Estimation of the concentration of melarsoprol (Mel B) and Mel W in biological fluids by bioassay with trypanosomes in vitro

Abstract
A technique for the bioassay of melarsoprol and similar compounds is described; it depends upon measuring the in vitro trypanosomicidal power of the compound and of biological fluids containing it. The concentration of melarsoprol which kills 90 per cent. of trypanosomes is related to time according to the equation C0.49 x t = 4.45 where C = concentration in μg. per ml. and t = time in hours. For a related compound, Mel W C0.34 t = 9.33. With 24 hours' exposure, melarsoprol is 2.4 times as active in vitro as Mel W. The plasma of four patients was examined during treatment with melarsoprol or Mel W. The two compounds were equally effective in producing trypanosomicidal activity in the plasma; any difference in therapeutic effectiveness is not due to differences of equivalent blood concentration. Immediately after intravenous injection the concentration of active melarsoprol in the plasma is high, but it falls to about 0.1 μg. per ml. in 6 hours, and to insignificant amounts in 24 hours. With doses on 3 successive days there is a small tendency to accumulation. The highest concentrations observed were approximately 1 μg. ml. at 1 hour after doses of 180 mg. per patient. The concentration in the cerebrospinal fluid (taken 6 hours after doses on 3 successive days) was small, less than 1 per cent. of the concentration in the plasma at the same time. These trivalent arsenical compounds, melarsoprol and Mel W, apparently do not readily pass through the blood-brain barrier. The pentavalent compound, melarsen would probably produce a higher trypanosomicidal activity in the cerebrospinal fluid, and it is recommended that melarsen should be tried in the cases of Rhodesian trypanosomiasis affecting the brain.

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