Z Ben-Zvi

Ben-Gurion University of the Negev, Be'er Sheva`, Southern District, Israel

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Publications (86)359.88 Total impact

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    ABSTRACT: Objectives. Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus. We evaluated the impact of cannabidiol (CBD), a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp) for comparison). Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24–72 h) exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3) and rhodamine123(rh123)). Cyclosporine A (CsA) served as a positive control. Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3) and rh123) was inhibited upon short-term exposure to CBD. Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function. We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics.
    PeerJ 09/2013; 1(1):e153. DOI:10.7717/peerj.153 · 2.11 Impact Factor
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    ABSTRACT: Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exert its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2h) exposure to cannabidiol (CBD), a major phytocannabinoid, on human placental Breast Cancer Resistance Protein (BCRP) function. The in vitro effect of short-term exposure to CBD on BCRP in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with Mitoxantrone (MX) uptake, and Nicardipine was used as positive control. The ex vivo perfused cotyledon system was used for testing the effect of CBD on glyburide transport across the placenta. Glyburide (200ng/ml) was introduced to maternal (M) and fetal (F) compartments through a re-circulating 2h perfusion, and its transplacental transport was tested with [n=8] or without [n=8] CBD. 1) CBD inhibition of BCRP-dependent MX efflux was concentration dependent and of a non-cell type specific nature (p<0.0001); 2) In the cotyledon perfusion assay, the administration of CBD to the maternal perfusion media increased the F/M ratio of glyburide concentrations (1.3±0.1 vs 0.8±0.1 at 120 min. of perfusion, p<0.001). 1) Placental BCRP function is inhibited following even a short term exposure to CBD; 2) the ex vivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and 3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are BCRP substrates is questionable during cannabis consumption by pregnant women.
    American journal of obstetrics and gynecology 08/2013; 209(6). DOI:10.1016/j.ajog.2013.08.005 · 4.70 Impact Factor

  • American Journal of Obstetrics and Gynecology 01/2013; 208(1):S239. DOI:10.1016/j.ajog.2012.10.724 · 4.70 Impact Factor
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    ABSTRACT: Objective Ibuprofen is a safe and effective non steroidal anti-inflammatory drug (NSAID). Ibuprofen suppositories are marketed in Europe; but data regarding pharmacokinetics of rectal vs. oral ibuprofen in humans is scarce. The objective of this study is to compare the pharmacokinetics of single-dose rectal vs. oral ibuprofen in healthy adult volunteers.Methods Ten healthy adult male volunteers, aged 20-37 years, received in a non-blind, cross-over setting, two formulations of ibuprofen. First, a 400 mg (about 5 mg/kg) of racemic ibuprofen suppository; second (after a three week washout period) the same dosage of ibuprofen syrup. Blood samples were collected before dosing and for 12 hours after administration. Pharmacokinetics analysis was preformed.ResultsMean peak plasma concentration (Cmax) of rectal ibuprofen was considerably lower, and the mean time to peak (Tmax) considerably longer, compared to oral ibuprofen. Absorption of rectal ibuprofen was considerably lower than oral ibuprofen, with a relative bioequivalence of 63%. Rectal ibuprofen reached therapeutic plasma concentration (>10 µg/ml) 45 minutes after dosing and remained in that range for four hours. The values of Vd/F and CL/F also differ significantly after rectal and oral administration, while no difference was found in the elimination rate constant (Kel) or half-life elimination (t1/2). Conclusions Racemic ibuprofen suppository has lower bioavailability compared with ibuprofen syrup. Therapeutic plasma concentrations of ibuprofen were reached 45 minutes after dosing and remained in that range for 4 hours. Ibuprofen suppositories can contribute to the management of fever and pain when the oral route is not available.
    The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique 12/2012; 19(2):e179-86.
  • Tamar Eshkoli · Eyal Sheiner · Zvi Ben-Zvi · Gershon Holcberg ·
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    ABSTRACT: It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. In recent years, research on human placental transporters has been developing due to the increase of knowledge technology in pharmacology. In this review we will focus on the main placental transporters which are known today. The P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP/ABCG2) and Multidrug resistance associated protein 2 (MDR2) transporters are expressed at the apical surface of the syncytiotrophoblast, and have a protective effect. Transporters for 5-HT (SERT) and NE (NET) are also expressed at the apical surface and regulate extracellular concentrations of monoamines. The physiologic function of Multidrug resistance associated protein (MRP) transporters (which is expressed at the basal surface of the syncytiotrophoblast) may be the removal of metabolic end products from the fetus. Some of the members of the organic anion transporters are also expressed at the basolateral surface of the syncytiotrophoblast.
    Current pharmaceutical biotechnology 02/2011; 12(5):707-14. DOI:10.2174/138920111795470877 · 2.51 Impact Factor

  • American Journal of Obstetrics and Gynecology 01/2011; 204(1). DOI:10.1016/j.ajog.2010.10.129 · 4.70 Impact Factor
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    ABSTRACT: To determine the role of BCRP in nitrofurantoin (NF) transport in JAr cells and the possible contribution of OATP2B1, P-gp and MRPs to this transport. Cells were incubated with various BCRP, P-gp, MRPs, organic anion transporting polypeptide (OAT) and OATP2B1 inhibitors for 15 min, followed by incubation for 30 min with NF, with or without the inhibitors mentioned earlier. NF cytotoxicity was examined using neutral red (NR) assay. Intracellular NF levels were analyzed by HPLC. NR assay showed that incubation conditions with NF (as carried out in our experiments) were not cytotoxic. Incubation with specific inhibitors of BCRP (FTC, Chrysin and Novobiocin), showed a significant increase in NF accumulation in the cells. Inhibitors of OATP2B1 (EGCG and BSP) had no influence on NF accumulation. Specific inhibitors of P-gp and MRPs (Verapamil and Indomethacin, respectively) also had no influence on NF accumulation in JAr cells. NF is probably a specific substrate of BCRP, and BCRP has a major active role in NF transport in JAr cells. For the first time, we showed, that P-gp, MRPs, and the OATP2B1, probably have a negligible contribution to NF transport in JAr cells.
    Archives of Gynecology 11/2009; 281(6):1037-44. DOI:10.1007/s00404-009-1286-7 · 1.36 Impact Factor
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    ABSTRACT: Placental transfer of Levofloxacin (LF), a broad spectrum fluoroquinolone antibiotic, and its inhibition was investigated in BeWo cells, a human trophoblast cell line. The experiments of LF uptake by BeWo cells were performed after preincubation and in the presence of the P-glycoprotein inhibitors (Cyclosporin A, Verapamil and Quercetin), the organic anion/cation transporter inhibitor (Cimetidine) and the MCT substrates (lactic acid and salicylic acid). P-glycoprotein inhibitors increased the uptake of LF by BeWo cells. The increase in LF accumulation by Cyclosporin A, Verapamil and Quercetin was by 30, 90 and 80%, respectively. Cimetidine, the organic cation inhibitor, increased the transport of LF by 48%. Lactic acid and salicylic acid, the MCT substrates, initially decreased the accumulation of LF by 30% and subsequently increased the uptake of LF by 500 and 53%, respectively. The uptake of LF by human trophoblast cells is mediated by multiple transporters as well as passive diffusion.
    Archives of Gynecology 08/2009; 281(5):833-8. DOI:10.1007/s00404-009-1177-y · 1.36 Impact Factor
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    ABSTRACT: One of the most important hormones synthesized by the placenta during pregnancy is progesterone. The regulating mechanisms of progesterone synthesis and the mechanism responsible for the spontaneous onset of labor in women are still not fully understood. Progesterone is thought to have been involved in human parturition. The objective of this study was to compare the levels of progesterone in the human placentas, at the end of the gestation (37-41 weeks) in vaginal versus cesarean deliveries, and to evaluate the pattern of progesterone accumulation, instantly following its synthesis by the human placenta at the end of the pregnancy. Progesterone levels in human placental tissue were determined by immunochemiluminescent analysis, following tissue homogenization. Progesterone secretion and accumulation pattern in the placental tissue was demonstrated using the ex vivo, closed, dual perfusion system of isolated human placental cotyledon. Immunochemiluminescent analysis of progesterone levels in human normal and cesarean-delivered placentas showed that placentas following normal vaginal delivery store higher concentrations of progesterone, and produce progesterone more intensively. Results obtained from 120-min perfusions (of vaginal and cesarean-delivered placentas) showed that progesterone tended to accumulate in the maternal rather than the fetal compartment. These data indicate that progesterone levels continuously rise till the end of pregnancy, with no apparent drop in progesterone levels during the labor process. In addition, progesterone is released from the syncytiotrophoblast preferably into the maternal component of the placental tissue.
    Archives of Gynecology 06/2009; 281(3):387-92. DOI:10.1007/s00404-009-1125-x · 1.36 Impact Factor
  • Habib Edery · Yona Grunfeld · Zvi Ben-Zvi · Raphael Mechoulam ·

    Annals of the New York Academy of Sciences 12/2006; 191(1):40 - 53. DOI:10.1111/j.1749-6632.1971.tb13985.x · 4.38 Impact Factor
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    ABSTRACT: To investigate the transfer of therapeutically important fluoroquinolones: ciprofloxacin, ofloxacin and levofloxacin, through the isolated perfused human placenta, from the maternal to the fetal compartment. Isolated placental cotyledons from normal human term placentae were dually perfused with M199 medium enriched with 3g/l bovine serum albumin and 1g/l glucose. Perfusion rates were 12 and 6 ml/min in the maternal and fetal circulation, respectively. Maternal and fetal closed circulation was used to evaluate steady-state concentrations and transplacental gradient formation. Eighteen placentae were used in our study: six for each experiment with ciprofloxacin, ofloxacin and levofloxacin were added to the maternal circulation. Samples were collected from the maternal and fetal compartments. Antipyrine was used as a reference drug that crosses the placenta by simple diffusion. The concentrations of ciprofloxacin, ofloxacin, levofloxacin and antipyrine were measured by specific HPLC (high performance liquid chromatography) methods. Results are presented as mean+/-S.D. In all the placentae, ciprofloxacin, ofloxacin, levofloxacin crossed the placenta from the maternal to the fetal compartment. The mean transplacental transfer percent of ciprofloxacin was 3.2+/-0.7% and the transplacental transfer index, the ratio of transplacental transfer between ciprofloxacin and antipyrine was 0.34+/-0.12. The mean transplacental transfer percent of ofloxacin was 3.7+/-2.4% and the transplacental transfer index was 0.33+/-0.3. The mean transplacental transfer percent of levofloxacin was 3.9+/-1.5% and the transplacental transfer index was 0.34+/-0.2. Only a small fraction of ciprofloxacin, ofloxacin and levofloxacin passed from the maternal to the fetal compartment. This fraction is significantly smaller compared to antipyrine. This may indicate that there is a barrier to the transport of fluoroquinolones in human placenta.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 10/2005; 122(1):61-5. DOI:10.1016/j.ejogrb.2004.11.031 · 1.70 Impact Factor
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    ABSTRACT: Zebularine (2(1H)-pyrimidinone riboside, Zeb), a synthetic analogue of cytidine that is a potent inhibitor of cytidine deaminase, has been recently identified as a general inhibitor of DNA methylation. This inhibition of DNA methyltransferase (DNMT) is hypothesized to be mechanism-based and result from formation of a covalent complex between the enzyme and zebularine-substituted DNA. Metabolic activation of Zeb thus requires that it be phosphorylated and incorporated into DNA. We have quantitatively assessed the phosphorylation and DNA incorporation of Zeb in T24 cells using 2-[(14)C]-Zeb in conjunction with gradient anion-exchange HPLC and selected enzymatic and spectroscopic analyses. The corresponding 5'-mono-, di- and triphosphates of Zeb were readily formed in a dose- and time-dependent manner. Two additional Zeb-containing metabolites were tentatively identified as diphosphocholine (Zeb-DP-Chol) and diphosphoethanolamine adducts. Intracellular concentrations of Zeb-TP and Zeb-DP-Chol were similar and greatly exceeded those of other metabolites. DNA incorporation occurred but was surpassed by that of RNA by at least seven-fold. Equivalent levels and similar intracellular metabolic patterns were also observed in the Molt-4 (human T-lymphoblasts) and MC38 (murine colon carcinoma) cell lines. For male BALB/c nu/nu mice implanted s.c. with the EJ6 variant of T24 bladder carcinoma and treated i.p. with 500mg/kg 2-[(14)C]-Zeb, the in vivo phosphorylation pattern of Zeb in tumor tissue examined 24h after drug administration was similar to that observed in vitro. The complex metabolism of Zeb and its limited DNA incorporation suggest that these are the reasons why it is less potent than either 5-azacytidine or 5-aza-2'-deoxycytidine and requires higher doses for equivalent inhibition of DNMT.
    Biochemical Pharmacology 08/2005; 70(1):121-33. DOI:10.1016/j.bcp.2005.04.010 · 5.01 Impact Factor
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    ABSTRACT: To determine the effect of quinidine and verapamil, known antiarrhythmic agents and P-glycoprotein (Pgp) inhibitors, on digoxin transport from the maternal to the fetal compartment in the isolated perfused human placenta. Isolated placental cotyledons from normal human placentae (n=20) were dually perfused with M199 medium enriched with albumin (0.3%) and glucose (0.1%). The maternal and the fetal circulation flow rates were 12 and 6 ml/min, respectively. Closed circulations were used to evaluate steady state transplacental gradient formation. In six placentae quinindine was added to the maternal circuit; after 45 min of perfusion, digoxin was added to the maternal circulation. The effect of verapamil on digoxin transfer from the maternal to the fetal compartments was explored in five placentae. In six additional placentae the transfer of digoxin was studied in the absence of quinidine. Transplacental passage of digoxin was calculated from repeated fetal and maternal perfusate samples. Digoxin levels were determined in perfusate samples by fluorescence polarization immunoassay. Antipyrine was added to the maternal reservoir of all placentae as reference substance. The transfer of digoxin (alone) and in the presence of quinidine or verapamil was 10.93+/-3.71, 9.00+/-5.2 and 12.94+/-4.86%, respectively. The levels of digoxin in the fetal compartment, 0.62+/-0.20, 0.48+/-0.29 and 0.60+/-0.26 ng/ml, respectively, were not significantly affected by quinidine and verapamil. These Pgp modulators, also did not influence significantly the steady state levels of digoxin in the maternal compartment. Neither quinidine nor verapamil affected the transplacental transfer of digoxin in vitro in normal human placentae. In contrast to the other tissues, they do not inhibit Pgp activity in term human placentae.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 09/2003; 109(2):133-7. DOI:10.1016/S0301-2115(02)00513-4 · 1.70 Impact Factor
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    ABSTRACT: The conformationally rigid nucleoside, N-methanocarbathymidine [(N)-MCT] exerts a potent antiproliferative effect both in vitro and in vivo against murine colon cancer cells (MC38) expressing the herpes simplex virus thymidine kinase gene (MC38/HSV-tk). Metabolic studies have revealed that high levels of (N)-MCT triphosphate accumulate in transduced cells and are incorporated into DNA, resulting in cell death. The objective of the present study was to assess the pharmacokinetic profile of (N)-MCT in C57BL/6 mice bearing nontransduced MC38 and MC38/HSV-tk tumors. Male black C57BL/6 mice bearing subcutaneous tumors derived from wildtype and HSV-tk-transduced MC38 murine colon cancer cells in the left and right flank, respectively, were treated i.p. with radiolabeled (N)-MCT (100 mg/kg). Mice were killed at each of the predetermined times after drug administration. Blood, urine, tumors and various organs and tissues were obtained for measurement of drug levels. Plasma and tissue concentrations of (N)-MCT peaked at 0.25-0.5 h. The major pharmacokinetic parameters calculated for (N)-MCT in plasma were: T(1/2)beta 4.7 h, AUC 147 micro g.h/ml, CL 0.69 l/kg per h. The penetration of (N)-MCT into brain and testes was slow. Between 4 and 24 h after drug administration, the levels of (N)-MCT measured in HSV-tk-expressing tumors were significantly higher than in wildtype tumors. HPLC analysis of methanolic extracts of plasma and urine obtained at various times after drug administration revealed no (N)-MCT metabolites in the plasma, and the compound was secreted unchanged in the urine. After i.p. injection into mice, (N)-MCT was rapidly absorbed and distributed in all organs examined. No drug metabolites were detectable in plasma and the compound was secreted unchanged in urine. These results are essential for the future development and in postulating the most efficient use of (N)-MCT in the HSV-tk enzyme prodrug system for gene therapy approaches for the treatment of cancer.
    Cancer Chemotherapy and Pharmacology 12/2002; 50(5):360-6. DOI:10.1007/s00280-002-0505-8 · 2.77 Impact Factor
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    ABSTRACT: N-Methanocarbathymidine [(N)-MCT], a thymidine analogue incorporating a pseudosugar with a fixed Northern conformation, exhibits antiherpetic activity against both herpes simplex virus (HSV) HSV-1 and HSV-2, with a potency greater than that of the reference standard, ganciclovir (GCV). In the present study, we have assessed the cytotoxic activity in vitro of (N)-MCT in wild-type murine colon cancer cells (MC38) and in cells expressing the herpes simplex thymidine kinase gene (MC38/HSV-tk), and the antitumor activity of (N)-MCT in vivo against HSV-tk transduced and nontransduced MC38 murine tumors. In vitro, when assessed over a 48-h period, the growth-inhibitory activity (IC50) of (N)-MCT toward MC38/HSV-tk cells was 2.9 microM. In parallel studies, the cytostatic activity of the reference compound GCV in these tumor lines was 3.0 microM. In studies in vivo, both (N)-MCT and GCV (100 mg/kg) given twice daily for 7 days completely inhibited the growth of HSV-tk-transduced MC38 tumors while exhibiting no effect on nontransduced MC38 tumors in mice. In nontransduced cells both in vitro and in vivo, only low levels of (N)-MCT and its monophosphate could be detected after administration of the parent drug, whereas in HSV-tk-transduced cells (N)-MCT was phosphorylated to its respective mono-, di-, and triphosphates. Furthermore, data showed that (N)-MCT incorporated in high levels into cellular DNA whereas trace levels were measured into RNA. These observations indicate that (N)-MCT may be a useful candidate prodrug for HSV-tk suicide gene therapy of cancer.
    Molecular Cancer Therapeutics 07/2002; 1(8):585-93. · 5.68 Impact Factor
  • A Lowenthal · N Meyerstein · Z Ben-Zvi ·
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    ABSTRACT: 6-Mercaptopurine is used therapeutically for its immunosuppressant and cytotoxic properties. It is deactivated by thiopurine methyltransferase (TPMT), which shows genetic polymorphism in many populations. In North American populations, TMPT activity exhibits a trimodal activity pattern. In Oriental populations, TPMT shows almost a unimodal pattern of activity. The purpose of the present study was to assess the activity of TPMT in a Jewish male population sample in Israel. The study was approved by the Israeli Ministry of Health. Blood samples of 2.5 ml were collected in heparinized tubes from 134 males. The red blood cell (RBC) fraction of each individual was washed and hemolyzed. TPMT activity in the RBC hemolysate was determined using a radioactive assay with tritiated S-adenosyl methionine as a methyl donor. The activity of TPMT ranged from 3.2 nmol/h/ml to 42.9 nmol/h/ml packed RBCs with mean and median activities of 18.6 nmol/h/ml and 17.9 nmol/h/ml packed RBCs, respectively. The distribution frequency of TPMT was very close to the unimodal by analysis of normal distribution. The pattern of distribution of TPMT in the Jewish population of Israel is closer to that of East Asian populations than European and North American populations. This observation may have relevance for the usage of 6-mercaptopurine and azathioprine as therapeutic agents in the Jewish population.
    European Journal of Clinical Pharmacology 05/2001; 57(1):43-6. DOI:10.1007/s002280100267 · 2.97 Impact Factor
  • M Tsadkin · G Holcberg · O Sapir · M Hallak · M Huleihel · M Katz · H Polachek · M Mazor · Z Ben-Zvi ·
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    ABSTRACT: To determine the effects of albumin (BSA) concentration in perfusion medium on digoxin transfer in isolated perfused human placental cotyledon. Isolated placental cotyledons from 13 normal human placentas were dually perfused after cannulating artery and vein of the chorionic plate and piercing 4 catheters through the corresponding basal plate with M199 medium enriched with BSA and glucose. Flow rates were 12 and 6 ml/min in the maternal and fetal circuits, respectively. Digoxin was added to the maternal reservoir at a final concentration of 5.51 +/- 1.00 ng/ml. BSA in maternal and fetal perfusate was kept at 3 concentrations: 1, 3 and 5 mg/ml (Groups I, II, III). Transplacental passage of digoxin was calculated from repeated fetal and maternal perfusate samples collected over 3 hours in the 3 groups. Digoxin levels were measured by FPIA (TDx, Abbott). There was no transfer of digoxin from the maternal to fetal compartment when the concentration of BSA was 1 mg/ml. Increasing the concentration of BSA led to a substantial increase in the transfer of digoxin to the fetal compartment. Steady state levels of digoxin in the fetal compartment were 0.61 +/- 0.19 ng/ml at 3 mg/ml of BSA. Maternal and fetal serum concentration of BSA affect digoxin transfer in isolated perfused human placentas. Three mg/ml are considered to be the optimal albumin concentration.
    International journal of clinical pharmacology and therapeutics 05/2001; 39(4):158-61. DOI:10.5414/CPP39158 · 1.22 Impact Factor
  • E Amsallem-Holtzman · Z Ben-Zvi ·
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    ABSTRACT: The activities of selected hepatic and renal drug-metabolizing enzymes of the ostrich, chicken and rats were compared. The concentration of glutathione in the liver and kidneys of the avian species was significantly lower than in the rat. The activity of ostrich hepatic glutathione S-transferase was 2-fold higher than that of the chicken and the rat and the renal glutathione S-transferase of the ostrich was 10 times higher than that of the rat. The activity of ostrich hepatic UDP-glucuronyl transferase was significantly lower than that of the rat. The activities of hepatic cytochrome P450 1A and 2B1/2 as measured by the dealkylation of ethoxy- and methoxyresorufin, respectively, were higher int he avian species than the rat; no difference was noticed in the activity of aniline hydroxylase. The results show that the activity of ostrich drug-metabolizing enzyme system is quantitatively different from the rat and in many cases also from the chicken.
    Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology 02/1997; 116(1):47-50. DOI:10.1016/S0742-8413(96)00136-3
  • D Mazor · E Golan · V Philip · M Katz · A Jafe · Z Ben-Zvi · N Meyerstein ·
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    ABSTRACT: The permeability of red blood cells (RBCs) to thiol containing compounds, reduced glutathione (GSH) and N-acetyl cysteine (NAC), has been studied in control adult and neonatal cells and after oxidative stress. NAC penetrates the cell membrane easily while GSH hardly permeates. We measured their capacity to enhance intracellular non-protein thiols (NPSH), after inducing damage to the membrane by formation of defects. Diamide, phenazine methosulfate (PMS) and t-butyl hydroperoxide (BHP) were chosen as exogenous oxidants, each inducing damage by a different mechanism. Our data indicate that although neonatal cells are more sensitive to oxidative stress, only membrane damage induced by diamide, renders adult and neonatal cells permeable to GSH. NAC treatment enhances thiol levels in cells exposed to oxidizing agents, as well as in control cells.
    European Journal Of Haematology 10/1996; 57(3):241-6. DOI:10.1111/j.1600-0609.1996.tb01370.x · 2.07 Impact Factor
  • Z Ben-Zvi · E Gussarsky · C van Creveld · R Yagil ·
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    ABSTRACT: In the present study the bioavailability of febantel paste and febantel suspension was investigated in the fully hydrated and the dehydrated camel. The serum concentrations of febantel and its metabolites, fenbendazole, oxfendazole and fenbendazole sulfone were determined by high performance liquid chromatography following extraction with ether. The exposure to febantel and its metabolites in fully hydrated camels was significantly higher in camels dosed with febantel paste compared to febantel suspension, as measured by AUC and Cmax. The AUC and Cmax of fenbendazole and oxfendazole were significantly lower in dehydrated camels as compared to control camels dosed with febantel paste. The systemic availability of febantel suspension in control and dehydrated camels was very low and differences between dehydration and control phases were insignificant. The low systemic availability of febantel in camels dosed with febantel suspension may cause nematodes to become resistant to this anthelmintic. It is, thus, suggested to increase the dose of febantel paste in dehydrated camels in order to increase the exposure to febantel and its metabolites. The binding of febantel, fenbendazole, oxfendazole and fenbendazole sulfone to camels' serum proteins was over 85%. Oxfendazole was only about 70% bound. Dehydration of 10 days did not affect the binding of these benzimidazole derivatives to serum proteins.
    Journal of Veterinary Pharmacology and Therapeutics 09/1996; 19(4):288-94. DOI:10.1111/j.1365-2885.1996.tb00051.x · 1.19 Impact Factor

Publication Stats

940 Citations
359.88 Total Impact Points


  • 1980-2013
    • Ben-Gurion University of the Negev
      • • Department of Clinical Biochemistry and Pharmacology
      • • Faculty of Health Sciences
      • • Division of Pediatrics
      Be'er Sheva`, Southern District, Israel
  • 1972-2006
    • Hebrew University of Jerusalem
      • School of Pharmacy
      Yerushalayim, Jerusalem District, Israel
  • 1985-1988
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 1984
    • National Institutes of Health
      • Laboratory of Molecular Pharmacology
      베서스다, Maryland, United States