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Biomedical subjects

D Vaughan

Publications and source records attributed to D Vaughan.

At least 55 records · Page 3Linked to original sources
PubMed1987

Myopericarditis as an initial presentation of meningococcemia. Unusual manifestation of infection with serotype W135.

Acute meningococcemia is a dramatic clinical syndrome from infection with the gram-negative diplococcus, Neisseria meningitidis. Although pericarditis may complicate the course of meningococcemia, it is distinctly unusual as a presenting sign. A case of disseminated meningococcemia presenting as acute myopericarditis is reported. The serotype isolated, type W135, was a sporadic cause of N. meningitidis in the Boston area. Although the patient had meningitis, bacteremia, and myopericarditis, his course was uncomplicated with early institution of antibiotic therapy.

Humans↗
PubMed1982

Evidence for a sodium-induced activation of central neurogenic mechanisms in one-kidney, one-clip renal hypertensive rats.

The mechanisms sustaining high blood pressure in conscious one-kidney, one-clip Goldblatt rats were evaluated with the use of SK&F 64139, a phenylethanolamine N-methyltransferase inhibitor capable of crossing the blood-brain barrier and of captopril, an angiotensin converting enzyme inhibitor. The rats were studied 3 weeks after left renal artery clipping and contralateral nephrectomy. During the developmental phase of hypertension, two groups of rats were maintained on a regular salt (RNa) intake, whereas two other groups were given a low salt (LNa) diet. On the day of the experiment, the base-line mean blood pressure measured in the LNa rats (177.4 +/- 5.2 mm Hg, mean +/- S.E., n = 15) was similar to that measured in the RNa rats (178.7 +/- 5.4 mm Hg, n = 16). SK&F 64139 (12.5 mg p.o.) induced a significantly more pronounced (P less than .001) blood pressure decrease in the RNa rats (-25.6 +/- 3.6 mm Hg, n = 8) than in the LNa rats (-4.3 +/- 3.3 mm Hg, n = 7) during a 90-min observation period. On the other hand, captopril (10 mg p.o.) normalized blood pressure in LNa rats (n = 8), but produced only a 13.4 mm Hg blood pressure drop in RNa rats (n = 8). RNa rats treated with SK&F 64139 were found to have decreased phenylethanolamine N-methyltransferase activity by an average 80% in selected brain stem nuclei when compared with nontreated rats. No significant difference in plasma catecholamine levels was found between the RNa and LNa rats. These results suggest that, in this experimental model of hypertension, the sodium ion might increase the model of hypertension, the sodium ion might increase the vasoconstrictor contribution of the sympathetic system via a centrally mediated neurogenic mechanism while at the same time it decreases the renin-dependency of the high blood pressure.

Animals↗
PubMed1979

Mucocutaneous lymph node syndrome in a young adult.

Mucocutaneous lymph node syndrome (MLNS) is an acute febrile illness of unknown cause first described in Japan but more recently reported in the United States. The mean age in confirmed cases was 3.8 years (range, 3 months to 13 years), and the mortality is 1% to 2% when associated with coronary artery thrombosis and aneurysm. We describe the first case of MLNS in a young adult, with the additional clinical finding of associated arthritis.

Adolescent↗
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 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↗
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↗
PubMed1977

Quantitative aspects of pyrimethamine-sulfonamide synergism.

The experiments described in this report have dealt with the dimensions of therapeutic potentiation achieved when combinations of pyrimethamine and sulfadiazine were administered to rhesus monkeys infected with a drug-susceptible strain of Plasmodium cynomolgi or its pyrimethamine-resistant variant and to owl monkeys infected with strains of P. falciparum and P. vivax of varying degrees of resistance to this pyrimidine. These evaluations showed: 1) that when delivered in combination, the activities of both pyrimethamine and sulfadiazine against infections with any of the above strains were enhanced significantly; 2) that in infections with the Ro and Ro/PM strains of P. cynomolgi and the Vietnam Palo Alto strain of P. vivax, concomitant delivery of the two agents resulted in a 32-fold increase in the activity of pyrimethamine and a 50- to 100-fold increase in the activity of sulfadizine; 3) that as a result of this synergism, infections with the pyrimethamine resistant Ro/PM and Palo Alto strains could be cured with a fraction of the maximum tolerated dose of this drug; 4) that in marked contrast to the above result, infections with the Malayan Camp and Vietnam Smith strains of P. falciparum could not be cured regularly by combination regimens which included the maximally tolerated dose of pyrimethamine. This poor response has been attributed to the high levels of pyrimethamine-resistance possessed by these strains. It is believed that the comparatively small but not insignificant incidences of treatment failures associated with delivery of pyrimethamine-sulfonamide combinations to both patients and human volunteers infected with multidrug-resistant strains of P. falciparum rest on a similar basis.

Animals↗