Combating Helminths with Antiparasitic Pharmaceuticals

I. Introduction

Helminths are a diverse group of parasitic worms that belong to the phylums Platyhelminthes (flatworms), Nematoda (roundworms), and Acanthocephala (thorny-headed worms). Soil-transmitted helminths are responsible for parasitic infections in as much as a quarter of the human population worldwide. [WHO, 2012] The following is a brief overview of these three major categories of helminths:

Figure 1: The three phyla of helminths (Platyhelminthes, Nematoda, and Acanthocephala). Acanthocephala do not typically infect humans. Panel a) Botulus microporus, which lives in the intestines of lancetfish. The image was originally curated by the Wikipedia user Anilocra. b) an adult Taenia saginata beef tapeworm. The image was originally curated by the US Centers for Disease Control and Prevention (CDC). Lower left panel: adult Ascaris lumbricoides worms. The image was originally curated by the Sustainable Sanitation Alliance (SuSanA). Lower right panel: Acanthocephala originally posted by Zlatko Nedi? on ResearchGate.

Flatworms (Platyhelminthes)

There are two main types of flatworms, namely Trematoda and Cestoda. Trematodes, commonly known as flukes, are flatworms characterized by their flattened, leaf-like bodies. They typically have complex life cycles involving multiple hosts, including snails as intermediate hosts. Examples of flukes include the Schistosoma spp., which causes the disease schistosomiasis, also known as snail fever, bilharzia, and Katayama fever.

According to the World Health Organization (WHO) at least 251.4 million people were estimated to require preventive treatment for schistosomiasis in 2021, out of which more than 75.3 million people were reported to have been treated. [WHO, 2023]

Cestodes, or tapeworms, are ribbon-like flatworms that inhabit the intestines of their hosts. They lack a digestive system and absorb nutrients directly through their body surface. Examples of cestodes include Taenia spp., responsible for diseases like taeniasis and cysticercosis.

Roundworms (Nematoda)

Nematodes, commonly referred to as roundworms, have elongated, cylindrical bodies. They are one of the most diverse and abundant groups of animals on Earth. Some nematodes are free-living in soil and water, while others are parasitic. Parasitic nematodes can infect a wide range of hosts, including humans, causing various diseases. Examples of parasitic nematodes include Ascaris lumbricoides (causing ascariasis), Trichuris trichiura (causing trichuriasis), and Enterobius vermicularis (causing enterobiasis). (Nemaplex, 2022)

Thorny-headed worms (Acanthocephala)

Thorny-headed worms, or acanthocephalans, are parasitic worms characterized by a retractable proboscis with spines or hooks at its tip. They use this proboscis to attach to the intestinal walls of their hosts. Acanthocephalans are unique among helminths in this respect. While they primarily infect animals, including fish and birds, they can occasionally infect humans through the consumption of infected intermediate hosts. (Tikkanen, 2010)

Life Cycle

The typical life cycle of a helminth often involves several stages: (Libretexts, 2022)

       a) Egg Stage: The life cycle begins with the production of eggs by adult female helminths. These eggs are often passed out of the host's body through feces.

       b) Larval Stage: Once in the environment, the eggs hatch into larvae. These larvae may develop further and can vary in form, such as miracidia, cercariae, or filariform larvae, depending on the type of helminth.

       c) Intermediate Host (if applicable): In some helminth species, the larvae must go through an intermediate host, like a snail, fly, fish, pig or cow, where they develop and multiply.

       d) Infective Stage: After undergoing necessary transformations, the larvae become infective to the definitive host, which is the host where the adult helminths will ultimately reside.

       e) Transmission to Definitive Host: The infective larvae typically enter the definitive host through ingestion, skin penetration, or another mode of entry.

       f) Maturation and Reproduction: Inside the definitive host, the larvae mature into adult worms. Adult helminths can then reproduce, and the life cycle continues when the eggs are excreted from the host.

The specifics of this life cycle can vary greatly between different helminth species. Some helminths have complex life cycles that involve multiple hosts and stages, while others have more straightforward life cycles. Additionally, the clinical impact and health consequences of helminth infections can vary widely, from mild discomfort to severe disease, depending on the species and the host's immune response.

In summary, helminths encompass a diverse group of parasitic worms, including flatworms (trematodes and cestodes), roundworms (nematodes), and thorny-headed worms (acanthocephalans), each with distinct characteristics and life cycles. Many helminths can cause diseases in their hosts, including humans.

II. Popular Drugs to Treat Helminth Infection

Drugs that treat human helminth infection interfere with the worm's biology through several mechanisms:

·        Inhibition of microtubule synthesis leading to paralysis and impaired movement

·        Inhibition of glucose uptake

·        Neurotransmission disruption causing muscle spasms and paralysis

·        Disruption of tegument, damaging the worm's surface structure making it more vulnerable to the host's immune system

·        Altered ion transport through ion channels leading to paralysis.

These mechanisms collectively result in the expulsion or death of the helminth parasites from the human host.

Albendazole/ Mebendazole

Albendazole is a benzimidazole anthelmintic used to treat parenchymal neurocysticercosis and other helminth infections, including tapeworms (e.g. Taenia solium), flukes (e.g. Clonorchis sinensis), and nematodes (e.g. Ascaris spp.). It is a broad-spectrum anti-helminthic. [Merative, 2023] [Marie, 2023] [Sutrave, 2023]

The principal mode of action for Albendazole is by its inhibitory effect on tubulin polymerization, which results in the loss of cytoplasmic microtubules in the tegument and or intestines of helminths. This process ultimately leads to energy depletion and death of the organism. [Albendazole, 2023] Mebendazole has the same mechanism of action as Albendazole and is sometimes used interchangeably. [Mebendazole, 2023]

Triclabendazole

Triclabendazole is an anthelmintic drug used to treat fascioliasis, an infection caused by the liver fluke parasite, Fasciola hepatica with around 10,000 cases per year. Infections with a liver fluke usually occur after eating contaminated water plants, such as watercress or algae, or animals that eat these plants. [Merative, 2023] [Triclabendazole, 2019] [Sutrave, 2023]

The mechanism of action of Triclabendazole against helminths involves the absorption of the drug and its active metabolites (sulfoxide and sulfone) by the outer body covering of the immature and mature worms. This leads to a reduction in the resting membrane potential, inhibition of tubulin function, and disruption of protein and enzyme synthesis necessary for the survival of the helminth. As a result, the parasite's energy production is diminished, leading to its immobilization and eventual death. [DrugBank, 2021]

Ivermectin

Ivermectin is an antiparasitic medication used for the treatment of various parasitic diseases caused by helminths such as river blindness, strongyloidiasis, and lymphatic filariasis. [Ivermectin, 2023] Evidence suggests it is also effective for the treatment of scabies, which is a parasitic skin infection by the mite Sarcoptes scabiei. [CDC, 2019] It is a semisynthetic derivative of avermectin, which is derived from the soil mold Streptomyces avermitilis. Ivermectin works by opening glutamate-sensitive chloride channel currents in helminths, which may be its mechanism of action. This process interferes with the nerve and muscle functions of worms, paralyzing and killing them. [UpToDate, 2023]

Praziquantel

Praziquantel is a quinoline derivative used to treat a number of helminth infections including the infamous Bilharzia disease endemic in Africa, Asia, and South America. [ChemicalBook, 2023] [Sutrave, 2023] [CDC, 2018] It is also used in most schistosome and many cestode infections.

Praziquantel’s mechanism of action causes severe spasms and muscle paralysis in worms, likely due to a rapid influx of calcium ions. Morphological alterations and increased exposure to schistosome antigens at the parasite surface also occur. As a result the worms are either destroyed in the intestine or passed in the stool. [DrugBank, 2023]

Others

Other popular anthelmintics include diethylcarbamazine, pyrantel, nitazoxanide, and oxamniquine.

III. Market Growth and Size

The market for anthelmintics is expected to show continued growth over the medium to long term. The global market is expected to grow at a CAGR of 4.5% from US$ ~2.4 billion today, reaching US$ 3.2 billion by 2030. [Global, 2020]

Around 60% of small molecule medicinal products on the market are taken by mouth and this is thought to hold true for anthelmintics which are also available in injectable formats. Furthermore, according to recent estimates, roughly 90% of drugs actually sold/ used globally are orally formulated. [Alqahtani, 2021]

IV. Conclusion

Helminths pose a significant threat to human health, causing a range of debilitating diseases, particularly in regions with poor sanitation. However, there is a promising opportunity to combat these infections through ongoing research, drug development, and public health interventions. The future direction of the market should focus on innovative treatments, prevention strategies, and equitable access to interventions to reduce the burden of helminth infections worldwide, with a special emphasis on collaboration between governments, NGOs, and pharmaceutical companies to reach the most vulnerable populations and address the evolving nature of these parasitic threats.

V. Sources

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Alqahtani, Mohammed S., et al. “Advances in oral drug delivery.” Frontiers in Pharmacology, vol. 12, 19 Feb. 2021, https://doi.org/10.3389/fphar.2021.618411.

CDC. “CDC - Scabies - Resources for Health Professionals - Medications.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 2 Oct. 2019, www.cdc.gov/parasites/scabies/health_professionals/meds.html.

CDC. “CDC - Schistosomiasis - Epidemiology & Risk Factors.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 22 June 2018, www.cdc.gov/parasites/schistosomiasis/epi.html.

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DrugBank. “Praziquantel.” Uses, Interactions, Mechanism of Action, DrugBank Online, 19 Oct. 2023, go.drugbank.com/drugs/DB01058.

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“Global Anthelmintic Drugs Market by Type (Oral Drugs, Injectables), by Application (for Human, for Animal) and by Region (North America, Latin America, Europe, Asia Pacific and Middle East & Africa), Forecast from 2022 to 2030.” Industry Growth Insights, 10 Feb. 2020, industrygrowthinsights.com/report/anthelmintic-drugs-market/.

“Ivermectin (Oral Route) Description and Brand Names.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 1 Feb. 2023, www.mayoclinic.org/drugs-supplements/ivermectin-oral-route/description/drg-20064397.

Libretexts, “5.2: Parasitic Helminths.” Biology LibreTexts, 5 Mar. 2022, bio.libretexts.org/Bookshelves/Microbiology/Microbiology_%28OpenStax%29/05%3A_The_Eukaryotes_of_Microbiology/5.02%3A_Parasitic_Helminths.

Marie, Chelsea, and William A Petri Jr. “Clonorchiasis - Infectious Diseases.” MSD Manual Professional Edition, MSD Manuals, 16 Oct. 2023, www.msdmanuals.com/professional/infectious-diseases/trematodes-flukes/clonorchiasis.

“Mebendazole.” Uses, Interactions, Mechanism of Action, DrugBank Online, 17 Oct. 2023, go.drugbank.com/drugs/DB00643.

Merative. “Albendazole (Oral Route) Proper Use.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 1 Oct. 2023, www.mayoclinic.org/drugs-supplements/albendazole-oral-route/proper-use/drg-20061505.

Merative. “Triclabendazole (Oral Route) Description and Brand Names.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 1 Sept. 2023, www.mayoclinic.org/drugs-supplements/triclabendazole-oral-route/description/drg-20455931.

Nemaplex, “Introduction to Nematodes.”, UC Davis, 9 May 2022, nemaplex.ucdavis.edu/General/Intronem.htm.

Sutrave, Smita, and Martin Heinrich Richter. “The truman show for human Helminthic parasites: A review of recent advances in in vitro cultivation platforms.” Microorganisms, vol. 11, no. 7, 29 June 2023, p. 1708, https://doi.org/10.3390/microorganisms11071708.

Tikkanen, Amy. “Spiny-Headed Worm.” Encyclop?dia Britannica, Encyclop?dia Britannica, Inc., 12 Aug. 2010, www.britannica.com/animal/spiny-headed-worm.

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WHO. “Soil-Transmitted Helminth Infections.” WHO, World Health Organization, 16 Aug. 2012, web.archive.org/web/20120820003930/www.who.int/mediacentre/factsheets/fs366/en/.

VI. About The Author

David  Orchard-Webb, Ph.D., is a technical writer with broad interests including  health & technology writing, plus extensive training and knowledge of  biomedicine and microbiology. My Ph.D. and postdoc were in oncology and  developing cancer medicines. I provide technical medical and other writing  services for projects ranging from “knowledge automation” to pure pharma, to  food safety, to the history of science, and everything in between. I also  provide white papers, ebooks, meta-analysis reviews, editing, consulting,  business, and market research-related activities in biomedicine, technology,  and health. In addition to its well-known role in the development of  medicines, I am a big believer in biotechnology’s ability to revolutionize  industries such as food-tech, agtech, textiles & fashion.