Behavior of mixtures of oxophenarsine-resistant and unmodified strains of Trypanosoma equiperdum in the rat

Cantrell, William

doi:10.1016/0014-4894(56)90013-3

Cited by 13 publications

(9 citation statements)

References 6 publications

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“…Following treatment, blood samples were obtained from mice in each of groups A, B, and C after 5, 10, 15, 30, 40, and 45 min and 1, 1.5, 2, 3, 4,6,8,10,12,14,16,18,21,24, and 48 h. Since ion pair extraction of diminazene from blood (2) requires a volume of 1 ml, samples from two treated mice were pooled in a 3-ml potassium-EDTA-containing Vacutainer (Becton Dickinson) tube for each time. Furthermore, at each sampling time, 10 mice were used to obtain five replicate samples.…”

Section: Methodsmentioning

confidence: 99%

“…The dynamics of growth of mixed populations of trypanosomes within the same host have received considerable interest, and it appears that rapidly growing strains competitively outgrow, and dominate, slowly growing subpopulations (46). There is also evidence to suggest that some drug-susceptible trypanosomes grow at relatively faster rates than drug-resistant strains, which may explain why, in the absence of chemotherapy, drug-susceptible populations appear to outgrow drug-resistant populations in vivo (12,21,36,49). While the frequencies with which drugsusceptible and drug-resistant trypanosomes occur in vivo are unknown, we have shown in goats that the majority of trypanosomes which repopulate the blood following treatment with diminazene aceturate appear to remain susceptible to the drug dosage that was used (28).…”

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confidence: 99%

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Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

Mamman¹,

Gettinby²,

Murphy³

et al. 1995

Antimicrob Agents Chemother

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The frequency of trypanosomes resistant to diminazene aceturate at a dose of 25 mg/kg of body weight was investigated for populations of Trypanosoma congolense IL 3274 which reappeared in infected mice after intraperitoneal treatment with diminazene aceturate at the same dosage. At inoculum sizes of 10 2 , 10 3 , 10 4 , 10 5 , and 10 6 trypanosomes per mouse, the relapse populations were used to initiate infections in five groups of 100 mice each by the intravenous route. Immediately after infection, 50 mice in each group were treated intraperitoneally with diminazene aceturate at the aforementioned dosage; the other 50 mice functioned as untreated controls. Thereafter, all animals were monitored for 100 days for the presence of trypanosomes. In each group, trypanosomes were detected in 50 of 50 control mice, indicating 100% infectivity for all five inoculum sizes. In contrast, in the groups of 50 mice infected with 10 2 , 10 3 , 10 4 , 10 5 , and 10 6 trypanosomes and treated with diminazene aceturate, trypanosomes were detected in 4, 11, 13, 28, and 39 of 50 mice, respectively. By logistic regression, a good fit was found between the number of mice identified as parasitemic and the inoculum sizes. Maximum likelihood estimates for the proportions of trypanosomes resistant to diminazene aceturate at 25 mg/kg of body weight for the inoculum of 10 2 , 10 3 , 10 4 , 10 5 , and 10 6 organisms were 8.335 ؋ 10 ؊4 , 2.485 ؋ 10 ؊4 , 3.02 ؋ 10 ؊5 , 8.3 ؋ 10 ؊6 , and 1.6 ؋ 10 ؊6 , respectively. These findings indicate that the majority of the relapse trypanosomes were susceptible to the drug dosage used for selecting the population and that, surprisingly, the calculated proportion of organisms which survived drug exposure varied inversely with the inoculum size. Further experiments with mice indicated that the inverse relationship did not result from alterations in the pharmacokinetics of the drug with different inoculum sizes. The data therefore suggest that parasite inoculum size and drug dosage are important factors in estimating the apparent frequency of diminazeneresistant trypanosomes in populations of T. congolense occurring in vivo.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

Mamman¹,

Gettinby²,

Murphy³

et al. 1995

Antimicrob Agents Chemother

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show abstract

“…Laveran and Rundsky (1912) noticed that oxazine-resistant stocks of T. brucei and T. evansi which did not have a visible ldnetoplast (acentrosomic) displaced the drug-sensitive stocks in mixed infections, despite the "well known tendency of acentrosomic trypanosomes to disappear from naturally occurring mixtures" (Cantrell, 1956). The reduced growth-rate was significant in only one done, however, in which suramin sensitivities differed 3,000 fold (KETRI 2476 CLI and C122).…”

Section: The Means and Ranges Of Generation Times Of T Evansi Strainmentioning

confidence: 99%

Growth rates of suramin-sensitive and resistantTrypanosoma evansi

Mutugi¹,

Boid

Luckins

1996

Trop Anim Health Prod

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In the presence of a trypanocidal drug, trypanosomes which have acquired resistance to that drug have an obvious selective advantage over their drug-sensitive counterparts. In the absence of the drug, the situation probably changes and drugresistant parasites are selected against, otherwise resistance wouldspread much faster than has been observed (Mutugi, 1993). In the present work, the relationship between growth rates of stocks of Trypanosoma evansi and their resistance to suramin was determined in rats. This was to investigate whether differential growth rates of suramin-resistant and sensitive trypanosomes could limit the spread of suramin resistance.One month old male Wistar albino rats weighing between 150 to 200 g were used. The suramin sensitivities of 3 cameline stocks of T. evansi were determined by titration experiments. KETRI 2454 and KETRI 2476 were resistant, in mice, to suramin at a dose rate of 0.005mg/kg but sensitive at 0-01 mg/kg. KETRI 3136 was resistant, in mice, to suramin at 160mg/kg. Two clones from each of stocks of KETR12454 and KETRI 2476 were also included in the study (Table I). By exposing trypanosomes to sub-curative suramin doses in mice, resistance to suramin had been induced in one of the clones from each stock, while the other was its unmodified parent. Thus, KETRI 2454 CL9 was a strain in which resistance was induced starting with KETRI 2454 CL1, a clone of the field isolate KETRI 2454; while KETRI 2476 CL22 was an induced resistant strain from KETRI 2476 CLI, a clone of KETRI 2476.Each stock was infected into groups of 5 rats by intraperitoneal (i/p) injection with approximately 1 x 106 trypanosomes and the onset of parasitaemia in each rat was determined using the haematocrit centrifugation technique (Woo, 1970). Starting the following day, the rats were bled 5 times daily (at 09.00 h, 11.00 h, 13.00 h, 15.00 h and 17.00 h) for 9 days. Parasitaemia was determined by haemocytometer counting. Growth curves of each stock of trypanosomes were obtained by plotting the log trypanosome numbers against the time of bleeding and the increase of parasitaemia on the first day of the first parasitaemic wave was calculated, on the assumption that it would be the time when parasites had least interference from the host's immune response. In each rat, the growth rate of trypanosomes in terms of generation time was calculated using the formula of Topley and Wilson (1955). The mean generation time of each trypanosome stock was then determined and compared using either the Kruskal-Wallis or Mann-Whitney tests. A number of major assumptions were made; namely, that parasites were evenly distributed in the blood, all trypanosomes were capable of multiplying, trypanosome death rate was constant in all the stocks and errors of trypanosome counting were constant.

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“…The practical implication of these differences in growth rates is that, after several passages in the absence of the drug in question, suramin-sensitive clones may outgrow resistant ones resulting in their disappearance or presence in small numbers in the population as observed by Oehler (1914) and Cantrell (1956) in T. equiperdum. When the drug is introduced into such a population, the resistant parasites are then at an advantage and might proliferate, resulting in expression of resistance.…”

mentioning

confidence: 98%

“…Laveran and Rundsky (1912) noticed that oxazine-resistant stocks of T. brucei and T. evansi which did not have a visible kinetoplast (acentrosomic) displaced the drug-sensitive stocks in mixed infections, despite the "well known tendency of acentrosomic trypanosomes to disappear from naturally occurring mixtures" (Cantrell, 1956). The reduced growth-rate was significant in only one clone, however, in which suramin sensitivities differed 3,000 fold (KETRI 2476 CL1 and C122).…”

mentioning

confidence: 99%

Growth rates of suramin-sensitive and resistantTrypanosoma evansi

Mutugi

Boid

Luckins

1996

Trop Anim Health Prod

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In the presence of a trypanocidal drug, trypanosomes which have acquired resistance to that drug have an obvious selective advantage over their drug-sensitive counterparts. In the absence of the drug, the situation probably changes and drugresistant parasites are selected against, otherwise resistance wouldspread much faster than has been observed (Mutugi, 1993). In the present work, the relationship between growth rates of stocks of Trypanosoma evansi and their resistance to suramin was determined in rats. This was to investigate whether differential growth rates of suramin-resistant and sensitive trypanosomes could limit the spread of suramin resistance.One month old male Wistar albino rats weighing between 150 to 200 g were used. The suramin sensitivities of 3 cameline stocks of T. evansi were determined by titration experiments. KETRI 2454 and KETRI 2476 were resistant, in mice, to suramin at a dose rate of 0.005mg/kg but sensitive at 0,01 mg/kg. KETRI 3136 was resistant, in mice, to suramin at 160mg/kg. Two clones from each of stocks of KETRI 2454 and KETRI 2476 were also included in the study (Table I). By exposing trypanosomes to sub-curative suramin doses in mice, resistance to suramin had been induced in one of the clones from each stock, while the other was its unmodified parent. Thus, KETRI 2454 CL9 was a strain in which resistance was induced starting with KETRI 2454 CLI, a clone of the field isolate KETRI 2454; while KETRI 2476 CL22 was an induced resistant strain from KETRI 2476 CL1, a clone of KETRI 2476.Each stock was infected into groups of 5 rats by intraperitoneal (i/p) injection with approximately 1 x 106 trypanosomes and the onset of parasitaemia in each rat was determined using the haematocrit centrifugation technique (Woo, 1970). Starting the following day, the rats were bled 5 times daily (at 09.00h, ll.00h, 13.00h, 15.00h and 17.00h) for 9 days. Parasitaemia was determined by haemocytometer counting. Growth curves of each stock of trypanosomes were obtained by plotting the log trypanosome numbers against the time of bleeding and the increase of parasitaemia on the first day of the first parasitaemic wave was calculated, on the assumption that it would be the time when parasites had least interference from the host's immune response. In each rat, the growth rate of trypanosomes in terms of generation time was calculated using the formula of Topley and Wilson (1955). The mean generation time of each trypanosome stock was then determined and compared using either the Kruskal-Wallis or Mann-Whitney tests. A number of major assumptions were made; namely, that parasites were evenly distributed in the blood, all trypanosomes were capable of multiplying, trypanosome death rate was constant in all the stocks and errors of trypanosome counting were constant. 2 Present address: 12 Sholtery Road, Greystone Park, Harare, Zimbabwe. 147 148 MUTUGI ETA/,. TAet~ I The means and ranges of generatian times ofT. evansi strains with different sensitivities to suramin Stock

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Behavior of mixtures of oxophenarsine-resistant and unmodified strains of Trypanosoma equiperdum in the rat

Cited by 13 publications

References 6 publications

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

Growth rates of suramin-sensitive and resistantTrypanosoma evansi

Growth rates of suramin-sensitive and resistantTrypanosoma evansi

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