Autonomous precision resuscitation during ground and air transport of an animal hemorrhagic shock model.

We tested the ability of a physiologically driven minimally invasive closed-loop algorithm, called Resuscitation based on Functional Hemodynamic Monitoring (ReFit), to stabilize for up to 3 h a porcine model of noncompressible hemorrhage induced by severe liver injury and do so during both ground and air transport. Twelve animals were resuscitated using ReFit to drive fluid and vasopressor infusion to a mean arterial pressure (MAP) > 60 mmHg and heart rate < 110 min-1 30 min after MAP < 40 mmHg following liver injury. ReFit was initially validated in 8 animals in the laboratory, then in 4 animals during air (23nm and 35nm) and ground (9 mi) to air (9.5nm and 83m) transport returning to the laboratory. The ReFit algorithm kept all animals stable for ~ 3 h. Thus, ReFit algorithm can diagnose and treat ongoing hemorrhagic shock independent to the site of care or during transport. These results have implications for treatment of critically ill patients in remote, austere and contested environments and during transport to a higher level of care.

Early Physiologic Numerical and Waveform Characteristics of Simulated Hemorrhagic Events With Healthy Volunteers Donating Blood.

OBJECTIVES: Early signs of bleeding are often masked by the physiologic compensatory responses delaying its identification. We sought to describe early physiologic signatures of bleeding during the blood donation process. SETTING: Waveform-level vital sign data including electrocardiography, photoplethysmography (PPG), continuous noninvasive arterial pressure, and respiratory waveforms were collected before, during, and after bleeding. SUBJECTS: Fifty-five healthy volunteers visited blood donation center to donate whole blood. INTERVENTION: After obtaining the informed consent, 3 minutes of resting time was given to each subject. Then 3 minutes of orthostasis was done, followed by another 3 minutes of resting before the blood donation. After the completion of donating blood, another 3 minutes of postbleeding resting time, followed by 3 minutes of orthostasis period again. MEASUREMENTS AND MAIN RESULTS: From 55 subjects, waveform signals as well as numerical vital signs (heart rate [HR], respiratory rate, blood pressure) and clinical characteristics were collected, and data from 51 subjects were analyzable. Any adverse events (AEs; dizziness, lightheadedness, nausea) were documented. Statistical and physiologic features including HR variability (HRV) metrics and other waveform morphologic parameters were modeled. Feature trends for all participants across the study protocol were analyzed. No significant changes in HR, blood pressure, or estimated cardiac output were seen during bleeding. Both orthostatic challenges and bleeding significantly decreased time domain and high-frequency domain HRV, and PPG amplitude, whereas increasing PPG amplitude variation. During bleeding, time-domain HRV feature trends were most sensitive to the first 100 mL of blood loss, and incremental changes of different HRV parameters (from 300 mL of blood loss), as well as a PPG morphologic feature (from 400 mL of blood loss), were shown with statistical significance. The AE group (n = 6) showed decreased sample entropy compared with the non-AE group during postbleed orthostatic challenge (p = 0.003). No significant other trend differences were observed during bleeding between AE and non-AE groups. CONCLUSIONS: Various HRV-related features were changed during rapid bleeding seen within the first minute. Subjects with AE during postbleeding orthostasis showed decreased sample entropy. These findings could be leveraged toward earlier identification of donors at risk for AE, and more broadly building a data-driven hemorrhage model for the early treatment of critical bleeding.

Neurocardiac Injury Assessed by Strain Imaging Is Associated With In-Hospital Mortality in Patients With Subarachnoid Hemorrhage.

OBJECTIVES: This study sought to test the hypothesis that speckle tracking strain echocardiography can quantify neurocardiac injuries in patients with aneurysmal subarachnoid hemorrhage (SAH), which is associated with worse clinical outcome. BACKGROUND: SAH may be a life-threatening disease associated with variable degrees of neurocardiac injury. Strain imaging has the potential to detect subtle myocardial dysfunction which is additive to conventional measurements. METHODS: A total of 255 consecutive patients were prospectively enrolled with acute SAH, who were admitted to the intensive care unit with echocardiography studies within 72 h. Left ventricular (LV) and right ventricular (RV) strains were acquired from standard apical views. Abnormal LV global longitudinal strain (GLS) and RV free-wall strain were pre-defined as <17% and <23% (absolute values), respectively. RESULTS: Performing LV GLS was feasible in 221 patients (89%) 53 ± 10 years of age, 71% female, after excluding those with previous cardiac disease. Abnormal LV GLS findings were observed in 53 patients (24%) and were associated with worse clinical severity, including a Hunt-Hess grade >3 (34% vs. 15%; p = 0.005) and biomarker evidence of neurocardiac injury and higher troponin values (1.50 [interquartile range (IQR): 0.01 to 3.87] vs. 0.01 [IQR: 0.01 to 0.22] ng/ml; p < 0.001). A reverse Takotsubo pattern of segmental strain was observed in 49% of patients (apical sparing and reduced basal strain). Importantly, LV GLS was more strongly associated with in-hospital mortality than left ventricular ejection fraction (LVEF), even after adjusting for clinical severity (odds ratio [OR]: 3.11; 95% confidence interval [CI]: 1.12 to 8.63; p = 0.029). RV strain was measured in 159 subjects (72%); abnormal RV strain was added to LV GLS for predicting in-hospital mortality (p = 0.007). CONCLUSIONS: Neurocardiac injury can be detected by LV GLS and RV strain in patients with acute SAH. LV GLS was significantly associated with in-hospital mortality. RV strain, when available, added prognostic value to LV GLS. Abnormal myocardial strain is a marker for increased risk of in-hospital mortality in SAH and has clinical prognostic utility.

Vasopressor Infusion After Subarachnoid Hemorrhage Does Not Increase Regional Cerebral Tissue Oxygenation.

INTRODUCTION: Vasopressors are commonly used after aneurysmal subarachnoid hemorrhage (aSAH) to sustain cerebral pressure gradients. Yet, the relationship between vasopressors and the degree of cerebral microcirculatory support achieved remains unclear. This study aimed to explore the changes in cerebral and peripheral regional tissue oxygen saturation (rSO2) as well as blood pressure (BP) before and after vasopressor infusion in patients with aSAH. METHODS: Continuous noninvasive cerebral and peripheral rSO2 was obtained using near-infrared spectroscopy for up to 14 days after aSAH. Within-subject differences in rSO2 before and after the commencement of vasopressor infusion were analyzed controlling for Hunt and Hess grade and vasospasm. RESULTS: Of 45 patients with continuous rSO2 monitoring, 19 (42%) received vasopressor infusion (all 19 on norepinephrine, plus epinephrine in 2 patients, phenylephrine in 4 patients, and vasopressin in 2 patients). In these 19 patients, their vasopressor infusion times were associated with higher BP (systolic [b = 15.1], diastolic [b = 7.3], and mean [b = 10.1]; P = .001) but lower cerebral rSO2 (left cerebral rSO2 decreased by 4.4% [b = -4.4, P < .0001]; right cerebral rSO2 decreased by 5.5% [b = -5.5, P = .0002]). CONCLUSIONS: Despite elevation in systemic BP during vasopressor infusion times, cerebral rSO2 was concurrently diminished. These findings warrant further investigation for the effect of induced hypertension on cerebral microcirculation.

Clinical Presentation to the Emergency Department Predicts Subarachnoid Hemorrhage-Associated Myocardial Injury.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently seen in emergency departments. Secondary injury, such as subarachnoid hemorrhage-associated myocardial injury (SAHMI), affects one third of survivors and contributes to poor outcomes. SAHMI is not attributed to ischemia from myocardial disease but can result in hypotension and arrhythmias. It is important that emergency nurses recognize which clinical presentation characteristics are predictive of SAHMI to initiate proper interventions. The aim of this study was to determine whether patients who present to the emergency department with clinical aSAH are likely to develop SAHMI, as defined by troponin I ≥0.3 ng/mL. METHODS: This was a prospective descriptive study. SAHMI was defined as troponin I ≥0.3 ng/mL. Predictors included demographics and clinical characteristics, severity of injury, admission 12-lead electrogardiogram (ECG), initial emergency department vital signs, and pre-hospital symptoms at time of aneurysm rupture. RESULTS: Of 449 patients, 126 (28%) had SAHMI. Patients with SAHMI were more likely to report seizures and unresponsiveness with significantly lower Glasgow coma score and higher proportion of Hunt and Hess grades 3 to 5 and Fisher grades III and IV (all P < .05). Patients with SAHMI had higher atrial and ventricular rates and longer QTc intervals on initial ECG (P < .05). On multivariable logistic regression, poor Hunt and Hess grade, report of prehospital unresponsiveness, lower admission Glasgow coma score, and longer QTc interval were significantly and independently predictive of SAHMI (P < .05). DISCUSSION: Components of the clinical presentation of subarachnoid hemorrhage to the emergency department predict SAHMI. Identifying patients with SAHMI in the emergency department can be helpful in determining surveillance and care needs and informing transfer unit care. Contribution to Emergency Nursing Practice.

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma.

BACKGROUND: This study determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. METHODS: All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. RESULTS: A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. CONCLUSIONS: Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet-derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity.

A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies.

BACKGROUND: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel. METHODS: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1. RESULTS: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 +/- 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 +/- 0.51. CONCLUSIONS: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.

Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.

PURPOSE: This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients. PATIENTS AND METHODS: Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long. RESULTS: The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose. CONCLUSION: Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.

Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis.

PURPOSE: A phase I study of intrathecal (IT) gemcitabine was performed to define a safe dose and characterize the toxicity profile and CSF pharmacokinetics of gemcitabine and its major metabolite 2',2'-difluoro-deoxyuridine (dFdU) in patients 3 years of age and older with neoplastic meningitis. EXPERIMENTAL DESIGN: Gemcitabine was administered via Ommaya reservoir or lumbar puncture at three dose levels: 5 mg weekly, 5 mg twice-weekly, and 10 mg twice-weekly using a standard phase I dose escalation design. Serial CSF samples were obtained for pharmacokinetic studies in seven patients with Ommaya reservoirs. Serial blood samples for pharmacokinetic studies were also obtained from three patients. RESULTS: Ten patients were enrolled in this study. Significant neurological toxicities occurred in two patients including myelitis in a patient at the 5 mg twice-weekly dose level and somnolence in a patient at the 10 mg twice-weekly dose level. No complete responses were seen; however, three patients had stable disease. Gemcitabine was rapidly eliminated from the CSF with a terminal half-life of 61 +/- 50 min. No gemcitabine or dFdU was detected in plasma. CONCLUSIONS: IT gemcitabine was associated with significant neurotoxicity; therefore, its further development for IT use is not recommended.

Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas.

BACKGROUND: The pyrimidine analogue gemcitabine (2', 2'-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CL(tb)) and low incidence of local toxicity make it an excellent candidate for evaluation as intraperitoneal (IP) therapy. We designed a dosing schema that used multiple sequential exchanges of a peritoneal dialysate containing dFdC in an effort to produce prolonged IP dFdC exposure. METHODS: As part of a study involving multi-modality therapy for advanced pancreatic adenocarcinoma, patients were treated with four 6-h IP dwells of dFdC (50 mg/m(2) in 2 l) over a 24-h period. A second 24-h cycle of IP dFdC therapy was repeated 1 week later. Each exchange of dialysate contained 50 mg/m(2) dFdC in 2 l of commercial 1.5% dextrose dialysis solution. Plasma and peritoneal fluid were analyzed by HPLC to determine concentrations of dFdC and its inactive metabolite 2', 2' difluorodeoxyuridine (dFdU). Clinical data were recorded to note drug toxicity and response. RESULTS: Nine patients underwent IP dFdC therapy, and eight were able to receive two cycles. There were no recorded significant toxicities. Low plasma dFdC concentrations (<1 microg/ml) were present transiently in seven of nine patients, and dFdC was not detectable in the plasma of the other two. Plasma dFdU concentrations were low but increased gradually until 12 h and then declined little if any. IP dFdC concentrations declined rapidly, and dFdC was seldom measurable prior to administration of the next scheduled 6-h dwell. dFdU concentrations in peritoneal fluid were very low (<0.5 microg/ml) throughout treatment. The mean area under the concentration versus time curve (AUC) for dFdC in peritoneal fluid was 182 microg/ml x h, which was approximately 70x the AUC of dFdC reported in the ascites of a patient undergoing systemic dFdC therapy. CONCLUSIONS: IP dFdC was well tolerated, and no significant toxicities were noted. The rapid decrease in peritoneal dFdC concentrations and low concentrations of IP dFdU imply almost total absorption of IP-administered dFdC. Little, if any, dFdC could be detected in plasma, but the steady-state plasma dFdU concentrations also imply absorption and inactivation of virtually all IP-administered dFdC. These findings are consistent with the known high CL(tb) and low incidence of local toxicity of dFdC and argue for its further evaluation as a drug for IP therapy.

Phase I and pharmacokinetic study of imatinib mesylate (Gleevec) and gemcitabine in patients with refractory solid tumors.

PURPOSE: Preclinical data shows improvements in response for the combination of imatinib mesylate (IM, Gleevec) and gemcitabine (GEM) therapy compared with GEM alone. Our goals were to determine the maximum tolerated dose of GEM and IM in combination, the pharmacokinetics of GEM in the absence and in the presence of IM, and IM pharmacokinetics in this combination. PATIENTS AND METHODS: Patients with refractory malignancy, intact intestinal absorption, measurable/evaluable disease, adequate organ function, Eastern Cooperative Oncology Group PS 0-2, and signed informed consent were eligible. Initially, treatment consisted of 600 mg/m2 of GEM (10 mg/m2/min) on days 1, 8, and 15, and 300 mg of IM daily every 28 days. Due to excessive toxicity, the schedule was altered to IM on days 1 to 5 and 8 to 12, and GEM on days 3 and 10 every 21 days. Two final cohorts received IM on days 1 to 5, 8 to 12, and 15 to 19. RESULTS: Fifty-four patients were treated. IM and GEM given daily at 500 to 600 mg/m2 on days 1, 8, and 15 produced frequent dose-limiting toxicities. With the modified scheduling, GEM given at 1,500 mg/m2/150 min was deliverable, along with 400 mg of IM, without dose-limiting toxicities. Three partial (laryngeal, renal, and mesothelioma) and two minor (renal and pancreatic) responses were noted at GEM doses of 450 to 1,500 mg/m2. Stable disease >24 weeks was seen in 17 patients. CA19-9 in 7 of 10 patients with pancreatic cancer was reduced by approximately 90%. IM did not significantly alter GEM pharmacokinetics. CONCLUSION: The addition of intermittently dosed IM to GEM at low to full dose was associated with broad antitumor activity and little increase in toxicity.

Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies.

PURPOSE: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. EXPERIMENTAL DESIGN: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. RESULTS: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. CONCLUSIONS: Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.

Disposition of imatinib and its metabolite CGP74588 in a patient with chronic myelogenous leukemia and short-bowel syndrome.

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by means of cytochrome P450 3A and excreted primarily in the bile. Although the bioavailability of imatinib mesylate is more than 97%, the exact gastrointestinal site of its absorption is unknown. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP74588 in the plasma and jejunostomy output of a patient with newly diagnosed chronic myelogenous leukemia. She had previously lost most of her small bowel and all of her colon as a result of mesenteric artery thrombosis and radiation-induced colitis and/or proctitis. Imatinib pharmacokinetics in plasma indicated that approximately 20% of the patient's 400-mg dose was absorbed. The jejunostomy output contained 338 mg of imatinib, which was consistent with 320 mg of a nonabsorbed dose plus approximately 23% of the absorbed dose being excreted unchanged in the bile. These data indicate the importance of considering gastrointestinal anatomic abnormalities or disease states when oral imatinib is dosed.

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts.

PURPOSE: 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) is a water-soluble analogue of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a compound currently in clinical trials. These preclinical studies: (1) characterized 17DMAG concentrations in plasma, normal tissues, and tumor after i.v. delivery to mice; and (2) correlated tumor and normal tissue 17DMAG concentrations with alterations in heat shock protein 90 (HSP90) and selected HSP90-chaperoned proteins. METHODS: At specified times after i.v. administration of 75 mg/kg 17DMAG, SCID mice bearing s.c. MDA-MB-231 human breast xenografts were killed and plasma and tissues were retained. 17DMAG concentrations were determined by HPLC. Raf-1, heat shock protein 70 (HSP70), and HSP90 in tissues were determined by Western blotting. RESULTS: Peak plasma 17DMAG concentration was 15.4+/-1.4 microg/ml. The area under the plasma 17DMAG concentration versus time curve was 1072 microg/ml min, corresponding to a total body clearance of 70 ml/kg/min. Peak 17DMAG concentrations in liver (118.8+/-5.7 microg/g), kidney (122.9+/-10.6 microg/g), heart (81.3+/-8.1 microg/g), and lung (110.6+/-25.4 microg/g) occurred at 5-10 min, while peak concentrations in spleen (70.6+/-9.6 microg/g) and tumor (9.0+/-1.0 microg/g) occurred at 30-45 min. At 48 h, 17DMAG was detectable in tumor but not in any normal tissue. Raf-1 in tumors of 17DMAG-treated mice killed at 4, 7, 24 and 48 h was about 20% lower than in tumors from vehicle-treated mice. HSP90 and HSP70 in tumors of 17DMAG-treated animals were significantly lower than in tumors of control animals at 4, 7, and 24 h. Hepatic Raf-1 was decreased by more than 60% at all times after 17DMAG treatment; however, hepatic HSP90 was not affected. HSP70 was undetectable in livers of vehicle-treated mice or mice killed at 2 or 4 h after 17DMAG treatment, but was detected in livers at 7, 24 and 48 h. 17DMAG did not affect renal Raf-1. In contrast, renal HSP70 and HSP90 were decreased by more than 50% at 2 and 4 h after 17DMAG treatment. Renal HSP70 increased approximately twofold above that in kidneys from vehicle-treated control mice at 7 and 24 h, while HSP90 relative protein concentration was no different from that in controls. CONCLUSIONS: Plasma pharmacokinetics of 17DMAG in tumor-bearing mice were similar to those previously reported in nontumor-bearing mice. 17DMAG was distributed widely to tissues but was retained for longer in tumors than normal tissues. Raf-1, HSP90, and HSP70 were altered to different degrees in tumors, livers, and kidneys of 17DMAG-treated animals. These data illustrate the complex nature of the biological responses to 17DMAG.

Biliary excretion of imatinib mesylate and its metabolite CGP 74588 in humans.

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

Effect of St John's wort on imatinib mesylate pharmacokinetics.

OBJECTIVE: Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity. Thus we examined the effects of St John's wort on imatinib pharmacokinetics. METHODS: This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John's wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry. RESULTS: St John's wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 microg . h/mL to 24.2 +/- 7.0 microg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 microg/mL versus 1.8 microg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John's wort dosing, but the AUC from 0 to 72 hours was not altered. CONCLUSIONS: These data indicate that St John's wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John's wort. Concomitant use of enzyme inducers, including St John's wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.

Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats.

PURPOSE: 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG) is an analogue of the benzoquinone ansamycin compound 17-(allylamino)-17-demethoxygeldanamycin (17AAG), which is currently being evaluated in clinical trials. Studies were performed in mice and rats to: (1) define the plasma pharmacokinetics, tissue distribution, and urinary excretion of 17DMAG after i.v. delivery; (2) define the bioavailability of 17DMAG after i.p. and oral delivery; (3) characterize the biliary excretion of 17DMAG after i.v. delivery to rats; and (4) characterize, if possible, any metabolites of 17DMAG observed in plasma, tissue, urine, or bile. MATERIALS AND METHODS: Studies were performed in female, CD2F1 mice or male Fischer 344 rats. In preliminary toxicity studies and subsequent i.v. pharmacokinetic studies in mice, 17DMAG i.v. bolus doses of 33.3, 50, and 75 mg/kg were used. In bioavailability studies, i.p. and oral 17DMAG doses of 75 mg/kg were used. In preliminary toxicity studies in rats, i.v. bolus doses of 10 and 20 mg/kg were used, and in i.v. pharmacokinetic studies 10 mg/kg was used. Compartmental and noncompartmental analyses were applied to the plasma concentration versus time data. In mice and rats, concentrations of 17DMAG were determined in multiple tissues. Urine was collected from mice and rats treated with each of the i.v. doses of 17DMAG mentioned above, and drug excretion was calculated until 24 h after treatment. Biliary excretion of 17DMAG and metabolites was studied in bile duct-cannulated rats given a 10 mg/kg i.v. bolus dose of 17DMAG. 17DMAG metabolites were identified with LC/MS. RESULTS: A 75 mg/kg dose of 17DMAG caused no changes in appearance, appetite, waste elimination, or survival of treated mice as compared to vehicle-treated controls. Bolus i.v. delivery of 17DMAG at 75 mg/kg produced "peak" plasma 17DMAG concentrations between 18 and 24.2 microg/ml in mice killed at 5 min after injection. Sequential reduction in the 17DMAG dose to 50 and 33.3 mg/kg resulted in "peak" plasma 17DMAG concentrations between 9.4 and 14.4, and 8.4 and 10.5 microg/ml, respectively. Plasma 17DMAG AUC increased from 362 to 674 and 1150 microg/ml x min when the 17DMAG dose increased from 33.3 to 50 and 75 mg/kg, respectively, corresponding to a decrease in 17DMAG CLtb from 92 ml/min per kg to 75 and 65 ml/min per kg. Plasma 17DMAG concentration versus time data were best fit by a two-compartment open linear model. No potential 17DMAG metabolites were observed in plasma. 17DMAG bioavailability was 100% and 50% after i.p. and oral delivery, respectively. In rats, an i.v. bolus dose of 10 mg/kg produced peak plasma 17DMAG concentrations between 0.88 and 1.74 microg/ml. Plasma 17DMAG concentrations had fallen below the lower limit of quantitation by 180 min and were best fit by a one-compartment open linear model. The plasma 17DMAG AUC was 104 microg/ml x min, corresponding to a 17DMAG CLtb of 96 ml/min per kg. 17DMAG distributed rapidly to all mouse and rat tissues except brain and testes. Only mouse liver contained materials consistent with potential metabolites of 17DMAG, but their concentrations were below the limit of quantitation of the HPLC assay used. Within the first 24 h after delivery, urinary excretion of 17DMAG by mice and rats accounted for 10.6-14.8% and 12.5-16%, respectively, of the delivered dose. By 15 min after i.v. delivery of 10 mg/kg of 17DMAG, rat bile contained 11 new materials with absorbance similar to that of 17DMAG. Four of these proposed metabolites had an Mr of 633, indicating addition of an oxygen. Two of these proposed metabolites had an Mr of 603, implying the loss of one methyl group, and one had an Mr of 589, implying the loss of two methyl groups. The remaining four proposed metabolites had an Mr of 566, 571, 629, and 645, respectively. Biliary excretion of 17DMAG and metabolites accounted for 4.7 +/- 1.4% of the delivered dose, with 17DMAG accounting for 50.7 +/- 3.4% of the biliary excretion. CONCLUSIONS: 17DMAG has excellent bioavailability when given i.p. and good bioavailability when given orally. 17DMAG is widely distributed to tissues and is quantitatively metabolized much less than is 17AAG. The pharmacokinetic and metabolite data generated should prove relevant to the design of additional preclinical studies as well as to contemplated clinical trials of 17DMAG and could be useful in their interpretation.