Pituitary-adrenal function in uncomplicated falciparum malaria

To investigate pituitary-adrenal function in acute uncomplicated falciparum malaria, we performed an overnight dexamethasone suppression test in 13 Vietnamese adults with acute malaria and 6 healthy controls. After blood samples were taken for serum cortisol and plasma ACTH at 23.00 hours on the admission day, 1 mg dexamethasone was given and further samples were taken at 08.00, 16.00 and 23.00 hours the next day. The patients received conventional antimalarial and supportive treatment. Baseline plasma ACTH concentrations in the patients [3.9 (0.2-41.2) pmol/l] and controls [3.4 (1.1-4.3) pmol/l] were similar (p=0.51), and exhibited a similar fall after dexamethasone to 0.6 (0.2-2.5) and 0.9 (0.7-1.6) pmol/l at 08.00 hours respectively (p<0.03 vs 23.00 hour values). Serum cortisol levels before dexamethasone were higher in the patients than in the controls [456 (102-821) vs 145 (64-183) nmol/l respectively; p=0.007] and the overnight fall was less in the patients [208 (26-340) and 23 (15-46) nmol/l at 08.00 hours respectively; p<0.001 vs 23.00 hour values and between groups]. Between 08.00 and 23.00 hours, plasma ACTH and serum cortisol remained suppressed in the controls. In the patients, the serum cortisol continued to fall progressively towards control values. These data suggest that there is a raised set point for cortisol inhibition of ACTH secretion but normal corticotrophin responsiveness to dexamethasone in uncomplicated malaria. A raised serum cortisol after dexamethasone in the patients might reflect the combination of a prolonged cortisol half-life and the stimulatory effects of cytokines on the adrenal cortex, with a consequent protective effect against complications such as hypoglycemia.     

Anti-NANP antibody and treatment efficacy in patients with acute uncomplicated falciparum malaria attacks

African patients originating from the hypoendemic, urban area of Greater Dakar (Senegal, West Africa) who presented with an acute Plasmodium falciparum infection were studied using an in-vivo chloroquine sensitivity assay for 28 days. Forty-seven patients with acute malaria infections were treated with 25 mg/body weight of chloroquine. Adequate responses to treatment were observed in 24 patients (51%), whereas 23 (49%) were resistant. On the day of admission, these two groups of patients were comparable with respect to age, level of parasitemia and delay before initiation of treatment, but not with respect to gametocyte prevalence which was higher in patients resistant to therapy (48%) than in those who responded to treatment (17%). In order to evaluate whether the therapeutic response was associated with any given specific immune response, antibody activities against different stages of the parasite cycle were evaluated: anti-NANP repeats (i.e. antisporozoite stage antigen), anti-Pfs 45 kDa (i.e. antigametocyte stage antigen), and anti-MSP3 (i.e. antimerozoite stage antigen) antibodies were measured by ELISA at day 0 (i.e. on the day of admission and before initiation of treatment), day 7 and day 28. No significant differences between treatment-sensitive and treatment-resistant infections were observed for antibody prevalences and optical densities, except at day 0, when the prevalence of antibodies against NANP repeats was 2.4 times more frequent in the group of patients with a propitious response to treatment: 62.5% of the patients with an infection sensitive to chloroquine had anti-NANP antibodies, whereas only 26.1% of the patients resistant to chloroquine treatment had such a humoral response. These observations are discussed in relation to (1) the finding that gametocyte prevalence was markedly increased at a time when resistance to antimalarial treatment was observed; (2) the possibility that the efficacy of the therapeutic response could be the result of the combined effects of treatment and the individual immune status of the patients at the time of drug cure; and (3) the presence of detectable anti-NANP activity as potential indicator of the level of premunition acquired in an area of low and seasonal malaria transmission.     

Pharmacokinetics of mefloquine with dihydroartemisinin as 2-day regimens in patients with uncomplicated falciparum malaria

The objective of this study was to investigate the pharmacokinetics of mefloquine (MQ) when given as 750 mg at two different times in combination regimens with dihydroartemisinin (DHA) in patients with acute uncomplicated falciparum malaria. A total of 12 Vietnamese patients (6 in each group) were randomized to receive two MQ-DHA regimens as follows: regimen-A: an initial oral dose of 300 mg DHA, followed by 750 mg MQ and 300 DHA 6 and 24 hours later; regimen-B: an initial dose of 300 mg DHA, followed by 300 mg DHA and 750 mg MQ at 24 hours. Both combination regimens were well tolerated. All patients responded well to treatment with no recrudescence during a 42 day follow-up period. The pharmacokinetics of MQ following both regimens were similar but pooled data from both groups suggest that the kinetics of MQ was different from that observed in Vietnamese healthy subjects reported in a previous study. The median (95% CI) time period for maintenance of whole blood MQ concentrations above 500 ng/ml was 16 (0-24) days. It was concluded that since no pharmacokinetic drug interaction was observed, MQ dose given 24 hours after an initial dose of DHA is a preferable combination treatment regimen with regard to patient compliance.     

Thiamin deficiency and uncomplicated falciparum malaria in Laos

OBJECTIVE: Thiamin deficiency complicates severe Plasmodium falciparum malaria in Thailand and may contribute to acidosis. We therefore estimated the frequency of biochemical thiamin deficiency in patients presenting with uncomplicated falciparum malaria in southern Laos. METHODS: Red cell transketolase activation coefficients (alpha) were measured in 310 patients presenting with uncomplicated falciparum malaria and 42 days after starting treatment. RESULTS: Twelve per cent of patients had biochemical evidence of severe deficiency (alpha values >1.31) at presentation, declining to 3% 42 days later. CONCLUSION: Thiamin deficiency was common in Lao patients admitted with uncomplicated P. falciparum infection and was reduced following treatment of malaria and multivitamin supplementation. The role of this preventable and treatable disorder in malaria and other acute infections, and the incidence of beriberi in rural Laos, needs further investigation.     

Effect of mefloquine on electrocardiographic changes in uncomplicated falciparum malaria patients.

Asymptomatic sinus bradycardia and sinus arrhythmia have been noted in malarial patients receiving mefloquine. The present study was designed to assess the effect of mefloquine on electrocardiogram in malarial patients. The study was carried out in 102 acute uncomplicated falciparum malarial patients who were treated with mefloquine 750 mg and 1,250 mg regimens and 18 healthy male volunteers receiving 750 mg of mefloquine. Electrocardiogram was performed at intervals after mefloquine administration for a period of 42 days. PR, QRS, QT, QTc, RR interval and cardiac arrhythmia were measured and read by EKG-analyser with confirmation by a cardiologist. Sinus bradycardia and sinus arrhythmia were found in 61.8% and 45.1%, respectively during the first week after treatment. The patients' heart rate decreased significantly on day 6 after mefloquine administration when compared to day 0. The occurrence of sinus bradycardia and sinus arrhythmia were significantly higher in malarial patients when compared with findings in healthy subjects of the same age group. It is unlikely that these changes are associated with mefloquine concentration as mefloquine peaks around 12-24 hours after administration. There were no significant changes in PR-interval, QRS-interval and QTc interval on the electrocardiogram. The findings in this study suggest that cardiotoxicity from mefloquine is unlikely. Bradycardia may be the result of autonomic control modulation after resolution of high fever.     

Rapid clearance of Plasmodium falciparum hyperparasitaemia after oral amodiaquine treatment in patients with uncomplicated malaria

Amodiaquine is one of the possible alternative therapeutic options to treat chloroquine-resistant Plasmodium falciparum infections in Africa. In this study, its efficacy to treat patients with acute uncomplicated falciparum malaria and high parasitaemia (> or =5% of infected erythrocytes in the peripheral blood) was assessed by using the standard protocol developed by the World Health Organization. The mean pre-treatment parasitaemia was 10.8% (range, 5.0-35%). All 32 patients who completed the study (four lost to follow-up) had an adequate clinical and parasitological response on day 14. As compared with the pre-treatment parasitaemia, the mean parasitaemia decreased by 97.8% on day 2 (two patients with negative smears) and 99.97% on day 3 (22 patients with negative smears; the other ten patients had low residual parasitaemia ranging from 24 to 400 asexual parasites/microl). Our results suggest that, in areas of stable transmission in Africa, hyperparasitaemic patients with uncomplicated malaria can be safely treated with oral amodiaquine provided that their clinical and parasitological responses are closely monitored for the first 3 days and controlled on day 7 and 14.     

Relationship of hepcidin with parasitemia and anemia among patients with uncomplicated Plasmodium falciparum malaria in Ghana

The pathogenesis of malarial anemia is incompletely understood. Hepcidin, a recently discovered peptide hormone, is a major regulator of iron metabolism and is thought to play a central role in the anemia of chronic inflammation. The specific aim of the study was to characterize the association between urinary hepcidin, hemoglobin, and parasitemia in 199 patients presenting for evaluation of Plasmodium falciparum malaria in Ghana. Urinary hepcidin was semi-quantitatively assessed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Urinary hepcidin (intensity/mmol creatinine) was associated with log parasitemia in 86 children (beta = 0.086, standard error [SE] = 0.035, P < 0.017), 31 pregnant women (beta = 0.218, SE = 0.085, P < 0.016), and 82 adults (beta = 0.184, SE =0.043, P < 0.0001). Urinary hepcidin was not significantly associated with hemoglobin or anemia. Urinary hepcidin is more strongly associated with parasitemia than hemoglobin or anemia among patients with acute P. falciparum malaria in Ghana.     

Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria

The synergistic antifolate combination of chlorproguanil with dapsone (CPG-DDS; LAPDAP) is being developed by a public-private partnership as a low-cost treatment for uncomplicated falciparum malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this. A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency and African licencing authorities. The team working on LAPDAP has also started to develop the triple combination of chlorproguanil-dapsone-artesunate (CDA) as a low-cost combination therapy for uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and development of CDA is at an early stage), the development team is keen to communicate with public health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated public health issues.     

Antibodies against malaria sporozoites in patients with acute uncomplicated malaria and patients with cerebral malaria

Serum samples from 95 patients with acute uncomplicated falciparum malaria (AM) and 95 patients with cerebral malaria (CM) were tested by the indirect immunofluorescent assay (IFA) for IgG and IgM antibodies against Plasmodium falciparum and P. vivax sporozoites. Forty-six (48%) CM patients were positive for antibodies against P. falciparum sporozoites whereas only 23 (24%) were positive for antibodies against P. vivax sporozoites (P less than 0.002). A similar result was obtained in AM patients. However, CM patients had significantly lower mean IgG anti-sporozoite titer for P. falciparum than did AM patients (P less than 0.05), especially when only anti-sporozoite antibody-positive CM and AM patients were compared (P less than 0.0005), suggesting that CM patients had relatively less exposure and were probably less immune to malaria than were AM patients. The persistence of anti-sporozoite antibodies also was investigated in paired sera taken 63 days apart from 108 patients with acute falciparum malaria. There were significant decreases in the mean antibody titers in the follow-up sera during the period of stay in the malaria-free area. It was proposed that determination of anti-sporozoite antibody be made as a substitute for, or in addition to, anti-blood stage antibody for seroepidemiological study of malaria, especially in the monitoring of the success of the malaria control program.     

Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon

BACKGROUND: The development of novel artemisinin-combination therapies suitable for the treatment of pediatric patients suffering from malaria is a research priority. The aim of this study was to investigate a novel fixed-dose pyronaridine-artesunate combination for the treatment of uncomplicated falciparum malaria in Gabonese patients 2-14 years old. METHODS: The study was designed as an open-label dose-escalation study recruiting 60 pediatric patients sequentially in 4 treatment cohorts: study drugs were administered once daily for 3 days, as tablet coformulations (pyronaridine:artesunate ratios of 6:2, 9:3, and 12:4 mg/kg) and as a granule coformulation (pyronaridine:artesunate ratio of 9:3 mg/kg). The primary end points were tolerability, safety, and pharmacokinetics of pyronaridine-artesunate treatment. Efficacy was treated as a secondary outcome measure. RESULTS: The drugs had a good tolerability and safety profile, at all dose levels. Pharmacokinetic analysis revealed a dose-dependent increase in the maximum plasma/blood concentration and the area under the curve, as well as comparable relative bioavailability for the granule coformulation. Polymerase chain reaction-corrected cure rates at day 28 were 100% in per-protocol analysis, at all dose levels. CONCLUSIONS: Pyronaridine-artesunate is a promising novel artemisinin-combination therapy for pediatric patients with uncomplicated Plasmodium falciparum malaria, and the development of both the tablet and the granule coformulations is warranted.     

Short report: effects of pyronaridine on gametocytes in patients with acute uncomplicated falciparum malaria.

The effects of pyronaridine and chloroquine on mature Plasmodium falciparum gametocytes were compared in 161 patients treated with chloroquine or pyronaridine. Neither pyronaridine nor chloroquine showed gametocytocidal activity. The relative risks of post-treatment gametocytemia after pyronaridine and chloroquine treatment in the presence of chloroquine-resistant isolates were 1.25 and 11.5, respectively, suggesting that the use of chloroquine was associated with a high risk of favoring post-therapeutic gametocytemia in chloroquine-resistant infections.     

Changes in platelet count in uncomplicated and severe falciparum malaria

This study investigated alterations in platelet counts pre- and post-treatment with artemisinin derivatives in uncomplicated and severe falciparum malaria. Serial platelet counts were taken over 4 weeks for 110 uncomplicated and 110 severe falciparum malaria patients admitted to the Hospital for Tropical Diseases during 2005-2008. On admission, prior to treatment, thrombocytopenia was found in 73.6% of uncomplicated falciparum malaria patients and 90.9% of severe falciparum malaria cases. Platelet levels significantly lower in severe malaria cases. Although initial platelet counts were lower than normal in both study groups, they slowly increased significantly over time, and approached normal levels by several weeks post-treatment. No bleeding was evident during treatment, and none of the patients required a platelet transfusion. Platelet transfusions are not required for malaria patients with thrombocytopenia who have no bleeding.     

Quinine pharmacokinetics and toxicity in cerebral and uncomplicated falciparum malaria

Acute pharmacokinetics of intravenously infused quinine were studied in 25 patients with cerebral malaria and 13 with uncomplicated falciparum malaria. In patients with cerebral malaria receiving the standard dose of 10 mg/kg every eight hours, plasma quinine concentrations consistently exceeded 10 mg/liter, reaching a peak 60 ± 25 hours (mean ± 1 S.D.) after treatment was begun and then declining. Quinine total clearances (CI) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (CI, 0.92 ± 0.42 compared with 1.35 ± 0.6 ml/min/kg, p = 0.03; Vd, 1.18 ± 0.37 compared with 1.67 ± 0.34 liter/kg, p = 0.0013). There was no significant difference between the two groups in elimination half-times (t/2) or renal clearances (C_u) (t/2, 18.2 ± 9.7 compared with 16 ± 7.0 hours; C_u, 0.21 ± 0.16 compared with 0.21 ± 0.08 ml/min/kg). In nine patients studied following recovery, CI (3.09 ± 1.18 ml/min), Vd (2.74 ± 0.47 liter/kg), and C_u (0.53 ± 0.22 ml/min/kg) were significantly greater (p < 0.0004), and t/2 was significantly shorter (11.1 ± 4.1 hours, p = 0.006) than during the acute illness. C_u accounted for approximately 20 percent of CI in all groups. Renal failure did not alter the disposition kinetics in cerebral malaria. There was no clinical or electrocardiographic evidence of cardiotoxicity and no permanent neurotoxicity. Quinine toxicity in cerebral malaria has probably been overemphasized. The benefits of high plasma concentrations in the acute phase of this life-threatening disease appear to outweigh the risks, particularly in view of the increasing resistance of Plasmodium falciparum to quinine in Southeast Asia.     

Serum procalcitonin in uncomplicated falciparum malaria: a preliminary study

BACKGROUND: Procalcitonin (PCT) has been found elevated in complicated forms of Plasmodium falciparum malaria. Its usefulness has almost never been assessed in uncomplicated falciparum malaria. METHOD: We assessed diagnostic and prognostic value of PCT in a prospective series of 25 adults with uncomplicated P. falciparum malaria. Patients originated mainly from western Africa and were infected during a stay back in their native country (19 semi-immune and 6 non-immune subjects; 11 had not received any chemoprophylaxis). RESULTS: Parasitaemia ranged from 0.01 to 3%. Eighteen patients had their first PCT determined at admission or within 24h thereafter (mean +/- SD: 3.0 +/- 4.6 ng/ml; range: 0.1-19.7). PCT was higher than 0.5 ng/ml in 14 patients (78%), higher than 2 ng/ml in 7 (39%). PCT correlated with parasitaemia (r = 0.53; p = 0.027), not with C-reactive protein (CRP). Delay between first symptoms and diagnosis was much longer among patients with PCT higher than 2 ng/ml than among those with a lower PCT. CONCLUSION: PCT was often elevated in uncomplicated malaria, especially when delay between first symptoms and diagnosis was long or parasitaemia was high (prognostic marker).     

Oral clindamycin in the treatment of acute uncomplicated falciparum malaria

Clinical trials on oral clindamycin as an antimalarial in hospitalized patients and residents of endemic communities were conducted in the Philippines between May 1984 and December 1985. Seven and 9 qualified subjects in hospital were treated with 300 mg (regimen A) and 600 mg (regimen B) respectively, twice daily for 5 days. Eighteen patients seen at a rural health unit were given the lower dosage. On the basis of the 28-day extended in vivo test of WHO, P. falciparum in all but one patient showed susceptibility to the drug as a blood schizontocide hence, the clinical cure of malaria. Side effects were few and self-limiting. Ten other patients on regimen A were cured within the 7- and/or 28-day extended test period. Clindamycin per se is currently one of the few alternatives in the treatment of clinically moderate drug-resistant malaria.     

High-dose dexamethasone in quinine-treated patients with cerebral malaria: a double-blind, placebo-controlled trial

We compared placebo and dexamethasone (initial dose, 3 mg/kg; total, 11.4 mg/kg per 48 h) in a double-blind trial involving 10 stuporous and 28 comatose patients with cerebral malaria. Patients were 18 mo to 42 y of age (geometric mean, 10.2 y), and the 19 patients in each group were comparable on admission. All patients received intravenous quinine therapy. Four patients (21%) in each group died. There were no significant differences between the placebo- and dexamethasone-treated groups in time until patients became afebrile (median, 51 vs. 19 h), the level of consciousness became normal (mean, 80 vs. 83 h), or parasitemia was cleared (mean, 2.1 vs. 3.4 d) or in the incidence of complications. Coma or hyperparasitemia (greater than or equal to 5% of erythrocytes parasitized) at the time of admission and hypoglycemia at any time during hospitalization were significantly correlated with a fatal outcome, which was not improved by using dexamethasone. We conclude that high-dose dexamethasone is not indicated for treating cerebral malaria.     

Alanine metabolism in acute falciparum malaria

We investigated the integrity of the gluconeogenic pathway in severe malaria using alanine metabolism as a measure. Alanine disposition and liver blood flow, assessed by indocyanine green (ICG) clearance, were measured simultaneously in 10 patients with falciparum malaria (six severe and four moderately severe malaria). After intravenous infusion of alanine (0.3 g/kg), glucose increments (AUC0-55 min) were lower in patients with severe malaria than in those with moderately severe malaria (median = 508 vs. 808 mmol/min/l; P = 0.055). There were no significant differences in the other metabolite increments (alanine, lactate and pyruvate; P >/= 0.27). The two fatal cases had markedly delayed alanine removal (larger AUC0-55 min), prolonged T(1/2) and slower clearance (P /= 0.07) but the increments of lactate and pyruvate were lower in convalescence. Thus, the ratio of the increments of alanine to those of lactate and pyruvate were significantly higher in the convalescent study (P 相似文献   

Pyrimethamine-sulfadoxine treatment of uncomplicated Plasmodium falciparum malaria in Lao PDR

A 28-day in vivo treatment trial to evaluate the efficacy of pyrimethamine/sulfadoxine (Fansidar, PS) was conducted in 21 Lao patients with uncomplicated Plasmodium falciparum malaria. Sixteen patients (76%) were completely cured with PS without any reappearance of asexual stage parasitemia during the follow-up examination. On the other hand, 5 patients (24%) failed to respond to this trial medication, resulting in recrudescence of asexual stage P. falciparum malaria. PS resistance resulted in higher prevalence of post-treatment gametocytemia, 25% gametocyte carriers among PS sensitive cases versus 75% of the resistant cases. These findings suggest that although the level of PS resistance is still valid for treatment of malaria in the study area of Lao PDR, post-treatment induction of gametocytemia among resistant cases may result an increase in transmission rate of PS resistant falciparum malaria.     

Emergence and clearance of gametocytes in uncomplicated Plasmodium falciparum malaria

We reviewed the records of 1,175 patients with uncomplicated Plasmodium falciparum malaria to determine the prevalence of gametocytemia. All patients were admitted and received artemisinin combination therapy. Blood films were checked daily until discharge. Circulating gametocytes were observed in 240 (20.2%) of patients and in most cases (222 of 240, 92.5%) gametocytemia was detected during the first 24 hours after admission. Gametocytes were first seen in 174 cases on admission, in 24 cases at 12 hours, and in 24 cases at 24 hours. The longest interval between admission and first appearance of gametocytes was 192 hours. The median gametocyte clearance time was 163 hours (range = 12-806) in the 219 patients in whom gametocytemia resolved. However, 21 patients (9.8%) still had gametocytemia on discharge. Gametocytemia generally is present within the first 24 hours after admission, and emerges in only 1.9% of patients later on during treatment with artemisinin.