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- Baselga, J, et al.
(författare)
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Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
- 2002
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 20:21, s. 4292-4302
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
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- Werren, John H, et al.
(författare)
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Functional and evolutionary insights from the genomes of three parasitoid Nasonia species.
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 327:5963, s. 343-8
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Tidskriftsartikel (refereegranskat)abstract
- We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N. giraulti, and N. longicornis. Parasitoids are important regulators of arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model, particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia, and Nasonia; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.
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- Frisoni, G. B., et al.
(författare)
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Dementia prevention in memory clinics: recommendations from the European task force for brain health services
- 2023
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Ingår i: Lancet Regional Health-Europe. - : Elsevier BV. - 2666-7762. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence sup-ports the efficacy of preventive interventions on persons with intact cognition and high dementia risk. We report recommendations for the deployment of second-generation memory clinics (Brain Health Services) whose mission is evidence-based and ethical dementia prevention in at-risk individuals. The cornerstone interventions consist of (i) assessment of genetic and potentially modifiable risk factors including brain pathology, and risk stratification, (ii) risk communication with ad-hoc protocols, (iii) risk reduction with multi-domain interventions, and (iv) cognitive enhancement with cognitive and physical training. A roadmap is proposed for concept validation and ensuing clinical deployment.
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- Jayson, G.C., et al.
(författare)
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Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer
- 2005
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 41:4, s. 555-563
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the tolerability, safety, pharmacokinetics and dose-limiting toxicity (DLT) of the recombinant humanized IgG4 anti-vascular endothelial growth factor (VEGF) monoclonal antibody, HuMV833, in patients with advanced cancer. Cohorts of patients with progressive solid tumours received escalating doses of HuMV833 as a 1-h intravenous (I.V.) infusion on days 1, 15, 22, and 29. Twenty patients (median Eastern Cooperative Oncology Group (ECOG) score 1) were accrued. HuMV833 infusions were well tolerated and there were no grade III or IV toxicities definitely related to the antibody. Grade I or II toxicities probably related to the antibody included fatigue, dyspnoea and rash. There were two episodes of asymptomatic hypocalcaemia, one at grade III and one grade IV, which were recorded in early follow-up. There were eight grade I episodes of asymptomatic elevation of activated partial thromboplastin time (APTT) and two grade III events, one in a patient receiving 1 mg/kg and the other receiving extended doses of 10 mg/kg. Pharmacokinetic analysis revealed a non-linear kinetic and an elimination half-life of between 8.2 (0.3 mg/kg) and 18.7 (10 mg/kg) days. One patient with ovarian cancer experienced a partial response (PR) of 9 months duration and eight had disease stabilisation (SD) including one patient with colorectal carcinoma whose disease was stable for 14 months. In 13 of the 14 samples taken from 12 patients, the plasma concentration of hepatocyte growth factor (HGF) was reduced 24 h after drug administration. HuMV833 is safe and lacked DLT at doses up to 10 mg/kg on this schedule. Multiple doses were well tolerated, despite occasional asymptomatic elevations in APTT. By combining pharmacokinetic, pharmacodynamic and toxicity data, we can identify doses of 1 and 3 mg/kg for further investigation. HuMV833 appears to possess some clinical activity. © 2004 Published by Elsevier Ltd.
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- LoRusso, Patricia M, et al.
(författare)
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Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors
- 2003
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 9:6, s. 2040-2048
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The feasibility and utility of assessing quality of life (QoL) and disease-related symptoms in patients with advanced cancer have been evaluated in two Phase I clinical trials of p.o. administered ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced cancer. EXPERIMENTAL DESIGN: Functional Assessment of Cancer Therapy (FACT) questionnaires, including disease-specific subscales for lung, head and neck, colorectal, prostate, and ovarian cancer, were completed by patients in two open-label, Phase I, escalating multiple-dose safety and tolerability trials. RESULTS: In 157 patients, 92% of whom had received prior therapy, compliance in returning FACT questionnaires was 87% (European/Australian trial) and 57% (United States trial). This did not appear to be influenced by dose level or tumor type. For patients with colorectal, prostate, or ovarian cancer, median QoL [FACT and Trial Outcome Index (TOI)] scores deteriorated over time. In contrast, for patients with non-small cell lung cancer (NSCLC) or head and neck cancer, median FACT and TOI scores did not deteriorate significantly, and in the United States trial, head and neck cancer scores improved significantly over time. In patients with NSCLC, symptom-related scores measured by the Lung Cancer Subscale of FACT-L appeared sensitive to clinical change. CONCLUSIONS: QoL (FACT-L) questionnaires were used successfully in the Phase I clinical trials of ZD1839. They appeared to be a sensitive tool to monitor clinical changes for the five tumor types in these trials and showed that ZD1839 has the potential to improve patients' QoL.
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