Herbal anthelmintic agents:a narrative review

Manjusa Adak,Pradeep Kumar

Manjusa Adak,Pradeep Kumar,Department of Pharmaceutical Sciences and Natural Products,Central University of Punjab,Ghudda,Bathinda,Punjab 151401,India

Abstract Helminths or Parasitic worms of humans may cause chronic and sometimes deadly diseases,considered as neglected tropical diseases (NTDs) that infect around two billion people worldwide.Plants have been used as anthelmintics from ancient times.This review is a compilation of plants as source of anthelmintic drug.All information presented in this review article regarding the anthelmintic activities of plants from 2005 and has been acquired by approaching various electronic databases,including Scopus,Google scholar,Web of science and PubMed.Literature was surveyed for anthelmintic activity of plants which showed that secondary metabolites of plants like terpenes,glycosides,saponins,flavonoids,tannins and alkaloids were having anthelmintic activity.Since this review is a compilation of anthelmintic activity of plants from the year 2005,it will definitely be a fruitful study for researchers working in this field.

Keywords:helminths;helminthiasis;anthelmintics;biological products;anthelmintics

1.INTRODUCTION

Parasitic worms or helminths cause chronic and sometimes deadly diseases that have a major socio-economic impact worldwide.1In humans,the disease caused by the parasitic worms is about 14 million globally,also called neglected tropical diseases (NTD).2In agricultural animals,diseases caused by parasites led to losses of about billions of dollars per year throughout the world.3,4

Gastrointestinal nematodes (GI),such as hookworms,whipworms,and roundworms affected under 15 years most.5Approximately more than 10% of the population is infected by GI nematodes worldwide.6

As of now,no vaccines are available in the market,so,control of helminths lies on the some of effective drugs,called anthelmintics,but their inadequate use causes serious drug resistance problems worldwide,so,urgent need is there for isolating,identifying new anthelmintic drugs,7for humans,its lies on chemotherapy.8Parasitic nematodes in human are two types :intestinal nematodes and tissue or blood nematodes.9Intestinal nematodes includes -Ancylostoma duodenale,Trichuris trichiura,Ascaris lumbricoides,Enterobius vermicularis,and Strongyloides stercoralis,etc.10

Helminths lives in the GI tract of their hosts,and feed off living hosts,taking nutrients from host and causing infection/diseases and normally more prone to children,soil-transmitted schistosomiasis and helminthiasis are the most significant helminthiases,responsible for neglected tropical disesses.11,12It also causes indirect disease burden through the immune system impairment,leads to malaria,tuberculosis,or human immunodeficiency virus/acquired immunodeficiency syndrome.13

Adult parasites survive for a long time in their human host and feeds directly from the blood of their hosts,thus helminths cause iron-deficiency anemia.14Chronic helminth infections are characterized by a Type II helper T cells type response.15-19

2.HELMINTHS AND ANTHELMINTICS

Helminths cause a number of diseases in humans and animals,which are summarized in Table 1.

Table 1 Diseases caused by helminths

2.1.Anthelmintics

Anthelmintics,the term used for a group of drugs,used to treat several infections of humans and animals,mainly caused by parasitic worms.33

2.1.1 Secondary metabolites of plants having anthelmintic activity

Allelochemicals of plants are produced from all plants,34primary metabolites acts as precursors of different secondary metabolites.35Secondary metabolites includeing Alkaloids,Terpenes,Flavonoids,Resins and Phenolic compounds are responsible for colour,flavour,fragrance of different plant.36Terpinen-4-ol was having LC50=4.1 mM and LC90=20.2 mM.Secondary metabolites having anthelmintic activity are summarized in Figure 1.

Figure 1 Secondary metabolites having anthelmintic activity

Terpenes:terpenes are the combination of different isoprene units (C5H8).36Its shows anthelmintic activities causing intestinal damage to the parasite.37Examples are terpinen-4-ol,borneol,and β-elemene showed activity againstH.contortusby inhibiting egg hatching.38Terpenes having anthelmintic activity are given in Figure 2.

Figure 2 Terpenes having anthelmintic activity

Glycosides:glycosides,have potent activity against different helminths.39,40Cardenolide causes disturbance of sodium and potassium ions transportation into helminths,thus,causing death of helminths.41Glycosides having anthelmintic activity are given in Figure 3.

Figure 3 Glycosides having anthelmintic activity (LC50=80.4 µM)LC50:lethal concentration 50.

Saponins:saponins contains triterpene or sometimes steroidal-aglycone with sugar chains.42Saponins show their anthelmintic activity by inhibiting acety-lcholinesterase and thus cause worm paralysis leading to death.43They are reported to have inhibitory activity against animal parasitic nematodes,like-Haemonchus contortus.44β-Sitosterol was having IC50value 58 µM.Saponins having anthelmintic activity are given in Figure 4.Flavonoids:flavonoids,helps in UV protection,flower coloring,allelopathy,and auxin transport inhibition.45Flavonoidal plant,showing activity by blocking the phosphorylation reaction,thus inhibit the energy production within the parasitic worms,leading to death.46Quercetin was having paralysis time at 10 mg/mL=2.23± 4.51 min.Flavonoids having anthelmintic activity are given in Figure 5.

Tannins:tannins,water-soluble,polyphenolic group of compounds,help in the killing of nematodes,by interfering with nutrients absorption of worms from the host cell46or when the condensed tannins are ingested by larvae,the tannin binds to the intestinal mucosa of the parasitic worms and thus causes autolysis.47Epigallocatechin was having IC50value 49 µM.Tannins having anthelmintic activity are given in Figure 6.

Alkaloids:alkaloids have shown anthelmintic activity by targeting acetylcholine receptor and suppressing glucose uptake,thus helminths died due to starvation.48Dicentrine was having EC90=6.3 µg/mL and sanguinarine was having IC50=58 µM.Alkaloids having anthelmintic activity are given in Figure 7.

Non-protein amino acids:non-protein amino acid are the nitrogen-containing compounds having ammonia derivatives compounds with hydrogen atoms.They damage the parasitic worms by affecting the CNS of parasitic worms,leading to paralysis and followed to death.49Mimosine was having IC50=16.8 µM Nonprotein amino acids having anthelmintic activity are given in Figure 8.Target Sites of anthelmintics Target sites for anthelmintic are summarized in Tables 2 and 3.

Table 2 Ion-channels as target sites for anthelmintics

Table 3 Target sites for anthelmintics (other than ion-channels)

Table 4 Plants having anthelmintic activity

Table 4 Plants having anthelmintic activity (continued)

2.1.3 Classes of natural products having anthelmintic activity Different classes of natural products are reported to have anthelmintic activities.

Phenols:phenolic compounds contain a functional heterogenous group attached with its aromatic ring.Groups like-flavonoids,isoflavonoids and tannins are included in the phenolic compounds,45showing activity by changing the phosphatase enzyme in the helminths tegument.50

Phenols having anthelmintic activity include:

Monophenols (cresols,thymols,and carvacrol):carvacrol and thymol showed activity againstC.elegansandAscaris suum.51Monophenols having anthelmintic activity are given in Figure 9.

Benzene diols (resorcinols and catechols):gallic acid analogues,catechin-3-O-gallate and four related proanthocyanidins showed activity againstC.elegansandO.ochengi.52Benzene diols having anthelmintic activity are given in Figure 10.

Substituted benzoic acids(vanillic acids and gallic acids):showed activity against nematodeC.elegansandOnchocerca ochengi.53Substituted benzoic acids having anthelmintic activity are given in Figure 11.

Figure 4 Saponins having anthelmintic activity

Figure 5 Flavonoids having anthelmintic activity

Figure 6 Tannins having anthelmintic activity

Figure 7 Alkaloids having anthelmintic activity

Cinnamic acid:cinnamic acid exhibited action by inhibiting egg hatching,example of some are p-coumaric,caffeic acid,ferulic acid,naringenin,quercetin and luteolin,procyanidins are having anthelmintic activity.53

Cinnamic acid derivatives having anthelmintic activity are given in Figure 12.Prenyl derivatives:farnesyl pyrophosphate and geranyl pyrophosphate,precursors of prenyl groups,linalool,active againstBrugia malayiandDirofilaria immitis.54Prenyl derivatives having anthelmintic activity are given in Figure 13.

Figure 8.Non-protein amino acids having anthelmintic activity

Macrocyclic Lactones:macrocycles includes macrolide and glyco lipopeptide,having anti-nematocidal activities,avermectins (Figure 14) and their aglycons are produced by soil microorganismStreptomycesspecies.55

Miscellaneous compounds:piperine fromPiper nigrumand strychnine fromStrychnos nux-vomicashowed activityagainst several helminths.Structures of piperine and strychnine are given in Figure 15.

Figure 9.Monophenols having anthelmintic activity

Figure 10 Benzene diols having anthelmintic activity

Figure 11 Substituted benzoic acids having anthelmintic activity

Figure 12 Cinnamic acid derivatives having anthelmintic activity

Figure 13 Prenyl derivatives having anthelmintic activity

Figure 14 Macrocyclic lactone having anthelmintic activity

Figure 15 Piperine and strychinine

2.1.4 Plants having anthelmintic activity

A number of plants are reported to have anthelmintic activities.Some of them are as follows:

Commiphora molmol:there are a number of reports indicating that over 90% of humans are suffering from schistosomiasis,fascioliasis.56Myrrh was effective againstTrichinella spiralisat a dose of 0.01 mL per infective mouse (Trichinella spiralisinfective mouse),half maximal effective concentration (EC50) value forCommiphora molmolwas 0.20 mg/mL.57

Ocimum sanctum:Occimum sanctumshowed its activity at a dose of 62.15 mg/mL againstCaenorhabditis elegans.58Crude hydro-alcoholic extract was tested at dose concentration of 20 and 40 mg/mL againstPheritima posthuma.For 20 mg/mL paralysis at (6.0 ±0.5) min and death at (13.5 ± 1.2) min.59

Melia azedarach:hexane extract ofM.azedarachfruits,effective against parasites,showed a significant lethal concentration 50 (LC50) value at 572.2 μg/mL and lethal concentration 99 (LC99) value at 1137.8 μg/mL.60

Artemisia annua:the plant crude leaves extract was tested againstH.contortus,showed lowest LC99at 1.27 μg/mL in egg hatch test assay,and in the larval development test assay,showed LC99at 23.8 μg/mL.61

Carica papaya:the latex of the plantCarica papayatested againstPheretima posthuma,with different concentrations (20%,50% and 100%),at 100%concentration,it shows paralysis time,P=24.5 min and death time,D=56 min.62

Nigella sativa:ethanolic extract,tested againstCotylophoron cotylophorumat 5% concentration,it showed 81.02 % inhibition of the motility after the exposure of 8 h.63

Flemingia vestita:the isoflavones of the plantFlemingia vestitawere tested againstRallietina echinobothridawith paralysis time for glucose 6-phosphate dehydrogenase is 0.880 ± 0.006 and for pyruvate carboxylase is 9.2 ± 0.2 and for fructose 1,6-bisphosphatase is 0.98 ± 0.15.64

Juglans regia:crude acetone extract showed anthelmintic activity at 10 mg/mL,with paralysis time(52.00 ± 0.20) min and death at (114.00 ± 0.14) min.Crude methanolic extract showed its anthelmintic activity at 10 mg/mL,with paralysis time (100.00 ± 0.14)min and death at (133.00 ± 0.18) min whentested againstEicinia feotid.65

Mimusops elengi:the methanolic extract was tested againstPheretima posthuma,showing anthelmintic activity at 5 mg/mL,causing paralysis and death of the helminths at 163.3,223.2 min respectively.66

Punica granatum:the crude methanolic tested againstHaemonchus contortus,at 10 mg/mL it produced mortality atP <0.05,hatching inhibition at 0.1 mg/mL upto 49.33% and 46.33%.67

Thymus vulgaris:essential oil ofThymus vulgariswas tested againstH.contortus,90% inhibition was observed at concentrations 50 to 0.781 mg/mL,and half maximal inhibitory concentration (IC50) value was 0.436 mg/mL.97.0% larval motility inhibition observed at concentrations 50 to 3.125 mg/mL and IC50value 0.338 mg/mL.68Ferula foetida:aqueous extracts were treated againstPheretima posthuma,exhibited activity at 100 mg/mL in 6 min (caused paralysis of the worms).Aqueous extract of the plant at 25 mg/mL caused helminths paralysis in(24.00 ± 0.14) min anddeath in (56.00 ± 0.17) min.69

Embelia ribes:methanolic extracts was tested againstAscaridia galli,at a dose of 60 mg/mL it showed activity 38.67% ± 4.10% and 38.67% ± 1.86%,after 48 h of incubation.70

Vernonia anthelmintica:ethanoic extracts were tested againstHaemonchus contortus,survival rate reduced significantly at a dose conc.of 80 μg/mL.71

Chenopodium ambrosioides:the ethanolic extract was tested againstHaemonchus contortus,showed lethal effect (about 96.3%) at 40 mg/mL,after 72 h incubation72and the EC50value ofChenopodium ambrosioideswas(0.26 ± 0.02) mg/mL.73Hydro-alcoholic extract tested againstSchistosoma mansoni,larvae died at different doses after 180 min.74

Piliostigma thonningii:the ethanolic extractwas tested againstAscardia galli,showing anthelmintic activity,about 60% of larval paralysis at a dose conc.of 4.4 mg/mL within 24 h of exposure.75

Ginkgo biloba:aqueous extract of plant was tested againstS.papillosus,3.0% of plant extract solution,mortality rate of nematode larvae was 92.3% ± 2.9%,in 0.75% of plant extract solution.76Petroleum-ether extract tested againstPseudodactylogyrus,at 6.0 and 2.5 mg/L,its having median effective dose (ED50) value 2.88 and 0.72 mg/L,respectively.77

Asparagus racemosus:rhizome extract at a dose of 5 mg/ml showed mortality time (2.30 ± 0.29) h.At a dose of 10 mg/mL,plant extract showed mortality time (2.09 ±0.05) h,etc.78

Trifolium repens:aerial shoot extract tested against the tapewormHymenolepis diminutawith different compoundsi.e.1 mg/mL betulinic acid,0.50 mg/mL ursolic acid and 0.25 mg/mL biochanin A.Among them betulinic acid showed the best anthelmintic effect with a mortality time of (3.40 ± 0.66) h.79Aerial shoot extract tested againstHymenolepis diminuta,at a dose concentration of 200 and 500 mg/kg,decreased the faecal egg 47.72% and 54.59% respectively.80

Ficus insipida:The latex was tested againstColossoma macropomum gills,immobilization of the parasite occurred after 4h on treatment with 250 µL/L of latex and with 500 µL/L,immobilization occurred after 2 h.81

Cucurbita maxima:the peel extract was tested againstPheritima posthuma,at a concentration of 50 mg/mL,the paralysis time of the earthworm took place in (90± 2) min and the death time of the earthworm was (11± 2) min.82

Trachyspermum ammi:for aqueous extract,LC50value was found at 0.1698 mg/mL and for methanolic extract,LC50values was found at 0.1828 mg/mL.75The seeds extract of the plant was also tested against GIT nematodes,showed activity at a dose of 3 g/kg,the maximum reduction in egg count occurred.83

Syzygium aromaticum:the ethanolic extract,tested againstPheritma posthuma,at a dose 2.5 mg/mL,causing paralysis of the worm in (4.27 ± 0.25) min and death within (45.00 ± 2.00) min.At 5mg/mL,the paralysis in (2.43 ± 0.31) min and death occurred within(35.00 ± 4.35) min.84When tested againstCotylophoron cotylophorum,ethanolic extract at 0.5 mg/mL,showing motility (86.27%) after 8 h of treatment.85

Trichilia claussenii:anthelmintic activity of the plantTrichilia clausseniiwas studied against gastrointestinal nematodes,methanol extract of leaves showed a significant LC50value at 263.8 μg/mL and LC99value at 522.5 μg/mL.86

Withania somnifera:crude extracted hydro-alcoholic solution tested againstPheritima posthumaat dose concentration of 20 and 40 mg/mL,paralysis was shown in (6.5 ± 0.5) min and (2.8 ± 0.8) min and death occurred(13.9 ± 1.2) min and (7.1 ± 0.9) min respectively.87

Pleurospermum amabile:the crude methanolic extract when tested against whipworms and blood flukes,bergapten showed an IC50value 8.6 μg/mL againstS.mansoniand 10.6 μg/mL againstT.muris.88

Macleaya cordata:the crude extract when treated againstToxocara canis,Sanguinarine was showed IC50value 58 μΜ after 24 h.89

Ajania nubigena:the crude extract was tested againstTrichuris muris.Linalool and Luteolin were showed IC50value 20.4 μg/mL and 9.7 μg/mL,respectively after 12 h.89Leucaena leucocephala:the crude extract was tested againstC.elegans.Mimosine was showed an IC50value 16.8 μΜ after 24 h.89The EC50 valuecotyledon extract was 0.48 mg mL–1and seed extracts showed EC50 value 0.33 mg/mL.90

Warburgia ugandensis:the crude extract was tested againstC.elegans,Mimosine showed mortality after 24 h with IC50value (70.1 ± 17.5) μΜ against.89Plants having anthelmintic activity are summarized in Table 4.

3.CONCLUSIONS

A number of plants/extracts are reported to have anthelmintic activity.Most of the studies reportedin vitroactivity and only a few studies reportin vivoactivity.So,more research is needed to investigate the molecular mechanism of action of the reported anthelmintic plants/extracts as well as there is a need to either modify existing anthelmintic agents or explore new molecular targets to get next generation anthelmintic agents.

3.1.Future perspectives

Now a days novel anthelmintic targets like lysine deacetylases,lysine deacetylases,KDAC inhibitors,kinase inhibitors are explored.Modification of chemical structure and combination of known anthelmintics is also one of the ways to combat this challenge.Drug repurposing is also an emerging trend in anthelmintic drug discoverye.g.trichlorfon,a broad-spectrum organophosphorus insecticide has recently proved as anthelmintic agent.

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