Drug induced mitochondrial toxicities potential idiosyncratic toxicities. Medical search. Frequent questions

The low incidence of idiosyncratic drug-induced liver injury (DILI), together with the lack of a reliable diagnostic biomarker and robust preclinical and in vitro toxicology test systems for the condition have limited our ability to define the mechanisms of DILI. (nih.gov)
Biochemical mechanisms in drug-induced liver injury: Certainties and doubts World J Gastroenterol. (toxbank.net)
Drug-induced liver injury should be considered in any acute liver injury or jaundice without evidence of biliary obstruction. (bsg.org.uk)
Idiosyncratic drug-induced liver injury (DILI) is an unpredictable type of liver injury following exposure to medication within the recommended dose which is distinctive from liver injury caused by drug overdosage, commonly caused by paracetamol overdose (POD). (bsg.org.uk)
Following a large national audit in the UK of 881 consecutive patients admitted with jaundice, where a biliary obstruction was ruled out by imaging, idiosyncratic DILI was the second most common cause of liver injury (15% of cases) after alcoholic liver disease (2). (bsg.org.uk)
Drug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. (wjgnet.com)
The second section will address novel agents associated with liver injury in 2014 (referred to as "signals"), especially in terms of clinical, research and drug development implications. (wjgnet.com)
Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset // Gastroenterology. (lvrach.ru)
Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland // Gastroenterology. (lvrach.ru)
Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study. (greenmedinfo.com)

In fact, MDMA has addictive psychoactive properties and unpredictable toxicity, and its abuse has led to an alarming number of emergency department (ED) visits worldwide. (medscape.com)
This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. (wjgnet.com)
Most importantly, many of the adverse effects mediated via RMs are idiosyncratic and hence unpredictable. (awametox.com)
9 Only three drugs - paracetamol, erythromycin and carbamazepine - have been associated with overdose pancreatitis in children, while most of the reactions appear to be idiosyncratic and therefore unpredictable, non-dose-dependent and with low incidence. (pharmaco-vigilance.eu)

This Review highlights new developments regarding the potential role of reactive metabolites, mitochondrial toxicity, host immune-response pathways and biliary transporters in the etiopathogenesis of DILI. (nih.gov)
Reactive metabolites, formed via drug metabolism in the body, are electrophilic species which can bind covalently to macromolecules such as proteins and DNA, affecting their function and potentially leading to toxicity. (cyprotex.com)
Screening and structural characterization of reactive metabolites, as one of the major efforts to reduce attrition in drug development, has increasingly become an integral part of the ADMET-guided lead optimization process in drug discovery. (cyprotex.com)

A careful review of the laboratory, clinical and histological phenotype of patients with DILI can provide potential clues to the mechanisms of disease pathogenesis, as observed with fialuridine and valproate hepatotoxicity. (nih.gov)
Liver biopsy and HLA genotyping can help clinical management by differentiating DILI from AIH and excluding DILI secondary to certain drugs. (bsg.org.uk)
Traditionally, the in vitro toxicity assays that have been used to identify molecules that carry drug-related DILI risk factors include two-dimensional (2D) cell systems and other standard preclinical model… The principal application of this assay is to rapidly screen test compounds to identify those that induce acute liver cell toxicity. (holocausto.online)

13. Guengerich F. P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity // Chem Res Toxicol. (lvrach.ru)

Reactive metabolite formation is thought to be one of the primary causes of idiosyncratic adverse drug reactions, often associated with drug-induced skin, liver and hematopoietic toxicities. (cyprotex.com)

It is important to understand the mechanisms of action and the pharmacokinetics of antiepileptic drugs (AEDs) so that these agents can be used effectively in clinical practice, especially in multidrug regimens (see the image below). (medscape.com)
The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action (see the image below). (medscape.com)
In vitro, chemicals such as drugs and pesticides have different cytotoxicity mechanisms such as destruction of cell membranes, prevention of protein synthesis, irreversible binding to receptors etc. (holocausto.online)
Cuprizone treatment is the most frequently used among the toxicant-induced MS models, which include lysolecithin and ethidium bromide, and is used to study mechanisms of oligodendrocyte turnover, astrogliosis, and microgliosis ( Blakemore and Franklin, 2008 ). (msdiscovery.org)
The mechanisms of damage can be different: immune-mediated or hypersensitivity, direct drug, inflammatory or mitochondrial toxicity. (pharmaco-vigilance.eu)

One of the unique features of mitochondria is that they contain their own small, circular DNA (deoxyribonucleic acid) and independent machinery of ribosomal and transfer RNAs (ribonucleic acid) and ribosomes for synthesis of 13 proteins encoded by the mitochondrial DNA essential for oxidative phosphorylation. (fda.gov)
Amiodarone shows typical toxicity associated with redox cycling agents: inhibition of electron transport in oxidative phosphorylation plus inhibition of fatty acid β-oxidation, which causes steatosis. (toxbank.net)
Kroll A(1), Pillukat MH, Hahn D, Schnekenburger J. The in vitro assays covered baseline toxicity in bacteria, oxidative stress, cytotoxicity in mammalian cells and yeast, estrogenicity, and anti-androgenicity. (holocausto.online)
H … In vitro assays covered baseline toxicity, oxidative stress responses, and estrogenic and antiandrogenic activity. (holocausto.online)

Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. (toxbank.net)
Hepatotoxicity (toxic effects on the liver) and cardiotoxicity (toxic effects on the heart) are the most severe problems encountered in drug development and the major reason for drug withdrawals. (holocausto.online)

or exemplifies an in vitro mechanism underlying one of these toxicities. (toxbank.net)
Prediction of Chemical Carcinogenicity in Rodents from in Vitro Genetic Toxicity Assays R AYMOND W. TENNANT, BARRY H. MARGOLIN, MICHAEL D. SHELBY, E RROL Z … As an in vivo toxicity endpoint, the acute lung inflammogenicity in a rat instillation model was compared with the in vitro toxicity endpoints comprising cytotoxicity, pro-inflammatory cytokine expression, or haemolytic potential. (holocausto.online)
In vitro toxicity assays are used to determine the potential of a new pharmaceutical, agrochemical, food additive, or other chemical product to be hazardous to humans.In vitro studies, which are performed on cultured bacterial or mammalian cells, can be used as an initial screen to avoid the unnecessary use of animals in determining which candidates should move forward for further safety testing. (holocausto.online)
The application of High Content Screening for in vitro toxicity testing is a relatively new approach in the preclinical research phase of drug development. (holocausto.online)
In regulatory testing situation these in vitro toxicity assays must be reliable, because from these tests it is only possible to generalize the data to … First Published 1995. (holocausto.online)
While toxicity test has been traditionally completed in the preclinical phase, in vitro toxicity studies in the early drug discovery stages could significantly reduce failures at a later stage and prevent economic loss. (holocausto.online)
Considering the ethical issues and the cost of in-vivo animal tests, the pharmaceutical industry now relies more on in-vitro methods for toxicity testing in the drug development phase. (holocausto.online)
The positive control induced a high degree of toxicity in all in vitro tests performed, indicating that the toxicity observed in the direct contact assay was due to in situ extraction of toxic components. (holocausto.online)

Other recognized categories of chronic liver disease include conditions induced by toxins or drugs (e.g., alcohol) and autoimmune chronic liver diseases such as primary sclerosing cholangitis, primary biliary cirrhosis and autoimmune hepatitis. (aafp.org)
Aetna considers laboratory testing for manganese medically necessary for persons with specific signs and symptoms of manganese toxicity (dyscoordination, loss of balance, confusion) who have a history of likely exposure to high levels of manganese (e.g., occupational exposures to manganese aerosols or dust in the welding or steel industries, exposure to high levels of manganese in contaminated drinking water, suspected manganese toxicity in persons on chronic total parenteral nutrition). (aetna.com)
Prolonged cuprizone exposure induces chronic demyelination and impairs the capacity of the brain to repair. (msdiscovery.org)

Incidence of drug-induced hepatic injuries: a French population-based study // Hepatology. (lvrach.ru)
Concomitant use may enhance drug efficacy by mobilizing hepatic stores and elevating plasma concentrations, particularly in very-low-birth-weight (VLBW) neonates with bronchopulmonary dysplasia. (interactionsguide.com)

On this page you will find links to comprehensive gene information for five species and a listing of NCTR publications on understanding the mechanism of mitochondrial toxicity and development of biomarkers to predict toxicity. (fda.gov)
Because there are FDA-regulated drugs (e.g., anti-HIV drugs, anti-cancer drugs) that cause mitochondrial injury, it is important to understand the mechanism of mitochondrial injury and to develop measures for prevention of mitochondrial damage. (fda.gov)
NCTR has published several papers illustrating the mechanism of mitochondrial toxicity in response to different drugs in the mouse and rat. (fda.gov)
While mitochondrial energy is vital for the survival of cells, these organelles also play an important role in the execution of apoptosis (programmed cell death), a process that serves as a major defense mechanism to remove unwanted and potentially dangerous cells. (fda.gov)
Antiepileptic drugs can be grouped according to their major mechanism of action. (medscape.com)
Some antiepileptic drugs work by acting on combination of channels or through some unknown mechanism of action. (medscape.com)
Additional references under Biochemical mechanism of toxicity. (toxbank.net)
In line with this, the levels of activated EGFR signaling drop at 48 hours and are comparable in knockout and wild-type mice, suggesting that the EGFR is inactivated through a mig-6-independent mechanism and, that other pathways, like the MET receptor pathway are induced and drive hepatocyte proliferation. (jnksignaling.com)

This NCTR MitoChip webpage is created to provide comprehensive knowledge and resources on mitochondrial function, mitochondrial injury, and mitchondrial toxicity, while also reporting progress on NCTR's contributions to mitochondrial research. (fda.gov)
Rarely, an acute idiosyncratic hepatocellular injury resembling viral hepatitis or cholestatic hepatitis occurs. (toxbank.net)
Beyond sepsis-induced inflammation, a mechanical ventilation regimen can also propagate ventilator-related injury that may precipitate ARDS. (ceufast.com)

Statin drugs increase the risk of diabetes and cause abnormal liver enzyme elevations. (greenmedinfo.com)

Destroy epithelial cells group by esterification by some drugs aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory patients. (esupport.ws)

1. Lazarou J., Pomeranz B. H., Corey P. N. Incidence of adverse drug reactions in hospitalized patients // JAMA. (lvrach.ru)

Impairment in mitochondrial function, therefore, can be injurious to these organs. (fda.gov)

Additionally, NCTR scientists have developed MitoChips for human and non-human primates for better prediction of toxicity, in addition to our findings in rodents. (fda.gov)

Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD. (bmj.com)

The effect on mitochondrial membrane potential is biphasic, with increased potential at low dose and decreased potential at high dose, implying multiple points of interaction. (toxbank.net)
10 ] derived from membrane phospholipids4 ( Figure ) radicals, one of the two drugs displaced from binding. (esupport.ws)

Continuous updates regarding new alerts, drugs, experimental compounds, and new references keep you at the knowledge front-line. (awametox.com)
Designed as a didactic tool, SpotRM with a solid knowledge base will hopefully lead to a deeper understanding of potential toxicity risks with planned test compounds and thus result in a more efficient lead selection and optimization. (awametox.com)
The drug has shown clinical adverse effects that have a proven or highly probable association with bioactivation to RMs or, regarding preclinical compounds, experiments have shown extensive formation of RMs. (awametox.com)

and the limiting toxicity in humans is normally pulmonary, with adverse events observed in 5% of patients. (toxbank.net)

The cationic amphiphilic drug and its major metabolite desethylamiodarone accumulate in hepatocyte lysosomes and mitochondria and in bile duct epithelium. (toxbank.net)
however, we cannot rule out that other proteins are induced and act together with the EGFR in driving GSK1120212 manufacturer hepatocyte proliferation. (jnksignaling.com)

5) pattern is associated with drugs such as carbamazepine, lamotrigine, phenytoin and sulfonamides (4). (bsg.org.uk)

Aetna considers laboratory testing medically necessary for heavy metal poisoning (e.g., arsenic, cadmium, copper, gold, iron, mercury) for members with specific signs and symptoms of heavy metal toxicity and/or a history of likely exposure to heavy metals. (aetna.com)

Antiepileptic drugs should be used carefully, with consideration of medication interactions and potential side effects. (medscape.com)

Human lungs are susceptible to the toxicity induced by soluble xenobiotics. (holocausto.online)

In this review, we will explain the current state and future perspective of computational toxicology related to drug safety assessment from the viewpoint of ontology thinking. (go.jp)

it should not be used against bacteria that are sensitive to drugs with a narrower spectrum of activity, such as penicillins and cephalosporins. (wikipedia.org)

In spite of having a RM alert in the structure the clinical information is insufficient to classify the drug into any of the other categories. (awametox.com)
Aetna considers the dimercaptosuccinic acid (DMSA) or ethylenediaminetetraacetic (EDTA) provocative chelation/mobilization test experimental and investigational as a means of diagnosing lead toxicity because of insufficient evidence of its effectiveness. (aetna.com)

Mitochondrial dysfunction has been implicated in the toxicities of certain diseases and many drugs. (fda.gov)
Often the drug is implicated as concause in the presence of other risk factors, typically genetic (this is the case with thiopurins) or for other underlying diseases (this is the case with Crohn's disease). (pharmaco-vigilance.eu)

Most patients with MDMA overdose improve with supportive care, but life-threatening complications may result from severe toxicity (see Treatment ). (medscape.com)
Liver failure and damage are rare but severe unintended consequences of statin drug use. (greenmedinfo.com)

Furthermore, in the "Go" or "No-Go" decision of drug development, supportive utilization of a scientifically interpretable computational toxicology system is required for human safety evaluation. (go.jp)

9. Wysowski D. K., Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions // Arch Intern Med. (lvrach.ru)

The rest of approximately 1,900 proteins (in humans) required for the performance of various mitochondrial functions are encoded by the nuclear DNA. (fda.gov)

Amiodarone has been shown to induce steatosis in both animal models and humans. (toxbank.net)

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives The Journal of Pharmacology and Experimental Therapeutics 2006 Vol. 319, No. 3. (toxbank.net)

In both the popular press and the scientific literature, linezolid has been called a "reserve antibiotic"-one that should be used sparingly so that it will remain effective as a drug of last resort against potentially intractable infections. (wikipedia.org)

For example, nickel nanoparticles (NiNPs) are used in electric capacitors, and their consumption is increasing, but there have been few reports of their toxicity and environmental effects. (go.jp)
Before MDMA became a Schedule I drug, some therapists used MDMA as an experimental therapeutic aid in marriage counseling and psychoanalysis due to its enactogenic effects, the ability to "touch within" and for increasing self-awareness. (medscape.com)
To add to this, it is generally agreed that many drugs have side-effects caused by multiple types of metabolic conversions. (awametox.com)
The drug contains an alert included in SpotRM, and there have been some reports of adverse effects that have been discussed in terms of RM formation. (awametox.com)
Despite having triggered an RM alert, the drug has been used clinically without reported findings of adverse effects that can be associated with RM formation. (awametox.com)
[ 3 ] Major causes of acquired neutropenia are infection, drugs (through direct toxicity or immune effects), and autoimmunity. (medscape.com)
Chemotherapeutic agents interact with vitamin A in various ways, from adjunctive vitamin A for nutritive support and amelioration of adverse drug effects to cotherapy using retinoids as chemotherapeutic agents. (interactionsguide.com)
Concurrent supplementation with multivitamin providing modest levels of A, D, E, and K with folate, carotenoids, and mixed tocopherols can counter potential adverse effects with little risk and minimal expense. (interactionsguide.com)
Explain to the blood that the youth last will and testament necessary to stay the pediatric endocrinologist every 3 to 6 months to track for growth, against potential adverse effects, and an eye to compliance with therapy. (mein-schoenefeld.info)

Amiodarone inhibits the mitochondrial b-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. (toxbank.net)
Unlike other toxicant-induced models, which are introduced in the brain by stereotaxic microinjections and result in focal demyelination, oral administration of cuprizone produces a global insult. (msdiscovery.org)

Mitochondria-related genes are regions on DNA (deoxyribonucleic acid), which encode proteins that are important for mitochondrial structure and function. (fda.gov)

Patients with MDMA toxicity may present with central nervous system, cardiovascular, gastrointestinal, skin, and other manifestations (see Presentation ). (medscape.com)

A drug used clinically has been withdrawn or bears regulatory warnings. (awametox.com)

2004) Drug−protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. (cyprotex.com)

At the root of MDMA's widespread popularity is the mistaken belief that it is a safe drug with little toxicity and a long duration of action. (medscape.com)
The antiarrhythmic effect of Amiodarone is due to at least two major properties: a prolongation of the myocardial cell action potential duration and refractory period (potassium channel inhibition) and noncompetitive α- and β-adrenergic inhibition. (toxbank.net)

Nsaid drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, the! (esupport.ws)

Features that represent a direct effect of the drug on the liver and that are common to the majority of long-term recipients are ultrastructural phospholipidosis, unaccompanied by clinical liver disease. (toxbank.net)

Some authors have recommended that combinations of cheaper or more cost-effective drugs (such as co-trimoxazole with rifampicin or clindamycin) be tried before linezolid in the treatment of SSTIs when susceptibility of the causative organism allows it. (wikipedia.org)
In 1940, phenytoin (PHT) was found to be an effective drug for the treatment of epilepsy, and since then it has become a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures. (medscape.com)
Ethosuximide has been used since 1958 as a first-choice drug for the treatment of absence seizures without generalized tonic-clonic seizures. (medscape.com)
It became the drug of choice in primary generalized epilepsies and in the mid 1990s was approved for treatment of partial seizures. (medscape.com)

If electron microscopic examination is expected for a potential metabolic disease, additional tissue should be fixed in 3% buffered glutaraldehyde. (basicmedicalkey.com)

In short, every structural alert is assigned a severity value of 1 to10 based on our reading of the literature and authorization documentation for the drugs most relevant to the specific alert. (awametox.com)

Details on the available acute oral and dermal toxicity studies are provided in Tables 7 and 8 . (canada.ca)

Anatomy10

Organisms12

Diseases46

Chemicals and Drugs102

Analytical, Diagnostic and Therapeutic Techniques and Equipment60

Phenomena and Processes30

Disciplines and Occupations3

Technology, Industry, Agriculture4

Information Science3

Health Care16

Liver Injury10

Unpredictable4

Metabolites3

DILI3

Chem Res Toxicol1

Reactive1

Mechanisms5

Oxidative4

Hepatotoxicity2

Vitro8

Chronic3

Hepatic2

Mechanism8

Injury3

Abnormal liver1

Inflammatory1

Incidence1

Organs1

Prediction1

Autoimmune1

Membrane2

Compounds3

Pulmonary1

Hepatocyte2

Carbamazepine1

Exposure1

Antiepileptic drugs1

Lungs1

Assessment1

Bacteria1

Insufficient2

Diseases2

Severe2

Toxicology1

Reactions1

Nuclear1

Humans1

Hepatocellular1

Potentially1

Effects9

Produces2

Proteins1

Cardiovascular1

Clinically1

Development1

Duration2

Inhibitors1

Direct1

Treatment4

Electron1

Severity1

Studies1