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A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid (1996)

Laohavinij, Sudsawat ; Wedge, Stephen R. ; Lind, Micheal J. ; [et al.]

Springer

Investigational new drugs 14 (1996), S. 325-335

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ISSN: 1573-0646

Keywords: lometrexol ; lometrexol-toxicity ; lometrexol-clinical efficacy ; lometrexol and folic acid ; DDATHF

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00194536

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1H NMR studies of human urine: Urinary elimination of the anticancer drug carboplatin (1991)

Ranford, John D. ; Sadler, Peter J. ; Balmanno, Katherine ; [et al.]

Chichester : Wiley-Blackwell

Organic Magnetic Resonance 29 (1991), S. S125

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ISSN: 0749-1581

Keywords: 1H NMR ; Urine ; Metabolites ; Platinum anticancer drug ; Carboplatin ; Paraplatin ; CBDCA ; Chemistry ; Analytical Chemistry and Spectroscopy

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: Samples of urine from a patient obtained before and after treatment with 300 mg of the anticancer drug [Pt(II)(NH3)2(CBDCA)] (carboplatin, “Paraplatin”, where CBCDA is 1,1-dicarboxycyclobutane) have been analysed using 500 MHz 1D and 2D 1H NMR spectroscopy. Peaks for the intact drug and the free ligand CBDCA have been assigned and are present in a mol ratio of ca. 5:1. Only about one half of the total Pt in the sample was present as intact drug. Relative to creatinine and citrate, the excretion of hippurate increased by a factor of ca. 4 after drug treatment. This work suggests that NMR spectroscopy can play a valuable rǒle in studies of carboplatin metabolism.

Additional Material: 2 Ill.