The experimental chemotherapy of leishmaniasis, IV

Abstract

A description is given of two methods for investigating the action of drugs against a viscero-tropic Leishmania in mice. The parasite employed was isolated from a patient with kala-azar in Ethiopia. It is designated ‘L. infantum LV9’ and produces a visceral infection in NMRI mice. The biochemical typing characters of the parasite are described.

In Method A, infected animals were treated from the 5th or 6th day after infection (D+5 or D+6) for five consecutive days. They were sacrificed 24 hours after the completion of drug treatment and an estimate was made of the amastigote load in the liver. A comparison of this with untreated controls gives an index of activity of a test drug, from 0 to 3.

Method B is similar except that the ED₅₀ and ED₉₀ are determined by graphic analysis of data from graded drug doses. A comparison is made with sodium stibogluconate used as a positive drug control to yield a ‘Pentostam Index’.

The course of infection in BALB/c and NMRI mice is compared with that in random-bred Swiss mice in which ‘L. infantum LV9’ produces an inconsistent infection. An inoculum of 10⁷ amastigotes produces a peak parasite intensity between D+15 and D+20.

The ED₅₀ and ED₉₀ of sodium stibogluconate (Pentostam) (as Sb^v) in Method B are 22·5 and 46·5 mg/kg sc daily × 5. (By Method A the single dose figures are 65 and 280 mg/kg.) For routine use a standard dose level of 120 mg/kg sc daily × 5 of Pentostam (Sb^v) is used in Method B. The ED₅₀ and ED₉₀ of meglumine antimoniate (Glucantime) (as Sb^v) in Method B are 11·6 and 66·7 mg/kg sc daily × 5. Data are given for other antimonials in Method A.

Pentamidine and diminazene aceturate proved to have a slow action which was more readily demonstrated if the observation period was prolonged. Amphotericin B was moderately active but toxic to the host.

The relevance of these models and a comparison of data found in the mouse and hamster are debated.