Langman, Loralie J.

AbstractBackground: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements.Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry.Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results.Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine.Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083–90. ©2018 AACR.

Study Objective The extended‐release ( ER ) form of venlafaxine is preferred because of improved patient adherence, but the immediate‐release (IR) form is frequently used after Roux‐en‐Y gastric bypass ( RYGB ) surgery because of concerns for malabsorption. The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER capsules occurs after RYGB . Design Prospective nonblinded single‐dose pharmacokinetic study. Setting Clinical research unit at a large tertiary care medical practice. Patients Ten adult pre–bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls. Interventions Patients were administered one venlafaxine ER 75‐mg capsule at two visits—the first visit at least 1 week before undergoing RYGB and the second visit 3–4 months after RYGB . Blood samples were collected at predetermined intervals over 48 hours after each dose, and the pharmacokinetics of venlafaxine were measured. Measurements and Main Results Plasma levels of venlafaxine and its primary metabolite, O ‐desmethylvenlafaxine ( ODV ), were compared at baseline and 3–4 months after RYGB . The areas under the serum concentration–time curves from 0–24 hours ( AUC 0–24 ) for venlafaxine (mean ± SD 734 ± 602 vs 630 ± 553 ng·hr/ml, p=0.22) and ODV (mean ± SD 894 ± 899 vs 1083 ± 972 ng·hr/ml, p=0.07) were similar before and after RYGB . Using a bioequivalence approach, differences in pre‐ RYGB and post‐ RYGB values of AUC 0–24 , peak serum concentration, and time to peak serum concentration were not statistically significant for either venlafaxine or ODV. Conclusion This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite, ODV , absorbed from a venlafaxine ER capsule or the time over which it is absorbed.

Background: Tumescent anesthesia antibiotic delivery (TAAD) consists of subcutaneous infiltration of antibiotic(s) dissolved tumescent lidocaine anesthesia. Tumescent lidocaine anesthesia contains lidocaine (≤ 1 g/L), epinephrine (≤ 1 mg/L), sodium bicarbonate (10 mEq/L) in 0.9% saline. Our aim was to measure cefazolin and metronidazole concentrations over time in subcutaneous tumescent interstitial fluid (TISF) after TAAD, in serum after TAAD and after intravenous antibiotic delivery (IVAD). We hypothesize that the pharmacokinetic/pharmacodynamic profiles of TAAD + IVAD are superior to IVAD alone for the prevention of surgical site infections and biofilms. Methods: Concentrations of cefazolin and metronidazole in TISF and serum following TAAD and in serum following IVAD were compared in 5 female volunteers. Subjects received cefazolin or cefazolin plus metronidazole by IVAD alone and by TAAD alone. One subject also received concomitant IVAD and TAAD of these 2 antibiotics. Sequential samples of serum or subcutaneous TISF were assayed for antibiotic concentration. Results: Cefazolin (1 g) by TAAD resulted in an area under the curve of the concentration–time profile and a maximum concentration (Cmax) in subcutaneous tissue that were 16.5 and 5.6 times greater than in serum following 1 g by IVAD. Metronidazole (500 mg) by TAAD resulted in an area under the curve and Cmax that were 8.1 and 24.7 times greater in TISF, than in serum after 500 mg by intravenous delivery. IVAD + TAAD resulted in superior antibiotic concentrations to IVAD alone. Conclusions: TAAD + IVAD produced superior antibiotic bioavailability in both subcutaneous interstitial fluid and serum compared with IVAD alone. There was no evidence that TAAD of cefazolin and metronidazole poses a significant risk of harm to patients.

Background: Reliability of continuous glucose monitors (CGM) is a prerequisite for therapeutic dosing of insulin without the need for confirmatory blood glucose meter measurements. Interference of CGMs with commonly prescribed substances has not been extensively evaluated. Methods: We sought to undertake a novel pilot study to determine the susceptibility of FDA-approved CGM systems (Medtronic Guardian Sof-Sensor, Dexcom G4 Platinum) to erroneous readings in the presence of common medications. CGMs were placed on the abdomen of healthy subjects 48 hours prior to study. Subjects were admitted to the Clinical Research Trials Unit (CRTU) on the evening before study and fed a standard supper. The following morning, an oral medication was administered in the fasted state and blood was sampled for 9 hours. CGM values were compared to ambient glucose (measured with YSI) to observe variations in CGM readings. Microdialysis catheters were also placed in the abdomen to sample interstitial fluid (ISF) for drug concentrations. Results: Nineteen healthy drug-naïve subjects without diabetes participated in the study. A drug/substance was tested up to a maximum of nine times on separate occasions. Comparison of CGM glucose patterns to actual plasma glucose concentrations show several drugs, including lisinopril, albuterol, and acetaminophen, appear to interfere with commonly used CGM devices. Wine also interfered with CGM readings. Conclusions: We conclude there is some evidence of CGM interference with lisinopril, albuterol, acetaminophen, atenolol, and red wine. Future studies are required to address interference with newer sensors being approved or in the process of approval.

ObjectiveTo study the relationship between serum hydroxychloroquine (HCQ) concentrations and flares of systemic lupus erythematosus (SLE) in a longitudinal cohort of patients.MethodsPatients who fulfilled ≥4 American College of Rheumatology classification criteria for SLE and had been treated with HCQ for >6 months were studied. Blood was assayed for HCQ levels by tandem mass spectrometry. Patients were serially assessed for disease activity, using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and flares (SELENA flares instrument). Comparison of the mean summated SLEDAI scores over time and rates of flares in groups with different HCQ levels was performed by the Kruskal‐Wallis test.ResultsA total of 276 SLE patients were studied (93% women, mean ± SD age 41.0 ± 13.8 years). The proportion of patients with HCQ levels <10 (total noncompliance), 10–500 (subtherapeutic), and >500 ng/ml (therapeutic) was 11%, 77%, and 12%, respectively. HCQ levels correlated significantly with the prescribed dose but not with body weight or renal function. The prescribed HCQ dose also correlated significantly with baseline SLEDAI scores, indicating that higher doses were used for more active manifestations. After a mean ± SD observation period of 32.5 ± 5.5 months, the mean summated SLEDAI score and the incidence of SLE flares was not statistically different among patients with different baseline HCQ levels. In a subgroup of 73 patients with serologic and clinical remission and having therapeutic HCQ levels, a trend of lower disease activity and fewer incidences of flares was observed.ConclusionNoncompliance and subtherapeutic serum HCQ levels were seen frequently in these SLE patients, which was partly due to the low prescribed dose. In patients in remission, higher HCQ concentrations were associated with a trend showing fewer flares over time.

SummaryBackgroundThe optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg·L−1.MethodsAdolescents aged 12–19 years undergoing idiopathic scoliosis correction were administered 0.25 mg·kg−1 racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70‐kg person using allometric models.ResultsA three‐compartment linear disposition model best described observed time–concentration profiles. Population parameter estimates (between‐subjects variability) were central volume (V1) 19.1 (126%) L 70 kg−1, peripheral volumes of distribution V2 65.5 (60%) L 70 kg−1, V3 485 (23%) L 70 kg−1, clearance (CL) 9.3 (11%) L·h−1·70 kg−1, and inter‐compartment clearances Q2 282 (95%) L·h−1 70 kg−1, Q3 139 (42%) L·h−1 70 kg−1. The terminal elimination half‐life was 44.4 h. The mean observed methadone concentration was <58 mcg·L−1 by the first hour after administration.ConclusionsCurrent pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg‐1) with an infusion (0.1–0.15 mg·kg−1·h−1 for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.

Abstract A recent report indicated significant interference of naproxen with total bilirubin measurement when using the Jendrassik and Grof method. We explored the possibility of avoiding this interference by using a different method. We observed that naproxen has no effect on total bilirubin measurement by any method, but O-desmethylnaproxen (the naproxen metabolite) interfered significantly with total bilirubin assays using the Jendrassik and Grof method (Beckman Coulter [Brea, CA] and Siemens [Tarrytown, NY] bilirubin method). The Roche (Indianapolis, IN) bilirubin assay based on a different method was not affected. When serum samples of 9 patients receiving naproxen were analyzed for total bilirubin level, we observed good correlation in total bilirubin values measured by all 3 methods in 7 of 9 patients with therapeutic naproxen concentrations. In contrast, in 2 patients with elevated naproxen levels, the total bilirubin values observed by using the Beckman and Siemens methods were significantly higher than the value obtained by the Roche assay. The naproxen metabolite interferes with assays based on the Jendrassik and Grof method but not with the Roche bilirubin assay.