure's inventor used it for years to measure toxicity concentrations of chemical warfare agents actually, their simulants, primarily in the form of pesticides and herbicides plus assorted toxic reagents, waterbottom samples, drilling fluids, even blood. While the procedure is more precise, cheaper, and faster than most bioassays, until recently it was immobile. Now it is deployable in the field. The laboratory apparatus has been proven to be sensitive to toxins in concentrations as low as a few parts per billion, repeatable within a variation of 10% or less, and unlike some other bioassays effective in turbid or colored media. The laboratory apparatus and the hand-held tester have been calibrated with the EPA protocol that uses the shrimplike Mysidopsis bahia. The test organism tolerates transportation well, but must be rested a few hours at the test site for regeneration of its light-producing powers. Toxicity now can be measured confidently in soils, water columns, discharge points, and many other media in situ. Most significant to the oil industry is that drilling fluids can be monitored continuously on the rig

  3. Lead toxicity: current concerns.

    OpenAIRE

    Goyer, R A

    1993-01-01

    Over the 20-year period since the first issue of Environmental Health Perspectives was published, there has been considerable progress in the understanding of the potential toxicity of exposure to lead. Many of these advances have been reviewed in published symposia, conferences, and review papers in EHP. This brief review identifies major advances as well as a number of current concerns that present opportunities for prevention and intervention strategies. The major scientific advance has be...

  4. Toxic Substances Control Act

    Energy Technology Data Exchange (ETDEWEB)

    1992-05-15

    This Reference Book contains a current copy of the Toxic Substances Control Act and those regulations that implement the statute and appear to be most relevant to DOE activities. The document is provided to DOE and contractor staff for informational purposes only and should not be interpreted as legal guidance. Questions concerning this Reference Book may be directed to Mark Petts, EH-231 (202/586-2609).

  5. Toxicity of nitrogen pentoxide

    Energy Technology Data Exchange (ETDEWEB)

    Diggle, W M; Gage, J C

    1954-01-01

    Two ppM N/sub 2/O/sub 5/ for 4 h or 1 ppM, 4 h/day for 12 days produced acute pulmonary edema in rats. Ten daily 4-h exposures to 0.5 ppM produced no edema but respiratory distress. NO/sub 2/ produced no edema (some hemorrhage) at 80 mg/m/sup 3/. Nitric acid vapor (63 mg/m/sup 3/) had no obvious toxic effect.

  6. The 5-day continuous infusion of cis-platinum: An update on toxicity pattern

    International Nuclear Information System (INIS)

    Salem, P.; Hashimi, L.; Jabboury, K.; Khalyl, M.

    1986-01-01

    In an attempt to further diminish the toxicity of Cis-Diamminodichloroplatinum (II) (DDP), clinical trials with the drug administered by 5-day continuous IV infusion were initiated in 1976. DDP cytotoxicity to asynchronous human lymphoma cells in culture was enhanced by prolonged exposure to the drug. Ninety-six patients patients with a varioty of histologically proven neoplastic diseases were intered in this study. All patients had a serum creatinine less than or equal to 1.5 mg/dl. Prior treatment was discontinued 3 to 4 weeks before initiation of cisplatin (DDP). Toxicity tables are presented of the general pattern of toxicity produced by 5-day DDP infustion and the gastrointestinal toxicity produced during the same period. A new dose schedule is presented which is apparently much less toxic than the bolus IV injection, in terms of immediate and delayed toxicities and allows the use of DDP for more prolonged periods of time in conjunction with radiation therapy

  7. Separations chemistry of toxic metals

    International Nuclear Information System (INIS)

    Smith, P.; Barr, M.; Barrans, R.

    1996-01-01

    Sequestering and removing toxic metal ions from their surroundings is an increasingly active area of research and is gaining importance in light of current environmental contamination problems both within the DOE complex and externally. One method of separating metal ions is to complex them to a molecule (a ligand or chelator) which exhibits specific binding affinity for a toxic metal, even in the presence of other more benign metals. This approach makes use of the sometimes subtle differences between toxic and non-toxic metals resulting from variations in size, charge and shape. For example, toxic metals such as chromium, arsenic, and technetium exist in the environment as oxyanions, negatively charged species with a characteristic tetrahedral shape. Other toxic metals such as actinides and heavy metals are positively charged spheres with specific affinities for particular donor atoms such as oxygen (for actinides) and nitrogen (for heavy metals). In most cases the toxic metals are found in the presence of much larger quantities of less toxic metals such as sodium, calcium and iron. The selectivity of the chelators is critical to the goal of removing the toxic metals from their less toxic counterparts. The approach was to build a ligand framework that complements the unique characteristics of the toxic metal (size, charge and shape) while minimizing interactions with non-toxic metals. The authors have designed ligands exhibiting specificity for the target metals; they have synthesized, characterized and tested these ligands; and they have shown that they exhibit the proposed selectivity and cooperative binding effects

  8. Ethambutol/Linezolid Toxic Optic Neuropathy.

    Science.gov (United States)

    Libershteyn, Yevgeniya

    2016-02-01

    To report a rare toxic optic neuropathy after long-term use of two medications: ethambutol and linezolid. A 65-year-old man presented to the Miami Veterans Affairs Medical Center in December 2014 for evaluation of progressive vision decrease in both eyes. The patient presented with best-corrected visual acuities of 20/400 in the right eye and counting fingers at 5 feet in the left eye. Color vision was significantly reduced in both eyes. Visual fields revealed a cecocentral defect in both eyes. His fundus and optic nerve examination was unremarkable. Because vision continued to decline after discontinuation of ethambutol, linezolid was also discontinued, after which vision, color vision, and visual fields improved. Because of these findings, the final diagnosis was toxic optic neuropathy. Final visual outcome was 20/30 in the right eye and 20/40 in the left eye. Drug-associated toxic optic neuropathy is a rare but vision-threatening condition. Diagnosis is made based on an extensive case history and careful clinical examination. The examination findings include varying decrease in vision, normal pupils and extraocular muscles, and unremarkable fundoscopy, with the possibility of swollen optic discs in the acute stage of the optic neuropathy. Other important findings descriptive of toxic optic neuropathy include decreased color vision and cecocentral visual field defects. This case illustrates the importance of knowledge of all medications and/or substances a patient consumes that may cause a toxic reaction and discontinuing them immediately if the visual functions are worsening or not improving.

  9. Toxic epidermal necrolysis successfully treated with etanercept.

    Science.gov (United States)

    Gubinelli, Emanuela; Canzona, Flora; Tonanzi, Tiziano; Raskovic, Desanka; Didona, Biagio

    2009-03-01

    Toxic epidermal necrolysis (TEN) is a rare and acute severe adverse reaction to drugs, characterised by massive apoptosis and widespread epidermal and mucosal detachment. Although no gold standard therapy exists, human i.v. immunoglobulins have recently been described as an effective treatment for this disease. We report a case of phenobarbital-induced TEN in a 59-year-old white woman where the epidermal detachment stopped 48 h after beginning the etanercept treatment with complete healing after 20 days. To the best of our knowledge, this is only the second reported case of TEN successfully treated with etanercept.

  10. Alimentary, metabolic and toxic osteopathies in adults

    International Nuclear Information System (INIS)

    Ellegast, H.H.

    1986-01-01

    Skeletal changes in deficient or badly balanced nutrition (alimentary osteopathies) and osseous changes accompanying chronic desease of internal organs and metabolic disorders (metabolic osteopathies) are discussed. Basically, the classical generalised skeletal changes such as osteoporosis, osteomalacia, fibroosteoclacia and sklerosis of the bone can occur in their pure form or as a combination of two or more of these disorders. Finally the exogenic toxic osteopathies are discussed, nowadays fluorosis being the most important. Other external factors may be drugs like methotrexate and antiepileptic medications. (orig.) [de

  11. Acute toxic neuropathy mimicking guillain barre syndrome

    Directory of Open Access Journals (Sweden)

    Muhammed Jasim Abdul Jalal

    2015-01-01

    Full Text Available Case: A 30 year old male presented with numbness of palms and soles followed by weakness of upper limbs and lower limbs of 5 days duration, which was ascending and progressive. Three months back he was treated for oral and genital ulcers with oral steroids. His ulcers improved and shifted to indigenous medication. His clinical examination showed polyneuropathy. CSF study did not show albuminocytological dissociation. Nerve conduction study showed demyelinating polyneuropathy. His blood samples and the ayurvedic drug samples were sent for toxicological analysis. Inference: Acute toxic neuropathy - Arsenic

  12. MicroRNA Biomarkers of Toxicity in Biological Matrices

    Science.gov (United States)

    Biomarker measurements that reliably correlate with tissue injury and can be measured from sampling accessible biofluids offer enormous benefits in terms of cost, time, and convenience when assessing environmental and drug-induced toxicity in model systems or human cohorts. Micro...

  13. The bioaccumulation and toxicity induced by gold nanoparticles in ...

    African Journals Online (AJOL)

    It is essential to characterize the bioaccumulation and toxicity of gold nanoparticles (GNPs) in blood prior to using them in drug delivery, diagnostics, and treatment. The aim of the present study was to evaluate the blood absorbance spectra after intraperitoneal administration of 50 μl of 10, 20, and 50 nm GNPs in rat for ...

  14. In vivo toxicity of cationic micelles and liposomes

    DEFF Research Database (Denmark)

    Knudsen, Kristina Bram; Northeved, Helle; Ek, Pramod Kumar

    2015-01-01

    This study investigated toxicity of nanocarriers comprised of cationic polymer and lipid components often used in gene and drug delivery, formulated as cationic micelles and liposomes. Rats were injected intravenously with 10, 25 or 100 mg/kg and sacrificed after 24 or 48 h, or 24 h after the las...

  15. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    International Nuclear Information System (INIS)

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-01-01

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed

  16. Party drugs - use and harm reduction.

    Science.gov (United States)

    Frei, Matthew

    2010-08-01

    Party drug use, the intermittent use of stimulants, ecstasy and so-called 'designer drugs' at dance parties or 'raves', is now part of the culture of many young Australians. This article discusses the risks associated with the use of 'party drugs' and describes an useful approach to general practitioner assessment and management of patients who may be using party drugs. Party drug use is associated with a range of harms, including risks associated with behaviour while drug affected, toxicity and overdose, mental health complications and physical morbidity. Multiple substance use, particularly combining sedatives, further amplifies risk. If GPs have some understanding of these drugs and their effects, they are well placed to provide an effective intervention in party drug users by supporting the reduction of harm.

  17. The risk of contamination of food with toxic substances present in animal feed

    NARCIS (Netherlands)

    Kan, C.A.; Meijer, G.A.L.

    2007-01-01

    Toxic substances such as dioxins, mycotoxins, heavy metals, pesticides, veterinary drugs and polycyclic aromatic hydrocarbons are almost ubiquitous in the environment. Thus, they are also present in ingredients for animal feed. Adequate risk management depends on knowledge of absorption, metabolism,

  18. Nonconvulsive status epilepticus and Creutzfeldt–Jakob-like EEG changes in a case of lithium toxicity

    Directory of Open Access Journals (Sweden)

    B.K. Madhusudhan

    2014-01-01

    This case highlights the importance of therapeutic drug-level monitoring of lithium, especially where toxicity is suspected, and the important role electroencephalography plays in diagnosing NCSE and its management.

  19. Thyroid cancer in toxic and non-toxic multinodular goiter

    Directory of Open Access Journals (Sweden)

    Cerci C

    2007-01-01

    Full Text Available Background : Many authors have claimed that hyperthyroidism protects against thyroid cancer and believed that the incidence of malignancy is lower in patients with toxic multinodular goiter (TMG than in those with non-toxic multinodular goiter. But in recent studies, it was reported that the incidence of malignancy with TMG is not as low as previously thought. Aim : To compare the thyroid cancer incidence in patients with toxic and non-toxic multinodular goiter. Settings and Design : Histology reports of patients treated surgically with a preoperative diagnosis of toxic and non-toxic multinodular goiter were reviewed to identify the thyroid cancer incidence. Patients having a history of neck irradiation or radioactive iodine therapy were excluded from the study. Materials and Methods : We reviewed 294 patients operated between 2001-2005 from toxic and non-toxic multinodular goiter. One hundred and twenty-four of them were toxic and 170 were non-toxic. Hyperthyroidism was diagnosed by elevated tri-iodothyroinine / thyroxine ratios and low thyroid-stimulating hormone with clinical signs and symptoms. All patients were evaluated with ultrasonography and scintigraphy and fine needle aspiration biopsy. Statistical Analysis Used : Significance of the various parameters was calculated by using ANOVA test. Results : The incidence of malignancy was 9% in the toxic and 10.58% in the non-toxic multinodular goiter group. Any significant difference in the incidence of cancer and tumor size between the two groups could not be detected. Conclusions : The incidence of malignancy in toxic multinodular goiter is not very low as thought earlier and is nearly the same in non-toxic multinodular goiter.

  20. Developmental toxicity of low generation PAMAM dendrimers in zebrafish

    International Nuclear Information System (INIS)

    King Heiden, Tisha C.; Dengler, Emelyne; Kao, Weiyuan John; Heideman, Warren; Peterson, Richard E.

    2007-01-01

    Biological molecules and intracellular structures operate at the nanoscale; therefore, development of nanomedicines shows great promise for the treatment of disease by using targeted drug delivery and gene therapies. PAMAM dendrimers, which are highly branched polymers with low polydispersity and high functionality, provide an ideal architecture for construction of effective drug carriers, gene transfer devices and imaging of biological systems. For example, dendrimers bioconjugated with selective ligands such as Arg-Gly-Asp (RGD) would theoretically target cells that contain integrin receptors and show potential for use as drug delivery devices. While RGD-conjugated dendrimers are generally considered not to be cytotoxic, there currently exists little information on the risks that such materials pose to human health. In an effort to compliment and extend the knowledge gleaned from cell culture assays, we have used the zebrafish embryo as a rapid, medium throughput, cost-effective whole-animal model to provide a more comprehensive and predictive developmental toxicity screen for nanomaterials such as PAMAM dendrimers. Using the zebrafish embryo, we have assessed the developmental toxicity of low generation (G3.5 and G4) PAMAM dendrimers, as well as RGD-conjugated forms for comparison. Our results demonstrate that G4 dendrimers, which have amino functional groups, are toxic and attenuate growth and development of zebrafish embryos at sublethal concentrations; however, G3.5 dendrimers, with carboxylic acid terminal functional groups, are not toxic to zebrafish embryos. Furthermore, RGD-conjugated G4 dendrimers are less potent in causing embryo toxicity than G4 dendrimers. RGD-conjugated G3.5 dendrimers do not elicit toxicity at the highest concentrations tested and warrant further study for use as a drug delivery device

  1. Precision-cut intestinal slices as an in vitro model to predict NSAID induced intestinal toxicity

    NARCIS (Netherlands)

    Niu, Xiaoyu; van der Bijl, Henk; Groothuis, Geny; de Graaf, Inge

    2013-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with high prevalence of gastro-intestinal side-effects. In vivo studies suggest that uncoupling of oxidative phosphorylation is an important cause of the toxicity and that the toxicity is aggravated by enterohepatic circulation.

  2. COPD - control drugs

    Science.gov (United States)

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

  3. [Orphan drugs].

    Science.gov (United States)

    Golocorbin Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojsa; Mikov, Momir

    2013-01-01

    Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in "adopting" them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. THE BEGINNING OF ORPHAN DRUGS DEVELOPMENT: This problem was first recognized by Congress of the United States of America in January 1983, and when the "Orphan Drug Act" was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs.

  4. Toxicity of the sulfhydryl-containing radioprotector dithiothreitol

    International Nuclear Information System (INIS)

    Held, K.D.; Biaglow, J.E.

    1987-01-01

    The toxicity of the sulfhydryl-containing radioprotector dithiothreitol (DTT) has been studied in Chinese hamster V79 cells growing in monolayer. Under the conditions used here DTT causes a biphasic toxic response in which low concentrations of the drug (0.5 to 1.0 mM) are more toxic than are lower (0.2 mM) or higher (10 mM) concentrations. This response is similar to that seen by others with other sulfhydryl compounds. This DTT-induced toxicity is prevented by catalase, glutathione, and lowered temperatures. The toxicity is enhanced by some metal chelators (EDTA) but prevented by others (desferal). Metals (copper and iron) can either enhance or decrease the toxicity depending on their concentration and whether the exposure is in medium or in buffered salt solution. The results suggest a complex chain of chemical reactions and interactions with a role of H/sub 2/O/sub 2/ and perhaps . OH in this DTT toxicity. This is discussed

  5. Toxic potential of palytoxin.

    Science.gov (United States)

    Patocka, Jiří; Gupta, Ramesh C; Wu, Qing-hua; Kuca, Kamil

    2015-10-01

    This review briefly describes the origin, chemistry, molecular mechanism of action, pharmacology, toxicology, and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids (i.e. Palythoa), and Cyanobacteria (Trichodesmium). Palytoxin is a very large, non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na(+)/K(+)-ATPase with a Kd of 20 pM and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 pS. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous, intraperitoneal, intramuscular, subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal, yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation, cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals, and currently this toxin is of great concern worldwide.

  6. Metal metabolism and toxicity

    International Nuclear Information System (INIS)

    Bhattacharyya, M.H.; Larsen, R.P.; Whelton, B.D.; Moretti, E.S.; Peterson, D.P.; Oldham, R.D.

    1985-01-01

    This research focuses on the role of pregnancy and lactation in susceptibility to the toxic effects of cadmium and lead. Responses under investigation include lead-induced changes in pathways for vitamin D and calcium metabolism and cadmium-induced alterations in kidney function and skeletal structure. The second area focuses on the gastrointestinal absorption of plutonium and other actinide elements. Studies currently being conducted in nonhuman primates to develop a procedure to determine GI absorption values of uranium and plutonium that does not require sacrifice of the animal. 6 refs

  7. Control of air toxics

    International Nuclear Information System (INIS)

    Livengood, C.D.

    1995-01-01

    For more than 10 years, Argonne National Laboratory has supported the US DOE's Flue Gas Cleanup Program objective by developing new or improved environmental controls for industries that use fossil fuels. Argonne's pollutant emissions research has ranged from experiments in the basic chemistry of pollution-control systems, through laboratory-scale process development and testing, to pilot-scale field tests of several technologies. The work on air toxics is currently divided into two components: Investigating measures to improve the removal of mercury in existing pollution-control systems applied to coal combustion; and, Developing sensors and control techniques for emissions found in the textile industry

  8. AIDSinfo Drug Database

    Science.gov (United States)

    ... AIDS Drugs Clinical Trials Apps skip to content Drugs Home Drugs Find information on FDA-approved HIV/ ... infection drugs and investigational HIV/AIDS drugs. Search Drugs Search drug Search Icon What's this? Close Popup ...

  9. Linking Drugs to Obscure Illnesses

    DEFF Research Database (Denmark)

    Bennett, Charles L; Starko, Karen M; Thomsen, Henrik S

    2012-01-01

    Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998......-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial...... decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off...

  10. The current status of biomarkers for predicting toxicity

    Science.gov (United States)

    Campion, Sarah; Aubrecht, Jiri; Boekelheide, Kim; Brewster, David W; Vaidya, Vishal S; Anderson, Linnea; Burt, Deborah; Dere, Edward; Hwang, Kathleen; Pacheco, Sara; Saikumar, Janani; Schomaker, Shelli; Sigman, Mark; Goodsaid, Federico

    2013-01-01

    Introduction There are significant rates of attrition in drug development. A number of compounds fail to progress past preclinical development due to limited tools that accurately monitor toxicity in preclinical studies and in the clinic. Research has focused on improving tools for the detection of organ-specific toxicity through the identification and characterization of biomarkers of toxicity. Areas covered This article reviews what we know about emerging biomarkers in toxicology, with a focus on the 2012 Northeast Society of Toxicology meeting titled ‘Translational Biomarkers in Toxicology.’ The areas covered in this meeting are summarized and include biomarkers of testicular injury and dysfunction, emerging biomarkers of kidney injury and translation of emerging biomarkers from preclinical species to human populations. The authors also provide a discussion about the biomarker qualification process and possible improvements to this process. Expert opinion There is currently a gap between the scientific work in the development and qualification of novel biomarkers for nonclinical drug safety assessment and how these biomarkers are actually used in drug safety assessment. A clear and efficient path to regulatory acceptance is needed so that breakthroughs in the biomarker toolkit for nonclinical drug safety assessment can be utilized to aid in the drug development process. PMID:23961847

  11. Riboflavin ameliorates cisplatin induced toxicities under photoillumination.

    Directory of Open Access Journals (Sweden)

    Iftekhar Hassan

    Full Text Available BACKGROUND: Cisplatin is an effective anticancer drug that elicits many side effects mainly due to induction of oxidative and nitrosative stresses during prolonged chemotherapy. The severity of these side effects consequently restricts its clinical use under long term treatment. Riboflavin is an essential vitamin used in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Besides, it has excellent photosensitizing property that can be used to ameliorate these toxicities in mice under photodynamic therapy. METHODS AND FINDINGS: Riboflavin, cisplatin and their combinations were given to the separate groups of mice under photoilluminated condition under specific treatment regime. Their kidney and liver were excised for comet assay and histopathological studies. Furthermore, Fourier Transform Infrared Spectroscopy of riboflavin-cisplatin combination in vitro was also conducted to investigate any possible interaction between the two compounds. Their comet assay and histopathological examination revealed that riboflavin in combination with cisplatin was able to protect the tissues from cisplatin induced toxicities and damages. Moreover, Fourier Transform Infrared Spectroscopy analysis of the combination indicated a strong molecular interaction among their constituent groups that may be assigned for the protective effect of the combination in the treated animals. CONCLUSION: Inclusion of riboflavin diminishes cisplatin induced toxicities which may possibly make the cisplatin-riboflavin combination, an effective treatment strategy under chemoradiotherapy in pronouncing its antineoplastic activity and sensitivity towards the cancer cells as compared to cisplatin alone.

  12. Genetic tests for predicting the toxicity and efficacy of anticancer chemotherapy.

    Science.gov (United States)

    Mladosievicova, B; Carter, A; Kristova, V

    2007-01-01

    The standard anticancer therapy based "on one size fits all" modality has been determined to be ineffective or to be the cause of adverse drug reactions in many oncologic patients. Most pharmacogenetic and pharmacogenomic studies so far have been focused on toxicity of anticancer drugs such as 6-mercaptopurine, thioguanine, irinotecan, methotrexate, 5-fluorouracil (5-FU). Variation in genes are known to influence not only toxicity, but also efficacy of chemotherapeutics such as platinum analogues, 5-FU and irinotecan. The majority of current pharmacogenetic studies focus on single enzyme deficiencies as predictors of drug effects; however effects of most anticancer drugs are determined by the interplay of several gene products. These effects are polygenic in nature. This review briefly describes genetic variations that may impact efficacy and toxicity of drugs used in cancer chemotherapy.

  13. Nuclear track microfilters in controlled drug delivery against chronic skin disease

    International Nuclear Information System (INIS)

    Gopalani, D.; Jodha, A.S.; Saravanan, S.; Kumar, S.

    2003-01-01

    Nuclear track microfilters have been developed for transdermal therapeutic system. The transdermal therapeutic method reduces the toxicity of the drug as compared to other conventional methods. For this purpose a slow drug release system containing the nuclear track microfilter was developed. This device was applied to the patients suffering from psoriasis and cellulites diseases. The delivery of the drug to the patient was confirmed through high performance liquid chromatography. The preliminary results have shown that patients are responding to drugs with minimum toxicity

  14. Nuclear track microfilters in controlled drug delivery against chronic skin disease

    Energy Technology Data Exchange (ETDEWEB)

    Gopalani, D. E-mail: deflab@sancharnet.in; Jodha, A.S.; Saravanan, S.; Kumar, S

    2003-06-01

    Nuclear track microfilters have been developed for transdermal therapeutic system. The transdermal therapeutic method reduces the toxicity of the drug as compared to other conventional methods. For this purpose a slow drug release system containing the nuclear track microfilter was developed. This device was applied to the patients suffering from psoriasis and cellulites diseases. The delivery of the drug to the patient was confirmed through high performance liquid chromatography. The preliminary results have shown that patients are responding to drugs with minimum toxicity.

  15. In silico toxicology: computational methods for the prediction of chemical toxicity

    KAUST Repository

    Raies, Arwa B.; Bajic, Vladimir B.

    2016-01-01

    Determining the toxicity of chemicals is necessary to identify their harmful effects on humans, animals, plants, or the environment. It is also one of the main steps in drug design. Animal models have been used for a long time for toxicity testing. However, in vivo animal tests are constrained by time, ethical considerations, and financial burden. Therefore, computational methods for estimating the toxicity of chemicals are considered useful. In silico toxicology is one type of toxicity assessment that uses computational methods to analyze, simulate, visualize, or predict the toxicity of chemicals. In silico toxicology aims to complement existing toxicity tests to predict toxicity, prioritize chemicals, guide toxicity tests, and minimize late-stage failures in drugs design. There are various methods for generating models to predict toxicity endpoints. We provide a comprehensive overview, explain, and compare the strengths and weaknesses of the existing modeling methods and algorithms for toxicity prediction with a particular (but not exclusive) emphasis on computational tools that can implement these methods and refer to expert systems that deploy the prediction models. Finally, we briefly review a number of new research directions in in silico toxicology and provide recommendations for designing in silico models.

  16. In silico toxicology: computational methods for the prediction of chemical toxicity

    KAUST Repository

    Raies, Arwa B.

    2016-01-06

    Determining the toxicity of chemicals is necessary to identify their harmful effects on humans, animals, plants, or the environment. It is also one of the main steps in drug design. Animal models have been used for a long time for toxicity testing. However, in vivo animal tests are constrained by time, ethical considerations, and financial burden. Therefore, computational methods for estimating the toxicity of chemicals are considered useful. In silico toxicology is one type of toxicity assessment that uses computational methods to analyze, simulate, visualize, or predict the toxicity of chemicals. In silico toxicology aims to complement existing toxicity tests to predict toxicity, prioritize chemicals, guide toxicity tests, and minimize late-stage failures in drugs design. There are various methods for generating models to predict toxicity endpoints. We provide a comprehensive overview, explain, and compare the strengths and weaknesses of the existing modeling methods and algorithms for toxicity prediction with a particular (but not exclusive) emphasis on computational tools that can implement these methods and refer to expert systems that deploy the prediction models. Finally, we briefly review a number of new research directions in in silico toxicology and provide recommendations for designing in silico models.

  17. Toxicity of tritium

    International Nuclear Information System (INIS)

    Dobson, R.L.

    1979-01-01

    Among radionuclides of importance in atomic energy, 3 H has relatively low toxicity. The main health and environmental worry is the possibility that significant biological effects may follow from protracted exposure to low concentrations in water. To examine this possible hazard and measure toxicity at low tritium concentrations, chronic exposure studies were done on mice and monkeys. During vulnerable developmental periods animals were exposed to 3 HOH, and mice were exposed also to 60 Co gamma irradiation and energy-related chemical agents. The biological endpoint measured was the irreversible loss of female germ cells. Effects from tritium were observed at surprisingly low concentrations where 3 H was found more damaging than previously thought. Comparisons between tritium and gamma radiation showed the relative biological effectiveness (RBE) to be greater than 1 and to reach approximately 3 at very low exposures. For perspective, other comparisons were made: between radiation and chemical agents, which revealed parallels in action on germ cells, and between pre- and postnatal exposure, which warn of possible special hazard to the fetus from both classes of energy-related byproducts

  18. Toxic compounds in honey.

    Science.gov (United States)

    Islam, Md Nazmul; Khalil, Md Ibrahim; Islam, Md Asiful; Gan, Siew Hua

    2014-07-01

    There is a wealth of information about the nutritional and medicinal properties of honey. However, honey may contain compounds that may lead to toxicity. A compound not naturally present in honey, named 5-hydroxymethylfurfural (HMF), may be formed during the heating or preservation processes of honey. HMF has gained much interest, as it is commonly detected in honey samples, especially samples that have been stored for a long time. HMF is a compound that may be mutagenic, carcinogenic and cytotoxic. It has also been reported that honey can be contaminated with heavy metals such as lead, arsenic, mercury and cadmium. Honey produced from the nectar of Rhododendron ponticum contains alkaloids that can be poisonous to humans, while honey collected from Andromeda flowers contains grayanotoxins, which can cause paralysis of limbs in humans and eventually leads to death. In addition, Melicope ternata and Coriaria arborea from New Zealand produce toxic honey that can be fatal. There are reports that honey is not safe to be consumed when it is collected from Datura plants (from Mexico and Hungary), belladonna flowers and Hyoscamus niger plants (from Hungary), Serjania lethalis (from Brazil), Gelsemium sempervirens (from the American Southwest), Kalmia latifolia, Tripetalia paniculata and Ledum palustre. Although the symptoms of poisoning due to honey consumption may differ depending on the source of toxins, most common symptoms generally include dizziness, nausea, vomiting, convulsions, headache, palpitations or even death. It has been suggested that honey should not be considered a completely safe food. Copyright © 2013 John Wiley & Sons, Ltd.

  19. Thallium toxicity in humans.

    Science.gov (United States)

    Cvjetko, Petra; Cvjetko, Ivan; Pavlica, Mirjana

    2010-03-01

    Thallium is a naturally occurring trace element, widely distributed in the earth's crust, but at very low concentrations. It does not have a known biological use and does not appear to be an essential element for life. It has been considered one of the most toxic heavy metals.Occasionally, there are reports on thallium poisoning as results of suicide or murder attempt or accident. The main threat to humans is through occupational exposure, environmental contamination, and accumulation in food, mainly in vegetables grown on contaminated soil. Increasing use in emerging new technologies and demanding high-tech industry constantly raise concern about exposure risk to all living organisms. Thallium is considered a cumulative poison that can cause adverse health effects and degenerative changes in many organs. The effects are the most severe in the nervous system. The exact mechanism of thallium toxicity still remains unknown, although impaired glutathione metabolism, oxidative stress, and disruption of potassium-regulated homeostasis may play a role. The lack of data about mutagenic, carcinogenic, or teratogenic effects of thallium compounds in humans calls for further research.

  20. Molecular toxicity of nanomaterials.

    Science.gov (United States)

    Chang, Xue-Ling; Yang, Sheng-Tao; Xing, Gengmei

    2014-10-01

    With the rapid developments in the fields of nanoscience and nanotechnlogy, more and more nanomaterials and their based consumer products have been used into our daily life. The safety concerns of nanomaterials have been well recognized by the scientific community and the public. Molecular mechanism of interactions between nanomaterials and biosystems is the most essential topic and final core of the biosafety. In the last two decades, nanotoxicology developed very fast and toxicity phenomena of nanomaterials have been reported. To achieve better understanding and detoxication of nanomaterials, thorough studies of nanotoxicity at molecular level are important. The interactions between nanomaterials and biomolecules have been widely investigated as the first step toward the molecular nanotoxicology. The consequences of such interactions have been discussed in the literature. Besides this, the chemical mechanism of nanotoxicology is gaining more attention, which would lead to a better design of nontoxic nanomaterials. In this review, we focus on the molecular nanotoxicology and explore the toxicity of nanomaterials at molecular level. The molecular level studies of nanotoxicology are summarized and the published nanotoxicological data are revisited.

  1. Veterinary drugs in the environment and their toxicity to plants

    Czech Academy of Sciences Publication Activity Database

    Bártíková, H.; Podlipná, Radka; Skálová, L.

    2016-01-01

    Roč. 144, FEB (2016), s. 2290-2301 ISSN 0045-6535 R&D Projects: GA ČR(CZ) GA15-05325S Institutional support: RVO:61389030 Keywords : Veterinary antibiotics * Growth promoters * Phytotoxicity Subject RIV: CE - Biochemistry Impact factor: 4.208, year: 2016

  2. Pharmacogenomics of serious drug induced toxicity in pediatric oncology

    NARCIS (Netherlands)

    Visscher, H.

    2015-01-01

    Survival of children with cancer has been increasing over the last decades for all malignancies due to improvements in treatment protocols and supportive care. However, this increasing survival has come at the cost of severe lifelong adverse effects of treatment for many survivors. Identifying

  3. Comparative Resuscitation Measures for Drug Toxicities Utilizing Lipid Emulsions

    Science.gov (United States)

    2015-01-13

    CARPA like reactions (major cardiovascular depression) after lipid infusions. Other studies have shown a transient increase in pulmonary hypertension ...reuptake inhibitor. The most common symptoms from overdose include sinus tachycardia, hypertension , drowsiness, lethargy, agitation, nausea and vomiting...Walker R (2007) Pain and combat injuries in soldiers returning from Operations Enduring Freedom and Iraqi Freedom: Implications for research and

  4. Etanercept therapy for toxic epidermal necrolysis.

    Science.gov (United States)

    Paradisi, Andrea; Abeni, Damiano; Bergamo, Fabio; Ricci, Francesco; Didona, Dario; Didona, Biagio

    2014-08-01

    Toxic epidermal necrolysis (TEN) is a severe and potentially lethal drug reaction for which no standard treatment is available. To describe a case series of patients with TEN treated with a single dose of etanercept. We observed 10 consecutive patients with TEN. For each patient, we recorded the presence of comorbidities and all the drugs recently started (ie, in the last month). In all cases, 50 mg of etanercept was administered in a single subcutaneous injection. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale. Using the probabilities of death linked to each level of SCORTEN score, we calculated the expected probability of death in our patients. Healing was defined as complete reepithelialization, and a time to healing curve was then obtained using the Kaplan-Meier method. All patients promptly responded to treatment, reaching complete reepithelialization without complications or side effects. The median time to healing was 8.5 days. This is a small, uncontrolled case series. These preliminary results suggest the possibility that tumor necrosis factor-alfa may be an effective target for control of TEN, a dangerous skin condition for which no effective cure has yet been found. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  5. [Acute onset pulmonary toxicity associated to amiodarone].

    Science.gov (United States)

    Ferreira, Pedro Gonçalo; Saraiva, Fátima; Carreira, Cláudia

    2012-01-01

    Amiodarone is a potent anti-arrhythmic drug with a well-known potential chronic pulmonary toxicity. We describe a case of acute pulmonary toxicity (APT) induced by amiodarone in a 57 year old patient submitted to a perfusion of 900 mg in just 6 hours, to control an auricular flutter with rapid ventricular response. During the administration, the patient developed hemodynamic instability and oxygen dessaturation that led to an electrical cardioversion with return of sinus rhythm. Still, the patient continued in progressive respiratory deterioration with acute bilateral infiltrates on chest x-ray and apparent normal cardiac filling pressures confirmed by echocardiography. Anon-cardiogenic pulmonar edema progressing to clinico-physiological ARDS criteria was diagnosed. Expeditive therapeutic measures were undertaken, namely by initiation of non-invasive positive airway pressure support, that attained a good result.Albeit rare, amiodarone-induced APT might have severe consequences, namely progression to ALI/ARDS with a high mortality index.As it is a frequently prescribed drug, there should be a high clinical suspicion towards this phenomenon, allowing precocious therapeutic measures to be taken in a timely fashion to prevent the associated unfavorable outcome.

  6. Clinical Management of HIV Drug Resistance

    Science.gov (United States)

    Cortez, Karoll J.; Maldarelli, Frank

    2011-01-01

    Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. PMID:21994737

  7. Drug Facts

    Medline Plus

    Full Text Available ... Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of Abuse What ... Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800- ...

  8. Drug Facts

    Medline Plus

    Full Text Available ... Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of Abuse What is Addiction? ... Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800-662- ...

  9. Antineoplastic Drugs

    Science.gov (United States)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  10. Drugged Driving

    Science.gov (United States)

    ... Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College-Age Adults in 2016 Monitoring the Future 2016 Survey Results Drug and Alcohol Use in College-Age Adults in 2015 View All NIDA Home ...

  11. Progressive anticonvulsant hypersensitivity syndrome associated with change of drug product

    DEFF Research Database (Denmark)

    Sabroe, T.P.; Sabers, A.

    2008-01-01

    This report describes the laboratory and physical manifestations of lamotrigine-like toxicity in a young man with refractory epilepsy receiving lamotrigine presenting as anticonvulsant hypersensitivity syndrome (AHS) associated with an abrupt change of drug product Udgivelsesdato: 2008/6...

  12. Wild lettuce (Lactuca virosa) toxicity

    OpenAIRE

    Besharat, Sima; Besharat, Mahsa; Jabbari, Ali

    2009-01-01

    Wild lettuce (Lactuca virosa) can cause toxic effects when eaten. Wild lettuce grows in the north of Iran and some natives consume it unaware of its adverse side effects. We describe eight patients with manifestations of wild lettuce toxicity, admitted to a general hospital affiliated to the Golestan University of Medical Sciences. All the patients recovered (although one had to spend 48 h in the intensive care unit) and no chronic complications were reported. A clinical suspicion of toxicity...

  13. Drug repurposing based on drug-drug interaction.

    Science.gov (United States)

    Zhou, Bin; Wang, Rong; Wu, Ping; Kong, De-Xin

    2015-02-01

    Given the high risk and lengthy procedure of traditional drug development, drug repurposing is gaining more and more attention. Although many types of drug information have been used to repurpose drugs, drug-drug interaction data, which imply possible physiological effects or targets of drugs, remain unexploited. In this work, similarity of drug interaction was employed to infer similarity of the physiological effects or targets for the drugs. We collected 10,835 drug-drug interactions concerning 1074 drugs, and for 700 of them, drug similarity scores based on drug interaction profiles were computed and rendered using a drug association network with 589 nodes (drugs) and 2375 edges (drug similarity scores). The 589 drugs were clustered into 98 groups with Markov Clustering Algorithm, most of which were significantly correlated with certain drug functions. This indicates that the network can be used to infer the physiological effects of drugs. Furthermore, we evaluated the ability of this drug association network to predict drug targets. The results show that the method is effective for 317 of 561 drugs that have known targets. Comparison of this method with the structure-based approach shows that they are complementary. In summary, this study demonstrates the feasibility of drug repurposing based on drug-drug interaction data. © 2014 John Wiley & Sons A/S.

  14. E-Cigarette Toxicity?

    Science.gov (United States)

    Tegin, Gulay; Mekala, Hema Madhuri; Sarai, Simrat Kaur; Lippmann, Steven

    2018-01-01

    Tobacco smoking is the most preventable cause of morbidity and mortality. In just a few short years, electronic cigarettes (e-cigarettes) have become increasingly popular, especially for younger individuals. Many people believe that e-cigarettes are safe. The inhaled aerosols of e-cigarettes contain numerous potential toxicities, some of which could be dangerous for health with long-term use. The safety of prolonged aerosol exposure is not known. The use of e-cigarettes as a harm-reduction tool at stopping tobacco smoking is not uniformly successful. E-cigarettes may be safer than tobacco products, but repeated prolonged exposure to their aerosols has its own considerable potential risk. The long-term health consequences of their use remain to be established. Physicians should vigorously discourage the use of e-cigarettes and tobacco products, with special emphasis on abstinence for younger people and during pregnancy or lactation.

  15. Children's Ability to Recognise Toxic and Non-Toxic Fruits

    Science.gov (United States)

    Fancovicova, Jana; Prokop, Pavol

    2011-01-01

    Children's ability to identify common plants is a necessary prerequisite for learning botany. However, recent work has shown that children lack positive attitudes toward plants and are unable to identify them. We examined children's (aged 10-17) ability to discriminate between common toxic and non-toxic plants and their mature fruits presented in…

  16. Therapeutic drug monitoring in pregnancy.

    Science.gov (United States)

    Matsui, Doreen M

    2012-10-01

    Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.

  17. Differential involvement of mitochondrial dysfunction, cytochrome P450 activity, and active transport in the toxicity of structurally related NSAIDs

    NARCIS (Netherlands)

    van Leeuwen, J.S.; Unlü, B; Vermeulen, N.P.E.; Vos, J.C.

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. However, this group of drugs is associated with serious adverse drug reactions. Previously, we studied the mechanisms underlying toxicity of the NSAID diclofenac using Saccharomyces cerevisiae

  18. Toxicity management of angiogenesis inhibitors: resolution of expert panel

    Directory of Open Access Journals (Sweden)

    Pavel O. Rumiantsev

    2017-12-01

    Full Text Available On 22 June 2017 in St. Petersburg the expert panel was held on the topic “Management of toxicity of angiogenesis inhibitors”, which discussed current issues of systemic therapy of advanced differentiated thyroid cancer resistant to radioactive iodine therapy, advanced kidney cancer and questions of efficacy and safety of new target drugs in the treatment of these diseases. The reports and discussions of experts raised the following questions: 1. Own experience of using lenvatinib in patients with differentiated thyroid cancer refractory to therapy with radioactive iodine and kidney cancer. 2. Profile of efficacy and safety of modern targeted therapy with multikinase inhibitors. 3. Prophylaxis and management of predictable toxicity.

  19. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs.

    Science.gov (United States)

    Oleaga, Carlota; Bernabini, Catia; Smith, Alec S T; Srinivasan, Balaji; Jackson, Max; McLamb, William; Platt, Vivien; Bridges, Richard; Cai, Yunqing; Santhanam, Navaneetha; Berry, Bonnie; Najjar, Sarah; Akanda, Nesar; Guo, Xiufang; Martin, Candace; Ekman, Gail; Esch, Mandy B; Langer, Jessica; Ouedraogo, Gladys; Cotovio, Jose; Breton, Lionel; Shuler, Michael L; Hickman, James J

    2016-02-03

    We report on a functional human model to evaluate multi-organ toxicity in a 4-organ system under continuous flow conditions in a serum-free defined medium utilizing a pumpless platform for 14 days. Computer simulations of the platform established flow rates and resultant shear stress within accepted ranges. Viability of the system was demonstrated for 14 days as well as functional activity of cardiac, muscle, neuronal and liver modules. The pharmacological relevance of the integrated modules were evaluated for their response at 7 days to 5 drugs with known side effects after a 48 hour drug treatment regime. The results of all drug treatments were in general agreement with published toxicity results from human and animal data. The presented phenotypic culture model exhibits a multi-organ toxicity response, representing the next generation of in vitro systems, and constitutes a step towards an in vitro "human-on-a-chip" assay for systemic toxicity screening.

  20. Predictive typing of drug-induced neurological sufferings from studies of the distribution of labelled drugs

    International Nuclear Information System (INIS)

    Takasu, T.

    1980-01-01

    A drug given to an animal becomes widely distributed throughout the body, acting on the living mechanisms or structures, and is gradually excreted. Some drugs can remain in some parts of the body for a long period. For example, 14 C-chloramphenical was found to remain preferentially in the salivary gland, liver and bone marrow of mice 24 hours after its oral administration. If such a drug is given repeatedly, it could possibly accumulate gradually in these organs. Thus, when its accumulation in a particular part of the body exceeds a certain level, the living mechanism or structure may possibly be injured. The harmful effects of a drug in repeated administration are called its chronic toxicity. The author discusses whether it is possible to predict the toxicity of a drug by studying its distribution in relation to time, and, if possible, the points in time. This problem is studied especially in relation to the nervous system. (Auth.)

  1. Drug Facts

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  2. Drug Facts

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  3. Drug Facts

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  4. Drug Facts

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  5. Drug Metabolism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 3. Drug Metabolism: A Fascinating Link Between Chemistry and Biology. Nikhil Taxak Prasad V Bharatam. General Article Volume 19 Issue 3 March 2014 pp 259-282 ...

  6. Drugged Driving

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  7. Club Drugs

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  8. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    behind metabolic reactions, importance, and consequences with several ... required for drug action. ... lism, which is catalyzed by enzymes present in the above-men- ... catalyze the transfer of one atom of oxygen to a substrate produc-.

  9. Drug Facts

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  10. Drug Facts

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    Full Text Available ... 800-662-HELP (4357) at any time to find drug treatment centers near you. I want my ... is making positive changes in her life. She finds support from family and friends who don't ...

  11. Drug Facts

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  12. Drug Facts

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    Full Text Available ... Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? ... of Health (NIH) , the principal biomedical and behavioral research agency of the United States Government. NIH is ...

  13. Drug Reactions

    Science.gov (United States)

    ... Kids and Teens Pregnancy and Childbirth Women Men Seniors Your Health Resources Healthcare Management End-of-Life Issues Insurance & Bills Self Care Working With Your Doctor Drugs, Procedures & Devices Over-the- ...

  14. Drug Facts

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    Full Text Available ... prescription drugs. The addiction slowly took over his life. I need different people around me. To stop ... marijuana, "Cristina" is making positive changes in her life. She finds support from family and friends who ...

  15. Drug Resistance

    Science.gov (United States)

    ... Drug-resistance testing is also recommended for all pregnant women with HIV before starting HIV medicines and also in some pregnant women already taking HIV medicines. Pregnant women will work with their health ...

  16. Drug Facts

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    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  17. Drug Addiction

    Science.gov (United States)

    ... as hearing colors Impulsive behavior Rapid shifts in emotions Permanent mental changes in perception Rapid heart rate ... Drug use can negatively affect academic performance and motivation to excel in school. Legal issues. Legal problems ...

  18. Drug Facts

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    Full Text Available ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) ...

  19. The role of metabolism in diclofenac-induced intestinal toxicity in rat and human in vitro

    NARCIS (Netherlands)

    Niu, Xiaoyu; Makkinje, Miriam; de Graaf, Inge; Groothuis, Genoveva

    The use of Diclofenac (DCF), a non-steroidal anti-inflammatory drug is associated with severe gastro-intestinal side-effects. The mechanisms of drug-induced intestinal toxicity are largely unknown due to the lack of in vitro models. In vivo rat studies suggested that reactive metabolites of DCF

  20. Effects of synthetic and natural toxicants on livestock.

    Science.gov (United States)

    Shull, L R; Cheeke, P R

    1983-07-01

    Synthetic and natural toxicants are constituents of soil, air, water and foodstuffs. Their impact on animal agriculture has resulted from acute and chronic intoxication and residues transferred into meat, dairy and poultry products. Recent advances in analytical chemistry and the sciences associated with toxicology have allowed better assessment of the hazard of toxicants on animals including man. Historically, natural toxicants (phytotoxins, mycotoxins and minerals) that are associated with many common feedstuffs accounted for toxicity episodes of epidemic proportions. Most synthetic chemicals (pesticides, nonpesticidal organic chemicals and drugs) have been introduced in increasing numbers since the 1940's. In the 1960's and '70's, recognition of the need to control their environmental distribution stimulated the introduction of numerous laws and regulations. In the last decade, several problematic synthetic chemicals have been banned, particularly those found to persist in the environment or those confirmed or suspected as carcinogens in humans. At the farm level, the development of various preventative management strategies has decreased the exposure of livestock to natural toxicants. In the future, the impact of natural toxicants on animal agriculture is expected to lessen as their existence, etiology and toxicology are determined. On the other hand, synthetic chemicals will continue to threaten animal health as greater numbers and quantities are released into the environment. These challenges should stimulate a greater involvement of animal scientists in toxicology.

  1. Ethnically diverse pluripotent stem cells for drug development.

    Science.gov (United States)

    Fakunle, Eyitayo S; Loring, Jeanne F

    2012-12-01

    Genetic variation is an identified factor underlying drug efficacy and toxicity, and adverse drug reactions, such as liver toxicity, are the primary reasons for post-marketing drug failure. Genetic predisposition to toxicity might be detected early in the drug development pipeline by introducing cell-based assays that reflect the genetic and ethnic variation of the expected treatment population. One challenge for this approach is obtaining a collection of suitable cell lines derived from ethnically diverse populations. Induced pluripotent stem cells (iPSCs) seem ideal for this purpose. They can be obtained from any individual, can be differentiated into multiple relevant cell types, and their self-renewal capability makes it possible to generate large quantities of quality-controlled cell types. Here, we discuss the benefits and challenges of using iPSCs to introduce genetic diversity into the drug development process. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. A Review of the Toxicity of Compounds Found in Herbal Dietary Supplements.

    Science.gov (United States)

    Hudson, Amy; Lopez, Elizabeth; Almalki, Ahmad J; Roe, Amy L; Calderón, Angela I

    2018-04-19

    Use of herbal dietary supplements by the public is common and has been happening for centuries. In the United States, the Food and Drug Administration has a limited scope of regulation over marketed herbal dietary supplements, which may contain toxic botanical compounds that pose a public health risk. While the Food and Drug Administration has made efforts to prohibit the sale of unsafe herbal dietary supplements, numerous reports have proliferated of adverse events due to these supplements. This literature review investigates bioactive plant compounds commonly used in herbal dietary supplements and their relative toxicities. Using primarily the National Library of Medicine journal database and SciFinder for current reports, 47 toxic compounds in 55 species from 46 plant families were found to demonstrate harmful effects due to hepatic, cardiovascular, central nervous system, and digestive system toxicity. This review further contributes a novel and comprehensive view of toxicity across the botanical dietary market, and investigates the toxicity of the top ten botanical dietary supplements purchased in the United States of America to gauge the exposure risk of toxicity to the public. The criteria of measuring toxicity in this review (plant compound, family, quantity, and toxicity effects) across the entire market in the United States, with special attention to those supplements whose exposure to the consumer is maximal, provides a unique contribution to the investigation of botanical supplements. Georg Thieme Verlag KG Stuttgart · New York.

  3. One Health and Toxic Cyanobacteria

    Science.gov (United States)

    One Health and toxic cyanobacteria Blooms of toxic freshwater blue-green algae or cyanobacteria (HABs) have been in the news after HABs associated with human and animal health problems have been reported in Florida, California and Utah during 2016. HABs occur in warm, slow moving...

  4. Toxic Leadership in Educational Organizations

    Science.gov (United States)

    Green, James E.

    2014-01-01

    While research on the traits and skills of effective leaders is plentiful, only recently has the phenomenon of toxic leadership begun to be investigated. This research report focuses on toxic leadership in educational organizations--its prevalence, as well as the characteristics and early indicators. Using mixed methods, the study found four…

  5. Building a developmental toxicity ontology.

    Science.gov (United States)

    Baker, Nancy; Boobis, Alan; Burgoon, Lyle; Carney, Edward; Currie, Richard; Fritsche, Ellen; Knudsen, Thomas; Laffont, Madeleine; Piersma, Aldert H; Poole, Alan; Schneider, Steffen; Daston, George

    2018-04-03

    As more information is generated about modes of action for developmental toxicity and more data are generated using high-throughput and high-content technologies, it is becoming necessary to organize that information. This report discussed the need for a systematic representation of knowledge about developmental toxicity (i.e., an ontology) and proposes a method to build one based on knowledge of developmental biology and mode of action/ adverse outcome pathways in developmental toxicity. This report is the result of a consensus working group developing a plan to create an ontology for developmental toxicity that spans multiple levels of biological organization. This report provide a description of some of the challenges in building a developmental toxicity ontology and outlines a proposed methodology to meet those challenges. As the ontology is built on currently available web-based resources, a review of these resources is provided. Case studies on one of the most well-understood morphogens and developmental toxicants, retinoic acid, are presented as examples of how such an ontology might be developed. This report outlines an approach to construct a developmental toxicity ontology. Such an ontology will facilitate computer-based prediction of substances likely to induce human developmental toxicity. © 2018 Wiley Periodicals, Inc.

  6. Polish Toxic Currency Options

    Directory of Open Access Journals (Sweden)

    Waldemar Gontarski

    2009-06-01

    Full Text Available Toxic currency options are defined on the basis of the opposition to the nature (essence of an option contract, which is justified in terms of norms founded on the general law clause of characteristics (nature of a relation (which represents an independent premise for imposing restrictions on the freedom of contracts. So-understood toxic currency options are unlawful. Indeed they contravene iuris cogentis regulations. These include for instance option contracts, which are concluded with a bank, if the bank has not informed about option risk before concluding the contract; or the barrier options, which focus only on the protection of bank’s interests. Therefore, such options may appear to be invalid. Therefore, performing contracts for toxic currency options may be qualified as a criminal mismanagement. For the sake of security, the manager should then take into consideration filing a claim for stating invalidity (which can be made in a court verdict. At the same time, if the supervisory board member in a commercial company, who can also be a subject to mismanagement offences, commits an omission involving lack of reaction (for example, if he/she fails to notify of the suspected offence committed by the management board members acting to the company’s detriment when the management board makes the company conclude option contracts which are charged with absolute invalidity the supervisory board member so acting may be considered to act to the company’s detriment. In the most recent Polish jurisprudence and judicature the standard of a “good host” is treated to be the last resort for determining whether the manager’s powers resulting from criminal regulations were performed. The manager of the exporter should not, as a rule, issue any options. Issuing options always means assuming an obligation. In the case of currency put options it is an absolute obligation to purchase a given amount in euro at exchange rate set in advance. On the

  7. Drug cocktail optimization in chemotherapy of cancer.

    Directory of Open Access Journals (Sweden)

    Saskia Preissner

    Full Text Available BACKGROUND: In general, drug metabolism has to be considered to avoid adverse effects and ineffective therapy. In particular, chemotherapeutic drug cocktails strain drug metabolizing enzymes especially the cytochrome P450 family (CYP. Furthermore, a number of important chemotherapeutic drugs such as cyclophosphamide, ifosfamide, tamoxifen or procarbazine are administered as prodrugs and have to be activated by CYP. Therefore, the genetic variability of these enzymes should be taken into account to design appropriate therapeutic regimens to avoid inadequate drug administration, toxicity and inefficiency. OBJECTIVE: The aim of this work was to find drug interactions and to avoid side effects or ineffective therapy in chemotherapy. DATA SOURCES AND METHODS: Information on drug administration in the therapy of leukemia and their drug metabolism was collected from scientific literature and various web resources. We carried out an automated textmining approach. Abstracts of PubMed were filtered for relevant articles using specific keywords. Abstracts were automatically screened for antineoplastic drugs and their synonyms in combination with a set of human CYPs in title or abstract. RESULTS: We present a comprehensive analysis of over 100 common cancer treatment regimens regarding drug-drug interactions and present alternatives avoiding CYP overload. Typical concomitant medication, e.g. antiemetics or antibiotics is a preferred subject to improvement. A webtool, which allows drug cocktail optimization was developed and is publicly available on http://bioinformatics.charite.de/chemotherapy.

  8. Toxic releases from power plants

    International Nuclear Information System (INIS)

    Rubin, E.S.

    1999-01-01

    Beginning in 1998, electric power plants burning coal or oil must estimate and report their annual releases of toxic chemicals listed in the Toxics Release Inventory (TRI) published by the US Environmental Protection Agency (EPA). This paper identifies the toxic chemicals of greatest significance for the electric utility sector and develops quantitative estimates of the toxic releases reportable to the TRI for a representative coal-fired power plant. Key factors affecting the magnitude and types of toxic releases for individual power plants also are discussed. A national projection suggests that the magnitude of electric utility industry releases will surpass those of the manufacturing industries which current report to the TRI. Risk communication activities at the community level will be essential to interpret and provide context for the new TRI results

  9. VARIATIONS IN REPRODUCTIVE TOXICANT IDENTIFICATION

    Energy Technology Data Exchange (ETDEWEB)

    Simmons, F

    2008-05-13

    Reproductive toxicants are a very important class of compounds. They present unique hazards to those of child bearing ages, perform their 'dirty work' using a wide variety of mechanisms on a number of different organs, and are regulatorily important. Because of all of this, properly identifying reproductive toxicants is important, but fraught with difficulty. In this paper we will describe types or reproductive toxicants, their importance, and both mistakes and good practices that people who are not experts in reproductive toxicology may use in their attempts to identify them. Additionally, this paper will focus on chemical reproductive toxicants and will not address biological agents that could affect reproductive toxicity although many principles outlined here could be applied to that endeavor.

  10. Functionalization of protein-based nanocages for drug delivery applications.

    Science.gov (United States)

    Schoonen, Lise; van Hest, Jan C M

    2014-07-07

    Traditional drug delivery strategies involve drugs which are not targeted towards the desired tissue. This can lead to undesired side effects, as normal cells are affected by the drugs as well. Therefore, new systems are now being developed which combine targeting functionalities with encapsulation of drug cargo. Protein nanocages are highly promising drug delivery platforms due to their perfectly defined structures, biocompatibility, biodegradability and low toxicity. A variety of protein nanocages have been modified and functionalized for these types of applications. In this review, we aim to give an overview of different types of modifications of protein-based nanocontainers for drug delivery applications.

  11. Recreational Use, Analysis and Toxicity of Tryptamines

    Science.gov (United States)

    Tittarelli, Roberta; Mannocchi, Giulio; Pantano, Flaminia; Romolo, Francesco Saverio

    2015-01-01

    The definition New psychoactive substances (NPS) refers to emerging drugs whose chemical structures are similar to other psychoactive compounds but not identical, representing a “legal” alternative to internationally controlled drugs. There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews. Aim: To review the scientific literature regarding tryptamines and their derivatives, providing a summary of all the available information about the structure of these compounds, their effects in relationship with the routes of administration, their pharmacology and toxicity, including articles reporting cases of death related to intake of these substances. Methods: A comprehensive review of the published scientific literature was performed, using also non peer-reviewed information sources, such as books, government publications and drug user web fora. Conclusions: Information from Internet and from published scientific literature, organized in the way we proposed in this review, provides an effective tool for specialists facing the emerging NPS threat to public health and public security, including the personnel working in Emergency Department. PMID:26074742

  12. Anaerobic biodegradability and toxicity of complex or toxicant wastewater

    International Nuclear Information System (INIS)

    Wills Betancur, B.A.

    1995-01-01

    As a first approximation to wastewater classification in susceptibility terms to treatment by anaerobic biological system, anaerobic biodegradability trials are accomplished to leached of sanitary landfill, to wastewater of coffee grain wet treatment plant and to wastewater of fumaric acid recuperation plant. In the last Plant, anaerobic toxicity trials and lethal toxicity on the Daphnia pulex micro-crustacean are made too. Anaerobic biological trials are made continuing the Wageningen University (Holland) Methodology (1.987). Lethal toxicity biological trials are made following the Standard Methods for the Examination of Water and Wastewater(18th edition, 1992). In development of this investigation project is found that fumaric acid recuperation plant leached it has a low anaerobic biodegradability, a high anaerobic toxicity and a high lethal toxicity over Daphnia pulex, for such reasons this leached is cataloged as complex and toxic wastewater. The other hand, wastewater of coffee grain wet treatment plant and wastewater of sanitary landfill they are both highly biodegradability and not-toxic, for such reasons these wastewaters are cataloged as susceptible to treatment by anaerobic biological system

  13. Membrane specific drugs as radiosensitizers

    Energy Technology Data Exchange (ETDEWEB)

    George, K.C.; Mishra, K.P.; Shenoy, M.A.; Singh, B.B.; Srinivasan, V.T.; Verma, N.C.

    1981-01-01

    Procaine, paracetamol, and chlorpromazine showed inhibition of post irradiation repair. The chlorpromazie effect could be further augmented by treatment of cells with procaine. Chlorpromazine was also found to be preferentially toxic to hypoxid bacterial cells, and the survivors showed extreme radiosensitivity to gamma rays. Chlorpromazine was found to inhibit tumour growth in swiss mice when given intraperitoneally as well as when injected directly into the tumour. When combined with single x-ray doses, significant radiosensitization was observed in two in vivo tumours sarcoma 180A and fibrosarcoma. These results indicated that chlorpromazine may prove a good drug for combined chemo-radiotherapy of solid tumours. Investigations continued studying various aspects such as effectiveness in other tumour lines, distribution in healthy and tumour bearing animals, hyperthermia and drug combination effects, and encapsulation of the drug in artificial liposomes and blood cells. (ERB)

  14. The toxicity of plutonium

    International Nuclear Information System (INIS)

    Ramsden, D.; Johns, T.F.

    1977-01-01

    Reference is made to recent publications concerned with the radiotoxicity of inhaled insoluble Pu compounds. The publications are a paper by Thorne and Vennart (Nature 263:555 (1976)), a report entitled 'The Toxicity of Plutonium', (London (HMSO), 1975), and the 'Sixth Report of the Royal Commission on Environmental Pollution', (Cmnd. 6618, London (HMSO), 1976). Thorne and Vennart concluded that the previously accepted value for the maximum permissible annual intake (MPAI) of such compounds may be too high by a factor of about five, and a similar conclusion was reached in the other two publications. It is thought by the present authors that the methods which have been used to suggest new values for the MPAI are unduly pessimistic for high-fired PuO 2 ; calculations have been based on the lung model of ICRP Publication 19 'The Metabolism of Compounds of Plutonium and the Other Actinides', (International Commission of Radiological Protection, 1972). This involves concluding that the risks to bone and liver are comparable to those for lung. This is discussed and it is thought that the previously established idea that the lung is the critical organ remains substantially correct for the case of high-fired PuO 2 . (U.K.)

  15. Personalized Medicine: Pharmacogenomics and Drug Development

    Directory of Open Access Journals (Sweden)

    Somayeh Mirsadeghi

    2017-03-01

    Full Text Available Personalized medicine aims is to supply the proper drug to the proper patient within the right dose. Pharmacogenomics (PGx is to recognize genetic variants that may influence drug efficacy and toxicity. All things considered, the fields cover a wide area, including basic drug discovery researches, the genetic origin of pharmacokinetics and pharmacodynamics, novel drug improvement, patient genetic assessment and clinical patient administration. At last, the objective of Pharmacogenomics is to anticipate a patient’s genetic response to a particular drug as a way of presenting the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and decrease the incidence of adverse side effect.

  16. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  17. Organelle targeting: third level of drug targeting

    Directory of Open Access Journals (Sweden)

    Sakhrani NM

    2013-07-01

    Full Text Available Niraj M Sakhrani, Harish PadhDepartment of Cell and Molecular Biology, BV Patel Pharmaceutical Education and Research Development (PERD Centre, Gujarat, IndiaAbstract: Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.Keywords: intracellular drug delivery, cancer chemotherapy, therapeutic index, cell penetrating peptides

  18. Clinical relevance of drug binding to plasma proteins

    Science.gov (United States)

    Ascenzi, Paolo; Fanali, Gabriella; Fasano, Mauro; Pallottini, Valentina; Trezza, Viviana

    2014-12-01

    Binding to plasma proteins highly influences drug efficacy, distribution, and disposition. Serum albumin, the most abundant protein in plasma, is a monomeric multi-domain macromolecule that displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds, such as fatty acids and most acidic drugs. α-1-Acid glycoprotein, the second main plasma protein, is a glycoprotein physiologically involved in the acute phase reaction and is the main carrier for basic and neutral drugs. High- and low-density lipoproteins play a limited role in drug binding and are natural drug delivery system only for few lipophilic drugs or lipid-based formulations. Several factors influence drug binding to plasma proteins, such as pathological conditions, concurrent administration of drugs, sex, and age. Any of these factors, in turn, influences drug efficacy and toxicity. Here, biochemical, biomedical, and biotechnological aspects of drug binding to plasma proteins are reviewed.

  19. eMolTox: prediction of molecular toxicity with confidence.

    Science.gov (United States)

    Ji, Changge; Svensson, Fredrik; Zoufir, Azedine; Bender, Andreas

    2018-03-07

    In this work we present eMolTox, a web server for the prediction of potential toxicity associated with a given molecule. 174 toxicology-related in vitro/vivo experimental datasets were used for model construction and Mondrian conformal prediction was used to estimate the confidence of the resulting predictions. Toxic substructure analysis is also implemented in eMolTox. eMolTox predicts and displays a wealth of information of potential molecular toxicities for safety analysis in drug development. The eMolTox Server is freely available for use on the web at http://xundrug.cn/moltox. chicago.ji@gmail.com or ab454@cam.ac.uk. Supplementary data are available at Bioinformatics online.

  20. Targeted drugs in radiation therapy

    International Nuclear Information System (INIS)

    Favaudon, V.; Hennequin, C.; Hennequin, C.

    2004-01-01

    New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neo-angiogenesis promoters, TGF-β, cyclooxygenase or the transcription factor NF-κB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms. (authors)

  1. Legal Drugs Are Good Drugs and Illegal Drugs Are Bad Drugs

    OpenAIRE

    Indrati, Dina; Prasetyo, Herry

    2011-01-01

    ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing s...

  2. Protein Nanoscaffolds for Delivering Toxic Inorganic Cargo to Cancer Cells

    Science.gov (United States)

    Cioloboc, Daniela

    Targeted delivery of anticancer drugs or prodrugs to tumors can minimize systemic toxicity and side effects. This study develops platforms for targeted delivery of two potentially less systemically toxic prodrugs by exploiting the native and/or bioinorganic properties of two ferritins, both of which function naturally as iron storage proteins. Two delivery approaches were investigated. The first system was designed to serve as either an enhancement or alternative to traditional photodynamic therapy by generating hydroxyl radical in addition to singlet oxygen as the toxic reactive oxygen species. This system used Escherichia coli bacterioferritin (Bfr) loaded with 2,500 irons and multiple zinc-porphyrin (ZnP) photosensitizers. Ferrous iron was released by photoreduction of ferric iron stored within the Bfr protein shell. Hydroxyl radicals were generated via the Fenton reaction between hydrogen peroxide and the released ferrous iron. The outer surface of the Bfr protein shell was coated with peptides that specifically bind to a receptor known to be overexpressed in many tumor cells and tumor vasculature. The iron-loaded peptide-ZnP-Bfr was endocytosed by melanoma cells, where it showed photo-triggered release of iron and light-dependent cytotoxicity. The second system, built around human heavy chain ferritin (HFn), was loaded with arsenate as a less toxic "prodrug" and designed to release arsenic in its toxic, therapeutically effective reduced form, arsenic trioxide (ATO). The Hfn shell was coated with peptides targeting receptors that are hyperexpressed in triple negative breast cancers. The arsenate/iron-loaded-Hfn was endocytosed by a breast cancer cell line and showed cytotoxicity equivalent to that of free ATO on an arsenic basis, whereas the "empty" or iron-only loaded Hfn showed no cytotoxicity. Although HFn has previously been used to deliver organic drugs and imaging agents, these new results demonstrate that both Bfr and HFn can be manipulated to function

  3. Drugs@FDA: FDA Approved Drug Products

    Science.gov (United States)

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing ... Download Drugs@FDA Express for free Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  4. Drug-drug interactions of antifungal agents and implications for patient care.

    Science.gov (United States)

    Gubbins, Paul O; Amsden, Jarrett R

    2005-10-01

    Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

  5. Molecular toxicity mechanism of nanosilver

    Directory of Open Access Journals (Sweden)

    Danielle McShan

    2014-03-01

    Full Text Available Silver is an ancient antibiotic that has found many new uses due to its unique properties on the nanoscale. Due to its presence in many consumer products, the toxicity of nanosilver has become a hot topic. This review summarizes recent advances, particularly the molecular mechanism of nanosilver toxicity. The surface of nanosilver can easily be oxidized by O2 and other molecules in the environmental and biological systems leading to the release of Ag+, a known toxic ion. Therefore, nanosilver toxicity is closely related to the release of Ag+. In fact, it is difficult to determine what portion of the toxicity is from the nano-form and what is from the ionic form. The surface oxidation rate is closely related to the nanosilver surface coating, coexisting molecules, especially thiol-containing compounds, lighting conditions, and the interaction of nanosilver with nucleic acids, lipid molecules, and proteins in a biological system. Nanosilver has been shown to penetrate the cell and become internalized. Thus, nanosilver often acts as a source of Ag+ inside the cell. One of the main mechanisms of toxicity is that it causes oxidative stress through the generation of reactive oxygen species and causes damage to cellular components including DNA damage, activation of antioxidant enzymes, depletion of antioxidant molecules (e.g., glutathione, binding and disabling of proteins, and damage to the cell membrane. Several major questions remain to be answered: (1 the toxic contribution from the ionic form versus the nano-form; (2 key enzymes and signaling pathways responsible for the toxicity; and (3 effect of coexisting molecules on the toxicity and its relationship to surface coating.

  6. Evaluation of genetic diversity between toxic and non toxic Jatropha ...

    African Journals Online (AJOL)

    Massimo

    Indian varieties and a non-toxic variety of Mexican origin by means of about 400 RAPD ... evaluate the level of polymorphism and the capacity to discriminate between the ..... Population genetic software for teaching and research. Mol. Ecol.

  7. Study Drugs

    OpenAIRE

    Lam, Stephanie Phuong; Roosta, Natalie; Nielsen, Mikkel Fuhr; Meyer, Maria Holmgaard; Friis, Katrine Birk

    2016-01-01

    In recent years, students around the world, started to use preparations as Ritalin and Modafinil,also known as study drugs, to improve their cognitive abilities1. It is a common use among thestudents in United States of America, but it is a new tendency in Denmark. Our main focus is tolocate whether study drugs needs to be legalized in Denmark or not. To investigate this ourstarting point is to understand central ethical arguments in the debate. We have chosen twoarguments from Nick Bostrom a...

  8. Experience with second line drugs in frequently relapsing and steroid dependent childhood nephrotic syndrome in a large Saudi center

    Directory of Open Access Journals (Sweden)

    Khalid Alsaran, M.D.

    2017-06-01

    Conclusion: All the second line drugs in our study were equally effective. However, we recommend that the initial treatment of FR/SD nephrotic syndrome should be chosen with the least toxic yet equally efficacious drug Levamisole.

  9. Comparative analysis of three drug-drug interaction screening systems against probable clinically relevant drug-drug interactions: a prospective cohort study.

    Science.gov (United States)

    Muhič, Neža; Mrhar, Ales; Brvar, Miran

    2017-07-01

    Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs. A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated. Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems. DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.

  10. Toxicity of Uranium Adsorbent Materials using the Microtox Toxicity Test

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jiyeon [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Jeters, Robert T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Gill, Gary A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kuo, Li-Jung [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bonheyo, George T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-10-01

    The Marine Sciences Laboratory at the Pacific Northwest National Laboratory evaluated the toxicity of a diverse range of natural and synthetic materials used to extract uranium from seawater. The uranium adsorbent materials are being developed as part of the U. S. Department of Energy, Office of Nuclear Energy, Fuel Resources Program. The goal of this effort was to identify whether deployment of a farm of these materials into the marine environment would have any toxic effects on marine organisms.

  11. A COMPREHENSIVE REVIEW OF TOXIC LEADERSHIP

    Science.gov (United States)

    2016-02-05

    characteristics of a toxic leader , but labels the characteristics - leader types.  Deceptive  Autocratic  Egotistic  Incompetent  Ignorant...3 Characteristics of a Toxic Leader ...5 Table 2: Toxic Leader Characteristics

  12. National Air Toxic Assessments (NATA) Results

    Data.gov (United States)

    U.S. Environmental Protection Agency — The National Air Toxics Assessment was conducted by EPA in 2002 to assess air toxics emissions in order to identify and prioritize air toxics, emission source types...

  13. Pharmacologic treatment of acute pediatric methamphetamine toxicity.

    Science.gov (United States)

    Ruha, Anne-Michelle; Yarema, Mark C

    2006-12-01

    To report our experience with the use of benzodiazepines and haloperidol for sedation of pediatric patients with acute methamphetamine poisoning. We performed a retrospective chart review of 18 pediatric patients who were admitted to an intensive care unit for methamphetamine toxicity from January 1997 to October 2004 and treated with benzodiazepines or haloperidol. Clinical features, dose of drug received, and laboratory test results were noted. Adverse effects from the use of haloperidol such as prolonged QTc, dystonic reactions, and torsades de pointes were recorded. Eighteen patients received a benzodiazepine, the dose of which varied depending on the agent used. Twelve patients also received parenteral haloperidol. No complications developed from the use of either haloperidol or benzodiazepines. In this case series of pediatric patients poisoned with methamphetamine, parenteral benzodiazepines and haloperidol were used to control agitation. No serious adverse effects were observed from the use of these agents.

  14. THE ART OF DATA MINING THE MINEFIELDS OF TOXICITY ...

    Science.gov (United States)

    Toxicity databases have a special role in predictive toxicology, providing ready access to historical information throughout the workflow of discovery, development, and product safety processes in drug development as well as in review by regulatory agencies. To provide accurate information within a hypothesesbuilding environment, the content of the databases needs to be rigorously modeled using standards and controlled vocabulary. The utilitarian purposes of databases widely vary, ranging from a source for (Q)SAR datasets for modelers to a basis for

  15. Comprehensive Analysis of Homologous Proteins for Specific Drug ...

    African Journals Online (AJOL)

    ... minimize drug failures by predicting drug efficacy and toxicity. One of the most important pathogenic bacterium is Aeromonas species which causes tissue damage, acute gastroenteritis and neonatal septicemia. Bacterial proteins are the ultimate target to inhibit their growth and these are the executors of cellular function.

  16. Microreactor for electrochemical conversion: in drug screening and proteomics

    NARCIS (Netherlands)

    van den Brink, Floris Teunis Gerardus

    2016-01-01

    The majority of marketed drugs are metabolized through oxidation by enzymes of the cytochrome P450 family, thereby producing phase I metabolites. For pharmaceutical companies it is essential to thoroughly screen candidate drugs for potentially toxic metabolites, in order to avoid high costs

  17. Computational Modeling and Simulation of Developmental Toxicity: what can we learn from a virtual embryo? (RIVM, Brussels)

    Science.gov (United States)

    Developmental and Reproductive Toxicity (DART) testing is important for assessing the potential consequences of drug and chemical exposure on human health and well-being. Complexity of pregnancy and the reproductive cycle makes DART testing challenging and costly for traditional ...

  18. Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients

    Directory of Open Access Journals (Sweden)

    Shuyao Zhang

    2016-01-01

    Conclusion: These results indicated that the PTX Tc > 0.05 correlated with therapeutic efficacy and drug toxicity. Therefore, monitoring the PTX Tc > 0.05 other than blood concentration of PTX is necessary to optimize individual treatment.

  19. Ecotoxicogenomic assessment of diclofenac toxicity in soil.

    Science.gov (United States)

    Chen, Guangquan; den Braver, Michiel W; van Gestel, Cornelis A M; van Straalen, Nico M; Roelofs, Dick

    2015-04-01

    Diclofenac is widely used as nonsteroidal anti-inflammatory drug leaving residues in the environment. To investigate effects on terrestrial ecosystems, we measured dissipation rate in soil and investigated ecotoxicological and transcriptome-wide responses in Folsomia candida. Exposure for 4 weeks to diclofenac reduced both survival and reproduction of F. candida in a dose-dependent manner. At concentrations ≥ 200 mg/kg soil diclofenac remained stable in the soil during a 21-day incubation period. Microarrays examined transcriptional changes at low and high diclofenac exposure concentrations. The results indicated that development and growth were severely hampered and immunity-related genes, mainly directed against bacteria and fungi, were significantly up-regulated. Furthermore, neural metabolic processes were significantly affected only at the high concentration. We conclude that diclofenac is toxic to non-target soil invertebrates, although its mode of action is different from the mammalian toxicity. The genetic markers proposed in this study may be promising early markers for diclofenac ecotoxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Toxicokinetics and toxicity of atorvastatin in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Herron, C.E. [Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States); Brueckner, C.C. [Scinovo, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States); Chism, J.P. [Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States); Kemp, D.C.; Prescott, J.S. [Safety Assessment, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States); Smith, G.A. [Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States); Melich, D.H. [Safety Assessment, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States); Oleas, N. [Charles River Laboratories, Preclinical Services Montreal, 22022 Transcanadienne, Senneville, QC, Canada, H9X 3R3 (Canada); Polli, J.W., E-mail: joseph.w.polli@gsk.com [Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709 (United States)

    2015-11-15

    HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose–exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemic exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use. - Highlights: • Atorvastatin is given to reduce cholesterol and is available as a generic drug. • Co-dosing of multiple products to treat hypercholesterolemia is increasing. • This work characterized the toxicokinetics and toxicity of atorvastatin in dogs. • The toxicokinetics of two hydroxylated metabolites were

  1. Toxicokinetics and toxicity of atorvastatin in dogs

    International Nuclear Information System (INIS)

    Herron, C.E.; Brueckner, C.C.; Chism, J.P.; Kemp, D.C.; Prescott, J.S.; Smith, G.A.; Melich, D.H.; Oleas, N.; Polli, J.W.

    2015-01-01

    HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose–exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemic exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use. - Highlights: • Atorvastatin is given to reduce cholesterol and is available as a generic drug. • Co-dosing of multiple products to treat hypercholesterolemia is increasing. • This work characterized the toxicokinetics and toxicity of atorvastatin in dogs. • The toxicokinetics of two hydroxylated metabolites were

  2. Drug Facts

    Medline Plus

    Full Text Available ... Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the button ... sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse (NIDA) | ...

  3. Drugs reviews

    African Journals Online (AJOL)

    Angel_D

    tests (LFTs) to monitor hepatotoxicity (liver [hepatic] damage) is uncommon in many resource-poor ... cholesterol ester storage disease. ... The problem with many patients is that they are taking several drugs often ... Urine, saliva and other body fluids may be coloured orange-red: this can be very alarming to patients.

  4. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

  5. Drug Facts

    Medline Plus

    Full Text Available ... Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the ... información sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse ( ...

  6. Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

    Science.gov (United States)

    Mocellin, Simone; Pilati, Pierluigi; Da Pian, Pierpaolo; Forlin, Marco; Corazzina, Susanna; Rossi, Carlo Riccardo; Innocente, Federico; Ori, Carlo; Casara, Dario; Ujka, Francesca; Nitti, Donato; Lise, Mario

    2007-02-01

    In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3-4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1-6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize

  7. [Research progress on potential liver toxic components in traditional Chinese medicine].

    Science.gov (United States)

    Wu, Hao; Zhong, Rong-Ling; Xia, Zhi; Huang, Hou-Cai; Zhong, Qing-Xiang; Feng, Liang; Song, Jie; Jia, Xiao-Bin

    2016-09-01

    In recent years, the proportion of traditional Chinese medicine in scientific research and its clinical use increased gradually. The research result also becomes more and more valuable, but in the process of using traditional Chinese medicine, it also needs to pay more attention. With the gradual deepening of the toxicity of traditional Chinese medicine, some traditional Chinese medicines have also been found to have the potential toxicity, with the exception of some traditional toxicity Chinese medicine. Traditional Chinese medicine in the growth, processing, processing, transportation and other aspects of pollution or deterioration will also cause the side effects to the body. Clinical practice should be based on the theory of traditional Chinese medicine to guide rational drug use and follow the symptomatic medication, the principle of proper compatibility. The constitution of the patients are different, except for a few varieties of traditional Chinese medicines are natural herbs with hepatotoxicity, liver toxicity of most of the traditional Chinese medicine has idiosyncratic features. The liver plays an important role in drug metabolism. It is easy to be damaged by drugs. Therefore, the study of traditional Chinese medicine potential liver toxicity and its toxic components has become one of the basic areas of traditional Chinese medicine research. Based on the review of the literatures, this paper summarizes the clinical classification of liver toxicity, the pathogenesis of target cell injury, and systematically summarizes the mechanism of liver toxicity and toxic mechanism of traditional Chinese medicine. This paper provided ideas for the study of potential liver toxicity of traditional Chinese medicine and protection for clinical safety of traditional Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

  8. Drug-induced cholestasis: mechanisms, models, and markers.

    Science.gov (United States)

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

    Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Gut microbiota modulation of chemotherapy efficacy and toxicity.

    Science.gov (United States)

    Alexander, James L; Wilson, Ian D; Teare, Julian; Marchesi, Julian R; Nicholson, Jeremy K; Kinross, James M

    2017-06-01

    Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.

  10. Toxicity of heavy metals in the environment

    National Research Council Canada - National Science Library

    Oehme, F.W

    1978-01-01

    ... as the fundamental mechanisms of toxicity resulting from heavy metal chemicals. The more common toxic heavy metals, along with their biochemistry and associated clinical syndromes, are then described...

  11. 2011 NATA - Air Toxics Monitors

    Data.gov (United States)

    U.S. Environmental Protection Agency — This dataset includes annual (2005 - 2013) statistics of measured ambient air toxics concentrations (in micrograms per cubic meter) and associated risk estimates for...

  12. Borocaptate sodium (BSH) toxicity issues

    International Nuclear Information System (INIS)

    LaHann, T.

    1995-01-01

    ISU's Center for Toxicology Research has been conducting toxicity testing of borocaptate sodium (BSH) to aid in assessing if proposed human studies of BSH are likely to be acceptably safe. This report describes BSH interactions with other biological agents

  13. The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment

    Directory of Open Access Journals (Sweden)

    Shoshana Rudin

    2017-04-01

    Full Text Available Pediatric acute lymphoblastic leukemia (ALL affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP and methotrexate (MTX, are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT, nudix hydrolase 15 (NUDT15, and potentially inosine triphosphatase (ITPA, which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1 and dihydrofolate reductase (DHFR. Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1 and thymidylate synthetase (TYMS, but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

  14. Drug abuse first aid

    Science.gov (United States)

    ... use of these drugs is a form of drug abuse. Medicines that are for treating a health problem ... about local resources. Alternative Names Overdose from drugs; Drug abuse first aid References Myck MB. Hallucinogens and drugs ...

  15. Acute toxicity of ingested fluoride.

    Science.gov (United States)

    Whitford, Gary Milton

    2011-01-01

    This chapter discusses the characteristics and treatment of acute fluoride toxicity as well as the most common sources of overexposure, the doses that cause acute toxicity, and factors that can influence the clinical outcome. Cases of serious systemic toxicity and fatalities due to acute exposures are now rare, but overexposures causing toxic signs and symptoms are not. The clinical course of systemic toxicity from ingested fluoride begins with gastric signs and symptoms, and can develop with alarming rapidity. Treatment involves minimizing absorption by administering a solution containing calcium, monitoring and managing plasma calcium and potassium concentrations, acid-base status, and supporting vital functions. Approximately 30,000 calls to US poison control centers concerning acute exposures in children are made each year, most of which involve temporary gastrointestinal effects, but others require medical treatment. The most common sources of acute overexposures today are dental products - particularly dentifrices because of their relatively high fluoride concentrations, pleasant flavors, and their presence in non-secure locations in most homes. For example, ingestion of only 1.8 ounces of a standard fluoridated dentifrice (900-1,100 mg/kg) by a 10-kg child delivers enough fluoride to reach the 'probably toxic dose' (5 mg/kg body weight). Factors that may influence the clinical course of an overexposure include the chemical compound (e.g. NaF, MFP, etc.), the age and acid-base status of the individual, and the elapsed time between exposure and the initiation of treatment. While fluoride has well-established beneficial dental effects and cases of serious toxicity are now rare, the potential for toxicity requires that fluoride-containing materials be handled and stored with the respect they deserve. Copyright © 2011 S. Karger AG, Basel.

  16. The Toxicity of Depleted Uranium

    OpenAIRE

    Briner, Wayne

    2010-01-01

    Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a c...

  17. Drug-induced liver injury associated with HIV medications.

    Science.gov (United States)

    Jain, Mamta K

    2007-08-01

    Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.

  18. Cyclodextrins in drug carrier systems.

    Science.gov (United States)

    Uekama, K; Otagiri, M

    1987-01-01

    One of the important characteristics of cyclodextrins is the formation of an inclusion complex with a variety of drug molecules in solution and in the solid state. As a consequence of intensive basic research, exhaustive toxic studies, and realization of industrial production during the past decade, there seem to be no more barriers for the practical application of natural cyclodextrins in the biomedical field. Recently, a number of cyclodextrin derivatives and cyclodextrin polymers have been prepared to obtain better inclusion abilities than parent cyclodextrins. The natural cyclodextrins and their synthetic derivatives have been successfully utilized to improve various drug properties, such as solubility, dissolution and release rates, stability, or bioavailability. In addition, the enhancement of drug activity, selective transfer, or the reduction of side effects has been achieved by means of inclusion complexation. The drug-cyclodextrin complex is generally formed outside of the body and, after administration, it dissociates, releasing the drug into the organism in a fast and nearly uniform manner. In the biomedical application of cyclodextrins, therefore, particular attention should be directed to the magnitude of the stability constant of the inclusion complex. In the case of parenteral application, a rather limited amount of work has been done because the cyclodextrins in the drug carrier systems have to be more effectively designed to compete with various biological components in the circulatory system. However, the works published thus far apparently indicate that the inclusion phenomena of cyclodextrin analogs may allow the rational design of drug formulation and that the combination of molecular encapsulation with other carrier systems will become a very effective and valuable method for the development of a new drug delivery system in the near future.

  19. Toxic element contamination of natural health products and pharmaceutical preparations.

    Directory of Open Access Journals (Sweden)

    Stephen J Genuis

    Full Text Available BACKGROUND: Concern has recently emerged regarding the safety of natural health products (NHPs-therapies that are increasingly recommended by various health providers, including conventional physicians. Recognizing that most individuals in the Western world now consume vitamins and many take herbal agents, this study endeavored to determine levels of toxic element contamination within a range of NHPs. METHODS: Toxic element testing was performed on 121 NHPs (including Ayurvedic, traditional Chinese, and various marine-source products as well as 49 routinely prescribed pharmaceutical preparations. Testing was also performed on several batches of one prenatal supplement, with multiple samples tested within each batch. Results were compared to existing toxicant regulatory limits. RESULTS: Toxic element contamination was found in many supplements and pharmaceuticals; levels exceeding established limits were only found in a small percentage of the NHPs tested and none of the drugs tested. Some NHPs demonstrated contamination levels above preferred daily endpoints for mercury, cadmium, lead, arsenic or aluminum. NHPs manufactured in China generally had higher levels of mercury and aluminum. CONCLUSIONS: Exposure to toxic elements is occurring regularly as a result of some contaminated NHPs. Best practices for quality control-developed and implemented by the NHP industry with government oversight-is recommended to guard the safety of unsuspecting consumers.

  20. A review on proniosomal drug delivery system for targeted drug action

    OpenAIRE

    Radha, G. V.; Rani, T. Sudha; Sarvani, B.

    2013-01-01

    Proniosomes are dry formulation of water soluble carrier particles that are coated with surfactant. They are rehydrated to form niosomal dispersion immediately before use on agitation in hot aqueous media within minutes. Proniosomes are physically stable during the storage and transport. Drug encapsulated in the vesicular structure of proniosomes prolong the existence of drug in the systematic circulation and enhances the penetration into target tissue and reduce toxicity. From a technical po...