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Biomedical subjects

G A Butcher

Publications and source records attributed to G A Butcher.

At least 19 recordsLinked to original sources
PubMed1992

The in vitro and in vivo antimalarial activity of some Mannich bases derived from 4-(7'-trifluoromethyl-1',5'-naphthyridin-4'-ylamino)phenol, 2-(7'-trifluoromethyl-quinolin-4'-ylamino)phenol, and 4'-chloro-5-(7''-trifluoromethylquinolin-4''-ylamino)biphenyl -2-ols.

A series of di-Mannich base derivatives (4 and 5) from 4-(7'-trifluoromethyl-1',5'-naphthyridin-4'-ylamino)phenol and 2-(7'-trifluoromethylquinolin-4'-ylamino)phenol, respectively, and mono-Mannich base derivatives (6) from 4'-chloro-5-(7''-trifluoromethylquinolin-4''- ylamino)biphenyl-2-ol were assayed for activity against the chloroquine-sensitive (FCQ-27) isolate of cultured Plasmodium falciparum using the inhibition of uptake of radiolabelled hypoxanthine. All seven di-Mannich base derivatives (5) revealed a higher activity than chloroquine, whereas the di-Mannich base derivatives (4) were slightly less active (with some derivatives more active and some less active than chloroquine). The mono-Mannich base derivatives (6) were less active than chloroquine. Comparative tests of selected compounds of (4 and 5) using a morphological assay revealed no significant differences in activity between the chloroquine-sensitive (FCQ-27) and chloroquine-resistant (K-1) isolates. Selected di-Mannich bases (4 and 5) and the mono-Mannich bases 5-7''-bromo (and 7-trifluoromethyl)-1'',5''-naphthyridin-4''-ylamino)-3-(t- butylaminomethyl)-4'-chlorobiphenyl-2-ols (7, X = Br, CF3) markedly suppressed parasitaemia in Plasmodium vinckei vinckei infected mice when administered (i.p.) in a single dose of 200 mg kg-1.

Animals↗
PubMed1992

Phospholipid-containing toxic malaria antigens induce hypoglycaemia.

Hypoglycaemia is associated with severe malaria and is an important prognostic indicator. Molecules liberated during overnight incubation of erythrocytes infected with Plasmodium yoelii induce marked hypoglycaemia in normal mice, with a delayed time course compared with insulin; some, though weaker, activity could also be obtained by overnight incubation of uninfected erythrocytes. The active component shares many properties with the phospholipid-containing molecules which we have previously shown to be toxic and to induce the release of tumour necrosis factor (TNF) from macrophages. However a MoAb which neutralizes the cytotoxicity of tumour necrosis factor in vitro did not prevent this induction of hypoglycaemia, whereas antiserum against the toxic antigens did, as did immunization of normal (but not the immunoglobulin-deficient SCID) mice with the same material. Furthermore, normal mice injected with the antigens after immunization with phosphatidyl inositol or inositol monophosphate did not develop hypoglycaemia; the latter compound was also inhibitory when mixed with the antigens before injection. These compounds were previously shown to block the induction of TNF by the antigens and to induce the production of inhibitory antibodies. The role of these molecules in the etiology of the hypoglycaemia of malaria is discussed.

Animals↗
PubMed1990

Antimalarial action of flavin analogues seems not be due to inhibition of glutathione reductase of host erythrocytes.

A series of 10-(4'-chlorophenyl)-3-substituted flavins (1a-f) were examined with respect to their antimalarial properties. They were tested against Plasmodium falciparum in vitro and Plasmodium vinckei vinckei in vivo. The proposition that they might act through glutathione reductase (GR) (EC 1.6.4.2) inhibition has been studied. Inhibition of P. falciparum in vitro by these compounds shows only slight variation between analogues; in contrast, inhibition of human erythrocyte GR by members of the same series is highly variable, indicating that this is probably not their primary mode of antimalarial action. Results of the P. vinckei vinckei screen showed that 10-(4'-chlorophenyl)-3-methyl,3-ethyl and 3-propyl substituted flavins are active in vivo over the dose range screened (10-70 mg/kg).

Animals↗
PubMed1990

In vitro responses of human peripheral blood mononuclear cells to Plasmodium falciparum antigen.

Immunity to malaria involves cell-mediated and humoral responses. The cell-mediated reaction is thought to focus particularly on the activity of cells of the macrophage lineage. The ability of antigen-stimulated human peripheral blood lymphocytes to undergo proliferation and produce factors capable of causing macrophage inhibition of parasite growth has been examined. While lymphocyte proliferation, gamma-interferon production, and anti-malarial antibody levels of malaria-exposed Papua New Guinea donors were correlated, and significantly different from Australian subjects, macrophage parasite inhibition was no different in these two groups. Further, there was no evidence for acquired, persistent, cell-mediated immunity, as judged by the monocyte procoagulant test. The results are discussed within the context of human acquired resistance to malaria.

Animals↗
PubMed1990

TNF and inhibition of growth of Plasmodium falciparum.

The mechanism of intra-erythrocyte death of Plasmodium chabaudi in vivo has not yet been elucidated. Here we summarise recent experiments in which serum from mice undergoing a successful immune response to this parasite did not inhibit Plasmodium falciparum in vivo unless the P. chabaudi infection and TNF levels were high enough to cause illness in the host. This was true for the 556KA and DS strains of P. chabaudi in intact mice, but not for 556KA in nude mice, which did not generate inhibitory activity at any parasitaemia. Tumour necrosis factor (TNF) inhibits malaria parasites via some undefined secondary mediator. 10 mg of r hu TNF generated this inhibitory activity, as measured against P. falciparum in vitro, in the serum of mice only if they were pretreated with Corynebacterium parvum, which activates macrophages and sensitises the mice to the toxic effects of TNF. This implies a role for activated macrophages downstream from TNF in the process involved in intra-erythrocytic death of parasites.

Animals↗
PubMed1990

The inhibition of Plasmodium falciparum growth in vitro by sera from mice infected with malaria or treated with TNF.

Despite some years of enquiry, the mechanism that leads to intra-erythrocytic death of malarial parasites during the host's response to infection has not been elucidated. We report here that serum from mice undergoing a successful immune response to Plasmodium chabaudi does not inhibit Plasmodium falciparum unless the Pl. chabaudi is virulent enough to rise to at least 50% parasitaemia and to cause illness. This appears to be true of the 556 KA and DS strains of Pl. chabaudi, and also other murine malaria parasites. In mice infected with Pl. chabaudi 556 KA inhibitory activity coincided with the presence of TNF in their serum. Exogenous TNF generated inhibitory activity in the serum of mice only if the animals were pretreated with Proprionobacterium acnes, implying a role for activated macrophages downstream from TNF in this process. The difference in inhibitory activity against Pl. falciparum in serum from mice infected with Pl. chabaudi of more or less virulence may be one of degree. Alternatively two distinct mechanisms may operate, the second coming into operation only in ill mice, with higher parasite burdens.

Animals↗
PubMed1989

Mechanisms of immunity to malaria and the possibilities of a blood-stage vaccine: a critical appraisal.

Resistance developed by the immune system in response to blood-stage malaria is complex in nature, involving humoral and non-antibody effector mechanisms. Different species of malarial parasites may vary in their ability to elicit, or their susceptibility to, those immune effectors. This complexity is enhanced by the different results obtained in vaccinated as opposed to drug-controlled infections. It is therefore important that some attempt be made to unravel these interactions. This is particularly so when we have to decide on methods for assessing the potentiality of antigens to induce protective immunity. In this review the limitations of some in vitro assays of immunity, as well as those of various host-parasite models, are discussed. The relative importance of cell-mediated and humoral immunity in laboratory models and natural infections is also considered in the context of vaccine development.

Animals↗
PubMed1987

Inhibition of murine malaria (Plasmodium chabaudi) in vivo by recombinant interferon-gamma or tumor necrosis factor, and its enhancement by butylated hydroxyanisole.

Cell-mediated immunity to malaria may involve macrophages, the monokines that mediate endotoxicity, and reactive oxygen species. Since interferon-gamma activates macrophages to release reactive oxygen species, and tumor necrosis factor-alpha (TNF-alpha) helps both to mediate endotoxicity and to induce leukocytes to secrete reactive oxygen, we monitored the effects of administering recombinant forms of these cytokines on Plasmodium chabaudi adami infections in mice. We also fed infected mice a diet containing 0.75% butylated hydroxyanisole, a scavenger of free radicals. Infections were suppressed by daily i.p. injections of 5 x 10(4) U of recombinant mouse interferon-gamma from day -1 or by recombinant human TNF released from i.p. osmotic pumps at the rate of 6 x 10(3) U/hr. Degenerate intraerythrocytic parasites (crisis forms) were evident much sooner in the course of the suppressed infections, and parasitemias fell correspondingly earlier. The butylated hydroxyanisole diet, in contrast, enhanced the infections. In these mice crisis forms were seen later, and at higher parasitemias, than they normally occur. These observations are consistent with the concept that T cell-dependent, macrophage-derived mediators are central to the type of malarial immunity that kills parasites inside circulating red cells. They also suggest, but do not prove, that both TNF and reactive oxygen species are involved, and that the role of TNF may be more indirect, although no less important, than that of reactive forms of oxygen.

Administration, Oral↗
PubMed1987

Toxicity of certain products of lipid peroxidation to the human malaria parasite Plasmodium falciparum.

Aldehydes generated during radical-induced lipid peroxidation, in particular 4-hydroxynonenal, are known to inhibit growth of certain cells. To extend our arguments that free radicals might be involved in the host response against malaria parasites we tested 26 carbonyls (n-alkanals, C6-C11; 2-alkenals, C3-C9; 2,4-alkadienals, C7, C9, C10; 4-OH-2-alkenals, C6, C8, C9; 2-alkanones, C3-C9; and malonyldialdehyde) against Plasmodium falciparum in vitro. We had previously detected many of these substances in oxidant-stressed, malaria-infected erythrocytes. Three 2,4-alkadienals (C7, C9 and C10) and three 4-OH-2-alkenals (C6, C8 and C9), at 20-100 microM concentrations, markedly inhibited incorporation of [3H]-hypoxanthine by P. falciparum. Acrolein had low effect, and none of the other compounds (12 aldehydes and 7 ketones) were active at concentrations up to 100 microM. Malonyldialdehyde was without effect at concentrations up to 450 microM. The aldehydes found to be inhibitory against P. falciparum could contribute to both the non-antibody host responses against this parasite and the antimalarial effects of radical-generating compounds such as t-butyl hydroperoxide, hydrogen peroxide, alloxan, isouramil, divicine and primaquine.

Animals↗
PubMed1987

Inhibition of intra-erythrocytic growth of Plasmodium falciparum by human sera from Papua New Guinea.

Plasmodium falciparum was cultured through a single intra-erythrocytic cycle of growth in the presence of sera from various areas of Papua New Guinea. Of 194 sera tested from healthy individuals or subjects with hyperreactive malarious splenomegaly (HMS), 107 (55%) significantly inhibited parasite development. Inhibition did not correlate with malaria experience or HMS, though it was to some extent a seasonal phenomenon. Sera with inhibitory activity lost this after dialysis. A possible explanation for these findings is the occurrence of a dietary toxin with antimalarial properties detectable in vitro.

Adolescent↗
PubMed1987

Antimalarial activity of a riboflavin analog against Plasmodium vinckei in vivo and Plasmodium falciparum in vitro.

The riboflavin analog 10-(4'-chlorophenyl)-3-methylflavin was found to have significant activity against Plasmodium vinckei vinckei when administered orally and parenterally; it was active against P. falciparum in culture. It inhibited mouse erythrocyte glutathione reductase in a dose-dependent manner. When administered orally, 5-deazariboflavin was not active in vivo although it has been shown to have activity against P. falciparum in vitro.

Administration, Oral↗
PubMed1987

Possible roles of tumor necrosis factor in the pathology of malaria.

The authors have earlier proposed that tumor necrosis factor (TNF) might contribute to the pathology of malaria. Here they report the outcome of injecting recombinant human TNF/cachectin into normal mice and others with low parasitemias (6-35%) of Plasmodium vinckei. The object was to see how precisely the pathologic features of the terminal stages of this infection could be produced, when parasitemias are 70-80%. Hypoglycemia, mid-zonal liver damage, and pulmonary accumulation of neutrophils in the pulmonary vasculature, all of which are seen in severe P vinckei infection, occurred within 4-12 hours after the mildly infected mice received TNF/cachectin. Uninfected mice were much less susceptible. TNF/cachectin also increases plasma lactate, a change seen in both the human and rodent diseases. From these findings and the recent literature on TNF/cachectin, including its detection in serum from malarial patients, it seems likely that excessive release of this monokine could account for certain of the unexplained pathologic features of human malaria.

Animals↗
PubMed1986

Structure and development of the surface coat of erythrocytic merozoites of Plasmodium knowlesi.

The surface of extracellular merozoites of P. knowlesi is covered with a coat 15-20 nm thick, made up of clusters of filaments standing erect on the plasma membrane. Filaments have stems 2 nm thick, the peripheral ends of which are complex, branching or ending in long trailing threads. Coat filaments occur on the surface of the parasite in regular rows at an early schizont stage, and persist until well after merozoite release. They are sensitive to trypsin and papain, and bind ethanolic phosphotungstate, indicating a proteinaceous nature. They are also removed by exposure to phosphate-buffered saline. Filaments bear negative charges, binding cationised ferritin throughout the depth of the coat and staining with ruthenium red. They cover the whole merozoite surface and mediate intercellular adhesion at distances of 15-150 nm, membrane to membrane. It is suggested that these filaments correspond to a major merozoite surface protein, and are important in the initial capture of red cells.

Animals↗