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K R Harrap

Publications and source records attributed to K R Harrap.

At least 91 records · Page 5Linked to original sources
PubMed1983

Studies on the pharmacokinetics of chlorambucil and prednimustine in man.

1 Chlorambucil (10 mg) and prednimustine (20 mg), the prednisolone ester of chlorambucil, were administered orally on separate occasions to six patients. 2 Chlorambucil was rapidly absorbed such that the parent compound was observed in the plasma 30 min after administration. 3 A preliminary comparison of chlorambucil levels following oral and intravenous administration, and after repeat oral dosage indicated that chlorambucil was well (greater than 70%) and consistently absorbed. 4 Following prednimustine no parent drug or alkylating metabolites (chlorambucil or phenyl acetic mustard) could be detected in the plasma. 5 In studies with intravenously administered chlorambucil plasma levels of the parent drug were described by a two-compartment open model with first-order kinetics. Significant levels of the cytotoxic metabolite phenyl acetic mustard were detected. 6 It is concluded that: a. the bioavailability of orally administered prednimustine is much lower than that of chlorambucil. Thus the use of prednimustine in routine combination therapy is not recommended. b. due to the lower therapeutic index of phenyl acetic mustard in experimental systems, the production of this metabolite in man may be disadvantageous. Thus research aimed at producing chlorambucil analogues, which cannot be metabolised, seems justified.

Administration, Oral↗
PubMed1982

Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II.

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 beta 2-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 greater than 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.

Adult↗
PubMed1982

The comparative pharmacokinetics of pentamethylmelamine in man, rat, and mouse.

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 = less than 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 microM) than in the rat (211 microM), whilst in man they were undetectable (less than 50 microM). 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.

Altretamine↗
PubMed1982

Modulation of the toxicity and antitumour activity of alkylating drugs by steroids.

The steroids prednisolone and progesterone significantly altered the therapeutic indices of the alkylating agents, nitrogen mustard, melphalan, cyclophosphamide, phenyl acetic mustard and chlorambucil. For nitrogen mustard, chlorambucil and phenyl acetic mustard, prednisolone reduced host toxicity in the rat and enhanced the antitumour effectiveness against alkylating-agent-resistant strains of the Yoshida sarcoma and Walker carcinosarcoma. Progesterone also increased the therapeutic index of chlorambucil in the rat by decreasing its systemic toxicity. Two other alkylating agents, melphalan and cyclophosphamide, exhibited lower therapeutic indices in combination with prednisolone against alkylating-agent-sensitive tumours. This was due to the greater host toxicity of the combination than of the alkylating agent alone. In alkylating-agent-resistant tumours, however, a significant increase in growth delay was achieved if prednisolone was combined with the alkylating agent.

Alkylating Agents↗
PubMed1981

The pharmacokinetics of prednimustine and chlorambucil in the rat.

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 (less than 5 microM) 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 microM) 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 chlorambucil 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.

Animals↗
PubMed1981

Studies on the mechanism of action of LS 1727, a nitrosocarbamate of 19-nortestosterone.

LS 1727, a nitrosocarbamate of 19-nortestosterone, was active against lymphoid, antimetabolite-sensitive, cell lines in vitro especially L1210 and Ehrlich ascites tumour lines. It was less effective against alkylating agent-sensitive lines such as the Walker 256 carcinosarcoma. These results suggested a possible antimetabolite mode of action but LS 1727 had no effect on deoxy-or ribonucleotide pool sizes in L1210 cells. Studies on macromolecular synthesis showed an early inhibition of DNA synthesis whilst RNA and protein synthesis continued for 24-48 hours. This was reminiscent of a classic alkylating agent-like effect. In vivo studies with specific alkylating agent-sensitive, or antimetabolite-sensitive tumours showed no antitumour activity although significant inhibition of Ehrlich ascites tumour cell growth was observed at high doses. In vitro cytotoxicity studies showed LS 1727 to be inactivated in the presence of mouse, rat and dog liver supernatants. This would explain the poor antitumour effects in vivo compared with the in vitro observations. Because LS 1727 is a nitrosocarbamate its possible mutagenic activity was investigated. LS 1727 was highly mutagenic but this property was also lost in the presence of a rat liver microsomal fraction. Although an effective cytotoxic agent in vitro LS 1727 is only effective in vivo at toxic doses.

Alkylating Agents↗
PubMed1981

Methotrexate with thymidine, inosine, and allopurinol rescue: a phase I clinical study.

A phase I clinical study of a combination of thymidine (TdR), inosine (IR), and allopurinol used as rescue from 24-hour infusions of methotrexate (MTX) was undertaken following animal studies that had shown a better preservation of antitumor activity with this system than with folinic acid. TdR and IR were given in the dose ratio 5:1 by weight throughout. Rescue from MTX, 400 mg/m2, could be achieved with a TdR dose in the combination of 1 g/m2/24 hours. This same rescue was also effective when the MTX dose was increased to 800 mg/m2, but only partly effective at an MTX dose of 1.5 g/m2. It was not necessary to raise the levels of circulating nucleosides significantly above normal to achieve rescue. MTX-related skin lesions occurred more frequently than might be expected with the MTX dose used.

Adult↗
PubMed1980

Quantitative high-performance liquid chromatography of nucleosides and bases in human plasma.

A reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the estimation of purines, pyrimidines and their congeners in biological fluids. An initial HPLC separation allowed the collection of a number of effluent fractions, each of which contained a single component of interest. The re-application of these fractions to a second HPLC separation permitted the resolution and quantification of nanogram amounts of these components. Isocratic elution with volatile buffers renders the samples amenable to automatic sampling procedures or lyophilisation. Data are presented on the application of the method to the analysis of nucleosides and bases in human plasma.

Allopurinol↗
PubMed1980

The clinical pharmacology of the adenosine deaminase inhibitor 2'-deoxycoformycin.

2'-deoxycoformycin (2'-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2'-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kg X 1 to 0.25 mg/kg/day X 5; ado deaminase and 2'-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential (alpha and beta t 1/2 values about 1 and 10 h respectively). Recovery of unchanged 2'-dCF from urine (48 h) was 32%--48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2'-dCF/kg/day X 5.

Adenosine Deaminase Inhibitors↗
PubMed1980

Criteria for the selection of second-generation platinum compounds.

Our selection of a potential second-generation platinum compound began with an initial short list of 8 compounds selected on the basis of antitumour and toxicity studies in mice. We now report further, more detailed investigations of the renal toxicity and antitumour activity of one of these compounds, cis-dichloro trans-dihydroxy bis isopropylamine platinum (IV) (CHIP), in comparison with cis-dichloro diammine platinum (II) (Neoplatin). CHIP was a more effective anti-tumour agent against both alkylating-agent sensitive and resistant strains of the Yoshida sarcoma (YSS and YSR respectively) than was Neoplatin. In addition CHIP produced negligible kidney toxicity as measured by blood urea levels. We have also compared the effects of these two drugs on nuclear-protein phosphorylation, in an attempt to gain insight into their molecular mode of action. Both Neoplatin and CHIP induced increased nuclear-protein phosphorylation in the YSS tumour cells, and loss of condensed chromatin. However, CHIP also induced increased nuclear-protein phosphorylation and loss of condensed chromatin in the YSR tumour cells. These changes correlated well with cell death. In addition Neoplatin, but not CHIP, treatment caused increased nuclear-protein phosphorylation in kidney tissues. This correlated with kidney damage as measured by blood urea levels. These selection criteria suggested that CHIP would be a more selective antitumour agent than Neoplatin, and will provide a basis for its comparison with the other 7 compounds.

Animals↗
PubMed1980

Intracellular nucleotide pools and their significance in antimetabolite therapy.

The regulatory properties of several ribo- and deoxyribonucleotides are outlined as a basis for a discussion of the modes of action of selected antimetabolites. Particular attention is devoted both to the perturbations induced by these agents in nucleotide pools and to the stability of endogenous pools as determinants of cytotoxicity. Attempts to modulate the activites of antimetabolites, either with specific nucleic acid presursors, or with other agents are discussed briefly.

3-Deazauridine↗