Degree Type

Dissertation

Date of Award

2012

Degree Name

Doctor of Philosophy

Department

Biomedical Sciences

First Advisor

Richard J. Martin

Second Advisor

Alan P. Robertson

Abstract

Anthelmintic drugs apart from a regular treatment of worm infections, find their common use in prophylaxis. The prophylactic usage in farm animals and mass drug administrations (MDA) in humans are common due to an unavailability of effective vaccines. The anthelmintic resistance occurs when an anthelmintic drug is repeatedly used resulting in selection of resistant parasites. Reports of anthelmintics resistance are extensive in farm animals. Emerging reports of resistance in human parasites raises a serious concern. Under the present scenario, research as a part of my graduate program is aimed at countering anthelmintic resistance. I have addressed this aim by working on three different approaches / goals that are arranged into individual chapters in my dissertation. In my first goal (chapter 3), I have proposed a mechanism to potentiate cholinomimetic anthelmintics like levamisole. Levamisole acts on the nicotinic receptors of the somatic (body) muscle of the parasite to produce paralysis. Presently, levamisole resistance is reported in major livestock producing areas across the world. Using Ascaris suum a round worm of pigs as a model parasite, I have studied a mechanism to potentiate the levamisole and thus counter levamisole resistance in parasitic worms. I have used electrophysiological methods on the somatic muscle of A. suum to study the levamisole response. I have observed that, a brief application of AF2 caused potentiation of levamisole responses. AF2 neuropeptide has been isolated in abundant quantities across nematode species and shown to be excitatory on neuromuscular system of nematodes. I have proposed that AF2 receptors are attractive targets in order to potentiate other cholinomimetic anthelmintics like levamisole, pyrantel and oxantel.

The second goal (chapter 4) explores the study of anthelmintic combination Startect®. Combination of anthelmintic drugs is generally employed to slow the onset of resistance in parasites and to achieve synergism in therapy. Startect® consists of derquantel, a new anthelmintic drug that is combined with abamectin to treat resistant parasitic worms in sheep. Derquantel and abamectin have been hypothesized to interact synergistically to control worm infections. I have tested this hypothesis in isolated tissues (somatic muscle and pharynx) of parasitic nematode A. suum. In this study, I have concluded that these two drugs produced a greater than additive effect on the somatic muscle nicotinic receptors but, did not interact on the pharyngeal muscle glutamate receptors.

In the third goal (chapter 5) I have identified nicotinic receptor population in the pharynx of the parasitic worm A. suum and proposed them as novel drug targets. In my study, current cholinomimetic drugs did not act on the nicotinic receptors of pharynx. This demonstrated that they are novel targets. As current literature on pharyngeal nicotinic receptors is limited, I have explored their pharmacological properties. I have observed that the nicotinic receptors of pharynx are distinct from the nicotinic receptors of vertebrate host. Hence, these receptors are attractive targets for selective drug targeting of parasites and to minimize the side effects in vertebrate hosts.

DOI

https://doi.org/10.31274/etd-180810-3074

Copyright Owner

Sreekanth Puttachary

Language

en

File Format

application/pdf

File Size

242 pages

Included in

Pharmacology Commons

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