Potential of Anthelmintic Herbal Drugs against Gastrointestinal Nematodes in Farm Animals: A Review

Gastrointestinal (GI) nematode infections are one of the most prevalent and significant problems in livestock worldwide. This study aimed to review the potential of anthelmintic herbal drugs against gastrointestinal nematodes in farm animals


Introduction
Helminths can affect farm animals, humans, and livestock in the tropics 1 . Helminth infections in livestock are among the most prevalent diseases in developing countries. Globally, it is estimated that about 2 billion people are infected by intestinal nematodes 2 . Helminthborne diseases can be chronic and debilitating; they cause significant morbidity and economic and social deprivation among humans and animals 3 . Treatments of gastrointestinal (GI) nematodes in domesticated animals have an economic value as the disease may cause increased mortality, decreased live weight gain, reduced wool growth and yield, decreased fertility and milk production, rejection of carcasses or organs for human consumption, depressed appetite, impaired GI functions, changes in protein, energy, and mineral metabolism, change in water balance, and predispositions to other diseases 4 .
Today, anthelmintic resistance is recognized as a problem worldwide involving the leading anthelmintic families 5 . The definition of resistance varies in different publications. According to the World Association for the Advancement of Veterinary Parasitology (WAAVP), anthelmintic resistance occurs in ruminants and horses when a drug fails to reduce fecal nematode egg count by at least 95% 6 .
Tropical and subtropical climates favor for many gastrointestinal nematodes (GINs), such as Haemonchus contortus (H. contortus), Trichostrongylus, Nematodirus, and Strongyloides papillosus in domestic animals 7 . Among these GINs, H. contortus is the most pathogenic, widely prevalent, and dangerous worm, responsible for high morbidity and mortality in sheep and goats 8 . Synthetic anthelmintic drugs are frequently used to control GINs. However, the efficacy of synthetic anthelmintics has been reduced with the development of anthelmintic resistance. Herbal drugs are becoming more popular as cost-effective and sustainable alternatives to synthetic anthelmintic treatments 9 . Researchers have examined various plants' anthelmintic properties in vitro and in vivo 10 . Thus, continuous evaluation of efficacy for available drugs and alternate methods are necessary for controlling these GINs.

Albendazole
When used for short-term GI helminthiasis therapy, Albendazole rarely causes side effects. Epigastric pain, diarrhea, nausea, vomiting, headache, and dizziness, also allergic symptoms, such as edema, rashes, and urticaria, are transient signs of Albendazole toxicity in animals 14 . Albendazole could negatively impact children's growth when they have asymptomatic trichuriasis 15 . The most frequent adverse reaction of Albendazole in humans is an increase in serum aminotransferase activity; occasionally, jaundice or cholestasis may be observed. According to the previous pharmacoepidemiologic analysis, most of the adverse drug reactions in humans linked to anthelmintic therapy were caused by long-term treatment of echinococcosis or cysticercosis with high-dose Albendazole 15 .

Mebendazole
High dosage administration of Mebendazole in animals resulted in transient symptoms of abdominal pain, distention, and diarrhea. In human patients receiving high doses of Mebendazole, allergic reactions, alopecia, reversible neutropenia, agranulocytosis, and hypospermia are common side effects 16 . In this population, the reversible elevation of serum transaminases is common. Occipital seizures may occur during Mebendazole therapy in children 16 . Mebendazole is a potent teratogen and embryotoxic in laboratory animals; negative effects in pregnant rats have been reported at single oral doses as low as 10 mg/kg 17 . Mebendazole should not be administered to infants younger than two years old or taken by pregnant women 16 .

Praziquantel
Praziquantel's side effects in animals, including stomach pain, nausea, diarrhea, are temporary and dose-related 18 . Human's side effects are fever, pruritus, urticaria, rashes, arthralgia, and myalgia and parasite burden are often related to these side effects. Praziquantel -induced inflammatory reactions in neurocysticercosis can result in meningism, seizures, and pleocytosis of the cerebrospinal fluid.

Ivermectin
At very high doses, Ivermectin results in CNS toxicity in farm animals that manifests as lethargy, ataxia, mydriasis, tremors, and eventually death 19 . Most of the time, mazzotti-like reactions to dying microfilariae develop in infected humans injected with Ivermectin due to hypertensives reaction to dead microfilariae. The severity and type of these reactions depend on the microfilariae's burden as well as the type of filarial infection 20 .

Plants
Humans and animals with parasitic infections have been treated with various medicinal plants in history. However, there are numerous issues, such as effective dose, and lethal dosage duration of administration with the development of naturally occurring compounds as drugs for humans and animals 21 . Therefore, it would be essential to investigate the possibility of creating effective anthelmintic substances. In recent years, herbal products have gained the researchers' attention due to their anthelmintic effects, ability to control parasites, minimal adverse environmental effects. In addition, an increase in synthetic anthelminthic drug resistance necessitates the need to find a substitution for synthetic anthelminthic drugs 22 . Using plants with anthelmintic properties appears to have two benefits 23 . Plant products develop resistance more slowly and a mixture of components that synergize, producing an anthelminthic effect in plant products 24 . On the contrary, synthetic drugs have one molecule acting on the parasite when not in a combination formulation. In addition, plant-produced secondary metabolites act as active ingredients in pharmaceutical formulations 25 . The primary methods of preparation used in traditional medicine are infusions and aqueous decoctions. Recognition of some plants' therapeutic properties is essential to the efficacy and credibility of herbal medicines. Therefore, experimental proof is crucial to determine plant products' efficacy as anthelmintics.

Nicotiana tabacum
Known for its narcotic properties, Nicotiana tabacum is commonly referred to as tobacco. Nicotine has been identified as the primary alkaloid in the plant, and it is often cited as an efficient pesticide 26 . There have been few studies on the anthelmintic effects of tobacco on gastrointestinal parasites in sheep, swine ascariasis, adult fleas (Ctenocephalides felis), blowfly (Lucilia cuprina) larvae, nematodes (Caenorhabditis elegans), and ticks (Rhipicephalus sanguineus larvae and adults, Ixodes ricinus nymphs), and Ascaridia galli 27,28 . In addition, Nicotiana tabacum potentially impacts strongyle infections, particularly in horses 29 .

Allium sativum (Garlic)
Allium sativum (Garlic) is an antioxidant that inhibits lipid peroxidation, which has a hepatoprotective effect 30 . Its main constituent, allicin, is the most abundant component, representing about 70% of the overall thiosulfinate present in garlic cloves 31 . It is responsible for its flavor and aroma as well as its potential antibacterial, antiparasitic, antiviral, and anticancer properties. Moreover, one of the most crucial elements in garlic that are essential for most of its pharmacological effects is its organosulfur compounds 32 . Ajoene, diallyl trisulfide (DTS), and allyl methyl sulfide have been identified as the primary compounds in garlic that play an important role in its antifungal, antibacterial, antiprotozoal, anthelmintic, and antiviral properties 33 . In addition, garlic can positively affect cryptosporidial infection in swine 34 .

Vaividang (Embelia ribes)
The family Primulaceae includes the herb known as Embelia ribes, which is a woody climber plant. It is also known as false black pepper or Vaividang. The primary chemical constituent extracted from this plant is embelin, which carries excellent medicinal value and is used to cure various ailments and diseases 35 . Vaividang is used to treat obesity, mouth ulcers, fungus infections, mouth sores, pneumonia, mental disorders, constipation, and abdominal pain 36 . In addition, the plant has historically been used to treat skin conditions, toothaches, tonsillitis, arthritis, jaundice, bloating, and gastrointestinal nematodes 37 . In addition, it possesses several therapeutic and pharmacological properties, including antibacterial, antioxidant, anti-inflammatory, wound healing, and anthelmintic properties 38 .

Biophytum petersianum (Oxalidaceae)
Biophytum petersianum has been used to treat malaria, different types of pain, and dermatitis, as well as mouthwashes and laxatives 39,40,41 . In a study in Indonesia on sheep infected with Strongyloides, fecal egg count decreased when sheep received Biophytum petersianum extract 42 .

Calotropis procera (Madar)
Calotropis procera, a member of the Apocynaceae family, is a softly wooded, perennial shrub with few stems, branches, and leaves that are concentrated near the growing tip and have antimicrobial, anthelmintic, antioxidant, antimalarial, nematocidal, anticancer, antiinflammatory properties 43,44 . A study indicated that Calotropis procera leaf powder and amprolium had comparable activity against coccidiosis in chickens 46 . In addition, Calotropis Procera extract can inhibit egg hatching, larval development, and motility of the adult worms of H. contortus 47 .

Melia azedarach
Melia azedarach (M. Azedarach), also known as white cedar, is indigenous to Indomalaya and Australasia and is a member of the Meliaceae family 48

Benincasa hispida
Ash Gourd (Benincasa hispida) is believed to have originated in Java, Indonesia. The fruit could be effective in treatment of some serious illnesses, such as convulsions, asthma, cough, urinary retention, and internal bleeding 52 . Additionally, it has beneficial effects on treating tapeworms 53 . Extract of leaves of Benincasa hispida causes paralysis, leading to the death of H. contortus, especially at very high concentrations of 50 mg/ml, within a short period 52 .

Bridelia retusa
Extracts of Bridelia retusa bark exhibit anthelmintic activity on Trichostrongylus species in sheep 54 .

Lantana camara
Lantana camara, also known as big sage, is a member of the verbanaceae family. Lantana leaf has fungicidal, insecticidal, and antimicrobial activities 55 . It has also been used traditionally in herbal medicines as anthelmintic and various illnesses, such as ulcers, leprosy, chicken pox, rabies, itching skin, and cancer 56 . A study reported the antionchocercal (Onchocerca volvulus) activities of Lantana camara 58 .

Conclusion
In conclusion, it is of utmost importance to provide alternative drugs due to side effects and increased resistance to synthetic anthelmintic drugs. Some herbs are traditionally used as anthelmintic drugs, and some studies have indicated such effects of some herbs on parasites. In addition, due to their fewer side effects, herbal drugs have gained significant importance in medicine over the past few years. However, more studies are needed to evaluate the effect of herbal medicine on farm animal parasites and the effective dosage of herbal drugs.

Competing interests
There is no conflict of interest.

Authors' contribution
The final manuscript draft was reviewed by all authors, who also gave their approval.

Funding
No funding.

Ethical considerations
Ethical issues (including plagiarism, consent to publish, misconduct, data fabrication and/or falsification, double publication and/or submission, and redundancy) have been checked by all the authors.