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Pediculus Humanus Studies into the insecticidai activity and mode of action of monoterpenoid constituents of essentiai oiis against the human iouse, Pediculus humanus. A thesis presented by Caroline Mary Priestley For the degree of Doctor of Philosophy Centre for Pharmacognosy and Phytotherapy, Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, Faculty of Medicine, University of London. 2002 Abstract The incidence of head lice, 'Pediculus humanus capitis^ in the West is increasing, with insecticide resistance the likely cause. Previous studies have explored the utility of essential oils, and some of their constituent monoterpenoids, in the treatment of head lice. This investigation examines the relative short-term toxicity of a range of different monoterpenoid structures on adult clothing lice, Pediculus humanus corporis, and their eggs; a structure-activity series was generated for the adults, and partially for eggs. The most effective monoterpenoid against adult Hce was (+)-terpinen-4-ol, with monocyclic compounds containing a single O-atom having the highest activities. Furthermore, there appear to be important differences between the relative potencies of monoterpenoids on lice and eggs, as nerolidol was particularly effective against eggs but completely ineffective against adult lice. To investigate the insecticidal mechanism of action of monterpenoids, various pediculicidal structures were screened for activity on an insect ionotropic GABA receptor, composed of the Drosophila melanogaster svhum t RDL^^, expressed in Xenopus oocytes. Thymol, eugenol and carvacrol potentiated GABA responses at this receptor, and possessed agonist activity at high concentrations. This is the first documentation of monoterpenoid bioactivity at an isolated insect receptor known to be representative of an in vivo insecticidal target. Thymol also had potentiating and agonist effects on human al|33Y2s GABA^ receptors expressed in Xenopus oocytes, and 50 p,M thymol induced a leftwards shift of the GABA dose-response curve. Further work on this receptor examined the interaction of thymol with previously characterised modulator binding sites. The results of functional studies suggest that thymol does not share a binding site with benzodiazepines, barbiturates, steroids, propofol, (3-carbolines or loreclezole. The direct involvement of insect GABA receptors in monoterpenoid insecticidal activity remains to be confirmed, as does the location of the thymol binding site on insect and mammalian ionotropic GABA receptors. Acknowledgements I am very grateful to my supervisor, Dr Elizabeth Williamson, for her guidance, support and enthusiasm throughout the course of my studies. I would also like to thank my collaborators, Mr Ian Burgess and Dr John Maunder (MEG Ltd, Cambridge), Dr David Sattelle (MRC Functional Genetics Unit, Oxford University) and Dr Keith Wafford (Merck, Sharp and Dohme, Terling’s Park, U.K.) for allowing me to work in their laboratories and for supplying specialist equipment and advice. I also thank my second supervisor. Professor Michael Heinrich for encouragement and his successful regeneration of the Centre for Pharmacognosy and Phytotherapy at The University of London School of Pharmacy. I must also thank the following people for their scientific advice: Dr Emmanuel Culetto and Dr Valerie Raymond (MRC Functional Genetics Unit, Oxford University), Dr Nigel Mongan (formerly of The Babraham Institute, University of Cambridge), Dr Lucy Horoszock (formerly a visitor to The Babraham Institute, University of Cambridge), Dr Michael Postlethwaite, Mr Gus Ronngren (The School of Pharmacy, University of London), Miss Rachael Cooper, Miss Beth Basham, and Mr David Thompson (MEC Ltd). Special thanks go to Mike & Rita Priestley, Matt Southward, Nic Newling, Nessie Ramm and Suzy Vaughan-Schiele for their out-of-hours support. This research was funded by a School of Pharmacy Studentship and a University of London Central Research Fund Grant Contents Abstract____________________________________________________________________2 Acknowledgements__________________________________________________________3 C ontents___________________________________________________________________4 Table of Figures____________________________________________________________7 Chapter 1 Introduction_______________________________________________________8 1.1 Concepts of head louse control _____________________________________________8 1.2 The taxonomy and anatomy of human lice and their interrelationship _____________9 1.3 The life cycle and population structure of Pediculus species____________________12 1.4 Symptoms and consequences of pediculosis capitis____________________________13 1.5 Transmission and epidemiology of Pediculus humanus capitis___________________16 1.6 Methods to control Pediculus humanus capitis_______________________________18 1.6.1 Historical aspects of louse control_______________________________________________________18 1.6.2 Resistance group 1 pediculicides: DDT and related compounds_____________________________19 1.6.3 Resistance group 11 pediculicides: The cyclodienes and cyclohexanes_______________________19 1.6.4 Resistance group 111 pediculicides: The organophosphates________________________________20 1.6.5 Resistance group IVpediculicides: The carbamates_______________________________________21 1.6.6 Resistance group Vpediculicides: The pyrethrins andpyrethroids__________________________22 1.6.7 Miscellaneous louse control methods____________________________________________________25 1.7 Shortcomings of head lice treatments ______________________________________26 1.7.1 Insecticide resistance__________________________________________________________________26 1.7.2 Toxicity towards humans _______________________________________________________________29 1.7.3 Incomplete ovicidal activity____________________________________________________________30 1.7.4 Product formulation___________________________________________________________________30 1.7.5 Treatment utilisation___________________________________________________________________31 1.8 Will more pediculicidal agents help to control head lice? _______________________31 1.9 The potential for natural products in pediculosis therapy ______________________32 1.10 Plant derived insecticides _______________________________________________32 1.11 Plant derived pediculicides ______________________________________________34 1.12 Essential oils and terpenoids _____________________________________________36 Evidence for the efficacy of essential oils and monoterpenoids as pediculicides ________________40 1.13 Rationale for investigating monoterpenoid mode of action ____________________41 1.14 GABAergic neurotransmission___________________________________________42 1.15 Structure and function of ionotropic GABA receptors ________________________43 1.16 Vertebrate GABA^ receptors: Molecular biology and subunit composition _______45 1.17 Insect GABA receptors: Molecular biology and subunit composition ____________46 1.18 Ionotropic GABA receptors: Allosteric proteins_____________________________48 1.19 Ionotropic GABA receptors: Pharmacology ________________________________51 Barbiturates ______________________________________________________________________________54 Steroids and propofol ______________________________________________________________________55 Hexachlorocyclohexanes __________________________________________________________________55 Benzodiazepines _________________________________________________________________________55 1.20 Natural Products provide potential and confirmed GABA receptor ligands ______57 1.21 Monoterpenoids and other volatile natural products affect the activity and ionic balance of nerve and muscle cells _____________________________________________60 Summary and direction ____________________________________________________________________63 Chapter 2 Monoterpenoids and essential oils as pediculicidal agents_____________64 2.1 Methods______________________________________________________________64 2.1.1 The Orlando strain of clothing louse as a model organism in for vitro pediculicide bioassays_ 64 2.1.2 The in vitro pediculicide bioassay________________________________________________________69 2.1.3 Observing physiological and behavioural effects of test substances_________________________70 2.1.4 Method for assaying effects of test substances on movement and behaviour of___________ lice 70 2.1.5 In vitro assessment o f ovicidal assay_____________________________________________________71 2.1.6 Method for assessing ovicidal activity ___________________________________________________71 2.1.7 A potential alternative pediculicide screen - The house dust m__________________________ ite 74 2.1.8 The house dust mite: Method of propagation_____________________________________________77 2.1.9 Testing for acaricidal activity___________________________________________________________77 2.1.10 The ‘mite chamber’ acaricidal bioassay_________________________________________________78 2.2 Results and discussion ___________________________________________________79 2.2.1 Monoterpenoids as pediculicidal agents__________________________________________________79 The relative pediculicidal activity of monoterpenoids ________________________________________79 The relationship between monoterpenoid structure and peduculicidal activity __________________80 Development of the pediculicidal test for use as a screen in pharmacognosy ____________________85 2.2.2
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