Current Pharmaceutical Biotechnology - Volume 13, Issue 6, 2012

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Carbon monoxide (CO) is a colourless and odourless gas that has long been considered as a potent respiratory poison. Recent advances have demonstrated its production by haem oxygenases in both mammals and microbes, and it has roles as a gasotransmitter in higher organisms. This review concentrates on the application of CO, via carbon monoxidereleasing molecules (CO-RMs), as an anti-bacterial agent. Currently, the scope of literature on the effects of CO on bacteria is small, and we have included discussions on the production of CO by bacteria via haem oxygenase enzymes, the use of CO as an energy source, and existing knowledge on CO sensors in bacteria. CO is known to target haem proteins and is an effective inhibitor of respiration, even when provided at concentrations much higher than prevailing oxygen. We review here data suggesting that CO-RMs are more effective inhibitors of respiration than is CO gas, perhaps due to the ability of CO-RMs to deliver CO selectively to intracellular targets. We also consider the recently reported transcriptomic consequences of CO-RM treatment of Escherichia coli, revealing a myriad of unexpected targets for CO and potential CO sensors. Finally, we consider the use of CO and CO-RMs as anti-bacterial agents in vivo, and the future prospects for this gaseous molecule.

Chronic obstructive pulmonary disease (COPD) is a disease involving airways restriction, alveolar destruction, and loss of lung function, primarily due to cigarette smoke (CS) exposure. The inducible stress protein heme oxygenase-1 (HO-1) has been implicated in cytoprotection against the toxic action of many xenobiotics, including CS. HO-1 also protects against elastase-induced emphysema. Differential expression of HO-1 in epithelial cells and macrophages may contribute to COPD susceptibility. Genetic polymorphisms in the HO-1 gene, which may account for variations in HO-1 expression among subpopulations, may be associated with COPD pathogenesis. Carbon monoxide (CO), a primary reaction product of HO-1 has been implicated in cytoprotection in many acute lung injury models, though it’s precise role in chronic CS-induced lung injury remains unclear. CO is a potential biomarker of CS exposure and of inflammatory lung conditions. To date, a single clinical trial has addressed the possible therapeutic potential of CO in COPD patients. The implications of the cytoprotective potential of HO-1/CO system in CS-induced lung injury and COPD are discussed.

Despite modern clinical practice in critical care medicine, acute lung injury still causes unacceptably high rates of morbidity and mortality. Therefore, the challenge today is to identify new and effective strategies in order to improve the outcome of these patients. Carbon monoxide, endogenously produced by the heme oxygenase enzyme system, has emerged as promising gaseous therapeutic that exerts protective effects against inflammation, oxidative and mechanical stress, and apoptosis, thus potentially limiting acute lung injury. In this review we discuss the effects of inhaled carbon monoxide on acute lung injury that results from ischemia-reperfusion, transplantation, sepsis, hyperoxia, or mechanical ventilation, the latter referred to as ventilator-induced lung injury. Multiple investigations using in vivo and in vitro models have demonstrated anti-inflammatory, anti-apoptotic, and anti-proliferative properties of carbon monoxide in the lung when applied at low dose prior to or during stressful stimuli. The molecular mechanisms that are modulated by carbon monoxide exposure are still not fully understood. Carbon monoxide mediated lung protection involves several signaling pathways including mitogen activated protein kinases, nuclear factor-7kappa;B, activator protein-1, Akt, peroxisome proliferating- activated receptor-γ, early growth response-1, caveolin-1, hypoxia-inducible factor-1α, caspases, Bcl-2-family members, heat shock proteins, or molecules of the fibrinolytic axis. At present, clinical trials on the efficacy and safety of CO investigate whether the promising laboratory findings might be translatable to humans.

During the degradation of heme by the enzyme heme oxygenase (HO), Carbon monoxide (CO) is generated. Although it is considered as a non - significant and potentially toxic waste gas of heme catabolism, CO is a key signaling molecule used to regulate different cardiovascular functions. In this review, we focus the protective roles of CO in vascular injury/disease, which may be important to explore the overall protective roles of HO-1/CO system in the pathogenesis of human vascular disease.

Although a potentially toxic gaseous molecule, carbon monoxide recently gains rising scientifically and clinical interest as its beneficial effects and mechanisms of action are defined substantially in various in vitro and in vivo experiments. Its anti-inflammatory, anti-apoptotic and anti-proliferative properties but its increasing impact concerning numerous disease models in means of protection, well describe this gas as a new and challenging therapeutic alternative. In this review, we focus on the extensively analyzed advantageous value of pre- and postconditioning with inhaled carbon monoxide in the context of lung and kidney injury, induced by the low perfusion during and after cardiopulmonary bypass. Mechanisms like the heat shock response as well as an expanded view regarding toxicity and side effects are described broadly.

Carbon monoxide is generally believed to be a ‘toxic’ gas molecule due to its binding capability with hemoglobin. Overexposure to carbon monoxide leads to a hypoxic state that may cause the death of a mammalian. In contrast, directly exposure of carbon monoxide may protect cells or organs from various disease insults. The paradox effects of carbon monoxide might vary on the ways of exposure and the amounts being exposed. Here we highlighted the characteristics of this gas molecule and summarized its protective effects and therapeutic potentials in liver diseases and liver transplantation.

Carbon monoxide (CO), often referred to as the silent killer, is a colorless, odorless and tasteless gas. It combines with hemoglobin to produce carboxyhemoglobin, which is ineffective for delivering oxygen to animal and human tissues. On the other hand, CO is endogenously produced in the body as a byproduct of heme degradation catalyzed by the heme oxygenase (HO) enzymes. In the past decade, evidence has accumulated to suggest important physiological roles for CO in mammalian tissues. In the pancreas, modulation of endogenous CO production or administration of exogenous CO may represent a therapeutic option for the treatment of endocrine and exocrine pancreatic disorders. In cell culture, CO exerts anti-diabetic effects and brief exposure of purified mouse islets to CO ameliorates functional performance after transplantation. Recent advances include the observation that CO carriers possess potent anti-proliferative effects in an in vitro model of pancreatic fibrosis. In vivo, CO confers tissue protection in animal models of pancreatic disease, including those with hyperglycemia and inflammatory injury of the gland. However, there are still a number of unanswered questions surrounding its physiological and pathophysiological relevance and the preferred route of CO administration in the pancreas still remains to be settled. This brief review focuses on the roles, effects and mechanisms of action of CO in the pancreas.

Carbon monoxide (CO) is an endogenously produced gas resulting from the degradation of heme by heme oxygense or from fatty acid oxidation. Heme oxygenase (HO) enzymes are constitutively expressed in the kidney (HO-2) and HO-1 is induced in the kidney in response to several physiological and pathological stimuli. While the beneficial actions of HO in the kidney have been recognized for some time, the important role of CO in mediating these effects has not been fully examined. Recent studies using CO inhalation therapy and carbon monoxide releasing molecules (CORMs) have demonstrated that increases in CO alone can be beneficial to the kidney in several forms of acute renal injury by limiting oxidative injury, decreasing cell apoptosis, and promoting cell survival pathways. Renal CO is also emerging as a major regulator of renal vascular and tubular function acting to protect the renal vasculature against excessive vasoconstriction and to promote natriuresis by limiting sodium reabsorption in tubule cells. Within this review, recent studies on the physiological actions of CO in the kidney will be explored as well as the potential therapeutic avenues that are being developed targeting CO in the kidney which may be beneficial in diseases such as acute renal failure and hypertension.

Carbon monoxide (CO) is an invisible, chemically inert, colorless and odorless gas and is toxic at high concentrations due to its interference with oxygen delivery. However, CO is endogenously and physiologically generated in mammalian cells via the catabolism of heme in a rate-limiting step of heme oxygenase systems, and CO potently protects against cellular injury. CO relaxes blood vessels and exerts anti-thrombotic effects by inhibiting platelet aggregation and derepressing fibrinolysis. In addition, CO reduces ischemia/reperfusion injury and inflammatory responses. CO inhibits apoptosis of endothelial and epithelial cells and reduces proliferation of smooth muscle cells, fibroblasts and T lymphocytes. Thus, there is accumulating evidence to support the notion that CO treatment of transplant donors, organs, or recipients can prevent graft dysfunction due to rejection or ischemia/reperfusion injury. This invited review discusses recent advances and current knowledge pertaining to CO research in the field of transplantation. In addition, we will discuss the clinical applicability of CO as a promising therapeutic strategy for the treatment of transplant patients.

Carbon monoxide (CO) has long been considered a purely toxic by-product of incomplete combustion processes. Acute exposure to high concentrations of CO is one of the leading causes of fatal poisoning in industrial countries. However, after two decades of intensive research, there is ample evidence that CO endogenously produced by heme oxygenase enzymes has essential physiological functions and is of vital importance for cellular hemostasis. Furthermore, exogenously applied CO in low concentrations mediates potent cytoprotective effects. An overwhelming number of different in vitro and in vivo models demonstrated the protective action of CO application, e.g., in ischemia/reperfusion, transplantation, oxidative stress, inflammation, and others. Protection by this gaseous molecule could be illustrated for most organs, most species, and for different routes of administration. Now being on the verge of entering clinical trials, the question emerges whether the administration of low-dose CO would be safe for patients when used as a potential therapeutic. Therefore, this review summarizes in particular toxicological data obtained from low-dose CO exposure and discusses its impact on a possible clinical application.

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The macrocyclic lactones enjoy a position of prominence in the control of parasites, and their history may be of interest, and even of use, in an age in which the search for chemotherapeutic agents has been transformed by modern technology. Much of their history has been recorded piecemeal in a wide variety of publications. The present review provides additional detail, and offers a personal perspective on the history of ivermectin and related avermectins. Brief notes are included on the subsequent development of other macrocyclic lactones. Milbemycin preceded the avermectins as a macrocyclic lactone of agricultural importance, but was used for a different purpose. Development of the avermectins arose from the isolation, in the laboratories of the Kitasato Institute, of a novel soil-dwelling bacterium and its transmittal (in 1974) to the laboratories of Merck & Co., Inc. There it was found (in 1975) to produce a potent anthelmintic substance, which was then identified and transmuted by interdisciplinary research into an antiparasitic product. Initially the focus was on its applicability to veterinary science and animal husbandry; and after developmental research by many scientific teams, the product was introduced commercially (in 1981) for the control of endoparasitic nematodes and ectoparasitic arthropods in livestock. Subsequently, special applications in human medicine were developed, and were successfully implemented in partnership with World Health Organization and several non-governmental organizations (NGOs).

Macrocyclic lactones (MLs), exemplified by the prototype of the class, ivermectin (IVM), are mainstays of programs for the control of nematode and arthropod parasites and pests. Since their introduction 30 years ago, research has revealed that they act on a family of ligand-gated chloride channels gated by glutamate, which is largely restricted to animals in the phyla Nematoda and Arthropoda. Studies on IVM in model organisms have contributed greatly to our understanding of ML pharmacology, but our understanding of the basis for differences among species and among MLs in potency and spectrum remains far from complete.

Resistance to the macrocyclic lactones (MLs) has been confirmed or suspected in many target organisms and is a serious problem in some. For some species, such as parasitic nematodes of small ruminants, ML resistance has become severe enough to threaten effective worm control worm control. Resistance is also a major concern in horse parasites and an emerging problem in cattle. Despite this, we have insufficient understanding of the mechanisms of ML resistance, especially in nematodes. Some insect and mite agricultural pests express higher levels of detoxifying enzymes, leading to cross-resistance to other pesticide classes. A major difficulty is in the identification of true resistance and distinguishing this from other causes of treatment or prophylaxis failure – some in vitro assays for ML resistance are available but more are badly needed. Changes in the way anthelmintic drugs are used in livestock farming have been proposed, based on the treatment of those animals that would benefit most, and schemes have been devised for identifying those animals, flocks and herds. The continued sustainable use of these invaluable drugs may depend on the adoption and improvement of such schemes, as resistance is likely to become an ever more serious problem.

The macrocyclic lactones have pharmacokinetic properties which enhance their use against endo- and ectoparasites in animals and man. The most consistent physico-chemical feature of the group which contributes to their kinetic characteristics is high lipid solubility. This appears to be necessary for their pharmacodynamic action as well as common kinetic features such as large volumes of distribution and the influence of body fat composition on their disposition. They are used in all domestic animal species and are undoubtedly influenced by the anatomical and physiological differences in these species, however body fat composition also appears to exert a major influence on distribution, metabolism and persistence between species and between breeds and individuals. A myriad of formulations have been developed to enhance the convenience of administration in the different domestic animals and the macrocyclic lactones are delivered orally, subcutaneously and topically to good effect. Lipid based excipients have been developed in “depot” formulations to extend the period of effective prevention of parasite re-infection. Subtle structural changes have been made to the macrocyclic lactone molecules to reduce distribution to the central nervous system and mammary gland, thus allowing use of some compounds such as selamectin (SLM) in “toxicity sensitive” breeds of collie dog which lack P-glycoprotein efflux systems in their central nervous systems and the use of eprinomectin (EPM) in dairy cattle with a nil-milk withdrawal period. Gender differences exist in the pharmacokinetics of these compounds which may be associated with body (fat) composition or metabolism. Feeding may also reduce the availability of macrocyclic lactones which bind particulate digestive material and parasitism may impact the kinetics of the drugs because parasitized animals have altered pathophysiological processes, especially in the gastro intestinal tract but also because of the impact which parasitism may have on the body condition (and fat deposition) in animals. The pharmacokinetics of macrocyclic lactones may be affected by coadministration with compounds which interfere with P-glycoprotein transporters and these interactions have been explored as possible mechanisms for enhancing the effectiveness of these antiparasitics. The objective of this article is to provide a comprehensive review of the pharmacokinetics of macrocyclic lactones and to interpret where that information may prove clinically useful.

Macrocyclic lactones (MLs) are antiparasitic drugs used against endo-ectoparasites. Regarding the wide use of MLs in different species, it is likely that drug-drug interactions may occur after their co-administration with other compounds. A new paradigm was introduced in the study of the pharmacology of MLs during the last years since the interactions of MLs with ATP-binding cassete (ABC) transporters have been described. The current review article gives an update on the available information concerning drug-drug interactions involving the MLs. The basis of the methodological approaches used to evaluate transport interactions, and the impact of the pharmacology-based modulation of drug transport on the MLs disposition kinetics and clinical efficacy, are discussed in an integrated manner. A different number of in vitro and ex vivo methods have been reported to study the characterization of the interactions between MLs and ABC transporters. The production of the ABC transporters knockout mice has provided valuable in vivo tools to study this type of drug-drug interaction. In vivo trials performed in different species corroborated the effects of ABC transporter modulators on the pharmacokinetics behaviour of MLs. Important pharmacokinetic changes on plasma disposition of MLs have been observed when these compounds are co-administered with P-glycoprotein modulators. The modulation of the activity of P-glycoprotein was evaluated as a strategy not only to increase the systemic availability of MLs but also to improve their clinical efficacy. The understanding of the MLs interactions may supply relevant information to optimize their use in veterinary and human therapeutics.

The characterisation of ivermectin pharmacokinetics can be used to predict and to ensure an optimal activity in the target species and for designing programmes aimed for parasite control. Ivermectin pharmacokinetic studies performed in several minor ruminant species are reviewed in this paper with the aim of facilitating the adoption of rational basis for the establishment of appropriate dosage schedules.

A review of the developments on the analysis of residues of avermectins and milbemycins (both macrocyclic lactones) is presented. The macrocyclic lactones (MLs) are an important class of chemicals, which are used worldwide as veterinary drugs and as crop protection agents. As a result, residues of MLs are important from both a food safety and environmental perspective. A review of the developments in ML residues in food was carried out in detail in 2006. As a result, this paper covers recent developments in the area of food analysis, which are mainly multi-residue assays based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A brief coverage of HPLC fluorescence (HPLC-FLD) based methods is included for completeness. The paper will carry out a comprehensive review of ML residues in environmental samples. These additional sections are reflective of the growing number of research papers published on LC-MS/MS and environmental applications in recent years.

The macrocyclic lactone endectocides typified by ivermectin are safe and effective drugs when used according to label directions. However, off-label use, misuse and overdosing can result in toxicity in animal patients as revealed by pharmacovigilance activities. Preclinical toxicity studies demonstrates that the major clinical signs of toxicity are those associated with neurotoxic effects and these are the most common adverse drug reactions noted in overdosed treated animals. Subpopulations of some strains or breeds of some species appear to be uniquely sensitive to the neurotoxic effects of the macrocyclic lactones due to enhanced brain penetration by these drugs as a result of a deficiency in P-glycoprotein arising as a result of a mutation in the MDR1 gene.

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.