Ectoparasites can cause various skin diseases and serve as a vector for a number of infectious diseases. In dogs and cats, fleas are the most important ectoparasite worldwide. Among several species that can infest companion animals, the cat flea (Ctenocephalides felis) is most widely found. Repeated flea bites cause discomfort to animals and annoy humans as well (Rust & Dryden, 1997; Mencke & Jeschke, 2002). The bloodsucking of fleas in heavily infested animals can also lead to anemia, especially in young animals. Moreover, fleas cause allergic dermatitis in dogs and cats (Mencke & Jeschke, 2002; Rust, 2005). They are also vectors of a number of bacteria, including Rickettsia typhi, Rickettsia felis, and Bartonella henselae. In addition, fleas can be an intermediate host for tapeworm Dipylidium caninum, the common intestinal cestode of dogs and cats, which occasionally infects human as well.
The recently introduced insect nicotinic acetylcholine receptor (nAChR) agonists are important novel insecticides that are used to control fleas in companion animals. These compounds are highly selective for insect nAChRs, and thus are effective and safe to eliminate fleas in dogs and cats. To date, there are no records of cross-resistance of insect nAChR agonists with other ectoparasiticides, e.g., carbamates, organophosphates, or pyrethroids, making them important for management of insecticide resistance. Imidacloprid was the first neonicotinoid, the nicotine-like compound, introduced to the market in 1991 and quickly it became one of the most important insecticides in agriculture and veterinary medicine (Tomizawa & Casida, 2003). Subsequently, two other neonicotinoids, nitenpyram and dinotefuran, were also approved for flea control in veterinary practice and in agriculture. Their rapid fleacidal action is one of the advantages compared with other slower acting flea adulticides such as fipronil and selamectin (Schenker et al., 2003). This is an important feature when dealing with ectoparasites that are vectors for zoonotic bacteria (Mencke & Jeschke, 2002).
Spinosad is a mixture of two natural occurring macrocyclic lactones (spinosyn A and spinosyn D) and it acts primarily as a nAChR agonist. Spinosad has a secondary action in insects, which opens chloride channels like other macrocyclic lactones (Millar & Denholm, 2007). Spinosad was introduced into the market in 1997 for the control of a number of pest insects in agriculture and as an oral flea adulticide in 2007 (Millar & Denholm, 2007; Snyder et al., 2007).
In this review, we discuss the pharmacology of neonicotinoids and spinosad on insect nAChRs and their therapeutic use for the flea control in small animals.
Insect nAChRs vs. vertebrate nAChRs
Biochemistry of nAChRs. These receptors are prototypical members of the cys-loop ligand-gated ion channel superfamily, consisting of five subunits that are arranged around a central cation permeable pore (Sine & Engel, 2006). There are ∼500 amino acids in each subunit; each subunit is encoded by a separate gene and possesses four transmembrane domains (TM1–TM4). Usually there are two agonist binding sites on the extracellular surface of the receptor-cation-channel. The agonist binding site is formed at the interface of two adjacent subunits on the N-terminal extracellular domains of the subunits. The agonist binding site is formed by six distinct amino-acid loops (loops A–F). Loops A–C are formed on the α-subunits and loops D–F are on the adjacent non-α-subunits (or β-subunits in insects) (Figs 1 & 2) (Corringer et al., 2000; Thany et al., 2007). Some nicotinic receptor-cation-channels are formed from five α7, α8, or α9 subunits and these are known as homomeric receptors. These receptors have five agonist binding sites formed by loops A–F on adjacent edges of the subunits (Matsuda et al., 2005).
In vertebrates, nAChRs are located on the skeletal muscle at the neuromuscular junction (muscle-type nAChR) and also on the neurons expressed in the peripheral and central nervous system (CNS) (neuronal-type nAChR) (Millar & Denholm, 2007; Millar & Gotti, 2009). They are assembled in pentameric combinations from 10 α (α1–α 10), 4 β (β1–β4), γ, δ, and ε subunits (Fig. 2). The muscle-type nAChR is made up of two α1, β1, γ (or ε in adult), and δ subunits, whereas the neuronal-type nAChR is assembled in combinations of α2–α10 and β2–β4 (Tomizawa & Casida, 2001; Millar & Gotti, 2009). The pharmacological classification includes two groups based on sensitivity to α-bungarotoxin (a toxin from the elapid snake Bungarus multicinctus, α-BGT). The α7–α10 subunits are responsible for α-BGT-sensitive receptors, whereas α2–α6 and β2–β4 subunits are involved in assembling the α-BGT-insensitive subtypes. The most abundant subtype in vertebrate brain is the α7 subtype (α-BGT-sensitive), which is considered to be a homopentameric structure, and the α4β2 subtype (α-BGT-insensitive), which is heteropentameric including two different stoichiometries of two α4 and three β2 or three α4 and two β2 subunits (Millar & Gotti, 2009). The agonist- or ligand-binding site is located at the interface region between subunits (Fig. 2). The specific subunit combinations confer differences in sensitivity to acetylcholine (ACh) and/or pharmacological profiles among the nAChR subtypes. The ligand-binding site in all subtypes consists of a conserved core of aromatic amino acid residues and the differences in the neighboring residues define the pharmacological properties of each subtype (Corringer et al., 2000; Tomizawa & Casida, 2005).
In insects, nAChRs distribute widely and predominantly in the CNS. These receptors are responsible for rapid neurotransmission and are also important targets for insecticides (Tomizawa & Casida, 2003). The excitatory synaptic transmission at the neuromuscular junction in insects is glutamatergic, while it is cholinergic in vertebrates and in several invertebrates such as nematodes (Usherwood, 1994). In addition, glutamate is the main excitatory neurotransmitter in mammalian brain, whereas ACh is the main excitatory neurotransmitter in insects (Millar & Denholm, 2007). These characteristics contribute to the usefulness of insect nAChRs as selective targets for neurotoxic insecticides (Millar & Denholm, 2007).
The subtypes of native nAChRs in insects remain unclear; however, studies have shown that insect neurons can express different nAChR subtypes and the pharmacological data have shown that there are at least two different classes of insect nAChRs, α-BGT-sensitive and -insensitive (Thany et al., 2007).
Insect nAChR subunits are less well understood than those of vertebrates. Ten subunits of insect nAChR gene families have been described in Drosophila melanogaster, which include seven Dα (α1–α7) and three Dβ (β1–β3) (Sattelle et al., 2005); the same number of nAChR subunits is the case for Anopheles gambiae, which include nine Agamα (α1–α9) and one Agamβ (β1) (Jones et al., 2005). Eleven subunits have been described in Apis mellifera, which include nine Amelα (α1–α9) and two Amelβ (β1–β2) (Jones et al., 2006). In cat fleas, the nAChR family consists of at least seven subunits (Cfα1, Cfα2, Cfα3, Cfα4, Cfα7, Cfα8, and Cfβ1) (Bass et al., 2006). The largest insect nAChR gene family is found in silkworm (Bombyx mori), which has nine α-type subunits and three β-type subunits (Shao et al., 2007).
The neonicotinoids, one of the new classes of insecticides, are very potent for protecting crops against piercing-sucking insects (Tomizawa & Casida, 2003). Some of them are also used in veterinary medicine, especially for controlling fleas in cats and dogs (Mencke & Jeschke, 2002; Schenker et al., 2003). These insecticides include imidacloprid, nitenpyram, acetamiprid, thiacloprid, thiamethoxam, clothianidin, and dinotefuran. Based on the differences in chemical structure, these neonicotinoids are divided into three subclasses: ‘chloronicotinyl’ (the first-generation neonicotinoids, e.g., imidacloprid, nitenpyram, acetamiprid, and thiacloprid), ‘thianicotinyl’ (the second-generation neonicotinoids, e.g., thiamethoxam and clothianidin) and ‘furanicotinyl’ (the third-generation neonicotinoids, e.g., dinotefuran) (Maienfisch et al., 2001; Wakita et al., 2003). The classification, first, second or third generation coming from differences in their chemical structures, has no relation with their selectivity of binding of insect/vertebrate nAChR or therapeutic advantages. In this review, we focus on three neonicotinoids that are used in veterinary medicine, including imidacloprid, nitenpyram, and dinotefuran (Fig. 3).
Neonicotinoid-binding sites in insects. Like vertebrate nAChRs, insect nAChR-binding sites are at the interface region between subunits of nAChRs and both α and β subunits influence pharmacological properties (Tomizawa et al., 2005). In fact, the hybrid receptors expressed in Xenopus laevis oocytes between Drosophila (D)-chicken Dα2-β2 and Dα1-β2 show that the neonicotinoid ligands studied activate the Dα2-β2 receptors, but not Dα1-β2 receptors (Ihara et al., 2003). These findings indicate that the α-subunit contributes to the selectivity of neonicotinoids for insect nAChRs and those specific residues in the Dα2 subunit could account for the enhancement of neonicotinoid affinity (Ihara et al., 2003; Tomizawa et al., 2005). In addition, the insect/vertebrate hybrid receptors of Dα3/Rat β2 exhibit higher binding affinity for imidacloprid than those of Dα3/Rat β4, Dα3/Rat γ, and Dα3/Rat δ (Lansdell & Millar, 2000). These findings define the role of β subunits in the pharmacological properties of neonicotinoids (Lansdell & Millar, 2000).
Why neonicotinoids are so safe in animals? The high-affinity [3H]imidacloprid-binding site is conserved in neonicotinoid sensitivity and specificity across a broad range of insects (Tomizawa & Casida, 2003). The high affinity of neonicotinoids for insect nAChRs and very low affinity for vertebrate nAChRs may explain the high toxicity of neonicotinoids for insects and the low toxicity for vertebrates (Matsuda et al., 2001). Neonicotinoids have little or no binding to the vertebrate peripheral (muscular) nAChR α1γα1δβ1 subtype or some neuronal subtypes [α3β2 (and/or β4)α5, α4β2, and α7] and the minor structural modifications of neonicotinoids confer differential subtype selectivity in vertebrate nAChRs (Tomizawa & Casida, 2005). The comparisons of IC50 of neonicotinoids between insects and vertebrate neuronal nAChRs (α4β2) are shown in Table 1, which strongly suggest that neonicotinoids are very safe for vertebrate species.
|Compound||IC50 (nm)||Selectivity ratio|
Mechanism of action of neonicotinoids Neonicotinoids act selectively by binding to nAChRs, leading to opening of a nonselective cation channel, promoting the influx of extracellular Na+/Ca2 + and efflux of intracellular K+ to disrupt the balance of the membrane potential (Tomizawa & Casida, 2003). As the nAChR agonist-induced Na+ influx dominates over K+ efflux, it results in depolarization. Neonicotinoids cannot be inactivated by acetylcholinesterase, and thus persistently depolarize neurons, leading to the paralyzing action in insects (Mencke & Jeschke, 2002; Tomizawa & Casida, 2003).
Therapeutic use of neonicotinoids. Imidacloprid: Imidacloprid [Advantage® (9.1% imidacloprid w/w); Bayer Animal Health, Shawnee, KS, USA] a first-generation neonicotinoid insecticide, was first marketed by Bayer Animal Health as Advantage® in 1996. It has strong insecticidal activity against sucking insects. Imidacloprid is used topically (7.5–10 mg/kg b.w.) once a month as a spot-on product in dogs and cats that are ≥4 weeks old (Arther et al., 1997). However, the approved dose range is wider (8.8–20 mg/kg). It rapidly kills adult fleas on dogs and cats and breaks the flea life cycle before eggs being laid (Arther et al., 1997; Jacobs et al., 1997). About 96% of adult fleas are killed within 8 h of imidacloprid application and the fleacidal effect is persistent for 34 days, as it is stored in the sebaceous glands of the animals and is not washed out by shampooing (Arther et al., 1997).
Imidacloprid is also available as a mixture with permethrin [K9 Advantix® (8.8% imidacloprid + 44.0% permethrin w/w); Bayer Animal Health] to kill and repel ticks in dogs (Epe et al., 2003) and with moxidectin [Advantage Multi® (10% imidacloprid + 1% moxidectin for cats (2.5% for dogs) w/w; Bayer Animal Health] to prevent heartworm disease and to treat and control gastrointestinal (GI) nematodes and mites in dogs and cats (Arther et al., 2003, 2005).
Pharmacokinetics of imidacloprid: By topical application, imidacloprid spreads over the skin surface and throughout the hair coat of dogs and cats within 12 h (Fichtel, 1998; Mehlhorn et al., 1999). Imidacloprid is localized in the water-resistant lipid layer of the skin surface (Mehlhorn et al., 1999) and is released slowly over a period of time. This characteristic can account for its prolonged insecticidal action of ∼1 month. As this insecticide is applied topically, but not systemically absorbed, in dogs and cats, the pharmacokinetics in these species is not well understood.
The pharmacokinetics of systemic imidacloprid has been studied in rats. When administered orally to rats, 92–99% of imidacloprid is absorbed from the GI tract and is widely distributed throughout the body [California Environmental Protection Agency (CEPA) (2006) Imidacloprid-Risk Characterization Document: Dietary and drinking water exposure. Available at: http://www.cdpr.ca.gov/docs/risk/rcd/imidacloprid.pdf. FDA-Federal Register (2000) Imidacloprid (Admire, Provado, Gaucho) – Pesticide Petition Filing, 65, 7010]. The drug reaches the maximum plasma concentration (Cmax) at 1.1 and 2.5 h after the administration of 1 and 20 mg/kg b.w., respectively. The distribution volume (Vd) is ∼84% of the total body volume and the distribution half-life (t½) is ∼3 h for both i.v. and oral administrations.
There are two major pathways for the metabolism of imidacloprid in rats. First, imidacloprid is cleaved into desnitro-imidacloprid and 6-chloronicotinic acid. The desnitro-imidacloprid is eliminated in the urine. The 6-chloronicotinic acid is conjugated with glutathione to form mercapturic acid and then mercaptonicotinic acid. The mercaptonicotinic acid ultimately conjugates with glycine to form hippuric acid for excretion. In the second pathway, there is hydroxylation in the imidazolidine ring which is followed by the formation of olefinic imidacloprid (the unsaturated metabolite). The metabolism pathways are similar among hens, goats, and rats. Within 24–48 h of administration, the metabolites are excreted mainly in the urine and a small amount in the feces. These findings suggest that the systemically absorbed imidacloprid is eliminated rapidly from the body, which contributes to its safety in animals.
Nitenpyram: Nitenpyram [Capstar® (11.4 or 57 mg of nitenpyram); Novartis Animal Health, Greensboro, NC, USA] another-first generation neonicotinoid, was first marketed in 1995 by Takeda Chemical Industries, Ltd. It provides rapid flea relief in dogs and cats and has the highest initial overall percent kill when compared with fipronil, a blocker of GABA-gated Cl− channels, imidacloprid, selamectin, a macrocyclic lactone, and cythioate, an organophosphate (Schenker et al., 2003). Nitenpyram is ≥99% effective against fleas on cats and dogs within 3 h of administration, and 100% effective against fleas in both cats and dogs within 8 h of administration (Schenker et al., 2003).
Nitenpyram is administered orally (1 mg/kg b.w.) for the short-term control of fleas in dogs and cats. Fleas begin to fall from the animals 30 min postadministration (Dobson et al., 2000) and one dose can protect animals for 1–2 days (Rust et al., 2003).
The fast fleacidal action of nitenpyram is particularly important for animals suffering from flea-bite allergic dermatitis and for the fast control of adult fleas in an integrated flea control strategy (Schenker et al., 2003). However, this drug alone cannot protect animals for more than 48 h after administration. It is normally used in combination with lufenuron [Program® (lufenuron); Novartis], an insect development inhibitor, to provide continuous flea control.
Pharmacokinetics of nitenpyram: As nitenpyram is highly lipophilic, it should be administered orally after the meal in order to increase bile flow to help dissolve the chemical, thereby increasing GI absorption of the drug. It is rapidly absorbed from the GI tract with the time to reach maximum concentration (Tmax) of 1.21 h in dogs and 0.63 h in cats and the Cmax of 4.8 μg/mL in dogs and 4.3 μg/mL in cats (Schenker et al., 2001). The plasma t½ of nitenpyram in dogs and cats are 2.8 and 7.7 h, respectively (Schenker et al., 2001). Nitenpyram undergoes hydroxylation, which is followed by conjugation in the liver. The conjugates of nitenpyram are excreted in the urine and nitenpyram is not accumulated in body tissues. The metabolites of nitenpyram are completely excreted in urine within 48 h of oral administration to dogs and cats (Schenker et al., 2001).
Dinotefuran: Dinotefuran [Vectra 3D® (4.95% dinotefuran + 0.44% pyriproxyfen + 36.08% permethrin w/w); Summit VetPharm, Fort Lee, NJ, USA] is a third-generation neonicotinoid, which was first marketed in 2002 by Mitsui Chemicals Group. It has a characteristic (±)-tetrahydro-3-furylmethyl moiety instead of the pyridine-like moiety of other neonicotinoids (Wakita et al., 2003).
Dinotefuran is used as a topical spot-on product (7–16 mg/kg b.w.) and has a slightly faster knockdown action than imidacloprid (killing 96% fleas in 6 h and 100% within 12 h) [Bowmann, D.D. & Ball, C.A. (2007) Introducing a brand new flea technology. Summit VetPharm, 1(4). Available at: http://www.summitvetpharm.com]. The retaining residual activity can prevent flea larvae for 44 days and control adult fleas up to 16 days (spray formulation) or 23 days (spot-on formulation) (Correia et al., 2008). It is available as a mixture with permethrin (to kill ticks) for use in dogs and pyriproxifen, an insect growth regulator (to kill larvae), for use in cats. The combinations of these compounds effectively break the life cycle of the fleas, including larvae and adults, thereby preventing re-infestations.
Pharmacokinetics of dinotefuran: The pharmacokinetics of dinotefuran has been studied in rats, but not in dogs or cats. After oral administration, the absorption is >90% regardless of the dose and the drug is distributed throughout the body [EPA (2004) Dinotefuran: Pesticide Fact Sheet 2004. Available at: http://www.epa.gov/opprd001/factsheets/dunotefuran.pdf]. The Cmax in milk and fetal tissues is identified as 0.5 h after oral administration. The plasma t½ is 3.6 h at the low dose and 15.2 h at high dose. Most of the dinotefuran is excreted as the parent compound into urine and only a small amount is excreted into feces within 24 h of oral administration (Ford & Casida, 2006). Less than 10% of dinotefuran can be metabolized into numerous minor metabolites by N-demethylation, nitro reduction, tetrahydrofuran hydroxylation, and N-methylene hydroxylation and amine cleavage (Ford & Casida, 2006).
Spinosad [Comfortis® (spinosad); Eli Lilly, Greenfield, IN, USA] is not a neonicotinoid. It is a mixture of two natural macrocyclic lactones (spinosyn A and spinosyn D, Fig. 4) that are isolated from the soil bacterium Saccharopolyspora spinosa that is an actinomycete (Millar & Denholm, 2007).
Spinosad-binding sites in insect neurons. The binding sites for spinosad in insect neurons are still not well defined. However, mutagenesis studies have identified that the Drosophila nAChR Dα6 subunit is the target site for spinosad (Millar & Denholm, 2007). A null mutation of the nAChR subunit Dα6 in D. melanogaster causes the resistance to spinosad (Perry et al., 2007). Radioligand binding studies have shown that neonicotinoid insecticides do not bind to Dα6-containing nAChRs (Lansdell & Millar, 2004). These findings suggest that spinosad and neonicotinoids act on different α-subunits of the nAChRs (Salgado & Saar, 2004), with spinosad acting on the Dα6 subunit and neonicotinoids acting on the Dα2 subunit (Ihara et al., 2003; Tomizawa et al., 2005). If this is indeed the case, then resistance to neonicotinoids may not lead to resistance to spinosad or vice versa.
Spinosad is very safe in animals, but toxic to insects with oral LD50 in mice and honey bees being >5000 mg/kg b.w. and 0.06 μg/bee, respectively [EPA (1997) Spinosad Pesticide Fact Sheet No. HJ 501C. EPA, Office of Pesticides and Toxic Substances. http://www.epa.gov]. These results suggest that spinosad binds poorly to vertebrate nAChRs, but greatly to invertebrate nAChRs, just like neonicotinoids. Unfortunately, to our best knowledge, no radioligand binding studies have been performed to compare the effectiveness of spinosad on the binding of vertebrate and invertebrate nAChRs.
Mechanism of action of spinosad. Spinosad appears to act primarily by binding to nAChRs, leading to hyperexcitation, and disruption of the insect CNS. This effect causes involuntary muscle contractions and tremors, resulting from the widespread excitation of neurons in the CNS (Salgado, 1998; Salgado et al., 1998). The prolonged spinosad-induced hyperexcitation results in paralysis, which is due to neuromuscular fatigue (Salgado, 1998). This activity of spinosad is similar to that of neonicotinoids.
There are additional actions of spinosad. It has an action to increase the opening of Cl− channels in neurons of the insect CNS, which could result in hyperpolarization (Sparks et al., 2001; Watson, 2001). This action is expected to modulate the effect of spinosad on insect nAChRs. In addition, spinosad inhibits responses to γ-aminobutyric acid (GABA) in small-diameter cockroach neurons, suggesting that it has potent effects on the function of GABA-gated Cl−channels in insect neurons (Watson, 2001). There are at least two types of Cl− channels in arthropods, namely glutamate-gated Cl− channels and GABA-gated Cl− channels (Janssen et al., 2007). It is important to explore the effects of spinosad on these two types of channels in insects. As indicated before, spinosad opens cation channels of the nAChR, leading to depolarization of the neuronal membrane (Salgado, 1998; Salgado et al., 1998), while its opening of Cl− channels can lead to hyperpolarization of the membrane (Watson, 2001). Further research is warranted to determine whether spinosad’s effect on Cl− channels would modulate its effect on neuronal depolarization.
Pharmacokinetics of spinosad. The pharmacokinetics of spinosad has been studied in rats, in which spinosad is readily absorbed from the GI tract following oral administration. It takes ∼1 h to reach Cmax at the low dose (10 mg/kg b.w.) and 6 h (male rats) to 12 h (female rats) to reach Cmax at the higher dose (100 mg/kg b.w.) [International Program on Chemical Safety (IPCSINCHEM) (2001) Spinosad – toxicological evaluations. Pesticide Residues in Food. Available at: http://www.inchem.org/documents/jmpr/jmpmono/2001pr12.htm]. The plasma t½ is 6 h for males and 12 h for females at the low dose and 12 h for male and 24 h for female, at the higher dose, respectively. The insecticide is distributed throughout the tissues and systems in the body and is rapidly excreted via feces (81–88%, mostly in the first 24 h) and via urine (6–10%). The major pathway of metabolism is the conjugation with glutathione either directly or after O- or N-demethylation for both spinosyns A and D. Dow AgroSciences (1997) Spinosad Technical Bulletin 15]. In addition, the cysteine conjugates are also a part of the metabolites of spinosyns A and D. The metabolites are eliminated via feces and urine, as conjugates in the case of spinosyn A, and an unchanged form in the case of spinosyn D.
In dogs, after oral administration of spinosad together with wet foods, the insecticide needs ∼2 h for spinosyn A and ∼3 h for spinosyn D to reach the Cmax of 2.5 and 0.5 μg/mL for spinosyn A and spinosyn D, respectively. In contrast to the short t½ in rats, the plasma t½ of this insecticide in dogs is ∼10 days [FDA (2007) NADA 141-277. Available at: http://www.fda.gov/cvm/FOI/141-277o092507.pdf]. This information accounts for the prolonged fleacidal effect of spinosad in dogs and suggests a species difference, at least between dogs and rats, in the pharmacokinetics of spinosad.
Therapeutic use of spinosad. Spinosad was introduced by Dow AgroSciences LLC for controlling the lepidopterous pests in cotton in 1997. In veterinary medicine, spinosad is an FDA-approved oral drug for use as a flea adulticide. It is highly effective (97–100% 30 days after the treatment) and safe in dogs. The repeated monthly oral administrations with spinosad at 30 mg/kg b.w. provide sustained control of Ctenocephalides felis in dogs (Millar & Denholm, 2007). It is available as chewable tablets for dogs, administered orally once a month. However, spinosad has not been approved by the FDA for use in cats.
Adverse effects of insect nAChR agonists
The three approved neonicotinoids and spinosad are very effective and safe flea adulticides in dogs and cats, because they have high affinity for insect nAChRs and extremely low affinity for vertebrate nAChRs (Matsuda et al., 2001; Schenker et al., 2003; Millar & Denholm, 2007). However, overdose of the nAChR agonist can cause vomiting in dogs and cats. There are no noticeable chronic adverse effects associated with these insect nAChR agonists at the recommended dose regimen.
According to the FDA Adverse Drug Experiences report, concurrent use of spinosad and high doses of ivermectin (0.4–0.6 mg/kg b.w./day) in the treatment of canine demodicosis has caused increased frequency of ivermectin toxicity than without spinosad [FDA (2008) CVM update. Available at: http://www.fda.gov/cvm/CVM_Updates/comfortisSafety.htm, accessed on 24 June 2008]. Therefore, one should avoid concurrent administration of spinosad and high doses of ivermectin. As spinosad is a macrocyclic lactone, it may cause additive adverse effects when used concurrently with a large dose of a macrocyclic lactone. Further research is needed to investigate the mechanisms underlying the drug interaction between spinosad and other macrocyclic lactones.
Environmental impact of insect nAChR agonists
Insect nAChR agonists imidacloprid, clothianidin and spinosad are registered for use to kill crop pests. There has been a controversy in Europe over a possible link between honey bee colony declines and the use of imidacloprid on sunflower crops (Bonmatin et al., 2003). The damages on honey bees are probably through the sublethal doses of the neonicotinoids (Abbott et al., 2008). In fact, bees have greater chances to be exposed to sublethal doses than lethal doses of these insecticides. When exposed to the sublethal doses of neonicotinoids, the foraging activity of bees is severely decreased (Decourtye et al., 2003; Yang et al., 2008). In addition, the activity of bee hive entrance is also markedly hampered (Suchail et al., 2001). These effects of neonicotinoids on bees may be attributable to the difficulties in movement, coordination, orientation, and learning induced by the insecticides (Suchail et al., 2001). Fortunately, the use of insect nAChR agonists in veterinary medicine has not caused significant problems in beneficial insects.