BIOTIN INTERFERENCE WITH ROUTINE CLINICAL IMMUNOASSAYS: UNDERSTAND THE CAUSES AND MITIGATE THE RISKS.

OBJECTIVE: The objectives of this report are to review the mechanisms of biotin interference with streptavidin/biotin-based immunoassays, identify automated immunoassay systems vulnerable to biotin interference, describe how to estimate and minimize the risk of biotin interference in vulnerable assays, and review the literature pertaining to biotin interference in endocrine function tests. METHODS: The data in the manufacturer's "Instructions for Use" for each of the methods utilized by seven immunoassay system were evaluated. We also conducted a systematic search of PubMed/MEDLINE for articles containing terms associated with biotin interference. Available original reports and case series were reviewed. Abstracts from recent scientific meetings were also identified and reviewed. RESULTS: The recent, marked, increase in the use of over-the-counter, high-dose biotin supplements has been accompanied by a steady increase in the number of reports of analytical interference by exogenous biotin in the immunoassays used to evaluate endocrine function. Since immunoassay methods of similar design are also used for the diagnosis and management of anemia, malignancies, autoimmune and infectious diseases, cardiac damage, etc., biotin-related analytical interference is a problem that touches every area of internal medicine. CONCLUSION: It is important for healthcare personnel to become more aware of immunoassay methods that are vulnerable to biotin interference and to consider biotin supplements as potential sources of falsely increased or decreased test results, especially in cases where a lab result does not correlate with the clinical scenario. ABBREVIATIONS: FDA = U.S. Food & Drug Administration FT3 = free tri-iodothyronine FT4 = free thyroxine IFUs = instructions for use LH = luteinizing hormone PTH = parathyroid hormone SA/B = streptavidin/biotin TFT = thyroid function test TSH = thyroid-stimulating hormone.

Geographic Variation in Rosiglitazone Use Surrounding FDA Warnings in the Department of Veterans Affairs.

BACKGROUND: Geographic variation in the use of prescription drugs, particularly those deemed harmful by the FDA, may lead to variation in patient exposure to adverse drug events. One such drug is the glucose-lowering drug rosiglitazone, for which the FDA issued a safety alert on May 21, 2007, following the publication of a meta-analysis that suggested a 43% increase in the risk of myocardial infarction with the use of rosiglitazone. This alert was followed by a black box warning on August 14, 2007, that was updated 3 months later. While large declines have been documented in rosiglitazone use in clinical practice, little is known about how the use of rosiglitazone and other glucose-lowering drugs varied within the Department of Veterans Affairs (VA), surrounding the FDA alerts. Understanding this variation within integrated health care systems is essential to formulating policies that enhance patient protection and quality of care. OBJECTIVE: To document variation in the use of rosiglitazone and other glucose- lowering drugs across 21 Veterans Integrated Service Networks (VISNs). METHODS: We conducted a retrospective analysis of drug use patterns for all major diabetes drugs in a national cohort of 550,550 veterans with diabetes from 2003 to 2008. This included the time periods when rosiglitazone was added to (November 2003) and removed from (October 2007) the VA national formulary (VANF). We employed multivariable logistic regression models to statistically estimate the association between a patient's location and the patient's odds of using rosiglitazone. RESULTS: Aggregate rosiglitazone use increased monotonically from 7.7%, in the quarter it was added to the VANF (November 4, 2003), to a peak of 15.3% in the quarter when the FDA issued the safety alert. Rosiglitazone use decreased sharply afterwards, reaching 3.4% by the end of the study period (September 30, 2008). The use of pioglitazone, another glucose-lowering drug in the same class as rosiglitazone, was low when the FDA issued the safety alert (0.4%) but increased sharply afterwards, reaching 3.6% by the end of the study period. Insulin use increased monotonically; metformin use remained relatively flat; and sulfonylurea use exhibited a general declining trend throughout the study period. Statistically significant geographic variation was observed in rosiglitazone use throughout the study period. The prevalence range, defined as the range of minimum to maximum use across VISNs was 3.7%-12.4% in the first quarter (January 1 to March 31, 2003); 1.0%-5.5% in the last quarter of study period (July 1 to September 30, 2008); and reached a peak of 9.6%-25.5% in the quarter when the FDA safety alert was issued (April 1 to March 31, 2007). In 5 VISNs, peak rosiglitazone use occurred before the FDA issued the safety alert. The odds ratio of using rosiglitazone in a given VISN varied from 0.55 (95% CI = 0.52-0.59; VISN 10) to 1.58 (95% CI = 1.50-1.66; VISN 15), with VISN 1 being the reference region. The variation was higher in the periods after the FDA issued the safety alert. Much less variation was observed in the use of pioglitazone, metformin, sulfonylurea, and insulin. CONCLUSIONS: Our results show statistically significant variation in the way VISNs within the VA responded to the FDA alerts, suggesting a need for mechanisms that disseminate information and guidelines for drug use in a consistent and reliable manner. Further study of regions that adopted ideal practices earlier may provide lessons for regional leadership and practice culture within integrated health care systems.

Vitamin E prevents ethanol-induced inflammatory, hormonal, and cytotoxic changes in reproductive tissues.

Ethanol causes decreased function of the hypothalamic-pituitary-gonadal (HPG) axis. Ethanol resulted in inflammatory changes in HPG manifested by increased concentrations of pro-inflammatory cytokines. Since, such cytokines have deleterious effects on functions of HPG, it seemed possible that ethanol's suppressive action could be due, at least in part, to this inflammation. Since oxidative stress can cause inflammation, we have used the antioxidant vitamin E to test, whether reducing inflammation might protect reproductive functions from ethanol. Rats were fed an ethanol diet or pair fed identically without ethanol for a 3-week period. For the last 10 days, animals were given 30 IU/kg or 90 IU/kg or vehicle. Ethanol significantly increased hypothalamic, pituitary and testicular TNF-alpha and IL-6, all changes prevented by the higher dose of vitamin E. Also, ethanol induced changes in LHRH, LH, testosterone, and testicular germ cell apoptosis were similarly prevented by vitamin E. These data strikingly show that vitamin E protects the HPG from deleterious effects of ethanol and suggests that the mechanism of this protection might be both anti-inflammatory and antioxidant.

Effects of chronic ethanol (EtOH) administration on pro-inflammatory cytokines of the hypothalamic-pituitary-gonadal (HPG) axis in female rats.

We and others have investigated the effects of acute and chronic ethanol (EtOH) administration on function of the hypothalamic-pituitary-gonadal (HPG) axis in female rats, consistently finding EtOH to be detrimental. There are now substantial data that pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6), have anti-reproductive effects. If EtOH increased levels of these cytokines, such data would be consistent with, though not necessarily prove, a cytokine mediated mechanism for EtOH's deleterious effects on reproduction. Young adult female Sprague Dawley rats were used. In the experiment reported here, the Lieber DeCarli diet was used, with animals fed a 36% EtOH containing diet or pair fed an identical diet which contained dextrimaltose instead of EtOH. This was done for 4 to 6 weeks. TNFalpha and IL-6 were measured in the hypothalamus, pituitary, and ovary by ELISA. EtOH exposure resulted in significant increases in TNFalpha and IL-6 in hypothalami, pituitaries, and ovaries. The data reported here are the first to show consistent stimulatory effects of EtOH exposure on cytokines in the reproductive axis of female rats. Because the effects of these cytokines are generally anti-reproductive, these data provide a rational for more rigorous testing of the notion that part of EtOH's deleterious HPG effects may be due to such immuno-endocrine interactions.

The impact of burn injury and ethanol on the cytokine network of the mouse hypothalamus: reproductive implications.

Nearly 50% of the patients admitted to hospitals for burn injuries have detectable levels of alcohol (EtOH) in their circulation. In fact, EtOH is often a causal factor in their injury. It is well known that EtOH as well as burn injury disrupt function of the hypothalamic-pituitary-gonadal (HPG) axis. The cellular mechanisms by which EtOH and/or burn impacts on the HPG are not entirely understood. In the studies reported here, we tested the hypothesis that these injuries mediated their effects by local hypothalamic inflammation. Young adult male mice were subjected to either a 15% total body surface area, full thickness scald, to EtOH, or to both and compared to appropriate controls. They were sacrificed 48 h later. EtOH and burn, as well as the combined injury, consistently and impressively reduced serum testosterone, while increasing hypothalamic concentrations of all three of the pro-inflammatory cytokines, TNFalpha, IL-1beta, and IL-6. In general, the increases induced by burn were greater than those caused by EtOH and the effect of the combined insult was not additive. Hypothalamic concentrations of LHRH were also increased. The data are consistent with the idea that EtOH and/or burn, as models of critical illness, medicate their hypothalamic suppressive effects via increase in pro-inflammatory cytokines.