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C D Fitch

Publications and source records attributed to C D Fitch.

At least 73 records · Page 4Linked to original sources
PubMed1975

Amodiaquin accumulation by mouse erythrocytes infected with Plasmodium berghei.

[14C]amodiaquin accumulation by washed erythrocyte preparations was characterized to permit comparisons with chloroquine accumulation. Erythrocytes infected with Plasmodium berghei CS (chloroquine-susceptible) accumulate amodiaquin by a saturable process that has an apparent dissociation constant for amodiaquin of 7.6 X 10(-8) M and is competitively inhibited by chloroquine, quinine and quinacrine, as is the process of chloroquine accumulation. Within experimental error, the K1 of 8 X 10(-7) M estimated for chloroquine is the same regardless of whether the drug being accumulated is [14C]amodiaquin or [14C]chloroquine. Likewise, the K1 for amodiaquin is the same regardless of which drug is being accumulated. In addition, glucose stimulates and hydrogen ion, cold or interruption of glycolysis inhibits amodiaquin as well as chloroquine accumulation. These findings are evidence that a single process serves to accumulate both drugs. In the absence of substrate, erythrocytes infected with P. berghei CR (chloroquine-resistant) accumulate twice as much amodiaquin as chloroquine, and they accumulate more amodiaquin than do erythrocytes infected with P. berghei CS. These differences occur because P. berghei CR infects polychromatophilic erythrocytes possessing a high-affinity, substrate-independent process of accumulation to which amodiaquin has greater access than chloroquine. In the presence of glucose, amodiaquin accumulation by erythrocytes infected with P. berghei CR, when plotted as a function of amodiaquin concentration in the medium, describes a sigmoid curve.

Amodiaquine↗
PubMed1974

Chloroquine-resistant Plasmodium falciparum: effect of substrate on chloroquine and amodiaquin accumulation.

Glucose stimulates the high-affinity processes of chloroquine and amodiaquin accumulation in owl monkey erythrocytes infected with a chloroquine-susceptible strain of Plasmodium falciparum. Although these erythrocytes have greater ability to accumulate amodiaquin than chloroquine, glucose has relatively less effect on amodiaquin accumulation than on chloroquine accumulation. In contrast to these findings with chloroquine-susceptible P. falciparum, glucose stimulates amodiaquin but not chloroquine accumulation in erythrocytes infected with chloroquine-resistant P. falciparum. This lack of function of a substrate-dependent component of chloroquine accumulation distinguishes chloroquine-resistant from chloroquine-susceptible P. falciparum.

Amodiaquine↗
PubMed1974

High-affinity accumulation of chloroquine by mouse erythrocytes infected with Plasmodium berghei.

Washed erythrocytes infected with chloroquine-susceptible (CS) or with chloroquine-resistant (CR) P. berghei were used in model systems in vitro to study the accumulation of chloroquine with high affinity. The CS model could achieve distribution ratios (chloroquine in cells: chloroquine in medium) of 100 in the absence of substrate. 200-300 in the presence of 10 mM pyruvate or lactate, and over 600 in the presence of 1 mM glucose or glycerol. In comparable studies of the CR model, the distribution ratios were 100 in the absence of substrate and 300 or less in the presence of glucose or glycerol. The presence of lactate stimulated chloroquine accumulation in the CR model, whereas the presence of pyruvate did not. Lactate production from glucose and glycerol was undiminished in the CR model, and ATP concentrations were higher than in the CS model. Cold, iodoacetate, 2,4-dinitrophenol, or decreasing pH inhibited chloroquine accumulation in both models. These findings demonstrate substrate involvement in the accumulation of chloroquine with high affinity.In studies of the CS model, certain compounds competitively inhibited chloroquine accumulation, while others did not. This finding is attributable to a specific receptor that imposes structural constraints on the process of accumulation. For chloroquine analogues, the position and length of the side chain, the terminal nitrogen atom of the side chain, and the nitrogen atom in the quinoline ring are important determinants of binding to this receptor.

Acetates↗
PubMed1973

Chloroquine-resistant Plasmodium falciparum: difference in the handling of 14C-amodiaquin and 14C-chloroquine.

(14)C-amodiaquin and (14)C-chloroquine were used to study drug binding by preparations of owl monkey erythrocytes infected either with a chloroquine-susceptible (CS) or with a chloroquine-resistant (CR) strain of P. falciparum. Both of these drugs are derivatives of 4-aminoquinoline, but they differ in their side chains, and there are differences in the way they are handled by preparations of erythrocytes infected with malaria parasites. Although the apparent association constant for the binding of either drug is approximately 10(7) mol(-1), two to three times more radioactivity was bound from (14)C-amodiaquin than from (14)C-chloroquine. Furthermore, there was no apparent difference between CS and CR parasites with respect to (14)C-amodiaquin binding, whereas erythrocytes infected with CR parasites have a deficiency of (14)C-chloroquine binding. This difference in the handling of amodiaquin probably accounts for its superiority in the treatment of the owl monkey and of humans infected with CR P. falciparum.

Amodiaquine↗
PubMed1969

Chloroquine resistance in malaria: a deficiency of chloroquine binding.

Chloroquine-(14)C was used to study the processes which concentrate chloroquine in mouse red blood cells infected with chloroquine-sensitive or with chloroquine-resistant Plasmodium berghei. The initial rates of uptake and exchange of chloroquine-(14)C were both too fast to measure, yet large concentration gradients were maintained by the cells. When red blood cells were exposed to 10(-8)M chloroquine at 22 degrees C, with pH between 7.2 and 7.4, steady-state gradients of chloroquine-(14)C were approximately 600:1 (cells:medium) for cells infected with chloroquine-sensitive parasites, 100:1 for cells comparably infected with chloroquine-resistant parasites, and 14:1 for uninfected cells. The processes responsible for these gradients were saturable, in agreement with the proposal of chloroquine binding to cellular constituents. No degradation of chloroquine was detected. The major difference between the chloroquine-sensitive and -resistant parasites was deficiency of high-affinity binding of chloroquine by cells infected with chloroquine-resistant parasites. This deficiency explains the reduced ability of chloroquine-resistant parasites to concentrate chloroquine, and it suggests that chloroquine resistance is due to a decrease in the number, affinity, or accessibility of chloroquine receptor sites on a constituent of the malaria parasite.

Animals↗