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Almog S.,Institute of Clinical Pharmacology and Toxicology | Almog S.,Tel Aviv University | Kurnik D.,Institute of Clinical Pharmacology and Toxicology | Kurnik D.,Tel Aviv University | And 8 more authors.
Biology of Blood and Marrow Transplantation | Year: 2011

High-dose busulfan (Bu) is frequently used in preparative myeloablative conditioning (MAC) regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). MAC and reduced-intensity conditioning (RIC) protocols for i.v. Bu infusion have been developed to achieve reliable systemic exposure while minimizing toxicity and treatment failure (relapse). The objectives of the present study were to (1) compare the pharmacokinetics (PK) of i.v. Bu in different dosing protocols, (2) compare intrasubject variability of Bu PK over repeated administrations; (3) examine the effect of concomitant administration of fludarabine on Bu PK, and (4) examine the effect of plasma concentrations of glutathione (GSH), the cosubstrate in Bu metabolism, on Bu clearance. We studied Bu PK twice in each of 46 HSCT patients (after the first and then after the middle dose of the treatment cycle) receiving one of 4 dosing protocols, 2 MAC (cumulative dose, 12.8 mg/kg) and 2 RIC (cumulative dose, 6.4 mg/kg), with daily doses administered either as an individual infusion (3.2 mg/kg) or as 4 infusions of 0.8 mg/kg each. Blood samples were obtained for 6-24 hours after dosing for measurement of Bu plasma concentrations. PK parameters were estimated using compartmental analyses. In a subgroup of patients (n = 14), GSH blood concentrations were determined before Bu administration. Dose- and weightcorrected Bu PK parameters (clearance, 0.173 ± 0.051 L/hour · kg; volume of distribution, 0.7±0.17 L/kg; half-life time, 3.0 ± 0.7 hours) did not differ among treatment protocols (all P>14) and remained stable between the first and mid-cycle doses. Fludarabine did not affect Bu PK. Blood GSH concentrations before Bu dosing were positively correlated with Bu clearance (adjusted R 2 = 0.45; P5=.009). Our data indicate that Bu PK parameters are linear, stable, and predictable in different i.v. protocols and are unaffected by coadministration of fludarabine. Differences in whole blood GSH might contribute to variability in Bu clearance. © 2011 American Society for Blood and Marrow Transplantation.


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.


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.


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.


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.


Kendler M.,University of Leipzig | Makrantonaki E.,Dessau Medical Center | Makrantonaki E.,Institute of Clinical Pharmacology and Toxicology | Kratzsch J.,University of Leipzig | And 5 more authors.
Journal of Vascular Surgery | Year: 2010

Introduction: High serum levels of estradiol are associated with clinical evidence of varicose veins in women; however, the relationship between serum sex steroid hormones and varicose veins in men is unclear. To address this issue, serum levels of testosterone, estradiol, and androstenedione were determined in the great saphenous (GSV) and cubital veins of men with varicose veins. Messenger RNA (mRNA) expression of sex steroid hormones, metabolizing enzymes, and their receptors was investigated in tissue samples of leg veins. Methods: This prospective study included 40 men, comprising 20 with varicose veins and reflux of the GSV (VM) and 20 with healthy veins (HM). All limbs were assessed by duplex ultrasound scanning of selected superficial and deep leg veins. Blood samples were taken from the cubital vein and from the GSV. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis for sex steroid hormones, their metabolizing enzymes, and receptors in saphenous veins was performed in tissue samples of varicose (n = 6) and healthy veins (n = 6). Results: The VM group had significantly higher (P < .001) mean levels for serum testosterone (44.9 nmol/L; range, 8.8-225.1) and estradiol (242.2 pmol/L; range, 79-941) in varicose saphenous veins compared with cubital veins (testosterone, 15.5 nmol/L; range, 8.4-23.3; estradiol, 93.2 pmol/L; range, 31-147). Moreover, significantly (P < .001) higher mean serum estradiol levels (133.2 pmol/L; range, 63-239) were detected in the saphenous veins of the HM group compared with cubital veins (88.15 pmol/L; range, 37-153). Both groups had similar blood counts and serum androstenedione levels in the upper and lower extremity. Interestingly, qRT-PCR revealed that the mRNA expression of 5α-reductase type 1, 5α-reductase type 2, 17, 20 lyase, 17β-hydroxysteroid dehydrogenase (17β-HSD), aromatase and 3β-HSD type 2, androgen and estrogen receptor 1 was down-regulated (P < .05) in all samples of varicose veins vs veins obtained from healthy men. Conclusion: Elevated serum estradiol and testosterone levels were detected in men with varicose veins and reflux in the GSV compared with the patient's own arm veins. Enzymes and hormonal receptors involved in steroid metabolism were down-regulated in patients with GSV reflux and varicose veins, suggestive of a negative feedback regulation. These data support the notion of a possible causal relationship between sex steroids and varicose veins in men. © 2010 Society for Vascular Surgery.


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.


Yahalom G.,Institute of Clinical Pharmacology and Toxicology | Kivity S.,Institute of Clinical Pharmacology and Toxicology | Kivity S.,Tel Aviv University | Segev S.,Institute of Clinical Pharmacology and Toxicology | And 4 more authors.
European Journal of Preventive Cardiology | Year: 2014

Background: While moderate and severe chronic kidney disease is an established independent risk factor for cardiovascular disease (CVD), the association of estimated glomerular filtration rate (eGFR) differences within the normal to mildly reduced range (from 60 to >90 ml/min/1.73m2) and CVD is less clear. Our aim was to examine the association of eGFR with incident CVD in a cohort of predominantly healthy subjects with normal to mildly reduced renal function. Design: Retrospective cohort study. Methods: We collected demographic, clinical, and laboratory parameters of subjects free of diabetes mellitus or CVD who attended annual medical screening examinations between 2001 and 2009. Main outcome measures were a new diagnosis of coronary artery disease (CAD) or cerebrovascular events (CVE). Results: During a median follow up of 4.3 years, among 10,909 subjects (mean eGFR 78.5±12.2 ml/min/1.73m2), 10.3% were diagnosed with CAD (n=1025) or CVE (n=94). Compared with subjects in the highest eGFR quintile (7≥88.8 ml/min/1.73m2), subjects in the lowest quintile (≤68.2 ml/min/1.73m2) had a hazard ratio (HR) of 1.64 (95% CI 1.35-2.00; p<0.001) for a CAD outcome, but this association was no longer significant after adjustment for age and other confounders (adjusted HR 1.08; p=0.55). Similar findings were obtained for the association of eGFR with CVE. Conclusions: In a predominantly healthy population with normal to mildly reduced renal function, lower eGFR is associated with higher risk for CVD; however, this association is not independent but merely reflects the association of age and other cardiovascular risk factors with reduced eGFR. © The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/ journalsPermissions.nav.


Lurie Y.,Institute of Clinical Pharmacology and Toxicology | Lurie Y.,Tel Aviv University | Lurie Y.,Technion - Israel Institute of Technology | Loebstein R.,Institute of Clinical Pharmacology and Toxicology | And 7 more authors.
British Journal of Clinical Pharmacology | Year: 2010

The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation. © 2010 The British Pharmacological Society.


PubMed | Institute of Clinical Pharmacology and Toxicology
Type: Journal Article | Journal: The Israel Medical Association journal : IMAJ | Year: 2013

Body packers swallow multiple packets filled with illicit drugs, mainly cocaine, in order to smuggle them across international borders. In recent years, an increasing number of body packers have been hospitalized after their detention by the police upon arrival in Israel.To characterize the clinical features and outcomes of body packers hospitalized at the Sheba Medical Center.We conducted a retrospective case series of body packers hospitalized between January 2010 and October 2012 in our medical center. Electronic medical records and imaging files were reviewed to extract clinical, laboratory and radiological data as well as details on medical treatments.We identified 23 body packers (mean age 38 +/- 10 years), 20 of whom smuggled cocaine from South America. The number of packets transported ranged from 1 to 242 (median 42) and duration of hospitalization from 1 to 14 days (median 2). Two subjects required surgical intervention. All others were treated conservatively by polyethylene glycol-electrolyte lavage solution, laxatives, or watchful waiting. Ten patients underwent a urinary screen for illicit drugs, 7 of whom tested positive for cocaine and 2 for cannabinoids. Abdominal X-rays were performed in all patients at admission, and 14 had follow-up imaging, including abdominal CT scans without contrast media in 8.The main treatment goals for body packers are the rapid excretion of drug packets and early detection of complications, i.e., drug intoxication and bowel obstruction. We suggest the use of a structured treatment approach for the in-hospital management of body packers.

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