Diethylcarbamazine: A review of its modes of action.

Filariases are neglected tropical diseases caused by Clade III parasitic nematodes transmitted by biting insects as microfilaria which mature into female and male adults in the host. One example of filariasis is lymphatic filariasis or elephantiasis, caused by three species of filaria: Brugia malayi, Wuchereria bancrofti, and/or Brugia timori. Elephantiasis results from the occlusion of lymphatic vessels by adult parasites and subsequent swelling of the limbs. It is a disfiguring disease that occurs in 120 million people worldwide. Another filarial disease is onchocerciasis caused by Onchocerca volvulus. Microfilaria of this parasite invade the eye producing corneal scarring and blindness. The infected female blackflies that transmit these microfilaria belong to the Simulium genus, and breed in fast flowing rivers. Onchocerciasis occurs near these rivers and gives rise to the common name of the disease, i.e., "river blindness." Diethylcarbamazine (HetrazanR) was described as effective for treating filariases over 75 years ago by Yellapragada Subbarow and collaborators and is currently still in use. Diethylcarbamazine is characterized by a simple but flexible structure that provides it with the ability to combine with several target proteins, and a complex mode of action with effects on both filarial parasites and hosts. This Chapter reviews new observations on the activation of Transient Receptor Potential (TRP) ion-channels of B. malayi and older observations on the mechanisms of action of diethylcarbamazine. Diethylcarbamazine has three major effects: 1) A direct activating effect on filaria TRP channels producing transient inhibition of motility; 2) Reduction of host and parasite PGI2 and PGE2 production, thereby reducing host immune suppression; and 3) Activation and adhesion of host granulocytes which attack the filaria. We emphasize recent observations that include activation of TRP channels by diethylcarbamazine, an underappreciated mode of action of this classic anthelmintic.