Pharmacokinetics of high-dose oseltamivir in healthy volunteers.

The effects of loading doses and probenecid coadministration on oseltamivir pharmacokinetics at four increasing dose levels in groups of eight healthy adult Thai volunteers (125 individual series) were evaluated. Doses of up to 675 mg were well-tolerated. The pharmacokinetics were dose linear. Oseltamivir phosphate (OS) was rapidly and completely absorbed and converted (median conversion level, 93%) to the active carboxylate metabolite. Median elimination half-lives (and 95% confidence intervals [CI]) were 1.0 h (0.9 to 1.1 h) for OS and 5.1 h (4.7 to 5.7 h) for oseltamivir carboxylate (OC). One subject repeatedly showed markedly reduced OS-to-OC conversion, indicating constitutionally impaired carboxylesterase activity. The coadministration of probenecid resulted in a mean contraction in the apparent volume of distribution of OC of 40% (95% CI, 37 to 44%) and a reduction in the renal elimination of OC of 61% (95% CI, 58 to 62%), thereby increasing the median area under the concentration-time curve (AUC) for OC by 154% (range, 71 to 278%). The AUC increase for OC in saliva was approximately three times less than the AUC increase for OC in plasma. A loading dose 1.25 times the maintenance dose should be given for severe influenza pneumonia. Probenecid coadministration may allow considerable dose saving for oseltamivir, but more information on OC penetration into respiratory secretions is needed to devise appropriate dose regimens.

The use of the multi-organ-dysfunction score to discriminate different levels of severity in severe and complicated Plasmodium falciparum malaria.

Clinical presentation of Plasmodium falciparum malaria reflects a continuum from asymptomatic to multi-organ manifestation and death. Severe malaria is defined by the World Health Organization as a qualitative variable. We used the multi-organ dysfunction score (MODS) as a quantitative approach for severity in 29 patients with severe and complicated P. falciparum malaria to test its usefulness in discriminating different severity levels. The MODS on admission was highly correlated with the duration of symptoms after admission (r = 0.73, P < 0.001) and the serum level of tumor necrosis factor alpha (r = 0.41, P = 0.03). In addition, the simplified MODS, based mainly on clinical findings, was also correlated with liver and renal dysfunction during hospitalization (alanine transaminase, r = 0.42, P = 0.02; blood urea nitrogen, r = 0.45, P = 0.015). A score >or= 16 was associated with significantly longer disease duration (P = 0.018). Thus, this score might provide a predictive value for morbidity in P. falciparum malaria.

An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria.

The combination of artesunate and mefloquine is currently one of the most effective treatments for multidrug-resistant Plasmodium falciparum malaria. Simultaneous, rather than sequential treatment with the two drugs, would allow better patient compliance. We therefore evaluated three-day treatment with artesunate combined with either 2 or 3 days of mefloquine co-administered once a day with artesunate. The study was an open, randomized trial for acute, uncomplicated falciparum malaria and was conducted at the Bangkok Hospital for Tropical Diseases. One hundred and twenty adult patients were randomized to two treatment groups. Group 1 patients received 4 mg/kg/day of artesunate for 3 days and 3 daily doses of 8.0 mg/kg/day mefloquine given with artesunate. Group 2 patients received the same dose of artesunate and the same total dose of mefloquine (25 mg/kg). However, the mefloquine was given as 15 mg/kg on the first day and 10 mg/kg/ on the second day, again with artesunate. The baseline demographic and clinical characteristics of the patients in the two groups were similar. The cure rates for the 3-day and 2-day mefloquine regimens were 100% and 99%, respectively. There were no significant differences in either median fever clearance times (group 1=32 hours; group 2=33 hours) or mean parasite clearance times (group 1=42.3 hours; group 2=43.3 hours). Both regimens were well tolerated and there were no significant differences in the incidence of adverse effects. Nausea or vomiting occurred in 3.8% of patients in both groups and transient dizziness occurred in 4% of group 1 and 9% of group 2 patients. These results suggest that a 3-day regimen of mefloquine administered with artesunate is effective and well tolerated. This practical regimen could improve patient compliance.

An open randomized clinical trial of Artekin vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria.

Malaria remains a major cause of morbidity and mortality in tropical countries and subtropical regions in the world. Southeast Asia has the most resistant malaria parasites in the world, which has limited treatment options in this region. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The combination of dihydroartemisinin (DHA) and piperaquine (PQP) in the form of Artekin has been developed as an alternative to established combinations, such as artesunate-mefloquine, primarily to reduce treatment costs and toxicity. We conducted a study comparing a standard treatment for acute uncomplicated falciparum malaria (artesunate 4 mg/kg/day together with mefloquine 8 mg/kg/day oral route once a day for 3 days) (Group A) and a combination of dihydroartemisinin 40 mg and piperaquine 320 mg in the form of Artekin given once a day for 3 days (Group B) to determine safety, efficacy, and tolerability. One hundred and eighty patients were randomly enrolled at the ratio of 1:2 into groups A:B. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time or parasite clearance time between both groups. The 28-day cure rates were high, at 100% and 99%, in groups A and B, respectively. We conclude that Artekin was as effective and well-tolerated as artesunate-mefloquine, and can be used alternatively as the current treatment for multidrug-resistant P. falciparum malaria.

Case-control studies on host factors in severe malaria.

Although molecular biology has illustrated the phenotypic heterogeneity of Plasmodium falciparum, there are still no specific markers of virulence. As parasite virulence is an important determinant of severe malaria, the choice of comparison groups in the study of host factors influencing severity is a delicate issue. Ignoring parasite factors in the selection of controls potentially leads to biased comparisons between a majority of cases with virulent parasites and a majority of controls with non-virulent parasites. This article discusses how to avoid this virulence bias in the absence of specific markers of virulence.

Association of hepatomegaly and jaundice with acute renal failure but not with cerebral malaria in severe falciparum malaria in Thailand.

We conducted a case record study comparing liver tests abnormalities in 20 malaria-related acute renal failure cases without cerebral malaria, 52 cerebral malaria cases without other organ impairment, 189 cases of nonsevere malaria associated with a high parasite burden, and 131 cases of mild Plasmodiumfalciparum malaria. Jaundice and hepatomegaly were significantly associated with renal failure (adjusted odds ratio [AOR], 3.3, 95% confidence interval [CI], 1.3-8.6, P = 0.01; and AOR, 1.7 95% CI, 1.13-2.4, P = 0.01) but not with cerebral malaria (AOR, 1, 95% CI, 0.5-2, P = 0.8; and AOR, 1.08, 95% CI, 0.8-1.8, P = 0.5). Patients with acute renal failure were significantly older and had increased liver abnormalities compared with other groups. Although an increase in the proportion of mature schizonts over ring forms was significantly associated with cerebral malaria, it did not seem to have affected acute renal failure. These results suggested that cytoadherence was not the main determinant for renal failure and that jaundice itself may have potentiated the effects of hypovolemia.

Helminth infections are associated with protection from malaria-related acute renal failure and jaundice in Thailand.

Following studies showing an association between helminth infections and protection from cerebral malaria, we compared 22 patients with malaria-associated acute renal failure with 157 patients with moderately severe malaria. Helminths were associated with protection from renal failure (adjusted odds ratio [AOR], 0.16 [0.03-0.85], P = 0.03). Helminth-infected controls were less likely to have jaundice (AOR, 0.39 [0.16-0.96], P = 0.04) or to have peripheral mature schizonts (AOR, 0.2 [0.07-0.62], P = 0.005) than controls without helminths. This suggested that preexisting helminth infections may have been protective by influencing sequestration and obstructive jaundice, 2 possible determinants of acute tubular necrosis.

Association of helminth infection with decreased reticulocyte counts and hemoglobin concentration in Thai falciparum malaria.

Following a study showing an association between Ascaris and protection from cerebral malaria, we conducted a cross-sectional study comparing admission hemoglobin concentrations in relation to exposure to helminth infection in 2 separate groups of patients: 111 cerebral malaria cases and 180 mild Plasmodium falciparum malaria cases. Hookworm infections were excluded. Mean hemoglobin concentrations were significantly lower in helminth-infected patients compared to those without helminths, both in the cerebral malaria group (10.1+/-3 [n = 47] versus 11.2+/-2.4 g/dl [n = 64], P = 0.04) and the mild malaria group (11+/-2.5 [n = 89] vs 12.2+/-2.7 g/dl [n = 91], P = 0.004). Median reticulocyte counts, only available in the cerebral malaria group, were lower in helminth-infected patients compared to those without helminths (15,340/23,760 per microl, P = 0.03). Adjustments for confounders such as body mass index did not alter these associations. These data are consistent with a mechanism causing anemia linked to differences in the immune response of helminth-infected patients during malaria.

Association of helminth infections with increased gametocyte carriage during mild falciparum malaria in Thailand.

The objective of this study was to determine whether pre-existing helminth infections could affect sexual forms of Plasmodium falciparum. A cross-sectional case record study compared 120 mild P. falciparum malaria cases with patent gametocyte carriage and 187 without gametocytes for helminth exposure. Relevant crude odds ratios and potential confounders were included in a logistic regression model. Helminth infections were associated with the presence of gametocytes with a crude odds ratio of 1.9 (95% confidence interval = 1.1-3.3) (P = 0.01). A positive linear trend was observed between the odds of having patent gametocytemia and the number of different helminth species (P = 0.003). However, when adjusting for hemoglobin concentration the significance of the association between helminths and gametocytes disappeared (P = 0.15). Pre-existing helminth infections may increase the severity of malarial anemia and therefore increase the likelihood of carrying gametocytes. At a population level, helminth infections may thus have a significant influence on malaria transmission.

Artesunate and mefloquine given simultaneously for three days via a prepacked blister is equally effective and tolerated as a standard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand.

The combination of artesunate and mefloquine is currently one of the most effective treatments against multidrug-resistant Plasmodium falciparum malaria. To improve patient compliance to such a combination, the two agents have been combined in a prepacked single blister. Patients were instructed to simultaneously co-administer the drugs once a day for three days. In the present randomized, double-blind, parallel group, comparative, single center study in Thailand, this concept was investigated in 204 adults and children with acute, uncomplicated P. falciparum malaria. Patients were randomized into two treatment groups and received once a day over a three-day period the following: Group A received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, approximately 8.5 mg/kg/day, simultaneously. Group B received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, sequentially (i.e., no mefloquine dose on the first day, 15 mg/kg on the second day, and 10 mg/kg on the third day). Both treatment groups showed no relevant differences in baseline demographic and clinical characteristics. Intent-to-treat analysis revealed a cure rate at day 28 (primary endpoint) of 100% in group A and 99% in group B (difference not significant). The secondary endpoints of mean time to fever clearance (group A = 34 hours, group B = 31 hours) and mean time to parasite clearance (group A = 44 hours group B = 48 hours) were similar between groups (both differences not significant). Tolerability was good in both treatment groups, with no difference in the overall incidence of adverse events. There was a low incidence of nausea/vomiting (4.9% in both groups) and central nervous system side effects (4.9% in group A versus 8.8% in group B). These were comparable between groups and generally of a mild nature. The three-day combination of artesunate and mefloquine (Artequin, Mepha, Ltd., Aesch, Switzerland) with the introduction of mefloquine on day 1 offers a practical dosing regimen that is highly effective and well tolerated in patients of different ages with uncomplicated P. falciparum malaria. It is likely that the prepacked blister approach translates clinically into a better patient compliance, thereby contributing to limit the development of drug resistance.

A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand.

The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (> or = 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] = 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI = 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria.

Use of the multi-organ dysfunction score as a tool to discriminate different levels of severity in uncomplicated Plasmodium falciparum malaria.

The usual criteria for severe malaria are not always sufficient to identify patients who subsequently develop this disease. The multi-organ dysfunction score (MODS) was assessed in 22 patients with uncomplicated Plasmodium falciparum malaria to test its usefulness in discriminating different severity levels. The MODS on admission was highly correlated with the baseline concentration of tumor necrosis factor--alpha (r = 0.83, P < 0.001) and the duration of symptoms after admission (r = 0.54, P = 0.01). The MODS was also correlated with parasite count (r = 0.52, P = 0.014), parasite clearance time (r = 0.54, P = 0.009), and fever clearance time (r = 0.58, P = 0.005). The above correlations remained significant after controlling for the initial parasitemia (P = 0.03 and 0.005). The MODS is simple and easy to apply and needs a recording time of less than three minutes. Thus, this score might provide a quantitative approach for determining severity in Plasmodium falciparum malaria.

Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand.

To define the current efficacy of Fansidar (F. Hoffmann-La Roche Ltd., Basel Switzerland) (pyrimethamine and sulfadoxine), primaquine in a high dose, and artesunate for treating acute Plasmodium vivax malaria, we conducted a comparative clinical trial of these 3 drugs in an open-label study. Patients (15-65 years old) were assigned to 1 of 4 treatments regimens in a serial order. Ninety percent of the patients were infected at Thailand-Myanmar border. Patients in group I (n = 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day), group II (n = 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day) and then received primaquine (30 mg a day for 14 days), group III (n = 23) received primaquine (30 mg a day for 14 days), and group IV (n = 23) received artesunate (200 mg once a day for 3 days) and then primaquine (30 mg a day for 14 days). Cure rates on day 28 of follow-up were 40%, 100%, 100%, and 100% in groups I, II, II, and IV, respectively. There were 4 and 5 patients in group I showing post-treatment reappearance of parasitemia at < or = 16 days and between 17 and 28 days, respectively. Patients in the other 3 groups showed negative parasitemias within 7 days after treatment. Artesunate plus primaquine (group IV) cleared parasitemia faster than the other 3 regimens. There is a high proportion of ineffectiveness of Fansidar for treatment of P. vivax malaria and it should be no longer used for treatment of P. vivax malaria acquired at the Thailand-Myanmar border. A high dose of primaquine is safe and effective in the treatment of P. vivax malaria during the 28-day follow-up period.

Clinical trial of sequential treatments of moderately severe and severe malaria with dihydroartemisinin suppository followed by mefloquine in Thailand.

One hundred and fifty patients with severe falciparum malaria were administered sequential combination of dihydroartemisinin suppository followed by an oral mefloquine tablet. Dihydroartemisinin suppositories (80 mg/capsule) were given rectally once daily for 3 days with a total dose of 8-10 mg/kg. Two doses of mefloquine, 15 mg/kg/dose and 10 mg/kg/dose, were given at 72 hr and 84 hr, respectively. The mean [SD] parasite clearance time and fever clearance time were 46.1 [15.7] hr and 82.5 [59.6] hr, respectively. No death or major adverse drug effects occurred. The cure rate at 28 days of inpatient follow-up was 95% (113 of 119 patients). In severe malaria, dihydroartemisinin suppository followed by oral mefloquine is a suitable alternative treatment to parenteral drugs.

Massive pulmonary cryptococcosis in an immunocompetent patient.

A 64-year-old man presented with progressive dyspnea. The symptom of severe hypoxia requiring mechanical ventilator, and bilateral pulmonary infiltrates on the chest film led to the clinical diagnosis of adult respiratory distress syndrome. Autopsy demonstrated widespread cryptococci and mucinous material in alveoli with mild inflammatory response.

Frequency of early rising parasitemia in falciparum malaria treated with artemisinin derivatives.

To define the frequency of the early rising of parasitemia in falciparum malaria patients treated with artemisinin derivatives, a retrospective chart review of 497 patients admitted to the Hospital for Tropical Diseases, Bangkok in 1996 was carried out. Early rising parasitemia, defined as an increase in the parasite count over the baseline pretreatment level during the first 24 hours of treatment, was found in 59/229 episodes (25.8%) of uncomplicated, and 111/268 episodes (41.3%) of complicated falciparum malaria. All uncomplicated cases were successfully treated without developing any complications. There were 2 deaths and 13 changes of drug regimen in the complicated group. Only one of these unfavorable responses was due to parasite response. Early rising parasitemia was very common in falciparum malaria treated with artemisinin derivatives, despite their ability to clear the parasitemia, and did not indicate failure of the drug used.

Plasmodium vivax malaria in Southeast Iran in 1999-2001: establishing the response to chloroquine in vitro and in vivo.

Chloroquine-resistant Plasmodium vivax is emerging in Oceania, Asia and Latin America. The drug sensitivity of P. vivax to chloroquine both in vivo and in vitro in the southern part of Iran was assessed; chloroquine-resistant Plasmodium falciparum has already been documented in this area. The in vitro sensitivity of 39 P. vivax isolates was assessed: the mean IC50 and IC90 were 189 ng/ml and 698 ng/ml blood respectively; for in vivo testing, all 39 vivax malaria patients were treated with a standard regimen of chloroquine and followed-up at 28 days: the mean parasite clearance time was 67.2 +/- 22.5 hours. The in vitro development of young parasites to mature schizonts in standard test medium was compared with that obtained in McCoy's 5A medium: no significant difference was observed. Synchronization of the blood-stage parasites was performed according to Lambros' method: the method was not suitable because it was detrimental to the parasites. A number of in vitro tests were performed using both our own laboratory-predosed microplates and WHO microplates: there was no significant difference between the results.

An open randomized clinical trial of Artecom vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand.

The efficacy and safety of Artecom were assessed in an open randomized trial in adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand. Three hundred and fifty-two patients were randomly enroled at the ratio of 2:1 into group A:B and received Artecom (group A) and the standard combination of artesunate and mefloquine (group B) respectively. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time and parasite clearance time between the two groups. The 28-day cure rates were high as 97% in both groups. Artecom was effective and well-tolerated as artesunate-mefloquine, the current treatment in this area of multidrug-resistant P. falciparum malaria.

A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand.

Recently, a combination of artesunate and mefloquine has proved effective, although is contraindicated in early pregnancy and young children. Azithromycin, a widely used antibiotic and has antimalarial effects, replace mefloquine as a new alternative antimalarial regimen. Two hundred and two uncomplicated falciparum malaria patients were randomly assigned to 1 of 3 regimens. Patients in group I (n = 68) received artesunate 200 mg once daily for 3 days, group II (n = 67) received artesunate 200 mg together with mefloquine 10 mg/kg on the first 2 days and artesunate 200 mg together with mefloquine 5 mg/kg on the third day, and group III (n = 67) received artesunate 200 mg together with azithromycin 50 mg once daily for 3 days. The 28 day cure rates were 44, 98 and 56%, respectively. The median time to recrudescence was significantly longer in group III. In conclusion, a combination of artesunate and azithromycin might be useful in treating children in whom bacterial and malarial infections may be concomitant. However, further work is required in order to enhance its clinical efficacy.

Is there any artemisinin resistance in falciparum malaria?

We reported two cases of complicated falciparum malaria who had poor response to artesunate with delayed parasite clearance times. They were splenectomized patients who were treated with high doses of artemisinin derivatives. Our cases showed the importance of the spleen in the clearance of malaria parasites and had different clinical outcome, one fatal and one recovery. The host factors, the parasitemia count, the quality of antimalarial chemotherapy and blood level of the antimalarial drugs must be considered in relation to the causes of the delayed clearance of parasitemia.