Protozoa as Pharmacological Tools: The Antihistamines

Sanders and Nathan used two protozoa—Ochromonas malhamensis and Tetrahymena pyriformis—to study three antihistamines: diphenhydramine, tripelennamine, and pheniramine. Both organisms require exogenous histidine, making them suitable models for investigating antihistamine action. Growth inhibition assays identified the drugs' potency and biochemical sites of action, while motility experiments in Tetrahymena examined side effects analogous to drowsiness in humans. Results showed that histidine effectively reversed antihistamine-induced growth inhibition in both organisms, suggesting the drugs interfere with histidine metabolism or a related biochemical pathway. Ornithine and proline also partially reversed inhibition. The three antihistamines differed in potency and side effects: diphenhydramine and tripelennamine were roughly five times more active than procaine in motility assays, while pheniramine showed fewer side effects than the other two. The authors propose these protozoan systems as preliminary screening tools for antihistamine development, allowing prediction of therapeutic indices and side-effect profiles without using higher animals.

Key findings

• Histidine effectively annulled growth inhibition by all three antihistamines in both Ochromonas malhamensis and Tetrahymena pyriformis, indicating the drugs target histidine metabolism or a related biochemical pathway
• Diphenhydramine and tripelennamine exhibited stronger anti-motility effects than pheniramine, correlating with clinical observations of drowsiness as a side effect
• The antihistamines showed pH-dependent potency, requiring 100-fold higher concentrations at pH 5.0 than pH 7.0, reflecting cell membrane penetration differences
• Ornithine and proline together partially reversed antihistamine toxicity, suggesting multiple amino acid pathways are affected
• Protozoan assay systems can predict therapeutic indices and relative side-effect profiles of antihistamines in humans