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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and biotransformation studies of ormaplatin in conjunction with a phase I clinical trial (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 347-354 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Ormaplatin is a second-generation platinum (Pt) analogue with in vitro activity against some cisplatin-resistant malignant cell lines. We have evaluated the pharmacokinetics and biotransformations of ormaplatin during a phase I trial in which ormaplatin was administered by daily 30-min infusions on 5 consecutive days every 28 days. Sixteen patients received 25 courses at doses ranging from 5.0 to 11.6 mg/m2 per day. Pharmacokinetic parameters determined for ultrafilterable Pt measured by atomic absorption spectrophotometry revealed a short half-life (t1/2 16 min), moderate volume of distribution (Vd 12 l/m2), and relatively fast systemic clearance (Cls 544 ml/min per m2). Cls and percentage of drug unbound decreased during the 5-day administration period. Average systemic exposure increased with dose; however, inter-individual variability in Cls produced overlap in systemic exposure between the dose levels. The major active biotransformation product [PtCl2(dach)] was evaluated at the highest dose level by HPLC. This product decayed monoexponentially with a mean t1/2 of 13 min and a higher degree of pharmacokinetic variability than that of ultrafilterable Pt at this dose. No unreacted ormaplatin was detected; however, several inactive biotransformation products persisted for at least 120 min. Approximately 32% of the dose was excreted in the urine during the first day, one-third of this during the initial 1.5 h. The human pharmacokinetic characteristics of ormaplatin resemble those of cisplatin; however, additional study will be required to discern which analyte of ormaplatin correlates best with clinical effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685911
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and biotransformation studies of ormaplatin in conjunction with a phase I clinical trial (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 347-354 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ormaplatin is a second-generation platinum (Pt) analogue with in vitro activity against some cisplatin-resistant malignant cell lines. We have evaluated the pharmacokinetics and biotransformations of ormaplatin during a phase I trial in which ormaplatin was administered by daily 30-min infusions on 5 consecutive days every 28 days. Sixteen patients received 25 courses at doses ranging from 5.0 to 11.6 mg/m2 per day. Pharmacokinetic parameters determined for ultrafilterable Pt measured by atomic absorption spectrophotometry revealed a short half-life (t1/2 16 min), moderate volume of distribution (Vd 12 l/m2), and relatively fast systemic clearance (Cls 544 ml/min per m2). Cls and percentage of drug unbound decreased during the 5-day administration period. Average systemic exposure increased with dose; however, inter-individual variability in Cls produced overlap in systemic exposure between the dose levels. The major active biotransformation product [PtCl2(dach)] was evaluated at the highest dose level by HPLC. This product decayed monoexponentially with a mean t1/2 of 13 min and a higher degree of pharmacokinetic variability than that of ultrafilterable Pt at this dose. No uncreacted ormaplatin was detected; however, several inactive biotransformation products persisted for at least 120 min. Approximately 32% of the dose was excreted in the urine during the first day, one-third of this during the initial 1.5 h. The human pharmacokinetic characteristics of ormaplatin resemble those of cisplatin; however, additional study will be required to discern which analyte of ormaplatin correlates best with clinical effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685911
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  • 3
    Electronic Resource
    Electronic Resource
    Phase II trial of menogaril in adenocarcinoma of the pancreas (1991)
    Springer
    Investigational new drugs 9 (1991), S. 77-78 
    Details
    ISSN: 1573-0646
    Keywords: phase II ; menogaril ; pancreas ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194550
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  • 4
    Electronic Resource
    Electronic Resource
    Hypersensitivity reactions to trimetrexate (1990)
    Springer
    Investigational new drugs 8 (1990), S. 211-214 
    Details
    ISSN: 1573-0646
    Keywords: trimetrexate ; hypersensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Trimetrexate is a nonclassical antifol currently being tested for efficacy in cancer patients and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. We have now received the first reports of hypersensitivity reactions in Phase II cancer trials. Two types of reactions were noted. The most severe reaction, immediate hypotension with loss of consciousness, occurred in only one patient. Four other patients exhibited an immediate systemic effect with one or more of the following symptoms: facial flushing, fever, shaking, pruritus, bronchospasm, periorbital edema, and difficulty in swallowing. Immediate hypersensitivity should now be considered a known side effect of trimetrexate therapy, occurring in 〈 2% of patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00177263
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  • 5
    Electronic Resource
    Electronic Resource
    The effects of hip contact aberrations on stress patterns within the human femoral head (1980)
    Springer
    Annals of biomedical engineering 8 (1980), S. 75-92 
    Details
    ISSN: 1573-9686
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract A two-dimensional finite element model incorporating cancellous bone inhomogeneity is used to study femoral head stress alterations caused by changes from the usual articular contact patterns. The contact stress distributions, calculated from an earlier mathematical analysis by Greenwald and O'Connor (16), are found to influence not only the adjacent subchondral bone, but relatively distant parts of the head as well. Both abnormally large joint incongruity and abnormally low cartilage compliance cause load to shift away from the superior “weight-bearing” area, out toward the periphery of the contact region. As a consequence, transverse compressive stresses, which are of appreciable magnitude but which do not contribute to weight bearing, are built up throughout much of the superior and central portions of the femoral head. Most small changes in the overall cartilage thickness or in its thickness distribution, when considered in isolation from hip compliance changes, have only minor effects on the internal stress distribution. An important exception is cartilage thinning at the superior margin, which can result in abrupt longitudinal compressive stress concentrations. It is suggested that such alterations of the normal patterns of stress transmission may contribute to sclerosis or to the formation of osteophytes or cysts in the osteoarthritic hip.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02363172
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  • 6
    Electronic Resource
    Electronic Resource
    Phase II trial of gemcitabine (2,2′-difiuorodeoxycytidine) in patients with adenocarcinoma of the pancreas (1994)
    Springer
    Investigational new drugs 12 (1994), S. 29-34 
    Details
    ISSN: 1573-0646
    Keywords: pancreas ; adenocarcinoma ; gemcitabine ; 2,2′-difluorodeoxycytidme ; phase II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 103/μl (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 103/μl (range 0.4–7.2). Thrombocytopenia - 100.0 × 103/μl was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873232
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  • 7
    Electronic Resource
    Electronic Resource
    Cardiovascular rhythm effects of gamma recombinant DNA interferon (1989)
    Springer
    Investigational new drugs 7 (1989), S. 275-280 
    Details
    ISSN: 1573-0646
    Keywords: gamma interferon ; cardiac rhythm disturbances
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty patients receiving recombinant DNA gamma interferon were prospectively assessed for cardiac rhythm disturbances. All patients were evaluated with baseline electrocardiograms, pretreatment ambulatory monitoring and ejection fraction determination. Each patient was then monitored continuously during drug administration. Quantitative ventricular ectopy was not increased, nor were average heart rate, maximal heart rate, or quantitative supraventricular ectopy when comparing baseline to during therapy parameters. Complex cardiac ectopy and noteworthy cardiac events (NCE) were defined and identified in 2/20 (10%) patients pretreatment, and in 8/18 patients (44%) with normal baseline tracings during treatment (p = .02). This difference was not apparent when corrected for total days monitored pre and post treatment (p 〉 .2). These consisted predominantly of nonsustained short duration ventricular tachycardia (seven of eight patients). We conclude that life threatening cardiac events are uncommon with gamma interferon therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00170873
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  • 8
    Electronic Resource
    Electronic Resource
    A phase I clinical and pharmacokinetic study of the oral and the oral/ intravenous administration of menogaril (1993)
    Springer
    Investigational new drugs 11 (1993), S. 17-27 
    Details
    ISSN: 1573-0646
    Keywords: menogaril ; phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m2 IV; 250–500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic antiemetics at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2, leukopenia 〈 3000/μl occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with nonsmall cell lung cancer experienced a 30% reduction in metastatic tumor nodules. For the patients receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intravenous administration. The harmonic mean (±SD) terminal disposition half-life after oral dosing was 29.3 ±9.2 hours; mean systemic bioavailability was 33.6±10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00±0.96% and 0.44±0.16%, respectively. Because of the poor tolerance of oral menogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873906
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  • 9
    Electronic Resource
    Electronic Resource
    Phase II trial of trimetrexate in advanced esophageal cancer: A southwest oncology group study (1995)
    Springer
    Investigational new drugs 13 (1995), S. 363-365 
    Details
    ISSN: 1573-0646
    Keywords: phase II study ; trimetrexate ; advanced esophageal cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Trimetrexate (TMQ) is a synthetic folate antagonist that has demonstrated non-cross resistance with methotrexate in preclinical screens. A phase II trial was performed with TMQ given to patients with advanced squamous cell carcinoma of the esophagus. TMQ was administered as an i.v. bolus on a daily × 5 schedule, every 3 weeks; a starting dose of 12 mg/m2 was used for patients with no prior irradiation, and of 8 mg/m2 for patients with prior irradiation. Twenty-four patients were entered onto study, with 23 patients eligible, and a median of 2 courses of TMQ administered per patient. Twenty-three patients were evaluable for toxicity. Toxicities of SWOG grade ≥ 3 included granulocytopenia (9 patients), leukopenia (7 patients), thrombocytopenia (4 patients), anemia (3 patients), mucositis (3 patients), nausea and vomiting (2 patients), dermatitis (1 patient), diarrhea (1 patient), and fever (1 patient). Fifteen patients had some hematologic toxicity, and eleven patients had hematologic toxicity of grade ≥ 3. Two treatment related deaths occurred in association with myelosuppression. One patient achieved a complete response and one patient achieved a partial response, with response durations of 8.5 months and 6 months, respectively. The overall response rate was 8% [95% confidence interval of 1 to 28%], with a median survival for the 23 eligible patients of 5.1 months.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873146
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  • 10
    Electronic Resource
    Electronic Resource
    Phase II trial of echinomycin in advanced colorectal cancer (1991)
    Springer
    Investigational new drugs 9 (1991), S. 113-114 
    Details
    ISSN: 1573-0646
    Keywords: phase II ; echinomycin ; colorectal ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194561
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