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PubMed1999

Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis.

Analysis of the gene cluster from Streptomyces avermitilis that governs the biosynthesis of the polyketide anthelmintic avermectin revealed that it contains four large ORFs encoding giant multifunctional polypeptides of the avermectin polyketide synthase (AVES 1, AVES 2, AVES 3, and AVES 4). These clustered polyketide synthase genes responsible for avermectin biosynthesis together encode 12 homologous sets of enzyme activities (modules), each catalyzing a specific round of polyketide chain elongation. The clustered genes encoding polyketide synthase are organized as two sets of six modular repeats, aveA1-aveA2 and aveA3-aveA4, which are convergently transcribed. The total of 55 constituent active sites makes this the most complex multifunctional enzyme system identified to date. The sequenced DNA region contains 14 additional ORFs, some of which encode polypeptides governing other key steps in avermectin biosynthesis. Between the two sets of polyketide synthase genes lie two genes involved in postpolyketide modification, one of which encodes cynthochrome P450 hydroxylase that probably catalyzes furan ring formation at C6 to C8a. Immediately right of the large polyketide synthase genes is a set of genes involved in oleandrose biosynthesis and its transglycosylation to polyketide-derived aglycons. This cluster includes nine genes, but one is not functional in the biosynthesis of avermectin. On the left side of polyketide synthase genes, two ORFs encoding methyltransferase and nonpolyketide synthase ketoreductase involved in postpolyketide modification are located to the left of the polyketide synthase genes, and an adjacent gene encodes a regulatory function that may be involved in activation of the transcription of avermectin biosynthetic genes.

Anthelmintics↗
PubMed1984

Field studies with in-feed medication of pigs in the Netherlands using the anthelmintic thiophanate with particular reference to efficacy against Ascaris suum.

Studies on the efficacy in pigs of low level in-feed medication with the anthelmintic thiophanate at a minimum intake of 6 mg/kg/day for fourteen days are reported. A trial was conducted to compare a group of medicated fattening pigs with a similar unmedicated group on premises known to have a high challenge of Ascaris spp. Daily growth rate was improved whilst feed conversion ratio and the liver condemnation rate were reduced in the treatment group. Routine medication of a whole herd using this regime contributed to a great improvement of the herd production when assessed by the above criteria. User studies in various geographical areas of the Netherlands involving 1500 adult pigs and 1200 fattening pigs medicated with thiophanate in-feed for fourteen days demonstrated that the compound eliminated the faecal worm egg output and was readily accepted and tolerated by pigs.

Animal Feed↗
PubMed1997

A survey of anthelmintic resistance in nematodes of sheep in The Netherlands.

The prevalence of anthelmintic resistance in nematodes of sheep was surveyed in 1994 on 70 farms in the Netherlands. An in vitro egg hatch assay, faecal egg count reduction (FECR) 14 days after treatment, and larval cultures were used as methods of investigation. Oxfendazole was tested on 69, ivermectin on 51, and levamisole on 36 farms. The median effective dose (ED50) of thiabendazole could be determined on 64 farms. On 60 farms (94%) the ED50 value was > or = 0.12 microgram ml-1, which is indicative of the presence of benzimidazole (BZ) resistance. On two farms egg output was too low to do a FECR test. Based on the results of the FECR test, BZ resistance was present on 56 farms (84%), on 2 farms there was a suspicion of resistance and on 9 farms no resistance could be found. No clear indications were found for the presence of resistance against ivermectin or levamisole. BZ resistance was demonstrated in Haemonchus contortus, Cooperia curticei, Ostertagia spp. and/or Trichostrongylus spp. No resistance was observed in species from the genus Nematodirus, Chabertia ovina and/or Oesophagostomum spp.

Animals↗
PubMed1998

Anthelmintic efficacy of oxibendazole against some important nematodes in dogs and cats.

The anthelmintic efficacy and safety of the oxibendazole component in a combination oxibendazole-niclosamide paste were investigated in dogs and cats and in litters of pups with naturally acquired nematode infections. A single dose of 15 mg oxibendazole/kg body weight given to 70 dogs and to 29 cats reduced faecal worm egg counts (EPG) by 97.6% for Toxocara canis, 95.7% for Trichuris vulpis, 94.6% for Ancylostoma caninum, and 100% for Toxascaris leonina. In cats, 96.7% efficacy was demonstrated against Toxocara cati. In a second trial, 119 pups in 22 litters were treated with the same dosage at 2, 4, and 6 weeks of age. After treatment on two consecutive days, 95% of the pups did not shed T. canis eggs, compared with 85% after only a single treatment. Side effects were rare and only recorded in young animals. A 2-day treatment schedule is recommended for unweaned pups.

Ancylostoma↗
PubMed2001

Anthelmintic treatment of rural Bangladeshi children: effect on host physiology, growth, and biochemical status.

BACKGROUND: The effect of helminth infestation on the nutrition, growth, and physiology of the host is still poorly understood. Anthelmintic treatment of children in developing countries has had varying success in terms of growth improvements. OBJECTIVE: The objective of this study was to assess the effect of regular deworming on child growth, physiology, and biochemical status. DESIGN: The study was a 12-mo longitudinal intervention in 123 Bangladeshi children aged 2-5 y. Treatment (mebendazole) or placebo tablets were administered every 2 mo for 8 mo and again at 12 mo. Weight, height, midupper arm circumference, intestinal permeability, plasma albumin, alpha(1)-antichymotrypsin, and total protein concentration were assessed every 2 mo. RESULTS: Treatment with mebendazole reduced the prevalence of Ascaris lumbricoides from 78% to 8%, of Trichuris trichiura from 65% to 9%, and of hookworm from 4% to 0%. There was no significant difference in the growth of treated children compared with those given placebo tablets. No changes in intestinal permeability or plasma albumin were observed after deworming. Significant decreases in total protein (P<0.001) and alpha(1)-antichymotrypsin (P<0.001) were observed in the treatment group, indicating possible reductions in inflammation and immunoglobulin concentration after deworming. A significant increase in the prevalence of Giardia intestinalis (from 4% to 49%) in the treatment group was associated with a short-term reduction in weight (P = 0.02) and higher intestinal permeability (P <0.001) in infected subjects. No long-term effects of G. intestinalis on growth were observed. CONCLUSION: Low-intensity helminth infections, predominantly of A. lumbricoides and T. trichiura, do not contribute significantly to the poor growth and biochemical status of rural Bangladeshi children.

Animals↗
PubMed1977

Phase 1 tolerability and searching dose studies with 4-isothiocyanato-4'-nitrodiphenylamine (C.9333-Go/CGP 4540), a new anthelmintic.

1 Phase 1 and 2 studies were carried out in thirteen volunteers and thirty patients with hookworm anaemia with a new anthelmintic, 4-isothiocyanato-4'-nitrodiphenylamine (C.9333-Go/CGP 4540). Single and multiple doses were administered by mouth under careful supervision by the staff of the clinical pharmacology unit. 2 4-Isothiocyanato-4'-nitrodiphenylamine (C.9333-Go/CGP 4540) was well tolerated in volunteers up to a single dose of 1750 mg and in patients up to 3000 mg in divided doses. Side effects were rare, transient and mild. One patient had moderate giddiness for 24 h after the compound. The laboratory investigations did not show any adverse effects on organ functions. Transient non-specific changes in the T-wave were occasionally observed in the e.c.g. 3 Multiple doses (125 mg, 250 mg or 1000 mg X 3) of the compound were highly effective in eradicating hookworm infection, as judged by almost 100% reduction in faecal egg counts and significant recovery of parasites from 24 h stool samples. The compound also showed activity against A. lumbricoides, T. trichiura and E. vermicularis. The compound appears to be promising and more studies, in a field situation, are desirable.

Adolescent↗
PubMed1985

Potentiation of the anthelmintic activity of oxfendazole by parbendazole.

The ability of parbendazole (PBZ) to potentiate co-administered oxfendazole (OFZ) was investigated. Administration of a range (1.35-36.0 mg/kg) of doses of PBZ with 4.53 mg OFZ/kg demonstrated that significant potentiation occurred at 4.5 mg PBZ/kg. At 4.5 mg PBZ/kg, the area under the plasma OFZ concentration curve was about twice that obtained from oral administration of OFZ alone. When tested against benzimidazole-resistant Haemonchus contortus and Trichostrongylus colubriformis, the mixture of 4.5 mg PBZ + 4.53 mg OFZ/kg was significantly more effective than 4.53 mg OFZ/kg alone, and PBZ alone showed no activity against these resistant nematodes. The demonstration of PBZ-OFZ potentiation has indicated a means of obtaining a more effective use of currently available anthelmintics in the treatment of helminthiasis.

Animals↗
PubMed2004

Interrelationships among physicochemical properties, absorption and anthelmintic activities of 2-desoxoparaherquamide and selected analogs.

The interrelationships between physicochemical properties, absorption and potency of 2-desoxoparaherquamide and five analogs, representing a new anthelmintic class, were evaluated in in vitro and in vivo assays. At pH 7.5, rates of drug absorption by the gastrointestinal nematode Haemonchus contortus and jird small intestine, parameterized by the permeability coefficient, P(e), ranged from 1.2-2.4 x 10(-4) cm/min (nematode) to 2.5-5.5 x 10(-3) cm/min (jird). In the jird intestine, absorption was pH-dependent, with P(e) at pH 7.5 being twice that at pH 4.5, reflecting the negative influence of protonation on transport of these weakly basic molecules. Each compound rapidly paralyzed H. contortus during in vitro exposure to therapeutically relevant concentrations (1-10 microm). The kinetics of drug action on motility in vivo mirrored their in vitro effects; motility concentrations were reduced in nematodes collected from jird stomach 3 h following oral drug dosing, by which time > or =50% clearance of the parasites had occurred. The nematode/medium partition coefficient K ranged from 10.1 to 16.1, consistent with the lipophilic nature of the compounds. The time required to reduce motility in vitro by 50% (t50*) and P(e) were used to determine C(n)*, the concentration of drug in the nematode at t50*, as an indicator of intrinsic potency. In the jird, the apparent potencies of the compounds were insensitive to route of administration (i.e. oral = i.v. = i.p. = i.m.) for H. contortus and two other gastrointestinal nematodes, Ostertagia ostertagi and Trichostrongylus colubriformis; topical administration, however, required three to 10-fold higher doses for equivalent efficacy.

Absorption↗
PubMed1970

Aspects of the pharmacology of a new anthelmintic: pyrantel.

1. The pharmacological properties of an anthelmintic, pyrantel, and some of its analogues have been described and compared with piperazine in a variety of vertebrate and helminth preparations.2. Pyrantel and its analogues in common with nicotine and decamethonium cause spastic paralysis in chicks and contracture of the chick semispinalis and toad rectus abdominis muscles.3. In the soleus and anterior tibialis muscles of the cat, pyrantel in large amounts caused a short-lived neuromuscular block that was preceded by initial depolarization.4. In preparations from cat and rat, pyrantel showed properties common to both competitive and depolarizing neuromuscular blocking drugs.5. Pyrantel blocked the contracture evoked by transmural stimulation and caused a marked contracture of the worm. Piperazine caused a gradually developing reduction in the responses to transmural stimulation and no contracture.6. Pyrantel and its analogues caused a slowly developing contracture of strip preparations of Ascaris, being more than 100 times more active than acetylcholine in this respect. Piperazine caused a relaxation of Ascaris strip preparations and in common with (+)-tubocurarine blocked the responses to acetylcholine and pyrantel analogues on this preparation.7. Pyrantel caused depolarization and increased spike discharge frequency in single muscle cells of Ascaris, these changes being accompanied by increase in tension. Piperazine, on the other hand, caused hyperpolarization and reduction in spike discharge frequency and relaxation, and antagonized the effects of pyrantel.

Animals↗
PubMed1996

Activation and cooperative multi-ion block of single nicotinic-acetylcholine channel currents of Ascaris muscle by the tetrahydropyrimidine anthelmintic, morantel.

1. We have investigated activation and block, by the tetrahydropyrimidine anthelmintic, morantel, of nicotinic-acetylcholine receptor (AChR) currents in membrane vesicles isolated from somatic muscle cells of the nematode parasite Ascaris suum. Standard single-channel recording techniques were employed. Morantel in the pipette (6 nM to 600 microM), activated single nicotinic AChR currents. 2. Kinetic properties of the main-conductance state of morantel-activated currents were investigated in detail throughout the concentration range, 0.6 microM to 600 microM. Open-time distributions were best fitted by a single exponential. Mean open-times were slightly voltage-dependent, increasing from 0.9 ms at +75 mV to 1.74 ms at -75 mV in the presence of 0.6 microM morantel. At low concentrations, closed-time distributions were best fitted by the sum of two or three exponential components. 3. As the concentration of morantel was increased (100-600 microM), fast-flickering open channel-block was observed at positive potentials, even though morantel, a cation, was only present at the extracellular surface of the membrane. The block rate was dependent on morantel concentration and both block rate and duration of block increased as the potential became less positive. A simple channel-block mechanism did not explain properties of this block. 4. At negative potentials, as the morantel concentration increased, a complex block was observed. With increases in morantel concentration two additional gap components appeared in closed-time distributions: one was short with a duration (approximately 13 ms) independent of morantel concentration; the other was long with a duration that increased with morantel concentration (up to many minutes). In combination, these two components produced a marked reduction in probability of channel opening (Po) with increasing morantel concentration. The relationship between the degrees of block and morantel concentration had a Hill coefficient of 1.6, suggesting the involvement of at least two blocking molecules. The data were analysed by use of a simple sequential double block kinetic model.

Acetylcholine↗
PubMed1996

Hypovolaemic shock after anthelmintic treatment of canine angiostrongylosis.

Canine angiostrongylosis was diagnosed in a whippet with typical signs of respiratory and circulatory distress. Subclinical Angiostrongylus vasorum infections were also demonstrated in two other whippets belonging to the same owner. All three dogs were given standard anthelmintic levamisole treatment combined with corticosteroids. Two days after initiation of treatment, one of the subclinically infected dogs developed severe hypovolaemic shock that required intravenous fluid therapy and corticosteroids to save its life. The shock is believed to have been caused by an anaphylactic reaction triggered by the rapid release of a large amount of worm antigen in the blood due to the rapid death of adult worms by levamisole. Thus, dog owners should be instructed to monitor dogs undergoing levamisole treatment against A vasorum. Alternatives to levamisole treatment of canine angiostrongylosis should be considered.

Adrenal Cortex Hormones↗
PubMed1978

Effectiveness of broad spectrum anthelmintics against selected strains of Trichostrongylus colubriformis.

A field population of Trichostrongylus columbriformis was divided into 4 lines for exposure to selection in the laboratory. The first line was selected with 50 mg/kg thiabendazole, the second with 4 mg/kg morantel tartrate, the third with 50 mg/kg thiabendazole followed by 4 mg/kg morantel tartrate and the fourth line was not selected for drug resistance. Following at least 9 generations of selection there was no difference in LD50 OR LD95 between the unselected and single selected strains of worms. The strain selected by both tiabendazole and morantel tartrate had a significantly higher LD50 against thiabendazole, morantel tartrate and levamisole than did the other three strains. The single selected strains had LD95's of 172, 21.5 and 2.3 mg/kg for thiabendazole, morantel tartrate and levamisole respectively, compared with corresponding values of 111, 17.3 and 2.4 in the unselected strain and 124, 15.5 and 3.0 in the double selected strain. The estimated efficiency of the recommended dose of each anthelmintic against the unselected field strain was;-thiabendazole (44 mg/kg) 50% efficient, morantel tartrate (8.8 mg/kg) 76% efficient and levamisole (7.0 mg/kg) 99.9%efficient.

Administration, Oral↗
PubMed1979

Effectiveness of anthelmintic treatments against levamisole-resistant Ostertagia.

Adult worms from a population of Ostertagia consisting of 88% O. circumcincta and 12% O. trifurcata were found to survive a double drench (14 mg/kg) of levamisole. An anthelmintic assay on this population found that against levamisole the LD50 was 11.95 mg/kg and the LD99 was 67.75 mg/kg. Three benzimidazoles were also tested against this population and the LD50 and LD99 were respectively thiabendazole 11.8 and 144.9 mg/kg, oxfendazole 0.17 and 6.10 mg/kg and albendazole 0.08 and 2.55 mg/kg. The percentage of worms killed by the recommended dose rate was levamisole 24%; thiabendazole 91%; oxfendazole 99% and albendazole 99%.

Animals↗
PubMed1992

The survival and fecundity of buffalo flies after treatment of cattle with three anthelmintics.

Two anthelmintics with known insecticidal action (ivermectin and closantel) and one with no recorded effect on insects (levamisole) were tested to evaluate their effects on buffalo fly (Haematobia irritans exigua). Blood from animals given closantel or levamisole had no significant effect on mortality of buffalo flies in an in-vitro assay. In contrast, blood from animals given ivermectin showed a dose-dependent effect on the mortality of buffalo flies. At 24 h after one injection of the recommended dose of ivermectin, 98% of the flies applied to cattle in an in-vivo assay are killed. Blood from cattle injected with ivermectin killed 95% of flies 8 d after injection and still killed 15% of flies at 18 days after injection. Surviving flies laid almost no eggs and this effect on flies was significant up to 33 d after injection. The results indicate that ivermectin may be useful to control buffalo fly populations in the field.

Animals↗
PubMed1987

Anthelmintic properties of Polygonum glabrum.

A pure anthelmintic substance (PGA) has been isolated from the methanol-aqueous extract of the leaf of Polygonum glabrum Willd., a semi-aquatic Sudanese species of the family Polygonaceae. The antiparasitic in-vitro activity of several fractions isolated from the plant, has been examined comparatively with that of PGA. PGA also showed molluscicidal activity against Biomphalaria glabrata and Limnea truncatula Müll. Structural determination of PGA was attempted following data analysis of UV, IR, 13C NMR, 1H NMR and MS spectra and suggests that PGA is a terpenoid.

Animals↗
PubMed2005

Transport of anthelmintic benzimidazole drugs by breast cancer resistance protein (BCRP/ABCG2).

Methylcarbamate benzimidazoles [albendazole (ABZ), fenbendazole (FBZ), and their respective sulfoxide derivatives, albendazole sulfoxide (ABZSO) and oxfendazole (OXF)] are therapeutically important anthelmintic agents with low bioavailability. We studied their in vitro interaction with the apical ATP-binding cassette (ABC) drug efflux transporters, breast cancer resistance protein (BCRP/ABCG2), P-glycoprotein (ABCB1), and MRP2 (ABCC2) using MDCKII cells transduced with human MDR1, MRP2, and BCRP, and murine Bcrp1 cDNAs. These ABC drug efflux transporters extrude a wide range of xenotoxins from cells in intestine, liver, and other organs, thus affecting the bioavailability of many compounds. In transport experiments, ABZSO and OXF were transported efficiently by murine Bcrp1 and moderately by human BCRP, but not by MDR1 or MRP2. ABZ and FBZ were not found to be Bcrp1, MRP2, or P-glycoprotein substrates in vitro. OXF was found to be a good BCRP/Bcrp1 inhibitor, with somewhat higher potency in the MDCKII-BCRP cell line. The latter results were confirmed by flow cytometry experiments demonstrating inhibition by OXF of murine Bcrp1- and human BCRP-mediated mitoxantrone transport. Further studies of interactions between OXF and known BCRP/Bcrp1 substrates will be of interest. The use of efficacious BCRP/Bcrp1 inhibitors might increase the extent and duration of systemic exposure to ABZSO and OXF, with possible therapeutically beneficial effects in extra-intestinal infections.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Avermectins, new family of potent anthelmintic agents: producing organism and fermentation.

The avermectins are a complex of chemically related agents which exhibit extraordinarily potent anthelmintic activity. They are produced by a novel species of actinomycete, NRRL 8165, which we have named Streptomyces avermitilis. The morphological and cultural characteristics which differentiate the producing organism from other species are described. The avermectins have been identified as a series of macrocyclic lactone derivatives which, in contrast to the macrolide or polyene antibiotics, lack significant antibacterial or antifungal activity. The avermectin complex is fully active against the gastrointestinal nematode Nematospiroides dubius when fed to infected mice for 6 days at 0.0002% of the diet. Fermentation development, including medium modification and strain selection, resulted in increasing the broth yields from 9 to 500 mug/ml.

Anthelmintics↗
PubMed1979

Avermectins, new family of potent anthelmintic agents: isolation and chromatographic properties.

The avermectins, a family of new anthelmintic agents, were isolated from the mycelia of Streptomyces avermitilis. Four closely related major components and four homologous minor components were separated from the complex. Solvent extraction, solvent partition, and adsorption methods were used to isolate and purify the complex; novel partition chromatography systems using Sephadex LH-20 were used to separate the components. A reverse-phase high-pressure liquid chromatography assay for the quantitative determination of all components was used extensively to monitor the purification methods.

Anthelmintics↗