A most active biologue of
disodium cromoglycate (DSCG) available,
lodoxamide tromethamine (LT), has been studied and characterized pharmacologically, in animal and human models of
asthma. It has self-tachyphylaxis, but has oral activity (
lodoxamide ethyl) in rats, primates, and man. In rats (LT) was 2,500 X more active than DSCG (ID50 = 0.001 mg/kg), in primates the
drug was also active by several routes (inhalation 1 microgram/kg, IV 0.001 mg/kg, and oral 10 mg/kg). In isolated rat peritoneal mast cells, the compound displayed a biphasic dose response inhibition to histamine release initiated by (48/80,
anti-IgE, and the
calcium ionophore A23,187) with IC50 values of 0.1-50 microM. The consistent finding relating to its mode of action was its ability to inhibit 45calcium flux into the mast cell in response to
antigen or A23,187. Clinical evaluations of
lodoxamide tromethamine showed that at
aerosol doses of 1.0 mg or less, it demonstrated significant inhibitory activity against
antigen or
exercise induced bronchospasm. However, in pilot evaluation studies in clinical
asthma settings, the compound could not be shown to spare
bronchodilator usage, relative to placebo, or be shown to be more effective than placebo treated patients based on other clinical endpoints. The reason for rat and primate models not being predictive for human long-term clinical
asthma in the characterization of anti-release compounds is not known.