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Kivity S.,The Chaim Sheba Medical Center | Kivity S.,Zabludovicz Center for Autoimmune Diseases | Zafrir Y.,Zabludovicz Center for Autoimmune Diseases | Loebstein R.,Institute of Clinical Pharmacology and Toxicology | And 3 more authors.
Autoimmunity Reviews | Year: 2014

Objective: Low dose (10-25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center. Patients and methods: We conducted a retrospective case series of all adult (> 18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity. Results: We identified 28 patients (age: 70.4 ± 13.7 years, range: 33-88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis ± arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n = 20, mean 0.04 ± 0.07 μg/mL range: 0-0.3) did not correlate with the degree of either neutropenia (r = - 0.36; p = 0.18) or thrombocytopenia (r = 0.44; p = 0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n = 6; mean: 0.05 ± 0.04 μg/mL) and those who survived the toxicity (n = 14 mean 0.04 ± 0.08; p = 0.45). Conclusions: Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity. © 2014 Elsevier B.V. All rights reserved. Source


Jaffe D.H.,Hebrew University of Jerusalem | Siman-Tov M.,National Health Research Institute | Gopher A.,Institute of Clinical Pharmacology and Toxicology | Peleg K.,National Health Research Institute | Peleg K.,Tel Aviv University
Journal of Forensic Sciences | Year: 2013

The breath analyzer is an indispensable tool for identifying alcohol levels among drivers. While numerous studies have shown high correlations between blood and breath alcohol concentrations, most are limited by the study design. This study seeks to assess this relationship by minimizing potential measurement bias, document time from alcohol consumption to testing, and adjusting for potential confounders. A blinded study was performed using conditions closely resembling those in the field. The Draeger 7110 MKIII IL breath analyzer was used to assess breath alcohol concentrations (BrAC). Participants were 61 healthy volunteers aged 21-37 years with body mass index ≤30 and no history of alcoholism. A total of 242 valid blood/breath tests were performed in four test sets. The study results showed a high correlation coefficient between BrAC and blood alcohol concentration (BAC) levels (r = 0.983) with high sensitivity (97%) and specificity (93%). This strong association between the breath analyzer and BAC persisted even after adjustment for various stages of alcohol absorption. These results illustrate the high diagnostic sensitivity of the breath analyzer in field-tested conditions. © 2013 American Academy of Forensic Sciences. Source


Adefurin A.,Vanderbilt University | Ghimire L.V.,Vanderbilt University | Kohli U.,Vanderbilt University | Muszkat M.,Vanderbilt University | And 6 more authors.
Hypertension | Year: 2013

Blacks have increased hemodynamic responses to both physiological and pharmacological adrenergic stimulation compared with whites, and this may contribute to the greater prevalence of hypertension in this ethnic group. A small study suggested enhanced α1-adrenoreceptor-mediated arterial vasoconstriction in the forearm vasculature of blacks compared with whites, but it is unknown whether this reflects a generalized vascular phenomenon. The objective of this study was to examine the hypothesis that there are ethnic differences in venous α1-adrenoreceptor responsiveness. Using a linear variable differential transformer, we measured local dorsal hand vein responses to increasing doses of the selective α1-adrenoreceptor agonist, phenylephrine, in 106 subjects (64 whites and 42 blacks). There was wide interindividual variability in responses to phenylephrine. The dose that produced 50% of maximal constriction (ED50) ranged from 11 to 5442 ng/min, and maximal venoconstriction (Emax) ranged from 13.5% to 100%. Blacks (geometric mean ED50 =172 ng/min; 95% confidence interval, 115-256 ng/min) were more sensitive to phenylephrine than whites (310 ng/min; 95% confidence interval, 222-434 ng/min; unadjusted P=0.026; adjusted P=0.003). Median Emax was slightly higher in blacks (89%; interquartile range, 82% to 98%) compared with whites (85%; interquartile range, 75% to 95%; P=0.07). Taken together with previous findings in arterial vessels, our results suggest a generalized increased sensitivity to α1-adrenoreceptor-mediated vasoconstriction in blacks. Increased vascular α-adrenoreceptor sensitivity could predispose to hypertension, and future studies addressing the contribution of this mechanism to ethnic differences in the prevalence of hypertension will be of interest. © 2013 American Heart Association, Inc. Source


Pietsch J.,Free University of Berlin | Pietsch J.,Institute of Clinical Pharmacology and Toxicology | Sickmann A.,Leibniz Institute for Analytical Sciences | Weber G.,FFE Service GmbH | And 6 more authors.
Proteomics | Year: 2011

The human cell lines FTC-133 and CGTH W-1, both derived from patients with thyroid cancer, assemble to form different types of spheroids when cultured on a random positioning machine. In order to obtain a possible explanation for their distinguishable aggregation behaviour under equal culturing conditions, we evaluated a proteomic analysis emphasising cytoskeletal and membrane-associated proteins. For this analysis, we treated the cells by ultrasound, which freed up some of the proteins into the supernatant but left some attached to the cell fragments. Both types of proteins were further separated by free-flow IEF and SDS gel electrophoresis until their identity was determined by MS. The MS data revealed differences between the two cell lines with regard to various structural proteins such as vimentin, tubulins and actin. Interestingly, integrin α-5 chains, myosin-10 and filamin B were only found in FTC-133 cells, while collagen was only detected in CGTH W-1 cells. These analyses suggest that FTC-133 cells express surface proteins that bind fibronectin, strengthening the three-dimensional cell cohesion. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Pea F.,Institute of Clinical Pharmacology and Toxicology | Pea F.,University of Udine | Cojutti P.,Institute of Clinical Pharmacology and Toxicology | Cojutti P.,University of Udine | And 8 more authors.
Annals of Pharmacotherapy | Year: 2011

OBJECTIVE: To describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM). CASE SUMMARY: A 63-year-old man with morbid obesity (body mass index 81.6 kg/m2) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53. DISCUSSION: High-dose daptomycin plus continuous infusion meropenem may ensure adequate empiric antimicrobial coverage in patients with possible early necrotizing fasciitis. However, in patients with morbid obesity and changing renal function, significant challenges may arise because of the hydrophilic nature of these drugs and the inaccuracy of standard methods of estimating renal function. CONCLUSIONS: Real-time TDM may represent an invaluable approach in optimizing drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function. Source

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