The Bert Strassburger Lipid Center

Tel Aviv, Israel

The Bert Strassburger Lipid Center

Tel Aviv, Israel
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Gueta I.,Institute of Clinical Pharmacology and Toxicology | Gueta I.,Tel Aviv University | Loebstein R.,Institute of Clinical Pharmacology and Toxicology | Loebstein R.,Tel Aviv University | And 10 more authors.
European Journal of Clinical Pharmacology | Year: 2017

Purpose: The purpose of this study is to determine the rate of QTcP and associated risk factors in patients treated with voriconazole. Methods: We conducted a retrospective chart review of all patients treated with voriconazole in a large tertiary center between 2009 and 2015, using paired comparison of QTc intervals on and off voriconazole treatment, adjusted for comorbidities, electrolyte abnormalities, and concurrent medications. Results: Fifty-four patients were included, of whom 53 were diagnosed with oncologic/hemato-oncologic disease. Mean QTc during voriconazole therapy (448.0 ± 52.9 msec) was significantly longer compared to QTc off voriconazole (421.8 ± 42.2 msec; p = 0.002). QTcP ≥30 msec and ≥60 msec was demonstrated in 43% (23 patients) and 28% (15 patients), respectively. Multivariate analysis showed that QTcP was significantly associated with baseline QTc ≥ 450 msec (upper QTc quartile) (p < 0.01) and low serum potassium levels (p < 0.01). Contrarily, no significant association was found between mean voriconazole daily and cumulative dose and QTcP. Conclusion: Our findings indicate that hemato-oncologic patients treated with voriconazole are at increased risk for QTcP, especially in the presence of baseline QTc ≥ 450 msec and low serum potassium levels. © 2017 Springer-Verlag GmbH Germany


Kamari Y.,The Bert Strassburger Lipid Center | Kamari Y.,Tel Aviv University | Shaish A.,The Bert Strassburger Lipid Center | Shemesh S.,The Bert Strassburger Lipid Center | And 12 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

Objective: Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production. Methods: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/- Results: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. Conclusion: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages. © 2011 Elsevier Inc.


Grosskopf I.,The Bert Strassburger Lipid Center | Shaish A.,The Bert Strassburger Lipid Center | Charach G.,Tel Aviv Sourasky Medical Center | Charach G.,Tel Aviv University | And 5 more authors.
Hormone and Metabolic Research | Year: 2015

Hypertension, advanced age, postprandial hyperlipidemia, and insulin resistance are major risk factors for atherosclerosis. The calcium channel blocker nifedipine is reported to ameliorate insulin resistance possibly by activating PPARγ. This is expected to become accentuated in elderly individuals due to age-related insulin resistance. Insulin resistance modulates lipoprotein metabolism. Therefore, we reasoned that nifedipne offers the potential for improving postprandial lipemia in association with increasing age. We studied the effect of nifedipine on fasting lipids, postprandial lipemia, insulin sensitivity, and plasma lipolytic activity in 24 and 15 hypertensive subjects aged 70–75 years and 40–45 years, respectively. As expected, nifedipine significantly lowered systolic and diastolic blood pressure. Nifedipine decreased fasting triglyceride level (23%) and increased HDL-C (15%) in the elderly group. At baseline, postprandial triglyceride levels were remarkably elevated in elderly compared to younger patients (1 288±798 vs. 501±260 mg·dl−1·h, p<0.05), as was retinyl palmitate (surrogate marker for intestinally-derived cholesterol) in the chylomicrons (45.0±26.5 vs. 23.4±10.6 mg·l−1·h, p<0.05) and chylomicron remnant (15.2±5.4 vs. 11.7±4.7 mg·l−1·h, p<0.05) fractions. Importantly, while the level of chylomicron remnants in the group of younger subjects remained unchanged after treatment, nifedipine was associated with a significantly decreased chylomicron remnants retinyl palmitate in the elderly group, which dropped to levels, observed in younger subjects. This was accompanied by enhanced insulin sensitivity and augmented plasma lipolytic activity. The present work suggests that nifedipine has favorable metabolic effects that are beyond the known enhancement of insulin sensitivity. The improvement in postprandial lipidemia by nifedipine may add to its anti-atherogenic effects in hypertensive patients. Copyright © 2015, Georg Thieme Verlag KG. All rights reserved.


PubMed | The Bert Strassburger Lipid Center and Tel Aviv Sourasky Medical Center
Type: Journal Article | Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | Year: 2016

Hypertension, advanced age, postprandial hyperlipidemia, and insulin resistance are major risk factors for atherosclerosis. The calcium channel blocker nifedipine is reported to ameliorate insulin resistance possibly by activating PPAR. This is expected to become accentuated in elderly individuals due to age-related insulin resistance. Insulin resistance modulates lipoprotein metabolism. Therefore, we reasoned that nifedipne offers the potential for improving postprandial lipemia in association with increasing age. We studied the effect of nifedipine on fasting lipids, postprandial lipemia, insulin sensitivity, and plasma lipolytic activity in 24 and 15 hypertensive subjects aged 70-75 years and 40-45 years, respectively. As expected, nifedipine significantly lowered systolic and diastolic blood pressure. Nifedipine decreased fasting triglyceride level (23%) and increased HDL-C (15%) in the elderly group. At baseline, postprandial triglyceride levels were remarkably elevated in elderly compared to younger patients (1288798 vs. 501260mgdl(-1)h, p<0.05), as was retinyl palmitate (surrogate marker for intestinally-derived cholesterol) in the chylomicrons (45.026.5 vs. 23.410.6mgl(-1)h, p<0.05) and chylomicron remnant (15.25.4 vs. 11.74.7mgl(-1)h, p<0.05) fractions. Importantly, while the level of chylomicron remnants in the group of younger subjects remained unchanged after treatment, nifedipine was associated with a significantly decreased chylomicron remnants retinyl palmitate in the elderly group, which dropped to levels, observed in younger subjects. This was accompanied by enhanced insulin sensitivity and augmented plasma lipolytic activity. The present work suggests that nifedipine has favorable metabolic effects that are beyond the known enhancement of insulin sensitivity. The improvement in postprandial lipidemia by nifedipine may add to its anti-atherogenic effects in hypertensive patients.


PubMed | The Bert Strassburger Lipid Center and Tel Aviv University
Type: Journal Article | Journal: Thrombosis research | Year: 2014

The acute effect of heparin on lipoprotein clearance is well characterized. Yet, the effect of prolonged low-molecular-weight-heparin (LMWH) administration on post-prandial lipemia has remained so far unexplored. Recent reports suggest that LMWH could modify lipid and carbohydrate metabolism by diminishing TNF-mediated inflammatory response. This, together with the known negative effect of TNF- on insulin sensitivity, prompted us to hypothesize that LMWH would favorably affect post-prandial lipoprotein disposal.Twenty four patients were given a vitamin A-fat loading meal at the end of 6-week enoxaparin treatment and after 3-month washout period. Post-prandial lipemia was assessed by measuring retinyl-palmitate (RP) during 8hours following the meal. Insulin sensitivity index (ISI), plasma lipolytic activity and plasma TNF- were measured.Enoxaparin did not impact fasting plasma lipids and lipoproteins levels. Enoxaparin increased RP clearance in the chylomicron remnant (CMR) fraction by 32% (P<0.01). Additionally, enoxaparin decreased plasma TNF- by 22% (P<0.01), increased hepatic lipase (HL) activity by 81% (P<0.01), along with a 2-fold increase in ISI (P<0.01). The decrease in CMR correlated with the reduction in TNF and the increase in ISI and HL activity (R=0.48, -0.68, -0.56, respectively, p<0.05). Significant correlations were also found between the reduction in TNF and both the increase in ISI and increase in HL activity (R=-0.43, -0.54, respectively, P<0.05).The association of the effect on post-prandial metabolism, plasma TNF level and HL activity during prolonged enoxaparin treatment may support the hypothesis that the beneficial outcome of enoxaparin may possibly be linked to anti-inflammatory and lipase-potentiating impact.


PubMed | The Bert Strassburger Lipid Center
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2011

Interleukin (IL)-1 and IL-1 are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1s. Whereas several studies demonstrate the proatherogenic properties of IL-1, the role of IL-1 in atherogenesis remains unclear. We assessed whether IL-1 and IL-1 from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1 or IL-1 deficiency on degradation of LDL and cytokine production.We generated strains of double knock-out (KO) mice (apoE-/-/IL-1-/- and apoE-/-/IL-1-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1-/- and apoE-/-/IL-1-/-.The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1 or IL-1 in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1-/- or IL-1-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNF and IL-12 similarly to IL-1+/+ macrophages; however, IL-1 deficient macrophages secreted reduced levels of IL-1 (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10.We show for the first time that it is IL-1 from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1 in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.

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