Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A review of all available evidence supports the hypothesis that FP is the receptor for chloroquine and mediator of its antimalarial activity. In accord with this hypothesis, previously unpublished experiments are described which demonstrate no effect of verapamil on chloroquine accumulation when chloroquine-resistant malaria parasites are nearly totally deficient in FP. Not all chloroquine-resistant parasites are so deficient in FP, however. It is important, therefore, to understand how the concentration of the toxic form of FP, which binds chloroquine, is regulated in erythrocytes infected with pigmented malaria parasites. This regulatory process involves the conversion of toxic FP to nontoxic aggregates (oligomers) of FP which have low oxygen contents. It is also possible that toxic FP is detoxified by decomposition, for example, by hydrogen peroxide.
 ...
PMID:Ferriprotoporphyrin IX: role in chloroquine susceptibility and resistance in malaria. 267 16

Evidence is accumulating that the illness and pathology observed in malaria are not caused directly by parasite products, but by normal components of the immune response, mainly monokines such as tumor necrosis factor (TNF), produced in excess. These mediators are released from the host's monocytes and macrophages, apparently in response to stimulation by parasite products. Recombinant TNF, if injected into a range of animal species or into tumour patients, is demonstrably toxic, giving rise to changes typical of acute malaria, and several groups have detected circulating TNF in serum from patients acutely ill with malaria. The short serum clearance time of TNF and TNF tolerance have to be considered when interpreting such data. Current studies indicate that some malarial antigens, in the absence of lipopolysaccharide, can trigger release of TNF. This and other monokines could contribute to cerebral malaria in at least 2 ways: by increasing thrombospondin secretion, and hence favouring local sequestration of knob-bearing parasitized red cells, and, as has been demonstrated in clinical trials in tumour patients, by causing neurological symptoms directly. In addition, it seems that TNF does not act alone, but as part of an interdependent synergizing network of polypeptide mediators. These evidently act together to induce secretion of other cell products, such as platelet-activating factor, prostaglandins, reactive oxygen species and procoagulant activity, that actually cause illness, biochemical change and tissue damage. Understanding these processes should lead to a range of new therapeutic interventions.
 ...
PMID:Roles of tumour necrosis factor in the illness and pathology of malaria. 269 75

Oxidative stress in malaria infected human erythrocytes is augmented and the anti-oxidant system is attenuated as compared with normal RBC's. Exacerbation of intra-erythrocytic oxidative stress might provide a means to kill the parasites. Sodium artesunate (SA), an effective Chinese anti-malaria drug, markedly increased the levels of active oxygen species and production of malonyldialdehyde in normal red blood cells and, to a greater extent, in malaria infected red blood cells. SA caused a remarkable decrease of unsaturated fatty acids content in normal red blood cell membrane. These suggest that the anti-oxidative system in red blood cells infected with malaria is jeopardized. Certain active oxygen species generated and accumulated in such red blood cells might in turn kill the parasites. SA augmented intracellular O2-. and H2O2 production, and this may partly account for its antimalaria action.
 ...
PMID:Effect of sodium artesunate on malaria infected human erythrocytes. 269 76

The interaction of certain metabolites of the 8-aminoquinoline antimalarial primaquine with both normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes and with haemoglobin preparations was studied in an attempt to elucidate the mechanisms of methaemoglobin formation and haemolytic anaemia associated with the use of primaquine. Studies using erythrocytes revealed that oxidation of haemoglobin and reduced glutathione (GSH) was due to the metabolites rather than the parent drug. Incubation of free haemoglobin with 5-hydroxylated metabolites of primaquine also led to oxidation of oxyhaemoglobin and GSH. Oxidation of GSH also occurred in the absence of oxyhaemoglobin. The results suggest a dual mechanism for these oxidative effects, involving autoxidation of the 5-hydroxy-8-aminoquinolines and their coupled oxidation with oxyhaemoglobin. The initial products of these processes would be drug metabolite free radicals, superoxide radical anions, hydrogen peroxide and methaemoglobin. Further free radical reactions would lead to oxidation of GSH, more haemoglobin and probably other cellular constituents. NADPH had no effect on the oxidative effects of the primaquine metabolites in these experiments. In the G6PD-deficient erythrocyte, the oxidation of haemoglobin and GSH leads to Heinz body formation and eventually to haemolysis, the mechanisms of which are as yet unclear. The possible role of oxygen free radicals in the mode of action of 8-aminoquinolines against the malaria parasite is also briefly discussed.
 ...
PMID:Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine. 283 99

In 12 patients comatose with cerebral malaria, cerebral blood flow was 52.2 (SE 4.0) ml/100 g per min, within the reported range for healthy controls, but cerebral vascular resistance was raised at 1.66 (0.19) mm Hg/ml per 100 g per min. Cerebral oxygen consumption (1.90 [0.23] ml/100 g per min), and cerebral arteriovenous oxygen content difference (3.5 [0.43] ml/dl) were subnormal, while cerebral venous pO2 (5.7 [0.2] kpA) was raised. After recovery of consciousness there were significant decreases in arterial lactate concentration (2.44 [0.45] to 1.19 [0.45] mumol/l) and cerebral lactate production (17.4 [7.9] to 5.6 [1.1] mmol/100 g per minute). These results provide evidence of cerebral anaerobic glycolysis associated with inadequate oxygen delivery to the brain consistent with either inhibition of cerebral oxidative metabolism or the microcirculatory obstruction envisaged in the "mechanical" hypothesis for cerebral malaria.
 ...
PMID:Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria. 290 Sep 21

To test the hypothesis that the resistance of sickle trait (AS Hgb) erythrocytes (rbcs) to malaria may be mediated by increased production of activated oxygen species, the production of superoxide anion (O2-) and hydrogen peroxide (H2O2) by AS rbcs and normal (AA Hgb) rbcs was measured under defined conditions. Formation of O2- and H2O2 was time, temperature and oxygen saturation dependent. Reproducible measurement of O2- formation required the presence of 0.2 mmol l-1 KCN to inhibit a cytochrome oxidase activity found in the cytochrome C preparation used. There was an inverse relationship between cell concentration and O2- and H2O2 formation. Use of the inhibitor of superoxide dismutase (SOD), diethyldithiocarbamic acid, increased the amount of O2- measured. When rbcs from blacks with AS Hgb and with AA Hgb were incubated under standardized conditions, significantly (P less than 0.05) more O2- was formed by AS than AA cells (24.3 v. 14.5 mmol per mol Hgb). These findings show that AS rbcs can generate more O2- than AA rbcs. The increased formation of O2- by rbcs containing AS Hgb may contribute to the resistance of AS rbcs to malarial parasitism.
 ...
PMID:Generation of superoxide anion and hydrogen peroxide by erythrocytes from individuals with sickle trait or normal haemoglobin. 301 34

The role of monocytes, macrophages and neutrophils in killing malaria parasites is well documented, and their involvement in malaria pathology has been suggested. However, the underlying mechanisms are not clear. The present study reports on the role of P. falciparum-parasitized erythrocytes, free merozoites, and culture supernatant antigens in the generation of reactive oxygen radicals by human peripheral blood monocytes and neutrophils. Blood neutrophils and monocytes obtained from healthy individuals were isolated by density gradient separation. A human isolate of P. falciparum was grown in continuous culture. Parasitized erythrocytes and free merozoites were prepared from synchronized cultures. Soluble antigens from culture supernatants were purified by affinity chromatography using CNBr-Sepharose 4B columns bound to specific IgG. Oxidative burst response of neutrophils and monocytes were determined by oxygen consumption, superoxide production, and chemiluminescence. It was found that P. falciparum merozoites and the soluble antigens were capable of activating neutrophils and monocytes in vitro and resulting in the production of oxygen radicals by these cells. In conclusion, these findings demonstrate that malaria antigens are able to activate normal human blood phagocytes and result in generation of oxygen radicals by these cells. The released oxygen radicals can then contribute to both the destruction of the parasite and the pathology of malaria.
 ...
PMID:Generation of reactive oxygen radicals by human phagocytic cells activated by Plasmodium falciparum. 303 17

In May 1987 and January 1988 the chloroquine sensitivity of Plasmodium falciparum in the Ubombo and Ingwavuma districts of KwaZulu was determined by a modified in vitro microtest in which the patients' plasma was replaced with non-immune human AB serum and the test plates were incubated in an atmosphere of 3% oxygen, 4% carbon dioxide and 93% nitrogen. A success rate of 74% was achieved using this technique. All of 23 successfully tested isolates from malaria patients reporting to clinics and a hospital in these areas were found to be resistant to chloroquine, schizogony being inhibited at 32 pmol per well in the majority of tests. Seventy-five per cent of the isolates obtained through active surveillance in the Ubombo district were found to be resistant in varying degrees. Malarial parasites collected from clinics and a hospital in the endemic area did not change markedly in their in vitro response to chloroquine during the 8-month period May 1987-January 1988.
 ...
PMID:In vitro confirmation of chloroquine-resistant Plasmodium falciparum malaria in KwaZulu. 305 56

Crisis forms in malaria are degenerated intra-erythrocytic asexual parasites which appear at the time of immunologic crisis and thus may be part of the immune response to this disease. The factor(s) involved in this phenomenon are poorly understood, but are believed to be related to products of phagocyte activation. This hypothesis is supported by observations that animals, whose cell-mediated immune responses have been hyperstimulated by BCG, are protected from otherwise lethal malaria infections and their sera induce crisis forms in vitro. Many human serum samples collected from malaria-endemic areas of Sudan induce crisis forms in cultures of Plasmodium falciparum. Two popular models to explain this intra-erythrocytic, anti-parasitic action have been proposed: (i) the presence in the immune serum of a cytotoxic cytokine, crisis form factor, or (ii) that crisis forms result from oxidant stress generated during respiratory bursts associated with phagocyte activation, or indirectly by toxic products of lipid peroxidation produced by reactive oxygen species which appear in the serum during phagocyte respiratory bursts. Experimental evidence has been generated to support both of these hypotheses and both mechanisms may be involved in the induction of crisis forms.
 ...
PMID:Epidemiological and immunological aspects of human crisis form factor in falciparum malaria: cell-mediated responses? 305 68

Many classes of drugs exert anti-inflammatory activity through mechanisms which affect all or part of the inflammatory process. Some of these agents are beneficial in the practice of dermatology, while others, such as penicillamine, mast cell blockers and serotonin antagonists, find little or no application. Corticosteroids, for example, are nonspecific in their anti-inflammatory effects and remain a mainstay of therapy, despite their side effect profile. Other drugs, such as the non-steroidal anti-inflammatory agents or gold, can be used in the treatment of diseases associated with rheumatic or autoimmune states. Moreover, antihistamines play an important role in the control of itching, but are mainly indicated in controlling non-dermatological allergic sequelae. Interestingly, chloroquine and dapsone, which were originally developed for use in malaria prophylaxis and leprosy, respectively, have value in treating a wide range of dermatological conditions via mechanisms which include the inhibition of P-450 isoenzymes. In diseases characterised by disturbed cornification (e.g. psoriasis pustulosa), retinoids are of particular value. These drugs are thought to act by inhibition of collagenases, proteases and granulocyte migration. Undoubtedly, further investigation of drug classes such as oxygen radical controllers and immunomodulators will clarify their mechanisms and establish their therapeutic usefulness among the anti-inflammatory agents now available for dermatological use.
 ...
PMID:The present status of anti-inflammatory agents in dermatology. 307 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>