T. M. E. Davis

Erythrocyte survival in severe falciparum malaria

Erythrocyte survival was studied in 17 Thai patients (10 males, 7 females; aged 13-57 years) with severe falciparum malaria. To ensure radioisotopic labelling of cells before bone marrow recovery and survival analysis under near-steady state conditions, 51Cr labelling of autologous erythrocytes was performed at the time of admission (0 h) and calculation of mean cell lifespan (MCL) was based on semilogarithmic plots of corrected counts from 60 h onwards. Five patients received blood transfusions, all within 48 h of admission. The overall mean (+/- S.D.) MCL was short (44.1 +/- 21.7 days). Nontransfused patients had similar MCL values (43.6 +/- 20.4) to those of transfused patients (45.5 +/- 27.3 days, p greater than 0.8). Patients with and without palpable splenomegaly had MCL values which were not significantly different (54.1 +/- 28.8 vs. 37.2 +/- 12.3 days respectively, p greater than 0.1). There was no association between admission haematocrit or peripheral parasitaemia and MCL (p greater than 0.2 in each case), but there was an inverse correlation between total serum bilirubin and MCL (r = -0.49, p less than 0.025). There is accelerated destruction of non-parasitised erythrocytes in severe malaria resulting in a mean MCL that is half that found previously in healthy Thai volunteers (89.6 +/- 13.1 days, p less than 0.001) and significantly shorter than that reported previously in Thai patients with uncomplicated P. falciparum infections studied after parasite clearance (56.8 +/- 10.2 days, p less than 0.05).

Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria

Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmacokinetics in pregnancy, 9 untreated pregnant women aged 16-33 years and 8 non-pregnant females aged 16-38 years received an average of 15 (range 13-19) mg mefloquine/kg body-weight as single-dose treatment for uncomplicated falciparum malaria. Regular blood samples were taken during the subsequent 48 h and then intermittently for 3-26 d after treatment. Whole blood mefloquine concentrations were analysed by high-performance liquid chromatography and a one-compartment open pharmacokinetic model was fitted to the data. Peak mefloquine concentrations were significantly lower in the pregnant patients (median [range]; 1257 [650-1584] vs. 1617 [1051-3111] ng/mL) and the total apparent volume of distribution (Vd/f) was larger (10.8 [8.3-26.1] vs. 10.0 [4.8-13.9] L/kg; P < 0.05 in each case), consistent with an expanded circulating blood volume and increased tissue binding in pregnancy. There was no significant difference between the 2 groups in half-times of absorption or elimination (P > 0.1), and systemic clearance rates were also similar. These results suggest that pregnant patients need larger doses of mefloquine than non-pregnant women to achieve comparable blood levels, an important consideration in areas where multi-drug resistant falciparum malaria is emerging.

A study of the factors affecting the metabolic clearance of quinine in malaria

AbstractObjective: To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria. Patients: Sixteen adult Thai patients with severe or moderately severe falciparum malaria were studied, and 12 were re-studied during convalescence. Methods: The clearance of quinine, dihydroquinine (an impurity comprising up to 10% of commercial quinine formulations), antipyrine (a measure of hepatic mixed-function oxidase activity), indocyanine green (ICG) (a measure of liver blood flow), and iothalamate (a measure of glomerular filtration rate) were measured simultaneously, and the relationship of these values to the␣biotransformation of quinine to the active metabolite 3-hydroxyquinine was assessed. Results: During acute malaria infection, the systemic clearance of quinine, antipyrine and ICG and the biotransformation of quinine to 3-hydroxyquinine were all reduced significantly when compared with values during convalescence. Iothalamate clearance was not affected significantly and did not correlate with the clearance of any of the other compounds. The clearance of total and free quinine correlated significantly with antipyrine clearance (rs = 0.70, P = 0.005 and rs = 0.67, P = 0.013, respectively), but not with ICG clearance (rs = 0.39 and 0.43 respectively, P > 0.15). In a multiple regression model, antipyrine clearance and plasma protein binding accounted for 71% of the variance in total quinine clearance in acute malaria. The pharmacokinetic properties of dihydroquinine were generally similar to those of quinine, although dihydroquinine clearance was less affected by acute malaria. The mean ratio of quinine to 3-hydroxyquinine area under the plasma concentration-time curve (AUC) values in acute malaria was 12.03 compared with 6.92 during convalescence P=0.01. The mean plasma protein binding of 3-hydroxyquinine was 46%, which was significantly lower than that of quinine (90.5%) or dihydroquinine (90.5%). Conclusion: The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.

Disposition of oral quinine in acute falciparum malaria

SummaryPlasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l−1 compared to 5.7 mg·l−1 in convalescence.There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg−1·min−1, which was significantly lower than in convalescence — 2.67 ml·kg−·min−1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg−1·min−1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of α1 acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l−1 compared to 1.05 g·l−1 during convalescence.Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.

Electrocardiographic monitoring in severe falciparum malaria

Electrocardiographic monitoring over 24 h was performed with 53 patients with severe Plasmodium falciparum malaria (11 adults and 42 children) to assess the frequency of unrecognized cardiac arrhythmias. Nine patients (17%) died, 5 during the monitoring period and 4 afterwards. Pauses lasting 2-3 s were observed in 3 children, a single couplet in one, and a further child experienced frequent supraventricular ectopic beats which had not been detected clinically. In none of the patients who died could death be attributed to cardiac arrhythmia. Furthermore, no abnormality was detected which could have resulted from the often large doses of quinine, chloroquine or the artemisinin derivatives used for treatment. These results suggest that the heart is remarkably resilient even in the face of heavy parasite sequestration and other vital organ dysfunction, and that deaths from cardiac arrhythmias in severe malaria are rare. The need for routine cardiac monitoring of patients with severe and complicated P. falciparum malaria is questionable.

Dichloroacetate for lactic acidosis in severe malaria: A pharmacokinetic and pharmacodynamic assessment☆☆☆

Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.

Glucose Metabolism In Quinine‐Treated Patients With Uncomplicated Falciparum Malaria

To investigate host and drug effects on glucose metabolism in acute falciparum malaria, 10 previously untreated, fasting Thai males with uncomplicated infections were given a 2‐h intravenous glucose infusion (5 mg/kg ideal body weight min) with an infusion of quinine dihydrochloride (10 mg/kg body weight) during the second hour. Eight patients were restudied in convalescence. Fasting plasma glucose (mean ± SD) and insulin (geometric mean (— SD to + SD)) were higher during acute illness (5.5 ± 1.0 mmol/l and 6.2 (5.0–7.7) mU/l) than in convalescence (4.2 ± 0.25 mmol/l and 3.7 (2.1–6.7) mU/l; P <0.001 and P = 0.058 respectively). After 1 h, both plasma glucose (9.3 ± 1.4 vs 7.5 ± 0.8 mmol/l, P < 0.001) and insulin (21.2 (13.8–32.5) vs 15.2 (11.2–20.8) mU/l, P = 0.089) remained higher during acute illness; mathematical model (CIGMA) assessment of these values indicated lower tissue insulin sensitivity on admission (97% (71–134)) than in convalescence (139% (109–178), P < 0.025) but normal beta‐cell function on both occasions. Two‐hour plasma glucose (9.5 ± 2.0 mmol/l) and insulin (81.8 (51.5–129.9) mU/l) concentrations during acute illness were also significantly higher than in convalescence (7.2 ± 1.2 mmol/l and 40.1 (23.5–68.4) mU/l, P ± 0.025) despite similar end‐infusion free plasma quinine concentrations (P> 0.5). Basal plasma free fatty acid concentrations were increased in acute illness (0.68 ±.24 vs 0.21 ± 0.12 mmol/l, P < 0.001) but fell to low levels at 2 h in both studies. These data suggest tissue insulin resistance and augmented quinine‐stimulated insulin secretion in acute falciparum malaria, factors which are likely to influence the clinical situation in which malaria‐associated hypoglycaemia occurs.

Quinine pharmacokinetics in cerebral malaria: predicted plasma concentrations after rapid intravenous loading using a two-compartment model

To investigate the toxic potential of rapid intravenous quinine administration in severe malaria, the pharmacokinetic properties of low-dose quinine dihydrochloride injection (4 mg/kg body weight, equivalent to 3.3 mg base/kg) followed one hour later by infusion of 16 mg/kg over 3 h were studied in 7 patients with cerebral malaria. Plasma quinine concentrations closely followed a bi-exponential decline. Both the volumes of the central compartment (mean +/- SD: 0.17 +/- 0.10 litre/kg) and total volumes of distribution (0.74 +/- 0.30 litre/kg) were significantly smaller than those previously reported for healthy subjects. Based on the derived pharmacokinetic parameters, predicted plasma quinine concentrations following intravenous injection of the standard therapeutic dose (10 mg salt/kg) over 10-20 min are potentially toxic in severe malaria. Further reductions in administration time would produce disproportionately higher plasma quinine concentrations, especially as the distribution half-time (2.3 +/- 3.2 min) is approached. A theoretical regimen designed to achieve therapeutic, non-toxic plasma quinine concentrations promptly would be 7.0 mg quinine dihydrochloride/kg over 30 min. A subsequent maintenance infusion of 10 mg/kg over 4 h would allow for drug elimination and acute changes in pharmacokinetic parameters due to resuscitation and rehydration.

Lack of a significant adverse cardiovascular effect of combined quinine and mefloquine therapy for uncomplicated malaria

Quinine dihydrochloride (10 mg salt/kg infused over one hour) and mefloquine (15 mg base/kg) were given simultaneously to 13 adults with uncomplicated falciparum malaria. Supine and standing blood pressures were recorded and the electrocardiogram monitored. Plasma concentrations of the 2 drugs were similar to those reported previously for the 2 compounds given individually to a similar group of patients. Although postural hypotension was common (6 cases before treatment and 7 after) and the electrocardiogram QTc interval was prolonged by a mean of 12% (SD = 8) following drug treatment, there was no evidence of a clinically significant cardiovascular pharmacodynamic interaction between these 2 structurally related antimalarial compounds.

Abnormal circulatory control in falciparum malaria: the effects of antimalarial drugs

SummaryWe have studied blood pressure and heart rate responses to standing in 29 previously ambulant adult Thai patients with acute uncomplicated falciparum malaria before and after treatment with quinine or mefloquine.There was significant, symptomatic, and usually profound orthostatic hypotension in 12 patients (41%) before antimalarial treatment. The median maximum fall in systolic pressure was 24 mm Hg, significantly greater than the maximum fall in diastolic pressure 16 mm Hg.Blood pressure fell in two phases: an initial transient and usually asymptomatic fall immediately on standing, and a progressive, usually symptomatic fall, worsening over several minutes without a rise in pulse rate. Orthostatic hypotension was associated with core temperature (r=0.37, P=0.05).Antimalarial treatment accentuated the delayed orthostatic hypotension during malaria, despite (in the case of quinine) a significant reduction in fever. Both antimalarial drugs attenuated the cardioacceleratory response to symptomatic postural hypotension; the mean reduction in heart rate at the time of lowest blood pressure was 22 beats·min−1.The electrocardiograph ratio of RR intervals at the 30th and 15th beats was reduced significantly in acute malaria, but was not affected further by the drugs. When restudied in convalescence all the patients had normal postural cardiovascular responses.Acute falciparum malaria is associated with impaired circulatory control and the tendency to postural hypotension is worsened significantly by antimalarial treatment with the quinoline antimalarials quinine and mefloquine.