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  • 1980-1984  (3)
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Material
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Year
  • 1
    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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    Paper (German National Licenses)
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  • 2
    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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    Paper (German National Licenses)
    Fulltext
  • 3
    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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    Paper (German National Licenses)
    Fulltext
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