The Experts below are selected from a list of 18 Experts worldwide ranked by ideXlab platform
Katherine E Warren - One of the best experts on this subject based on the ideXlab platform.
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phase ii trial of intravenous Lobradimil and carboplatin in childhood brain tumors a report from the children s oncology group
2006Co-Authors: Katherine E Warren, Alberta Aikin, Brigitte C Widemann, Madeleine Libucha, Regina I Jakacki, Roger J Packer, Gilbert Vezina, Gregory H Reaman, D Shaw, Mark KrailoAbstract:Backround: Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of Lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. Patients and methods: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg·min/ml/cycle) intravenously over 15 min on 2 consecutive days and Lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. Results: Forty-one patients, age 2–19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n=9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n=8), medulloblastoma/PNET (n=6) and low-grade glioma (n=2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. Conclusion: The combination of Lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
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pharmacokinetics of carboplatin administered with Lobradimil to pediatric patients with brain tumors
2004Co-Authors: Katherine E Warren, Alberta Aikin, Anne C Gervais, Merrill J Egorin, Frank M BalisAbstract:To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, Lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors. Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and Lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of Lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mg⋅min/ml per dose ×2 (2.5 mg⋅min/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m2)=target AUC (mg⋅min/ml) × [0.93 × GFR (ml/min/m2)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min Lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/Lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity. The median GFR was 65 ml/min/m2 (range 38–95 ml/min/m2) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m2/day (124–235 and 179–360 mg/m2/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mg⋅min/ml target AUCs were 3.4 and 4.8 mg⋅min/ml (2.51–5.8 and 3.9–7.7 mg⋅min/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r 2=0.14). Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent Lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of Lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.
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phase i trial of Lobradimil rmp 7 and carboplatin in children with brain tumors
2001Co-Authors: Katherine E Warren, Mahendra C Patel, Alberta Aikin, Brigitte C Widemann, Madeleine Libucha, Peter C Adamson, Rachel B Neuwirth, David Benziger, Timothy Otoole, Kathleen M FordAbstract:Purpose: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of Lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. Methods: A group of 25 children with primary brain tumors received carboplatin and Lobradimil on two consecutive days every 28 days. The 10-min Lobradimil infusion began 5 min before the end of the carboplatin infusion. Four Lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg·min/ml per course (5.0 mg·min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). Results: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the Lobradimil infusion. The incidence and severity of Lobradimil toxicities were not dose-related and the Lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. Conclusions: The combination of carboplatin and Lobradimil is safe and tolerable. An MTD for Lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of Lobradimil is 600 ng/kg IBW.
Sungyoung Auh - One of the best experts on this subject based on the ideXlab platform.
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metabolically stable bradykinin b2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half life
2009Co-Authors: Hemant Sarin, Ariel S Kanevsky, Steve H Fung, John A Butman, Robert W Cox, Daniel R Glen, Richard C Reynolds, Sungyoung AuhAbstract:Background: The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas. Methods: Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadoliniumdiethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1 st bolus of Gd-DTPA over the first hour, and then reimaged with a 2 nd bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.
Alberta Aikin - One of the best experts on this subject based on the ideXlab platform.
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phase ii trial of intravenous Lobradimil and carboplatin in childhood brain tumors a report from the children s oncology group
2006Co-Authors: Katherine E Warren, Alberta Aikin, Brigitte C Widemann, Madeleine Libucha, Regina I Jakacki, Roger J Packer, Gilbert Vezina, Gregory H Reaman, D Shaw, Mark KrailoAbstract:Backround: Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of Lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. Patients and methods: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg·min/ml/cycle) intravenously over 15 min on 2 consecutive days and Lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. Results: Forty-one patients, age 2–19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n=9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n=8), medulloblastoma/PNET (n=6) and low-grade glioma (n=2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. Conclusion: The combination of Lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
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pharmacokinetics of carboplatin administered with Lobradimil to pediatric patients with brain tumors
2004Co-Authors: Katherine E Warren, Alberta Aikin, Anne C Gervais, Merrill J Egorin, Frank M BalisAbstract:To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, Lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors. Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and Lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of Lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mg⋅min/ml per dose ×2 (2.5 mg⋅min/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m2)=target AUC (mg⋅min/ml) × [0.93 × GFR (ml/min/m2)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min Lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/Lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity. The median GFR was 65 ml/min/m2 (range 38–95 ml/min/m2) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m2/day (124–235 and 179–360 mg/m2/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mg⋅min/ml target AUCs were 3.4 and 4.8 mg⋅min/ml (2.51–5.8 and 3.9–7.7 mg⋅min/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r 2=0.14). Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent Lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of Lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.
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phase i trial of Lobradimil rmp 7 and carboplatin in children with brain tumors
2001Co-Authors: Katherine E Warren, Mahendra C Patel, Alberta Aikin, Brigitte C Widemann, Madeleine Libucha, Peter C Adamson, Rachel B Neuwirth, David Benziger, Timothy Otoole, Kathleen M FordAbstract:Purpose: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of Lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. Methods: A group of 25 children with primary brain tumors received carboplatin and Lobradimil on two consecutive days every 28 days. The 10-min Lobradimil infusion began 5 min before the end of the carboplatin infusion. Four Lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg·min/ml per course (5.0 mg·min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). Results: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the Lobradimil infusion. The incidence and severity of Lobradimil toxicities were not dose-related and the Lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. Conclusions: The combination of carboplatin and Lobradimil is safe and tolerable. An MTD for Lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of Lobradimil is 600 ng/kg IBW.
Hemant Sarin - One of the best experts on this subject based on the ideXlab platform.
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metabolically stable bradykinin b2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half life
2009Co-Authors: Hemant Sarin, Ariel S Kanevsky, Steve H Fung, John A Butman, Robert W Cox, Daniel R Glen, Richard C Reynolds, Sungyoung AuhAbstract:Background: The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas. Methods: Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadoliniumdiethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1 st bolus of Gd-DTPA over the first hour, and then reimaged with a 2 nd bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.
Holger Heitsch - One of the best experts on this subject based on the ideXlab platform.
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the therapeutic potential of bradykinin b2 receptor agonists in the treatment of cardiovascular disease
2003Co-Authors: Holger HeitschAbstract:The nonapeptide bradykinin (BK) is a Janus-faced hormone, which exerts pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation of BK B(2) receptors. In various animal models and in humans it has been shown that the stimulation of BK B(2) receptors is not only implicated in the pathogenesis of inflammation, pain and tissue injury but also in powerful cardioprotective mechanisms. Either exogenous administration of BK or locally increased BK concentrations as a consequence of the inhibition of its metabolic breakdown by angiotensin-converting enzyme inhibitors, reveal the significant contribution of BK in powerful cardioprotective mechanisms. These are mainly triggered by the synthesis and release of the vasorelaxant, anti-hypertrophic and anti-atherosclerotic endothelial mediators nitric oxide, prostaglandins and tissue-type plasminogen activator, by ischaemic preconditioning and by an increase in insulin sensitivity. Consequently, BK B(2) receptor agonists may have important clinical value in the treatment and prevention of various cardiovascular disorders such as hypertension, ischaemic heart disease, left ventricular hypertrophy, ventricular remodelling and congestive heart failure as well as diabetic disorders by mimicking the reported beneficial effects of BK. However, none of the currently known potent and selective peptide and non-peptide agonists of BK B(2) receptors--RMP-7 (lobradamil, Cereport; Alkermes), JMV-1116 (Fournier), FR-190997 (Fujisawa) and FR-191413 (Fujisawa)--have been selected for a clinical assessment in cardiovascular indications. One major challenge of this approach is the still unanswered question of whether there is a sufficient safe therapeutic window between potential cardioprotective and pro-inflammatory effects following BK B(2) receptor agonism.