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  • 1
    Digitale Medien
    Digitale Medien
    REGIONAL BRAIN ACTIVATION IN HUMANS DURING RESPIRATORY AND BLOOD PRESSURE CHALLENGES (1998)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 25 (1998), S. 0 
    Details
    ISSN: 1440-1681
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: 1. The aim of the present study was to determine the brain sites mediating aspects of respiratory and cardiovascular control in adult humans using non-invasive functional magnetic resonance (/MRI) procedures, thereby avoiding the spatial and temporal sampling limitations associated with classic neural assessment techniques.2. We examined activity changes across the entire brain following application of respiratory loads and upon induction of blood pressure and heart rate alterations. Magnetic resonance signals were visualized with a 1.5Tesla scanner in healthy volunteers (22-52 years of age) using procedures that optimally assess changes in brain tissue microcirculation. Images were collected during a Valsalva manoeuvre, inspiratory loading, hypercapnia, cold pressor challenges to the hand and forehead and during intervening baseline states.3. Image values from experimental conditions were compared with corresponding baseline values on a pixel-by-pixel basis to identify brain regions in which the experimental conditions produced physiological activation.4. Ventilatory and pressor challenges elicited significant changes in regional image signal intensity in areas within the orbital cortex, amygdala, hypothalamus and hippocampus. Cerebellar, medullary and pontine areas were also recruited. However, while particular brain regions were only activated during specific stimuli, other regional signal changes occurred with multiple experimental manipulations.5. The findings indicate that respiratory and cardiac challenges elicit discrete activity changes over multiple brain sites. Activated regions include structures not often related to respiratory or cardiovascular regulation, such as the cerebellum; a prominent role for limbic forebrain structures in mediating the response is also suggested. The f MRI visualization procedures may greatly assist in the determination of neural structures that mediate respiratory and cardiovascular control in humans.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1111/j.1440-1681.1998.tb02240.x
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  • 2
    Digitale Medien
    Digitale Medien
    A phase I trial of 5-fluorouracil, leucovorin, and dipyridamole given by concurrent 120-h continuous infusions (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 297-302 
    Details
    ISSN: 1432-0843
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary A phase I trial of 5-fluorouracil (FUra) and leucovorin (LV) given with and without dipyridamole (DP) by concurrent 120-h continuous infusion was performed in 27 patients with advanced solid malignancies, 8 of whom had previously received FUra. The LV and DP doses were fixed at 500 mg/m2 daily and 7.7 mg/kg daily, respectively, whereas the FUra dose was escalated. Level 3 (450 mg/m2 FUra daily) represented the maximum tolerated dose for both FUra/LV+DP and FUra/LV. Dose-limiting stomatitis (≥grade 3 or grade 2 occurring during the infusion) was encountered in 75% of the first courses given at level 4 (600 mg/m2 daily). Stomatitis was observed in 44/78 (56%) courses.Diarrhea was infrequent and mild. DP infusions were complicated by mild to moderate headache, which was controlled with narcotic analgesics, and mild to moderate nausea/vomiting. FUra-related toxicity was not enhanced by DP administration. Limited pharmacokinetic sampling at levels 3 and 4 revealed mean steady-state FUra concentrations of around 1.0 μM with infusions of FUra/LV+DP. Among three paired courses given with and without DP, no statistically significant difference was found in the total body clearance of FUra (P=0.44). One partial response was seen in a patient with metastatic gastric carcinoma. For phase II trials, we recommend that concurrent 120-h continuous infusions of FUra (450mg/m2 daily) and LV (500 mg/m2 daily) be given with and without DP (7.7 mg/kg daily) every 21 days.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00686299
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  • 3
    Digitale Medien
    Digitale Medien
    Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies (1993)
    Springer
    Investigational new drugs 11 (1993), S. 291-300 
    Details
    ISSN: 1573-0646
    Schlagwort(e): granulocyte-macrophage colony-stimulating factor ; mitoxantrone ; clinical trials ; phase I trials
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Purpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF. Patients and methods Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m2 on day 1; GM-CSF (5 Μg/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC). Results Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m2/day. Therefore, we conclude the MTD was 37 mg/m2/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) 〈 500/mm3. Conclusion The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00874427
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  • 4
    Digitale Medien
    Digitale Medien
    Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812) (1999)
    Springer
    Investigational new drugs 17 (1999), S. 63-72 
    Details
    ISSN: 1573-0646
    Schlagwort(e): chemotherapy ; platinum (IV) analogues ; cisplatin resistance ; pharmacodynamics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4–128 mg/m2. The dose-limiting toxicity was reversible thrombocytopenia and granulocytopenia. Minimal myelosuppression was observed at dose levels ≤ 78 mg/m2, while grade 3 or 4 myelosuppression (thrombocytopenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m2 and 4/5 patients at 123 mg/m2. Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied. The mean total body clearance of UF-Pt was 135 ml/min/m2 and the mean elimination half-life (t1/2β) was 13.6 h. Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion. Urinary excretion of platinum accounted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m2 is recommended for testing in a patient population with cisplatin-refractory disease.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1006223100561
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  • 5
    Digitale Medien
    Digitale Medien
    Taxol administered as a 120 hour infusion (1992)
    Springer
    Investigational new drugs 10 (1992), S. 275-278 
    Details
    ISSN: 1573-0646
    Schlagwort(e): taxol ; phase I ; prolonged infusion
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary A Phase I trial of Taxol administered as a 120 h infusion once every 3 weeks was conducted in 20 patients with advanced cancer. The initial dose was 5 mg/m2/d (25 mg/m2 total dose) and patients received 10 mg/m2/d, 25 mg/m2/d, 30 mg/m2/d and 36 mg/m2/d. Forty-four courses of taxol were administered and all patients were evaluable for toxicity. Grade 4 leukopenia was the dose limiting toxicity observed in 50% of patients treated with 36 mg/m2/d. Significant mucositis was also observed at 30 and 36 mg/m2/d. All toxicity resolved within three weeks of treatment and no cumulative toxicity was observed. No neurotoxicity or cardiotoxicity was observed and no episodes of hypersensitivity reaction were noted. We conclude that 30 mg/m2/d is an appropriate dose for phase II testing of this schedule.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00944181
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  • 6
    Digitale Medien
    Digitale Medien
    Phase II evaluation of the AMAP, 773U82 mesylate, in pancreatic cancer (1994)
    Springer
    Investigational new drugs 12 (1994), S. 273-276 
    Details
    ISSN: 1573-0646
    Schlagwort(e): pancreatic cancer ; AMAP ; 773U82 ; chemotherapy
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Pancreatic cancer is the fifth leading cause in cancer related death among adults in the United States. Thirtythousand new cases of pancreatic cancer are diagnosed each year, most are metastatic at diagnosis and no effective systemic therapy is available. 773U82 mesylate is one of a series of compounds (arylmethylaminopropanediols-AMAPS) which was synthesized at the Wellcome Research Laboratories. AMAPS bind to DNA, show evidence of topoisomerase 2 inhibition and are active in a variety of murine and human preclinical screens. Based on these data a phase II trial of 773U82 mesylate administered at 800 mg/ m2 daily × 3 at a 4 h infusion repeated every three weeks was carried out. Patients eligible for these trials had histologic proof of adenocarcinoma, good performance status, and normal organ function. This was a multi-institutional trial. Nineteen patients were entered; 15 patients were fully eligible and 4 were ineligible, but were evaluated. Thirteen patients were fully evaluable for response and no response was seen. Median time to progressive disease among eligible patients was 56 days. Toxicity of 773U82 mesylate was myelosuppression which was not prohibitive. 773U82 mesylate is not active in pancreatic cancer.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00873040
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  • 7
    Digitale Medien
    Digitale Medien
    Effects of dexamethasone on induction of monocytic differentiation in human U-937 cells by dimethylsulfoxide (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 142 (1990), S. 261-267 
    Details
    ISSN: 0021-9541
    Schlagwort(e): Life and Medical Sciences ; Cell & Developmental Biology
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Biologie , Medizin
    Notizen: The present studies demonstrate that dimethylsulfoxide (DMSO) treatment of human U-937 myelomonocytic: leukemia cells is associated with induction of monocytic differentiation. The DMSO-induced U-937 monocytic phenolype was associated with (1) growth inhibition, (2) loss of clonogenic survival, (3) increases in á-naphthyl acetate esterase (NSE) staining, and (4) increases in cell surface expression of the monocyte marker Mac-1. DMSO treatment of U-937 cells was also associated with down-regulation of c-myc and c-myb gene expression as well as with increases in tumor necrosis factor (TNF) mRNA levels. The results further demonstrate that induction of U-937 monocytic differentiation by DMSO is accompanied by increases in phospholipase A2 activity. Moreover, this stimulation of phospholipase A2 was sensitive to dexamethasone. We therefore studied the effects of dexamethasone on DMSO-induced differentiation of U-937 cells. Although dexamethasone had no effect on growth inhibition or loss of clonogenic survival by DMSO, this glucocorticoid blocked increases in NSE staining and cell surface Mac-1 expression. Dexamethasone also had no effect on the down-regulation of c-myc and c-m/b expression but blocked the reappearance of c-myb transcripts after 6 hr of DMSO treatment. Finally, dexamethasone inhibited DMSO-induced increases in TNF gene expression. Taken together, the results demonstrate that dexamethasone inhibits multiple characteristics, including the stimulation of phospholipase A2 activity, associated with DMSO-induced monocytic differentiation of U-937 cells.
    Zusätzliches Material: 6 Ill.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1002/jcp.1041420207
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