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  • 1
    Electronic Resource
    Electronic Resource
    Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency (1989)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 32 (1989), S. 847-852 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00124a018
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  • 2
    Electronic Resource
    Electronic Resource
    A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve (1996)
    Springer
    Cancer chemotherapy and pharmacology 37 (1996), S. 429-434 
    Details
    ISSN: 1432-0843
    Keywords: Key words Carboplatin ; Pharmacokinetics ; Limited-sampling strategy ; AUC estimation ; Carboplatin AUC ; Single-sample assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to develop and validate a simple and rapid method for the estimation of the area under the free carboplatin plasma concentration versus time curve (AUC). The relationship between the carboplatin AUC and the total plasma platinum (Pt) concentration 24 h after treatment was studied using data from 49 patients treated with 20–1600 mg/m2 carboplatin as a 60–100 min infusion (median 60 min). The relationship was confirmed by the in vitro incubation of carboplatin in human plasma and prospectively validated in 13 ovarian cancer patients. Free carboplatin was separated by ultrafiltration (MW cut off 30,000), and free and total Pt measured by atomic absorption spectrophotometry. There was a linear relationship in vivo between the 24 h (median 24.4; range 16.3–27.3 h) total plasma Pt concentration (μM) and free carboplatin AUC (mg/ml.min): AUC=(24 h Pt+0.3)/0.82 (r 2=0.93, AUC median 5.8 (0.13–28)mg/ml.min, 24 h Pt median 4.4 (0.1–23) μM). A similar relationship was observed in vitro [AUC=(24 h Pt +0.1)/0.93 (r 2=0.98, AUC median 7.9 (2.0–17) mg/ml.min, 24 h Pt median 7.1 (1.8–15) μM)]. The relationship derived from the in vivo data gave an unbiased and reasonably accurate estimate of the measured carboplatin AUC in 13 patients (AUC=5.1–8.7 mg/ml.min, GFR=59–129 ml/min, infusion time 30–45 min, 24 h sampling time 22.9–24.5 h), giving a percentage mean error of −4.2% and root mean squared percentage error of 11.5%. These results show that the analysis of a single blood sample taken 24 h after carboplatin administration can be used to produce an unbiased and reasonably accurate measure of the free carboplatin AUC. Unlike published limited sampling strategies, this method is not complicated by the need to accurately control the duration of the carboplatin infusion or the time at which the sample is taken.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050408
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  • 3
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of the quinazoline antifolate ICID 1694 in mice and rats (1991)
    Springer
    Cancer chemotherapy and pharmacology 28 (1991), S. 331-338 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary N-(5-[N-(3,4-Dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-l-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitorN 10-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be an active anticancer agent in early clinical studies, but its use was limited by its relative insolubility at physiological pH. ICI D1694 has been shown to be a more active anticancer agent than CB 3717 in model systems, and it is devoid of the acute renal toxicity associated with the administration of the latter drug to mice. In the present study, the pharmacokinetics of ICI D1694 were studied in both mice and rats using reverse-phase HPLC. In rats, ICI D1694 clearance (CL) conformed to a two-compartment open model and was rapid (CL=10.7 ml min−1 kg−1,t1/2β=30 min). Excretion was mainly biliary (65% of the delivered dose in 4 h vs 12% in urine) in the rat following a 100-mg/kg i.v. bolus. A high degree of protein binding was seen in rat plasma (≥90% over the range of 20–100 μm). In mice, ICI D1694CL=27 ml min−1 kg−1 andt1/2β=30 min following 100 mg/kg i.v., which was significantly faster than CB3717 clearance (CL=6 ml min−1 kg−1,t1/2β=93 min). ICI D1694 was fully bioavailable following i.p. administration (AUC=3.73 mg ml−1 min i.v. 4.03 mg ml−1 min i.p.), but its bioavailability following oral administration appeared to be low (approximately 10%–20%). Tissue distribution and excretion studies in mice suggested that biliary excretion predominated, confirming the results obtained in rats. Following an i.v. dose of 500 mg/kg ICI D1694 in mice, drug was detectable at 24h, suggesting the presence of a third phase of plasma clearance. The initial HPLC assay could not detect this third phase following a dose of 100 mg/kg; hence, a more sensitive assay was developed that includes a solid-phase extraction step. The latter assay was used to define the third phase of ICI D1694 clearance in mice, and preliminary studies demonstrated a terminal half-life of 6.5±2.7 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685685
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  • 4
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of prednimustine and chlorambucil in the rat (1981)
    Springer
    Cancer chemotherapy and pharmacology 6 (1981), S. 85-91 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the rat prednimustine, the prednisolone ester of chlorambucil, is much less toxic than equimolar doses of chlorambucil, when administered subcutaneously (SC). This is due to differences in alkylating agent pharmacokinetics. Prednimustine injected SC produced low plasma concentrations (〈5 μM) of the alkylating metabolites chlorambucil and phenyl acetic mustard, which were maintained for 48 h. No unhydrolysed prednimustine could be detected. Chlorambucil, in contrast, was rapidly absorbed, peak levels (40 μM) occurring within 2 h, after which chlorambucil and phenyl acetic mustard plasma levels decreased with half-lives of 2.4 h and 2.9 h respectively. The toxicity of chlorambucil could be similarly reduced by administering either the methyl ester of clorambucil or by giving chlorambucil in a multiple-treatment low-dose schedule. Neither of these treatments inhibited the Yoshida alkylating agent-resistant tumour, however, whereas prednimustine or a combination of chlorambucil and prednisolone produced significant tumour growth inhibition. Prednisolone did not alter chlorambucil pharmacokinetics. Thus the reduced toxicity of prednimustine is due to chlorambucil esterification and the subsequent alteration in pharmacokinetics, whilst inhibition of alkylating agent-resistant tumours results from the combination of chlorambucil and prednisolone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00253015
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  • 5
    Electronic Resource
    Electronic Resource
    Preclinical toxicology, pharmacokinetics and formulation of N 2 , N 4 , N 6 -trihydroxymethyl-N 2 , N 4 , N 6 -trimethylmelamine (Trimelamol), a water-soluble cytotoxic s-triazine which does not require metabolic activation (1986)
    Springer
    Cancer chemotherapy and pharmacology 17 (1986), S. 251-258 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary N 2 , N 4 , N 6 -Trihydroxymethyl-N 2 , N 4 , N 6 -trimethylmelamine (Trimelamol) is a water-soluble synthetic s-triazine which, unlike hexamethylmelamine (HMM) and pentamethylmelamine (PMM), does not require metabolic activation. The physico-chemical characteristics of Trimelamol were studied with the aim of overcoming the problems of chemical instability, low solubility and polymerisation which had hindered the development of the drug for clinical use. Trimelamol had similar activity to PMM against the murine PC6 plasmacytoma, but enhanced activity with respect to PMM against the Walker 256 carcinosarcoma in the rat, a species which metabolises PMM less efficiently. Pharmacokinetic studies in mouse, rat and man did not show the major species differences characteristic of PMM. The drug exhibited similar toxicity to PMM against rodents, but had virtually no neurotoxicity. The potential advantages of Trimelamol over previously tested melamines are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00256694
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  • 6
    Electronic Resource
    Electronic Resource
    Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II (1982)
    Springer
    Cancer chemotherapy and pharmacology 9 (1982), S. 140-147 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients. Doses were given initially every 3 weeks and escalated from 20 to 520 mg/m2. Following this, doses were given every 4 weeks and escalated from 300 to 500 mg/m2. The dose-limiting toxicity, thrombocytopoenia, occurred in four-fifths of patients treated at 520 mg/m2, with the nadir occurring 3 weeks after treatment. Leucopoenia and anaemia also occurred but were less severe. Vomiting occurred in all patients receiving over 120 mg/m2 but seldom persisted beyond 24 h. Serial measurements of 51Cr-EDTA clearances, urinary N-acetylglucosaminidase, urinary leucine aminopeptidase, and β2-microglobulin did not reveal significant evidence of nephrotoxicity. Detriment to the audiogram has not been seen in the first 13 patients studied. Pharmacological studies showed that most of the dose of platinum was excreted in the urine, and that impairment of renal function may be associated with drug retention and an increased risk of myelosuppression. The previous therapy and age of the patient also affected the tolerance of the drug. Clinical responses were seen in patients with ovarian carcinoma receiving 〉120 mg/m2. A further dose escalation was performed on a 4-week schedule in patients under 65 with good renal function. The maximum dose it was possible to administer repeatedly without incurring myelosuppression was in the range 400–500 mg/m2. JM8 is not significantly nephrotoxic and is less emetic than cisplatin. It has antitumour activity in man and deserves wider evaluation, along with the other analogues under study in various centres, as an alternative to cisplatin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00257742
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  • 7
    Electronic Resource
    Electronic Resource
    The comparative pharmacokinetics of pentamethylmelamine in man, rat, and mouse (1982)
    Springer
    Cancer chemotherapy and pharmacology 8 (1982), S. 105-111 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of pentamethylmelamine (PMM) have been investigated in mouse (Balb C-, CBA/LAC, nude), rat (Wistar), and man. In all three species, PMM was extensively demethylated to N2,N2,N4,N6-tetramethylmelamine and N2,N4,N6-trimethylmelamine, although marked species differences in the rate of metabolism were observed. PMM metabolism was more rapid in the mouse (plasma t1/2 =〈15 min) than in the rat (plasma t1/2=40 min), and slower in man (plasma t1/2=102 min) than in either mouse or rat. Furthermore, the peak plasma concentrations of N-methylolmelamines, intermediates generated during oxidative N-demethylation, were correspondingly higher in the mouse (563–773 μM) than in the rat (211 μM), whilst in man they were undetectable (〈50 μM). In view of the highly cytotoxic nature of N-methylolmelamines, we conclude that these pharmacokinetic differences may be related to the antitumour effectiveness of PMM in mouse, rat, and man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292880
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: Effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels (1999)
    Springer
    Annals of oncology 10 (1999), S. 329-334 
    Details
    ISSN: 1569-8041
    Keywords: carboplatin ; drug-target interaction ; ovarian cancer ; pharmacokinetically based dosing ; pharmacokinetics ; platinum-DNA adducts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Platinum based drugs are active agents in epithelial ovarian cancer and increased platinum drug dose intensity is thought to lead to improved survival, because of the largely untested assumption that increased dose intensity results in an increased interaction of the platinum drug with its target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800–5), carboplatin dose intensity was increased by the use of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carboplatin dosing formula during high dose intensity therapy and evaluate the relationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes. Patients and methods: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the ‘Calvert formula’. Levels of drug-target interaction in peripheral blood leukocytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method. Results: The area under the curve of concentration of unbound carboplatin in plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml·min were: 5.6 ± 1.0, 7.3 ± 0.7 and 9.8 ± 0.5 mg/ml·min (mean ± S.D.). There was a good correlation between target and achieved dose intensities (r2 = 0.899) and the slope of the linear regression line was 0.95 (± 0.09 SD) not significantly different to 1.0 (P 〉 0.6). The levels of immunoreactive DNA adducts were not detectable at a target AUC of 5 mg/ml·min but increased progressively at the higher AUC levels. Accumulation of adducts between courses was not detected. Conclusions: Pharmacokinetically-based carboplatin dosing during high intensity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dose escalation study, peripheral blood leucocyte DNA platinum-DNA adduct levels were positively related to drug dose and drug AUC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008355506863
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  • 9
    Electronic Resource
    Electronic Resource
    Phase I trials in paediatric oncology — the European perspective (1996)
    Springer
    Investigational new drugs 14 (1996), S. 23-32 
    Details
    ISSN: 1573-0646
    Keywords: methodology ; paediatric oncology ; phase I trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The current recommendations for Phase I trials should allow more confident interpretation of the toxicity and efficacy of new agents by providing a framework for multicentre and international co-operation. An overview of the aims and designs of Phase I trials is presented, along with a summary of current and recently published United Kingdom Childrens Cancer Study Group Phase I trials, and a discussion of some of the difficulties faced in the methodology and evaluation of Phase I studies in children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173679
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