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· . STUDIES OF THE PHARMACODYNAMICS 
AND 
MODES OF ACTION OF ANTHELMINTIC DRUGS 
A THES I S  P RESENTED IN  PART IAL FULF I LMENT 
OF THE REQUIREMENTS FOR THE 
DEGREE OF DOCTOR  OF PHILOSOPHY  
AT  
MAS SEY  UNIVERS I TY 
U MIN SOE 
1977 
Abstract' of a thesis presented in partial fulfilment 
of the requirements for the Degree of Doctor of Philosophy 
STUDIES OF THE PHARMACODYNAMICS 
AND 
MODES OF ACTION OF ANTHELMINTIC DRUGS 
by  U M IN  SOE 
'ltl,e aim of this work is to extend existing knowledge both with respect to 
the mode of action of anthelmintics and the biochemical and physiological 
mechanisms which may be disrupted by drug action . The helminth species 
examined include nematodes , Ascari s suum, Ascaridia galli and Trichuris 
ovis and cestodes , Moniezi o" T. hydatigena , T. taenireformis and 
Echinoccocus granulosus; the anthelmintics studied were methyridine , 
diethylcarbamazine , pyrantel , morantel ,  tetramisole , levamisole , 
dichlorvos , vincofos , cambendazole and mebendazole . The helminth 
characteristics selected for most intensive study are (a)  the occurrence 
and properties of helminth cholinesterase and (b) the uptake of glucose . 
The breadth of the study was limited by the availability of fresh 
material and not all combinations of helminth and drug were investigated.  
The histochemical localisation of cholinesterase activity in whole 
mounts and sections of tapeworms using thiocholine esters revealed a 
complex network of tegumental receptors feeding a nervous system with 
efferents to suckers , rostellum and hook muscles . It  is suggested that 
tapeworms have reflex arcs involving these structures allowing them to 
maintain their position in the host intestine in  spite of peristaltic 
action . These arcs are susceptible to anticholinesterase anthelmintics . 
Other cholinesterase activity is associated with the scolex , cirrus , 
genital pore and sometimes the tegument. 
High cholinesterase specific activities against acetylthiocholine were 
measured in Echinococcus scoleces and tapeworms , but lower levels in 
nematodes .  Differential centrifugation of homogenates was used to 
ii 
iii 
study their occurrence in the tissue and facilitate further 
characterisation . However ,  the enzyme was widely distributed in these 
species although somewhat higher in the particulate fractions . Activity 
was increased little , if  any, by attempts to solubilise it  with the 
detergent ,  Triton X-IOO. Cholinesterase in some fractions particularly 
from T. ovis , had a high temperature optimum around 600C ,  but never 
showed the phenomenon of autoinhibition by substrate at concentrations 
up to IO-2M. Cholinesterase in species of worm with high levels  of 
enzyme was more sensitive to eserine inhibition than those with lower 
levels . 
In studies of glucose uptake from the medium by Ascaris and two 
tapeworms , it  was confirmed that transport into Ascaris was strongly 
inhibited by certain benzimidazole anthelmintics . Transport into 
Ascaris , but not the cestodes ,  was also discovered to be sensitive to 
local anaesthetics such as procaine or lignocaine . Uptake into 
tapeworms was inhibited by the absence of sodium ions , phlorizin , 
iodoacetate and dinitrophenol .  It  was less inhibited by benzimidazoles 
and not at all  by organophosphate anthelmintics , but was sensitive to 
phenolic drugs such as hexachlorophene and nitroxynil . 
In  the dog and sheep , a number of anthelmintic drugs administered 
intravenously showed predominantly nicotinic effects on blood pressure 
and respiration supporting the cholinergic action of these drugs . 
Although sheep red-cell  cholinesterase is  more sensitive to inhibition 
than that of all helminths tested , the oral route of administration 
of anthelmintics remains safe for the host and effective against 
intestinal parasitic worms . 
ACKNOWLEDGMENT 
I wish to express  my gratitude to my chief supervisor D1·L .  S .  Forbes ,  
who proposed the area of research covered in this thesis and for his 
suggestions and criticism and for the arrangements which were made for 
bringing this thesis to completion . 
I am greatly indebted to my other supervisor , Dr.R .M .  Greenway for his 
role in supervision , continued interest , and never-failing support and 
encouragement .  
iv  
I have much pleasure in  expressing my grateful thanks to Professor R .E . 
Munford , Head of the Department of Physiology and Anatomy , Massey 
University ,  for his computing and statistical analysis and the provision 
of laboratory facilities . 
I wish to expres s  my gratitude to Dr. D . O .  Heath and staff at 
Wallaceville Animal Research Centre , Wellington , for supplying 
T. ovis cysts and for valuable suggestions . 
I am indebted to Mrs Sharon Pickett for her technical assistance and 
typing of my manuscript and Mrs Fay Wicherts for her careful final 
typing . The enthusiastic technical assistance of Messrs R .N .  Ward , 
B .  O ' Sullivan , and R. Telfer and our photographer , Mr T .  Law are 
warmly appreciated . 
Acknowledgements are due to the staff of the library , especially 
Miss  E .M .  Green , from the interloan section of the library at Massey 
University , for facilities in verifying the references from different 
libraries throughout New Zealand and overseas . 
This investigation has been financially supported by the Burmese 
Government and the New zealand Government under bilateral aid 
arrangement of Colombo Plan Scholarship and I am much indebted to 
both Governments . 
Finally , I thank my mother Daw Kyaw Shin , who was deceased during the 
course of my studies , in Burma , for her upbringing and persistant 
encouragement and then my wife Kyi Kyi Nyunt and our son , Soe Wunna 
for their encouragement during our separation for the five years 
while I was engaged in this research in New zealand . 
CHAPTER 1 
CHAPTER 2 
CHAPTER 3 
CHAPTER 4 
CHAPTER 5 
CHAPTER 6 
CONTENTS  
Page  No  
The significance of helminth infections 
and their control 
M9des of action of anthelmintics 
1 
6 
Pharmacodynamic studies related to anthelmintic 
action and their effects on host cholinesterase 37 
Helminth cholinesterase and the influence of 
inhibitors and anthelmintics 
Helminth glucose uptake and the influence of 
inhibitors and anthelmintics 
Helminth cholinesterase: Histochemical 
studies and the influence of inhibitors 
77 
180 
241 
GENERAL DISCUSSION 285 
REFERENCES AND ADDENDUM 287 
v