Echinococcosis

Motivation and Background:
Echinococcosis is caused by parasitic tapeworms of the genus //Echinococcus//. The disease manifests in two primary conditions: cystic or alveolar echinococcosis, caused by //E. granulosus// and //E. multilocularis//, respectively. Classified as a neglected tropical disease by the WHO, echinococcosis is believed to affect over one million people at any given time, at a cost of US $3 billion [1]. Because the disease is primarily found in rural areas with poor diagnostic and medical resources, the mortality rate is 50-75%. Diagnosis usually requires sophisticated imaging techniques, such as CT scans and MRIs, which only display visible cyst-like structures and parasitic vesicles after the disease has progressed for many years. Treatment often requires radical surgery and long-term chemotherapy, as the vesicles wreak havoc on the internal tissue even after removal of the larval deposits. If the disease has progressed to become inoperable (which is common after years of undiagnosed parasitic activity), drug targeting is the only viable treatment [1].

Figure 1: Map of worldwide impact of echinococcosis in 2009 

Cystic echinococcosis, also referred to as hydatid disease, is highly endemic to rural areas of Africa, Europe, Asia, Central and South America, and the Middle East. The disease is rarely found in North America [3]. Dogs are the definitive host of the parasitic tapeworms. After ingesting the organs of animals containing hydatid cysts, these dogs shed the //E. granulosus// eggs in their feces. These eggs are transmitted to humans primarily through consumption of food, water, or soil contaminated by the fecal matter of infected dogs. As //Echinococcus// eggs remain viable in soil for up to a year, the possibility of accidental consumption is still viable even after apparent decay of the fecal matter [1].

Figure 2: Schematic of the parasitic life cycle of Echinococcus tapeworm 

The primary stage of cyst development in humans (after infection) is usually asymptomatic. However, these cysts may amass and officially present as hydatid disease, at which point they may cause pain, nausea, and vomiting. Though cysts primarily occur in the lungs and liver, they also may present in the spleen, kidneys, heart, bone, and central nervous system. Large cysts may rupture and release cystic fluid, which can cause anaphylactic reaction and, in severe cases, death. Treatment of these cysts requires a combination of medication and surgery before rupturing [1,3].

Figure 3: Hydatid cysts in the liver of patient afflicted by peritoneal echinococcosis 

Alveolar echinococcosis is the rarer and more serious infection. //E. multilocularis// is transmitted in a similar fashion as above, through ingestion of food or water contaminated with the tapeworm eggs. This species of Echinococcus is primarily found in foxes, coyotes, and wild cats, and is therefore primarily endemic to the northern latitudes of Asia, Europe, and North America [3]. //E. multilocularis// larvae, which characteristically hatch in the liver, do not cause mature into cysts, but do cause vesicles that invade the lung and brain tissue. Symptoms include pain, weight loss, and malaise. Alveolar echinococcosis progresses to cause liver failure and death due to surrounding tissue necrosis [1].

Figure 4: Adult //Echinococcus multilocularis// worm 

Target Information:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">The colchicine-binding site of the β-tubulin monomer of the cytoskeletal tubulin heterodimer is a common target site for drugs. When albendazole binds to the β-tubulin monomer, tubulin assembly is inactivated, and microtubule polymerization is suppressed. The compound binds to the exposed β-tubulin monomer, and prevents further microtubule polymerization and elongation by effectively capping it off. Once cytoplasmic microtubule function is inhibited, the glucose uptake of larval parasites is impaired; glycogen supplies, which are used in absence of glucose, are subsequently exhausted [4]. As the worms cannot maintain energy production, degeneration occurs in the endoplasmic reticulum and mitochondria of the germinal layer, effectively halting larvae maturation.

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Location: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Tubulin is found in microtubules of all cells, and is a major component of cellular cytoskeleton.

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Function in a normal cell: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">The polymerization and depolymerization of tubulin monomers allows microtubules to elongate or shorten, respectively, and function in cell growth and division.

<span style="color: #e01b1b; font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Figure 5: Schematic of colchicine binding to tubulin dimers, the mechanism of which is similar to that of albendazole <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; line-height: 0px;">

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Schematic figure of drug: //
<span style="color: #e31010; font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Figure 6: 3D conformer visualization of albendazole

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">//Side effects:// all present in less than 1% of patients
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Leukopenia - reduction of number of white blood cells in blood <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Granulocytopenia - reduction of number of granulocytes (WBC filled with digestive enzymes) <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Pancytopenia - deficiency of all three cellular components of blood (red blood cells, white blood cells, platelets) <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Thrombocytopenia - deficiency of platelets in bloodstream

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Other names: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Alworm, Andazol, Eskazole, Noworm, Zentel, Alben-G, ABZ

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Clinical Trials Info: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">There are approximately 4 completed clinical trials including any benzimidazoles as treatment for echinococcosis, with one more trial pending.

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Origin: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Albendazole is completely synthetic, and does not have an organic origin molecule. <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Benzimidazoles exhibited early efficacy as veterinary antihelmenthics. In 1962, thiabendazole was developed for human use. Though effective, it was found to be moderately toxic, and pharmaceutical companies developed benzimidazole carbamates as a result. Smith Kline & French Animal Health introduced albendazole in the UK during November of 1977. It was particularly effective because upon consumption, albendazole would be metabolized into albendazole sulphoxide, an active antihelmenthic, rather than an inactive compound [2].

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Alternatives to this drug: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">The only other benzimidazole widely used as treatment for echinococcosis is mebendazole. However, the efficacy of mebendazole is much less than that of albendazole, as mebendazole is metabolized into an inactive compound [1].

//<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Other uses: //
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Albendazole can be used for a variety of parasitic worm infections. It has proven to be effective in treating fluke, tapeworm, and nematode infestations [5]. It has also been used against myiasis (maggot infestation) As an antiprotozoal agent, albendazole has been used against giardiasis and microsporidiosis. It has also been used in attempts to halt transmission of lymphatic filariasis (elephantiasis) in Africa [2].

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">References:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">1. Centers for Disease Control and Prevention. Parasites: Echinococcosis. [] (accessed Feb 7, 2016).

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">2. Dayan, A. D., Albendazole, mebendazole and praziquantel, review of non-clinical toxicity and pharmacokinetics. Acta Trop 2003, 86, (n.i.), 141-59.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">3. Eckert, J.; Deplazes, P., Biological, epidemiological, and clinical aspects of echinococcosis, a zoonosis of increasing concern. Clin Microbio Rev 2004, 17, (1), 107-35.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">4. Lacey, E., Mode of action of benzimidazoles. Parasit Today 1990, 6, (4), 112-5.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">5. McCracken, R. O.; Stillwell, W. H., A possible biochemical mode of action for benzimidazole antihelmenthics. Int Journ Parasit 1991, 21, (1), 99-104.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">External links:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">http://www.mayoclinic.org/drugs-supplements/albendazole-oral-route/description/drg-20061505