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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chloroquine is widely used in malaria chemotherapy. Due to its weak base properties, this drug accumulates in the parasite food vacuole where it acts initially by raising the pH of this organelle, thereby reducing the digestion of hemoglobin by the parasite and preventing its growth. Nevertheless, alkalinization of the food vacuole and inhibition of lysosomal protein degradation could also be achieved by means of carboxylic ionophores such as monensin and nigericin. These drugs intercalate into intracellular organelle membranes and exchange protons for K+ or Na+. In the present study, we show that monensin and nigericin exhibit in vitro intrinsic antimalarial activities at nanomolar and picomolar range, respectively, on P.falciparum and thereby appear 25 fold and 30,000 fold more potent than chloroquine. The very low IC50 values exhibited by these two ionophores prompted us to test their antimalarial activities in vivo on Plasmodium vinckei petteri. We found that the ED50 and ED90 values were respectively 1.1mg/kg and 3.5 mg/kg for monensin; 1.8 mg/kg and 4.6 mg/kg for nigericin. In addition, when treated with monensin at 10 mg/kg, 100% of the infected mice were cured. Interestingly, nigericin can be combined with monensin and we show that this combination is synergic. Thus, this finding would allow the use of lower doses of these ionophores and prevent occurrence of drug resistance. Carboxylic ionophores can be viewed as a new strategy in malaria chemotherapy.
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PMID:Carboxylic ionophores in malaria chemotherapy: the effects of monensin and nigericin on Plasmodium falciparum in vitro and Plasmodium vinckei petteri in vivo. 889 Sep 52

The infectivity of P. berghei-infected TO mice to mosquitoes declines rapidly 2 to 5 days after blood inoculation, in spite of rising numbers of gametocytes in the blood. This pattern is typical of many malaria infections and various factors, particularly specific and nonspecific immune responses, have previously been implicated in the decline. Here we report that (1) simple physiological changes in the mouse blood, namely, falling pH and bicarbonate levels induced by high parasitaemias, are responsible for the sustained inhibition of infectivity; (2) the inhibition is reversible in vivo by the addition of sodium bicarbonate alone; (3) the inhibition occurs at the point of exflagellation; (4) contrary to previous observations (Kawamoto et al. 1992), exflagellation in P. berghei, like that in P. gallinaceum (Bishop and McConnachie 1956; Nijhout and Carter 1978; Nijhout 1979) and P. falciparum (Ogwan'g et al. 1993), is dependent on extracellular bicarbonate; and (5) induction of exflagellation by a mosquito factor is bicarbonate dependent. These new observations are critical to the design and interpretation of experiments on other transmission blocking phenomena.
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PMID:Plasmodium berghei: infectivity of mice to Anopheles stephensi mosquitoes. 894 26

Renal and systemic hemodynamics, plasma arginine vasopressin, plasma renin activity, plasma norepinephrine, blood volume and water loading test were studied in 10 patients with falciparum malaria without renal failure. Six patients responded to water load normally, while 4 patients had a decreased response to water load. The patients with a normal water load response had normal renal and systemic hemodynamics and a normal hormonal profile. The patients with a decreased response to water load had hyponatremia, hypervolemia, high cardiac index, low systemic vascular resistance, high plasma arginine vasopressin, high plasma renin activity, high plasma norepinephrine, low creatinine and p-aminohippurate clearances, low urine sodium and high urine osmolality. They had a lower mean arterial pressure during the acute phase of the disease than during the recovery phase. The findings suggest that a decreased response to water load is due to peripheral vasodilatation which results in a decreased effective blood volume leading to the release of vasopressin and norepinephrine, increased renin activity and decreased renal hemodynamics.
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PMID:Renal and systemic hemodynamics, in falciparum malaria. 895 63

Despite the wide use of artermisinin and its derivatives, concerns have been raised about their potential neurotoxicity. Accordingly, studies were undertaken on rats treated with high doses of arteether and on mouse neuroblastoma cells (Neu2a) treated with 3H-dihydroartemisinin. Rats uniformly developed neurologic symptoms following intramuscular administration of 50 mg/kg/day of arteether for 5-6 days. Acute neuronal necrosis associated with vacuolization and focal axonal swelling in the neuropil was observed in specific areas of the brain, especially the vestibular nuclei and red nuclei. Scattered swollen neurons were also evident in the cerebellar nuclei and the reticular formation. No neurologic symptoms, neuronal nuclei necrosis, nor gliosis was observed in rats administered 25 or 30 mg/kg/day for six or eight days. In vitro, Neu2a cells took up much less 3H-dihydroartemisinin than Plasmodium falciparum-infected red blood cells when incubated under identical conditions for 4 hr with 4.2 microM 3H-dihydroartemisinin. This selective uptake may explain why the artemisinin derivatives are selectively toxic to malaria parasites. Autoradiograms of sodium dodecyl sulfate-polyacrylamide gels run from 3H-dihydroartemisinin-treated cells showed that neuronal proteins with molecular weights of 27, 32, 40, and 81 kD were alkylated, although not nearly as strongly or rapidly as the P. falciparum proteins. The results indicate that while artemisinin derivatives have neurotoxic effects in rats and alkylate proteins in neuroblastoma cells, these effects only occur at high doses or after prolonged exposure.
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PMID:Artemisinin neurotoxicity: neuropathology in rats and mechanistic studies in vitro. 906 52

In a prospective study, hyponatraemia was observed in 52.6% of 19 children with cerebral malaria on admission, the plasma sodium ranging from 117 to 129 mumol/l. In addition, a further 10% developed hyponatraemia between 48 and 96 hrs after admission; in half of these, there was continuing urinary sodium loss. The clinical presentation of hypo- and normonatraemic children was similar except for vomiting and hypoglycaemia which were commoner in the normonatraemic and irritability and signs of lower respiratory tract infection which were commoner in the hyponatraemic groups. In hyponatraemic and normonatraemic children, there was a negative correlation between hyponatraemia and parasite density (r = -0.503, P < 0.05) and (r = -0.14, P < 0.05 respectively) and between parasite density and urinary sodium concentration during the first 24 hours of admission (r = -0.034; P < 0.05 and r = -0.045, P > 0.05 respectively). Irrespective of group, a relative increase in plasma sodium in the first 24 hours of admission (positive delta Na 24 h) was associated with a reduction in seizure frequency during this period as compared to the reported 24 hour of pre-admission seizure frequency, and, vice-versa. It is concluded that hyponatraemia is not uncommon in childhood cerebral malaria; urinary sodium loss may be contributory to the hyponatraemia seen in this condition.
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PMID:Hyponatraemia in severe falciparum malaria: a clinical study of nineteen comatose African children. 911 54

In order to get a better understanding in the mechanism by which tryptophan-N-formylated gramicidin (NFG) and gramicidin kill the malaria parasite Plasmodium falciparum in vitro, we studied the capacity of these peptides to change the potassium, as well as the sodium, composition of normal human erythrocytes, and their ability to cause cell lysis. It is shown that both peptides are able to induce potassium leakage from, and sodium flux into, erythrocytes in such a manner that it is most likely that they are able to form cation channels in the membrane of these cells. For both peptides, potassium efflux proceeds at a faster rate than sodium influx, but this difference is greater for NFG than for gramicidin. This explains the observation that gramicidin is more lytic than NFG is, even when comparing concentrations that show the same antimalarial activity. The finding that gramicidin is approximately 10 times more active than NFG in causing potassium efflux from normal erythrocytes, as well as in killing the malaria parasite, supports the hypothesis that peptide-induced parasite death is related to their capacity to induce potassium leakage from infected erythrocytes. Finally, the observation that erythrocytes are able to restore their normal ion contents after losing more than 50% of their potassium content by incubation with NFG or gramicidin, suggests that, in vivo, and upon treatment with drug concentrations that cause full inhibition of parasite growth, these cells would not be irreversibly damaged by action of the drugs.
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PMID:Effects of gramicidin and tryptophan-N-formylated gramicidin on the sodium and potassium content of human erythrocytes. 911 61

Both anopheline and culicine mosquitoes have been shown to incur a reduction in reproductive fitness when infected with malaria parasites. The agent of rodent malaria, Plasmodium yoelii nigeriensis, was used as a laboratory model to investigate changes in the accumulation of protein in the ovaries of Anopheles stephensi when infected with oocysts or when feeding on mice with heavy asexual parasitaemia but no mature gametocytes. Herein we report that during the early phases of the gonotrophic cycle the ovarian protein content increased normally; however, after 16 h post-blood-feeding there was a significant reduction in the total protein content in ovaries from infected mosquitoes. The development of ovaries from mosquitoes undergoing a second gonotrophic cycle and containing maturing oocysts was similarly affected. Ovarian protein profiles produced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a depletion of the yolk protein vitellin. Ovaries from mosquitoes feeding on a mouse with 31% parasitaemia, no detectable gametocytes and a low haematocrit (29% packed cell volume) also exhibited a reduction in protein content, although this did not occur until much later in the gonotrophic cycle. The role of blood-meal quality and malaria infection in the reduction in egg production is discussed.
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PMID:The effect of Plasmodium yoelii nigeriensis infection on ovarian protein accumulation by Anopheles stephensi. 913 61

Plasmodium falciparum lysate, prepared from 2.7 x 10(7) ring-infected erythrocytes and incubated with hemoglobin in sodium acetate at pH 5, incorporated a mean of 1.6 nmol of ferriprotoporphyrin IX (FP) into hemozoin in 18 to 22 hr. A similar preparation of trophozoite lysate incorporated a mean of 3.6 nmol of FP into hemozoin in 4 to 6 hr. These findings indicate differences between heme polymerase activity (hemozoin production) at the ring and trophozoite stages of malaria parasites. Intracellular hemozoin production was 90% inhibited at the ring and trophozoite stages by 0.5 and 7 nmol of chloroquine/10(6) infected erythrocytes. respectively. The inhibition killed the rings but not the trophozoites, suggesting that mature parasites may have a mechanism for protecting themselves against chloroquine-FP toxicity.
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PMID:Heme polymerase activity and the stage specificity of antimalarial action of chloroquine. 922 46

We compared the safety and efficacy of two treatment regimens using sodium artesunate in 91 randomized patients with uncomplicated falciparum malaria acquired in Thailand. One group of 45 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 4 days for a total of 1200 mg (group I: 5-day treatment). A second group of 46 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 6 days for a total of 1600 mg (group II: 7-day treatment). Both regimens were well tolerated. All patients were followed for a total of 28 days. By the third day of treatment, most patients were blood smear negative for parasites. Eighty-two patients completed the 28-day follow-up period and were used for describing the cure rate. All patients treated with the 5-day regimen were cured. In the 7-day treatment group, 98% (39 of 40) of the patients were cured; one patient developed late recrudescence (RI). There were no significant differences in fever clearance or parasite clearance between the two groups. However, 13 patients (five in group I and eight in group II) developed Plasmodium vivax infection during the follow-up period. We conclude that 5- or 7-day regimens of sodium artesunate with a total dose of 1200-1600 mg are effective and safe in treating falciparum malaria acquired in Thailand.
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PMID:Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens. 924 84

In a prospective study, 80 cases of fever with hepatosplenomegaly, anemia and leucopaenia coming from the hyperendemic zones for visceral leishmaniasis of North-Bihar, India were screened and subjected to bone marrow or splenic puncture for demonstration of Leishman-donovan bodies (LDB) and DIRECT AGGLUTINATION TEST (DAT) with antigen prepared by Harith et al. 59 cases were confirmed for Visceral Leishmaniasis (VL) by demonstration of LDB in which DAT was also positive in different titres ranging from 1:1600 onwards. Out of 21 cases in which the bone marrow was negative for parasite, DAT was positive in 10 cases. 8 Out of 10 cases responded to WHO regimen of treatment with sodium stibogluconate (SSG). Remaining two cases who did not respond to this therapy became positive for parasites on subsequent splenic aspirate. They were treated with pentamidine isethionate and were cured. 11 out of 80 cases showing a titre of 1:400 or lower in DAT, 6 proved to be cases of enteric fever and 5 of malaria. Thus DAT using Harith's antigen was found to be 100% sensitive and specific in detection of early cases of Indian VL.
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PMID:Direct agglutination test for early diagnosis of Indian visceral leishmaniasis. 925 70


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