Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury. But what does an elevated value mean? Not what it is ...too often mistakenly believed to indicate. It is not a test of liver function. It does not necessarily predict worse effects to come (in a given person). It is not a valid measure of severity of liver injury or dysfunction. It is too unspecific to be reliable in screening for relatively rare effects on the liver. Although these are substantial limitations, ALT is a very useful biomarker if understood and used properly. It is important to consider how and why these erroneous concepts came to have such wide acceptance, and how elevations of ALT activity for evaluating patients and subjects under study might be interpreted better.
Clinical Pharmacology & Therapeutics (2012); 92 3, 332–339. doi:10.1038/clpt.2012.108
Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a ...series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)–go to (
http://www.aasld.org/dili/Pages/default.aspx
). Observations by Dr. Hyman J. Zimmerman that “drug-induced hepatocellular jaundice is a serious lesion” with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x–y log–log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for
e
valuation of
Dr
ug-
I
nduced
S
erious
H
epatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury (DILI) in clinical trials.
Drug‐induced liver injury (DILI) is a major reason drugs fail during development or are withdrawn from the market.1 The ability to predict, detect, and avoid DILI through appropriate patient ...selection and effective monitoring has proved to be an elusive goal. Many approved drugs have labeling recommendations for serum enzyme monitoring intended to detect and prevent hepatotoxicity, but such monitoring is often seen as inconvenient, uncomfortable, costly, and inefficient by both patients and doctors, and thus monitoring recommendations are poorly followed, if at all. This review considers whether monitoring works to prevent DILI, whether monitoring recommendations are derived from data or opinions, and whether any better alternatives exist.
Clinical Pharmacology & Therapeutics (2009); 85, 3, 331–334 doi:10.1038/clpt.2008.262
Drug-Related Hepatotoxicity Navarro, Victor J; Senior, John R
The New England journal of medicine,
02/2006, Letnik:
354, Številka:
7
Journal Article
Recenzirano
Given its rarity, drug-related hepatotoxicity may not be seen during the initial clinical trials of a new medication. After approval, when many more patients are exposed, toxic effects that are very ...infrequent may emerge. This review explains the difficulties in identifying the cause of hepatotoxic effects in such situations and provides clinical guidance with regard to the detection, evaluation, and possible prevention of drug-related hepatotoxicity.
This review explains the difficulties in identifying the cause of hepatotoxic effects and provides clinical guidance with regard to the detection, evaluation, and possible prevention of drug-related hepatotoxicity.
In this review, we define hepatotoxicity as injury to the liver that is associated with impaired liver function caused by exposure to a drug or another noninfectious agent. The distinction between injury and function is important, because it is mainly when function is impaired that symptoms and clinically significant disease follow. We are especially concerned with serious drug-related hepatotoxicity that is disabling or life-threatening or that requires hospitalization. Although drug-related hepatotoxicity is uncommon — for many drugs, the reported incidence is between 1 in 10,000 and 1 in 100,000 patients
1
— its true incidence is difficult to determine. The numbers . . .
Currently there are three major problems in understanding drug-induced liver injury (DILI): (1) reliably establishing whether the liver disease was caused by the drug, or by another process; (2) ...determining the true incidence of and clinical risk factors for drug-induced hepatotoxicity; and (3) elaborating the mechanisms by which injury occurs to hepatocytes and other liver cells. We have focused here on the first two problems, as issues that may be amenable to actions in the near future, but the third may take substantially longer to work out. The first problem requires sufficient information for medical differential diagnosis. There are no pathognomonic indicators of DILI; even liver biopsy is not diagnostic. Making the correct attribution of causality requires analyzing the temporal relationship of drug exposure to illness and excluding all other possible causes. The second problem, determining incidence, cannot be done entirely adequately using currently available methods, whether by clinical trials, by spontaneous adverse event reports, or by retrospective epidemiologic studies. There is need for prospective safety studies to establish the true incidence of DILI caused by a drug, to identify risk factors for it, and to collect biologic materials for analytic studies toward better understanding mechanisms of DILI.
Myocardial contrast echocardiography (MCE) is a well-established imaging technique in the assessment of patients with known or suspected coronary artery disease. The use of ultrasound contrast agents ...has optimized the evaluation of left ventricular function and, moreover, permits simultaneous assessment of the myocardial perfusion. This technique utilizes microbubbles that remain in the intravascular space and the contrast intensity reflects the concentration of the microbubbles in the myocardium. A homogeneous opacification of the myocardium after destruction of the microbubbles during high-power imaging is regarded as normal perfusion and absence of CAD. If the replenishment rate is reduced, this is suggestive of significant CAD. In comparison with other techniques, MCE shows comparable sensitivity, specificity, and diagnostic accuracy while it is an easy-to-perform bedside technique that can be a valuable tool for the clinician.
Abstract Carotid arteries frequently receive significant incidental doses of radiation during the treatment of malignant diseases, including head and neck cancer, breast cancer and lymphoma. Vascular ...injury after treatment may result in carotid artery stenosis and increased risk of neurological sequelae, such as stroke and transient ischaemic attack. The long latent interval from treatment to the development of clinical complications makes investigation of this process difficult, particularly in regard to the design of interventional clinical studies. Nevertheless, there is compelling clinical evidence that radiation contributes to carotid atherosclerosis. This overview examines the effect of radiotherapy on the carotid arteries, the underlying pathological processes and their clinical manifestations. The use of serum biomarkers in risk-prediction models and the potential value of new imaging techniques as tools for defining earlier surrogate end points will also be discussed.
To determine which proteinases are responsible for the lung destruction characteristic of pulmonary emphysema, macrophage elastase-deficient (MME$^{-/-}$) mice were subjected to cigarette smoke. In ...contrast to wild-type mice, MME$^{-/-}$ mice did not have increased numbers of macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed MME$^{-/-}$ mice that received monthly intratracheal instillations of monocyte chemoattractant protein-1 showed accumulation of alveolar macrophages but did not develop air space enlargement. Thus, macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.
Aortic stenosis is one of the most common forms of acquired valvular heart disease. The development of symptoms, namely syncope, angina, or heart failure, in patients with severe aortic stenosis ...predicts a high likelihood of mortality. Aortic valve replacement is the current standard of care. In truly asymptomatic patients, the risk of sudden death is perceived to be low; therefore many advocate conservative management of these patients until symptoms develop. Emerging data suggest that certain markers may identify subsets of asymptomatic patients who are at a high risk of cardiac events. This review critically appraises the growing plethora of adverse prognostic markers that have been identified and evaluates how these parameters may influence clinical practice and potentially identify patients in whom early surgical intervention is warranted.
Currently, two main methods are used to take online measurement of the solids moisture in fluidised bed dryers, namely microwave resonance and near infrared spectroscopy. In this paper, a new online ...approach to solids moisture measurement of batch fluidised bed dryers by electrical capacitance tomography (ECT) is presented for the first time. Based on online measurement of solids moisture, it is possible to implement feedback control and process optimisation of batch fluidised bed drying processes, aiming to increase the operation efficiency and to improve product quality. A twin-plane ECT sensor with eight electrodes in each plane is mounted in the bottom of a glass fluidisation chamber. From the adjacent electrode pairs, the water content of the solids is estimated based on the correlation between the moisture content and the permittivity value. To reduce measurement error, the effect of temperature on moisture measurement is compensated. The fluidisation velocity is estimated by a semi-empirical function based on the measured water content. The acquired information is sent to a controller to adjust the air flow rate of the fluidised bed dryer. To validate the moisture measurement by ECT, a mathematical model has been developed, based on the measured temperature and relative humidity of the outlet air. The Landweber iteration method is applied to reconstruct images. The averaged solids concentration along the radial direction at different fluidisation conditions is given and compared with results by the linear back-projection (LBP) method. Results from batch drying processes with online measurement and feedback control are given and compared with no feedback control. To compare the operation efficiency, the thermal efficiency is considered and the results show the possibility of online control and optimisation of the fluidised bed drying processes, based on online measurement of solids moisture by ECT. Some challenges and future work are discussed.
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