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Biomedical subjects

J D Chulay

Publications and source records attributed to J D Chulay.

At least 73 records · Page 4Linked to original sources
PubMed1984

The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro.

Using an in vitro radioisotopic method, the activity was measured of proguanil, its metabolites cycloguanil and p-chlorophenylbiguanide (PBG), pyrimethamine, and chloroquine against seven Kenyan and three South East Asian strains of Plasmodium falciparum. Five Kenyan isolates were sensitive to both pyrimethamine and cycloguanil in vitro, while the Smith and two Kenyan strains were resistant to both these drugs. Cross-resistance was incomplete: the Camp strain was resistant to pyrimethamine but not cycloguanil, and the FVO strain was resistant to cycloguanil but not pyrimethamine. Both proguanil and PBG exhibited weak antimalarial activity in vitro, but inhibitory blood levels of either compound are unlikely to occur after a normal human dose of proguanil. The results indicate that the activity of proguanil against P. falciparum is due entirely to the action of its active metabolite cycloguanil.

Animals↗
PubMed1984

Synergistic antimalarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro.

Two strains of Plasmodium falciparum were tested in vitro for sensitivity to the dihydrofolate reductase inhibitor pyrimethamine, the p-aminobenzoic acid (PABA) analogue sulfadoxine, and combinations of both drugs. One strain was sensitive and one resistant to pyrimethamine in vitro. Parasites cultured in medium containing neither folic acid nor PABA were inhibited by 10(-6) M sulfadoxine, a concentration well below that achievable after therapeutic dosage. Folic acid added to this medium at a physiological concentration of 0.01 mg/liter caused a 1,000-fold reduction in sulfadoxine activity; a 100-fold higher concentration of folic acid caused a 10-fold reduction in pyrimethamine activity. Sulfadoxine in a concentration of 10(-7) M was able to potentiate pyrimethamine activity in PABA-free medium with no added folic acid or with 0.01 mg folic acid/liter. These data indicate that P. falciparum can utilize exogenous folic acid, and suggest that sulfadoxine may potentiate pyrimethamine activity by simultaneous inhibition of dihydrofolate reductase.

4-Aminobenzoic Acid↗
PubMed1984

In vitro antimalarial activity of tetrahydrofolate dehydrogenase inhibitors.

Three tetrahydrofolate dehydrogenase (dihydrofolate reductase = EC 1.5.1.3) inhibitors were tested for antimalarial activity against Plasmodium falciparum, using an in vitro radioisotopic technique. Activity of each drug was tested in both normal RPMI medium 1640 and in modified medium (containing no p-aminobenzoic acid and 2.27 X 10(-8) M folic acid) after a 24- or 48-hour exposure. Activity was increased 20- to 85-fold using the modified medium and the longer exposure time. Under all conditions, pyrimethamine and cycloguanil were of equal or greater potency than an experimental pyrimethamine analogue, M&B 35769, against pyrimethamine-sensitive strains, but M&B 35769 was more active than either pyrimethamine or cycloguanil against pyrimethamine-resistant strains.

Animals↗
PubMed1984

A new in vitro test for pyrimethamine/sulfadoxine susceptibility of Plasmodium falciparum and its correlation with in vivo resistance in Kenya.

A useful in vitro method for field evaluation of Plasmodium falciparum sensitivity to pyrimethamine/sulfadoxine is described. Thirty-five Kenyan schoolchildren infected with P. falciparum were treated with this drug combination and followed up for 5 weeks. In vitro tests for sensitivity to these drugs and to chloroquine were performed before starting treatment. All infections cleared within 7 days of treatment, but 5 children had recurrent parasitaemia within 35 days. The original isolates from 4 of these 5 children had an in vitro response to pyrimethamine/sulfadoxine similar to a known strain that was resistant to these drugs; only 4 of the remaining 30 isolates from patients in whom recurrent parasitaemia did not occur had a resistant in vitro response (P = 0.006). In the patient with recurrent parasitaemia whose initial isolate appeared sensitive to pyrimethamine/sulfadoxine, the recurrent isolate had a resistant pattern in vitro, suggesting either reinfection or selection of a resistant subpopulation following treatment. The in vitro response to this drug combination was correlated with the in vitro response to either drug alone and with the in vitro response to chloroquine. Two of the 5 infections with recurrent parasitaemia after initial pyrimethamine/sulfadoxine treatment were resistant to chloroquine in vivo. The in vitro test for pyrimethamine/sulfadoxine should be useful for mapping the spread of multidrug-resistant P. falciparum.

Adolescent↗
PubMed1983

Plasmodium falciparum: assessment of in vitro growth by [3H]hypoxanthine incorporation.

To evaluate rapidly Plasmodium falciparum growth in Vitro, [3H]hypoxanthine was added to parasite microcultures and radioisotope incorporation was measured. When culture parameters were carefully controlled, [3H]hypoxanthine incorporation was proportional to the number of parasitized erythrocytes present. Factors affecting [3H]hypoxanthine incorporation included initial parasitemia, duration of culture, duration of radioisotope pulse, parasite stage, concentration of uninfected erythrocytes, the use of serum or plasma to supplement growth, and the concentration of a variety of purines in the culture medium. The method described can be used to measure inhibition of P. falciparum growth by immune serum and has previously been used to study antimalarial drug activity in vitro.

Animals↗
PubMed1983

High-dose sodium stibogluconate treatment of cutaneous leishmaniasis in Kenya.

Cutaneous leishmaniasis caused by Leishmania aethiopica usually responds poorly to conventional doses of pentavalent antimonial drugs. We treated three patients with cutaneous leishmaniasis acquired in Kenya, presumed or documented to be caused by L. aethiopica, with intravenous sodium stibogluconate, 18 to 20 mg Sb/kg body-weight twice daily for 30 days. All patients had a good response to treatment, with disappearance of parasites from skin smears and cultures after 14 to 27 days, clinical healing of the lesions, and no recurrence during a three to 18-month follow-up. Side effects of treatment were minor. We conclude that this high dose sodium stibogluconate regimen is safe and effective for treating cutaneous leishmaniasis caused by L. aethiopica in Kenya.

Adolescent↗
PubMed1983

A comparison of three dosage regimens of sodium stibogluconate in the treatment of visceral leishmaniasis in Kenya.

A prospective randomized trial of three dosage regimens of sodium stibogluconate (Pentostam; Wellcome Foundation, London) to treat visceral leishmaniasis was conducted. Previously untreated patients were randomized to receive 31 doses of sodium stibogluconate (10 mg Sb/kg of body weight per dose) administered once daily for 31 days (group A), every 12 hr for 15 days (group B), or every 8 hr for 10 days (group C). Of the 29 patients who completed treatment, seven of 10 in group B and all of the patients in groups A and C responded to treatment and remained well for one year. One patient in group B failed to respond to treatment, and two others in group B initially responded to treatment but relapsed six weeks after discharge. None of the treatment regimens was toxic. Parasites disappeared from splenic aspirates most quickly and hemoglobin levels rose most rapidly in patients receiving sodium stibogluconate every 8 hr. Treatment of visceral leishmaniasis in Kenya with sodium stibogluconate at a dose of 10 mg Sb/kg every 8 hr for 10 days appears to be a safe alternative to conventional treatment. Its efficacy should be confirmed in a larger number of patients.

Adolescent↗
PubMed1983

Plasmodium falciparum in Kisumu, Kenya: differences in sensitivity to amodiaquine and chloroquine in vitro.

Sensitivity to amodiaquine and chloroquine was examined in 11 Plasmodium falciparum isolates from Kisumu, Kenya, and three chloroquine-resistant parasites. All 11 Kisumu isolates were sensitive to amodiaquine in vivo. Six of 10 Kisumu isolates successfully tested were more sensitive to amodiaquine in a microtest (minimal inhibitory concentration [MIC], less than or equal to 114 nM for amodiaquine vs 160 nM for chloroquine) and/or 48-hr in vitro tests (MIC, 60 nM for amodiaquine vs 100 nM for chloroquine). All nine successfully cultured Kisumu isolates had a lower 50% inhibitory dose (ID50) for amodiaquine (9.0-18.2 nM) than for chloroquine (24.9-75.4 nM) in a radioisotopic assay. Five were also more sensitive when retested in the 48-hr test. The chloroquine-resistant parasites had reduced in vitro sensitivity to chloroquine (ID50, greater than or equal to 103 nM; MIC, 300 nM) but not to amodiaquine (ID50, less than or equal to 22 nM; MIC, less than or equal to 100 nM). These data indicate that amodiaquine is more potent than chloroquine and should be evaluated for efficacy against P falciparum in areas where RI and RII chloroquine resistance occurs.

Amodiaquine↗
PubMed1983

Comparison of microscopy and culture in the detection of Leishmania donovani from splenic aspirates.

Three culture media were compared with Giemsa-stained smears for the detection of Leishmania in splenic aspirates from Kenyan patients with visceral leishmaniasis. Ninety-nine splenic aspirates obtained from 26 patients at various times before, during, and after treatment were cultured in Schneider's Drosophila medium and RPMI medium 1640 (each supplemented with 20% fetal bovine serum) and McConnell's modification of Senekje's medium overlayed with 0.9% saline. From 13 splenic aspirates obtained before treatment, amastigotes were identified microscopically in all and promastigotes were cultured in 12. During and after treatment, Schneider's medium was the most sensitive method for detecting parasites, followed by microscopic examination of stained smears which was more sensitive than either of the other two media tested. Results indicate that, for initial diagnosis, both culture and direct microscopy of aspirates should be employed.

Culture Media↗
PubMed1983

Quantitation of amastigotes of Leishmania donovani in smears of splenic aspirates from patients with visceral leishmaniasis.

During a 20-month period, more than 500 splenic aspirations were performed in 89 patients with suspected or proven visceral leishmaniasis. The two complications which occurred (intra-abdominal bleeding and penetration of the intestine in one patient each) both resolved with conservative management. Parasite density in splenic aspirate smears was graded on a logarithmic scale from 0 (no parasites in 1,000 microscopic fields) to 6+ (greater than 100 parasites per microscopic field). Among 46 newly diagnosed and 17 relapsed or drug-resistant patients with visceral leishmaniasis, the average initial parasite grade was 4.35 +/- 0.92 (mean +/- SD) and 4.15 +/- 1.37, respectively. The grading system was useful in measuring the speed of response to treatment, and in distinguishing slow responders from nonresponders. This was especially valuable for managing patients with drug-resistant visceral leishmaniasis. The system also provided a means of comparing the efficacy of different treatment regimens, and for calculating the optimum duration of treatment.

Adult↗
PubMed1983

Field evaluation in Kenya of a 48-hour in vitro test for Plasmodium falciparum sensitivity to chloroquine.

A 48-hour in vitro test for determining the chloroquine sensitivity of Plasmodium falciparum isolates was evaluated in Kisumu and Malindi, Kenya. P. falciparum isolates from 14 children, aged 5 to 13 years, were studied. In vivo and 48-hour in vitro tests were done on all 14. Successful Rieckmann macro and micro in vitro tests for chloroquine sensitivity were completed in nine isolates each. All 14 infections cleared within 3 days of beginning chloroquine treatment, and none recrudesced during a 7-day (8 patients) or 28-day (6 patients) follow-up period. The three in vitro tests gave comparable results. Although all isolates tested were chloroquine sensitive in vitro, different response patterns were observed. In the 48-hour test, 10 isolates were inhibited at chloroquine concentration less than or equal to 0.03 nmol/ml medium. These isolates were inhibited by less than or equal to 0.5 nmol of chloroquine per ml blood in the Rieckmann macro test and by 2-6 pmol/well in the micro test. The other four isolates had response patterns intermediate between those of previously reported sensitive and resistant strains. Complete inhibition did not occur until chloroquine concentrations of greater than or equal to 0.03 nmol/ml medium in the 48-hour test, greater than or equal to 0.5 nmol/ml blood in the macro test, and 6 pmol/well in the micro test. The results demonstrate that the 48-hour test is a useful addition to existing in vivo and in vitro methods for determining the chloroquine sensitivity of P. falciparum in the field.

Adolescent↗