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Biomedical subjects

R P Warrell

Publications and source records attributed to R P Warrell.

117 records · Page 7Linked to original sources
PubMed1982

Clinical evaluation of succinylated Acinetobacter glutaminase-asparaginase in adult leukemia.

We treated 13 adult patients with acute leukemia or chronic myelocytic leukemia (CML) in blast phase using succinylated Acinetobacter glutaminase-asparaginase (SAGA) administered on a daily dose schedule. SAGA reduced the peripheral blast count in two patients with acute lymphoblastic leukemia and two with blastic CML; however, no patient achieved either complete or partial remission. Marked central nervous system toxic effects (encephalopathy and coma) were observed, limiting treatment in patients whose disease appeared responsive; this effect finally prompted early discontinuance of the trial. Other toxic effects observed included nausea, hyperglycemia, and respiratory alkalosis. Hypersensitivity reactions to the enzyme were not seen. Pharmacologic analyses showed that prolonged blood glutamine depletion was achieved only by daily enzyme administration; however, we noted the importance of performing amino acid analysis on blood which was deproteinized immediately following phlebotomy. Our results demonstrate excessive central nervous system toxicity when glutaminase-asparaginase is administered on a daily schedule. Because of this effect, we propose that future trials of similar enzymes be limited to short courses of enzyme therapy, possibly with the addition of antimetabolites or amino acid analogs, which could enhance the antitumor effect without increasing toxicity.

Acinetobacter↗
PubMed1981

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma.

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl-GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.

Adult↗
PubMed1980

Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults.

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.

Acinetobacter↗
PubMed1979

Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in renal failure.

Factor VIII/von Willebrand factor antigen and von Willebrand factor activity (ristocetin assay) were studied in 12 patients in renal failure. A dramatic increase in both activities was observed (antigen 315 +/- 30 per cent in patients verus 104 +/- 9 per cent in control subjects; activity 402 +/- 48 per cent in patients versus 111 +/- 5 per cent in control subjects; p less than 0.001 for both). Since von Willebrand factor is thought to play at least a facilitative role in the development of arteriosclerosis, these increased activities may contribute to the premature arteriosclerosis reported in patients with chronic renal failure undergoing dialysis.

Blood Coagulation↗
PubMed1979

Phase II trial of pyrazofurin, alone and in combination with trifluorothymidine, in non-Hodgkin's lymphoma.

A phase II trial of pyrazofurin, alone and in combination with trifluorothymidine, was carried out in patients with advanced non-Hodgkin's lymphoma. None of the 19 patients evaluable for response had complete or partial remissions but 14 had minor regressions. Toxicity, consisting primarily of myelosuppression and stomatitis, was of moderate severity. These studies suggest that pyrazofurin, alone or in combination with trifluorothymidine, is of limited utility in advanced non-Hodgkin's lymphoma.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Phase I trial of homoharringtonine administered as a 5-day continuous infusion.

Homoharringtonine (HHT) has substantial cytotoxic activity against cell lines of experimental tumors. Moreover, the drug has been used extensively in the People's Republic of China for the treatment of patients with acute leukemia. Since rapid injections of HHT can produce serious hypotension and cardiac arrhythmias, we evaluated HHT administered as a continuous infusion for 5 days in patients with advanced cancer. Thirty-one patients were treated with HHT at doses which ranged from 0.2 to 3.75 mg/m2/day. Myelosuppression (both leukopenia and thrombocytopenia) was the dose-limiting toxic reaction. Platelet recovery was delayed in five patients; the median time to platelet nadir was 31 days in patients treated at the highest dose level. Sinus tachycardia occurred frequently, but the relation of this effect to drug administration was uncertain. Serious cardiac arrhythmias and hypotension were not observed using this schedule. We conclude that HHT can be safely administered as a continuous infusion. A daily dose of 3.25 mg/m2 x 5 days is recommended for phase II studies.

Adult↗
PubMedDate not supplied

Phase II. Trial of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in the treatment of advanced non-Hodgkin's lymphoma.

A disease-oriented trial of 4'-(9-acridinylamino)methanesulfon-m-anisidide) given once every 3 weeks was undertaken in patients with advanced non-Hodgkin's lymphoma. None of 15 adequately treated patients achieved complete or partial remissions. Toxicity was mild-to-moderate, consisting of myelosuppression (principally granulocytopenia) and malaise. The lack of any major responses in this number of patients suggests that, in this schedule, the drug is not useful in therapy for advanced non-Hodgkin's lymphoma.

Adult↗
PubMedDate not supplied

In vitro differential metabolism of merbarone by xanthine oxidase and microsomal flavoenzymes. The role of reactive oxygen species.

Merbarone (MB), a nonsedating derivative of thiobarbituric acid, was recently found to induce profound hypouricemia. When incubated with xanthine oxidase (XO) and hypoxanthine in vitro, MB is both an inhibitor of XO and degraded by the XO-hypoxanthine interaction. Compared with allopurinol (Ki = 0.025 microM), MB is a very weak inhibitor of XO (Ki = 51 +/- 8 microM). MB interacts with XO in the presence of hypoxanthine to yield three chromatographically separate products. One of these products has been identified by HPLC retention time and spectral characteristics as 2-oxo-2-desthiomerbarone (2-oxo-MB). The other two products are thought to be S-oxide intermediates in the oxidative desulfuration of this drug. Formation of these products was blocked by catalase, suggesting that the conversion was dependent on reactive oxygen species (especially H2O2) generated by the hypoxanthine-XO system. This suggestion was confirmed by incubating MB with H2O2. In vitro studies with rat liver microsomes have documented the formation of 2-oxo-MB and 4'-OH-MB (4'-OH-MB), the latter being identified by the characteristic HPLC retention time of its acetylated derivative. The formation of 4'-OH-MB has many characteristics of a cytochrome P-450-dependent monooxygenase reaction (NADPH requirement and SKF 525-A inhibition); formation of 2-oxo-MB occurs by a different mechanism that is, as yet, uncharacterized. Incubation of kidney microsomes with MB generated 2-oxo-desthiomerbarone but no detectable 4'-OH-MB.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetic Anhydrides↗