Biomedical subjects

Julie Wolf

Publications and source records attributed to Julie Wolf.

7 recordsLinked to original sources

PubMed2006

Phase I, pharmacokinetic, and biological study of erlotinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering erlotinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, in combination with paclitaxel and carboplatin, and to identify pharmacokinetic interactions, evaluate downstream effects of EGFR inhibition on surrogate tissues, and seek preliminary evidence for clinical activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated continuously with erlotinib at doses of 100, 125, and 150 mg/d orally along with fixed i.v. doses of paclitaxel 225 mg/m(2) and carboplatin AUC 6 mg x min/mL, both on day 1 every 3 weeks. RESULTS: Twenty evaluable patients were treated with 136 courses of erlotinib, paclitaxel, and carboplatin. Myelosuppression, skin rash, and diarrhea were the principal toxicities. Dose limiting diarrhea occurred in 1 of 6 patients at the 100 mg erlotinib dose level, whereas 0 of 9 evaluable patients at the 125 mg erlotinib dose level experienced dose limiting toxicity and 3 of 5 evaluable patients at 150 mg erlotinib experienced dose limiting skin rash and neutropenic sepsis. There was no evidence of pharmacokinetic interactions between paclitaxel and erlotinib; however, total carboplatin exposure trended higher in the presence of erlotinib. No consistent downstream effects on EGFR inhibition were found in skin. Durable objective responses were observed in non-small-cell lung and head and neck cancers. CONCLUSIONS: A dose level of erlotinib 125 mg combined with paclitaxel 225 mg/m(2) and carboplatin AUC 6 mg.min/mL is recommended for disease-directed studies. This phase I trial was followed by a randomized phase III study in non-small-cell lung cancer using a similar regimen.

Adult↗

PubMed2006

Erlotinib plus gemcitabine in patients with unresectable pancreatic cancer and other solid tumors: phase IB trial.

PURPOSE: The purpose of this phase IB trial was to evaluate the tolerability, pharmacokinetics and preliminary evidence of antitumor activity of erlotinib plus gemcitabine in patients with pancreatic cancer and other solid tumors. PATIENTS AND METHODS: Patients included those with advanced pancreatic adenocarcinoma or other malignancies potentially responsive to gemcitabine. In the escalating phase of the trial, patients were enrolled in sequential cohorts using 100 or 150 mg oral daily dosing of erlotinib. Gemcitabine dose was 1,000 mg/m(2) weekly x 7 (first cycle), then weekly x 3, every 4 weeks. RESULTS: Twenty-six patients completed at least one course on study. In Cohort IA, at the 100 mg/day dose of erlotinib, three patients have developed grade 3 transaminase elevations. After stricter inclusion criteria were adopted (Cohort IB), no additional events of grade 3 transaminase elevations were observed and the dose of erlotinib was escalated to 150 mg/day (Cohorts IB and IIB) without reaching dose-limiting toxicities. The most common toxicities included diarrhea, skin rash, fatigue and neutropenia. The pharmacokinetic analyses did not reveal any significant interactions between erlotinib and gemcitabine. Objective responses were seen in two patients: cholangiocarcinoma and pancreatic cancer. Patients with unresectable or metastatic pancreatic cancer (n = 15) had a median progression-free survival of 289 days, the estimated overall survival of 389 days (12.5 months), and a 1-year survival rate of 51%. CONCLUSION: The 150 mg/day dose of erlotinib can be safely administered in combination with standard dose gemcitabine in selected patients with pancreatic cancer and other advanced solid tumors. Promising antitumor activity has been observed in patients with pancreatic cancer.

Adenocarcinoma↗

PubMed2006

Automatic processing of emotional faces in high-functioning pervasive developmental disorders: An affective priming study.

This study examined automatic processing of emotional faces in individuals with high-functioning Pervasive Developmental Disorders (HFPDD) using an affective priming paradigm. Sixteen participants (HFPDD and matched controls) were presented with happy faces, fearful faces or objects in both subliminal and supraliminal exposure conditions, followed by Japanese ideographs for which the participants provided liking ratings. In the HFPDD group, affective priming was not found in either condition; the control group showed affective priming for both emotional faces under the subliminal condition and only for happy faces under the supraliminal condition. Results suggest that the social deficit in autism may derive in part from a failure in evaluating the emotional significance of emotional faces, a function for which the amygdala plays an important role.

Affect↗

PubMed2006

Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer.

OBJECTIVE: Our objective was to assess the pharmacokinetics of erlotinib in a large patient population with solid tumors, identify covariates, and explore relationships between exposure and safety outcomes (rash and diarrhea) in patients with non-small cell lung cancer receiving single-agent erlotinib. METHODS: The population pharmacokinetic analysis was performed by use of NONMEM based on 4068 concentration samples from 1047 patients receiving erlotinib as a single agent or in combination with chemotherapy. By use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on clearance and volume was examined. Spearman rank correlation analyses were performed to test for correlations between maximum grades of rash and diarrhea and erlotinib exposure in non-small cell lung cancer patients treated with single-agent erlotinib. RESULTS: On the basis of the final model developed from patients treated with erlotinib as a single agent, the oral clearance was 3.95 L/h, the oral volume of distribution was 233 L, and the absorption rate was 0.95 h(-1). The median erlotinib half-life based on this patient population was 36.2 hours. Total bilirubin, alpha1-acid glycoprotein, and smoking status were the most important factors affecting clearance. The clearance in current smokers was 24% faster than that in former smokers or those who never smoked. There was a statistically significant correlation between drug exposure and rash (P < .05). However, there was significant overlap in the range of values for patients who had no rash (grade = 0) and those who had any grade of rash. No significant correlation was found between exposure and diarrhea. CONCLUSIONS: The long half-life of erlotinib supports the current once-daily dosing regimen at 150 mg/d. Effects of covariates on erlotinib clearance and correlations with adverse event severity were provided to aid in the detection of a treatment-emergent effect.

Adult↗

PubMed2006

Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects.

A randomized, open-label, 2-period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150-mg tablet versus a 25-mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI-420, were measured after each dose. The ratios of geometric means for AUC(0-infinity) and Cmax of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%-63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150-mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.

Administration, Oral↗

PubMed2003

Responses and sustained interactions in children with mental retardation and autism.

Sustained interactions and responses to social bids made by children with autism and verbal-age-matched children with mental retardation were recorded in two naturalistic settings. Children with autism produced fewer positive responses and more "no responses" than children with mental retardation; both groups were more likely to make positive responses to adults and not to respond to other children. Furthermore, although the frequency of conversations was not different for the two groups, children with autism were significantly less likely to engage in sustained play compared to children with mental retardation. Results suggest that children with autism are able to master the more rote and need-oriented social skills, such as simple conversation, but may not develop other forms of social interactions, like play.

Adolescent↗

PubMedDate not supplied

Safety assessment of 4'-thio-beta-D-arabinofuranosylcytosine in the beagle dog suggests a drug-induced centrally mediated effect on the hypothalamic-pituitary-adrenal axis.

4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.

Adrenal Glands↗