Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum

Self Cite

Pilot appraisals of the activities of a selected group of 4-quinolinemethanols against acute Plasmodium falciparum infections in owl monkeys indicated that compounds of this class are equally active against infections with chloroquine-resistant and chloroquine-susceptible strains and that this efficacy is not compromised by concomitant resistance to pyrimethamine, and in addition, identified three derivatives with outstanding activity (WR-226,253; WR-142,490; and WR-184,806). WR-142,490, the second 4-quinolinemethanol evaluated in the above model, was five times as active as chloroquine against infections with the chloroquine-susceptible, pyrimethamine-resistant strain and had a much larger therapeutic index. Expanded evaluations designed to support projected studies in human volunteers provided full confirmation of the pilot appraisals and in addition showed: (i) that the activity of WR-142,490 was a function of the total dose delivered, single doses being as effective as three or seven fractional doses administered over as many days; (ii) that intravenous administration of this agent was feasible and effective; and (iii) that the compound was at least as active against infections with P. vivax as against infections with P. falciparum . Companion studies in rhesus monkeys infected with P. cynomolgi showed that WR-142,490 lacked prophylactic or radical curative activity, but that it was as effective as chloroquine as a companion to primaquine in a combination curative drug regimen. The results of human volunteer and field trials agree well with comparable segments of these experimental evaluations.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Antimalarial Activities of Various 4-Quinolinemethanols with Special Attention to WR-142,490 (Mefloquine)

Schmidt

Crosby

Rasco

et al. 1978

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“…A similar difference between chloroquine-susceptible and chloroquine-resistant parasites has been found in studies of P. falciparum (5). Moreover, the superiority of amodiaquine {4-[(7-chloro-4-quinolyl)-amino]-a-[diethylamino]-ocresol) in treating chloroquine-resistant P. falciparum (19) correlates with greater accumulation of amodiaquine than of chloroquine (7,10), despite the structural similarity of the two drugs (3,19). Finally, we have found that J?.…”

mentioning

confidence: 68%

Erythrocyte Surface: Novel Determinant of Drug Susceptibility in Rodent Malaria

Fitch

Chevli

1978

To study the role of the erythrocyte membrane in the process of chloroquine accumulation, surface polypeptides were digested with a nonspecific protease from Streptomyces griseus . This treatment activated a saturable process of chloroquine accumulation with an affinity and a specificity similar to those of mouse erythrocytes infected with Plasmodium berghei CS (chloroquine susceptible). Studies of competitive inhibitors of chloroquine accumulation yielded the following approximate values for K i : amodiaquine, 2 × 10 −7 M; quinacrine, 5 × 10 −7 M; quinine, 2 × 10 −6 M; and mefloquine, 2 × 10 −5 M. Lack of a substrate requirement distinguished this process from the one used by P. berghei and permitted the protease to be used in studies of infected erythrocytes. Protease treatment of erythrocytes infected with P. berghei CR (chloroquine resistant) produced a dramatic transformation. Instead of describing a sigmoid curve, the process of chloroquine accumulation became saturable and substrate dependent, with a K diss of approximately 10 −8 M; i.e., protease-treated erythrocytes infected with P. berghei CR now behaved similarly to those infected with P. berghei CS. Coating the erythrocyte surface with albumin completely inhibited the protease-activated process of chloroquine accumulation. These findings are presented as evidence that erythrocyte surface components determine the affinity with which chloroquine is accumulated and thereby determine whether or not the malaria parasite will be susceptible to the drug.

“…injection has been demonstrated in more than 700 patients suffering from acute Plasmodium falciparum or Plasmodium vivax malaria (8,9,16). Moreover, amopyroquin seems more active than other 4-aminoquinolines in monkeys infected with chloroquine-resistant strains of P. falciparum (18).…”

mentioning

confidence: 99%

Disposition of amopyroquin in rats and rabbits and in vitro activity against Plasmodium falciparum

Pussard

Verdier

Faurisson

et al. 1988

The disposition of amopyroquin was studied in rats after a single 50-mg/kg (body weight) oral dose of amopyroquin base. After a rapid absorption phase, the drug concentrations decreased in the plasma, with a terminal half-life of 14.5 h. The drug was widely distributed in the liver and lungs and, to a lesser extent, in the kidneys and spleen. In rabbits, the kinetic parameters were compared after a single 10-mg/kg dose of amopyroquin base through intravenous, intramuscular (i.m.), and oral routes. The similar bioavailability values (0.67 and 0.69) suggested that the drug could be used through i.m. or oral administration. Clearance and distribution volume did not differ significantly among the three modes of administration, and the terminal half-lives were 18.1 3.3, 23.9 + 6.7, and 25.7 5.4 h for intravenous, i.m., and oral routes, respectively. The ratio of concentrations in erythrocytes and plasma was about 5 in rats and rabbits. Three metabolites were detected in both animal species (one was tentatively identified as the primary amine derivative). The amopyroquin in vitro activity was tested against four chloroquine-susceptible and 11 chloroquine-resistant African Plasmodium falciparum strains. For all isolates, the 50% inhibitory concentrations of amopyroquin were much lower than those of chloroquine and monodesethylamodiaquine.Amopyroquin, a compound similar in structure to amodiaquine, has been used since about 1957, and its antimalarial clinical efficacy after a single intramuscular (i.m.) injection has been demonstrated in more than 700 patients suffering from acute Plasmodium falciparum or Plasmodium vivax malaria (8, 9, 16). Moreover, amopyroquin seems more active than other 4-aminoquinolines in monkeys infected with chloroquine-resistant strains of P. falciparum (18).Because suitable analytical methods were not available, little is known about the metabolism and pharmacokinetic behavior of this drug. Recently, a high-performance liquid chromatographic method for analyzing amopyroquin has been applied to the determination of its half-life (t1/2) in rats during the 8 h after a 60-or 120-mg/kg (body weight) dose of amopyroquin given intraperitoneally (5). However, the purpose of this study was not to describe drug metabolism. Recent studies in humans have demonstrated that the chemical analog amodiaquine is rapidly converted after oral administration to a monodesethyl derivative responsible for the pharmacologic activity of the drug (4, 14). It was thus necessary to determine the metabolism of amopyroquin and its kinetic parameters.The present study was undertaken (i) to describe the disposition of amopyroquin in rats after oral administration, MATERIALS AND METHODSAnimal studies. (i) Rats. A total of 72 male SpragueDawley rats weighing 194 ± 15 g, fed on standard rat food VAR AQ4, and housed in conventional cages with controlled lighting were separated into 12 groups. All were given 50 mg of amopyroquin base (Substantia-Parke Davis, Courbevoie, France) per kg by an esophageal tube. Each group was sacrif...