Dyserythropoiesis and ineffective erythropoiesis in Plasmodium vivax malaria.

Nine Thai adults with P. vivax malaria were investigated. Light and electron microscope studies of marrow aspirates revealed morphological evidence of dyserythropoiesis in six of them. Dyserythropoiesis was most marked in the four most anaemic patients. In these four patients the electron microscope also revealed the presence of erythroblasts at various stages of degradation within the cytoplasm of macrophages. Neither the dyserythropoiesis nor the ineffective erythropoiesis could be attributed to a deficiency of vitamin B12, folate or iron. The abnormalities of erythropoiesis seemed to result from the P. vivax infection itself. Other bone marrow reactions seen in this infection included macrophage hyperplasia, plasmacytosis and increased eosinophil granulocytopoiesis. Unlike in severe P. falciparum malaria, the microvasculature of the marrow was not obstructed by parasitized red cells

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

We 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

Glucose turnover in severe falciparum malaria.

To investigate glucose metabolism in acute falciparum malaria, [3-3H]glucose turnover was measured in 18 normoglycemic adult Thais (eight males, 10 females; median age, 28 years) with severe infections. Eleven patients were studied before quinine treatment, 15 while receiving quinine, and 10 during convalescence. In paired studies conducted before and after initial intravenous quinine, plasma glucose level decreased from a median (95% confidence limits) of 5.5 (3.0 to 6.6) to 4.6 (2.5 to 6.1) mmol/L (P < or = .027, n = 8), and plasma insulin level increased 9.3 (-3.2 to 30.0) mU/L (P = .02). Glucose turnover decreased during the 4-hour quinine infusion from 3.04 (2.12 to 4.23) to 1.89 (1.20 to 2.54) mg/kg.min-1 (P < .004), as did the metabolic clearance rate for glucose (2.87 [1.88 to 7.83] to 2.50 [1.43 to 4.55) mL/kg.min-1; P = .008). Glucose turnover and clearance measured both after initial quinine treatment and in convalescence were similar (P = .234 and .344, respectively; n = 7). In the series as a whole, there was an inverse association between pretreatment turnover and the simultaneous plasma glucose level (rs = -.76, P < .01; n = 11), a stronger inverse relationship between glucose clearance and plasma glucose level (rs = -.88, P < .001), and a positive association between pretreatment turnover and oral temperature (rs = .65, P < .025; n = 10). These data suggest that, as in other severe illnesses, glucose turnover is high in untreated patients, but that glycolysis by mature parasite forms may accelerate glucose disposal.(ABSTRACT TRUNCATED AT 250 WORDS

Glycerol metabolism in severe falciparum malaria.

Gluconeogenesis and liver blood flow (LBF) in severe falciparum malaria were assessed from the clearance and metabolic response to intravenously administered glycerol (0.3 g/kg) and Indocyanine Green ([ICG] 0.4 mg/kg), respectively. Fasting baseline blood glycerol concentrations (mean +/- SD) were significantly higher in acute malaria (133 +/- 65 mumol/L, n = 14), than in convalescence (65 +/- 31 mumol/L, n = 9, P = .01), but basal triacylglycerol concentrations were similar. Estimated glycerol turnover was also more than twice as high in acute malaria compared with convalescence (1.36 +/- 0.87 v 0.54 +/- 0.15 mumol.min-1.kg-1, P = .015). The increment in plasma glucose (AUC0-55 min) following glycerol infusion was greater during acute malaria compared with convalescence (median [range], +31.6 [-0.9 to +107.6] v +14.5 [-103 to +27.1] mmol.min-L-1, P < .05), but the insulin increments were similar (P = .9), indicating reduced tissue insulin sensitivity. The increment in venous lactate (AUC0-55 min) was higher in severely ill patients (17.2 [-7.8 to +53.4] mmol.min.L-1, n = 10) compared with patients with moderately severe malaria (-3.1 [-8.7 to 3.2] mmol.min-L-1, n = 4, P = .01). LBF estimated from ICG clearance was lower during acute illness than in convalescence (mean +/- SD, 15.5 +/- 2.3 v 18.6 +/- 2.9 mL.min-1.kg-1, P = .007) and correlated inversely with the basal venous lactate concentration (rs = .53, P < .05). LBFs less than 15 mL.min-1.kg-1 were associated with hyperlactatemia, and all four fatal cases had LBFs of less than 12 mL.min-1.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS

Intramuscular loading dose of quinine for falciparum malaria: pharmacokinetics and toxicity.

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets

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 less than 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 less than 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 less than 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 less than or equal to 0.025) despite similar end-infusion free plasma quinine concentrations (P greater than 0.5). Basal plasma free fatty acid concentrations were increased in acute illness (0.68 +/- 0.24 vs 0.21 +/- 0.12 mmol/l, P less than 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

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 less than 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 less than 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 less than 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 less than or equal to 0.025) despite similar end-infusion free plasma quinine concentrations (P greater than 0.5). Basal plasma free fatty acid concentrations were increased in acute illness (0.68 +/- 0.24 vs 0.21 +/- 0.12 mmol/l, P less than 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

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

OBJECTIVE: 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

Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine.

Mefloquine-sulphadoxine-pyrimethamine (MSP) in combination has proved effective against multiple-drug-resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15-51 years with uncomplicated chloroquine-resistant falciparum malaria, took 11.2-16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/- 29 h (mean +/- s.d.) and 52 +/- 24 h, respectively. The mean apparent absorption half-time (t1/2abs) of mefloquine was 4.89 h (range 2.25-9.72) and mean peak plasma concentration was 1815 ng ml-1 (range 725-3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml-1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study