Methylene blue (MB) and toluidine blue (TB) when administered in maximum tolerated oral doses to mice and to cotton rats are highly effective in preventing the usual lethal outcome of intraperitoneally induced infections with R. orientalis. This activity is manifest even when dye administration is delayed until a systemic infection has been well established. Methylene blue is also effective in cerebral infections in mice.
The toxicity of MB, however, limits parenteral (subcutaneous) administration of the dye to dosage levels which are much less effective than the maximum tolerated oral levels. The inability of mice to tolerate an adequately effective parenteral dose of MB suggests that the properties of the dye responsible for its toxicity may be separated from those upon which its antirickettsial effect depends.
The relationship between the response of mice to oral treatment with MB and such factors as the size of the infecting dose and the times of initiation and of withdrawal of treatment may be summarized as follows:
1. With a constant infecting dose, the time of initiation of treatment largely determines the degree of therapeutic effect.
2. The interval after infection beyond which further treatment does not increase the survival rate depends not upon the previous duration of treatment but upon the size of the infecting dose. Paradoxically, treatment can be discontinued sooner after a massive infecting dose than after a smaller one.