Related Articles

Background

The naturally fluorescent compound quinine has long been used to treat malaria infections. Although some evidence suggests that quinine acts in the parasite food vacuole, the mechanism of action of quinine has not yet been resolved. The Plasmodium falciparum multidrug resistance (pfmdr1) gene encodes a food vacuolar membrane transporter and has been linked with parasite resistance to quinine. The effect of multiple pfmdr1 copies on the subcellular localization of quinine was explored.

Methods

Fluorescence microscopy was used to evaluate the subcellular localization of quinine in parasites containing different pfmdr1 copy numbers to determine if copy number of the gene affects drug localization. The acidotropic dye LysoTracker Red was used to label the parasite food vacuole. Time-lapse images were taken to determine quinine localization over time following quinine exposure.

Results

Regardless of pfmdr1 copy number, quinine overlapped with haemozoin but did not colocalize with LysoTracker Red, which labeled the acidic parasite food vacuole.

Conclusions

Quinine localizes to a non-acidic compartment within the food vacuole possibly haemozoin. Pfmdr1 copy number does not affect quinine subcellular localization.

Quinine is a standard drug for treating severe malaria in Africa, and it is also increasingly used to treat uncomplicated disease. However, failures of quinine therapy are common, and it is unknown if failures in Africa are due to drug resistance. Recent studies have identified associations between in vitro quinine sensitivity and polymorphisms in genes encoding putative transporters, including well-described polymorphisms in pfcrt and pfmdr1 and varied numbers of DNNND or DDNHNDNHNND repeats in microsatellite 4760 (ms4760) of the predicted sodium-hydrogen exchanger, pfnhe1. To better characterize mediators of quinine response, we assessed associations between genetic polymorphisms, in vitro quinine sensitivity, and quinine treatment responses in Kampala, Uganda. Among 172 fresh clinical isolates tested in vitro, decreasing sensitivity to quinine was associated with accumulation of pfmdr1 mutations at codons 86, 184, and 1246. Nearly all parasites had pfcrt 76T, preventing analysis of associations with this mutation. pfnhe1 ms4760 was highly polymorphic. Parasites with 2 copies of either ms4760 repeat showed modest decreases in quinine sensitivity compared to those with 1 or ≥3 repeats, but the differences were not statistically significant. None of the above polymorphisms predicted treatment failure among 66 subjects treated with quinine for uncomplicated malaria. Our data suggest that quinine sensitivity is a complex trait and that known polymorphisms in pfcrt, pfmdr1, and pfnhe1, while associated with quinine sensitivity, are not robust markers for quinine resistance.

Peritoneal dialysis rapidly reduced blood ammonia concentration in this child with arginino-succinic acid-lyase deficiency, whereas exchange transfusion did not. Yet this reduction in plasma ammonia level did not produce clinical improvement. We speculate that the effects of ammonia intoxication on the highly susceptible neonatal metabolism are due to an accumulation of toxic products and to an altered energy metabolism. Both aspects must be considered in any attempt to treat congenital hyperammonaemia.

A 45-year-old Canadian man, who had recently returned from Cameroon, complained of fever lasting eight days. He had 40% parasitemia with Plasmodium falciparum. In spite of oral therapy with chloroquine, quinine, and tetracycline, the patient's condition deteriorated. Although his clinical condition improved more slowly, the patient's parasitemia improved considerably after exchange transfusion and the institution of parenteral quinidine therapy. Exchange transfusion may be life-saving in falciparum malaria and should be instituted early in severe cases.

Images

Glucose phosphate isomerase (GPI) deficiency with severe haemolysis and hydrops fetalis was found in the first child of unrelated, healthy Caucasian parents. The child died at 3 hours. Both parents were found to have 50% of normal red cell GPI activity and qualitative tests on their red cells and white cells showed that each was heterozygous for a different GPI variant allele associated with enzyme deficiency. Tests on the placenta showed that the propositus was a 'compound' heterozygote. Examination of amniotic cells obtained by amniocentesis on the mother at 28 weeks in her second pregnancy led to the prenatal diagnosis of GPI deficiency. This second child, a 'compound' heterozygote at the GPI locus indistinguishable from the first, was successfully treated by immediate exchange transfusion and subsequent blood transfusions.

Images

Quinine, the widely used antimalaria agent, was found to increase the cytotoxicity of epideoxorubicin (epiDXR) in resistant DHD/K12 rat colon cancer cells in vitro. Quinine appeared as slightly less effective than quinidine or verapamil for anthracycline potentiation but its weaker cardiotoxicity could counterbalance this disadvantage in vivo. Serum from six patients treated by conventional doses of quinine (25-30 mg kg-1 day-1) was demonstrated to enhance the accumulation of epiDXR in DHD/K12 cells as judged by fluorescence microscopy and HPLC assay (1.6 to 6-fold compared with control serum). In this patients quinine concentrations in serum ranged from 4.4 to 10.1 micrograms ml-1. Our results suggest that quinine could be safely used as anthracycline resistance modifier in clinical practice.

Images

Multicenter trials in Southeast Asia have shown better survival rates among patients with severe malaria, particularly those with high parasitemia levels, treated with intravenous (IV) artesunate than among those treated with quinine. In Europe, quinine is still the primary treatment for severe malaria. We conducted a retrospective analysis for 25 travelers with severe malaria who returned from malaria-endemic regions and were treated at 7 centers in Europe. All patients survived. Treatment with IV artesunate rapidly reduced parasitemia levels. In 6 patients at 5 treatment centers, a self-limiting episode of unexplained hemolysis occurred after reduction of parasitemia levels. Five patients required a blood transfusion. Patients with posttreatment hemolysis had received higher doses of IV artesunate than patients without hemolysis. IV artesunate was an effective alternative to quinine for treatment of malaria patients in Europe. Patients should be monitored for signs of hemolysis, especially after parasitologic cure.

Incubation of washed bacterial and ribosomal suspensions with optochin or quinine hydrochloride caused an increase in the turbidity of the suspensions and the appearance of electron-dense cytoplasmic aggregates in the treated cells. These effects were more pronounced with optochin hydrochloride than with quinine hydrochloride, and they did not correlate with the relative sensitivities of different bacteria to growth inhibition by optochin or quinine.

Images

Lead toxicity has gained increasing attention in the public media because of its ubiquitous distribution in the environment and the potentially serious medical complications that it can induce, particularly in children. We present a case of an asymptomatic Hispanic woman who exhibited a unique form of pica during her pregnancy. By serendipity, she agreed to enroll into a lead screening study at our medical center when she presented to deliver her child. Her blood lead level was 119.4 microg/dL at delivery, and simultaneous measurement of the neonate's cord blood lead level was 113.6 microg/dL. The infant underwent an exchange transfusion, and the mother was treated with oral 2,3-dimercaptosuccinic acid. Both demonstrated dramatic biochemical improvement.

Images

Sickle cell intrahepatic cholestasis (SCIC) is a rare complication of sickle cell anemia, characterized by marked hyperbilirubinemia and acute hepatic failure with an often fatal course. However, the few reported adult cases that were treated with exchange transfusion had a favorable outcome. We herein describe a 48-year-old African-American man with hemoglobin S/B thalassemia and previously treated hepatitis C with compensated cirrhosis, who presented with a total bilirubin of 59.7 mg/dL and direct bilirubin of 43.6 mg/dL in the absence of choledocholithiasis. Despite an exchange transfusion and aggressive packed red blood cell transfusions, which successfully decreased the hemoglobin S levels to <15%, he perished from progressive hepatic and renal failure. Autopsy demonstrated extensive intrahepatocellular and intracanalicular cholestasis in a background of cirrhosis. Our case suggests that poor prognostic factors for adult SCIC patients treated with exchange transfusion may include older age and underlying hepatic disease.

Images

Of 40 patients with thrombotic thrombocytopenic purpura, 17 were treated with plasma exchange, 15 with exchange transfusions, and 6 with both types of therapy. One patient died before being treated and another patient was seen but not treated. Plasma exchange was performed daily for a mean of seven exchanges per patient. The replacement fluid during plasma exchange was fresh frozen plasma in all cases. The complete response rates for each type of treatment were as follows: 88% for plasma exchange (15 patients), 47% for exchange transfusions (7 patients), and 67% for exchange transfusions and plasma exchange (4 patients). Clinical and laboratory factors were examined for any statistically significant association with therapy response. Treatment with plasma exchange was statistically the initial factor most strongly associated with prognosis. Paresis, paresthesias, seizures, mental status change, and coma showed no association with response to treatment. Some of the laboratory factors that did not show significant association with treatment response were the initial creatinine, hemoglobin, platelet count, lactate dehydrogenase, and total bilirubin. This study supports the hypothesis that plasma exchange has significantly improved the prognosis of patients with thrombotic thrombocytopenic purpura. These patients should be treated aggressively regardless of the severity of their symptoms.

The effects of adding rifampin to quinine were assessed in adults with uncomplicated falciparum malaria. Patients were randomized to receive oral quinine either alone (n = 30) or in combination with rifampin (n = 29). Although parasite clearance times were shorter in the quinine-rifampin-treated patients (mean ± standard deviation, 70 ± 21 versus 82 ± 18 h; P = 0.023), recrudescence rates were five times higher (n = 15 of 23; 65%) than those obtained with quinine alone (n = 3 of 25; 12%), P < 0.001. Patients receiving rifampin had significantly greater conversion of quinine to 3-hydroxyquinine and consequently considerably lower concentrations of quinine in their plasma after the second day of treatment (median area under the plasma drug concentration-time curve from day zero to day 7 = 11.7 versus 47.5 μg/ml · day, P < 0.001). Rifampin significantly increases the metabolic clearance of quinine and thereby reduces cure rates. Rifampin should not be combined with quinine for the treatment of malaria, and the doses of quinine should probably be increased in patients who are already receiving rifampin treatment.

The effects of exchange transfusion with Fluosol DA (FDA) or stroma-free hemoglobin on the outcome of pneumococcal infection in rats were determined. Rats were sham transfused or exchange transfused with 25 ml of FDA or stroma-free hemoglobin. They were then challenged intraperitoneally with Streptococcus pneumoniae type 3 and treated with penicillin for 120 h. Only 2 of 15 (13.3%) FDA-transfused rats were alive at 312 h compared with 11 of 15 (73.3%) concurrently studied sham-transfused control rats (P = 0.0016). Of 10 stroma-free hemoglobin-transfused rats and 10 concurrently studied sham-transfused control rats (P = 0.98), 8 from each group (80%) were alive at 312 h. Penicillin therapy only suppressed pneumococcal infection in FDA-transfused rats, and relapse occurred after therapy was stopped. This effect could not be attributed to interference with the bactericidal activity of penicillin against pneumococci, to an alteration in the pneumococcal burden before penicillin therapy or to an alteration of the leukocyte and polymorphonuclear leukocyte response by FDA. In contrast, pneumococcal infection in stroma-free hemoglobin-transfused rats was cured with penicillin therapy. These data showed that FDA altered the ability of rats to respond to pneumococcal infection.

Resistance to the amino alcohol quinine has been associated with polymorphisms in pfnhe, a sodium hydrogen exchanger. We investigated the role of this gene in quinine resistance in vitro in isolates from Kenya. We analyzed pfnhe whole-gene polymorphisms, using capillary sequencing, and pfcrt at codon 76 (pfcrt-76) and pfmdr1 at codon 86 (pfmdr1-86), using PCR-enzyme restriction methodology, in 29 isolates from Kilifi, Kenya, for association with the in vitro activities of quinine and 2 amino alcohols, mefloquine and halofantrine. In vitro activity was assessed as the drug concentration that inhibits 50% of parasite growth (IC50). The median IC50s of quinine, halofantrine, and mefloquine were 92, 22, and 18 nM, respectively. The presence of 2 DNNND repeats in microsatellite ms4760 of pfnhe was associated with reduced susceptibility to quinine (60 versus 227 nM for 1 and 2 repeats, respectively; P < 0.05), while 3 repeats were associated with restoration of susceptibility. The decrease in susceptibility conferred by the 2 DNNND repeats was more pronounced in parasites harboring the pfmdr1-86 mutation. No association was found between susceptibility to quinine and the pfcrt-76 mutation or between susceptibility to mefloquine or halofantrine and the pfnhe gene and the pfcrt-76 and pfmdr1-86 mutations. Using previously published data on the in vitro activities of chloroquine, lumefantrine, piperaquine, and dihydroartemisinin, we investigated the association of their activities with pfnhe polymorphism. With the exception of a modulation of the activity of lumefantrine by a mutation at position 1437, pfnhe did not modulate their activities. Two DNNND repeats combined with the pfmdr1-86 mutation could be used as an indicator of reduced susceptibility to quinine.

Background

The efficacy of intravenous quinine, which is the mainstay for treating severe malaria in children, is decreasing in South East Asia and Africa. Artemisinin derivatives are a potential alternative to quinine. However, their efficacy compared to quinine in treating severe malaria in children is not clearly understood. The objective of this review was to assess the efficacy of parenteral artemisinin derivatives versus parenteral quinine in treating severe malaria in children.

Methods

All randomized controlled studies comparing parenteral artemisinin derivatives with parenteral quinine in treating severe malaria in children were included in the review. Data bases searched were: The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2007), MEDLINE (1966 to February 2008), EMBASE (1980 to February 2008), and LILACS (1982 to February 2008). Dichotomous variables were compared using risk ratios (RR) and the continuous data using weighted mean difference (WMD).

Results

Twelve trials were included (1,524 subjects). There was no difference in mortality between artemisinin derivatives and quinine (RR = 0.90, 95% CI 0.73 to 1.12). The artemisinin derivatives resolved coma faster than quinine (WMD = -4.61, 95% CI: -7.21 to -2.00, fixed effect model), but when trials with adequate concealment only were considered this differences disappeared. There was no statistically significant difference between the two groups in parasite clearance time, fever clearance time, incidence of neurological sequelae and 28th day cure rate. One trial reported significantly more local reactions at the injection site with intramuscular quinine compared to artemether. None of the trials was adequately powered to demonstrate equivalence.

Conclusion

There was no evidence that treatment of children with severe malaria with parenteral artemisinin derivatives was associated with lower mortality or long-term morbidity compared to parenteral quinine. Future studies require adequately powered equivalence trial design to decide whether both drugs are equally effective.

A case of ocular quinine toxicity is described which showed the typical acute visual loss and subsequent recovery. Vermiform motion of the pupil was noted 48 hours after overdose. This acute effect has not been reported before. Although acute systemic intoxication may respond to removal of quinine from the gut and circulation, there is no evidence that any treatment affects the visual prognosis. The action of quinine on the retina is unknown. We suggest it may block cholinergic neurotransmission in the inner synaptic layer.

Admission of a patient to an intensive care unit for management of direct consequences of a hematologic or oncologic disease is occasionally necessary. Such problems included exchange transfusion, sepsis, compression of vital structures by malignant tumor, metabolic derangements, leukostasis, post-operative care, major sickling episodes in vital organs, and disseminated coagulopathy. More often, however, hematologic complications arise in the child critically ill from other causes, such as trauma or infections. The first two sections of this review address blood transfusion and hemostasis, topics likely to have wide application in the care of critically ill children. The last portion discusses problems unique to patients with sickling or malignant disease.

Images

Although sodium nitroprusside (SNP) is often used in pediatric intensive care units, cyanide toxicity can occur after SNP treatment. To treat SNP-induced cyanide poisoning, antidotes such as amyl nitrite, sodium nitrite, sodium thiosulfate, and hydroxycobalamin should be administered immediately after diagnosis. Here, we report the first case of a very young infant whose SNP-induced cyanide poisoning was successfully treated by exchange transfusion. The success of this alternative method may be related to the fact that exchange transfusion not only removes the cyanide from the blood but also activates detoxification systems by supplying sulfur-rich plasma. Moreover, exchange transfusion replaces cyanide-contaminated erythrocytes with fresh erythrocytes, thereby improving the blood's oxygen carrying capacity more rapidly than antidote therapy. Therefore, we believe that exchange transfusion might be an effective therapeutic modality for critical cases of cyanide poisoning.

An 18-month-old previous healthy girl who had ingested 442 mg elemental iron/kg was admitted to a paediatric intensive care unit. The child was treated with gastric lavage, whole bowel irrigation and intravenous deferoxamine. After 2 h of standard therapy serum iron had risen threefold to 1362 µg/dl (244 µmol/l). The child was treated with exchange transfusion (ET; 52 ml/kg) and serum iron fell to 134 µg/dl (24 µmol/l). The patient made an uncomplicated recovery. ET should be considered in severe iron poisoning when standard therapy is inadequate.

The activities of primaquine in combination with quinine or artesunate against asexual- and sexual-stage parasites were assessed in 176 adult Thai patients with uncomplicated Plasmodium falciparum malaria. Patients were randomized to one of the six following 7-day oral treatment regimens: (i) quinine alone, (ii) quinine with tetracycline, (iii) quinine with primaquine at 15 mg/day, (iv) quinine with primaquine at 30 mg/day, (v) artesunate alone, or (vi) artesunate with primaquine. Clinical recovery occurred in all patients. There were no significant differences in fever clearance times, rates of P. falciparum reappearance, or recurrent vivax malaria between the six treatment groups. Patients treated with artesunate alone or in combination with primaquine had significantly shorter parasite clearance times (mean ± standard deviation = 65 ± 18 versus 79 ± 21 h) and lower gametocyte carriage rates (40 versus 62.7%) than those treated with quinine (P ≤ 0.007). Primaquine did not affect the therapeutic response (P > 0.2). Gametocytemia was detected in 98 patients (56% [22% before treatment and 34% after treatment]). Artesunate reduced the appearance of gametocytemia (relative risk [95% confidence interval] = 0.34 [0.17 to 0.70]), whereas combinations containing primaquine resulted in shorter gametocyte clearance times (medians of 66 versus 271 h for quinine groups and 73 versus 137 h for artesunate groups; P ≤ 0.038). These results suggest that artesunate predominantly inhibits gametocyte development whereas primaquine accelerates gametocyte clearance in P. falciparum malaria.

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.

Quinine poisoning is rare but serious. Attempts at treatment by active removal have proved unsuccessful because of its high degree of protein binding. We describe two cases of non-accidental overdose of quinine (19.5 g and 15 g) with potentially fatal serum quinine levels. Both patients were treated by 2 periods of charcoal haemoperfusion during which quinine clearances of up to 125 ml/min were obtained. Both patients recovered, though one had some residual visual disturbance. We suggest that in cases of quinine poisoning, charcoal haemoperfusion may be a safe and effective method of drug removal, to be used with stellate ganglion block.

Calcium retained at binding sites of the sarcoplasmic reticulum membranes isolated from rabbit skeletal muscle requires 10-5 – 10-4 M ATP to exchange with 45Ca added to the medium. The ATP requirement for Ca exchangeability was observed with respect to the "intrinsic" Ca of the reticulum membranes and the fraction of Ca that is "actively" bound in the presence of ATP. Furthermore, a concentration of free Ca in the medium higher than 10-8 M is required for ATP to promote Ca exchangeability. This exchangeability is not influenced by caffeine, quinine, procaine, and tetracaine, and Ca that is either nonexchangeable (in the absence of ATP) or exchangeable (in the presence of ATP) is released by 1–5 mM quinine or tetracaine, but neither caffeine (6 mM) nor procaine (2–5 mM) has this effect. Quinine or tetracaine also releases Ca and Mg bound passively to the reticulum membranes. A possible role of ATP in maintaining the integrity of cellular membranes is discussed, and the effects of caffeine, quinine, and of local anesthetics on the binding of Ca by the isolated reticulum are related to the effects of these agents on 45Ca fluxes and on the twitch output observed in whole muscles.

Calcium retained at binding sites of the sarcoplasmic reticulum membranes isolated from rabbit skeletal muscle requires 10-5 - 10-4 M ATP to exchange with 45Ca added to the medium. The ATP requirement for Ca exchangeability was observed with respect to the "intrinsic" Ca of the reticulum membranes and the fraction of Ca that is "actively" bound in the presence of ATP. Furthermore, a concentration of free Ca in the medium higher than 10-8 M is required for ATP to promote Ca exchangeability. This exchangeability is not influenced by caffeine, quinine, procaine, and tetracaine, and Ca that is either nonexchangeable (in the absence of ATP) or exchangeable (in the presence of ATP) is released by 1–5 mM quinine or tetracaine, but neither caffeine (6 mM) nor procaine (2–5 mM) has this effect. Quinine or tetracaine also releases Ca and Mg bound passively to the reticulum membranes. A possible role of ATP in maintaining the integrity of cellular membranes is discussed, and the effects of caffeine, quinine, and of local anesthetics on the binding of Ca by the isolated reticulum are related to the effects of these agents on 45Ca fluxes and on the twitch output observed in whole muscles.

We report a case of quinine overdose in a 47-year-old man who presented with blindness. Fundus photography demonstrates the acute and subsequent retinal changes, and his visual recovery to normal acuity with visual field constriction is documented. Pupillary and electrodiagnostic findings are recorded. Stellate ganglion block has been widely advocated as a helpful therapeutic measure, but out patient was treated with a unilateral stellate ganglion block without apparent benefit to that eye. From a review of the literature we believe that quinine produces its effects by toxicity on the retina rather than by vasoconstriction and that stellate ganglion block probably does not alter the natural history of the retinal toxicity.

Images