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Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga
D Perrine1, J P Chenu, P Georges
1Centre d'Etude et de Recherche sur le Medicament de Normandie, Unité de Formation et de Recherche des Sciences Pharmaceutiques 14032 Caen, France.
Abstract:
The first medical cure of Acanthamoeba keratitis was obtained by use of propamidine isethionate. Since then, it has been the basic drug recommended for use in treatment. Because some Acanthamoeba strains have been reported to be resistant to propamidine and propamidine was found to be only weakly cysticidal, superior homologs such as butamidine, pentamidine, hexamidine, heptamidine, octamidine, and nonamidine were tested for their amoebicidal effects on two Acanthamoeba strains isolated from patients with keratitis. Trophozoicidal and cysticidal efficiencies were found to be increased from propamidine to nonamidine; i.e., when the alkyl chain connecting the two benzene rings in their molecular structures was elongated, in comparison with propamidine, hexamidine and octamidine were the most amoebicidal molecules. As a result of these data, a kinetic study carried out on propamidine, hexamidine, and octamidine demonstrated that the amoebicidal effects resulted from two events: the diffusion of molecules through the plasma membrane or the double wall of trophozoites or cysts, respectively, and the lethal effects of molecules on amoebic protoplasm. The diffusion kinetics were increased when the alkyl chain was elongated, i.e., with an increase in the lipophilic properties of molecules. In contrast, the lethal effect kinetics were found to be unchanged by this elongation, indicating that they originated from the cationic surface-active properties induced by the protonated amidine groups attached to each benzene ring, which themselves remained unchanged from one molecule to the other. These results strongly advocate the immediate replacement of propamidine by hexamidine in the medical treatment of Acanthamoeba keratitis; in France, 0.1% hexamidine eyedrops are available (Desomedine). The results also advocate clinical investigations on the efficiency and toxicity of octamidine, which appears to be the most amoebicidal diamidine in vitro.
Insights
Hexamidine and octamidine show superior amoebicidal activity against Acanthamoeba keratitis compared to propamidine. Elongating the molecular structure enhances efficacy, suggesting hexamidine as a replacement and octamidine for further study.
Area of Science:
- Ophthalmology
- Infectious Diseases
- Medicinal Chemistry
Background:
- Propamidine isethionate was the first medical cure for Acanthamoeba keratitis.
- Some Acanthamoeba strains exhibit resistance to propamidine, and its cysticidal activity is limited.
Purpose of the Study:
- To evaluate the amoebicidal effects of propamidine homologs against Acanthamoeba keratitis.
- To compare the trophozoicidal and cysticidal efficiencies of various diamidines.
Main Methods:
- Tested butamidine, pentamidine, hexamidine, heptamidine, octamidine, and nonamidine on Acanthamoeba strains.
- Conducted kinetic studies on propamidine, hexamidine, and octamidine.
Main Results:
- Amoebicidal efficiency increased with alkyl chain elongation in diamidines.
- Hexamidine and octamidine demonstrated the highest amoebicidal activity.
- Amoebicidal effect involves molecular diffusion and lethal action on amoebic protoplasm.
Conclusions:
- Hexamidine is recommended as an immediate replacement for propamidine in treating Acanthamoeba keratitis.
- Octamidine warrants further clinical investigation for its efficacy and toxicity.