phenanthrenes and Parasitemia

One hundred two patients aged 2-43 years diagnosed with acute malaria due to P. falciparum or P. vivax were treated with 3 doses of halofantrine (500 mg for > or = 18 year old patients and 8 mg/kg of patient body weight for 2-17 year olds), with each dose administered once in 6 hours and followed up for 28 days. Out of 102 patients 63 had P. falciparum, 36 had P. vivax and 3 had unidentified species. Following three dose therapy, 96.1% (98/102) of patients were cured, 0.98% (1/102) showed improvement from baseline, 1.96% (2/102) did not respond and were considered as treatment failures and one patient had indeterminate data. The lone patient, who relapsed after 120 hours post dose 1, was cured following re-treatment on day 7. The median parasite clearance and fever clearance times, from the first dose, were 26 hours and 30 hours, respectively. Eleven point eight percent (12/102) of patients reported adverse events, of which abdominal pain, reported by one subject, was considered to be probably related to the drug and required corrective therapy. There were no serious adverse events or fatalities and none of the patients had a change in QTc interval greater than 10%. Thirteen point seven percent (14/102) of patients had abnormal clinical laboratory parameters that normalized later.

Topics: Adolescent; Adult; Blood Cell Count; Blood Chemical Analysis; Child; Child, Preschool; Electrocardiography; Female; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Pakistan; Parasitemia; Phenanthrenes; Treatment Outcome

A novel Plasmodium falciparum gene, denoted cg2 gene, has been recently discovered, and a distinct genotype, characterized by 12 point mutations and 3 size polymorphisms, has been shown to be associated with chloroquine resistance in laboratory-adapted parasite strains. One of the polymorphic regions, denoted the omega region, consists of 16 tandem repeat units in chloroquine-resistant strains, while the chloroquine-sensitive strains have either < or = 15 or > or = 17 repeat units. In this study, the in vivo and in vitro responses were compared with the number of repeat units in the omega region of the cg2 gene for 75 Cameroonian isolates determined either by DNA sequencing or agarose gel electrophoresis. The 16-repeat units that characterize the resistant strains were found in 10 chloroquine-sensitive isolates (50% inhibitory concentration [IC50] < 100 nM) and 30 chloroquine-resistant isolates (IC50 > or = 100 nM). Thirty-five isolates (28 chloroquine-sensitive isolates and 7 chloroquine-resistant isolates) displayed < or = 15 or > or = 17 repeat units. Of the 18 patients responding with treatment failure, 15 were infected with parasites carrying 16 repeat units. Twenty-eight patients (11 with isolates carrying 16 repeat units and 17 with isolates carrying < or = 15 or > or = 17 repeat units) showed an adequate clinical response. The sensitivity, specificity, and predictive value were 81% (83%), 74% (61%), and 75% (58%), respectively compared with in vitro (or in vivo) responses. Neither the level of IC50 nor the key P. falciparum multidrug resistance gene 1 (pfmdr 1) allele at position 86 was associated with the number of omega repeat units. Although in vitro and in vivo resistance to chloroquine was statistically associated with the presence of 16 repeat units in the omega region (P < 0.05), the number of omega repeat units did not adequately discriminate patients infected with chloroquine-resistant parasites from those infected with chloroquine-sensitive parasites. Further studies on the cg2 gene are needed to determine whether cg2 gene is a reliable genetic marker for chloroquine resistance.

Topics: Adolescent; Adult; Animals; Antimalarials; Cameroon; Child; Chloroquine; DNA Primers; DNA, Protozoan; Drug Resistance; Electrophoresis, Agar Gel; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Naphthyridines; Parasitemia; Phenanthrenes; Plasmodium falciparum; Polymerase Chain Reaction; Regression Analysis; Repetitive Sequences, Nucleic Acid; Scintillation Counting; Sequence Analysis, DNA

The combination of halofantrine and primaquine therapies was calculated as a regimen for achieving radical curve of falciparum or vivax malaria in Irian Jaya, Indonesia, and compared with combined chloroquine and primaquine therapies. The patients who volunteered for the study [adult, male, Indonesian immigrants with no previous exposure to endemic malaria, normal glucose-6-phosphate dehydrogenase (G6PD) activity, uncomplicated malaria illness, no prior use of antimalarials, and parasitaemias of 0.001%-1.1%] were randomized to receive either halofantrine (24 mg base/kg bodyweight, in three equal doses over 12 h) or chloroquine (25 mg base/kg bodyweight over 48 h, in doses of 10, 10 and 5 mg base/kg at 24-h intervals). Each patient also received concurrent daily primaquine (0.5 mg base/kg bodyweight) for 14 days followed by the same dose on alternate days to day 28. A recurrent parasitaemia during the 28 days of follow-up constituted drug failure. Of the 40 cases of falciparum malaria and 26 cases of vivax malaria treated with halofantrine-primaquine, none had a recurrent parasitaemia (100% efficacy). In contrast, 20 of 30 patients with falciparum malaria and three of 27 with vivax malaria had recurrent parasitaemias after chloroquine-primaquine, giving efficacies of 33% and 89%, respectively. Halofantrine-primaquine was significantly more effective than chloroquine-primaquine against falciparum malaria (P < 0.001) but was similarly efficacious against vivax malaria (P = 0.23). On average, fever associated with falciparum or vivax malaria cleared 17 h faster with halofantrine-primaquine (P < 0.01) although there were no significant differences (P > 0.4) in parasite-clearance times between the two regimens. The halofantrine-primaquine regimen was also associated with a more rapid and significant decline in malaria-related physical complaints.

Topics: Adult; Antimalarials; Chloroquine; Drug Therapy, Combination; Follow-Up Studies; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Male; Parasitemia; Phenanthrenes; Primaquine; Recurrence; Treatment Outcome

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.

Topics: Acetaminophen; Adult; Aged; Analgesics, Non-Narcotic; Antimalarials; Biopterins; Drug Therapy, Combination; Female; Humans; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Neopterin; Parasitemia; Pentoxifylline; Phenanthrenes; Phosphodiesterase Inhibitors; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Tumor Necrosis Factor-alpha

3-Hydroxy-N'-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro.

Topics: Animals; Antimalarials; Chloroquine; Malaria; Mice; Parasitemia; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium berghei; Plasmodium falciparum; Rats; Structure-Activity Relationship

Using an in vitro model of human lung endothelial cells, we studied different characteristics of Plasmodium falciparum isolates as potential factors for malaria severity in 2 Thai patient groups: 27 with complicated malaria and 42 with uncomplicated malaria. In regard to binding properties, no association existed between cytoadherence and rosette phenotypes (P = 0.1) and hypothrombocytemia increased the cytoadherence level (P = 0.007). Cytoadherence was significantly associated with malaria severity (P = 0.05) in contrast to rosette formation (P = 0.9). Intercellular adhesion molecule-1 and chondroitin-4-sulfate were major receptors of cytoadherence in those with complicated malaria compared with those with uncomplicated malaria (P < 10(-4)). Chondroitin-4-sulfate could act as a putative receptor for malaria complications in non-pregnant women. CD36 was the main receptor in patients with uncomplicated malaria (P < 10(-3)). Vascular cell adhesion molecule-1 and E-selectin played a minor role in 2 groups (P = 0.6). Qinghaosu derivatives were more efficient than other antimalarial drugs, but a positive correlation was observed between the 50% inhibitory concentrations of halofantrine and quinine and the number of adhesive parasitized red blood cells, suggesting their influence on cytoadherence.

Topics: Adolescent; Adult; Animals; Antibodies, Monoclonal; Antimalarials; Binding, Competitive; Cell Adhesion; Cells, Cultured; Chondroitin Sulfates; Endothelium; Female; Humans; Intercellular Adhesion Molecule-1; Lung; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Phenanthrenes; Plasmodium falciparum; Quinine; Rosette Formation; Thailand

The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] = 7.8, 95% confidence interval [CI] = 3.7-16, P < 0.001), anemia (hematocrit <30%) (AOR = 3.9, 95% CI = 2.3-6.5, P < 0.001), no coincident P. vivax malaria (AOR = 3.5, 95% CI = 1.04-11.5, P < 0.04), presentation with a recrudescent infection (AOR = 2.3, 95% CI = 1.3-4.1, P < 0.004), and a history of illness longer than two days (AOR = 3.3, 95% CI = 1.7-6.6, P < 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks = 1.9, 95% CI = 1.3-2.7 and 2.8, 95% CI = 2.0-4.0, respectively; P < 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Carrier State; Child; Child, Preschool; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Multivariate Analysis; Parasitemia; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Quinine; Regression Analysis; Risk Factors; Seroepidemiologic Studies; Sesquiterpenes; Thailand

Artemisinin (QHS) and its derivatives are new antimalarials which are effective against Plasmodium falciparum parasites resistant to chloroquine (CQ). As these drugs are introduced it is imperative that resistance is monitored. In this paper we demonstrate that the inoculum size used in in vitro testing influences the measured in vitro susceptibility to QHS and its derivative dihydroartemisinin (DHA) and to mefloquine (MEF) and CQ over the range of parasitaemias routinely used in testing with the WHO in vitro microtest. An increase in parasitaemia and/or haematocrit was accompanied by a decrease in the measured sensitivity of 2 laboratory lines. In the context of a field study testing in vitro susceptibility of parasite isolates from patients with uncomplicated malaria in Fajara, The Gambia we demonstrate that failure to control for inoculum size significantly overestimates the level of resistance to QHS and DHA as well as MEF, halofantrine (HAL) and quinine (QUIN). When controlling for the inoculum effect, cross-resistance was observed between QHS, MEF and HAL suggesting the presence of a multidrug resistance-like mechanism. These studies underline the importance of inoculum size in in vitro susceptibility testing.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Gambia; Hematocrit; Humans; Malaria, Falciparum; Mefloquine; Parasitemia; Phenanthrenes; Plasmodium falciparum; Quinine; Scintillation Counting; Sensitivity and Specificity; Sesquiterpenes

Topics: Adolescent; Adult; Aged; Antimalarials; Child; Child, Preschool; Drug Administration Schedule; Follow-Up Studies; Humans; Malaria, Falciparum; Middle Aged; Pakistan; Parasitemia; Phenanthrenes

Fenozan B07, a 1,2,4-trioxane endoperoxide with potent blood schizontocidal activity against drug-sensitive and drug-resistant rodent malaria parasites, exerted a modest potentiating action when administered with chloroquine (CQ) to mice infected with parasites of the CQ-resistant P. yoelii ssp. NS, but not when given to mice infected with the CQ-sensitive P. berghei N strain. The reason why this potentiation may be of particular value in the treatment of severe falciparum malaria is discussed. Mefloquine and halofantrine displayed a similar level of potentiation with Fenozan B07 against the CQ-resistant parasites. However, antagonism was shown by combinations of Fenozan B07 with pyronaridine or the 8-aminoquinoline WR 238 605 when used against CQ-resistant parasites. Mefloquine with Fenozan B07 is also antagonistic against a highly mefloquine-resistant line of P. yoelii ssp. NS. The reasons behind such antagonism are not known. The importance is stressed of using carefully selected drug combinations of novel antimalarials, rather than single drugs, in order to impede the selection of drug-resistant parasites, but only after adequate, preclinical, toxicity testing.

Topics: Aminoquinolines; Animals; Antimalarials; Chloroquine; Drug Antagonism; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Malaria; Mefloquine; Mice; Naphthyridines; Parasitemia; Phenanthrenes; Phenylpropionates; Plasmodium berghei; Plasmodium yoelii

We compared the efficacy of azithromycin to the clinical antimalarial doxycycline in Plasmodium berghei-infected mice and in P. falciparum-infected Aotus monkeys. When mice were administered drug orally twice a day for three days, the minimum total dose of azithromycin that cured all mice was 768 mg/kg. Doxycycline at a dose of 1,536 mg/kg cured no mice. The efficacy of fast-acting blood schizonticides (quinine, halofantrine, artemisinin) against P. berghei was augmented by azithromycin. In monkey experiments in which there were two animals per experimental group, azithromycin (100 mg/kg/day for seven days) eliminated parasitemia; azithromycin (30 mg/kg/day) initially cleared 99.8-100% of the parasites with recrudescence in the one completely cleared case. Doxycycline (30 mg/kg/day) cleared 100% of the parasites with recrudescence in both cleared cases. Since azithromycin can be clinically administered at a somewhat higher daily dosage than doxycycline, the data suggest that it may be possible to replace drugs of the tetracycline class with azithromycin in combination with fast-acting blood schizonticides for the treatment of P. falciparum infection.

Topics: Administration, Oral; Animals; Antimalarials; Aotus trivirgatus; Artemisinins; Azithromycin; Disease Models, Animal; Doxycycline; Drug Therapy, Combination; Humans; Injections, Subcutaneous; Malaria; Malaria, Falciparum; Mice; Parasitemia; Phenanthrenes; Plasmodium berghei; Quinine; Sesquiterpenes

Lactate dehydrogenase, the terminal enzyme of anerobic Embden-Meyerhoff glycolysis, plays an important role in the carbohydrate metabolism of human malaria parasites. Based on the ability of malarial lactate dehydrogenase to use 3-acetylpyridine NAD as a coenzyme in a reaction leading to the formation of pyruvate from L-lactate, the enzymatic activity of fresh clinical isolates of Plasmodium falciparum and Plasmodium vivax was determined in relation to incubation time, asexual stages, and parasitemia and applied to a drug susceptibility assay. Lactate dehydrogenase activity was detectable at a parasitemia > 0.4%, at a hematocrit of 1.5%, and increased with parasitemia. Maximal lactate dehydrogenase activity was generally observed between 36 and 48 hr, when the trophozoites and schizonts predominated. The results of the in vitro drug susceptibility assays based on the inhibition of lactate dehydrogenase activity and on the incorporation of tritium-labeled hypoxanthine were correlated. For an optimal performance against fresh clinical malaria isolates, however, the enzymatic assay requires an initial parasitemia between 1 and 2% at a hematocrit of 1.5%.

Topics: Animals; Antimalarials; Chloroquine; Colorimetry; Erythrocytes; Humans; L-Lactate Dehydrogenase; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Parasitemia; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax; Quinine