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Hookworm burdens and faecal egg counts: an analysis of the biological basis of variation.

The relationships between various measures of faecal egg output and hookworm burdens were investigated in 84 villagers from West Bengal with mixed Necator americanus and Ancylostoma duodenale infections. The pattern of day to day variability in egg counts from individuals can be characterized by the linear relationship between the logarithms of the variances and means. Egg output is shown to be non-periodic in long runs of day-to-day records. The distribution of worm numbers per host is well described by the negative binomial probability model, and the relationship between per capita egg output and worm burden is non-linear where egg output declines as parasite burden rises. Density-dependent effects on fecundity are shown to act at comparatively low worm burdens in relation to the range of observed parasite loads. Egg output measures are shown to be qualitative as opposed to quantitative measures of worm burdens as a consequence of inherent sampling heterogeneity and variability induced by biological processes, such as density-dependent depression of parasite fecundity. The analyses suggest that it is possible, on the basis of egg counts, to discriminate between individuals with low and high hookworm burdens. The intrinsic per capita fecundities of the two species of hookworms are shown to be similar, but density-dependent constraints on egg production by N. americanus appear to be more severe than those acting on A. duodenale. This observation may help explain why A. duodenale appears to produce larger numbers of eggs per unit of time than N. americanus. The regulatory role of density-dependent fecundity and aggregated distributions of worm numbers per person are discussed in relation to the over-all transmission dynamics of hookworm parasites.

Adolescent↗

Brief application of AF2 produces long lasting potentiation of nAChR responses in Ascaris suum.

Resistance of parasitic nematodes to the cholinergic anthelmintic levamisole is associated with a reduction in the proportion of time that acetylcholine receptor ion-channels are in the open state decreasing the response of nematode parasites to the drug. Here we examine electrophysiological and contractile responses to acetylcholine and the cholinergic agonist, levamisole, in Ascaris suum muscle looking for a pharmacological approach that may be developed to increase the response to cholinergic agonists. We found that short application of the FMRFamide, AF2, produced modulation (long lasting potentiation) of the peak membrane potential response to acetylcholine but not to levamisole. Since levamisole preferentially activates L-type acetylcholine receptors, we also tested the effect of nicotine (selective activator of N-type acetylcholine receptors) and bephenium (selective activator of B-type acetylcholine receptors) and found again no effect of AF2 on peak membrane potential responses. We then tested atropine on the AF2 potentiation of acetylcholine and found it to inhibit the peak potentiation suggesting that AF2 receptors interact with muscarinic receptors to produce the potentiation of acetylcholine. We saw similar atropine sensitive potentiation of acetylcholine responses in our muscle contraction experiments. The potentiation of the acetylcholine responses shows that nematode acetylcholine receptors are capable of a level of plasticity. A model involving calcium release from the sarcoplasmic reticulum, CaM Kinase, calcineurin, muscarinic receptors and AF2 receptors is proposed to explain our observations. These observations are important because they point to a pharmacological approach that may be developed to counter resistance to cholinergic anthelmintics.

Acetylcholine↗

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

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 current-clamp recording technique revealed that methyridine acts as a cholinergic agonist on nematode muscle receptors (Ascaris suum). Methyridine (>30 microm) produced reversible concentration-dependent depolarizations and increases in input conductance. Mecamylamine (30 microm) and paraherquamide (0.3 microm) 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-beta-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-beta-erythroidine weakly antagonized the effects of methyridine (but had no effect on levamisole responses). The antagonism of methyridine (pA2, 5.9) and nicotine (pA2, 6.1) by paraherquamide was similar, but was less than the antagonism of levamisole (pA2, 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 L3 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, rhoL, for the L-type receptor (levamisole rhoL=1.0; pyrantel rhoL=0.93; methyridine rhoL=0.17; nicotine rhoL=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.

Animals↗

A comparative study of the relative efficacy of pyrantel pamoate, bephenium hydroxynaphthoate and tetrachlorethylene in the treatment of Necator americanus infection in Ceylon.

The clearance of hookworm (Necator americanus) ova by a single dose of tetrachlorethylene (T.C.E.) was compared with that produced by single and multiple dose regimes of bephenium hydroxynaphthoate and pyrantel pamoate. Single doses of bephenium and pyrantel were inferior to T.C.E. Three daily doses of bephenium or pyrantel produced effects comparable with a single dose of T.C.E. Because of the low cost and lack of side effects, T.C.E. remains the drug of choice in the treatment of N. americanus in infections; the only disadvantage of T.C.E. is its unnoticed deterioration under tropical conditions.

Administration, Oral↗

Evaluation of albendazole, pyrantel, bephenium, pyrantel-praziquantel and pyrantel-bephenium for single-dose mass treatment of necatoriasis.

An effective drug for single-dose mass treatment of necatoriasis was sought by testing three drugs and two drug combinations in Ethiopian immigrants to Israel found to have light infections. The drugs tested sequentially in single-doses were pyrantel pamoate (20 mg kg-1, 81 subjects); bephenium hydroxynaphthoate (2.5-5 g, 65 subjects); combined pyrantel and bephenium (25 subjects); combined pyrantel (20 mg kg-1) and praziquantel (40 mg kg-1) (16 subjects); and albendazole (400 mg, 77 subjects). Follow-up under conditions without likelihood of reinfection was by one stool examination. Cure rates with albendazole, pyrantel-bephenium and pyrantel-praziquantel were 84, 80 and 81% respectively; these rates were significantly higher than the 49% found for bephenium and the 51% for pyrantel (P less than 0.05). Egg reductions in those not cured were pyrantel (22%), bephenium (6%), pyrantel-bephenium (34%), pyrantel-praziquantel (3%) and albendazole (6%). Albendazole was the most promising single drug treatment; unexpected was the high effectiveness of pyrantel-praziquantel in combination.

Adolescent↗

Pediatrics: ridding children of common worm infections.

The most common worm infection in children in the United States is pinworm infection. In second place is roundworm infection. Agents that are effective against these nematodes in a high proportion of cases are available. In hookworm disease, generally seen in older children, tetrachloroethylene treatment is being supplanted by use of drugs less likely to have adverse side effect. Visceral larva migrans is difficult to diagnose and to treat, and our best hope for control lies in prevention.

Animals↗

Use of common salt fortified with iron in the control and prevention of anemia--a collaborative study. Report of the Working Group on Fortification of Salt with Iron.

The efficacy of salt fortified with iron (FePO4 and NaHSO4) to control anemia was investigated by large scale field trials in three rural areas and one urban area located in different parts of India, each covering a total population of 4000 to 6000. Hb levels were determined before the introduction of the fortified salt and at six monthly intervals thereafter. Iron-fortified salt was acceptable to the population and its consumption for a period of 12 to 18 months was without any untoward effects. At the end of 12 to 18 months of consumption of iron-fortified salt, a significant improvement in the Hb-levels and a significant reduction in the incidence of anemia was observed in all the test areas. In one of the rural areas tested, there was a high incidence of hookworm infestation and iron-fortified salt showed a significant impact on Hb levels even in this area. Deworming concomitant with distribution of iron-fortified salt was shown to have only a marginal additional benefit.

Adolescent↗

The interaction between anthelmintic drugs and histamine in Ascaris suum.

1 Piperazine reduced the histamine content of Ascaris suum, yet it greatly increased the uptake of histamine from the surrounding medium, the neuromuscular structures of the nematode preferentially increasing in amount. 2 Bephenium reduced the histamine content of Ascaris and the uptake of histamine from the surrounding medium. However, the relative amount in the neuromuscular structures increased. 3 The flaccid paralysing action of piperazine may thus involve increased histamine absorption whereas the spastic paralysing action of bephenium may be independent of histamine.

Amine Oxidase (Copper-Containing)↗