Current Pharmaceutical Biotechnology - Volume 13, Issue 6, 2012

P-glycoprotein, encoded by the multidrug resistance gene MDR1, is an ATP-driven drug efflux pump which is highly expressed at the blood-brain barrier of vertebrates. Drug efflux of macrocyclic lactones by P-glycoprotein is highly relevant for the therapeutic safety of macrocyclic lactones, as thereby GABA-gated chloride channels, which are confined to the central nervous system in vertebrates, are protected from high drug concentrations that otherwise would induce neurological toxicity. A 4-bp deletion mutation exists in the MDR1 gene of many dog breeds such as the Collie and the Australian Shepherd, which results in the expression of a non-functional P-glycoprotein and is associated with multiple drug sensitivity. Accordingly, dogs with homozygous MDR1 mutation are in general prone to neurotoxicity by macrocyclic lactones due to their increased brain penetration. Nevertheless, treatment of these dogs with macrocyclic lactones does not inevitably result in neurological symptoms, since, the safety of treatment highly depends on the treatment indication, dosage, route of application, and the individual compound used as outlined in this review. Whereas all available macrocyclic lactones can safely be administered to MDR1 mutant dogs at doses usually used for heartworm prevention, these dogs will experience neurological toxicity following a high dose regimen which is common for mange treatment in dogs. Here, we review and discuss the neurotoxicological potential of different macrocyclic lactones as well as their treatment options in MDR1 mutant dogs.

From a human safety perspective, the administration of ivermectin to food producing animal species entails potential risks related to the presence of drug residues in edible tissues, milk, and other derived products. The European Medicines Agency has established the maximum residue limits for ivermectin in the European Union, with values of 100 μg·kg-1 in fat and liver and 30 μg·kg-1 in kidney for all mammalian food producing species, in order to ensure that the amount of ivermectin that can be found in animal foodstuff is below dangerous levels for the consumers. According to these values, withdrawal periods after subcutaneous injection were recently established in the European Union (2009), in 49 days for products containing ivermectin as a single active substance or in combination with closantel, and in 66 days when combined with clorsulon. The marker residue for ivermectin was found to be H2B1a, which is the major component of the parent compound. The tissue distribution of residues and the overall ratios of marker to total residues were generally similar in most species, and the highest concentrations of ivermectin residues were found in fat and liver with high levels also detected in injection site muscles. Ivermectin is not licensed for use in animals from which milk is produced for human consumption, however its extra-label use should be considered regarding human safety, due to its long persistence in milk and milk-derived products.

Macrocyclic lactones, including avermectins and milbemycins, are novel parasiticides and insecticides that are produced through fermentation by soil-dwelling microorganisms. Although various macrocyclic lactones may differ in their potency and safety, all of them are believed to share common pharmacologic/toxicologic mechanisms, i.e. leading to paralysis and death of parasites and other target organisms via the activation of a glutamate-gated chloride channel in the invertebrate nerve and muscle cells and/or through the effect on gamma-aminobutyric acid (GABA) receptors. Ivermectin is the first macrocyclic lactone that was released for use in both animals and humans, and has demonstrated both excellent efficacy and high tolerability in the treatment of parasite infestations. Other macrocyclic lactones, such as abamectin, emamectin, and moxidectin were subsequently commercialized and have been used as insecticides and acaricides for crop protection or parasiticides for animal health. Although ivermectin therapy is generally well tolerated, adverse effects that are usually transient and mild-to-moderate can occur. Severe adverse effects are rare and can generally be effectively controlled by symptomatic measures. Non-therapeutic exposures to ivermectin and other macrocyclic lactones may also result in toxic effects; significant toxicity however probably develops only after large amount of oral ingestion. Although the exact mechanisms remain unclear, macrocyclic lactones in large doses may pass through the blood-brain barrier (BBB) to produce GABA-mimetic toxic effects. Severely poisoned patients usually present with coma, hypotension, respiratory failure, and even death. Despite the lack of specific therapy, the prognosis is likely to be favorable unless the poisoned patients are complicated with severe hypotension or respiratory failure.

The avermectins, milbemycins and spinosyns are collectively referred to as macrocyclic lactones (MLs) which comprise several classes of chemicals derived from cultures of soil micro-organisms. These compounds are extensively and increasingly used in veterinary medicine and agriculture. Due to their potential effects on non-target organisms, large amounts of information on their impact in the environment has been compiled in recent years, mainly caused by legal requirements related to their marketing authorization or registration. The main objective of this paper is to critically review the present knowledge about the acute and chronic ecotoxicological effects of MLs on organisms, mainly invertebrates, in the terrestrial and aquatic environment. Detailed information is presented on the mode-of-action as well as the ecotoxicity of the most important compounds representing the three groups of MLs. This information, based on more than 360 references, is mainly provided in nine tables, presenting the effects of abamectin, ivermectin, eprinomectin, doramectin, emamectin, moxidectin, and spinosad on individual species of terrestrial and aquatic invertebrates as well as plants and algae. Since dung dwelling organisms are particularly important non-targets, as they are exposed via dung from treated animals over their whole life-cycle, the information on the effects of MLs on dung communities is compiled in an additional table. The results of this review clearly demonstrate that regarding environmental impacts many macrocyclic lactones are substances of high concern particularly with larval instars of invertebrates. Recent studies have also shown that susceptibility varies with life cycle stage and impacts can be mitigated by using MLs when these stages are not present. However information on the environmental impact of the MLs is scattered across a wide range of specialised scientific journals with research focusing mainly on ivermectin and to a lesser extent on abamectin doramectin and moxidectin. By comparison, information on compounds such as eprinomectin, emamectin and selamectin is still relatively scarce.

The use of macrocyclic lactones has become the main stay for the treatment of endo- and ectoparasites in the cattle industry. Here we review those drugs that are currently approved for use in cattle in the United States. The general efficacy, tissue distribution and toxicity of each drug formulation are discussed. Included is a discussion regarding the current status for nematode anthelmintic resistance in cattle populations within the United States. Also provided is a current summary of ecological effects of macrocyclic lactones residues in manure.

Macrocyclic lactones (MLs) revolutionized parasite control in horses and other animals. They are unique in that they are effective against arthropods and nematodes. The first of the widely used avermectins was ivermectin. In 1983, it was marketed for use in horses as an injectable formulation but was withdrawn in 1984 after about a year and half on the market because of adverse problems. It was replaced by a paste formulation and an oral/stomach tube liquid formulation. Ivermectin is highly active on bots, ascarids, large and small strongyles, pinworms, strongyloides, stomach worms, and some other internal parasite species. Another ML, moxidectin, became available in 1997 as a gel formulation for oral administration. The parasiticidal activity of this compound is similar to ivermectin except efficacy is less on the common bot (Gastrophilus intestinalis) but high on encysted small strongyles. Recently however lower than initial activity on ascarids and small strongyles has been found for both ivermectin and moxidectin.

Macrocyclic lactones (MLs) have many anti-parasitic applications in small companion animal medicine. They were first developed as chemoprophylactics against heartworm (Dirofilaria immitis) infection to be applied monthly for retroactive killing of third- and fourth-stage larvae. ML-containing products formulated for oral (ivermectin, milbemycin oxime), topical (selamectin, moxidectin) or injectable sustained release (moxidectin, ivermectin) are approved for heartworm prevention in dogs or cats. Clearance of microfilariae and gradual or “soft” killing of adult heartworms constitute increasingly prevalent extra-label uses of MLs against D. immitis. Some commercial ML formulations contain sufficient levels of active ingredient (milbemycin oxime, selamectin, moxidectin) to support additional label claims against gastrointestinal nematode parasites such as hookworms (Ancylostoma spp.) and ascarid round worms (Toxocara spp. and Toxascaris leonina). Beyond these approved applications, safe, extra-label uses of MLs against nematodes parasitizing the urinary tract, such as Capillaria spp., and parasites of the tissues, such as Dipetalonema reconditum, Dirofilaria repens, Thelazia spp. and Spirocerca lupi, in dogs and cats as well as exotic pets have been reported. MLs as a group have intrinsic insecticidal and acaricidal activity, and topical or otic formulations of certain compounds (selamectin, moxidectin, milbemycin oxime or ivermectin) are approved for treatment and control of fleas, certain ixodid ticks, sarcoptiform and demodectic mange mites and psoroptiform ear mites. Extra-label applications of MLs against ectoparasites include notoedric mange mites, dermanyssids such as Ornythonussus bacoti, numerous species of fur mite (e.g. Cheyletiella spp. and Lynxacarus) and trombiculids (“chiggers”) in cats, dogs and nontraditional or exotic pets.

The main indication for use of avermectins in aquaculture-produced fish is infestations with ectoparasitic copepods. The compounds ivermectin and emamectin benzoate are predominantly used as in-feed formulations on salmonid fish against copepods in the family Caligidae: Lepeophtheirus salmonis, Caligus elongatus and C. rogercresseyi. These agents are well-documented as very effective on all developmental stages of the parasites. The duration of effect can be up to 10 weeks. The safety margin for ivermectin is narrow, but better for emamectin benzoate. Environmental impact from these chemicals on bottom-dwelling and sediment-dwelling organisms occurs, but these are restricted to the immediate area around the production site. Avermectins are incompletely absorbed from the intestine of the fish and slowly excreted. They penetrate the blood-brain barrier of the fish, ivermectin more than emamectin benzoate. Resistance has developed against these agents in L. salmonis in almost all major salmon producing areas. The situation must be viewed as serious and can render these agents completely ineffective for salmon lice control.

Ivermectin is a broad spectrum antiparasitic veterinary drug introduced in human medicine in 1987. It is considered the drug of choice in onchocerciasis and strongyloidiasis infections, and remains as a therapeutic option for mass treatment in lymphatic filariasis, for which it has widely proved its efficacy. While research continued for human use, new therapeutic targets for ivermectin have emerged. It is currently the better therapeutic option in the treatment of gnathostomiasis and crusted scabies, and could be an alternative option in ascariasis and Mansonella infections. Although these uses are already included in clinical guidelines, more trials are needed to increase their grade of evidence and to obtain their official approval. Concerning other minor uses such as the treatment of enterobiasis or against Trichuris trichiura, more research is still needed in order to test the real activity of ivermectin. The use of ivermectin in human medicine has shown an outstanding low rate of adverse reactions, with the exception of treatment of loiasis and onchocerciasis, where the death of a high microfilarial load may cause severe encephalopathy. However special attention must be paid to the emergence of the first documented cases of resistance in treatment of scabies.

The donation of Mectizan® by Merck & Co Inc. in 1987 “as much as was needed for as long as was needed for onchocerciasis control” was a major change from traditional corporate drug donations. The company realised that those who needed the drug most would never be able to purchase it, and so gave it away. The donation enabled the Onchocerciasis Control Programme in West Africa to add Mectizan distribution to its ongoing control strategy. For the first time there was hope for those living in other areas of Africa, Latin America and Yemen. Governments and non-governmental development organizations quickly got together to begin treatment in these new areas. Two new programmes and partnerships were created; the African Programme for Onchocerciasis Control and the Onchocerciasis Elimination Programme for the Americas. These programmes have been in the forefront of developing new strategies, including the Community Directed approach, which has now expanded into other disease control programmes at the community level, such as Vitamin A distribution and malaria control. This donation has led not only to the probability of elimination of onchocerciasis in the Americas in the near future, but is stimulating approaches to the elimination in Africa, in areas considered impossible five years ago. Other major pharmaceutical donations have followed, initiating the plan to eliminate lymphatic filariasis worldwide, and also stimulating interest in controlling other “neglected tropical diseases,” which affect the poorest billion of the world’s population, making this now a reality.