Plasmodium falciparum: Activity of artemisinin against Plasmodium falciparum cultured in sickle trait hemoglobin AS and normal hemoglobin AA red blood cells.

The presence of sickle hemoglobin causes accumulation of hemoglobin degradative products that favor oxidative reaction in erythrocytes. Artemisinin derivatives exert antiparasite effects through oxidative reactions within infected erythrocytes. Using [(3)H]-hypoxanthine incorporation, we therefore did an in vitro comparison of IC(50) values for artemisinin in Plasmodium falciparum-infected erythrocytes from sickle cell trait (AS) and normal (AA) individuals. IC(50) values for chloroquine served as control. Without drugs, parasite growth was similar in AA and AS erythrocytes. Gender, age and blood group of donors had no significant effects on parasite growth. IC(50) value for artemisinin was 27+/-14nM in AS (N=22) compared to 24+/-9nM (N=27) in AA erythrocytes (P=0.4). IC(50) values for chloroquine were also similar in AA (22+/-8nM) and AS (20+/-11nM) erythrocytes. These results show no evidence of elevated artemisinin activity on P. falciparum in AS erythrocytes in vitro.

Blockage of one class of potassium channel alters the effectiveness of halothane in a brain circuit of Drosophila.

At concentrations comparable to those used in the clinic, halothane has profound effects on a neuronal pathway devoted to the escape reflex of the fruit fly, Drosophila melanogaster. We studied the influence of the potassium channel that is encoded by the Shaker gene on the halothane sensitivity of this circuit. Shaker channels were specifically inactivated either by genetic means, using strains with two different severe Shaker mutations, or by pharmacologic means, using ingestion of millimolar concentrations of 4-aminopyridine. In all cases, halothane potency decreased substantially. To ensure that the genetic alteration was specific, both mutations were studied as stocks that had been repeatedly backcrossed to a control strain. The specificity of the pharmacologic inhibition was demonstrated by the fact that 4-aminopyridine had no effect on halothane potency in a Shaker mutant. Quantitative differences in the effects of channel inhibition between males and females suggested a sexual dimorphism in the functional brain anatomy of the reflex circuit.

Genetic effects on an anesthetic-sensitive pathway in the brain of Drosophila.

General anesthetics are known to inhibit the electrically induced escape response of the fruitfly through action within the brain. We examined this response and its sensitivity to anesthetics in several mutants that cause significant disruption of the mushroom body and other structures of the central brain in adult flies. Because we show here that anesthesia sensitivity is influenced by genetic background, we have used a set of congenic mutant lines. Sensitivity to halothane is normal in most of these lines, indicating that the anesthetic target is unaffected by the gross status of the central brain. Thus, for the escape response, anesthetic sensitivity is not a global feature but reflects action at a localized target. Only the mushroom body defect (mud) line showed an increased sensitivity of the escape response to halothane. Sensitivity to two other anesthetics is also perturbed in this line, albeit less dramatically so. The behavior of mud/+ heterozygotes and the comparison of brain anatomy among all the mutant lines imply that the effect of the mud mutation on anesthesia is not via gross alteration of central brain structures. The possibility that an adventitious mutation in the mud line is responsible for the effects on anesthesia is disfavored by the behavior of a heterozygote between two mud alleles. Although we do not yet know whether the mud gene encodes an anesthetic target or influences the functioning of an anesthetic-sensitive neuron in this pathway, our work indicates that this gene regulates the effects of halothane on a circumscribed pathway.

A system for the delivery of general anesthetics and other volatile agents to the fruit-fly Drosophila melanogaster.

The system described here provides a simple method of delivering anesthetic vapor to the fruit-fly Drosophila melanogaster. This system delivers known concentrations of volatile anesthetic vapor obtained from liquid anesthetics in a continuous gas stream of pure humidified air. It controls for evaporation, and absorption of volatile agents, whilst allowing for extracellular electrophysiological recordings. Recordings were made from the fly's escape muscles, the jump tergotrochanter muscle (TTM) and the flight dorsal longitudinal muscle (DLM). The system minimizes the quantity of anesthetic used, making the use of more expensive and more conventional anesthetics cost effective and practicable. It also permits monitoring the fly's movements during anesthesia.