AUC: area under the curve
CDC: Centers for Disease Control and Prevention
CNS: central nervous system
CYP: cytochrome P450
dADT: p-(1-dimethylamino ethylimino) aniline
DDVP: 2,2-dichlorovinyl dimethyl phosphate
GABA: γ-aminobutyric acid
LF: lymphatic filariasis
MDA: mass drug administration
OTC: over the counter
STH: soil-transmitted helminth
TPAC: terephalic acid
WHO: World Health Organization
Although a large number of anthelmintic drugs have been approved for human use, only a small number are widely used for treatment of helminth infections that occur worldwide (Figure 55–1). These include two drugs in the benzimidazole (BZ) class, albendazole and mebendazole, which are widely used for treatment of intestinal nematode and cestode infections; the macrocyclic lactone ivermectin, used to treat a variety of nematode and ectoparasite infections; and praziquantel, which is used to treat trematode and some cestode parasites. Because of their role in programs of mass drug administration (MDA), these drugs are amongst the most commonly used agents worldwide. WHO estimated that through MDA approximately 853 million people received one or more anthelmintic drugs in 2014 (WHO, 2016). In many resource-poor developing countries, several different anthelmintic drugs can be provided together through integrated programs of MDA to simultaneously target intestinal and filarial nematodes and trematodes (Webster et al., 2014). Key drugs, their indications, and important pharmacologic properties are listed in the Drug Facts table.
Relative incidence of helminth infections worldwide.
Although a large number of drugs in this class have been synthesized and several have undergone clinical development for treatment of parasitic infections of humans, only two are currently in wide use, namely, albendazole and mebendazole, with triclabendazole reserved for treatment of liver fluke infection caused by Fasciola hepatica. Thiabendazole was formerly recommended for treatment of strongyloidiasis, but ivermectin is more effective and better tolerated.
Albendazole, mebendazole, and triclabendazole are all poorly water soluble and only slightly soluble in methanol. The chemical structures of these drugs are shown in Figure 55–2.
Structure of Benzimidazoles.
The primary mechanism of action of BZs is thought to be inhibition of microtubule polymerization by binding to β-tubulin (Prichard, 1994). The selective toxicity of these agents against helminths results from their higher affinity for parasite β-tubulin than for the same target in higher eukaryotes. A range of other biochemical changes occurs in nematodes following BZ exposure, including inhibition of mitochondrial fumarate reductase, reduced glucose transport, and uncoupling of oxidative phosphorylation.
The low systemic bioavailability ...