Encyclopedia of Parasitology

2016 Edition
| Editors: Heinz Mehlhorn

Inhibitory-Neurotransmission-Affecting Drugs

Reference work entry
DOI: https://doi.org/10.1007/978-3-662-43978-4_1606
Overview see Table 1.
Inhibitory-Neurotransmission-Affecting Drugs, Table 1

Drugs active against micro- and macrofilariae

Year of introduction or discovery

Drug

Effects against filariae

Effect on other parasites

Drugs with predominantly microfilaricidal effects

Acetylcholine-neurotransmission-affecting drugs

1955

Metrifonate

Onchocerca volvulus microfilariae

Ascaris, S. haematobium, insects

1965

Levamisole

W. bancrofi, B. malayi

Intestinal nematodes

Inhibitory-neurotransmission-affecting drugs

1980

Ivermectin

Onchocerca volvulus, W. bancrofti, Loa loa; Dirofilaria immitis

Nematodes, arthropods

1980s

Milbemycin D

Dirofilaria immitis a

Nematodes, arthropods

1990

Milbemycin A4 oxime

Dirofilaria immitis; microfilariae in rodent modelsb

Nematodes, arthropods

1990

Moxidectin

Dirofilaria immitis; microfilariae in man and rodent modelsb

Nematodes, arthropods

1993

Doramectin

Microfilariae in man and rodent modelsb

Nematodes, arthropods

1999

Selamectin

Dirofilaria immitis

Nematodes, arthropods

2005

Latidectin

Dirofilaria immitis

Nematodes, arthropods

Membrane-function-disturbing drugs

1947/48

Diethylcarbamazine

W. bancrofti, Brugia spp., Onchocerca volvulus, Loa loa

 

Drugs with predominantly macrofilaricidal effects

Energy-metabolism-disturbing drugs

1916

Suramin

Wuchereria, Brugia (macrofilariae); adult O. volvulus

Trypanosomes

1984

Arsenamide (thiacetarsamide)

Dirofilaria immitis (dog)

 

Microtubule-function-affecting drugs

1971

Flubendazole, mebendazole, albendazole

Wuchereria, Brugia (macrofilariae), O. volvulus, also embryostatic effects

Nematodes, cestodes, trematodes, Giardia

Drug combinations

 

Ivermectin/DEC

Lymphatic filariasis

Mites/microsporidia

Ivermectin/albendazole

Drugs with macro- and microfilaricidal effects

1980

Benzothiazoles

Onchocerca, Brugia spp., Dipetalonema spp.

Cestodes

aMcKellar QA, Benchaoui HA (1996) J Vet Pharmacol Therap 19:331–351

bSchares G, Hofmann B, Zahner H (1994) Trop Med Parasitol 45:97–106

Structures

Figure 1.
Inhibitory-Neurotransmission-Affecting Drugs, Fig. 1

Structures of antiparasitic drugs affecting GABA- or glutamate-gated chloride channels

Piperazine

Synonyms

75 different synonyms (Chemotherapy of parasitic diseases (Campbell WC, Rew RS (eds), Plenum Press, New York and London, p. 629)).

Clinical Relevance

The antinematodal activity of piperazine is directed against   Ascaris lumbricoides , Enterobius, ascarids in dogs and cats, adult Oesophagostomum in pigs, adult horse  nematodes, and Ascaridia in chicken. Piperazine is only effective against large intestinal nematodes.

Molecular Interactions

Piperazine (Fig. 1) induces a reversible paralysis of Ascaris suum in vitro by exerting hyperpolarizing effects, thus acting as a selective GABA agonist (Fig. 2). The average duration of piperazine-induced channel openings is 14 ms, and is thus shorter than the GABA-produced openings with 32 ms. Piperazine is about 100 times less potent than GABA in A. suum. The difference in potency correlates with the need for higher piperazine concentrations to achieve a similar opening rate to GABA. The   Ascaris GABA receptor is pharmacologically distinguished from the vertebrate GABAa receptors. The action becomes potentiated by the presence of a high pCO2 probable by interaction of CO2 with the heterocyclic ring of piperazine which partially substitutes for the carboxylgroup of GABA.
Inhibitory-Neurotransmission-Affecting Drugs, Fig. 2

Model of the action of piperazine on the GABAergic neurotransmission

Macrocyclic Lactones

Important Compounds

Ivermectin, Abamectin, Doramectin, Eprinomectin, Latidectin, Milbemycin oxime, Moxidectin, Selamectin.

Synonyms

  • Ivermectin: Baymec, Ivomec, Ivomec-Premix Ivomec-S, Cardomec, Equell, Eqvalan, Furexel, Heartguard 30, Heartgard Chewable, Mectizan, Oramec, Rotectin, Strongid, Zymectrin; in: Ivomec-P, Heartgard Plus.

  • Abamectin: Avomec, Duotin, Enzec; in: Equimax.

  • Doramectin: Dectomax.

  • Eprinomectin: Eprinex.

  • Latidectin: Lifenal

  • Milbemycin oxime: Interceptor, Interceptor Flavor Tabs; in: Sentinel.

  • Moxidectin: Cydectin, Equest, Pro Heart, Quest.

  • Selamectin: Revolution, Stronghold.

Clinical Relevance

The group of these macrocyclic lactones is subdivided into two groups, the avermectins and milbemycins. To the avermectin anthelmintics belong avermectin (explored 1975), ivermectin (marketed 1980), abamectin (1980), doramectin (1993), eprinomectin (1996), selamectin (1999) and latidectin (2005). To the milbemycin anthelmintics belong milbemycin (explored 1973), milbemycin oxime and moxidectin (1993). Avermectin is produced by Streptomyces avermitilis, an actinomycete strain. Avermectin was isolated in 1975 and its antiparasitic activity discovered in mice infected with Nematospiroides dubius. The components avermectin B1a and B1b exert the highest anthelmintic activities. The chemical reduction leads to dihydro-derivatives with low toxicity. The mixture of 80 % dihydro avermectin B1a and 20 % B1b is named ivermectin.

Macrocyclic lactones are applied as broad-spectrum anthelmintics and ectoparasiticides in dogs, horses, cattle, sheep, pigs (Tables 1 and 2,  Microtubule-Function-Affecting Drugs, Table 1, 2). Ivermectin is the drug of choice against   Strongyloides stercoralis infections in immunosuppressed patients. In addition, this drug is used for  heartworm prophylaxis, in human onchocerciasis it is the drug of choice and it is of growing importance in  lymphatic filariasis (e.g.,   Wuchereria bancrofti infections) as single drug or in combination with DEC or albendazole (Table 1). It has microfilaricidal effects and leads to a suppression of embryogenesis in human onchocerciasis. It was introduced to Onchocerciasis Control Program of WHO in 1987 as Mectizan. In addition, ivermectin has some activity against male   Onchocerca volvulus in man as well as against microfilariae of W. bancrofti,   Loa loa . Ivermectin activity can be observed against Litomosoides carinii microfilariae in the circulating blood but not against microfilariae in the pleural cavity. Ivermectin has some in vitro activity against filarial parasites, e.g.,   Onchocerca spp. There is generally a great discrepancy between the good in vivo efficacy and the minor in vitro effects. In general, treatment with ivermectin is not accompanied by severe side effects.
Inhibitory-Neurotransmission-Affecting Drugs, Table 2

Antiparasitic spectrum of ivermectin, doramectin, eprinomectin, and moxidectin in cattle (according to the technical manuals of the suppliers)

Ivermectin

Doramectin

Eprinomectin

Moxidectin

1. Gastroinestinal nematodes (adults and L4 larvae)

Ostertagia ostertagi and arrested larvae

Ostertagia ostertagi and arrested larvae

Ostertagia ostertagi and arrested larvae

Ostertagia ostertagi and arrested larvae

O. lyrata

  

O. lyrata

Haemonchus placei

Haemonchus spp. H. similis

Haemonchus placei

Haemonchus spp. H. similis H. contortus

Trichostrongylus colubriformis

Trichostrongylus colubriformis

Trichostrongylus colubriformis

Trichostrongylus colubriformis

Trichostrongylus axei

 

Trichostrongylus axei

Trichostrongylus axei

Cooperia oncophora

Cooperia spp.

Cooperia oncophora

Cooperia oncophora

C. punctata

C. punctata

C. punctata

C. punctata

C. pectinata

C. pectinata

 

C. pectinata

   

C. spatulata

  

C. surnabada

 

Bunostomum phlebotomum

Bunostomum phlebotomum

Bunostomum phlebotomum

Bunostomum phlebotomum

Oesophagostomum radiatum

Oesophagostomum radiatum

Oesophagostomum radiatum

Oesophagostomum radiatum

Nematodirus helvetianus a

Nematodirus helvetianus a

Nematodirus helvetianus

Nematodirus helvetianus

N. spathiger a

N. spathiger a

 

N. spathiger

Strongyloides papillosus a

Strongyloides papillosus a

  
 

Trichuris spp.

Trichuris spp.

Trichuris discolor

2. Lungworms (adults and L4 larvae)

Dictyocaulus viviparus

Dictyocaulus viviparus

  
 

Dictyocaulus viviparus

Dictyocaulus viviparus

 

3. Grubs/Myiasis

Dermatobia hominis larvae

Dermatobia hominislarvae

 

Cochliomyia hominivorax b

Cochliomyia hominivorax

Hypoderma bovis

Hypoderma bovis

 

Hypoderma lineatum

 

Hypoderma lineatum

   

4. Lice

   

Linognathus vituli

Linognathus vituli

Linognathus vituli

Linognathus vituli

Haematopinus eurysternus

Haematopinus eurysternus

Haematopinus eurysternus

 

Solenopotes capillatus

Solenopotes capillatus

Solenopotes capillatus

Solenopotes capillatus

Damalinia bovis c

Damalinia bovis c

Damalinia bovis

 

5. Mites

Psoroptes ovis

Psoroptes ovis

 

Psoroptes ovis

Sarcoptes scabiei var. bovis

 

Sarcoptes scabiei

 

Chorioptes bovis

 

Chorioptes bovis

 

6. Ticks

Boophilus microplus

Boophilus microplus

 

Boophilus microplus

Boophilus decoloratus

   

Ornithodorus savignyi

   

7. Flies

Haematobia irritans

Haematobia irritans

aOnly adult stages

bProphylactic (injection) or curative (topical) treatment

cParasitic control

Molecular Interactions

Macrocyclic lactones act at the junction of ventral cord interneurons and motorneurons resulting in the immobilization of nematodes and at the neuromuscular junction of arthropods causing paralysis. Macrocyclic lactones are taken up by many gastrointestinal and filarial nematodes via the cuticula and presumably with equal importance by oral ingestion ( Acetylcholine-Neurotransmission-Affecting Drugs, Fig. 3), while in blood-sucking parasites (  Haemonchus contortus , arthropod ectoparasites) the oral absorption is by far more important. This view is supported by the observation that macrocyclic lactones exert greater activities against sucking  lice (Haematopinus eurysternus, Linognathus vituli) than biting lice (Damalina bovis). They also have high efficacy against  mites (Sarcoptes scabiei var bovis), which are known to be blood consumers.

The mode of action of avermectins and milbemycins relies on the opening of the chloride ion channels in the neuronal membranes of nematodes and the muscle membranes of arthropods (Fig. 3). Thereby, cells become hyperpolarized and can no longer respond to incoming stimuli. All the physiological effects of avermectins and milbemycins can be reversed by picrotoxin, a specific blocker of the chloride ion channels. There is an ivermectin-induced increase of chloride permeability of nerve and muscles membranes of invertebrates observable. The structure and regulation of chloride ion channels of nematodes on the molecular level is unclear at present and also the identity of the target ion channel is controversial. Results from experiments with crayfish and Ascaris suum reveal that there is an interaction with receptors at chloride channels. The action is obviously not mediated by GABA-gated chloride channels. Expression experiments with Xenopus oocytes lead to a proposed action of avermectins on a glutamate-gated chloride channel (GluCl). Genes encoding ivermectin-sensitive glutamate-gated chloride channel subunits could be isolated from   Caenorhabditis elegans . Moreover, the avermectin-binding site could be purified from C. elegans. A 1.8–2.0 kbp mRNA of C. elegans encoding a chloride channel with sensitivity to both ivermectin and glutamate could be identified. The channel is presumably a pentamer similar to the nicotinic receptor and is selectively permeable for anions (chloride). The pentamer consists presumably of GluCl-α subunits with a glutamate-binding site and a GluCl-β subunit which contains the ivermectin-binding site. Molecularbiological experiments reveal that the GluCl-β subunit of the glutamate-gated channel is expressed in the pharyngeal muscle of C. elegans. There are considerable identities of α- and β- subunits of the glutamate-gated ion channels with the α- and β- subunits of mammalian GABA and glycine receptors.
Inhibitory-Neurotransmission-Affecting Drugs, Fig. 3

Model of the drugs affecting neuromuscular transmission by inhibitory neurotransmitters in protostomes

According to a hypothesis the pharyngeal pumping of nematodes is inhibited by ivermectin. In the pharyngeal muscle of A. suum a potentiation of the action of glutamate on glutamate receptors that gate chloride channels by ivermectin analogues could be observed. The hyperpolarization of the nerve and muscle membranes leads to a flaccid paralysis of the parasites. The CNS side effects of ivermectin are explained by the strong action on the receptors in rat brain through potentiation of GABA- and benzodiazepine-binding to open the channel. Nevertheless the relatively safe use of avermectins is due to the inability to cross the blood-brain barriers into the CNS in mammals with the exception of Collies. Moreover, the selectivity of macrocyclic lactones is due to different neurotransmitter functioning of glutamate in invertebrates (protostomes) where it acts as an inhibitory neurotransmitter in contrast to vertebrates where glutamate acts as an excitatory neurotransmitter.

Macrocyclic lactones like milbemycin oxime have only slight inhibitory and stimulatory concentration-dependent effects on the motility of filariae such as   Dirofilaria immitis . It is assumed that definite host factors are required, which are independent of a specific immune status of the host. In   Acanthocheilonema viteae an ivermectin-mediated cell adherence to the living microfilariae is observable and also cellular cytotoxicity by complement activation via the alternate pathway and/or antibodies. L. carinii microfilariae are killed without direct contact between cells and larvae. Here a very short-living mediator, which can be inhibited by the arginin-analogs such as NG-monomethyl-L-arginine and L-canavanine, seems to be involved in the drug’s action. Leucocytes are also required for the in vitro efficacy of ivermectin against microfilariae of Dirofilaria immitis. The immobilization of the larvae is necessary for cell adherence or cellular toxicity similar to ivermectin-induced paralysis of Acanthocheilonema suum. In addition, the paralysis of microfilariae of O. volvulus presumably facilitates the phagocytic cell-trapping. The effects of ivermectin on adult worms are not fully understood to date. Electron microscopic studies on Acanthocheilonema viteae reveal a vacuolization and an increased electron density in all organs beginning 8 days after treatment. In L. carinii a degeneration of intrauterine stages and an extreme folding of the uterine wall can be observed accompanied by a generally increased electron density.

Resistance

Resistance against macrocyclic lactones is probably inherited by a single dominant allele in Haemonchus contortus. The mechanism of ivermectin resistance on the molecular level is still unknown. Membranes of ivermectin-resistant and -susceptible larvae of H. contortus contain similar numbers of ivermectin-binding sites with the same affinity characteristics. It could recently be shown that ivermectin resistance may be caused by an altered P-glycoprotein homolog in H. contortus. Thereby the expression of P-glycoprotein mRNA is higher in the ivermectin-resistant H. contortus strain than in the susceptible strain. This multidrug-resistance mechanism can be reversed by verapamil and there is an increased efficacy of ivermectin and moxidectin against moxidectin-resistant Haemonchus in jirds (Meriones unguiculatus) in the presence of verapamil. The disruption of the mdr1a gene, which encodes P-glycoprotein in mice, results in hypersensitivity against ivermectin. In another report an involvement of P-glycoprotein in ivermectin resistance in H. contortus was excluded. Now there exists a Caenorhabditis elegans mutant with a high level of ivermectin resistance, which can serve as a tool for further investigations of alterations in the glutamate/ivermectin chloride channel receptor and mechanism of ivermectin resistance in future.

Cyclic Octadepsipeptides

PF1022A

Synonyms.

Clinical Relevance

This compound has potent antinematodal properties against   Toxocara canis , T. cati, and  hookworms in dogs and cats and Trichuris vulpis in dogs. In addition, it has high efficacies against gastrointestinal  nematodes in horses, sheep, chicken, and rodents.

Molecular Interactions

PF1022A is a 24-membered cyclic depsipeptide isolated from Mycelia sterilia, a fungus which belongs to the  microflora of the plant Camellia japonica. Recently the chemical synthesis of PF1022A and also the radiolabelled compound have been reported. The anthelmintic action on the molecular level remains obscure to date. It appears that it exerts its activity by interfering with the neuromuscular transmission of nematodes. At low concentrations, the motility of   Angiostrongylus cantonensis is depressed, and picrotoxin, bicucullin, and Ca++ can antagonize the action. Thus, the action is explained by an antagonism of acetylcholine receptors and/or gabaergic mechanisms. It could also be shown that PF1022A has a high affinity binding to the GABAA receptor in Ascaris suum.

Recent experiments show that PF1022A and emodepside bind to a latrophilin-like receptor in the parasitic nematode Haemonchus contortus and the free-living nematode Caenorhabditis elegans.

Emodepside

Synonyms

PF1022–221, Bay 44–4400, emodepside as part of the anthelmintic combination emodepside/praziquantel in Profender Spot-On® for cats.

Clinical Relevance

Anthelmintic research of the class of cyclic octadepsipeptides to which emodepside belongs started at the beginning of the 1990s. PF1022A, the starting material of emodepside, is a natural secondary metabolite of the fungus Mycelia sterilia, which belongs to the microflora of the leaves of Camellia japonica. PF1022A consists of four N-methyl-L-leucins, two D-lactic acids and two D-phenyllactic acids. These molecules build up a cyclic octadepsipeptide with an alternating L-D-L configuration. Emodepside is a semisynthetic derivative of PF1022A, which contains a morpholine attached in para-position at each of both D-phenyllactic acids.

Emodepside is effective against a wide variety of nematodes in cats, dogs, sheep, cattle, horse, poultry, mice, and rats. In cats after spot-on application of the all de-wormer Profender®, emodepside is highly efficacious against Toxocara cati and Ancylostoma caninum ( Microtubule-Function-Affecting Drugs, Table 2). In addition to its effects against gastrointestinal nematodes emodepside shows activities against lungworms in cattle, different larval stages of filariae in rodent models, and Trichinella spiralis larvae in mice.

Molecular Interactions

Emodepside binds to a presynaptic latrophilin-like receptor in the parasitic nematodes Haemonchus contortus, Ostertagia ostertagi, Cooperia oncophora, Ancylostoma caninum, and the free-living nematode Caenorhabditis elegans. Binding of drug to the latrophilin-like receptor is followed by the activation of a presynaptic signal transduction cascade (Fig. 4). The activation of Gqα protein and phospholipase-Cβ leads to mobilization of diacylglycerol (DAG). DAG then activates UNC-13 and synaptobrevin, two proteins which play an important role in presynaptic vesicle functioning. This finally leads to the release of a currently unindentified neurotransmitter. The transmitter (or modulator) exerts its effects at the postsynaptic membrane and induces a flaccid paralysis of the pharynx and the somatic musculature in nematodes.
Inhibitory-Neurotransmission-Affecting Drugs, Fig. 4

Proposed mechanism of action following activation of a presynaptic latrophilin receptor by emodepside. PLC Phospholipase, PIP2 phosphatidylinositol- 4,5-bisphosphate, DAG diacylglycerol

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