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

Pentoxifylline, a widely used methylxanthine, was tested for its capacity to prevent cerebral malaria (CM) in Plasmodium berghei ANKA-infected CBA/Ca mice. Nine of 12 control mice developed neurologic signs and died from CM approximately 2 weeks after infection. All 12 mice treated with daily intraperitoneal pentoxifylline (1 mg) for 10 days after infection did not develop CM. All surviving mice developed high parasitemia and severe anemia and died 2 weeks later without neurologic signs. In pentoxifylline-treated mice, serum tumor necrosis factor (TNF) bioactivity was nondetectable, whereas control mice had high TNF levels on day 6 after infection. These findings were supported by in vitro investigations of malaria antigen-induced TNF synthesis. Northern blot analysis of TNF mRNA from stimulated macrophages showed that pentoxifylline inhibited TNF expression at the transcription level, and TNF bioactivity in supernatants was strongly depressed. These findings make pentoxifylline a potential candidate for study as a supportive agent in human CM.
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PMID:Pentoxifylline prevents murine cerebral malaria. 186 48

In an open, randomized, controlled therapeutic trial, 56 children with cerebral malaria (CM) were randomly assigned to receive standard quinine regimen with or without pentoxifylline (10 mg/kg/day by continuous intravenous infusion). Pentoxifylline exerted an inhibitory effect on the synthesis of tumor necrosis factor (TNF), a possible mediator of CM. The 26 children who received pentoxifylline had significantly shorter comas than controls (median, 6 vs. 46 h; P < .001) Pentoxifylline recipients showed a trend toward a lower mortality, with a borderline significant difference (P = .055). The better outcome in the pentoxifylline group was associated with a decline in TNF serum levels on the third day of treatment in a few subjects that was not seen in controls. While alternative or concurrent mechanisms of action may be of some relevance, larger double-blind trials are needed to determine whether pentoxifylline has a therapeutic role in CM.
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PMID:Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. 775 9

The in vitro production of reactive nitrogen intermediates (RNI) by murine macrophages was evaluated in response to heat-stable malaria antigen and cytokines. Malaria antigen, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) induced RNI production in macrophages in a dose-dependent way. RNI production steadily increased over a 2-day period and was enhanced when the malaria antigen was co-incubated with IFN-gamma and/or TNF. RNI production induced by either IFN-gamma or malaria antigen or a combination of the two was suppressed by pentoxifylline in a dose-dependent manner. Pentoxifylline did not significantly influence TNF-induced RNI production. L-N-monomethyl arginine reduced malaria antigen, IFN-gamma and TNF-induced RNI production when these reagents were used in combination or alone. An anti-TNF monoclonal antibody (mAb) reduced IFN-gamma-induced RNI production, but did not significantly alter the malaria antigen-induced RNI synthesis by macrophages. The influence of inhibitors of nitric oxide synthase, L-N-monomethyl arginine and N omega-nitro-L-arginine, was studied in experimental cerebral malaria. They did not exert any significant effect on the development of cerebral malaria in Plasmodium berghei ANKA-infected CBA/J mice.
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PMID:Malaria antigen and cytokine-induced production of reactive nitrogen intermediates by murine macrophages: no relevance to the development of experimental cerebral malaria. 847 17

It is increasingly evident that sepsis triggers a complex host reaction that is responsible for a variety of pathophysiologic changes during the inflammatory process. Pentoxifylline (PTX) is a methylxanthine with selective anti-inflammatory activity. Because of the current concept of an exaggerated immune response during severe inflammatory response syndrome (SIRS), this drug has received interest as a potential beneficial modulator of SIRS. Animal studies suggest that randomized clinical trials should be carefully planned with regard to dose-response relationship, disease severity, etiologic pathogens, and mechanisms that result in SIRS. The efficacy of PTX has been promising in human malaria. It is probably also effective in other hyper-tumor necrosis factor (TNF) states. The effective dosage is unclear to date, and its use is restricted by intolerance. Potential adverse effects may be related to the selective depression of TNF expression and to the depression of granulocyte phagocytic activity and the neutrophil/endothelium interaction. However, it is unlikely that any single agent will prove to be the magic bullet in the therapy of sepsis and SIRS. Multiple agents, perhaps tailored to individual circumstances, will most probably be needed, raising dramatic economic and ethical challenges.
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PMID:Pentoxifylline in severe inflammatory response syndrome. 869 53

Pentoxifylline (POF) may suppress overproduction of tumor necrosis factor alpha (TNF alpha), which is thought to contribute to complications of human falciparum malaria. However, POF is believed to improve impaired capillary blood flow, which can be impaired in falciparum malaria. To test whether POF affects TNF alpha serum levels or other variables in this disease, we administered POF (20 mg/kg/day intravenously in 150 ml of saline for five days) randomized versus placebo (150 ml of saline without POF) in addition to standard antimalarial therapy. After recruitment of 51 patients with Plasmodium falciparum malaria, those receiving POF had more nausea and abdominal discomfort than the placebo group, as expected. Eleven of 27 patients receiving POF and three of 24 patients receiving placebo requested termination of the study medication (P < 0.05). Pentoxifylline did not change the decrease of TNF alpha levels or affect the clinical course in a significant way. Since POF failed to improve the clinical situation or to impact numerous laboratory parameters (including TNF alpha, thrombin-antithrombin III, thrombomodulin, and human neutrophil elastase), the study was terminated earlier than planned. While this study does not specifically address cerebral complications of malaria, the results suggest that POF is not useful as a routine adjunct to the standard therapy of falciparum malaria.
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PMID:Supportive pentoxifylline in falciparum malaria: no effect on tumor necrosis factor alpha levels or clinical outcome: a prospective, randomized, placebo-controlled study. 915 47

Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 micrograms/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF-alpha and IL-1 alpha secretion, but not IL-6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower inhibitory activity in vitro than pentoxifylline and HWA138. A small enhancement of cytokine secretion was induced by pentoxifylline and the two analogues at low concentrations. The drugs did not affect cell viability. Pentoxifylline, HWA138 and HWA448 also inhibited LPS induced TNF production in vivo in female CF1xBalb/c mice. The drugs were inhibitory at 0.5-1 mg per mouse when mixed with LPS, and 1 mg per mouse of the drugs was inhibitory when injected 1 h before LPS challenge. HWA448 had similar inhibitory activities in vivo compared to pentoxifylline and HWA138, possibly because of the longer serum half-life of HWA448. The pentoxifylline analogues may have lower toxicity than pentoxifylline itself and may therefore be useful in future treatment of diseases induced by endotoxic substances.
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PMID:Inhibition of LPS and Plasmodium falciparum induced cytokine secretion by pentoxifylline and two analogues. 916 Jan 1

The effect of quinine on fever induced by lipopolysaccharide and brewer's yeast has been investigated in rats. Oral administration of 50 or 100 mg kg(-1) quinine, doses which had no effect on normothermic rats, significantly reduced lipopolysaccharide- (50 microg kg(-1), i.m.) and yeast- (2 g kg(-1)) induced fever in rats. Pentoxifylline (100 mg kg(-1)), a tumour necrosis factor antagonist also attenuated the febrile response induced by lipopolysaccharide, but not that by yeast, in a manner similar to quinine. Piroxicam (5 mg kg(-1)), a cyclooxygenase inhibitor suppressed both types of fever with a longer duration of action. In addition to its anti-pyretic effect, quinine had a significant anti-inflammatory effect in the carrageenan model of acute inflammation in the hind-paw of rats. The results indicate the anti-inflammatory and anti-pyretic potential of quinine which might be important in addition to its anti-plasmodial action in the therapy of cerebral malaria.
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PMID:A study of the anti-pyretic effect of quinine, an alkaloid effective against cerebral malaria, on fever induced by bacterial endotoxin and yeast in rats. 953 Sep 92

Pentoxifylline, an inhibitor of tumor necrosis factor, was evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria admitted to the Bangkok (Thailand) Hospital for Tropical Diseases, in a 5-month period in 1994. All patients had 1 or more clinical manifestations of severe malaria, including cerebral malaria (n = 18), renal failure requiring dialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n = 30). Patients were randomly assigned to receive treatment for 72 hours with a combination of intravenously administered artesunate and either placebo (n = 15), low-dose (0.83 mg/kg/hour) pentoxifylline (n = 15), or high-dose (1.67 mg/kg/hour) pentoxifylline (n = 15). Overall severity was comparable in all 3 groups. Concentrations of tumor necrosis factor were reduced in all 3 groups 48 hours after treatment. There were no significant differences between groups in terms of parasite and fever clearance time, recovery time from coma in patients with cerebral malaria, duration of intubation in patients with respiratory distress, number of hemodialysis treatments required for patients with acute renal failure, or number of units of blood administered to patients in need of transfusion. These findings suggest that the addition of pentoxifylline to artesunate therapy for severe malaria produces no evident clinical benefit.
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PMID:Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand. 954 17