Ballou, W.R., J. Blood, T. Chongsuphajaisiddhi, D.M. Gordon, D.G. Heppner, D.E. Kyle, C. Luxemburger, F. Nosten, J.C. Sadoff, and P. Singhasivanon, Field trials of an asexual blood stage malaria vaccine: studies of the synthetic peptide polymer SPf66 in Thailand and the analytic plan for a phase IIb efficacy study. Parasitology, 1995. 110(Suppl): p. S25-36. [PubMed Link]
Several years ago the Walter Reed Army Institute of Research (WRAIR) initiated an independent analysis of the candidate malaria blood stage vaccine SPf66. WRAIR contracted for the synthesis and formulation of SPf66 in United States Food and Drug Administration (FDA) inspected laboratories within the U.S., and in 1992, filed an Investigational New Drug (IND) application with the FDA. Preclinical studies indicated that the vaccine could be synthesized to meet its release specifications, and when adjuvanted with alum, was essentially equivalent to Colombian produced SPf66 in regards to immunogenicity in preclinical studies of rodents and primates, and in human volunteers in Phase I studies. The goal of these efforts was ultimately to conduct a Phase IIb field trial to determine the safety and efficacy of SPf66 produced under current Good Manufacturing Practices (cGMP). Such a trial is currently underway in a malaria endemic refugee camp along the Thai-Burmese border. Here we briefly describe the study and present the formal analytic plan that was submitted to regulatory authorities in the United States for analysis of the study results. We believe such independent confirmatory studies are an essential part of the vaccine development process and are required to provide important data regarding the safety and efficacy of candidate vaccines in diverse geographical regions, and as a means to assess their role in the context of broader malaria control programmes.

Luxemburger, C., F. Nosten, S.D. Raimond, T. Chongsuphajaisiddhi, and N.J. White, Oral artesunate in the treatment of uncomplicated hyperparasitemic falciparum malaria. American Journal of Tropical Medicine and Hygiene, 1995. 53(5): p. 522-5. [PubMed Link]
Patients with uncomplicated hyperparasitemic falciparum malaria are usually given parenteral antimalarial treatment to prevent a progression to vital organ dysfunction and death. Since the oral artemisinin derivatives are more rapidly effective than other antimalarial drugs, we compared oral artesunate (4 mg/kg/day for three days with mefloquine 25 mg/kg on the second day) with an intravenous quinine loading dose (20 mg of salt/kg initially then 10 mg/kg every 8 hr, followed by mefloquine 25 mg/kg) in an open paired randomized trial in 60 patients with acute falciparum malaria and greater than 4% parasitemia, but no evidence of vital organ dysfunction. There were no deaths and none of the patients progressed to develop severe malaria. Oral artesunate treatment resulted in shorter median [range] times to fever clearance (19 hr [4-45] versus 47 hr [4-107]) (P < 0.0001), parasite clearance (36 hr [18-61] versus 82 hr [36-104]) (P < 0.0001), and discharge from the hospital (25 hr [12-44] versus 58 hr [24-115]) (P < 0.0001). There was no toxicity attributable to artesunate. The cure rates by day 28 were 70% (19 of 27) and 39% (11 of 27) in the artesunate and quinine groups, respectively (relative risk = 1.7; 95% confidence interval = 1.0-3.0). Oral artesunate was simpler, cheaper, safer, and more effective than intravenous quinine for the treatment of uncomplicated hyperparasitemia.

McGready, R. and F. Nosten, Falciparum malaria in pregnancy. Australia and New Zealand Journal of Obstetrics and Gynaecology, 1995. 35(4): p. 468-9.[PubMed Link]

Nosten, F. and R.N. Price, New antimalarials. A risk-benefit analysis. Drug Safety, 1995. 12(4): p. 264-73. [PubMed Link]
Although more than 40% of the world's population live in malaria endemic areas, there are only 6 available antimalarial drugs for the treatment of Plasmodium falciparum infections. Three of these have been developed in the last 20 years and are discussed in this review. Mefloquine is relatively well tolerated and has the advantage of a single day regimen. It has ideal properties for prophylactic use. However, although rare, serious adverse reactions do occur and the drug cannot be used in severe malaria. Resistance has already emerged in some parts of the world. Halofantrine is also well tolerated and has a rapid antimalarial activity. It is more expensive than other antimalarials and the existence of cross-resistance links its usefulness to the demise of mefloquine. The discovery of a potentially lethal cardiotoxicity associated with halofantrine casts a further shadow over its use. The artemisinin derivatives represent an exciting breakthrough in the treatment of malaria. They are cheap and have a very rapid action. They seem remarkably free from toxic adverse effects, although the neurotoxicity seen in animal studies with the liposoluble derivatives gives rise for concern. However, the lack of pharmacokinetic and toxicity data as yet preclude their approval by Western drug regulation authorities. All antimalarials are threatened by the emergence of parasite resistance. Combination therapy using mefloquine and an artemisinin derivative may provide a way in which resistance can be combated.

Pied, S., M.D. Tabone, G. Chatellier, M. Marussig, C. Jardel, F. Nosten, and D. Mazier, Non specific resistance against malaria pre-erythrocytic stages: involvement of acute phase proteins. Parasite, 1995. 2(3): p. 263-8.[PubMed Link]
Levels of different acute phase proteins were compared in sera from parasitaemic and non-parasitaemic women living in a Plasmodium falciparum endemic area of Thailand. The ability of their sera to interfere with hepatic stage development of the parasite was examined. Correlations were found between levels of alpha-1 antitrypsin, alpha-2 macroglobulin, hemopexin and the potential of sera to block hepatocyte invasion by the sporozoite.

Price, R.N., F. Nosten, C. Luxemburger, A. Kham, A. Brockman, T. Chongsuphajaisiddhi, and N.J. White, Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995. 89(5): p. 523-7.[PubMed Link]
To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai- Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001; relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective.

ter Kuile, F., C. Luxemburger, F. Nosten, K.L. Thwai, T. Chongsuphajaisiddhi, and N.J. White, Predictors of mefloquine treatment failure: a prospective study of 1590 patients with uncomplicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995. 89(6): p. 660-4.[PubMed Link]
The factors which identify patients at risk of treatment failure were characterized in 1590 children and adults with uncomplicated falciparum malaria treated with 15 or 25 mg/kg of mefloquine on the borders of Thailand. Six independent predictors of failure were identified using multiple logistic regression. Age < or = 2 years (odds ratio [OR] 4.54), 3-15 years (OR 4.4), vomiting < 30 min after a single dose of 25 mg/kg (despite re-administration of the dose) (OR 2.5) and diarrhoea after treatment (OR 3.6) were the strongest predictors of failure by day 7. Parasitaemias > 10 000/mm3 (OR 1.4), and fever with a history of recent vomiting (OR 1.6) were risk factors for recrudescence of the infection between days 10 and 28. Patients treated with mefloquine in the previous 2 months were also at increased risk of failure (OR 2.38), particularly if they were anaemic (haematocrit < 30%) (OR 5.96), which suggested that they had recrudescent infections at presentation. Combined, these 6 factors identified half of all treatment failures. Vomiting and diarrhoea accounted for 24% of the early failures in children. Patients at increased risk of treatment failure should be monitored closely and given early alternative treatment if fever and parasites persist for > or = 3 d.

ter Kuile, F., F. Nosten, C. Luxemburger, D. Kyle, P. Teja-Isavatharm, L. Phaipun, R. Price, T. Chongsuphajaisiddhi, and N.J. White, Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bulletin of the World Health Organization, 1995. 73(5): p. 631-42. [PubMed Link]
Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673 patients aged between 6 months and 88 years. Early vomiting (within 1 hour) is an important determinant of treatment outcome in these areas, despite re-administration of the dose. Overall, 7 % of the patients vomited within an hour. Significant risk factors were age < or = 6 years (relative risk (RR), 3.9) or > or 50 years (RR, 2.7), the higher mefloquine dose (M25) (RRm 2.7), vomiting < 24 hours before enrolment (RR, 2.5), axillary temperature > 38.0 degrees C (RR, 1.6), and parasitaemia > 10,000/microliter (RR, 1.3). In children < or = 2 years, 30% vomited with M25, and 13% did not tolerate a repeat dose. Vomiting was reduced 40% by splitting the higher dose (RR, 0.6; 95% CI, 0.4-0.8), and 50% by giving mefloquine on the second day in combination with artesunate (RR, 0.5; CI, 0.3-0.9). Anorexia, nausea, vomiting, dizziness, and sleeping disorders were 1.1-1.4 times more frequent with M25 than M15 in the three days following treatment, but were similar in the single or split-dose M25 groups, despite twofold higher mefloquine concentrations obtained with the latter. There was no evidence that diarrhoea, headache, and abdominal pain were associated with mefloquine use. High-dose mefloquine is well tolerated but should be given as a split dose.

Waller, D., S. Krishna, J. Crawley, K. Miller, F. Nosten, D. Chapman, F. ter Kuile, C. Craddock, C. Berry, and P.A. Holloway, Clinical features and outcome of severe malaria in Gambian children. Clinical Infectious Diseases, 1995. 21(3): p. 577-87. [PubMed Link]
The clinical and laboratory features of severe falciparum malaria in 180 Gambian children were studied between 1985 and 1989. Of the 180 children, 118 (66%) presented with seizures, 77 (43%) had cerebral malaria, 35 (20%) had witnessed seizures after admission, 29 (16%) were hypoglycemic, and 27 (15%) died. Respiratory distress was a common harbinger of a fatal outcome. The differences in admission parasite counts in the blood, hematocrit, and opening cerebrospinal pressures for patients who died and survivors were not significant. A multiple logistic regression model identified neurological status (coma, particularly if associated with extensor posturing), stage of parasite development on the peripheral blood film, pulse rate of > 150 or respiratory rate of > 50, hypoglycemia, and hyperlactatemia (plasma lactate level, > 5 mmol/L) as independent indicators of a fatal outcome. Biochemical evidence of hepatic and renal dysfunction was an additional marker of a poor prognosis, but, in contrast to severe malaria in adults, none of these children with severe malaria had acute renal failure.