Anthelmintic Activity of Methyridine Against Experimental Nematode Infections in Mice

Broome, A. W. J.; Greenhalgh, N.

doi:10.1111/j.1476-5381.1961.tb01119.x

Cited by 4 publications

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“…Methyridine was also observed to have a rapid paralyzing effect on intact nematode parasites in vitro , demonstrating that methyridine passes through the cuticle to get to the neuromuscular system. The effect of methyridine (10 μ g ml −1 =73 μ M ) on A. suum segments (Broome, 1961) was complete paralysis within 2 min. Interestingly, the effects were observed rapidly after applying methyridine to the preparation, and not reversed by the addition of acetylcholine and decamethonium.…”

Section: Discussionmentioning

confidence: 99%

“…Although a number of studies have characterized the range of parasites that methyridine is effective against, information concerning the mode of action of this compound is incomplete and based on three studies. Broome (1961) first suggested that the mode of action of methyridine was as a neuromuscular blocking agent; and then Eyre (1970), using rat isolated phrenic nerve diaphragm and chick isolated biventer cervicis muscle preparations, observed that methyridine behaved like the depolarizing muscle relaxant, succinylcholine. However, in the most recent study ( Raymond et al , 2000 ), methyridine in concentrations up to 1 m M was reported to have no effect on two AChR subtypes (chicken α ‐7 and C. elegans ACR‐16) expressed in Xenopus oocytes.…”

Section: Introductionmentioning

confidence: 99%

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Methyridine (2‐[2‐methoxyethyl]‐pyridine]) and levamisole activate different ACh receptor subtypes in nematode parasites: a new lead for levamisole‐resistance

Martin

Bai

Clark

et al. 2003

British J Pharmacology

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1 The development of resistance to all chemotherapeutic agents increases and needs to be addressed. We are interested in resistance in parasitic nematodes to the anthelmintic levamisole. During studies on methyridine, we found that it gave us a new insight into pharmacological changes associated with levamisole resistance. Initially, electrophysiological investigation using a two-micropipette currentclamp recording technique revealed that methyridine acts as a cholinergic agonist on nematode muscle receptors (Ascaris suum). Methyridine (430 mM) produced reversible concentration-dependent depolarizations and increases in input conductance. Mecamylamine (30 mM) and paraherquamide (0.3 mM) produced reversible antagonism of the depolarization and conductance responses to methyridine. These observations suggest that methyridine, like acetylcholine and levamisole, gates ion channels on the muscle of parasitic nematodes. 2 The antagonistic effects of dihydro-b-erythroidine and paraherquamide on methyridine-induced contractions of A. suum muscle flaps were then examined to determine if methyridine showed subtype selectivity for N-subtype (nicotine-sensitive) or L-subtype (levamisole-sensitive) acetylcholine receptors. Dihydro-b-erythroidine weakly antagonized the effects of methyridine (but had no effect on levamisole responses). The antagonism of methyridine (pA 2 , 5.9) and nicotine (pA 2 , 6.1) by paraherquamide was similar, but was less than the antagonism of levamisole (pA 2 , 7.0). The antagonist profiles suggested that methyridine has a selective action on the N-subtype rather than on the L-subtype. 3 A novel use for a larval inhibition migration assay was made using L 3 larvae of Oesophagostomum dentatum. Inhibitory effects of nicotine, levamisole, pyrantel and methyridine on the migration of larvae of levamisole-sensitive (SENS) and levamisole-resistant (LEV-R) isolates were tested at different concentrations. Levamisole and pyrantel (putative L-subtype-selective agonists) concentration -response plots were displaced to the right in LEV-R isolates. Nicotine (an N-subtype-selective agonist) and methyridine produced little shift in concentration -response plots in the LEV-R isolates. Resistance dose ratios were used to calculate the relative selectivity, r L , for the L-type receptor (levamisole r L ¼ 1.0; pyrantel r L ¼ 0.93; methyridine r L ¼ 0.17; nicotine r L ¼ 0.06). These observations reveal an N-subtype-selective action of methyridine and suggest that levamisole resistance may be associated with a loss of the L-subtype, but not the N-subtype receptors. The pharmacology of methyridine suggests an approach for the treatment of levamisole-resistant parasites. British Journal of Pharmacology (2003) 140, 1068-1076. doi:10.1038/sj.bjp.0705528 Keywords: Methyridine; levamisole; nicotine; pyrantel; levamisole-resistance; Ascaris suum; Oesophagostomum dentatum; ACh receptor subtypes; N-subtype; L-subtype.Abbreviations: ANOVA, analysis of variance; AChR, acetylcholine-gated ion-channel receptor; DMSO, dimethylsulfox...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methyridine (2‐[2‐methoxyethyl]‐pyridine]) and levamisole activate different ACh receptor subtypes in nematode parasites: a new lead for levamisole‐resistance

Martin

Bai

Clark

et al. 2003

British J Pharmacology

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“…Anthelmintic studies in laboratory animals (Broome & Greenhalgh,. 1961b) have shown that the drug is a more efficient anthelmintic when administered subcutaneously than when given orally.…”

Section: Discussionmentioning

confidence: 99%

“…Blood and gut concentrations of methyridine in mice. Groups of 20 mice were dosed with the optimum therapeutic dose of methyridine 400 mg/kg orally and subcutaneously (Broome & Greenhalgh, 1961b). After the appropriate time interval all animals were sacrificed and their blood was collected together with material from various regions of the alimentary canal.…”

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Studies on the Mode of Action of Methyridine

Broome¹

1961

British Journal of Pharmacology and Chemotherapy

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Methyridine [2-(,8-methoxyethyl)pyridine] reached the blood and all regions of the alimentary canal following oral or subcutaneous administration of therapeutic doses of the drug. Concentrations in the lower gut were highest following subcutaneous administration, and there was a close association between blood and intestinal levelssuggesting that the drug is excreted into the alimentary canal along its whole length. In vitro experiments with intact nematodes (Ostertagia spp. from sheep; Nematospiroides dubius and Heterakis spumosa from mice; and Nippostrongylus muris from rats) and with preparations of Ascaris sp. have demonstrated that methyridine passes through the cuticle and exerts an "irreversible " paralysing effect on the worms. This action is obtained within 1 hr at concentrations similar to peak levels shown to be present in the alimentary canal following the administration of therapeutic doses. Concentrations of the drug were found to be higher in the abomasum than in the intestine of sheep and yet the anthelmintic activity of methyridine is greatest against intestinal nematodes. No significant differences in the resistance of various nematode species to the drug were demonstrated, but the amount of methyridine entering ascarids was significantly greater at pH 8 than at pH 5 or 3. In addition, the in vitro anthelmintic activity of the compound was greatest in alkaline solutions, which probably accounts for the differences in anthelmintic activity noted in various parts of the alimentary canal. The paralysing effect of methyridine on nematodes isprobably due to a neuromuscular block of the decamethonium type, and this can also be produced in the host by over-dosage. It is suggested that nematode tissues are more sensitive to this action than vertebrate tissues.Experiments in laboratory animals (Broome & Greenhalgh, 1961a and b) and farm animals (Walley, 1961) have demonstrated considerable anthelmintic activity against nematode infections of the gastro-intestinal tract following treatment with the compound methyridine [2-(fi-methoxyethyl)pyridine; "Promintic "]. The same reports indicate a number of features which make the drug unique among known anthelmintics. In particular, it is a liquid which is extremely water-soluble and which is most effective when administered subcutaneously. These peculiarities clearly merited this study of its mode of action. In the work described below estimations have been made of the drug concentration in various parts of the body and of the effect of the drug in vitro against various nematodes. The results are then correlated in an attempt to show how the in vivo anthelmintic activity is achieved.M

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Comparative Activity of 29 Known Anthelmintics under Standardized Drug-Diet and Gavage Medication Regimens against Four Helminth Species in Mice

Brody¹,

Elward²

1971

The Journal of Parasitology

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Anthelmintic Activity of Methyridine Against Experimental Nematode Infections in Mice

Cited by 4 publications

References 4 publications

Methyridine (2‐[2‐methoxyethyl]‐pyridine]) and levamisole activate different ACh receptor subtypes in nematode parasites: a new lead for levamisole‐resistance

Methyridine (2‐[2‐methoxyethyl]‐pyridine]) and levamisole activate different ACh receptor subtypes in nematode parasites: a new lead for levamisole‐resistance

Studies on the Mode of Action of Methyridine

Comparative Activity of 29 Known Anthelmintics under Standardized Drug-Diet and Gavage Medication Regimens against Four Helminth Species in Mice

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