Biomedical subjects

L H Schmidt

Publications and source records attributed to L H Schmidt.

At least 37 records · Page 2Linked to original sources

PubMed1981

Comparative efficacies of quinine and chloroquine as companions to primaquine in a curative drug regimen.

A comparison has been made of the capacities of chloroquine and quinine to serve as companions to primaquine in curing established infections with sporozoites of the M or B strains of Plasmodium cynomolgi in rhesus monkeys. The results indicated that chloroquine was slightly but consistently more effective than quinine in this role. This finding provides support for use of chloroquine as the companion blood schizonticide in the current experimental animal-based search for improved tissue schizonticidal drugs, and bolsters the rather tenuous base for clinical use of this 4-aminoquinoline, rather than quinine, as a companion to primaquine in suppressive-curative and radical-curative regimens.

Animals↗

PubMed1981

Courses of infections with Plasmodium falciparum in own monkeys displaying a microfilaremia.

Infections with the Uganda Palo Alto, Malayan Camp-CH/Q, Vietnam Oak Knoll, and Vietnam Smith strains of Plasmodium falciparum in owl monkeys (Aotus trivirgatus griseimembra) with concomitant microfilaremias usually, but not always, followed a more benign course than infections with the same strains in monkeys free of filarial infections. Four distinct microfilariae were identified in systematic examinations of 26 monkeys, 5 with self-limited infections with P. falciparum, 9 with normally benign self-limited infections with P. vivax, and 12 without previous malaria. The microfilariae found included: Dipetalonema (Dipetalonema) gracile, Tetrapetalonema (Tetrapetalonema) barbascalensis, T. (T.) panamensis, and an unidentified species designated "Aotus C." Among 23 monkeys studied completely, 14 were infected with a single species, 4 had double infections, and 5 had triple infections. T. barbascalensis was identified in 16 monkeys, T. panamensis in 11. Although data were very limited, there was a suggestion that infections with P. falciparum were less intense in monkeys infected with T. barbascalensis, either alone or with other filariae, than in subjects infected only with T. panamensis.

Animals↗

PubMed1981

[Storage stability of 14 plasma proteins in ACD-AG banked blood].

In summarizing the results it can be stated that, when stored, the proteins haemopexin, alpha 1-antichymotrypsin, alpha 1-antitrypsin, which are rich of neuraminic acid, and IgA are predominantly characterized by a diminution of electrophoretic mobility and thus of concentration in electro-immunodiffusion, with the neuraminic acid content decreasing at the same time. These changes are probably caused by bacteria and/or virus neuraminidase. The decrease of pre-albumin concentration to be observed in radial-immunodiffusion and electro-immunodiffusion is caused by other mechanisms because pre-albumin contains no neuraminic acid. In accordance with these findings the most important changes of single proteins which can be measured by our equipment concern the percentage of non-proteins, whereas the antigen binding places will remain relatively stable during storage (ep. findings of radial immunodiffusion).

Blood Preservation↗

PubMed1980

The course of untreated Plasmodium inui infections in the rhesus monkey (Macaca mulatta).

This report deals with the major features of untreated infections with Plasmodium inui as exhibited in a group of 31 rhesus monkeys (27 inoculated with trophozoites, four with sporozoites). Infections in nine monkeys were followed to self-cure. In 22 subjects they were interrupted prematurely; in 17 by chemotherapy 454 to 3,931 days after onset of patency; in 5 by death 491 to 1,025 days after onset of patency. Substantial monkey-to-monkey variations were encountered in the intensity of the parasitemia and its cyclic undulations, in the morbid features of the disease, and in the duration of infection. Thus initial peak parasitemias varied by as much as 15-fold. Some post-peak parasitemias were sustained at relatively constant and moderately high levels for many months; others fluctuated cyclically between barely detectable and readily countable numbers. In most subjects, there was no evidence of morbidity attributable to malarial infection; in two, reactions were severe enough to lead to death. The duration of untreated infections could be as brief as 14 months or could approach 14 years. With due allowance for premature interruptions, the majority of infections could be expected to persist for 4--6 years.

Animals↗

PubMed1979

Antimalarial properties of floxacrine, a dihydroacridinedione derivative.

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 pyrimethamine, 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.

Acridines↗

PubMed1979

Studies on the 2,4-diamino-6 substituted quinazolines. I. Antimalarial activities of 2,4-diamino-6-[(3,4-dichlorobenzyl)-nitrosoamino]-quinazoline (CI-679) as exhibited in rhesus monkeys infected with the Ro or Ro/PM strains of Plasmodium cynomolgi.

This report summarizes the results of appraisals of various activities of CI-679 (a 2,4-diamino-6-amino-substituted quinazoline) in rhesus monkeys infected with the Ro and Ro/PM strains of Plasmodium cynomolgi. In subjects inoculated with sporozoites, CI-679, administered in appropriate schedules in doses up to and including the maximum tolerated level, neither prevented development of infections with these strains nor cured those already established. Although these evaluations showed that CI-679 was devoid of activity against both early and late tissue schizonts, they indicated that this compound had significant blood schizonticidal activity and suggested that such activity was much greater in infections with the Ro strain than in those with the Ro/PM strain. This latter suggestion, contrary to results of earlier experiments in mice infected with Plasmodium berghei, led to studies of the activities of CI-679 in trophozoite-induced infections. These showed that the total course dose of CI-679 required for cure of previously untreated infections with the Ro/PM strain was tenfold that required for cure of comparable infections with the Ro strain. They also showed that infections with either strain, treated previously with subcurative doses, were often not cured by doses of CI-679 that eradicated previously untreated infections regularly. Subsequent studies showed that emergency of parasites resistant to CI-679 was responsible for these retreatment failures and that this resistance was retained through mosquito transfer.

Animals↗

PubMed1979

Studies on the 2,4-diamino-6-substituted quinazolines. II. Activities of selected derivatives against infections with various drug-susceptible and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in owl monkeys.

Four 6-thio-, one 6-sulfinyl-, and two 6-sulfonyl-substituted 2,4-diaminoquinazolines were evaluated for capacities to cure established infections with the chloroquine-resistant Vietnam Oak Knoll and pyrimethamine-resistant Malayan Camp-CH/Q strains of Plasmodium falciparum in owl monkeys. As compared with the doses of standard drugs required for cure of infections with drug-susceptible strains or doses of the newly developed aminoalcohols required for cure of either drug-susceptible or drug-resistant strains, each of these quinazolines effected cure of infections with the Oak Knoll strain at a remarkably small daily dose. However, doses required for cure of infections with the Camp-CH/O strain were from 4-48 times those required for cure of infections with the Oak Knoll strain, suggesting that the activities of these quizanolines, like those of 6-amino-substituted derivatives, were compromised by pyrimethamine resistance. This suggestion received support from expanded studies involving WR-158,122 and WR-159,412, the most active of the agents examined, and the multidrug-resistant Vietnam Smith strain of P. falciparum and Vietnam Palo Alto strain of P. vivax, as well as the Oak Knoll and Camp-CH/Q strains. These studies also showed that significant fractions of infections with the Oak Knoll, Camp-CH/Q, and Palo Alto strains treated previously with subcurative doses of the above derivatives failed to respond to doses that regularly cured previously untreated infections. These treatment failures proved to be due to emergence of parasites resistant to the quinazolines.

Animals↗

PubMed1979

Studies on the 2,4-diamino-6-substituted quinazolines. III. The capacity of sulfadiazine to enhance the activities of WR-158,122 and WR-159,412 against infections with various drug-susceptible and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in owl monkeys.

Previous studies showed: 1) that the activities of the 2,4-diamino-6-substituted quinazolines. WR-158,122 and WR-159,412, against Plasmodium falciparum and Plasmodium vivax infections in owl monkeys, were seriously impaired when infecting strains were pyrimethamine-resistant; and 2) that primary treatment failure with either agent led frequently to emergence of parasites resistant to these derivatives. Taking advantage of the potencies of WR-158,122 and WR-159,412 as dihydrofolic acid reductase inhibitors, the current studies were aimed at determining whether the above liabilities could be reduced to manageable levels or eliminated by concomitant administration of a rho-aminobenzoic acid inhibitor such as sulfadiazine. Application of these combinations prevented emergence of parasites resistant to WR-158,122 or WR-159,412, but did not abolish the differences in effectiveness of either compound against infections with pyrimethamine-susceptible and pyrimethamine-resistant strains; however, activities against infections with either susceptible or resistant strains were enhanced markedly. With WR-158,122, this enhancement ranged from greater than 7-fold to 75-fold; with WR-159,412, it ranged from greater than 5-fold to 13-fold. Maximal increases in activity were attained with a remarkedly small dose of sulfadiazine, 5.0 mg per kg of body weight daily. With this augmentation of activity, acceptably small doses of WR-158,122 regularly cured infections with even the most highly pyrimethamine-resistant strain.

Animals↗

PubMed1978

Antimalarial activities of various 4-quinolonemethanols 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.

Administration, Oral↗

PubMed1978

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.

Animals↗

PubMed1978

Antimalarial activities of various 4-pyridinemethanols with special attention to WR-172,435 and WR-180,409.

Pilot appraisals of the activities of 10 specially selected 2,6-substituted-4-pyridinemethanols against acute Plasmodium falciparum infections in owl monkeys identified three derivatives that were two to three times as active as chloroquine against infections with a 4-aminoquinoline-susceptible strain and, at the same doses, were equally effective against infections with a strain fully resistant to treatment with maximally tolerated doses of chloroquine, quinine, and pyrimethamine. Two of these derivatives, WR-172,435 and WR-180,409, deemed worthy of evaluation in human volunteers, were studied in greater depth in owl monkeys infected with either the multidrug-resistant Smith strain of P. falciparum or the pyrimethamine-resistant Palo Alto strain of P. vivax. These studies showed (i) that at the same total oral dose, 3-day and 7-day treatment schedules were equally effective and slightly superior to a single-dose schedule; (ii) that WR-172,435 was slightly more active than WR-180,409 in each treatment regimen; (iii) that intravenous delivery of WR-180,409 phosphate was feasible and effective; (iv) that both compounds effected control of parasitemia more rapidly than any standard or newly discovered antimalarial drug; and (v) that WR-172,435 and WR-180,409 had therapeutic indexes at least four to eight times those exhibited by chloroquine in infections with 4-aminoquinoline-susceptible strains, indexes retained by these pyridinemethanols against infections with various drug-resistant strains.

Animals↗

PubMed1978

Antimalarial activities of WR-194,965, an alpha-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 (CD(90)s) were 27 and 37 mg/kg of body weight for the respective compounds, values almost identical to the CD(90) of mefloquine (a highly promising 4-quinolinemethanol) against infections with the same strain, and the CD(90)s 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 CD(90)s, 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.

Animals↗

PubMed1978

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.

Administration, Oral↗

PubMed1978

Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus). I. The courses of untreated infections.

This study, the first of three designed to determine the feasibility of using owl monkeys infected with human plasmodia in the search for new, more broadly active antimalarial drugs, dealt with the characteristics of untreated infections with eight strains of Plasmodium falciparum and two strains of P. vivax. Such infections, induced by standardized inocula of these strains in 1,733 monkeys, all Aotus trivirgatus griseimembra, were followed from day of inoculation to death of self-cure. The virulence of the various strains differed strikingly. Incidences of fatal reactions, ranging from 24.4--89.4% and 8.1--45.8%, respectively, in infections with strains of P. falciparum and P. vivax, were closely related to the rate at which parasitemia evolved, the height of parasitemia in the primary attack, and/or the time period over which a high parasite level was sustained. Antemortem symptom complexes and gross tissue and organ reactions in infections with P. falciparum varied with survival time, but within that boundary, were the same for infections with all eight strains of this plasmodium. Morbidity in both fatal and self-limited infections with both plasmodial species was related to height of parasitemia; however, at comparable parasite levels, symptoms exhibited in infections with P. vivax were more severe than in infections with P. falciparum. Overall, the characteristics of infections with these plasmodia in owl monkeys were remarkably similar to those of human infections. With respect to biological features, infections with P. falciparum and P. vivax in this simian host appear to have much to offer in the search for new antimalarial drugs.

Animals↗

PubMed1978

Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus). II. Responses to chloroquine, quinine, and pyrimethamine.

The studies described in this report were designed to determine the responses of established infections with eight strains of Plasmodium falciparum and two strains of P. vivax in owl monkeys to treatment with chloroquine, quinine, and pyrimethamine. Responses with these different strains ranged from cure via application of well-tolerated doses of two of the above drugs and refractoriness to treatment with maximally tolerated doses of the third, to complete resistance to maximally tolerated doses of all three compounds. The results of treatment exhibited in infected owl monkeys correlated well in two respects with those reported in humans infected with the same plasmodial species. First, calculated on a milligram per M2 basis, the doses of chloroquine, quinine, or pyrimethamine required for a CD90 response in owl monkeys infected with strains susceptible to these drugs were remarkably similar to the doses required and/or employed for cure of infections with so-called drug-susceptible strains in human patients. Secondly, with few exceptions, the responses to the above drugs in owl monkeys infected with the ten specially selected strains were essentially identical with those exhibited by human volunteers or patients infected with the same strains. Together, these findings and correlations provide strong support for use of owl monkeys infected with appropriate strains of P. falciparum and P. vivax in the search for more broadly effective antimalarial drugs.

Animals↗

PubMed1978

Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus). III. Methods employed in the search for new blood schizonticidal drugs.

This report describes, illustrates, and validates the major features of a procedure designed to provide primary assessments of the activities of potential antimalarial drugs against infections with chloroquine-resistant or pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys of Colombian origin. Studies with 14 specially selected compounds have shown that the test method has the capacity to identify and quantify diverse levels of therapeutic efficacy among agents that differ widely in chemical structure. Extended studies with two of the above compounds indicate that such assessments have an acceptable level of reproducibility. Experiments with two other agents, structurally different from those in the selected group, have shown that the impacts of pyrimethamine resistance (or chloroquine resistance) on the activity of a compound can be readily identified during routine application of the test procedure, as can emergence of parasites resistant to the test agent. The above body of information can usually be acquired in infections with two strains of P. falciparum, one chloroquine-resistant, the other pyrimethamine-resistant, with commitments of no more than 1.5 g of test compound and 12 owl monkeys. These modest requirements have made it possible to utilize human plasmodial infections in the owl monkey in the search for new blood schizonticidal drugs more broadly effective than those currently available.

Animals↗

PubMed1977

Spleen function in quartan malaria (due to Plasmodium inui): evidence for both protective and suppressive roles in host defense.

For investigation of the role of the spleen in host defense and chronicity in quartan malaria, the course of Plasmodium inui infection was studied in 39 intact rhesus monkeys, 16 monkeys splenectomized before infection, and 22 monkeys splenectomized after infection. Splenectomized animals consistently had peak parasitemias greater than 10-fold higher than those of intact animals, but the mortality rate at peak parasitemia was only higher in monkeys splenectomized before infection. Whereas intact animals had persistent infections for one to 13 years, splenectomized animals achieved self-cure (persistently negative blood smears for three or more months) within less than a year. These observations suggest that the spleen exerts a protective role during the acute stage and a suppressive role during the chronic stage of quartan malarial infection.

Animals↗

PubMed1977

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.

Aminoquinolines↗