Quinine and severe falciparum malaria in late pregnancy.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
K Silamut
Publications and source records attributed to K Silamut.
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.
Adult↗
Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria.
Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg-1) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 +/- 0.27 l kg-1 (+/- s.d.), elimination half-time (t1/2,z), 11.3 +/- 4.3 h, total clearance, 1.22 +/- 0.77 ml min-1 kg-1. There was no relationship between arterial blood pressure and plasma quinine concentrations. Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg l-1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P less than 0.05). The mean (+/- s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 +/- 0.14. Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg l-1; simultaneous maternal plasma quinine was 7.1 mg l-1 (ratio 0.39). Breast milk quinine concentrations and milk to plasma ratios were 0.5-3.6 mg l-1 (mean 2.6) and 0.11-0.53 (mean 0.31) in twenty-five women who were breast-feeding and had taken oral quinine sulphate for 1-10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg l-1 (mean 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Binding of quinine to plasma proteins in falciparum malaria.
Plasma protein binding of quinine was measured in 12 patients with cerebral malaria on the first and seventh day of treatment, and in 7 patients with uncomplicated falciparum malaria on admission and also one month later. Binding was significantly higher and therefore the proportion of free drug was lower in cerebral malaria patients (free: total quinine concentration; 7.2 +/- 3.5%, mean +/- SD, on admission; 7.4 +/- 5.3% on day 7) compared with uncomplicated malaria patients on admission (10.2 +/- 5.8%) or following recovery (11.0 +/- 5.5%, n = 6) P = 0.011. Binding was significantly correlated with the red cell/total concentration ratio r = 0.56, P less than 0.0001. The ratio of cerebrospinal fluid to free (unbound) plasma quinine was 0.55 +/- 0.33 which suggests that quinine does not freely cross the blood brain barrier. These findings are relevant to the interpretation of total plasma or serum concentration, and may explain the rarity of serious quinine toxicity in severe falciparum malaria.
Blood Proteins↗
Quinine disposition kinetics.
Intravenous quinine dihydrochloride (5 mg kg-1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/- 1 s.d.) after the infusion were 5.1 +/- 1.3 mg 1(-1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half-time (t 1/2, lambda 1) was 1.89 +/- 0.54 min (mean +/- 1 s.d.), elimination half-time (t 1/2, z) 11.1 +/- 2.1 h, apparent volume of the central compartment (V1) 0.57 +/- 0.32 1 kg-1, total apparent volume of distribution 1.80 +/- 0.37 1 kg-1 and total clearance 1.92 +/- 0.45 ml min-1 kg-1.
Adolescent↗
Red cell quinine concentrations in falciparum malaria.
Red cell concentrations of quinine were measured in cerebral malaria and in uncomplicated falciparum malaria both in the acute stage and 1 month after recovery. Red cell quinine elimination half times were significantly shorter than the corresponding plasma half times in cerebral malaria and convalescent uncomplicated cases (P less than 0.001), but not in acute uncomplicated cases (P = 0.12). The ratio of red cell:plasma concentration fell progressively from the 2nd day (0.49) to the 6th day (0.26) of treatment. On admission this ratio was positively correlated with the blood parasite count (P = 0.02). Red cell quinine concentration may be relevant to the assessment of drug resistance, and to the design of treatment regimens.
Adult↗
Arboreal green pit vipers (genus Trimeresurus) of South-East Asia: bites by T. albolabris and T. macrops in Thailand and a review of the literature.
In Thailand 29 patients were proved to have been bitten by arboreal green pit vipers: 24 by Trimeresurus albolabris and 5 by T. macrops. They were studied in order to define the clinical effects of envenoming, to characterize the haemostatic abnormalities and assess the efficacy of Thai Red Cross antivenom. T. macrops caused only local painful swelling, neutrophil leucocytosis and thrombocytopenia. T. albolabris caused more severe envenoming with local blistering and necrosis, shock, spontaneous systemic bleeding, defibrination, thrombocytopenia and leucocytosis. There was no evidence of disseminated intravascular coagulation, but fibrinolytic activity was increased. Platelet function was normal. The product of admission venom antigen concentration and the delay between bite and admission was significantly higher in defibrinated patients than in those without severe coagulopathy. Antivenom (5 ampoules intravenously) restored blood coagulability, but there was persistent venom antigenaemia, associated in some cases with recurrent coagulopathy. The literature on bites by south Asian green pit vipers of the genus Trimeresurus is reviewed; these bites are common medical problems and causes of morbidity. The identification of individual species is difficult, but may be important if antivenom is to be improved and used appropriately.
Adolescent↗
Relation of the stage of parasite development in the peripheral blood to prognosis in severe falciparum malaria.
Admission blood films from 72 patients who died of severe falciparum malaria (50 Thai adults, 22 Gambian children) were matched retrospectively for parasitaemia with equal numbers of survivors. The peripheral blood parasites from fatal cases were more mature than those from survivors. Tiny rings (TR) comprised > 50% of parasites in 47/72 (65%) survivors but only 12/72 (17%) of fatal cases (P < 0.001). Parasites containing visible pigment (MTS: mature trophozoites and schizonts) comprised < 20% of the total parasite count in 10/72 (14%) survivors compared with 31/72 (43%) fatal cases (P < 0.001). Of the 39 patients with > 10(4) MTS/microL, 30 (81%) died. These findings were confirmed in a prospective study of 279 adult Thai patients admitted sequentially with acute falciparum malaria. Only 4 of the 19 fatal cases (21%) had > 50% TR, compared with 130 of 260 (50%) survivors, whereas > 20% MTS were found in 10/19 (53%) fatal cases, compared with 28/108 (27%) severe malaria survivors, and 26/155 (17%) patients with moderately severe malaria (P = 0.001). As a predictor of fatal outcome, the finding of either > 10(4) MTS/microL or > 5 x 10(5) parasites/microL in severe malaria had a sensitivity of 90% (95% confidence interval [CI] = 75-97%) and a specificity of 72% (95% CI = 59-86%). These observations are consistent with the hypothesis that a predominance of mature parasites in the peripheral blood reflects a greater sequestered biomass, and thus more severe disease. Simple microscopical assessment of parasite maturity on an admission blood slide provides important pathophysiological and prognostic information in severe falciparum malaria.
Adult↗
A simple method for assessing quinine pre-treatment in acute malaria.
Administration of a loading dose of quinine in severe malaria may be dangerous if therapeutic blood concentrations are already present because of previous treatment. To assess the reliability of the history of pretreatment we conducted a prospective study of 379 adult patients with acute falciparum malaria admitted to a hospital in western Thailand. Admission plasma concentrations of quinine were measured by high performance liquid chromatography (HPLC), and compared with the patients' history of previous quinine treatment. The sensitivity of the history was 59% (95%) confidence interval [CI] 49-69%), the specificity was 79% (95% CI 74-84%), the positive predictive value was 53%, and the negative predictive value 82%. A rapid (10 min semi-quantitative estimate of plasma quinine concentrations, based on simple 'dipstick' method using a quinine-specific monoclonal antibody, proved considerably more sensitive and specific. The correlation between the dipstick estimate and the subsequent HPLC measurement of plasma quinine concentration was 0.85 (n = 404; P < 0.0001). In 404 admission samples, the negative predictive value of the dipstick estimate for plasma quinine concentrations > 1 microgram/mL was 100%. In Thailand the history of previous quinine treatment given by the patients or their relatives was unreliable but the quinine dipstick provided a simple and rapid means of assessment of quinine pre-treatment in acute falciparum malaria.
Acute Disease↗
A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria.
In some areas clinicians have combined parenteral artesunate and quinine in the belief that the 2 drugs would be additive or synergistic in severe malaria. A randomized comparison of the effectiveness of intravenous (i.v.) artesunate versus i.v. artesunate and i.v. quinine together on parasite clearance was conducted in 1998/99 amongst 69 patients with uncomplicated and severe Plasmodium falciparum malaria in western Thailand. The parasite clearance time did not differ significantly between the 2 treatment groups (P = 0.12), but adverse events were significantly more frequent in the artesunate plus quinine group (P = 0.05). Quinine did not have a significant antipyretic effect and artesunate did not affect the electrocardiographic QTc interval. There is no benefit evident from combining parenteral administration of these 2 antimalarial drugs in the acute phase of treatment.
Acute Disease↗
Ex-vivo short-term culture and developmental assessment of Plasmodium vivax.
A simple reproducible method for short-term ex-vivo Plasmodium vivax culture is presented in which glucose, ascorbic acid, thiamine, hypoxanthine, and 50% human AB+ serum are added to the standard P. falciparum in-vitro culture medium. Culture of freshly obtained blood samples from patients with acute vivax malaria with > 0.5% parasitaemia resulted in > 95% complete schizogony. Culture could be continued for 5-6 cycles without the addition of red cells. Criteria for staging the erythrocytic development of P. vivax in the first schizogonic cycle based on synchronous ex-vivo culture are presented. The asexual cycle was divided into 7 morphological stages: tiny ring (0-6 h), small ring (6-12 h), large ring (12-18 h), early trophozoite (18-28 h), late trophozoite (28-36 h), early schizont (36-42 h) and mature schizont (42-48 h). This simple method of culturing P. vivax ex vivo is suitable for antimalarial susceptibility and immunoparasitology studies.
Animals↗
Semi-quantitative measurement of Plasmodium falciparum antigen PfHRP2 in blood and plasma.
Plasmodium falciparum histidine rich protein 2 (PfHRP2) antigen was measured semi-quantitatively in whole blood, plasma, and supernatants and red blood cells of cultures in vitro using the dipstick ParaSight-F test and also by a quantitative antigen-capture enzyme-linked immunosorbent assay (ELISA). In vitro, PfHRP2 was secreted mainly during the second half of the asexual cycle with a marked rise during schizont development and rupture. The total PfHRP2 secreted before schizogony corresponded to approximately 4% of that contained in the red blood cells. In samples from 55 patients with acute falciparum malaria, the level of detection by ELISA corresponded to parasitaemias of 100/microL for whole blood and 1600/microL for separated plasma. Whole blood PfHRP2 levels were correlated significantly with admission parasitaemia (r = 0.76, P < 0.0001) and the stage of parasite development (r = 0.43, P < 0.01). Although whole blood PfHRP2 concentrations were higher in severe malaria, plasma concentrations of PfHRP2 were considerably higher in severe malaria (median titre 1:320, range zero to 1:1280) than in uncomplicated malaria (median titre 1:5, range zero to 1:80; P < 0.0001). The ratio of whole blood to plasma PfHRP2 was lower in severe than in uncomplicated malaria (median 4, range 0.25 to 256, versus 64, range 4 to 1280; P < 0.0001). With plasma samples the intensity of colour change on the dipstick correlated well with more precise measurement of optical density in the ELISA (r = 0.88, P < 0.0001). These results suggest that measurement of PfHRP2 in plasma could provide an alternative approach to the assessment of the parasite biomass, and thus prognosis, in severe malaria, and that this could be done simply by using the currently available dipsticks.
Adolescent↗
Two patients with falciparum malaria and poor in vivo responses to artesunate.
Explore the source record for details and available documents.
Animals↗
Red cell selectivity in malaria: a study of multiple-infected erythrocytes.
To characterize red cell susceptibility to invasion in malaria, a selectivity index (SI) was calculated as the ratio of observed number of multiple-infected red cells to that expected from a random process (Poisson distribution). In patients with falciparum malaria (n = 100) SI decreased with increasing parasitaemia (P < 0.001), and correlated inversely with plasma lactate concentrations, chosen prospectively as a measure of disease severity (r = -0.36, P < 0.001). For parasitaemias < 5%, the SI was lower in patients with severe malaria (geometric mean 1.35; 95% confidence interval 1.01-1.80) than in uncomplicated malaria (2.31; 1.89-2.81; P = 0.003), despite similar parasite counts. The geometric mean (range) SI in vivax malaria (n = 20), 7.69 (1.67, 29.75), was significantly greater than that in falciparum malaria at comparable parasitaemias (< or = 2%), 2.44 (0.45, 14.05), P < 0.001, suggesting that about 13% of circulating erythrocytes were susceptible to invasion by Plasmodium vivax. This translates into susceptibility for about 2 weeks after emergence from the bone marrow, if age is the sole determinant of this process. In falciparum malaria selectivity was inversely proportional to severity; lack of selectivity could reflect either a 'favourable' host red cell phenotype, or an indiscriminate parasite population. Both are dangerous for the host.
Animals↗