Harinasuta T

Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients.

High-dose dexamethasone was compared with placebo in a double-blind trial involving 100 comatose patients with strictly defined cerebral malaria. The two treatment groups, whose members were six to 70 years old, proved comparable on admission. There were eight deaths in the dexamethasone group and nine in the placebo group (no significant difference; P = 0.8); at post-mortem examination the brain showed features diagnostic of cerebral malaria in all but one patient who died. Dexamethasone prolonged coma among the survivors: the interval between the start of treatment and the full recovery of consciousness was 63.2 +/- 5.9 hours (mean +/- S.E.M.) in the dexamethasone group, as compared with 47.4 +/- 3.2 hours in the placebo group (P = 0.02). Complications, including pneumonia and gastrointestinal bleeding, occurred in 26 patients given dexamethasone and 11 given placebo (P = 0.004). Only five patients had neurologic sequelae. Results were similar in a subgroup of 28 children six to 14 years old. Dexamethasone is deleterious in cerebral malaria and should no longer be used.

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 (Cl) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (Cl, 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 (Cu) (t/2, 18.2 +/- 9.7 compared with 16 +/- 7.0 hours; Cu, 0.21 +/- 0.16 compared with 0.21 +/- 0.08 ml/min/kg). In nine patients studied following recovery, Cl (3.09 +/- 1.18 ml/min), Vd (2.74 +/- 0.47 liter/kg), and Cu (0.53 +/- 0.22 ml/min/kg) were significantly greater (p less than or equal to 0.0004), and t/2 was significantly shorter (11.1 +/- 4.1 hours, p = 0.006) than during the acute illness. Cu accounted for approximately 20 percent of Cl 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.

EFFECT OF PRIMAQUINE ON GAMETOCYTES OF PLASMODIUM FALCIPARUM IN THAILAND

Sm,—Mr Ledingham and his colleagues (May 31, p. 1168) reported interesting findings on central rewarming using a modified Sengstaken tube in ansesthetised dogs. The rate of rewarming will, to some extent, depend upon the integrity of autonomic reflexes which tend to restore normal body temperature. Anaesthetic agents disrupt normal temperature regu’ lation, and it is not surprising that the temperature of the control animals did not rise during the four hour study, notwithstanding the radiant heat bulb. From the temperature curves shown of one rewarmed dog, the high skin temperature seen when the core temperature was only 35°C, highlights this point. The technique would appear to be of great value in the type of case described, where a patient is effectively poikilothermic as a result of traumatic or drug induced brain dysfunction, but the response may be different in hypothermia induced by exposure to low ambient temperature in otherwise normal people.

Dynamic alteration in splenic function during acute falciparum malaria

Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated 51Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes [mean +/- SD] vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.

Do patients with cerebral malaria have cerebral oedema? A computed tomography study.

Computed tomography of the brain in 10 patients with severe cerebral malaria, 5 of whom died, showed evidence of cerebral oedema in only 2 fatal cases. Small areas of altered density were seen in 4 cases; these were not associated with focal neurological signs and were still visible in convalescent scans in 2 survivors. 4 patients, including 1 of the fatalities, had completely normal scans. Cerebral oedema may occur in severe cerebral malaria but is not a consistent feature of living patients and cannot, therefore, always be the cause of their coma.

High dose of primaquine in primaquine resistant vivax malaria

The efficacy of low dose chloroquine, characteristic pattern of relapse and the relapse rate in vivax malaria after high dose primaquine were investigated in 167 Thai patients. 87 patients were allocated at random to receive 300 mg, and 80 received 450 mg of chloroquine on the first day of admission. All patients in both groups showed a rapid response with comparable fever clearance times (27.3 vs. 26.1 h) and parasite clearance times (67.1 vs. 58.1 h). After recovery and clearance of parasitaemia, the patients were allocated at random (double blind) to receive 2 dosage regimens of primaquine, a daily dose of 15 mg or 22.5 mg for 14 d. Relapses in both groups occurred within 6 months; no patient relapsed beyond that period. The relapse rate in the primaquine 15 mg group was significantly higher than that in the 22.5 mg group (17.5% vs. 2.4%).

QUINIDINE IN FALCIPARUM MALARIA

Fourteen patients with falciparum malaria were successfully treated with oral quinidine. Twelve of these patients were followed for 35 days without recrudescence. In six patients the infection had already recrudesced after antimalarial treatment, which in two cases had included a full course of quinine. Quinidine caused no cardiotoxicity, although the electrocardiogram QTc interval was prolonged by more than 25% in four patients. In-vitro cultures from nine of these patients and a further seven patients with falciparum malaria showed that the minimum inhibitory concentration was consistently lower for quinidine than for quinine. Quinidine is an effective antimalarial drug for Plasmodium falciparum infections and may be more potent than quinine.

AN ECONOMICAL REGIMEN OF HUMAN DIPLOID CELL STRAIN ANTI-RABIES VACCINE FOR POST-EXPOSURE PROPHYLAXIS

Vaccine regimens using 0.1 ml human diploid cell strain vaccine (HDCSV) given intradermally (id) in single and multiple sites, or with aluminum hydroxide adjuvant given subcutaneously (sc), were compared with the regimens of HDCSV and Semple vaccine currently suggested by WHO. Some groups were also given human rabies-immune globulin (HRIG). Neutralising antibody titres were monitored for 3 months. Antibody was detected earliest in subjects given 0.1 ml HDCSV id at each of eight sites. The highest antibody titres from day 14 onwards were found after intramuscular (im) administration of HDCSV, but the multiple-site id regimen, which requires only one quarter of the volume of vaccine required for the im regimen, gave similar results, provided that a booster was given on day 91. This finding suggests that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. Adjuvanted vaccine gave similar results to the same amount of antigen given id. Semple vaccine produced the lowest titres. HRIG, given at the high dose of 40 IU per kg, suppressed the antibody response to some of the regimens.

Artemether-mefloquine combination in multidrug resistant falciparum malaria

Plasmodium falciparum in Thailand is highly resistant to chloroquine and sulfadoxine/pyrimethamine and there is increasing resistance to the alternative antimalarials, quinine and mefloquine. In eastern Thailand, the cure rates of mefloquine at 750 and 1250 mg were 30% and 55%, respectively. The use of drug combinations may be necessary in areas where drug-resistant parasites exist. 159 male Thai patients in Chantaburi, eastern Thailand, were allocated at random to receive either oral artemether at a single dose of 300 mg on the first day followed by mefloquine 750 mg at 24 h and 500 mg at 30 h (group A), or oral artemether at a single dose of 300 mg on the first day, mefloquine 750 mg at 24 h and placebo at 30 h (group B). The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Most patients in both groups had a rapid initial response to treatment, parasitaemia being cleared within 24 h and fever cleared within 48 h in both groups. The cure rates were 97% and 90%, respectively, for groups A and B. No serious adverse effect was seen in either group; mild and transient nausea, vomiting and loss of appetite were noted. The adverse effects did not differ between the 2 groups. The results suggested that a single oral dose of artemether (300 mg) can markedly improve the cure rate of mefloquine at a dose of 750 or 1250 mg in multiple drug-resistant falciparum malaria.

A comparative clinical trial of two different regimens of artemether plus mefloquine in multidrug resistant falciparum malaria

Plasmodium falciparum in Thailand is highly resistant to available antimalarial drugs. Artemether, a derivative of artemisinin, is a promising compound currently used to cope with this situation but the course of treatment has to be at least 5 d. An effective short treatment course of this drug is possible when used in combination with mefloquine. We now report a trial of different regimens of the combination artemether/mefloquine. Fifty-seven male Thai patients, admitted to the Bangkok Hospital for Tropical Diseases, were allocated at random to receive oral artemether 300 mg as an initial dose, followed by either the standard dose of mefloquine (750 mg) at 24 h or a higher dose of mefloquine (750 mg at 24 h, then 500 mg at 30 h). Patients were followed up in hospital for 42 d. Two patients, both in the high dose mefloquine group, were excluded as they failed to attend for follow-up. All patients had a rapid initial response to treatment with median parasite clearance times of 37 and 40 h, median fever clearance times of 33.5 and 30.5 h, and cure rates of 75 and 96% (P = 0.0248), for the standard and high doses of mefloquine respectively. No serious adverse effect was found; mild and transient dizziness, nausea, vomiting and diarrhoea were noted in half of the patients in each group. The results suggest that a 30 h short course of artemether plus mefloquine at high dose should be used in areas with documented mefloquine resistance.