The Activities of Chlorinated Lincomycin Derivatives against Infections with Plasmodium Cynomolgi in Macaca Mulatta *

Lh, Schmidt; Harrison, Joy; Ellison, R; P, Worcester

doi:10.4269/ajtmh.1970.19.1

Cited by 33 publications

(24 citation statements)

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“…Previous reports indicated that U-21 and U-24 were relatively slow in clearing P. cynomolgi in monkeys and suggested that this slowness of action might be a problem with fulminating infections such as P. falciparwn (7,9). Evidently these compounds affected parasites in the present study shortly after the first dose since changes in parasite morphology were seen within 24 hr.…”

Section: Discussionsupporting

confidence: 60%

“…Promising compounds in this regard are two chlorinated lincomycin analogues which are active against Plasmodium cynomolgi in rhesus monkeys (7,9) as well as chloroquine-resistant or normally sensitive strains of P. berghei in mice (3,7). These compounds, designated U-21 (clindamycin hydrochloride) and U-24 (Ndemethyl-4'-pentyl clindamycin hydrochloride), are prepared by chlorination of lincomycin hydrochloride at the 7 position and substitution of methyl and N-propyl in the amino-sugar moiety ( Fig.…”

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confidence: 99%

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Activity of Two Chlorinated Lincomycin Analogues Against Chloroquine-Resistant Falciparum Malaria in Owl Monkeys

Powers

Jacobs

1972

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

Activity of Two Chlorinated Lincomycin Analogues Against Chloroquine-Resistant Falciparum Malaria in Owl Monkeys

Powers

Jacobs

1972

Antimicrob Agents Chemother

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“…The B strain of P. cynomolgi was used in these studies. Reference should be made to earlier reports (10,(18)(19)(20) for detailed descriptions of: (i) the origin of this strain and its routine maintenance in this laboratory; (ii) procedures employed in obtaining batches of infected Anopheles freeborni and preparing, measuring, and delivenng sporozoite inocula; (iii) methods used for routine detection and quantification of parasitemias; (iv) characteristics of untreated sporozoite-induced infections; (v) responses of established infections to standard blood schizonticidal and tissue schizonticidal drugs; and (vi) procedures employed in assessing prophylactic and radical curative activities of new agents.…”

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confidence: 99%

“…In three, involving 19 The evaluation of the radical curative activity of floxacrine, carried out with well-established procedures (18,20), involved work with 17 monkeys. Eleven were infected specifically for this appraisal, receiving inocula ranging from 1.0 x 106 to 3.0 x 106 sporozoites.…”

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confidence: 99%

“…Doses of 5.0 mg/kg or greater were administered alone; however, when parasitemia reappeared, infections were retreated with chloroquine, at 5.0 mg of base per kg daily for 7 days. This retreatment procedure is a routine for discriminating between recrudescence due to persistence of small numbers of blood schizonts and relapse due to continued multiplication of tissue schizonts (18,20). Parasitemias were monitored on Giemsa-stained thick and thin blood films prepared on alternate days throughout the evaluation of curative activity.…”

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confidence: 99%

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Antimalarial Properties of Floxacrine, a Dihydroacridinedione Derivative

Schmidt

1979

Antimicrob Agents Chemother

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Evaluations of the activities of floxacrine [7-chloro-10-hydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydroacridine-1,9(2H, 10H)-dione] in owl monkeys infected with trophozoites of a chloroquine-quinine-resistant strain of Plasmodium falciparum, a strain of this plasmodium resistant to both of these quinolines and pyrnmethamine, or a strain of P. vivax resistant only to pyrimethamine showed that: (i) this compound regularly effected temporary clearance of parasitemia at daily doses of 1.25 to 2.5 mg/kg; (ii) doses required for the cure of established infections were larger by factors of 6 to 64 than those that effected parasite clearance; (iii) there was more than a 10-fold difference in doses required for the cure of infections with the different strains; and (iv) resistance to floxacrine developed rapidly. Evaluations of the activities of floxacrine in rhesus monkeys challenged with sporozoites of P. cynomolgi showed that: (i) 0.625-mg/kg doses administered daily throughout the incubation period provided complete protection against infection; (ii) single 40.0-mg/kg doses delivered 2 h before sporozoite challenge were without prophylactic activity; and (iii) daily doses of 40.0 mg/kg, the maximum tolerated level, productive of a hemorrhagic syndrome in some subjects, would not cure established infections. These observations suggest that the potential contribution of floxacrine to malaria therapy would be limited to the prophylactic area and for practical reasons would be restricted there by the requirement for daily dosage.Floxacrine (Fig. 1) identical doses of this dihydroacridinedione derivative were required for the cure of infections with the drug-susceptible strain and strains resistadnt to chloroquine, pyrimethamine, and sulfadoxine; (iii) floxacrine was approximately twice as active when administered subcutaneously as when delivered orally; and (iv) irrespective of route of administration, the compound had a favorable therapeutic index; i.e., the ratio of the 50% lethal dose to the dose required to cure 50% of infections (LD5o/CD5o) was in excess

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