Pentoxifylline as a Supportive Agent in the Treatment of Cerebral Malaria in Children

Perri, Giovanni Di; Perri, Haria Guasparri Di; Monteiro, Geraldo Badona; Bonora, Stefano; Hennig, Cornelia; Cassatella, Marco A.; Micciolo, Rocco; Vento, Sandro; Dusi, Stella; Bassetti, Dante; Concia, Ercole

doi:10.1093/infdis/171.5.1317

Cited by 101 publications

(55 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…28 However, a different study did find reduction of both TNF-␣ and duration of coma in cerebral malaria in children. 29 Interestingly, in P. vivax infection at the time of cri-sis, serum levels of TNF-␣ may be as high as in P. falciparum, with no cerebral symptoms in P. vivax. 30 An increase in the frequency of the TNF2 allele in humans reported from the Gambia, particularly in children with cerebral malaria, 31 suggests that TNF-␣ plays a dual role in malaria, perhaps by increasing the risk of cerebral malaria, but also by protecting against blood stages.…”

Section: Discussionmentioning

confidence: 99%

Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.

Shear¹,

Marino²,

Wanidworanun³

et al. 1998

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Previous studies demonstrated that Plasmodium yoelii 17XL, a lethal strain of rodent malaria, causes a syndrome in SW mice that resembles human cerebral malaria. The mouse brain pathology is characterized by cytoadherence of parasitized erythrocytes. Here, the possible mechanisms mediating cerebral malaria in this model were studied and the results were compared with a nonlethal strain of this parasite, P. yoelii 17XNL (nonlethal), which does not cause cerebral malaria. Immunostaining for intercellular adhesion molecule-1 (ICAM-1) revealed an increase in expression of this protein in the small venules and capillaries of the brains of infected mice that increased with time after infection. Staining was more pronounced during the lethal infection than the nonlethal infection. Some staining with monoclonal antibody to vascular cell adhesion molecule-1 was also observed, but it was quantitatively less than ICAM-1 staining and was limited to larger venules. During the lethal infection, levels of tumor necrosis factor-␣ (TNF-␣) increased rapidly, peaking on day 4. In contrast, mice infected with nonlethal P. yoelii had a slower serum TNF-␣ response that peaked on day 10, prior to the maximum parasitemia. In addition, mice with a targeted disruption of the TNF-␣ gene (TNF-␣Ϫ/Ϫ mice) were infected with the lethal and nonlethal strains of P. yoelii 17X. The TNF-␣Ϫ/Ϫ mice infected with the nonlethal parasite had significantly higher levels of parasitemia than controls, whereas TNF-␣Ϫ/Ϫ mice infected with the lethal strain had slightly higher levels of infected erythrocytes but were equally susceptible to death from this infection. Thus, TNF-␣ does not appear to be essential in mediating death. These results demonstrate that P. yoelii 17XL infection has features in common with human cerebral malaria and suggest that this model may be useful in testing strategies to alleviate this syndrome.Cerebral malaria refers to the severe complications of falciparum malaria in which vascular plugging of Plasmodium falciparum-infected red blood cells (RBCs) in the brain can lead to coma and death, often in children. 1,2 Cytoadherence of parasitized RBCs to endothelial cells, via ligands present on the erythrocyte membrane knobs, is thought to be responsible for this phenomenon. 3 However, exceptions to the requirement for knobs have been observed. 4 Others have postulated an important role for cytokines and nitric oxide in the pathogenesis of cerebral malaria. 5 The molecular mechanisms underlying the cytoadherence of P. falciparum-infected RBCs to the endothelium is under intensive investigation. Most laboratory-maintained and field isolates of infected RBCs appear to bind to CD36. However, binding to intercellular adhesion molecule-1 (ICAM-1) has also been observed. 4 Importantly, variation in specificity for endothelial ligands is common among different isolates. 6 Vascular cell adhesion molecule-1 (VCAM-1), a member of the same immunoglobulin-like superfamily as ICAM-1, and E-selectin have also been found to be receptors f...

show abstract

Section: Discussionmentioning

confidence: 99%

Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.

Shear¹,

Marino²,

Wanidworanun³

et al. 1998

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

show abstract

“…Since all controls were endotoxin-negative, the reason for the discrepancy between our and the previous study [11] regarding the number of endotoxin-positive samples could be related to occult bacteraemia in malaria [23,24] and/or contamination. Altogether, high levels of inflammatory cytokines and the resultant immune cell stimulation are probably implicated in sCD14 production [9,10,25,26] individual host, convalescence of bacterial infections or concomitant infections with LPS-producing organisms may vary the parasitaemia required to produce illness [27]. In this respect, LPS components have been used as malaria vaccine adjuvants to enhance the vaccine-directed immune response [28].…”

Section: Discussionmentioning

confidence: 99%

“…In an open trial in Burundian children with severe malaria, pentoxifylline exhibited a dramatic protective effect, as it significantly reduced the duration of coma, and even mortality [26]. Whether antagonism of CD14 could have an additional protective effect is not known.…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of soluble CD14 in serum of patients with acute Plasmodium falciparum malaria

Wenisch

Parschalk

et al. 1996

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Serum sCD14, tumour necrosis factor‐alpha (TNF‐α), IL‐6, and endotoxin were analysed in 45 patients with complicated malaria, in 14 patients with Gram‐negative septicaemia and in 24 healthy subjects by ELISA. Malaria patients with renal failure (n=16) had higher levels than patients without renal failure (n=29) (8116+1440 μg/lversus 9453+1017 μg/lP<0.05) and both had higher levels than patients with septicaemia (6155+1635μg/l) and normal subjects (2776+747 μg/l). A significant correlation between sCD14 and IL‐6 (r=0.756) and TNF (r=0.822) existed. However, no relation between sCD14 and serum endotoxin or indices of clinical disease severity (parasitaemia, fever, parasite or fever clearance time) was seen. Although the role of sCD14 in malaria remains to be determined, elevated levels may participate in the inflammatory response in complicated malaria.

show abstract

“…The children who received PTX had shorter comas than those treated with quinine alone [33]. Those who received PTX also showed a trend towards better survival than those treated with quinine alone, even though the study was not designed to evaluate differences in mortality.…”

Section: Discussionmentioning

confidence: 99%

“…A study performed in Burundi showed that intravenous infusion of PTX in combination with quinine treatment inhibited the synthesis of TNF-a in children with cerebral malaria [33]. The children who received PTX had shorter comas than those treated with quinine alone [33].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of LPS and Plasmodium falciparum Induced Cytokine Secretion by Pentoxifylline and Two Analogues

1997

View full text Add to dashboard Cite

Jakobsen PH, Koch C, Bendtzen K. Inhibition of LPS and Plasmodium falciparum Induced Cytokine Secretion by Pentoxifylline and Two Analogues. Scand J Immunol 1997;45:546-550 Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 mg/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF-a and IL-1a secretion, but not IL-6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower inhibitory activity in vitro than pentoxyfylline 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.

show abstract

Pentoxifylline as a Supportive Agent in the Treatment of Cerebral Malaria in Children

Cited by 101 publications

References 21 publications

Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.

Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.

Elevated levels of soluble CD14 in serum of patients with acute Plasmodium falciparum malaria

Inhibition of LPS and Plasmodium falciparum Induced Cytokine Secretion by Pentoxifylline and Two Analogues

Contact Info

Product

Resources

About