L. H. Schmidt

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

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.

Development of Resistance to Penicillin by Pneumococci

Summary The present study has shown the following: (1) Two strains of pneumococcus developed resistance to penicillin as a result of serial passage through mice treated with this drug. (2) The rate at which resistance developed and the degree of resistance acquired varied significantly with the different strains. (3) The resistance of the one strain tested was not impaired by 30 serial passages through normal mice, indicating that, once established, resistance to penicillin is retained for a considerable period. (4) The development of resistance to penicillin in vivo was accompanied by an increase in resistance to this drug in vitro. (5) The response of the pneumococci to sulfonamides was not altered by the development of resistance to penicillin.

Comparison of the Curative Antimalarial Activities and Toxicities of Primaquine and Its d and l Isomers

This investigation was undertaken to determine whether either d-primaquine or l-primaquine has sufficient advantage over primaquine to warrant evaluation for curative activity in human volunteers infected with Plasmodium vivax. It was found: (i) that the capacities of the isomers and the racemate to cure infections with Plasmodium cynomolgi in rhesus monkeys were essentially identical; (ii) that the subacute toxicities of the isomers and racemate for this monkey were qualitatively the same, but that l-primaquine was three to five times as toxic as d-primaquine and at least twice as toxic as primaquine; and (iii) that the acute single-dose toxicities of the isomers for mice were not only qualitatively different, but that the d isomer was at least four times as toxic as l-primaquine. Since previous appraisals of curative activity and tolerability of 8-aminoquinolines in rhesus monkeys have correlated well with appraisals in human volunteers, attention was focused on results acquired with these test subjects. The relevant evaluations showed that d-primaquine had a therapeutic index at least twice that of primaquine. If this advantage carries over to man, problems that now complicate routine use of primaquine might be obviated. Therefore, a critical comparison of d-primaquine and primaquine in human volunteers seems indicated.

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

The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine.

Studies on the Neurotoxicity of Ethambutol and Its Racemate for the Rhesus Monkey

A toxicological study in the rhesus monkey employing graded doses of the antituberculosis drug ethambutol revealed a series of neurological symptoms which, in general, were found to be associated with specific neuroanatomical changes. With the largest doses of ethambutol, 1200 to 1600 mg./kg. administered daily for 4 months or somewhat longer, neurological symptoms appeared within 2 to 3 months after the beginning of treatment and increased in severity until the death of the animal. Symptoms consisted principally of incoordination of the limbs and associated reactions, muscular weakness, and apparent loss of vision. The major neuroanatomical findings included: (1) an extensive, centrally placed lesion in the optic chiasm and optic tracts with complete necrosis and gitter cells in its interior, and lesions of varying intensities in the optic nerves; (2) a large, oval, bilateral lesion in the reticular formation of the lower medulla consisting of spongiform degeneration with gitter cells, continuing to a lesser degree into the upper cervical cord; (3) ehromatolysis of large cells in the nucleus ruber, and of varying numbers of motor reticular cells of the upper pons and anterior horn cells of the spinal cord; and (4) pronounced swelling and at least partial demyelination of fibers in the pyramidal decussation, crossed fibers, and lateral pyramidal tracts, extending as far as the upper cervical cord. Treatment with graded doses of ethambutol indicated that the first lesions to appear were those in the optic chiasm alone, or in the optic chiasm and optic tracts, followed shortly by those in the optic nerves. These were the only lesions of significance when small doses of ethambutol were given over a long period of time with slight ataxia as the only symptom, or when large, acutely toxic doses were administered for short periods with resultant severe neurological symptoms of brief duration. The lesion in the reticular formation of the medulla included the areas of the lateral reticulospinal tracts and only appeared after prolonged treatment with high doses of ethambutol and prolonged neurological symptoms. Chromatolysis of large cells in the nucleus ruber and other areas was a late development; the number of cells affected varied with the dosage employed and the duration of treatment. Swelling and demyclination of decussating and crossed pyramidal fibers was likewise a late development but appeared only after prolonged treatment with high doses of ethambutol. Although ethambutol-racemate was only half as active as ethambutol in the treatment of tubereulous disease, it had at least twice as much neurotoxicity. At doses of 400 or 800 mg., the racemate provoked similar, but much more severe, neurological symptoms and neuroanatomical lesions than comparable doses of ethambutol. After higher doses, the symptoms appeared sooner and persisted only briefly before death occurred. Prominent lesions were present in the optic chiasm, optic tracts, and optic nerves.

Antimalarial activities of various 9-phenanthrenemethanols with special attention to WR-122,455 and WR-171,669.

Pilot appraisals of the activities of 16 specially selected 9-phenanthrenemethanols against acute infections with Plasmodium falciparum in owl monkeys showed that all were more active than the reference compound, WR-33,063. WR-122,455, the most active derivative, and WR-171,669, ranked sixth, were selected for study in human volunteers. To assist this undertaking, appraisals of both compounds in owl monkeys infected with various strains of P. falciparum were expanded. These assessments showed: (i) that WR-122,455 was four times as active as chloroquine against infections with chloroquine-sensitive strains and that WR-171,669 equalled chloroquine in activity; (ii) that these compounds were fully active against infections with strains resistant to chloroquine, pyrimethamine, or quinine, or to all three standard drugs; (iii) that the activity of WR-122,455 was a function of total dose, single doses being as effective as the same amounts delivered in three or seven daily fractions; and (iv) that a single dose of WR-122,455 conferred extended, although only partial, protection against challenges with trophozoites. Complementary experiments in rhesus monkeys inoculated with sporozoites of P. cynomolgi showed that the activity of WR-122,455 was limited to blood schizonts and did not extend to early or late tissue schizonts. These evaluations were compatible with the results of preliminary studies of the activities of WR-122,455 and WR-171,669 in human volunteers.

Antimalarial activities of triazine metabolites of chlorguanide and dichlorguanide.

Summary The activities of the triazine metabolites of chlorguanide and dichlorguanide have been studied in P. cynomolgi infections in the rhesus monkey. The results show that the chlorguanide metabolite, CPT, has only one-half to one-fourth the activity of the parent drug, whereas the dichlorguanide metabolite, DCPT, has activity equal to that of chlorguanide. These findings are in marked contrast to reported results on P. gallinaceum infections in the chick, against which CPT and DCPT are respectively 10 and 100 times as effective as chlorguanide.

Natural Occurrence of Malaria in Rhesus Monkeys

A relatively high incidence of malarial infections has been noted in recent importations of rhesus monkeys from Pakistan. This finding, contraverting the widely held belief that rhesus monkeys are free of natively acquired malaria, is of substantial significance to those employing Pakistanian rhesus monkeys in their investigations.

Antimalarial Activities of WR-194,965, an α-Amino-o-Cresol Derivative

Pilot appraisals of the activities of WR-194,965 and WR-204,165, two closely related o-cresol derivatives (both Mannich bases), in owl monkeys infected with the multidrug-resistant Vietnam Smith strain of Plasmodium falciparum showed that these compounds had similar levels of efficacy. Total course doses effecting 90% cures (CD90s) were 27 and 37 mg/kg of body weight for the respective compounds, values almost identical to the CD90 of mefloquine (a highly promising 4-quinolinemethanol) against infections with the same strain, and the CD90s of chloroquine against infections with 4-aminoquinoline-susceptible strains. Expanded studies of the activities of WR-194,965 against infections with the Smith strain of P. falciparum and Vietnam Palo Alto strain of P. vivax, designed to guide projected evaluations in human volunteers, showed: (i) that the activity of this compound was a function of total dose administered, with single doses as effective as the same amount delivered in three or seven successive daily fractions; (ii) that all regimens effected rapid clearance of parasitemia; and (iii) that based on CD90s, this agent was twice as active against infections with the Palo Alto strain of P. vivax as against the Smith strain of P. falciparum. These findings, together with results of preclinical pharmacological studies pursued elsewhere, provided support for studies in human volunteers now underway.

Antimalarial Activities of the 4-Quinolinemethanols WR-184,806 and WR-226,253

WR-184,806 and WR-226,253, two 4-quinolinemethanols structurally similar to WR-142,490 (mefloquine), have been studied in depth in owl monkeys infected with various drug-resistant and drug-susceptible strains of Plasmodium falciparum and P. vivax in an effort to provide support and guidance for projected evaluations in human volunteers. The results of these studies, confirmatory of preliminary appraisals, showed that WR-184,806 was approximately one-third as active as WR-142,490 against infections with a multidrug-resistant strain of P. falciparum, whereas WR-226,253 was twice as active. Additionally, the current studies showed: (i) that both WR-184,806 and WR-226,253 were significantly more active against infections with blood schizonts of P. vivax than against those of P. falciparum; (ii) that their activities against established infections with either Plasmodium species were functions of the total doses delivered, single doses being as effective as three or seven fractional doses given on successive days; (iii) that WR-184,806 could be administered intravenously as the phosphate salt and was curative via this route in single doses; and (iv) that based on comparative curative doses, WR-184,806 was slightly more active and WR-226,253 was seven times more active against infections with a multidrug-resistant strain of P. falciparum than was chloroquine against infections with a 4-aminoquinoline-susceptible strain.