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Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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Effect of Itraconazole on the Pharmacokinetics of Atenolol
Basic & Clinical Pharmacology & Toxicology, 2005Co-Authors: Jari J. Lilja, Janne T. Backman, Pertti J. NeuvonenAbstract:Abstract: Our objective was to evaluate the effect of Itraconazole on the pharmacokinetics of atenolol in healthy volunteers. In a randomized cross-over study with two phases, 10 healthy volunteers had 200 mg Itraconazole orally or placebo for 2 days b.i.d., and in the morning of day 3, one hour after the last ingestion of Itraconazole or placebo, each subject received 50 mg atenolol. The plasma concentrations of atenolol and its excretion into urine were measured up to 33 hr. Blood pressures and heart rate were recorded up to 10 hr. Itraconazole had no statistically significant effect on any of the pharmacokinetic or pharmacodynamic variables of atenolol. If anything, Itraconazole increased the area under the plasma concentration-time curve (+12%; P=0.159), peak plasma concentration (+19%; P=0.165), and amount of atenolol excreted into urine (+13%; P=0.166) suggesting a slight increase of atenolol bioavailability. It can be concluded that Itraconazole does not have a clinically relevant effect on the pharmacokinetics of atenolol.
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Effect of Itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem
European Journal of Clinical Pharmacology, 1998Co-Authors: Harri Luurila, Kari T. Kivistö, Pertti J. NeuvonenAbstract:Objective: Zolpidem is a short-acting␣imidazopyridine hypnotic which is biotransformed in humans mainly by CYP3A4. Itraconazole strongly interacts with many substrates of CYP3A4 such as midazolam and triazolam. In this study, the effect of Itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem was investigated to uncover a possible clinically significant interaction. Methods: In a randomized cross-over study with two phases, ten healthy volunteers took either 200 mg Itraconazole or placebo once daily for 4 days. A single oral dose of 10 mg zolpidem was given on day 4. Plasma drug concentrations were measured up to 17 h and effects of zolpidem up to 9 h after the ingestion of zolpidem. Results: Itraconazole had no marked effects on the pharmacokinetics of zolpidem; the total area under the plasma zolpidem concentration–time curve (AUC0–∞) was 34% larger during the Itraconazole phase (759 ng · h · ml−1) than during the placebo phase (567 ng · h · ml−1). Exophoria of the eyes by the Maddox wing test was significantly increased by Itraconazole, but the results of the digit symbol substitution test, critical flicker fusion test, postural sway tests and the visual analogue scale tests for subjective drowsiness and overall drug effect did not differ between the phases. Conclusion: The pharmacokinetics and pharmacodynamics of zolpidem were not remarkably affected by Itraconazole in healthy volunteers. Therefore, unlike triazolam, for example, zolpidem can be used in normal or nearly normal doses together with Itraconazole and probably also with other CYP3A4 inhibitors.
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simvastatin but not pravastatin is very susceptible to interaction with the cyp3a4 inhibitor Itraconazole
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Pertti J. Neuvonen, Teemu Kantola, Kari T. KivistöAbstract:Background Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of Itraconazole with simvastatin and pravastatin. Methods Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg Itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, Itraconazole, and hydroxyItraconazole were determined. Results In study I, Itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-∞)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-∞) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t½) was increased by 25% (p < 0.05). The AUC(0-∞) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t½ were increased threefold (p < 0.001). In study II, Itraconazole slightly increased the AUC(0-∞) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t½ was not altered. The AUC(0-∞) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by Itraconazole. There were no differences in the serum concentrations of Itraconazole and hydroxyItraconazole between studies I and II. Conclusions Itraconazole greatly increased serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors, probably by inhibiting CYP3A-mediated metabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided or its dosage should be greatly reduced. Clinical Pharmacology & Therapeutics (1998) 63, 332–341; doi:
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Itraconazole increases plasma concentrations of quinidine
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Kirsi-maija Kaukonen, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:Background Quinidine is eliminated mainly by CYP3A4-mediated metabolism. Itraconazole interacts with some but not all of the substrates of CYP3A4; it is therefore important to study the possible interaction of Itraconazole with quinidine. Methods A double-blind, randomized, two-phase crossover study design was used with nine healthy volunteers. Itraconazole (200 mg) or placebo was ingested once a day for 4 days. A single 100 mg oral dose of quinidine sulfate was ingested on day 4. Plasma concentrations of quinidine, Itraconazole, and hydroxyItraconazole, as well as cumulative excretion of quinidine into urine, were determined up to 24 hours. The ECG, heart rate, and blood pressure were also recorded up to 24 hours. Results On average the peak plasma concentration of quinidine increased to 1.6-fold (p < 0.05), and the area under the concentration-time curve of quinidine increased to 2.4-fold (p < 0.01) by Itraconazole. The elimination half-life of quinidine was prolonged 1.6-fold (p < 0.001), and the area under the 3-hydroxyquinidine/quinidine ratio-time curve decreased to one-fifth (p < 0.001) by Itraconazole. The renal clearance of quinidine decreased 50% (p < 0.001) by Itraconazole, whereas the creatinine clearance was unaffected. The QTc interval correlated with the concentrations of quinidine during both Itraconazole and placebo phases (r2 = 0.71 and r2 = 0.79, respectively; p < 0.01), although only minor changes between the phases were observed in other pharmacodynamic variables. Conclusions Itraconazole increases plasma concentrations of oral quinidine, probably by inhibiting the CYP3A4 isozyme during the first-pass and elimination phases of quinidine. The decreased renal clearance of quinidine might be the result of the inhibition of P-glycoprotein-mediated tubular secretion of quinidine by Itraconazole. The concentrations of quinidine should be closely monitored if Itraconazole or some other potent CYP3A inhibitors are used with quinidine. Clinical Pharmacology & Therapeutics (1997) 62, 510–517; doi:
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Itraconazole Increases Serum Digoxin Concentration
Pharmacology & Toxicology, 1996Co-Authors: Juhani Partanen, Kirsi-maija Jalava, Pertti J. NeuvonenAbstract:: Itraconazole can interact with several drugs by inhibiting their metabolism. Many drugs known to increase serum digoxin concentration are inhibitors of CYP enzymes (e.g. verapamil, diltiazem, amiodarone, cyclosporine). Case reports suggest that Itraconazole, added to digoxin therapy, may induce digoxin intoxications; hence we wanted to study their possible interaction. In this two-phase study ten healthy young volunteers ingested 0.25 mg of digoxin daily for 20 days. Concomitantly, they received either 200 mg Itraconazole or placebo orally once daily for 10 days in a double-blind, randomized, cross-over study design. Serum concentrations of digoxin and Itraconazole were measured (12 hr after administration) on days 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 20. Digoxin concentrations were measured by fluorescence polarization immunoassay and confirmed (days 10 and 20) by affinity column-mediated immunoassay. Itraconazole increased serum digoxin concentration in each of the subjects. On the 10th day of the placebo phase serum digoxin concentration was 1.0±0.1 nmol/1, and on the 10th day of the Itraconazole phase 1.8±0.1 nmol/1 (P
Charles M Rudin - One of the best experts on this subject based on the ideXlab platform.
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phase 2 study of pemetrexed and Itraconazole as second line therapy for metastatic nonsquamous non small cell lung cancer
Journal of Thoracic Oncology, 2013Co-Authors: Charles M Rudin, Julie R Brahmer, Rosalyn A Juergens, Christine L Hann, David S Ettinger, Rosa Sebree, Ruth Smith, Blake T Aftab, Peng HuangAbstract:Introduction Preclinical studies have suggested that the oral antifungal agent Itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of Itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer. Methods The study enrolled patients with progressive nonsquamous non–small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m 2 on day 1, with or without Itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity. Results A total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on Itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone ( p = 0.11). Median progression-free survivals were 5.5 months (Itraconazole) versus 2.8 months (control) (hazard ratio=0.399, p = 0.089). Overall survival was longer in patients receiving Itraconazole (median 32 months) versus control (8 months) (hazard ratio=0.194, p = 0.012). There were no evident differences in toxicity between the study arms. Conclusion Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily Itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.
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Itraconazole inhibits angiogenesis and tumor growth in non small cell lung cancer
Cancer Research, 2011Co-Authors: Blake T Aftab, Irina Dobromilskaya, Charles M RudinAbstract:The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug Itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of Itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral Itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxiainducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that Itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral Itraconazole in patients with recurrent metastatic NSCLC. Cancer Res; 71(21); 6764–72. � 2011 AACR.
Blake T Aftab - One of the best experts on this subject based on the ideXlab platform.
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phase 2 study of pemetrexed and Itraconazole as second line therapy for metastatic nonsquamous non small cell lung cancer
Journal of Thoracic Oncology, 2013Co-Authors: Charles M Rudin, Julie R Brahmer, Rosalyn A Juergens, Christine L Hann, David S Ettinger, Rosa Sebree, Ruth Smith, Blake T Aftab, Peng HuangAbstract:Introduction Preclinical studies have suggested that the oral antifungal agent Itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of Itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer. Methods The study enrolled patients with progressive nonsquamous non–small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m 2 on day 1, with or without Itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity. Results A total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on Itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone ( p = 0.11). Median progression-free survivals were 5.5 months (Itraconazole) versus 2.8 months (control) (hazard ratio=0.399, p = 0.089). Overall survival was longer in patients receiving Itraconazole (median 32 months) versus control (8 months) (hazard ratio=0.194, p = 0.012). There were no evident differences in toxicity between the study arms. Conclusion Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily Itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.
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Itraconazole inhibits angiogenesis and tumor growth in non small cell lung cancer
Cancer Research, 2011Co-Authors: Blake T Aftab, Irina Dobromilskaya, Charles M RudinAbstract:The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug Itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of Itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral Itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxiainducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that Itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral Itraconazole in patients with recurrent metastatic NSCLC. Cancer Res; 71(21); 6764–72. � 2011 AACR.
Arunaloke Chakrabarti - One of the best experts on this subject based on the ideXlab platform.
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a randomized trial of Itraconazole vs prednisolone in acute stage allergic bronchopulmonary aspergillosis complicating asthma
Chest, 2018Co-Authors: Ritesh Agarwal, Ashutosh N Aggarwal, Mandeep Garg, Sahajal Dhooria, Inderpaul Singh Sehgal, Biman Saikia, Digambar Behera, Arunaloke ChakrabartiAbstract:Objective Whether Itraconazole monotherapy is effective in the acute stage of allergic bronchopulmonary aspergillosis (ABPA) remains unknown. The goal of this study was to compare the efficacy and safety of Itraconazole and prednisolone monotherapy in ABPA. Methods Treatment-naive subjects with ABPA complicating asthma (January 2012 to December 2013) were randomized to receive either oral Itraconazole or prednisolone for 4 months. The study was not blinded. The primary outcomes were proportion of subjects exhibiting a composite response after 6 weeks, percent decline in IgE after treatment, and numbers of subjects experiencing exacerbation. The secondary outcomes included the time to first exacerbation, change in lung function, and treatment-related adverse effects. Results A total of 131 subjects (prednisolone group, n = 63; Itraconazole group, n = 68) were included in the study. The number of subjects exhibiting a composite response was significantly higher in the prednisolone group compared with the Itraconazole group (100% vs 88%; P = .007). The percent decline in IgE after 6 weeks and 3 months and the number of subjects with exacerbations after 1 and 2 years of treatment were similar in the two groups. The time to first exacerbation (mean: 437 vs 442 days) and the improvement in lung function after 6 weeks was also similar in the two groups. The occurrence of side effects was significantly higher in the glucocorticoid arm ( P Conclusions Prednisolone was more effective in inducing response than Itraconazole in acute-stage ABPA. However, Itraconazole was also effective in a considerable number and, with fewer side effects compared with prednisolone, remains an attractive alternative in the initial treatment of ABPA. Trial Registry ClinicalTrials.gov; No.: NCT01321827; URL: www.clinicaltrials.gov).
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Itraconazole in chronic cavitary pulmonary aspergillosis a randomised controlled trial and systematic review of literature
Mycoses, 2013Co-Authors: Ritesh Agarwal, Gella Vishwanath, Ashutosh N Aggarwal, Mandeep Garg, Dheeraj Gupta, Arunaloke ChakrabartiAbstract:Summary Patients with aspergilloma can be safely managed with supportive therapy in absence of massive haemoptysis. We hypothesised that chronic cavitary pulmonary aspergillosis (CCPA) could also be managed on similar grounds. The aim of this prospective, randomised controlled trial was to evaluate the efficacy and safety of Itraconazole in CCPA. Consecutive patients of CCPA with presence of chronic pulmonary/systemic symptoms; and pulmonary cavities; and presence of Aspergillus (immunological or microbiological) were randomised to receive either supportive treatment alone or Itraconazole 400 mg daily for 6 months plus supportive therapy. Response was assessed clinically, radiologically and overall after 6 months therapy. A total of 31 patients (mean age, 37 years) were randomised to Itraconazole (n = 17) or the control (n = 14) group. The number of patients showing overall response was significantly higher in the Itraconazole group (76.5%) vs. the control (35.7%) group (P = 0.02). The numbers of patients demonstrating clinical or radiological response were also significantly higher in the Itraconazole group (P = 0.016 and 0.01 respectively). Adverse events were noted in eight patients in the Itraconazole group, however, none was serious or led to discontinuation of the study drug. Itraconazole was found to be superior to standard supportive treatment alone in stabilising cases of CCPA. (clinicaltrials.gov; NCT01259336).
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Treatment of deep mycoses with Itraconazole
Mycopathologia, 1991Co-Authors: Bhushan Kumar, Arunaloke Chakrabarti, Inderjeet Kaur, Vinod SharmaAbstract:Four patients with deep mycoses were treated with Itraconazole. Two patients had chromoblastomycosis, one patient each had aspergillosis and Rhinofacial zygomycosis. These patients were either resistant to or showed poor response to Amphotericin B and/or ketoconazole. After the initial clinical and mycological evaluation, Itraconazole was given in a daily dose of 200 mg orally. All patients responded to the drug very well. No adverse effects attributable to Itraconazole were detected.
Joong Sup Shim - One of the best experts on this subject based on the ideXlab platform.
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simultaneous targeting of npc1 and vdac1 by Itraconazole leads to synergistic inhibition of mtor signaling and angiogenesis
ACS Chemical Biology, 2017Co-Authors: Sarah A Head, Eun Ju Yang, Benjamin A Nacev, Sam Y Hong, Kalyan Kumar Pasunooti, Ruojing Li, Joong Sup ShimAbstract:The antifungal drug Itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of Itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by Itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by Itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of Itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and ch...
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antifungal drug Itraconazole targets vdac1 to modulate the ampk mtor signaling axis in endothelial cells
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Sarah A Head, Kalyan Kumar Pasunooti, Ruojing Li, Joong Sup Shim, Liang Zhao, Kirill Gorshkov, Yue Chen, Zhiyou DengAbstract:Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that Itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of Itraconazole that mediates this activity has remained unknown. Here we identify the major target of Itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by Itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by Itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.
