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Biomedical subjects

J M Whaun

Publications and source records attributed to J M Whaun.

4 recordsLinked to original sources
PubMed1990

Treatment of chloroquine-resistant malaria with esters of cephalotaxine: homoharringtonine.

The esters of cephalotaxine-harringtonine, homoharringtonine and deoxyharringtonine--have been reported by both Chinese and American oncologists as useful in the treatment of human nonlymphoblastic leukaemias and selected solid tumours of the head and neck. We report our results with homoharringtonine, currently a Phase II clinical trial drug with the National Cancer Institute, in the treatment of malaria. Homoharringtonine, 2.7-3.4 nM, was effective in causing 50% growth inhibition of two strains of chloroquine-resistant Plasmodium falciparum malaria in vitro. In vivo tests in mice infected with P. yoelii showed that this drug was effective in inhibiting parasite growth in this system as well. Histologically, the drug was associated with karyorrhexis. Drug-exposed cells showed decreased levels of putrescine and spermidine and increased spermine levels. Our findings not only demonstrate the potential usefulness of homoharringtonine in the treatment of chloroquine-resistant malaria, but also demonstrate the advantage of applying comparative biochemistry and an understanding of biological mechanisms in a rational approach to the development and treatment of diseases including malaria.

Animals↗
PubMed1985

Ornithine decarboxylase inhibition and the malaria-infected red cell: a model for polyamine metabolism and growth.

The addition of DL-alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, to human Plasmodium falciparum-infected red cells in continuous culture decreased both parasite growth and intracellular polyamine concentrations. Growth of P. falciparum in infected red cells was assessed by parasite counts and by assays for macromolecular syntheses of protein, DNA and RNA. Polyamine concentrations were measured by an automated high-performance liquid chromatography method. Concentrations of DL-alpha-difluoromethylornithine greater than 0.3 mM decreased intracellular levels of putrescine and spermidine, reduced ornithine decarboxylase activity and inhibited growth and maturation of the intracellular parasite at the trophozoite stage. There was a concomitant decrease in the synthesis of protein and nucleic acids in the infected cells. The use of this parasitized red cell model system together with polyamine inhibitors provide means of studying polyamine synthesis and cell growth in the design of new antimalarial therapy.

Cells, Cultured↗
PubMedDate not supplied

The effect of daunomycin on platelets in vitro.

Daunomycin (rubidomycin, daunorubicin), an anthracycline antimetabolite used in the therapy of acute leukemia, is highly toxic to both normal and malignant cells. Treatment with daunomycin may produce thrombocytopenia and bleeding which have been attributed to bone marrow toxicity. We have examined daunomycin to determine if a direct drug effect on platelet structure and function could contribute to a hemorrhagic diathesis in some patients on therapy. Normal citrated platelet-rich plasma was reacted in vitro with daunomycin and/or collagen with structural assessment by phase and electron microscopy and functional studies by platelet aggregation, [2-14C]5-hydroxytryptamine release studies and assays for released cytoplasmic marker enzyme, lactic dehydrogenase, in the supernatant fluid. High [greater than 0.04 mg/ml (greater than 0.07 mM)] concentrations of daunomycin were associated with structural changes, specifically by platelet swelling, vacuole formation and mitochondrial swelling with interruption of the trilaminar membrane. Platelets, exposed to low doses of daunomycin, 0.001 to 0.01 mg/ml (0.00177-0.0177 mM) of platelet-rich plasma, were dysfunctional with decreased aggregation with collagen and decreased [2-14C]5-hydroxytryptamine release. These studies indicate that daunomycin has a direct effect on platelets in vitro which may explain certain instances of bleeding observed in some patients undergoing therapy.

5-Hydroxytryptophan↗