Rapid absorption and clinical effectiveness of intragastric mefloquine in the treament of cerebral malaria in African children

Giovanni Di Perria,*, Piero Olliarob, Stephen Wardc, Benedetta Allegranzia, Stefano Bonoraa and Ercole Conciaa

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To obviate the lack of injectable quinine in a hospital in rural Burundi, mefloquine, only available as an oral formulation, was administered (25 mg/kg bodyweight) as a single dose by nasogastric tube to four small children with cerebral malaria. All patients recovered uneventfully after a mean coma duration of 20.5 h. Mefloquine was rapidly absorbed and therapeutic serum concentrations were achieved within a few hours in all subjects, with parasite reduction ratios after 48 h within the expected range for drug-sensitive parasites. These findings suggest that intragastric mefloquine deserves consideration whenever parenteral drugs are not available for the treatment of cerebral malaria.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
According to conservative estimates more than 500,000 African children die each year of cerebral malaria.1 Even when appropriate parenteral treatment with quinine or artemisinine derivatives is available the case fatality rate generally ranges between 10 and 40%.1

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Due to the bacterial contamination of a batch of quinine solution for injection, this drug was not available for 4 days for the parenteral treatment of malaria at the Hospital of Kiremba, a 140-bed facility in rural northern Burundi. We therefore decided to treat with intragastric mefloquine all malaria patients unable to take oral medications until injectable quinine was again available at the hospital. Despite those 4 days four patients with cerebral malaria were admitted to the hospital.

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


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Demographic and baseline clinical characteristics of the four patients investigated are shown in the Table together with the main parameters of outcome and the mefloquine blood levels measured in the 48 h following administration.


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Table. Demographic, baseline clinical characteristics, main parameters of outcome, parasitaemia and mefloquine blood concentrations of the four patients investigated
 
All patients recovered after a mean coma duration of 20.5 h (14–24 h) and no clinically detectable neurological sequelae were seen over a 4 week follow-up. The individual evolution under mefloquine treatment is graphically represented in the Figure.



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Figure. The individual response of the four patients after intragastric mefloquine treatment. Mefloquine (25 mg/kg bodyweight, single dose) was delivered at time 0. The times to 50%, 90% and total parasite clearance are also indicated for each patient. Number of circulating asexual forms of Plasmodium falciparum/µL, •; body temperature (°C), {square} and mefloquine serum levels, {circ}.

 
The mean parasite count at entry was 57,332/mL (32,880–81,120), the mean time to total parasite clearance was 57 h (51–65 h) with 50% and 90% mean parasite clearance times of 13 h (12–14 h) and 29.5 h (22–41 h) respectively. The mean parasite count 48 h after treatment was 1450 (420–4170) and the PRR at 48 ranged between 19.45 and 119.5. All patients had a negative blood film at day 28 and did not experience any further febrile illness during the 4 week follow-up period.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The treatment of cerebral malaria is by parenteral drugs and their administration requires a minimum of equipment and expertise. This implies that in rural endemic areas a significant proportion of patients have to be transported for a long distance before they can reach hospitals or health centres where an appropriate treatment can be delivered, with a consequent increase in the fatality risk. The present study, therefore, suggests that the intragastric administration of mefloquine could be an effective therapeutic option to be considered whenever and wherever parenteral treatment is unavailable.

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 (10–1000) 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.


    Acknowledgments
 
The work was supported financially by a grant from the University of Verona and received logistic support from Associazione per la Cooperazione Missionaria (ASCOM) of Legnago, Verona, Italy.


    Notes
 
Correspondence address. Cattdra di Malattie Infettive, Università di Verona, Ospedale Civile Maggiore, 37126 Verona, Italy. Tel: +39-045-8072073; Fax: +39-045-8340223; E-mail: diperri{at}borgotrento.univ Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Warrell, D. A., Molyneux, M. E. & Beals, P. F. (1990). Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, Suppl. 2, 1–65.[Medline]

2 . Pradines, B., Rogier, C., Fusai, T., Tall, A., Trape, J. F. & Doury, J. C. (1998). In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs. American Journal of Tropical Medicine and Hygiene 58, 354–7.[Abstract/Free Full Text]

3 . Abdi, Y. A., Gustafsson, L. L., Ericsson, O. & Hellgren, U. (1995). Mefloquine. In Handbook of Drugs for Tropical Parasitic Infections, 2nd edn, (Abdi, Y. A., Gustafsson, L. L., Ericsson, O. & Hellgren, U., Eds), pp. 82–88, Taylor and Francis, London.

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, 441–59.[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, 469–74.[ISI][Medline]

6 . Black, R. H., Canfield, C. J., Clyde, D. F., Peters, W. & Wernsdorfer, W. H. (1986). Drug resistance in malaria. In Chemotherapy of Malaria, (Bruce-Chwatt, L. J., Ed.), pp. 102–18, World Health Organization, Geneva.

7 . White, N. J. (1997). Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrobials Agents and Chemotherapy 41, 1413–22.

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, 1317–22.[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, 1028–36.[ISI][Medline]

10 . Karbwang, J. & White, N. J. (1990). Clinical pharmacokinetics of mefloquine. Clinical Pharmacokinetics 19, 264–79.[ISI][Medline]

Received 2 March 1999; returned 6 May 1999; revised 7 June 1999; accepted 14 June 1999





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