The Chemotherapeutic Action of Phenanthridine Compounds

Ja, Lock

doi:10.1111/j.1476-5381.1950.tb00589.x

Cited by 12 publications

(7 citation statements)

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“…exposure) only at 1/3,000 (Hawking, 1939). Under the same conditions quinapyramine kills T. equiperdum at 1 in 1 to 4 million (Hawking and Thurston, 1955) and dimidium kills T. rhodesiense (old laboratory strain) 1 in 1 million (Lock, 1950). These concentrations are all greater than are reached in vivo after therapeutic doses.…”

Section: Resultsmentioning

confidence: 92%

“…; but if they are inoculated into fresh animals, no infection develops, showing that some profound change has been produced in them (Hawking, 1938;Lock, 1950;Ormerod, 1951;Hawking and Thurston, 1955). By contrast, when trypanosomes are exposed to arsenicals and similar compounds, their infectivity is not usually diminished, unless all the trypanosomes have been obviously killed or damaged before they are inoculated.…”

Section: Resultsmentioning

confidence: 99%

“…In its early stages part of this combination is probably reversible, but, judging by the period of exposure needed to make most of the trypanosomes non-infective, an irreversible combination seems to occur with dimidium in 0.5 hr. (Lock, 1950), with quinapyramine in 2.5 hr. (Ormerod, 1951), and with suramin in 1 to 2 hr.…”

Section: Resultsmentioning

confidence: 99%

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The Trypanocidal Action of Homidium, Quinapyramine and Suramin

Hawking

Sen

1960

British Journal of Pharmacology and Chemotherapy

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Homidium, quinapyramine, and suramin (Group 1I compounds) produce their trypanocidal effect in vivo only after a latent period of 24 hr. or more, during which time the trypanosomes may continue to multiply; this is in contrast to trivalent arsenical and diamidine compounds (Group I compounds), which begin to act immediately. Group 11 compounds also differ from Group I compounds in that (a) they have only a slight tendency to combine with trypanosomes, (b) they have little trypanocidal action in vitro, but (c) they make trypanosomes non-infective to fresh subinoculated mice. To explain these features it is postulated that homidium, quinapyramine, and suramin first combine in small amounts with some receptor on the trypanosome and then block some biochemical system which produces a hypothetical substance X which is needed for cell division of the trypanosome; the trypanosome is supposed to contain a preformed store of this substance X sufficient for several divisions to take place; and it is only when this store is exhausted that cell division is prevented and the trypanosome eventually dies.The purpose of this paper is to describe certain characteristics of the trypanocidal action of homidium (Ethidium; B.Vet.C. Supp. 1959, p. 27), quinapyramine (Antrycide; B.Vet.C., 1955, p. 553), and suramin, and to offer a hypothesis to explain them. These compounds differ from other trypanocidal compounds such as trivalent arsenicals and diamidines in that their trypanocidal action in vivo is manifested only after a long latent period. Experiments were undertaken to study quantitatively the behaviour of the trypanosomes during this latent period. METHODSRats or mice were infected with trypanosomes by intraperitoneal inoculation When the blood contained scanty trypanosomes, blood from the tail was diluted in a W.B.C. or R.B.C. pipette with a fluid which lysed the erythrocytes and stained the trypanosomes; the trypanosomes were then counted in a haemocytometer slide under the microscope. A suitable fluid for this purpose was: 1% methylene blue, 2 ml.; glacial acetic acid, 0.25 ml.; water, 50 ml. In the case of Trypanasoma evansi, the number of trypanosomes in a drop of blood from the tail was probably the same as that in the main volume of circulating blood. T. congolense, on the other hand, tends to accumulate in the capillaries of the tail, and the count recorded may often have been much greater than that in the circulating blood; presumably, however, the two were proportional, and this discrepancy would not affect the general argument. The animal was then treated intraperitoneally with a dose of the drug approximately double the dose which was sufficient to remove all visible trypanosomes from the blood within four days. Counts of the trypanosomes were made at suitable intervals (usually morning and evening) until no further trypanosomes were found.The trypanosomes used were T. evansi, Mathura strain, described in a previous paper (Sen, Sharma, and Hawking, 1960) which was studied in rats; and T. congolense (N.I.M.R. strai...

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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The Trypanocidal Action of Homidium, Quinapyramine and Suramin

Hawking

Sen

1960

British Journal of Pharmacology and Chemotherapy

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“…Because of this, the CD50 was checked after these experiments had been completed in case any drug resistance had developed, but none was found. Lock (1950) was unable to infect mice with T. congolense taken from the tail blood of a mouse given an intravenous injection of 10 ,ug of dimidium bromide 24 hr previously. In view of our results with homidium we repeated this experiment, but could not confirm Lock's results.…”

Section: Resultsmentioning

confidence: 99%

“…In vivo/in vivo experiments of this kind have been carried out in the past by Lock (1950) with dimidium bromide and T. congolense and by Ormerod (1951) with antrycide and T. equiperdum. These authors also carried out in vitro/in vivo experiments similar to those described below, as did Hawking (1939) with suramin and T. rhodesiense.…”

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confidence: 99%

Studies on Isometamidium: The Effect of Isometamidium, Homidium and Pyrithidium on the Infectivity of Trypanosomas for Mice

Hill

1965

British Journal of Pharmacology and Chemotherapy

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During the course of an investigation into the antitrypanosomal activity of isometamidium, some phenanthridinium compounds were administered to mice infected with Trypanosoma rhodesiense or T. congolense; trypanosomes from these mice were subinoculated into fresh mice at various times after treatment, and the effect of the compounds on infectivity was noted. In vivo/in vivo experiments of this kind have been carried out in the past by Lock (1950) with dimidium bromide and T. congolense and by Ormerod (1951) with antrycide and T. equiperdum. These authors also carried out in vitro/in vivo experiments similar to those described below, as did Hawking (1939) with suramin and T. rhodesiense. But so far no one seems to have compared the activities of compounds against different species of trypanosome by either of these methods. METHODSThe Lugala II strain of T. rhodesiense was used. This was isolated in Uganda in 1955 and received by us from EATRO in 1958. Since then it has been passaged by blood inoculation through mice, which it kills in 3 to 4 days. The strain of T. congolense was an old laboratory one which produces an acute or subacute infection in mice, killing them in 7 to 20 days (Brown, Hill & Holland, 1961).Mice were infected intraperitoneally with approximately 750,000 trypanosomes each in 0.2 ml. of citrate-saline, as in a normal therapeutic experiment. They were treated with homidium, isometamidium or pyrithidium (Prothidium) 1 or 2 days later, when there were 1 to 10 trypanosomes per high power field in the peripheral blood-stream. One mouse was left untreated, as a control, in each experiment. At 2, 24 or 48 hr after treatment blood was taken from the tail of the treated mice with a syringe and a No. 18 hypodermic needle, diluted with citrate-saline and injected intraperitoneally into previously untreated and uninfected mice. Three such mice were subinoculated from each donor. Bloods from different donors were not mixed. Three control mice were similarly infected from the untreated control donor referred to above.Beginning 4 to 5 days after subinoculation, the peripheral blood of the donor and subinoculated mice was examined three times a week for up to 28 days after subinoculation. Failure to detect trypanosomes during this period in a donor was taken as an indication that it had been cured, or in a subinoculated mouse as an indication that the trypanosomes in the inoculum had been noninfective due to their exposure to the drug before subinoculation.Some preliminary experiments with T. congolense and isometamidium failed to reveal any difference between the effects on infectivity of the intravenous and subcutaneous administration of the drug, so the subcutaneous route was used in the later work with both parasites and all three compounds.

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The Chemotherapy of Trypanosomiasis and Leishmaniasis: Towards a more Rational Approach

Newton

1974

Novartis Foundation Symposia

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The Chemotherapeutic Action of Phenanthridine Compounds

Cited by 12 publications

References 4 publications

The Trypanocidal Action of Homidium, Quinapyramine and Suramin

The Trypanocidal Action of Homidium, Quinapyramine and Suramin

Studies on Isometamidium: The Effect of Isometamidium, Homidium and Pyrithidium on the Infectivity of Trypanosomas for Mice

The Chemotherapy of Trypanosomiasis and Leishmaniasis: Towards a more Rational Approach

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