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)

We have constructed a second generation malaria transmission-blocking vaccine candidate based on Pfs25, the predominate surface protein of Plasmodium falciparum zygotes, to overcome potential production problems with the original construct. Four modifications were made: (1) addition of the last cysteine residue of the fourth epidermal growth factor like-domain of Pfs25; (2) mutagenesis of asparagine-linked glycosylation sites with glutamine rather than alanine; (3) addition of a six histidine tag at the carboxy-terminus for highly efficient purification of recombinant protein on nickel-NTA agarose; and (4) fermentation that combines continuous glucose fed-batch methodology with pH-controlled glucose addition and a terminal ethanol feed. The resulting product, TBV25H (Transmission-Blocking Vaccine based on Pfs25 with a Histidine tag), appears to be a more potent antigen and immunogen than the original construct, and the fermentation and post-fermentation processing methodology easily lend themselves to technology transfer to the ultimate users, newly industrialized countries.
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PMID:Production, purification and immunogenicity of a malaria transmission-blocking vaccine candidate: TBV25H expressed in yeast and purified using nickel-NTA agarose. 776 8

In a retrospective study we analyzed the clinical and blood chemical data of 12 patients with severe tropical malaria in the intensive care units of the University Hospital Zurich and the Stadtspital Triemli, Zurich, between 1991 and 1994. None of the 12 patients had been exposed to malaria before or had taken drugs for chemoprophylaxis. 7 patients survived, 5 died from complications of malaria. According to the criteria of severe tropical malaria defined by the WHO, the following pathological clinical and blood chemical parameters were noted on admission: cerebral coma (2/12); blood hemoglobin < 5 g/dl (0/12), < 8 g/dl (2/12); serum creatinine > 265 mumol/l (3/12); blood glucose < 2.2 mmol/l (0.12); circulatory collapse/shock (0/12); bleeding/signs of disseminated intravascular coagulation in laboratory tests (4/12); acidosis with pH < 7.25 (1/12). Further signs of severe tropical malaria were: hyperparasitemia > 5% (9/12); qualitative and quantitative disturbances of consciousness (6/12); thrombocytopenia < 30 x 10(9)/l (9/12); hyponatremia 125-135 mmol/l (9/12), < 125 mmol/l (2/12); rhabdomyolysis with creatine kinase > 1000 U/l (4/12). The basic treatment consisted of parenteral quinine hydrochloride in all patients; doxycycline was added in 8 cases, clindamycin in 3. Adjuvant therapy with desferrioxamin was given in 3 cases. 6 patients had exchange transfusions. Parasitemia cleared in all patients within 5 to 6 days. Later in the course, 5 patients developed acute respiratory distress syndrome, 6 required hemofiltration due to oliguria, and one became comatose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Intensive care aspects in severe tropical malaria: clinical aspects, therapy and prognostic factors]. 777 Jul 59

The relation between the immune response and the clinical features of severe falciparum malaria was studied in Burundian adults with (n = 31) and without (n = 17) cerebral involvement. At the time of admission, mean values for age, temperature, and blood levels of hemoglobin, creatinine, bilirubin, and glucose were similar in the two groups. Plasma levels of tumor necrosis factor alpha, interferon gamma, interleukin 10 (IL-10), and soluble intercellular adhesion molecule 1 were similarly elevated in the two groups. Mean parasite counts and mean plasma levels of soluble E-selectin were higher in severe noncerebral malaria than in cerebral malaria and were correlated with each other. After adjustment for parasitemia, levels of soluble E-selectin remained higher in noncerebral malaria. All seven patients who died had cerebral disease. These patients had higher levels of creatinine, bilirubin, IL-10, and soluble E-selectin than did patients with nonfatal cerebral malaria. After adjustment for creatinine and bilirubin levels, IL-10 and soluble E-selectin concentrations were similar in fatal and nonfatal cases of cerebral infection. In these African adults, none of the immunologic variables investigated was specific to cerebral malaria or to a fatal outcome.
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PMID:Immunologic and biochemical alterations in severe falciparum malaria: relation to neurological symptoms and outcome. 781 67

Crithidia fasciculata was used to replace murine peritoneal wash cells as feeder cells for the adaptation of Plasmodium falciparum isolates to continuous culture in vitro, thus avoiding the need to sacrifice animals. Fourteen of 17 malaria parasite isolates in one study, and 12 of 12 isolates in a second study, were successfully adapted to continuous culture in the presence of C. fasciculata, while only 5 of 17 parallel control isolates in the first study, and 2 of 12 isolates in the second study, were adapted in the absence of any feeder cells. Biochemical assays were performed to investigate various hypotheses put forward to explain the mode of action of feeder cells. No effect of C. fasciculata feeder cells was observed on lactate removal, osmotic pressure, or glucose or amino acid content of the malaria culture media. This feeder cell system was shown to reduce the pH of the malaria culture medium. Neither this feeder system nor another system, murine peritoneal macrophages, had any effect on the cysteine content of the culture medium. C. fasciculata was shown to reduce the redox potential of the culture medium, as were other malaria growth enhancers including cysteine and glutathione. This effect on the redox potential of the culture medium is proposed to be a possible mode of action for the feeder cell systems studied.
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PMID:Crithidia fasciculata as feeder cells for malaria parasites. 782 16

1. Quinine is a front-line antimalarial drug but is prescribed most commonly in nonmalarious countries for cramps. Postural hypotension, hearing loss and hyperinsulinaemic hypoglycaemia occur in malaria and overdose but little is known of quinine kinetics and toxicity in the elderly. 2. We studied 12 non-insulin-dependent diabetics and 10 non-diabetic controls aged 51-79 years. Subjects attended on two occasions > 7 days apart. On each test day, subjects were given a 600 Cal meal at 18.00 h (0 h) and, on one occasion, quinine sulphate 600 mg at 22.00 h (4 h). Venous blood samples for glucose, insulin and quinine assay were drawn pre-prandially and then regularly over the next 38 h. Supine and erect blood pressures were taken and audiometry was performed at 4, 6, 8 and 14 h. A one-compartment open pharmacokinetic model was fitted to serum quinine concentrations. 3. Absorption and elimination half-times, volume of distribution and oral clearance of quinine were comparable in the two groups (P > 0.2) and there was a mean absorption lag-time of approximately 1 h. Basal and immediate post-prandial (< 4 h) serum glucose and insulin concentrations on both test days were similar in the diabetics and also in the non-diabetics, but quinine produced a mean reduction in serum glucose of 1.0 mmol l-1 from 3-5 h post-dose in both groups without affecting serum insulin concentrations. Quinine administration did not alter postural blood pressure changes or produce significant hearing loss in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pharmacokinetics and pharmacodynamics of quinine in the diabetic and non-diabetic elderly. 782 21

Twelve cases of cerebral malaria due to plasmodium falciparum, treated with loading dose of quinine (20 mg/kg salt in 500 ml of 5% glucose infused IV in 4 hrs) are compared with eleven age and sex matched cases treated with conventional dose of 10 mg/kg. The parasite clearance rate was significantly faster in loading dose group. There was no difference in recovery time: the interval between the initiation of treatment to full recovery of consciousness in both groups. One patient had pretreatment hypoglycaemia and two cases in the conventional dose group developed hypoglycaemia during therapy. One patient died in conventional dose group due to multi-organ failure. Two litres blood exchange transfusion was also tried for this case. Mild cinchonism occurred in two cases after loading dose while this was observed only in one case in conventional dose group. There was no significant hypotension or ECG changes in any patient. Loading dose of quinine seems to be well tolerated and may clear parasitaemia faster in case of malaria due to Plasmodium falciparum (PF).
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PMID:Experience on loading dose--quinine therapy in cerebral malaria. 786 10

The hexose monophosphate shunt (HMS) produces NADPH for reductive antioxidant protection and for metabolic regulation, as well as ribose-5-phosphate needed for the synthesis of nucleic acids. Since malaria-infected red blood cells (RBC) are under endogenous oxidant stress, it was interesting to determine HMS activity in intact infected cells, as well as in free parasites. HMS activity was determined by measuring the evolution of 14CO2 from D-[1-14C]glucose in normal RBC, in intact Plasmodium falciparum-infected RBC (IRBC) and in free parasites. The HMS activity of IRBC was found to be 78 times higher than that of normal RBC. This activity increased with parasite maturation from the ring stage toward the trophozoite stage, and declined at the schizont stage. The HMS activity of the parasite contributes 82% of the total observed in the intact IRBC, and that of the host cell is increased some 24-fold. The increased reducing capacity of IRBC and free parasites were also evidenced by the larger ability for reductive accumulation of methylene blue. Since the endogenous oxidative stress is produced by the parasite digestion of the host cell's hemoglobin, inhibition of this process with protease inhibitors, by alkalinization of the parasite's food vacuole, or by the application of antimalarial drugs, resulted in 20-44% inhibition of IRBC HMS activity. A similar inhibition was observed in the presence of scavengers of oxidative radicals, uric and benzoic acids. These inhibitors had only a minor effect on the HMS activity of free parasites. D-[1-14C]glucose and D-[6-14C]glucose contributed equally to newly synthesized nucleic acids, suggesting that ribose-5-phosphate needed for this synthesis is contributed by the non-oxidative activity of HMS. These results imply that a major portion of parasite HMS activity and the activated HMS of the host cell are devoted to counteract the endogenously generated oxidative stress.
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PMID:Hexose-monophosphate shunt activity in intact Plasmodium falciparum-infected erythrocytes and in free parasites. 783 86

Infection of mice with blood-stage Plasmodium yoelii and P. chabaudi malaria induced hypoglycaemia in normal mice and normalized the hyperglycaemia of mice made moderately diabetic with streptozotocin (STZ). Injection of parasite supernatants induced hypoglycaemia accompanied by hyperinsulinaemia in normal mice, and in STZ-diabetic mice induced a profound drop in blood glucose and restored insulin secretion; however, severely diabetic mice (two injections of STZ) remained hyperglycaemic with no change in insulin levels. We conclude that malaria infection and parasite-derived molecules lower blood glucose concentration, but only in the presence of some residual pancreatic function. Diabetic mice were less anaemic, exerted a significant control of parasitaemia, and showed enhanced phagocytic activity compared with normal mice.
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PMID:Blood-stage malaria infection in diabetic mice. 788 67

Gluconeogenesis and liver blood flow (LBF) in severe falciparum malaria were assessed from the clearance and metabolic response to intravenously administered glycerol (0.3 g/kg) and Indocyanine Green ([ICG] 0.4 mg/kg), respectively. Fasting baseline blood glycerol concentrations (mean +/- SD) were significantly higher in acute malaria (133 +/- 65 mumol/L, n = 14), than in convalescence (65 +/- 31 mumol/L, n = 9, P = .01), but basal triacylglycerol concentrations were similar. Estimated glycerol turnover was also more than twice as high in acute malaria compared with convalescence (1.36 +/- 0.87 v 0.54 +/- 0.15 mumol.min-1.kg-1, P = .015). The increment in plasma glucose (AUC0-55 min) following glycerol infusion was greater during acute malaria compared with convalescence (median [range], +31.6 [-0.9 to +107.6] v +14.5 [-103 to +27.1] mmol.min-L-1, P < .05), but the insulin increments were similar (P = .9), indicating reduced tissue insulin sensitivity. The increment in venous lactate (AUC0-55 min) was higher in severely ill patients (17.2 [-7.8 to +53.4] mmol.min.L-1, n = 10) compared with patients with moderately severe malaria (-3.1 [-8.7 to 3.2] mmol.min-L-1, n = 4, P = .01). LBF estimated from ICG clearance was lower during acute illness than in convalescence (mean +/- SD, 15.5 +/- 2.3 v 18.6 +/- 2.9 mL.min-1.kg-1, P = .007) and correlated inversely with the basal venous lactate concentration (rs = .53, P < .05). LBFs less than 15 mL.min-1.kg-1 were associated with hyperlactatemia, and all four fatal cases had LBFs of less than 12 mL.min-1.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glycerol metabolism in severe falciparum malaria. 802 14

The antimalaric drug chloroquine is a well known inhibitor of lysosomal proteolysis in vitro. The present study tests the hypothesis that therapeutic doses of the drug decrease proteolysis also in vivo in humans. Leucine kinetics were determined in 20 healthy volunteers given 12 and 1.5 h before the studies 250 and 500 mg, respectively, of chloroquine phosphate (n = 10) or similar tablets of placebo (n = 10). Chloroquine reduced the rates of leucine appearance, a measure of whole body proteolysis, from 2.45 +/- 0.08 to 2.19 +/- 0.08 mumol.kg-1.min-1 (P = 0.038) and those of nonoxidative leucine disposal, an estimate of whole body protein synthesis, from 2.16 +/- 0.08 to 1.95 +/- 0.06 mumol.kg-1.min-1 (P = 0.050). The drug resulted also in a marginally significant (P = 0.051) decrement in the plasma concentrations of glucose. The effects of chloroquine on protein turnover might be potentially useful in counteracting protein wasting complicating several catabolic diseases, whereas those on glucose metabolism can explain the sporadic occurrence of severe hypoglycemic episodes in malaria patients chronically treated with this drug.
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PMID:Chloroquine reduces whole body proteolysis in humans. 804 8


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