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)

Compounds that compete with folic acid (folic acid antagonists [FAAs]) become limited in their usefulness in the treatment of leukemia, malaria, and bacterial infections by the rapid development of resistance. Assays of the plasma levels of certain of these FAAs led to the observation, in about 25% of the determinations, that a higher density of growth of Streptococcus faecium var. durans (ATCC 8043) was obtained at an FAA concentration just below the completely inhibitory level than at one-half this concentration. This and other considerations suggested that FAAs may act not only as selective agents for resistant organisms but also as mutagens. Seven FAAs including amethopterin, pyrimethamine, trimethoprim, chlorguanide triazine, an experimental quinazoline, WR-158,122, and two experimental triazines, WR-99,210 and WR-38,839, were tested for mutagenicity in the Salmonella reversion assay developed by Ames et al. (1975). All were found to be negative for strains TA1535, TA1537, TA1538, TA98, and TA100, both with and without microsomal activation. These compounds were then tested as mutagens for three traits in the folic acid-requiring S. faecium. FAAs were shown to cause mutations to folic acid independence, rifampin resistance, and FAA resistance. It is postulated that the FAAs induce mutations by causing thymine deprivation in the folic acid-requiring host.
 ...
PMID:Mutagenic studies of folic acid antagonists. 32 58

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.
 ...
PMID:The effect of fever on quinine and quinidine disposition in the rat. 168 45

The antimalarial herb, Azadirachta indica, acts by redox perturbation in the form of the imposition of substantial oxidant stress during malarial infection. The aqueous leaf extract substantially inhibited NADPH cytochrome C(P-450) reductase activity in rats with a significant increase in the microsomal protein. The aniline hydroxylase activity and the phenobarbitone metabolism were also enhanced. The flavonoids quercetin-3-rhamnoside and quercetin-3-rutinoside (rutin) were isolated as the major constituents of the extract. The significance of these findings in clinical malaria chemotherapy is discussed.
 ...
PMID:Biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract. 308 17

Administration of a combination of chloroquine and the copper-lysine complex, copper(lysine)(2), an inhibitor of microsomal monooxygenases, considerably decreased the parasitaemia level of mice infected with a chloroquine-resistant strain of Plasmodium berghei. When given separately, chloroquine and the complex had no antimalarial effect. Use of a combination of monooxygenase inhibitors and chloroquine therefore appears to be a promising addendum to the chemotherapy of malaria caused by chloroquine-resistant parasites.
 ...
PMID:Suppression of the chloroquine resistance of Plasmodium berghei by treatment of infected mice with a microsomal monooxygenase inhibitor. 311 94

A microsomal fraction from the cells of the malaria parasite of rodent Plasmodium berghei was obtained. The spectral properties of microsomal preparations suggest that P. berghei microsomes contain cytochromes b5 and P-420. Electrophoretic separation of microsomal proteins revealed the presence of proteins whose molecular mass corresponds to NADPH-cytochrome c reductase, cytochrome P-450 and epoxide hydratase. The activities of NADPH-cytochrome c reductase and benzpyrene hydroxylase were determined. The spectral parameters, electrophoretic data and enzymatic activities of microsomal proteins indicate that P. berghei cells contain a cytochrome P-450 monooxygenase system. The interrelationship between the activity of the microsomal monooxygenase system and the resistance of P. berghei cells to the antimalaria preparation chloroquine is discussed.
 ...
PMID:[Detection of a system of microsomal monooxygenases in the rodent malaria parasite Plasmodium berghei]. 355 25

A relationship was found between resistance of malarial plasmodium to chloroquine and the increased activity of microsomal monooxygenases, metabolizing drugs in the parasite. A search for effective inhibitors of the enzymatic system was initiated. For this purpose inhibitory effects of 17 alpha-hydrodeoxycorticosterone (substance S), 21-acetate-17 alpha-hydroxydeoxycorticosterone (acetate of substance S), 4-bromomethyl-2,2,5,5-tetramethyl-3-imidazoline-3-oxide-1-oxyl (RBr), Cu(lysine)2 on activity of arylhydroxycarbone hydroxylase were studied using mice liver microsomes and homogenate of mice malaria cells Plasmodium berghei. Cu(lysine)2 and phenylhydrazine were found to be the most effective inhibitors of the enzyme in samples containing mice liver microsomes or malarial parasite. The data obtained suggest that the inhibitors of microsomal monooxygenases may serve as means for a decrease in malarial parasite resistance to chloroquine.
 ...
PMID:[Microsomal monooxygenase inhibitors as promising agents for overcoming the drug resistance of the malaria parasite]. 391 72

The action of non-detergent sulphobetaines (NDSBs) as new mild agents for protein purification is described. The solubilization effects of non-detergent sulphobetaines are shown in different examples; all obtained under non-denaturing conditions: (1) microsomal proteins extraction; (2) recovery after dialysis of nuclear proteins; (3) reduction of precipitation in isoelectric focusing experiments under non-denaturing conditions; and (4) purification of a membrane-bound serine protease from Plasmodium falciparum involved in erythrocyte invasion by malaria merozoites. The absence of a significant denaturation effect induced by NDSBs is demonstrated by tests on beta-galactosidase and alkaline phosphatase. A simple NDSB synthesis and some possible explanations of the action of NDSBs are also presented.
 ...
PMID:Non-detergent sulphobetaines: a new class of mild solubilization agents for protein purification. 782 51

A triple combination of mefloquine, sulfadoxine and pyrimethamine (MSP) was used with primaquine for the radical treatment of falciparum malaria in Thailand. Primaquine was reported to inhibit hepatic microsomal enzymes and drug metabolism in animal and man. 23 children hospitalized in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Bangkok, Thailand, were randomly allocated into two groups, group I received MSP equivalent to 20 mg base of mefloquine/kg body weight and group II received MSP plus primaquine (0.75 mg/kg). No statistical difference was noted for clinical response except the gametocyte clearance time was shorter in children given MSP plus primaquine (7 +/- 2.7 days) than the children given MSP alone (21.9 +/- 4.4 days) (P < 0.01). No serious side effects were recorded in this study. The plasma samples were obtained for kinetic calculations by HPLC in 18 children (11 in group I, 7 in group II). Mean Cmax was 7.4 +/- 5.2 h in group I and 6.6 +/- 7.0 h in group II. Mean t1/2, Cl/f and Vd/f were 9.8 +/- 1.6 days, 0.43 +/- 0.16 ml/min/kg and 8.84 +/- 4.21 l/kg in group I, 9.3 +/- 1.4 days, 0.41 +/- 0.12 ml/min/kg and 8.91 +/- 3.00 l/kg group II, respectively. The comparison of kinetic parameters in groups I and II revealed no significant difference (P > 0.05) suggesting no drug interaction. These kinetic values in children given MSP suspension were considerably different to those in adult patients with shorter tmax, t1/2 and MRT. The coadministration of MSP and primaquine in children would benefit by reducing the transmission of malaria in endemic areas.
 ...
PMID:Pharmacokinetic study of mefloquine in Thai children aged 5-12 years suffering from uncomplicated falciparum malaria treated with MSP or MSP plus primaquine. 795 48

Falciparum malaria is known to cause abnormalities in the liver. Hepatic metabolism in patients with falciparum was studied by caffeine clearance and the results were related to the severity of the disease. Caffeine (3.5 mg/kg) was administered orally to patients with severe (N = 10) or uncomplicated (N = 9) falciparum malaria. The plasma clearances during illness averaged 0.67 +/- 0.27 ml/min kg for the severe cases and 0.98 +/- 0.36 ml/min kg for the uncomplicated cases (P < 0.05). In the severe patients, clearances during illness (0.67 +/- 0.27 ml/min kg) were less than those in convalescence (2.15 +/- 0.91 ml/min kg) (P < 0.0001). However, in the uncomplicated cases, the clearances during illness and in convalescence were similar (P > 0.05) and clearance rates in convalescence were similar for the severe and uncomplicated cases (P > 0.05). Hepatic microsomal metabolism is apparently slow in severe falciparum malaria but reverts to normal in convalescence. Liver metabolic function does not appear to be significantly affected in uncomplicated malaria.
 ...
PMID:Hepatic metabolism in severe falciparum malaria: caffeine clearance study. 819 10

We have investigated the effect of malaria infection with the rodent parasite Plasmodium berghei and fever induced by Escherichia coli endotoxin on the metabolism of phenacetin to paracetamol by rat liver microsomes from young (4 weeks old) male Wistar rats (N = 5 in control and fever groups; N = 10 in malaria-infected group). Following determination of % parasitaemia, the malaria-infected group was divided into a low parasitaemia subgroup (N = 5; mean % parasitaemia = 9.87 +/- 2.6) and a high parasitaemia subgroup (N = 5; mean % parasitaemia = 36.6 +/- 8.1). The control group received normal saline. Total microsomal protein was not significantly affected by fever or malaria infection while cytochrome P450 levels were reduced by approximately 50% in the high parasitaemia subgroup, 20% in the low parasitaemia subgroup and 20% in the endotoxin-treated group. Phenacetin-O-deethylation kinetics were biphasic in both control and malaria-infected rats, but monophasic in endotoxin-treated rats. Total apparent intrinsic clearance (CL(int),total; calculated as Vmax/Km; Vmax is maximum velocity, Km is Michaelis constant) of phenacetin was reduced approximately 6-fold in low parasitaemia, 30-fold in high parasitaemia and 35-fold in fever. There was a poor correlation between CL(int),total and % parasitaemia (r = -0.6). However, log CL(int),total correlated inversely with % parasitaemia (r = -0.9), suggesting that Cl(int),total decreased exponentially with an increase in % parasitaemia. Phenacetin O-deethylation is a marker for cytochrome P4501A2 activity and the results of the present study suggest that both malaria infection and fever might specifically reduce P4501A2 activity in the rat.
 ...
PMID:Effect of malaria infection and endotoxin-induced fever on phenacetin O-deethylation by rat liver microsomes. 846 44


1 2 3 4 Next >>