Injury drug-induced

Rhabdomyolysis—The breakdown of muscle tissue and release of myoglobin and intracellular electrolytes into the circulation due to a variety of causes such as crush injuries, drug-induced immobilization, and status epilepticus. It often leads to acute renal failure. 

Popper H, Schaffner F. 1959. Drug induced hepatic injury. Ann Intern Med 51 1230-1252. 

D. (1991). The decrease of superoxide dismutase activity and depletion of sulfhydryl compounds in ethanol-induced liver injury. Drug Alcohol Depend. 28, 291-294. 

A. Muhlberg, C. Linz, E. Bern, L. Tucker, M. Ver-have, and R. Grand, Identifaction of nonsteroidal anti-inflammatory drug induced gastrointestinal injury in children with juvenile rheumatoid arthritis, J. Pediatr, 122, 647 (1993). 

Reprinted from J Gin Epidemiol, Vol 46, Danan C, Benichou C. Causality assessment of adverse reactions to drugs-4. A novel method based on the conclusions of international consensus meetings- Application to drug-induced liver injuries pages 1323-1330, Copyright 1993, with permission from Elsevier. 

Although the research is limited and the techniques relatively new, some hope exists that drug-induced thinking problems may be treated by what some have called cognitive rehabilitation. Many of these techniques were developed to help victims of strokes and other brain injuries improve and recover brain functions more rapidly than they would if they were left untreated. Some of these techniques arise from the philosophy that if you exercise it, you will not lose it, meaning exercising brain functions in this instance. 

We call attention also to the web site for the Drug-Induced Liver Injury Network (DILIN) sponsored since 2003 by the National Institutes of Health (NIH), Liver Disease Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). 

Parkinson s disease/syndrome and drug-induced extrapyramidai reactions Idiopathic Parkinson s disease (paralysis agitans) postencephalitic parkinsonism arteriosclerotic parkinsonism drug-induced extrapyramidai reactions symptomatic parkinsonism following injury to the nervous system by carbon monoxide intoxication. 

Lammert, C., Einarsson, S., Saha, C Niklasson, A., Bjornsson, E. and Chalasani, N. (2008) Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury search for signals. Hepatology (Baltimore, Md), 47, 2003-2009. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

In vivo, measuring bile acids in plasma and urine should be revived as potential biomarkers in the modern metabolomic era. Then the first-order scientific question will become whether early and time-controlled fasting-level measurement of bile acid concentration in plasma and urine can become a sensitive and specific biomarker for drug-induced cholestasis and ultimately liver injury at later time-points [117] Clinical trials should be conducted to evaluate whether such bile acid measurements can be used as part of a predictive panel to identify patients who are at increased risk of drug-induced cholestasis. 

Critical Review Is There a Link between BSEP Inhibition, Drug-Induced Cholestasis and Idiosyncratic Liver Injury ... 

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

Many patients have underlying liver disease with liver function abnormalities. It may be difficult to determine superimposed drug-induced liver injury in patients with viral hepatitis, passive congestion of the liver from heart failure, fatty liver... 

Xu, J.J. et al. (2009) Cellular imaging predictions of clinical drug-induced hver injury. Toxicolo al Sciences, in press. 

Lang, C. et al. (2007) Mutations and polymorphisms in the bde salt e5q)ort pump and the multidrug resistance protein 3 assodated with drug-induced liver injury. Pharmacogenet Genomics,... 

EDA (2007) Guidance for Industry Drug-Induced Liver Injury Premarketing Clinical Evaluation (draft document). 

Bleibel, W., Kim, S., D Silva, K. and Lemmer, E.R. (2007) Drug-induced liver injury review article. Digestive Disease and Sciences, 52, 2463—2471. 

Anti-TNF therapy can give rise to serious reactions, including anaphylaxis, sometimes fatal blood disorders, tuberculosis and other infections, rare reports of lymphoma and solid tissue cancers, rare reports of serious liver injury, rare reports of drug induced lupus and rare reports of demyelinating central nervous system disorders, which prompted the FDA to change the respective labeling of these drugs. 

It may be prudent to consider liver function testing of patients being treated with nefazodone. Periodic serum transaminase testing has not been proven to prevent serious injury, but it is generally believed that early detection of drug-induced hepatic injury, along with immediate discontinuation of the medication enhances the likelihood for recovery. 

It is used in musculoskeletal disorders, trauma, sports injuries, low backache, tension headache, sprains and strains, parkinsonism including the drug induced. 

Chemical injuries to the liver depend on the type of toxic agent, the severity of intoxication, and the type of exposure, whether acute or chronic. The six basic types of liver damage are fatty liver, necrois, hepatobiliary dysfuntions, viral-hke hepatitis, and (on chronic exposure) cirrhosis and neoplasia. A number of organic chemicals and drugs induce fatty liver and hver necrosis. 

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