[Show abstract][Hide abstract] ABSTRACT: Little is published about newborn drug testing in multiple gestations. The objective of this study was to review the results of meconium drug screening in multiple births to compare drug(s) and/or drug metabolite(s) detected. A retrospective analysis was conducted using data from a national reference laboratory and an academic medical center. The data were de-identified for the reference laboratory dataset. For the academic center data, a detailed chart review of the newborn and mother's medical record was performed on cases for which one or more drug(s) and/or metabolites(s) were identified and confirmed in meconium. Meconium was analyzed for amphetamine, methamphetamine, barbiturates, benzodiazepines, cannabinoid metabolites, cocaine metabolites, methadone, opiates, oxycodone, phencyclidine and propoxyphene. One hundred and forty-two of 1,084 sets of twins and 2 of 20 sets of triplets had mismatched results. The incidence of mismatched results among the individual drug or drug classes tested was 0.9% (208 of 23,848 total results). For the panel of drug testing performed, mismatches were seen in 13% (142 of 1,084) sets of twins and 10% (2 of 20) sets of triplets. Barbiturates (33%), opiates (30%) and benzodiazepines (28%) were the most common mismatches in the national reference laboratory dataset. Benzodiazepines (89%) and opiates (51%) were most common in the academic medical center dataset with most explained by iatrogenic medications administered to one infant but not the other. Mismatches for cannabinoids most often occurred when tetrahydrocannabinol metabolites were present at a low concentration (near lower reporting limit) in one infant but not the other. Mismatched results of meconium drug testing in multiples not explainable by differences in prescribed medications are uncommon and most often occur when an analyte is barely above reporting cutoff in only one infant. Administration of iatrogenic medications to one infant but not the other(s) is another frequent cause of such mismatches.
Journal of analytical toxicology 06/2014; · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the past twenty-one years, 17 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are clobazam, ezogabine (retigabine), eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. Therapeutic drug monitoring is often used in the clinical dosing of the newer anti-epileptic drugs. The drugs with the best justifications for drug monitoring are lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and zonisamide. Perampanel, stiripentol and tiagabine are strongly bound to serum proteins and are candidates for monitoring of the free drug fractions. Alternative specimens for therapeutic drug monitoring are saliva and dried blood spots. Therapeutic drug monitoring of the new antiepileptic drugs is discussed here for managing patients with epilepsy.
[Show abstract][Hide abstract] ABSTRACT: A challenge for drug of abuse testing is presented by 'designer drugs', compounds typically discovered by modifications of existing clinical drug classes such as amphetamines and cannabinoids. Drug of abuse screening immunoassays directed at amphetamine or methamphetamine only detect a small subset of designer amphetamine-like drugs, and those immunoassays designed for tetrahydrocannabinol metabolites generally do not cross-react with synthetic cannabinoids lacking the classic cannabinoid chemical backbone. This suggests complexity in understanding how to detect and identify whether a patient has taken a molecule of one class or another, impacting clinical care.
Journal of Cheminformatics 01/2014; 6:22. · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoverification is a process of using computer-based rules to verify clinical laboratory test results without manual intervention. To date, there is little published data on the use of autoverification over the course of years in a clinical laboratory. We describe the evolution and application of autoverification in an academic medical center clinical chemistry core laboratory.
[Show abstract][Hide abstract] ABSTRACT: Immunoassays are widely used in clinical laboratories for measurement of plasma/serum concentrations of steroid hormones such as cortisol and testosterone. Immunoassays can be performed on a variety of standard clinical chemistry analyzers, thus allowing even small clinical laboratories to do analysis on-site. One limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Interfering molecules include structurally related endogenous compounds and their metabolites as well as drugs such as anabolic steroids and synthetic glucocorticoids.
[Show abstract][Hide abstract] ABSTRACT: A rapid headspace-gas chromatography (HS-GC) method was developed for the analysis of ethylene glycol and propylene glycol in plasma and serum specimens using 1,3-propanediol as the internal standard. The method employed a single-step derivitization using phenylboronic acid, was linear to 200 mg/dL and had a lower limit of quantitation of 1 mg/dL suitable for clinical analyses. The analytical method described allows for laboratories with HS-GC instrumentation to analyze ethanol, methanol, isopropanol, ethylene glycol, and propylene glycol on a single instrument with rapid switch-over from alcohols to glycols analysis. In addition to the novel HS-GC method, a retrospective analysis of patient specimens containing ethylene glycol and propylene glycol was also described. A total of 36 patients ingested ethylene glycol, including 3 patients who presented with two separate admissions for ethylene glycol toxicity. Laboratory studies on presentation to hospital for these patients showed both osmolal and anion gap in 13 patients, osmolal but not anion gap in 13 patients, anion but not osmolal gap in 8 patients, and 1 patient with neither an osmolal nor anion gap. Acidosis on arterial blood gas was present in 13 cases. Only one fatality was seen; this was a patient with initial serum ethylene glycol concentration of 1282 mg/dL who died on third day of hospitalization. Propylene glycol was common in patients being managed for toxic ingestions, and was often attributed to iatrogenic administration of propylene glycol-containing medications such as activated charcoal and intravenous lorazepam. In six patients, propylene glycol contributed to an abnormally high osmolal gap. The common presence of propylene glycol in hospitalized patients emphasizes the importance of being able to identify both ethylene glycol and propylene glycol by chromatographic methods.
[Show abstract][Hide abstract] ABSTRACT: Testing for 25-hydroxyvitamin D [25(OH)D] has increased dramatically in recent years. The present report compares overall utilization and results for 25(OH)D orders at two academic medical centers - one in New York and one in Iowa -- in order to characterize the vitamin D status of our inpatient and outpatient populations. Results are also compared to those from a national reference laboratory to determine whether patterns at these two institutions reflect those observed nationally.
Retrospective data queries of 25(OH)D orders and results were conducted using the laboratory information systems at Weill Cornell Medical College / New York Presbyterian Hospital (WCMC), University of Iowa Hospitals and Clinics (UIHC), and ARUP Laboratories (ARUP). Chart review was conducted for cases with very high or low serum 25(OH)D levels in the WCMC and UIHC datasets.
The majority of tests were ordered on females and outpatients. Average serum 25(OH)D levels were higher in female versus male patients across most ages in the WCMC, UIHC, and ARUP datasets. As expected, average serum 25(OH)D levels were higher in outpatients than inpatients. Serum 25(OH)D levels showed seasonal periodicity, with average levels higher in summer than winter and correlating to regional UV index. Area plots demonstrated a peak of increased 25(OH)D insufficiency / deficiency in adolescent females, although overall worse 25(OH)D status was found in male versus female patients in the WCMC, UIHC, and ARUP datasets. Surprisingly, improved 25(OH)D status was observed in patients starting near age 50. Finally, chart review of WCMC and UIHC datasets revealed over-supplementation (especially of >= 50,000 IU weekly doses) in the rare cases of very high 25(OH)D levels. General nutritional deficiency and/or severe illness was found in most cases of severe 25(OH)D deficiency.
25(OH)D status of patients seen by healthcare providers varies according to age, gender, season, and patient location. Improved 25(OH)D status was observed later in life, a finding that may reflect the previously described increased use of vitamin D-containing supplements in such populations. Severe vitamin D deficiency is much more common than vitamin D toxicity.
[Show abstract][Hide abstract] ABSTRACT: Ethylene glycol is a toxic organic solvent implicated in thousands of accidental and intentional poisonings each year. Osmotic demyelination syndrome (ODS) is traditionally known as a complication of the rapid correction of hyponatremia.
Our aim was to describe how patients with ethylene glycol toxicity may be at risk for developing ODS in the absence of hyponatremia.
A 64-year old female patient was comatose upon presentation and laboratory results revealed an anion gap of 39, a plasma sodium of 150 mEq/L, a plasma potassium of 3.5 mEq/L, an osmolal gap of 218, an arterial blood gas pH of 7.02, whole blood lactate of 32 mEq/L, no measurable blood ethanol, and a plasma ethylene glycol concentration of 1055.5 mg/dL. The patient was treated for ethylene glycol poisoning with fomepizole and hemodialysis. Despite having elevated serum sodium levels, the patient's hospital course was complicated by ODS.
Rapid changes in serum osmolality from ethylene glycol toxicity or its subsequent treatment can cause ODS independent of serum sodium levels.
Journal of Emergency Medicine 11/2013; · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A method for qualitative detection of 57 drugs and metabolites in umbilical cord tissue using liquid chromatography time-of-flight (TOF) mass spectrometry is described.
Results from 32 deidentified positive specimens analyzed by an outside laboratory using "screen with reflex to confirmation" testing were compared with TOF results. In addition, 57 umbilical cord tissue specimens paired with corresponding chart review data and 37 with meconium test results were analyzed by TOF. Urine drug test results from mother (n = 18) and neonate (n = 30) were included if available. Cutoff concentrations, recovery, and matrix effects were determined by analyzing fortified drug-free cord tissue and negative specimens. Cutoffs (in nanograms per gram) ranged from 1 to 10 for opioids and opioid antagonists, 5-10 for benzodiazepines and nonbenzodiazepine hypnotics, 20-40 for barbiturates, 8 for stimulants, and 4 for phencyclidine. Adequate sensitivity for the detection of cannabis exposure could not be realized with this method.
Liquid chromatography time-of-flight mass spectrometry can provide accurate and sensitive detection of in utero drug exposure using umbilical cord tissue.
Therapeutic drug monitoring 09/2013; · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction. The increasing abuse of amphetamine-like compounds presents a challenge for clinicians and clinical laboratories. Although these compounds may be identified by mass spectrometry-based assays, most clinical laboratories use amphetamine immunoassays that have unknown cross-reactivity with novel amphetamine-like drugs. To date, there has been a little systematic study of amphetamine immunoassay cross-reactivity with structurally diverse amphetamine-like drugs or of computational tools to predict cross-reactivity. Methods. Cross-reactivities of 42 amphetamines and amphetamine-like drugs with three amphetamines screening immunoassays (AxSYM(®) Amphetamine/Methamphetamine II, CEDIA(®) amphetamine/Ecstasy, and EMIT(®) II Plus Amphetamines) were determined. Two- and three-dimensional molecular similarity and modeling approaches were evaluated for the ability to predict cross-reactivity using receiver-operator characteristic curve analysis. Results: Overall, 34%-46% of the drugs tested positive on the immunoassay screens using a concentration of 20,000 ng/mL. The three immunoassays showed differential detection of the various classes of amphetamine-like drugs. Only the CEDIA assay detected piperazines well, while only the EMIT assay cross-reacted with the 2C class. All three immunoassays detected 4-substituted amphetamines. For the AxSYM and EMIT assays, two-dimensional molecular similarity methods that combined similarity to amphetamine/methamphetamine and 3,4-methylenedioxymethampetamine most accurately predicted cross-reactivity. For the CEDIA assay, three-dimensional pharmacophore methods performed best in predicting cross-reactivity. Using the best performing models, cross-reactivities of an additional 261 amphetamine-like compounds were predicted. Conclusions. Existing amphetamines immunoassays unevenly detect amphetamine-like drugs, particularly in the 2C, piperazine, and β-keto classes. Computational similarity methods perform well in predicting cross-reactivity and can help prioritize testing of additional compounds in the future.
[Show abstract][Hide abstract] ABSTRACT: Many current experiments investigating the effects of diet, dietary supplements, and pre- and probiotics on the intestinal environments do not take into consideration the potential for using bile salts as markers of environmental change. Intestinal bacteria in vertebrates can metabolize bile acids into a number of different structures, with deamidation, hydroxyl group oxidation, and hydroxyl group elimination. Fecal bile acids are readily available to sample and contain a considerable structural complexity that directly relates to intestinal morphology, bile acid residence time in the intestine, and the species of microbial forms in the intestinal tract. Here we offer a classification scheme that can serve as an initial guide to interpret the different bile acid patterns expressed in vertebrate feces.
Advances in Nutrition 01/2013; 4(1):29-35. · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Hepatitis B virus (HBV) is a common cause of viral hepatitis with significant health complications including cirrhosis and hepatocellular carcinoma. Assays for hepatitis B surface antigen (HBsAg) are the most frequently used tests to detect HBV infection. Vaccination for HBV can produce transiently detectable levels of HBsAg in patients. However, the time course and duration of this effect is unclear. The objective of this retrospective study was to clarify the frequency and duration of transient HBsAg positivity following vaccination against HBV.
The electronic medical record at an academic tertiary care medical center was searched to identify all orders for HBsAg within a 17 month time period. Detailed chart review was performed to identify all patients who were administered HBV vaccine within 180 days prior to HBsAg testing and also to ascertain likely cause of weakly positive (grayzone) results.
During the 17 month study period, 11,719 HBsAg tests were ordered on 9,930 patients. There were 34 tests performed on 34 patients who received HBV vaccine 14 days or less prior to HBsAg testing. Of these 34 patients, 11 had grayzone results for HBsAg that could be attributed to recent vaccination. Ten of the 11 patients were renal dialysis patients who were receiving HBsAg testing as part of routine and ongoing monitoring. Beyond 14 days, there were no reactive or grayzone HBsAg tests that could be attributed to recent HBV vaccination. HBsAg results reached a peak COI two to three days following vaccination before decaying. Further analysis of all the grayzone results within the 17 month study period (43 results out of 11,719 tests) revealed that only 4 of 43 were the result of true HBV infection as verified by confirmatory testing.
Our study confirms that transient HBsAg positivity can occur in patients following HBV vaccination. The results suggest this positivity is unlikely to persist beyond 14 days post-vaccination. Our study also demonstrates that weakly positive HBsAg results often do not reflect actual HBV infection, underscoring the importance of confirmatory testing. This study also emphasizes that vaccination-induced HBsAg positives occur most commonly in hemodialysis patients.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: A 21-year old female suffered a cardiac arrest after a one week history of viral illness later shown to be caused by influenza B. The patient required extended cardiopulmonary resuscitation and had further complications including compartment syndrome. METHODS: Plasma myoglobin concentration was measured using the Roche Diagnostics electrochemiluminescent myoglobin assay. RESULTS: The myoglobin concentration was 205,590μg/l in an undiluted specimen, consistent with severe rhabdomyolysis. Subsequent myoglobin concentrations measured two days later showed dramatic decreases to approximately 1000μg/l, raising suspicion of a hook effect. Dilution and re-analysis of the specimens revealed that the actual myoglobin concentrations were >395,000μg/l, with one specimen possessing an estimated myoglobin concentration of >600,000μg/l. Interestingly, three specimens from this patient did not show evidence of hook effect, with undiluted specimens producing myoglobin concentrations as high as 284,000μg/l. Retrospective analysis of myoglobin results over an 8-year period did not reveal other cases with suspicion of hook effect. The case patient had the highest myoglobin concentrations out of 7301 specimens. CONCLUSIONS: This case illustrates that while the Roche myoglobin assay has a very wide dynamic range, hook effect can occur with extremely high concentrations of plasma myoglobin.
Clinica chimica acta; international journal of clinical chemistry 09/2012; 414C:179-181. · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: False-positive drug screen results for tetrahydrocannabinol (THC) have been observed. This study investigated the rate of unconfirmed positive screen results in infant and noninfant urine samples and evaluated possible reasons for differences.
The rate of unconfirmed positive THC screen results for urine samples was determined retrospectively in 2 independent data sets (n = 14,859, reference laboratory; n = 21,807, hospital laboratory) by comparing positive immunoassay-based drug screen results with the associated results of confirmation tests. We then assessed the rate of positive THC screens for samples with varying likelihoods of cannabinoid presence to evaluate the contribution of infant-specific urine constituents to positive results. Finally, a method to detect a THC metabolite (11-hydroxy-Δ⁹-THC) that occurs in meconium was developed to determine its prevalence in infant urine.
Positive screen results failed to confirm more frequently in samples from infants (47%) than in noninfants (0.8%). The hospital laboratory observed a similar discrepancy with a different immunoassay. Infant samples with a high likelihood of containing cannabinoids despite negative confirmatory results had a similar rate of positive screening results (50%, n = 20), whereas all samples with a low likelihood of containing cannabinoids screened negative (n = 23). 11-Hydroxy-Δ⁹-THC was not detected in any infant urine sample tested (n = 16).
Conventional confirmatory methods for THC may be inappropriate for urine samples from infants. Our results suggest that one or more currently unrecognized THC-associated compounds are responsible for positive THC screen results for infant urine, as opposed to an infant-associated interference.
[Show abstract][Hide abstract] ABSTRACT: Therapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard.
In this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations.
The results suggest that a measured free phenytoin should be obtained where possible to guide phenytoin dosing. If this is not feasible, then an adjusted phenytoin can supplement a total phenytoin concentration, particularly for patients with low plasma albumin.
BMC Medical Informatics and Decision Making 02/2012; 12:7. · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients ingesting ethylene glycol, isopropanol, methanol, and propylene glycol ('toxic alcohols') often present with non-specific signs and symptoms. Definitive diagnosis of toxic alcohols has traditionally been by gas chromatography (GC), a technique not commonly performed on-site in hospital clinical laboratories. The objectives of this retrospective study were: 1) to assess the diagnostic accuracy of the osmolal gap in screening for toxic alcohol ingestion and 2) to determine the common reasons other than toxic alcohol ingestion for elevated osmolal gaps.
Electronic medical records from an academic tertiary care medical center were searched to identify all patients in the time period from January 1, 1996 to September 1, 2010 who had serum/plasma ethanol, glucose, sodium, blood urea nitrogen, and osmolality measured simultaneously, and also all patients who had GC analysis for toxic alcohols. Detailed chart review was performed on all patients with osmolal gap of 9 or greater.
In the study period, 20,669 patients had determination of serum/plasma ethanol and osmolal gap upon presentation to the hospitals. There were 341 patients with an osmolal gap greater than 14 (including correction for estimated contribution of ethanol) on initial presentation to the medical center. Seventy-seven patients tested positive by GC for one or more toxic alcohols; all had elevated anion gap or osmolal gap or both. Other than toxic alcohols, the most common causes for an elevated osmolal gap were recent heavy ethanol consumption with suspected alcoholic ketoacidosis, renal failure, shock, and recent administration of mannitol. Only 9 patients with osmolal gap greater than 50 and no patients with osmolal gap greater than 100 were found to be negative for toxic alcohols.
Our study concurs with other investigations that show that osmolal gap can be a useful diagnostic test in conjunction with clinical history and physical examination.
[Show abstract][Hide abstract] ABSTRACT: Vertebrate xenobiotic receptors are ligand-activated nuclear receptors (NRs) that bind exogenous biologically active chemicals before activating the transcription of genes involved in xenobiotic metabolism and excretion. Typically, xenobiotic receptors have ligand binding domains (LBDs) that can accommodate a structurally diverse array of molecules and in addition display high levels of inter-taxa sequence diversity suggestive of positive selection. Pursuing the idea that xenobiotic receptors may adaptively evolve to bind toxic chemicals commonly present in an organism's environment/diet, we examined ligand binding by a xenobiotic receptor orthologue of a marine filter-feeding organism. The solitary tunicate Ciona intestinalis (Phylum Chordata) genome encodes an orthologue of the vertebrate pregnane X receptor (PXR) and vitamin D receptor (VDR), here denoted CiVDR/PXRα. In a luciferase reporter assay the CiVDR/PXRα was activated, at nanomolar concentrations, by two of four natural marine microalgal biotoxins tested (okadaic acid, EC50 = 18.2 ± 0.9 nM and pectenotoxin-2, EC50 = 37.0 ± 3.5 nM) along with 1 of 11 synthetic toxicants (esfenvalerate: EC50 = 0.59 ± 0.7 μM). Two related C. intestinalis NRs, orthologous to vertebrate farnesoid X receptor and liver X receptors, respectively, along with the PXR of a freshwater fish (zebrafish, Danio rerio), were not activated by any of the 15 chemicals tested. In contrast, human PXR was activated by okadaic acid at similar concentrations to CiVDR/PXRα (EC50 = 7.2 ± 1.1 nM) but not by pectenotoxin-2. A common features pharmacophore developed for the CiVDR/PXRα ligand consisted of an off-center hydrogen bond acceptor flanked by two hydrophobic regions. The results of this study are consistent with the original hypothesis that natural toxins, present in the diet of filter-feeding marine invertebrates, may have acted as selective agents in the molecular evolution of tunicate xenobiotic receptors. Bioassays based on tunicate xenobiotic receptor activation may find application in marine environmental monitoring and bioprospecting.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Many of the general anesthetics, currently used in clinical practice, work through interactions with GABA(A) receptors. The last 2 decades has witnessed substantial progress in defining the molecular mechanisms by which general anesthetics interact with GABA(A) receptor sites. However, despite progress in the basic scientific understanding of the mechanism of action of general anesthetics, introduction of novel general anesthetic agents into clinical practice has proven quite challenging. Areas covered: The focus of this review is on the potential for translating basic science advances into the design of new and improved anesthetics. The authors review general anesthetics in current practice as well as anesthetic drug candidates in development and discuss the potential for novel anesthetic drug development. Expert opinion: Opportunities for the discovery of new anesthetics include: computational-based ligand-design, structure-based design, re-exploration of old structure-activity data, absorption, distribution, metabolism, excretion and toxicity predictions and high-throughput screening. The authors believe a lack of high-resolution three-dimensional structures of mammalian GABA(A) receptors remains a significant limiting factor in structure-based anesthetic drug design.
Expert Opinion on Drug Discovery 11/2011; 6(11):1187-201. · 2.30 Impact Factor