UNIVERSITY of CAPE TOWN for a Dissertation in Partial Fulfilment of the Requirements for the Degree Town Mphil (Biomedical Forensic Science)

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UNIVERSITY of CAPE TOWN for a Dissertation in Partial Fulfilment of the Requirements for the Degree Town Mphil (Biomedical Forensic Science) Complementary and Alternate Medicines: A Forensic Analysis of the Potential Adulteration of Over-The-Counter Anorectics and “Lifestyle” Medicines in South Africa By Sandra Lynne Catterson CTTSAN003 SUBMITTED TO THE UNIVERSITY OF CAPE TOWN For a dissertation in partial fulfilment of the requirements for the degree Town MPhil (Biomedical Forensic Science) Faculty of HealthCape Sciences UNIVERSITY ofOF CAPE TOWN 14th August 2017 Division of Forensic Medicine and Toxicology Department of Pathology University of CapeUniversity Town Supervisor: Bronwen Davies; Division of Forensic Medicine and Toxicology Co-supervisors: Professor Peter Smith; Division of Pharmacology Marie Kathrina Mendoza Aukloo; Division of Forensic Medicine and Toxicology i The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgementTown of the source. The thesis is to be used for private study or non- commercial research purposes only. Cape Published by the University ofof Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University DECLARATION I, Sandra Catterson, hereby declare that the work on which this dissertation is based is my original work (except where acknowledgements indicate otherwise) and that neither the whole work nor any part of it has been, is being, or is to be submitted for another degree in this or any other university. I empower the university to reproduce for the purpose of research either the whole or any portion of the content in any manner whatsoever. 14th August 2017 Signature removed i ABSTRACT Background: Complementary and Alternate Medicines (CAMs) in South Africa are not yet subjected to the same rigorous testing required for allopathic (prescription) medication, yet they are freely available as over-the-counter medicines. Past research has shown the presence of a banned drug, sibutramine in natural anorectics and a schedule 6 prescription drug, sildenafil, found in natural erectile dysfunction preparations. Methods: Initially, 26 exhibits (18 erectile dysfunction medicines and 8 anorectics) were screened for active pharmaceutical ingredients using high performance liquid chromatography tandem mass spectrometry. An AB SCIEX 3200 TRAP® linear ion-trap quadrupole mass spectrometer was used to detect and subsequently quantitate these active pharmaceutical ingredients using a targeted multiple reaction monitoring mode. Samples were extracted with 50% v/v methanol in water. A method for the quantitation of sildenafil was subsequently partially validated. The intra- and inter-assay precisions were evaluated and the linearity of the method was investigated in the range of 20 ng/mL to 2000 ng/mL. The method was then successfully applied to a random selection of CAMs. A random sample (n=61) of erectile dysfunction CAMs were selected for quantitation from two different clusters. Cluster 1 comprised of supermarkets and cluster 2 of pharmacies. Results: The validation method for sildenafil showed that the limit of detection was 1.09 ng/mL and the limit of quantitation was 20 ng/mL. The correlation co-efficient and bias were less than 20%. Initial screening of the 26 exhibits indicated that sildenafil was present in 12 of the 18 samples tested and sibutramine in 6 of the 8 anorectics. Of the later 61 exhibits tested, 43 tested positive for sildenafil. The mass of sildenafil per sample ranged from 1.09 ng/mL to 123.7 mg/sample. Conclusion: The lack of label content, regulation and legislation exposes the consumer to the risk of consuming an active pharmaceutical ingredient which may very likely have an adverse effect on their health. There is a need to raise public awareness to the potential dangers of unregulated CAMs, encourage doctors to become more aware of their patients’ consumption of CAMs and to motivate the Medicines Control Council to follow through with their deadlines for the regulation of CAMs. ii ACKNOWLEDGEMENTS My deepest appreciation goes to Professor Peter Smith, Alicia Evans, Bronwen Davies, Marie Kathrina Mendoza Aukloo and Taahira Goolam Hoosen for their hours of input. Their dedication is a tribute to their professionalism and passion. This dissertation would not have been possible without their contribution, vast knowledge and experience and willingness to help. My heartfelt gratitude goes out to them all. iii TABLE OF CONTENTS Declaration ...................................................................................................................... i Abstract ........................................................................................................................... ii Acknowledgements ......................................................................................................... iii Abbreviations ................................................................................................................ viii List of Tables ................................................................................................................... ix List of Figures .................................................................................................................. xi CHAPTER 1: INTRODUCTION AND LITERATURE REVIEW ................... 1 1.1 Introduction ........................................................................................................... 2 1.2 Complementary and Alternate Medicines (CAMs) ................................................ 3 1.2.1 Definition .......................................................................................................... 3 1.2.2 Popularity, Consumption and Impact on the Economy ..................................... 4 1.2.3 Reasons for Increase in Procurement and Consumption ................................. 4 1.2.4 Dangers of Consumption and Adulteration ....................................................... 5 1.2.5 Legislation in South Africa ................................................................................ 6 1.2.6 Product Labelling .............................................................................................. 7 1.2.7 Education and Research .................................................................................. 7 1.2.8 Role of the Medical Practitioner ........................................................................ 9 1.2.9 Forensic Toxicology .......................................................................................... 9 1.3 Erectile Dysfunction .......................................................................................... 10 1.3.1 Sildenafil ......................................................................................................... 10 1.3.1.1 Mechanism of Action ............................................................. 10 1.3.1.2 Dangers of Sildenafil Consumption ..................................... 11 1.3.2 Complementary and Alternate Medicines for Erectile Dysfunction ................. 13 1.3.3 Adulteration of Complementary and Alternate Medicines for Erectile Dysfunction ....................................................................................................................... 13 1.4 Anorectics: ........................................................................................................ 14 iv 1.4.1 Sibutramine .................................................................................................... 14 1.4.1.1 Mechanism of Action ……………………………………………14 1.4.1.2 Dangers of Sibutramine Consumption .................................. 15 1.5 Complementary and Alternate Medicines for Weight-Loss and their Adulteration ............................................................................................................................ 16 1.6 Analytical Methods ............................................................................................. 17 1.6.1 Previous and Current Analytical Methods ....................................................... 17 1.6.2 Gap in South Africa ........................................................................................ 19 1.7 Rationale for the Study ...................................................................................... 20 1.8 Aim and Objectives ........................................................................................... 21 CHAPTER 2: MATERIALS AND METHODS ...........................................23 2.1 Materials .................................................................................................................................. 24 2.1.1 Certified Reference Standards ...................................................................... 24 2.1.2 Exhibit Samples ........................................................................................................... 24 2.1.3 Sample Storage and Management .................................................................................. 26 2.2 Method of Preparation of Standards, Exhibit Samples and Controls ................................. 26 2.2.1 The Standards .............................................................................................. 26 2.2.2 The Internal Standard ....................................................................................................... 26 2.2.3 Preparation of Exhibit Samples for Screening ............................................... 27 2.2.4 High performance Liquid Chromatography Tandem Mass Spectrometry (HPLC- MS/MS) ..........................................................................................................................
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