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PubMed1994

Parasites, animal production and sustainable development.

Ecologically sustainable development is aimed at reducing environmental degradation while enabling economic development with equity between the developed and developing worlds and between generations. Parasite control in livestock can both contribute to, and take advantage of, sustainable agriculture. This will tend towards less intensive, lower input, diversified crop and animal production with less risk of parasite-induced losses and greater opportunities for integrated control including the exploitation of grazing management. Chemotherapy will continue to play a part but the most serious problem is resistance in the target species. Except for a few isolated issues, currently used parasiticides are relatively minor contaminants of the food supply or the environment. Nevertheless, the compounds of the future will need to be narrow-spectrum, non-persistent and rapidly degraded, with convenience in the hands of the user reduced in importance. Environmentally friendly alternatives to chemotherapy, including genetic resistance of hosts, vaccines, and biological control, show considerable promise and must be pursued. Sustainable systems pose optimisation problems and more attention must be given to systems research, models and products to aid decisions. If governments are serious about sustainable development, greater support will be needed for longer-term patient, multi-disciplinary research.

Agriculture↗

PubMed1994

Thin-layer chromatographic detection of ivermectin in cattle serum.

A study was conducted on the detection of ivermectin (22,23-dihydroavermectin B1) in cattle serum by thin-layer chromatography (TLC) after derivatization of this parasiticide by the known reaction with trifluoroacetic anhydride-1-methylimidazole and visual examination of the chromatograms under long-wavelength ultraviolet light. By derivatization of reference samples of ivermectin in acetonitrile, approximately 0.1 ng of a highly fluorescent material, tentatively identified as 2,5,6-tetradehydro-5,7-dideoxy-22,23-dihydroavermectin B1, could be detected on silica-gel thin layer plates. Extraction of fortified serum samples with methyl tert.-butyl ether followed by derivatization, hydrolysis, partitioning between water-hexane and TLC gave a limit of detection of 1-2 ng/ml. With these simple techniques ivermectin could be detected in cattle serum for 3-4 weeks after subcutaneous treatment of Hereford heifers.

Animals↗

PubMed2006

Synthesis of 16-mercaptohexadecylphosphocholine, a miltefosine analog with leishmanicidal activity.

The alkylphosphocholine miltefosine (n-hexadecylphosphocholine, MT) has been introduced recently as a very effective drug for the oral treatment of human leishmaniasis. However, the parasiticidal mechanism of MT at a molecular level is far from being understood. Here we report the synthesis and biological characterization of 16-mercaptohexadecylphosphocholine, a thiol analog of MT which was designed to facilitate the search of MT interacting targets within the parasite by a variety of analytical methods. This analog presents the same leishmanicidal effect as the parent drug against Leishmania donovani promastigotes and Leishmania pifanoi axenic amastigotes, and has been used to develop an affinity chromatography method to attempt the isolation of putative Leishmania proteins that bind to the phosphocholine part of the molecule.

Animals↗

PubMed2005

Contribution of lymphatic transport to the systemic exposure of orally administered moxidectin in conscious lymph duct-cannulated dogs.

Moxidectin, a macrocyclic lactone (ML), is a potent parasiticide widely used in veterinary medicine and currently under development for use in humans. The contribution of the lymphatic route to the intestinal absorption and transport of moxidectin to the systemic circulation was evaluated in lymph duct-cannulated dogs. Beagle dogs were operated for lymph duct cannulation and were orally dosed with 38g of corn oil and moxidectin (0.2mg/kg, n=3). The lymph and plasma were collected over 24h and moxidectin and triglyceride concentrations were measured. Similarly, control dogs (n=5) were dosed orally with moxidectin and oil and subsequently with moxidectin intravenously. Pharmacokinetic parameters were calculated for moxidectin in the plasma of the dogs. Moxidectin readily accumulated in the lymph and reached a plateau 8h post-administration, paralleling triglyceride appearance. The percentage of moxidectin recovered in lymph was 22+/-3% of the total administered dose with 92% being associated with triglyceride-rich particles. The systemic bioavailability of oral moxidectin coadministered with lipid was only 40% in the lymph duct-cannulated dogs compared with 71% in the controls. Our data clearly indicate that the lymphatic transport process contributes significantly to the post-prandial intestinal absorption of moxidectin and subsequently to its systemic bioavailability. The lymphatic transport of moxidectin offers potential strategies based on lipid formulations to improve the bioavailability of MLs when administered orally.

Administration, Oral↗

PubMed2004

Evidence of complement-mediated killing of Discocotyle sagittata (Platyhelminthes, Monogenea) oncomiracidia.

Discocotyle sagittata oncomiracidia were rapidly killed when incubated in naïve plasma and immune sera from both rainbow trout (Oncorhynchus mykiss) and brown trout (Salmo trutta), the killing proceeding at a faster rate with blood material from the latter fish species. The lethal activity of naïve plasma and immune sera was comparable. This was abolished after incubation at 45 degrees C for 30 min and by the addition of EDTA but not EGTA supplemented with Mg(2+), indicating that complement acting via the alternative pathway is responsible for the parasiticidal effect observed. Scanning electron micrographs showed varying degrees of surface disruption in larvae exposed to fish plasma, suggesting that complement acts by breaching the oncomiracidial tegument. Control (untreated) oncomiracidia showed no damage. Ultrastructural damage was more extensive in oncomiracidia exposed to brown trout plasma than to rainbow trout plasma for equal periods, suggesting that the complement cascade may be involved in mediating host susceptibility.

Animals↗

PubMed2005

Expression and bioactivity of allatostatin-like neuropeptides in helminths.

Allatostatins are the largest family of known arthropod neuropeptides. To date more than 150 different arthropod type-A allatostatins have been identified and are characterized by the C-terminal signature, (Y/F)XFG(L/I)amide. Using specific allatostatin antisera, positive immunoreactivity has been identified within the central and peripheral nervous systems of the flatworm (platyhelminth) Procerodes littoralis and the roundworm (nematode) Panagrellus redivivus. Comparative analyses of the allatostatin-like immunoreactivity and that of other known helminth neuropeptides (FMRFamide-like peptides [FLPs]) indicate differences in the distribution of these peptide families. Specific differences in neuropeptide distribution have been noted within the pharyngeal innervation of flatworms and in the cephalic papillary neurons of nematodes. In arthropods, type-A allatostatins have functions that include potent myoactivity. In this study, seven members of the allatostatin superfamily induced concentration-dependent contractions of flatworm muscle fibres. Pharmacological studies indicate that these peptides do not interact with muscle-based FLP receptors. The type-A allatostatins, therefore, represent the second family of neuropeptides that induce muscle contraction in flatworms. Although the majority of arthropod type-A allatostatins examined did not affect the somatic body wall muscle or the ovijector of the pig nematode, Ascaris suum, two type-A allatostatins (GDGRLYAFGLamide and DRLYSFGLamide) exhibited significant inhibitory effects on the A. suum ovijector at 10 microM. These data suggest that allatostatin-like peptides and receptors occur in helminths. Further, although arthropod type-A allatostatins display inter-phyla activities, their receptors are less compelling as potential targets for broad-spectrum parasiticides (endectocides) than FLP receptors.

Animals↗

PubMed2004

Neuropeptide signalling: a repository of targets for novel endectocides?

The only available parasiticides with a spectrum of action that includes a broad range of helminth and arthropod parasites are the macrocyclic lactones. Designated endectocides, these drugs have action against both endoparasitic nematodes and ectoparasitic arthropods. Unfortunately, the discovery of such drugs is exceedingly rare and there is no evidence that novel endectocidal agents will be identified and developed in the short to medium term. However, the discovery of neuropeptides with motor-modulatory activities in both arthropods and helminths, coupled with recent progress in the characterization of invertebrate neuropeptide receptors, has the potential to propel neuropeptide signalling to the forefront of efforts to develop a novel endectocide.

Animals↗

PubMed2006

The FLP-side of nematodes.

The central role of FMRFamide-like peptides (FLPs) in nematode motor and sensory capabilities makes FLP signalling an appealing target for new parasiticides. Accumulating evidence has revealed an astounding level of FLP sequence conservation and diversity in the phylum Nematoda, and preliminary work has begun to identify the nematode FLP receptor complement in Caenorhabditis elegans, with a view to investigating their basic biology and therapeutic potential. However, much work is needed to clarify the functional aspects of FLP signalling and how these peptides exert their effects at the organismal level. Here, we summarize our current knowledge of nematode FLP signalling.

Animals↗

PubMed2004

Ectoparasites of livestock in Europe and the Mediterranean region.

Arthropod ectoparasites can have a major impact on the productivity and welfare of livestock. In recent years, many parts of Europe have seen important changes in the nature of animal husbandry and parasite control, which have increased the need for a precise understanding of the current distribution and prevalence of livestock ectoparasites. In some cases, these changes have been associated with moves towards increased productivity, such as higher-stocking densities, large-scale rearing units, indoor confinement, reduced genetic diversity and large-scale movement of animals and, in others, with a move towards organic farming. There have also been changes in parasite control, associated with the development of new parasiticides, such as the macrocyclic lactones, and concern over the continued use of some of the older neurotoxic compounds. These changes have been exacerbated by outbreaks of endemic disease, the threats of exotic disease introduction and fears of potential changes in arthropod distribution associated with climate change. This paper therefore, reviews the current status of livestock ectoparasites in Europe and the Mediterranean region.

Animal Husbandry↗

PubMed2005

Canine visceral leishmaniasis: comparison of in vitro leishmanicidal activity of marbofloxacin, meglumine antimoniate and sodium stibogluconate.

The control of canine leishmaniasis largely depends on the success of treatment. Drugs currently available to treat this disease are toxic and partially effective. The curative effect of marbofloxacin, a third-generation fluoroquinolone developed for veterinarian individual treatment, was evaluated in vitro in the presence of Leishmania infantum promastigotes and dog-monocyte-derived macrophages; meglumine antimoniate and sodium stibogluconate were used as comparative treatments. We observed that the killing of Leishmania promastigotes and intracellular amastigotes by marbofloxacin was dose-dependent. We demonstrated that successful treatment of canine infected macrophages for 48 h was possible with 500 microg/ml of marbofloxacin. Leishmanicidal activity acted through a TNF-alpha and nitric oxide pathway and correlated with the generation of nitric oxide (NO(2)) production by monocytes derived macrophages from infected (23+/-5 microM) or healthy (21+/-6 microM) dogs, in comparison with NO(2) concentration in infected/non-treated macrophages (< 3 microM, P<0.01). This significant induced parasiticidal effect correlated with extensive elimination of amastigotes by macrophages derived from infected (11+/-5) and healthy dogs (6+/-2), when compared to infected/non-treated macrophages (530+/-105 and 472+/-86 amastigotes, respectively, P< 0.01). Marbofloxacin was shown to be non-toxic at 500 microg/ml in vitro and no cell apoptosis was observed. The molecule was able to induce a parasitic process after significant elimination of amastigotes in leishmania-infected dog macrophages. We propose that marbofloxacin, compared to standard chemotherapeutic agents (meglumine antimoniate and sodium stibogluconate), could be an effective and pragmatic oral route alternative to treat canine leishmaniasis.

Animals↗

PubMed2026

Efficacy of afoxolaner (NexGard®) for the treatment of myiasis caused by the zoonotic tumbu fly, Cordylobia anthropophaga, in domestic dogs under field conditions.

Cordylobia anthropophaga is a major cause of furuncular myiasis in dogs and humans in sub-Saharan Africa, yet evidence for pharmacological control remains limited. Current management relies mainly on mechanical larval removal, and no controlled studies have assessed the efficacy of modern antiparasitic agents. This study evaluated the curative and preventive efficacy of a single dose of afoxolaner (NexGard®) in dogs with naturally acquired C. anthropophaga infestation under field conditions and explored a possible indirect protective effect in puppies after maternal treatment. A randomized, blinded, negative-controlled field study was conducted in Samburu County, Kenya, and included 104 naturally infested dogs allocated to a treated group (n = 53) or an untreated control group (n = 51). Clinical evaluations were performed on Days 0, 15 (±2), 30 (±2), and 45 (±2). Efficacy was assessed based on the presence of active nodules and clinical scores. Additional observational data were collected from puppies born to or nursing from treated bitches. Compared to the control group, parasiticide efficacy was 94% on Day 15 and 100% on Day 30. The number of parasite-free dogs reached 86.3% on Day 15, 100% on Day 30, and 95.3% on Day 45. Treated dogs showed a significant clinical improvement from the first post-treatment assessment, whereas infestation persisted in controls (nodules: OR = 0.003, 95% CI 0.001-0.017; skin lesions: OR = 0.010, 95% CI 0.002-0.051; lymph node: OR = 0.013, 95% CI 0.002-0.074; body condition: OR = 0.073, 95% CI 0.027-0.195; all p < .001), with large effect sizes at the final visit for all outcomes (r = 0.521-0.793). No C. anthropophaga infestations were detected in examined puppies from treated dams, including puppies exposed during pregnancy or lactation, up to 4 weeks after birth and up to 11 weeks of age, respectively. Afoxolaner appears effective to control canine cordylobiosis and may offer indirect protection to puppies, warranting further investigation.

Animals↗

PubMed2006

A combined bioinformatics and chemoinformatics approach for the development of new antiparasitic drugs.

A modern concept for the development of novel antiparasitic drugs is the combination of bioinformatics and chemoinformatics approaches. This covers, for example, the identification of target proteins serving as molecular points of attack for parasiticides--the idea is that, owing to some essential role, inhibition of a target protein should eradicate the parasite. To prevent toxicity problems for vertebrate host organisms, it is advantageous that these proteins show significant differences from their vertebrate counterparts. In the present work, we identified potential target proteins in parasitic nematodes (Ascaris suum, Brugia malayi, and Haemonchus contortus) and arthropods (Boophilus microplus and Rhipicephalus appendiculatus) using bioinformatic sequence comparison methods on expressed sequence tags. Interesting target proteins (e.g., S-adenosyl-l-methionine synthetase) were characterized in detail by subjecting them to in-depth bioinformatic analysis. S-Adenosyl-l-methionine synthetase was also used to elucidate chemoinformatics approaches like homology modeling and docking, which represent appropriate methods for generating valuable data for the development of new drug candidates.

Amino Acid Sequence↗

PubMed2000

Autoimmunity and malaria: what are they doing together?

A common feature of autoimmunity is the presence of autoantibodies (AAb). Two types of AAb have been described: the 'pathogenic' AAb, associated with autoimmune diseases (AID), and the so-called 'natural' AAb. The latter are present in all normal individuals and have been postulated to play a major role as a first defensive barrier of the organism. Both the 'pathogenic' and the 'natural' AAb can be detected at higher frequencies among individuals exposed to viral, bacterial and parasitic infections. The malaria associated AAb do not seem to result from a generalised polyclonal B-cell activation (PBA), have specificities that may differ according to the degree of clinical immunity and do not seem to be pathogenic. Malaria may offer a protective effect against AID, by diminishing its severity or by either preventing or retarding its expression. AAb could also participate in the immune protection against malaria, and this could happen in several ways: (i) AAb directed to modified Ag expressed on the red blood cell (RBC) membrane during parasitisation and (ii) AAb reactive with crypto- or neo-Ag revealed on both normal and infected RBC membranes, by destroying infected, and also normal, erythrocytes; (iii) anti-idiotype AAb specific of the binding site of anti-merozoite Ab, which would mimic the parasite ligand for the RBC receptor, by competing with parasites and blocking RBC invasion; (iv) AAb cross-reactive with parasite material - such as nuclear or cytoskeleton Ag - having a direct parasiticide activity; (v) the natural AAb network, through its 'anti-bacterial first defense barrier'; and finally (vi) anti-phospholipid (PL) AAb, by neutralizing the pathogenic properties of parasite-derived PL. Finally, in view of currently available knowledge, it is concluded that, since AAb are not always pathogenic, the price for an 'autoimmunity-mediated' protection in malaria would not necessarily be immunopathology and clinical autoimmunity, and a protective role of AAb could be exerted with no danger to the host.

Animals↗

PubMed2000

Intralesional autotherapy of cutaneous leishmaniasis with buffy coat cells: cytological findings.

The skin lesions of five patient volunteers with dry-type cutaneous leishmaniasis were treated by intralesional injection of auto-leukocytes prepared from buffy coat of the patient's own blood. Giemsa stained, air-dried cytological smear preparations were prepared from scrapings taken from the margins of the lesions. The cellular interaction between the organism and the inflammatory response of the host was studied. All lesions showed clinical evidence of regression. The cytological findings suggested progressive degradation of the Leishman donovan (LD) bodies within the parasitophorous vacuoles of the activated macrophages. The parasiticidal effect appeared to be induced by synergistic action of the injected neutrophils and lymphocytes. Due to lack of placebo controls in this study the possibility that, healing might not be related to therapy can not be excluded. This study illustrates the potential for intralesional autotherapy with buffy coat in dry-type cutaneous leishmaniasis.

Adolescent↗

PubMed2004

[Tribute to Paul Janssen (1926-2003): two discoveries per year"].

Paul Janssen (1926-2003) performed during fifty Years an intense pharmaceutical research activity. From 1953 to 2003, he discovered numerous new drugs in various fields of pharmacology. He widened the neuroleptic spectrum with haloperidol and risperidone, the opioid one with dextromoramide, fentanyl and its short-life derivates, constipating agents like loperamide, hypnotics, anaesthetics. In the field of anti-infectious agents, he discovered azole antifungals, parasiticides among which levamisole and mebendazole. Other therapeutic classes have been enriched by JANSSEN's works: vasodilatating agents, antihypertensive and anti-allergic drugs, etc. More recently, his research was oriented towards virology namely anti-HIV drugs. When Paul JANSSEN's life ended, his scientific production seemed to be one of the most eminent in the XXth century.

France↗

PubMed2001

Does myoglobin protect Trypanosoma cruzi from the antiparasitic effects of nitric oxide?.

The hemoflagellate protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, a progressive fatal cardiomyopathy widespread in South and Central America. Here, we postulate that the preferential colonization of cardiomyocytes by T. cruzi may reflect the role of myoglobin (Mb) as a nitric oxide (NO) scavenger, protecting the parasite from the trypanocidal effects of NO. The proposal of this novel function of Mb is based on knowledge that ferrous oxygenated Mb reacts rapidly and irreversibly with NO yielding nitrate and ferric oxidized Mb, which is reduced back to the physiologically active form by an intracellular reductase. The postulated protective role of Mb on the viability of T. cruzi is reminiscent of that postulated for hemoglobin in protecting intraerythrocytic Plasmodia from the parasiticidal effect of NO.

Animals↗

PubMed1997

Tumour necrosis factor and associated cytokines in the host's response to malaria.

Tumour Necrosis Factor (TNF) is produced at the initiation of malaria infections (pre-erythrocytic phase), as demonstrated by the release of bioactive TNF by peripheral blood mononuclear cells from individuals residing in endemic areas after stimulation with stage specific sporozoite antigens. During the erythrocytic phase, TNF production is greatly augmented by parasite antigens at the time of schizont rupture and merozoite release from infected erythrocytes. Some of the strongest inducers of TNF synthesis and release are malaria toxins, e.g. glycosylphosphatidylinositol moieties and malaria pigment. Because of TNF's well-known cytotoxic activity it was originally hypothesized that it alone was responsible for killing parasites directly or within host cells. Though earlier reports of the capability of serum containing TNF to kill plasmodia supported this idea, later experiments with recombinant TNF showed a lack of significant parasiticidal activity. Recent studies investigating related factors showed that they were involved with TNF in the control of infection. These factors included -ther cytokines, such as interleukin (IL)-1, IL-6, IL-12, interferon-gamma (IFN gamma) as well as nitric oxide intermediates (NOI) and reactive oxygen intermediates (ROI). This positioned TNF as a key regulator of the immune response against the malaria parasite. However, it must be noted that TNF and its associated factors are also responsible for the fever, aches and pains of acute illness, as well as the hypoglycemia, shock, bleeding and reversible coma of severe malaria seen in approximately 1 percent of individuals with malaria. Therein lies the rub; factors important in the control of malaria also appear to have detrimental properties. Research presented in this review characterizes TNF and associated cytokines' importance in the immune response to malaria.

Animals↗

PubMed2000

Liquid chromatographic determination of emamectin, milbemectin, ivermectin and abamectin in crops and confirmation by liquid chromatography-mass spectrometry.

Emamectin, milbemectin, ivermectin and abamectin are similar macrocyclic lactone chemicals used as an acaricides or parasiticides. We developed a simultaneous analytical method for determining the residual amounts of these compounds and emamectin metabolites in crops. A sample extracted with acetone was cleaned up with Bond Elut C18 and NH2. The sample was then fluorescence-derivatized with trifluoroacetic anhydride and 1-methylimidazole in acetonitrile. The analyte was measured by HPLC with fluorescence detection using an octadecylsilyl column with 3 microm particle size and gradient elution. In most crops, their recoveries by the developed method were ca. 80-110%. The detection limits of the analytes in vegetables were 0.1-0.3 ppt. Using the developed method, we surveyed the residues of these compounds in 20 commercial crops in Osaka, Japan. The result of the surveillance was that emamectin benzoate of 0.2-6.7 ppb was detected in nine cases and milbemectin of 16.7-279.3 ppb was detected in four cases. The detected samples were confirmed by LC-electrospray ionization (ESI) MS. The limit of detection by LC-ESI-MS was similar to the fluorescence detection level of 0.1-0.3 ppt in vegetables except for milbemectin.

Antinematodal Agents↗