a The Institute of Immunology and Infectious Diseases of the University of Verona, Italy b UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland c Department of Pharmacology of the University of Liverpool, UK
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Abstract |
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Introduction |
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Mefloquine, a 4-quinoline methanol derivative marketed for the oral treatment and prophylaxis of malaria, still retains a considerable level of activity against African isolates of Plasmodium falciparum, including the widespread chloroquine-resistant strains.2 In spite of its favourable pharmacokinetic properties (rapid intestinal absorption) and clinical effectiveness, the drug is not indicated for the treatment of cerebral malaria since it is only available as an oral formulation (250 mg base tablets).3 Furthermore, mefloquine is not currently recommended in children weighing less than 15 kg,3 who account for a sizeable proportion of cerebral malaria cases in endemic areas.
In order to overcome the transient lack of parenteral quinine in a small hospital in rural Burundi, we administered mefloquine by nasogastric tube to four small children with cerebral malaria and monitored clinical, parasitological and pharmacokinetic parameters in these subjects.
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Patients and methods |
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The diagnosis of cerebral malaria was made according to WHO standard criteria,1 including the detection of asexual forms of P. falciparumand exclusion of concurrent significant pathologies (by physical examination and cerebrospinal fluid analysis). The neurological assessment was made according to the Blantyre Coma Scale.4 A peripheral blood sample was taken on admission to determine haemoglobin, RBC, WBC, platelets (Coulter counter, Coulter, Miami, FL, USA), blood glucose (Reflotron analyzer, Boehringer, Mannheim, Germany) and parasitaemia.
Nasogastric tubes were inserted and mefloquine was administered at a dosage of 25 mg/kg bodyweight as a single dose. The drug was ground to obtain minute particles (smaller than a syringe neck) and the individual dose was determined by weighing the drug on a high-precision bench scale. Each individual dose was then partially dissolved in 20 mL of potable water and administered through the nasogastric tube. Additional potable water with glucose was given before and after the instillation of mefloquine to increase drug absorption and restore fluid and blood glucose balance.
Peripheral venous samples for measuring drug concentrations were taken from each patient in the first 12 h and at 24 h, and at 48 h from two patients. After centrifugation (5 min at 1500g) the sera were stored at 30°C and subsequently transported to the Department of Pharmacology of the University of Liverpool, where mefloquine concentrations were determined as described elsewhere.5 Parasitaemia was measured in triplicate (based on the ratio between parasites and WBC in 100 microscopic fields 100 x lens under oil immersion) at each venous sampling and every 8 h until clearance was established and at 3 h intervals when parasitaemia approached negativity. A final blood film was also taken from all patients at day 28 in order to fully establish the in-vivo response to mefloquine according to WHO criteria.6
As a measure of the pharmacodynamics we calculated the parasite reduction ratio (PRR) 48 h following the administration of mefloquine (the ratio between baseline parasitaemia and the parasite count at 48 h).7
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Results |
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Discussion |
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The characteristics of the four small children investigated here were not different from those usually seen in patients with cerebral malaria in this part of Africa.8 All patients experienced an uneventful recovery and regained consciousness after a mean period of coma (20.5 h) which is within the range of values expected for patients with comparable disease severity on admission given conventional parenteral quinine treatment.1,8 The PRR at 48 h, an informative indicator of drug efficacy,7 was within the expected range for mefloquine (101000) for drug-sensitive parasites and confirmed the maintained antimalarial effect of the drug in an area where its use is still extremely limited.
Previous concern about inadequate bioavailability of mefloquine in such severely ill patients was not borne out in the four small children we investigated.9 Even in the patient with the lowest mefloquine serum concentration in the first 12 h interval, the drug concentration was well above the minimum level required to exert a therapeutic action against mefloquine-susceptible P. falciparum isolates.6
The rapid mefloquine absorption documented here in very small children with cerebral malaria confirms previous findings obtained in older patients and in other pharmacokinetic studies,9,10 and indicates that intragastric mefloquine fulfils the fundamental requisite of quickly reaching therapeutic levels in the blood. By analogy, the importance of such a pharmacokinetic target is also supported by the recognized validity of the almost universally adopted quinine loading dose which is initially given to patients with cerebral malaria to provide a faster achievement of effective drug concentrations in the blood.1
Although under normal conditions the parenteral treatment of cerebral malaria remains optimal, these findings support the consideration of intragastric mefloquine as an effective solution whenever injectable drugs are not available, provided that the sensitivity of local P. falciparum strains is suitable.
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Acknowledgments |
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Notes |
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References |
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2
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4 . Molyneux, M. E., Taylor, T. E., Wirima, J. J. & Borgstein, A. (1989). Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Quarterly Journal of Medicine 71, 44159.[Medline]
5 . Riviere, J. H., Back, D. J., Breckenridge, A. M. & Howells, R. E. (1985). The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism. British Journal of Clinical Pharmacology 20, 46974.[ISI][Medline]
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7 . White, N. J. (1997). Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrobials Agents and Chemotherapy 41, 141322.
8 . Di Perri, G., Di Perri, I. G., Monteiro, G. B., Bonora, S., Hennig,C., Cassatella, M. A. et al. (1995). Pentoxifylline as supportive agent in the treatment of cerebral malaria in children. Journal of Infectious Diseases 171, 131722.[ISI][Medline]
9 . Chanthavanich, P., Looareesuwan, S., White, N. J., Warrell, D. A., Warrell, M. J., Di Giovanni, J. H. et al. (1985). Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria. American Journal of Tropical Medicine and Hygiene 34, 102836.[ISI][Medline]
10 . Karbwang, J. & White, N. J. (1990). Clinical pharmacokinetics of mefloquine. Clinical Pharmacokinetics 19, 26479.[ISI][Medline]
Received 2 March 1999; returned 6 May 1999; revised 7 June 1999; accepted 14 June 1999