Yoseph Caraco | The Hebrew University of Jerusalem (original) (raw)

Papers by Yoseph Caraco

Clinical Pharmacokinetics

Frontiers in Pharmacology

The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability... more The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability. The objective of the study was to compare CYP2C9 activity by using Phenytoin Metabolic Ratio (PMR) between Ethiopian and non-Ethiopian Jews. PMR was derived from the ratio of p-HPPH in 24 h urine collection to plasma phenytoin, 12 h (PMR24/12) or 24 h (PMR24/24) after the administration of 300 mg phenytoin. Analysis of CYP2C9*2, *3, *5, *6, *8, and *11 was carried by direct sequencing. PMR was significantly correlated with CYP2C9 genotype in both groups (p < 0.002). Mean PMR values were similar among Ethiopians and non-Ethiopians despite the fact that the fraction of non-carriers of CYP2C9 variant alleles was significantly different (85 vs. 53%, respectively, p < 0.001). However, among non-carriers of CYP2C9*2, *3, *5, *6, *8, and *11 variant alleles, PMR24/12 and PMR24/24 values were 30 and 34% greater respectively in the non-Ethiopians group (p < 0.001). In conclusion-CYP2C9 activity as measured by PMR is similar in Ethiopian and non-Ethiopian Jews. However, among non-carriers of CYP2C9 variant alleles accounting for 85% of Ethiopian Jews, CYP2C9 activity is decreased by approximately one third as compared with non-Ethiopian Jews. Unique genetic CYP2C9 polymorphisms occurring only in Ethiopians may account for this difference.

Blood, 2017

Introduction: Lifelong blood cell production is dependent on rare hematopoietic stem cells (HSCs)... more Introduction: Lifelong blood cell production is dependent on rare hematopoietic stem cells (HSCs) to perpetually replenish mature cells via a series of lineage-restricted intermediates. The bulk of HSCs are CD34+, however, most CD34+ cells are lineage-restricted progenitors and HSCs remain rare. HSCs can be enriched further based on CD45RA, Thy1 (CD90), and CD38 expression. Loss of CD90 expression was proposed to be sufficient to separate CD34+CD38−CD45RA− CD90+ HSCs from CD34+CD38−CD45RA− CD90- multipotent progenitors (MPPs). Recently, it was demonstrated that the expression CD49f is a specific HSC marker. Single CD49f(+) cells were highly efficient in generating long-term multilineage grafts, and the loss of CD49f expression identified transiently engrafting MPPs. Results: CD34+ cells were purified from BL-8040 and G-CSF mobilized grafts and stained for CD38, CD45RA, CD90, and CD49f. The percentage of CD34+CD38- hematopoietic stem and progenitors was similar in both grafts (Figure...

Supplemental Material for Lochmuller et al Neurology: Table e-1. Change from Baseline to Week 48 ... more Supplemental Material for Lochmuller et al Neurology: Table e-1. Change from Baseline to Week 48 in UEC and LEC Individual Muscle Groups with Hand-Held Dynamometry; Figure e-1. UX001-CL301 CONSORT Flow Diagram; UX001-CL301 Protoco

Objective: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), ... more Objective: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. Methods: UX001-CL301 was a Phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE Myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6g/day or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by Upper Extremity Composite (UEC) score. Key secondary endpoints included change in Lower Extremity Composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. Results: Eighty-nine patients were randomized (Ace-ER n = 45; Placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs Placebo -2.99 kg; LSM difference (confidence interval [CI]) 0.74 (-1.61, 3.09); p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83, 2.86); knee extension strength -0.40 (-2.38, 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01, 0.57). Gastrointestinal events were the most common AEs. Conclusions: Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy

Molecular Diagnosis & Therapy, 2016

Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requiremen... more Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CL) among healthy subjects carrying different CYP2C9 genotypes. Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n = 69), CL was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n = 41) CYP2C9*3 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Clinicaltrials.gov Identifier NCT00162474.

Clinical Pharmacology & Therapeutics, 2005

ABSTRACT AimTo examine the correlation between PMR, a phenotypic marker of CYP2C9, and formation ... more ABSTRACT AimTo examine the correlation between PMR, a phenotypic marker of CYP2C9, and formation clearance (CLf) of (S)-7-OH-warfarin (S7HW), the CYP2C9 mediated major metabolite of (S)-warfarin, in order to evaluate whether PMR is predictive of warfarin (W) maintenance dose.MethodsCYP2C9 activity was evaluated by way of PMR defined as the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) content in a 24 hours urine collection to mid-interval plasma phenytoin concentration on 31 hospitalized patients prior to W initiation. Once stable anticoagulation was reached, CLf of S7HW was derived from the ratio of urinary S7HW in a 24 hours collection to mid-interval plasma (S)-W concentration.ResultsA significant correlation was noted between PMR and CLf of S7HW (r=0.66, p=0.01), both of which exhibited marked inter-individual variability (49 and 31.9-fold, respectively). CLf of S7HW was greater in CYP2C9*1 homozygous (n=10,15.2±6.6 ml/min/kg*1000, 95% CI, 10.5 to 19.9) or carriers of one variant allele (n=17, 12.9±6.4 ml/min/kg*1000, 95% CI, 9.6 to 16.2) than in carriers of 2 variant alleles (n=4, 2.50±1.2 ml/min/kg*1000, 95% CI, 0.5 to 4.5, p<0.05).Conclusions These preliminary findings suggest that CYP2C9 activity as evaluated by PMR can be predictive of W oxidation to S7HW.Clinical Pharmacology & Therapeutics (2005) 77, P61-P61; doi: 10.1016/j.clpt.2004.12.122

Clinical Pharmacology & Therapeutics, 1996

To compare the pharmacokinetics and dynamics of omeprazole in white and Chinese subjects. This do... more To compare the pharmacokinetics and dynamics of omeprazole in white and Chinese subjects. This double-blind two-stage study, performed in the clinical research center of a university hospital, evaluated 15 healthy nonsmoking men (eight white subjects and seven Chinese extensive metabolizers of mephenytoin). Blood samples were obtained over 24 hours after the eighth omeprazole dose (40 mg/day). Omeprazole, omeprazole sulfone, and hydroxyomeprazole pharmacokinetics were calculated from the respective plasma concentration-time curves. Twelve- and 24-hour integrated plasma gastriun (AUCgas12 and AUCgas24) were calculated from the respective plasma gastrin concentrations. A week before the initiation of omeprazole the activities of CYP2D6, CYP2C19, and CYP3A4 were determined by previously established methods. Omeprazole concentrations were significantly lower (mean area under the plasma concentration time curve extrapolated to infinity [AUCO-infinity] +/- SEM; 7.53 +/- 1.21 versus 12.80 +/- 2.13 mumol.hr.L-1, respectively; p < 0.05) and its oral clearance greater (319 +/- 60 versus 183 +/- 35 ml/min, respectively; p < 0.05) in the white subjects than in the Chinese subjects. Omeprazole and omeprazole sulfone AUCO-infinity values were well correlated with the S/R mephenytoin ratio (r = 0.82 and r = 0.84, respectively; p < 0.001) and with urinary 4'-hydroxymephenytoin (r = -0.58 [p < 0.03] and r = -0.52 [p < 0.02], respectively). Fasting gastrin, AUCgas12, and AUCgas24 were significantly greater in the Chinese subjects than in the white subjects (30.0 +/- 6.4 versus 14.4 +/- 1.2 pmol, respectively [p < 0.02]; 661 +/- 114 versus 334 +/- 38 pmol.hr.L-1, respectively [p < 0.002]; and 1414 +/- 228 versus 747 +/- 99 pmol.hr.L-1, respectively [p < 0.004]). In addition, the S/R mephenytoin ratio and omeprazole AUCO-infinity correlated with the extent of omeprazole induced hypergastrinemia. The metabolism of omeprazole and the rise in gastrin concentration after its administration is genetically determined and ethnically dependent.

The Journal of pharmacology and experimental therapeutics, 1997

Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmac... more Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in ...

Clinical Pharmacology & Therapeutics, 2003

Clinical Pharmacology & Therapeutics (2003) 73, P78–P78; doi:

Pharmacotherapy

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders ... more Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.

Southern Medical Journal, 2000

EMPYEMA AFTER PNEUMONECTOMY is uncommon and occurs in 2% to 3% of patients, usually soon after su... more EMPYEMA AFTER PNEUMONECTOMY is uncommon and occurs in 2% to 3% of patients, usually soon after surgery. 1,2 The occurrence of delayed empyema is rare, probably reflecting the low survival rates of patients with lung cancer. Delayed-onset empyema is usually difficult to diagnose, which explains the high morbidity and mortality associated with this condition. 3-5 A new air-fluid level on chest x-ray film or the appearance of empyema necessitatis may lead to the correct diagnosis, but in most cases no specific clues are present. 5 We report a case of pleural empyema, which developed 3 1 / 2 years after pneumonectomy for lung cancer and was treated successfully by systemic antibiotic and pleural cavity irrigation.

Pharmacogenetics and Genomics, 2007

Single nucleotide polymorphisms at nucleotides 46, 79 and 491 of the beta2 adrenergic receptor (b... more Single nucleotide polymorphisms at nucleotides 46, 79 and 491 of the beta2 adrenergic receptor (beta2AR) gene modify its pharmacological properties and may alter the response to agonists. The purpose of this study was to evaluate the role played by beta2AR polymorphisms on isoproterenol-induced relaxation of internal mammary arteries ex vivo. Internal mammary leftover segments were collected from 96 patients undergoing coronary artery bypass operation. Vascular rings were allowed to reach equilibrium with physiological Krebs solution before precontraction with U46619. Using the organ bath technique, cumulative dose-response curve of isoproterenol was constructed and average EC50 calculated. beta2AR genotyping was performed using a PCR-RFLP analysis. Arterial segments obtained from Gly16 homozygotes displayed reduced sensitivity to isoproterenol compared with carriers of Arg16 allele(s) [Mean (-log) EC50+/-SD, 6.42+/-0.24, 95% confidence interval (CI) 6.32-6.53 vs. 6.67+/-0.25, 95% CI 6.62-6.73, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001]. Among Gly16 homozygotes, the presence of two Glu27 alleles restored vascular response to the level noted among Arg16 carriers (6.58+/-0.17, 95% CI 6.41-6.76). The least response to isoproterenol was noted in a single patient carrying the Gly16Gly-Gln27Glu-Thr164Ile combined genotype requiring almost six-fold higher isoproterenol concentration than carriers of the wild-type genotype to achieve half the maximal arterial dilatation (17.78 x 10(-7) vs. 3.01 x 10(-7) +/- 2.62 x 10(-7) mol/l). Vascular dilatation by isoproterenol is determined by a complex interaction between polymorphisms at nucleotides 46, 79 and 491 of the beta2AR gene. Further studies are warranted to evaluate the effect of additional polymorphisms in the coding and noncoding regions on vascular reactivity.

Pharmacogenetics, 2001

CYP2C9 mediates the oxidative metabolism of approximately 10% of drugs, some of which are charact... more CYP2C9 mediates the oxidative metabolism of approximately 10% of drugs, some of which are characterized by a narrow therapeutic index. We aimed to validate genotype method and phenotype methodology, for evaluation of CYP2C9 activity in vivo. Thirty-one healthy subjects (22 male) received a single 300 mg dose of phenytoin. Blood was drawn periodically and urine was collected at intervals for 96 h. Plasma phenytoin and 5-(4-hydroxyphenyl)-5phenylhydantoin (p-HPPH) and urine S and R enantiomers of p-HPPH were determined by high-performance liquid chromatography. CYP2C9 genotyping was obtained by polymerase chain reaction followed by digestion with Sau96I and StyI for the identi®cation of CYP2C9 Ã 2 and CYP2C9 Ã 3, respectively. Eighteen subjects were CYP2C9 Ã 1 homozygous, seven were CYP2C9 Ã 2 heterozygous, four were CYP2C9 Ã 3 heterozygous, one was CYP2C9 Ã 2 homozygous and one was compound CYP2C9 Ã 2/CYP2C9 Ã 3 heterozygous. The allele frequencies of CYP2C9 Ã 1, CYP2C9 Ã 2 and CYP2C9 Ã 3 were 0.76 [95% con®dence interval (CI) 0.73±0.79], 0.16 (95% CI 0.13±0.19) and 0.08 (95% CI 0.05±0.11), respectively. The CYP2C9-mediated production of (S)-p-HPPH represented the major metabolic pathway of phenytoin biotransformation as its excretion accounted for 95.6 + 0.9% of`total' p-HPPH excretion over the 96 h collection interval. Phenytoin metabolic clearance to produce (S)-p-HPPH (PMC), correlated signi®cantly with (S)-p-HPPH (or`total' p-HPPH) content in 0±8, 0±12 and 0±24 urine collections (r 0.88, 0.85 and 0.89, respectively) and with phenytoin metabolic ratio (PMR) de®ned as the ratio of urine (S)-p-HPPH (or`total' p-HPPH) to mid-interval plasma phenytoin (r 0.90, 0.88 and 0.94, respectively). PMC and PMR exhibited a gene±dose effect so that the highest and lowest values were noted in homozygous subjects CYP2C9 Ã 1 and subjects carrying two defective alleles, respectively, whereas heterozygous subjects had intermediate values. CYP2C9 genotyping and several phenytoin metabolic indices are correlated with CYP2C9 activity in vivo. The utility of phenytoin to predict the metabolism of other CYP2C9 substrates justi®es further evaluation.

Journal of Internal Medicine, 1990

Septic arthritis of the sternoclavicular joint (SCJ) is a rare disorder, and is usually associate... more Septic arthritis of the sternoclavicular joint (SCJ) is a rare disorder, and is usually associated with predisposing factors such as contiguous foci of infection, heroin addiction, rheumatoid arthritis and diabetes mellitus. Three cases in previously healthy adults are reported here. The aetiology, clinical manifestations and treatment are briefly reviewed. The considerable difficulty in diagnosing this disorder in adults is emphasized. In summary, diagnosis of septic arthritis of the SCJ in adults requires a high index of suspicion, and must be considered not only in patients with predisposing factors, but also in previously healthy adults.

European Journal of Clinical Pharmacology, 1999

A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, sinc... more A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. CSA concentrations over time were reduced after dipyrone (ANOVA, P < 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P < 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 +/- 2.6 h vs 2.1 +/- 0.6 h, P < 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration-time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.

Clinical Drug Investigation, 2000

Biopharmaceutics & Drug Disposition, 1990