Levamisole resistance

Figure 21.11A illustrates representative vesicle-attached recordings from a sensitive isolate (SENS), a pyrantel-resistant isolate (PYRR) and a levamisole-resistant isolate (LEVR) produced by 30 pM levamisole. There are differences in mean P-open values of receptors between sensitive and resistant isolates that would produce, on average, a reduction in the effect of the anthelmintic. However, one of the puzzling, but very consistent, observations is that there is a big range in the P-open values observed in different patches under the same experimental conditions in the same isolate (Fig. 21.1 IB). For example, the P-open values of the sensitive isolate were observed to vary between 0.090 and 0.003 at -50 mV with 30 pM levamisole, a 30-fold difference between the biggest and the smallest P-open...

Fleming, J.T., Squire, M.D., Barnes, T.M., Tornoe, C., Matsuda, K., Ahnn,J., Fire, A., Sulston, J.E., Barnard, E.A., Sattelle, D.B. and Lewis, J.A. (1997) Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor svlbxmixs,. Journal of Neuroscience 17, 5843-5857. 

Hoekstra, R., Visser, A., Wiley, L.J., Weiss, A.S., Sangster, N.C. and Roos, M.H. (1997) Characterization of an acetylcholine receptor gene of Haemonchus contortus in relation to levamisole resistance. Molecular and Biochemical Parasitology 84, 179—187. 

Lewis JA, Wu CH, Berg H, Levine JH. 1980. The genetics of levamisole resistance in the nematode Caenorhabditis elegans. Genetics 95 905-28... 

Martin RJ, Bai G, Clark CL, Robertson AP. Meth)fridine (2-[2-methoxyethyl]-pyridine) and levamisole activate different ACh receptor sub-types in nematode parasites a new lead for levamisole-resistance. Br J Pharmcol 2003 140(6) 1068-76. 

Levamisole [14769-73-9] (6-phenyl-2,3,5,6-tetrahydroimida2o[2,l- ]thia2ole, 8) C22H22N2S, was found to be effective against herpes vims infections in humans (15,16). It acts as a modulator of host resistance mechanisms, especially as an enhancer of cellular immunity. 

It has already been pointed out that resistant isolates have on average fewer active channels per patch than the sensitive isolates. In addition, the average proportion of time that the levamisole receptors were open (P-open) in the LEVR isolates was significantly less than the proportion of time that the levamisole receptors were open in the SENS isolates (Fig. 21.11). Thus, two factors can be identified that lead to a reduction in the current carried across the membrane by levamisole receptors in the resistant isolate when compared with the sensitive isolate. The factors are, again, a reduced density of active channels in LEVR isolates, and a reduced proportion of time that the active channels in the resistant isolate are open. These factors combine so that there is a tenfold reduction in the current carried across the membrane at 30 pM. 

Robertson, A.P., Bjorn, H. and Martin, R.J. (1999) Resistance to levamisole resolved at the single-channel level. FASEB Journal13, 749-760. 

Varady, M., Bjorn, H., Craven, J. and Nansen, P. (1997) In vitro characterization of lines of Oesophagostomum dentatum selected or not selected for resistance to pyrantel, levamisole and ivermectin. International Journal for Parasitology 27, 77-81. 

In 11 children with nephrotic syndrome, of whom five were glucocorticoid-sensitive, six glucocorticoid-resistant, and all resistant to other immunosuppressive drugs, levamisole 2.5 mg/kg was given every 48 hours for up to 18 months (7). Two patients were also given ciclosporin. All the patients in the steroid-sensitive group but none in the steroid-resistant group reacted favorably to levamisole, with disappearance of protein from the urine. There... 

Tenbrock K, Muller-Berghans J, Fnchshnber A, Michalk D, Querfeld U. Levamisole treatment in steroid-sensitive and steroid-resistant nephrotic syndrome. Pediatr Nephrol 1998 12(6) 459-62. 

There appears to be a considerable worldwide effort to develop treatments for viral diseases. The prophylaxis of some diseases by vaccines, where available, remains a valuable method. The acceleration of work with human interferon is gratifying. The concept of using small organic compounds of nuclease-resistant polymeric polynucleotides as interferon inducers has had dubious results in humans, but may still be viable if therapeutic ratios can be improved. Immunoenhancing substances such as tilorone, levamisole, BCG vaccine, and others under investigation have had a limited impact thus far. Neither approach represents chemotherapy in the classic sense and was therefore not discussed here. 

Sangster, N. C., Davis, C. W. and Collins, G. H. (1991) Effects of cholinergic drugs on longitudinal contractions in levamisole-susceptible and -resistant Haemonchus contortus. Int. 

This reporter is obviously encountered in the APAAP technique, but it can also be conjugated to biotin and used successfully in the ABC methods. The enzyme is sourced from calf intestine, this form being resistant to the blocking effect of levamisole, which is added to the substrate buffer and blocks all other types of endogenous alkaline phosphatase activity. Several chromogens can be used, the most popular being Fast Red TR salt which yields a bright red alcohol soluble reaction product (34). 

Fisher found that treatment of weaning rats with levamisole increased their resistance to infections with herpes virus and staphylococci. Immunosuppressed individuals respond to a greater extent to levamisole than do those with normal or near normal immune capability. In both groups, the response to suboptimum antigenic stimuli is relatively unaffected. ... 

The role played by fumarate reductase inhibition in the mode of action of anthelmintics was further studied. Enz3mie isolated from thiabendazole-sensitive Haemonchus was inhibited by thiabendazole, cambendazole, levamisole, morantel tartrate and disophenol, but not by mebendazole. Enzyme from a thiabendazole-resistant strain was similarly affected, except that the inhibitory effect of cambendazole was reduced and that of thiabendazole was not demonstrable. In lambs, after 4 generations of Haemonchus strain BPL-2 had been exposed successively to single doses of cambendazole at 5, 5, 10 and 20 mg/kg, this parasite was less susceptible to cambenda-... 

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