ANDREW G. MTEWA trained in Medicinal Chemistry for his PhD under the WCAIR at the University of Dundee in Scotland and also at the Mbarara University of Science and Technology in Uganda. He teaches Chemistry at the Malawi University of Science and Technology in Malawi. CHUKWUEBUKA EGBUNA, MICCON, AMRSC, is a chartered chemist, a chemical analyst, and an academic researcher. He obtained his BSc and MSc degrees in Biochemistry at Chukwuemeka Odumegwu Ojukwu University, Anambra State, Nigeria. He is a PhD fellow in Nutritional Biochemistry/Toxicology with the World Bank Africa Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port-Harcourt, Rivers State, Nigeria. DR. G. M. NARASIMHA RAO is an Associate Professor of Botany at Andhra University, where he also obtained his MSc in Botany and M.Phil in Marine Algal Ecology.

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• List of Contributors xviiList of Figures xxiList of Tables xxiiiPreface xxvEditors xxvii1 Historical Use of Toxic Plants 1Godwin Anywar1.1 Introduction to Toxic Plants 11.2 Poisonous Plants as Sources of Traditional and Modern Medicines 21.3 Toxic Plants and Justice 41.3.1 Toxic Plants in Capital Punishment 41.3.2 Trial by Ordeal 41.4 Toxic Plants in Poisoned Weapons 61.4.1 Arrow Poisons 61.5 Plant Fishing Poisons/Piscicides/Ichthyotoxins 61.6 Poisonous Plants as Food 71.7 Poisonous Plants as Biopesticides 91.8 Toxic Psychoactive Plants for Recreational and Religious Purposes 91.9 Poisonous Plants in Warfare and Bioterrorism 101.10 Poisonous Plants as Carcinogens and Teratogens 111.11 Conclusion 12References 122 Classification of Phytotoxins and their Mechanisms of Action 19Andrew G. Mtewa, Chukwuebuka Egbuna, Kennedy J. Ngwira, Fanuel Lampiao, Umang Shah, and Thokozani Kachulu Mtewa2.1 Introduction 202.1.1 Endophytic Phytotoxins 202.1.2 Secondary Metabolites 212.2 Possible Categorization 212.2.1 Biological Characteristics 212.2.2 Chemical Characteristics 222.3 Currently Available Classification Tools 242.4 Role of Phytotoxin Classification 252.4.1 Drug Discovery 252.4.2 Environmental Monitoring 252.4.3 Phytotoxins, Aquatic Life, and Water Quality 262.4.4 Air Contamination 262.4.5 Food Contamination 262.4.6 Security and Safety Services 272.4.7 Agricultural 272.5 Brief Mechanisms of Action 272.6 Conclusion 28References 283 Poisonous Plants as Sources of Anticancer and Other Drugs 31Félicien Mushagalusa Kasali, Andrew G. Mtewa, and Gaétan Tabakam3.1 Introduction 313.2 Poisonous Plants in the Treatment of Cancer and Other Diseases 323.3 Poisonous Plant-Based Anticancer Drugs that are on the Market 333.4 Poisonous Plant-Based Drugs Against Other Diseases that are on the Market 333.5 Conclusion 33References 754 Drugs in Clinical Practice from Toxic Plants and Phytochemicals 79Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo4.1 Introduction 804.2 Drugs in Clinical Practice from Toxic Plants 814.2.1 Curare 814.2.2 Drugs Acting on the Central Nervous System 814.2.2.1 Morphine 814.2.2.2 Cocaine 824.2.2.3 Ergot Alkaloids 834.2.3 Atropine, Scopolamine, and Hyoscyamine 844.2.4 Physostigmine and Other Acetylcholinesterase Inhibitors 854.2.5 Antitumor Agents 854.2.5.1 Podophyllotoxin and Etoposide 854.2.5.2 Taxanes 864.2.5.3 Vincristine and Vinblastine 874.2.6 Other Drugs 884.2.6.1 Cardiac Glycosides 884.2.6.2 Colchicine 894.2.6.3 Coumarins 894.2.6.4 Nicotine and the Neonicotinoids 90References 905 Toxicology and Health Benefits of Plant Alkaloids 95Ibrahim Chikowe, Andrew G. Mtewa, and Duncan C. Sesaazi5.1 Introduction 955.2 Pharmacological Properties of Alkaloids 975.3 Toxicological Properties of Alkaloids 1005.4 Acute and Chronic Toxicities 1005.4.1 Genotoxicity and Tumorigenicity 1015.4.2 Lung Toxicity, Neurotoxicity, and Teratogenicity 1025.5 Factors that Influence the Toxicological Profile of Alkaloids 1025.6 Conclusion 103References 1036 Chemical and Pharmacological Mechanisms of Plant-Derived Neurotoxins 109Amanjot Annu, Reuben S. Maghembe, Andrew G. Mtewa, and G.M. Narasimha Rao6.1 Introduction 1106.2 Nerve Agents 1106.3 Chemical Mechanisms of Neurotoxicity Induced by Organophosphate Nerve Agents 1116.4 Mustards 1126.4.1 Effect of HD on Skin 1136.4.2 Effect of HD on Other Organs 1136.4.3 The Activation of HD 1146.4.4 Mechanism of Action 1156.5 Plant Natural Neurotoxins 1166.6 Plant Glycosides 1186.7 Conclusion 119References 1197 Phytosedatives for Drug Discovery 123Shahira M. Ezzat, Ahmed Zayed, and Mohamed A. Salem7.1 Introduction 1237.2 Treatment of Neuropsychological Disorders: The Current Scenario 1247.3 Phytosedatives: Desirable Alternatives to Synthesized Drugs 1257.4 Different Classes of Phytosedatives 1257.4.1 Flavonoids 1267.4.2 Alkaloids 1287.4.3 Essential Oils 1297.4.4 Other Classes of Phytosedatives 1307.5 Plants with Reported Sedative Actions 1307.6 Conclusion 152References 1528 Mushroom Species and Classification: Bioactives in Poisonous and Edible Mushrooms 163Sadia Zafar, Farhat Jabeen, Muhammad Akram, Zarfishan Riaz, and Naveed Munir8.1 Introduction 1638.2 Classification of Mushrooms 1648.2.1 Edible Mushrooms 1658.2.2 Non-Edible Mushrooms 1658.3 Bioactive Agents in Mushroom Species 1658.4 Bioactive Agents in Non-Edible Mushroom Species 1668.4.1 Polysaccharides 1668.4.2 Glucans 1668.4.3 Polysaccharide–Protein Complexes 1748.4.4 Terpenes 1748.4.5 Phenolic Compounds 1758.4.6 Peptides and Proteins 1768.5 Other Bioactive Compounds of Mushroom Species 1768.6 Conclusion 176References 1779 Toxicity Protocols for Natural Products in the Drug Development Process 189Tamirat Bekele Beressa, Amanjot Annu, and Andrew G. Mtewa9.1 Introduction 1909.2 In Vitro Toxicity Testing for Natural Products 1909.2.1 Cell Culture Method for Toxicity Testing 1919.2.2 Cell Culture for Acute Toxicology Testing 1929.3 Methods Used for In Vitro Toxicity Studies 1939.3.1 MTT Assay 1939.3.2 Neutral Red Uptake Assay 1939.3.3 Lactate Dehydrogenase Assay 1949.4 In Vitro Models for Liver Toxicity 1949.5 In Vitro Models for Nephrotoxicity Studies 1949.6 In Vitro Model for Dermal Toxicity Testing 1959.7 Mutagenicity Testing In Vitro 1959.7.1 Bacterial Cell System 1969.8 Reproductive and Teratogenicity Studies In Vitro 1969.8.1 H295R Steroidogenesis Assay 1979.8.2 Embryonic Stem Cell Test 1979.8.3 Whole Rat Embryo Cultures 1979.9 In Vivo Toxicity Testing of Natural Products 1989.9.1 Acute Toxicity Testing 1989.9.2 Subchronic Toxicity Testing 2009.9.3 Chronic Toxicity Testing 2019.9.4 Dermal and Ocular Toxicity 2039.9.5 Toxicity Testing for Fertility and Reproduction 2049.9.6 Combined Repeated Dose Toxicity Study with Reproduction/Developmental Testing 2069.9.7 In Vivo Carcinogenicity Testing 2079.10 Conclusion 208References 20810 Quality Control for the Safety of Natural Products 213Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo10.1 Introduction 21410.2 Quality Assurance of Herbal Products 21510.3 Methods of Quality Control for Herbal Products 21610.3.1 DNA-Based Technologies 21610.3.2 Good Practice Guidelines 21610.3.3 Chemoprofiling 21710.3.4 Toxicology 21710.3.5 Monographs and Pharmacopeias 21710.3.6 Preclinical Evidence of Safety and Efficacy 21710.3.7 Systems Biology 21810.3.8 Animal Experimentation 21810.3.9 Clinical Evidence of Safety and Efficacy 21810.4 WHO Guidelines for Quality Standardization of Herbal Formulations 21910.4.1 Quality Control of Crude Material 21910.4.2 Identity of Plant Material 21910.4.3 Safety Assessment and Documentation 22010.5 Concept of Validation in Herbal Products 22010.6 Challenges Related to Quality Control and Monitoring the Safety of Herbal Products 221References 22211 Secondary Metabolites and Toxins of Microbial Origin for the Treatment of Diseases 225Dharmandra Baria, Umang Shah, Chukwuebuka Egbuna, and Andrew G. Mtewa11.1 Introduction 22611.2 Antimicrobial Agents from Microbial Sources 22711.3 Antifungal Agents from Microbial Sources 22911.4 Anticancer Agents from Microbial Sources 23011.5 Hypocholesterolemic Agents from Microbial Sources 23511.6 Immunosuppressants from Microbial Sources 23711.7 Enzyme Inhibitors from Microbial Sources 23911.8 Antiparasitic Agents from Microbial Sources 24011.9 Recent Advances in Drug Discovery from Microbial Sources 241References 24312 Development of Phyto-Antidotes Against Adverse Chemical Agents 249Roman Lysiuk, Petro Oliynyk, Halyna Antonyak, and Dmytro Voronenko12.1 Introduction 24912.2 Heavy Metals and their Effects on the Body 25112.3 Detoxification Properties of Biologically Active Substances of Plant-Based Foods 25312.3.1 Pectins 25312.3.2 Phytin 25412.3.3 Betalains 25512.3.4 Phytochelatins 25612.3.5 Ellagic Acid 25712.3.6 Miscellaneous 25812.4 Current State of Clinical Application of Phyto-Antidotes 25912.5 Further Prospects in the Search for Promising Phyto-Antidotes 26012.6 Conclusions 261References 26213 Nanoformulated Herbal Drug Delivery as Efficient Antidotes Against Systemic Poisons 269Prabir Kumar Kulabhusan, Shailaja Agrawal, Jaison Jeevanandam, and Michael K. Danquah13.1 Introduction 26913.2 Herbal Phytochemicals as Antidotes for Systemic Poisons 27113.2.1 Herbal Phytochemicals as Antidotes for Heavy Metal Poisoning 27213.2.2 Herbal Phytochemicals as Antidotes for Snake Venom Poisoning 27513.3 Nanoformulated Herbal Phytochemicals as Antidotes 27613.3.1 Inorganic Nanoparticles 27813.3.2 Micelles and Liposomes 27913.3.3 Polymeric Nanoparticles 28113.4 Mechanism of Nanoformulated Herbal Phytochemicals against Systemic Poisoning 28113.5 Future Perspectives 28313.6 Conclusion 285References 28514 Phytochemical-Based Nanoparticles as Foes and Friends 295Charles Oluwaseun Adetunji, Oluwaseyi Olaniyan, Juliana Bunmi Adetunji, and Itoan Roli14.1 Introduction 29514.2 Phytochemicals Used in the Synthesis of Nanoparticles 29714.3 Anti-Inflammatory Effects of Nanoparticles 29714.4 Wound-Healing Effects of Nanoparticles 29914.5 Antiparasitic, Antifungal, and Antibacterial Activities of Nanoparticles 30014.6 Neuroprotective Effects of Nanoparticles 30414.7 Cardioprotective Effects of Nanoparticles 30714.8 Anticancer Effects of Nanoparticles 30814.9 Advantages of Nanoparticles 31114.10 Disadvantages of Nanoparticles 31114.11 Conclusion and Future Directions 312References 31315 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 323Mohamed A. Salem, Ahmed Zayed, and Shahira M. Ezzat15.1 Introduction 32415.2 Traditional Use of Medicinal Plants 32515.3 Natural Products: Safety and Toxicity 32815.3.1 Safety 32815.3.2 Toxicity and Natural Killers 32915.4 Biological Systems in Phytochemical Poisoning and Remediation 33015.5 Metabolomics: An Important Functional Genomics Tool 33215.5.1 Essential Components of a Metabolomics Workflow 33315.5.2 Sample Preparation 33415.5.3 Analytical Methods in Metabolomics 33415.5.4 Metabolite Identification 33515.5.5 Data Processing and Analysis 33515.5.6 Pathway Analysis 33515.6 Assessment of Toxicity of Herbal Medicines Using Metabolomics 33515.7 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 33615.7.1 Hepatotoxicity of Triptolide 33715.7.2 Hepatotoxicity of Noscapine 33715.8 Conclusion 338References 33816 Methods for the Detection and Identification of Phytotoxins 349Senyo Botchie and Andrew G. Mtewa16.1 Introduction 35016.2 Phytotoxins 35016.2.1 Importance of Toxins 35116.3 Methods Generally Used for Phytotoxin Detection 35216.3.1 Biological Method Review of Detecting Phytotoxins 35216.3.2 Chemical and Microbiological Reagents 35216.4 Protease Inhibition Detection Protocol 35416.4.1 Exposure of the Protease Detection Plate to a Protease Inhibitor or Bacterial Growth (Step 1) 35416.4.2 Exposure to a Protease-Containing Solution (Step 2) 35516.4.3 Detecting Zones of Protease Inhibition (Step 3) 35516.5 Isolation of Phytotoxins from Microorganisms 35516.5.1 Detection of Phytotoxins Isolated from Fungi 35616.5.2 Purification of the Extracted Phytotoxins 35616.6 Conclusion 356References 35717 Categorization, Management, and Regulation of Potentially Weaponizable Toxic Plants 359Muhammad Akram and Rabia Zahid17.1 Introduction 35917.2 Management of Weaponized Natural Food Agents 36017.3 Techniques Used for Extraction, Segregation, and Decontamination of Phytochemicals 36117.3.1 Solvent-Based Extraction of Phenolic Compounds 36117.3.2 Microwave-Associated Extraction 36117.3.3 Ultrasound-Assisted Extraction 36217.4 Techniques for Identification of Bioactive Compounds 36217.4.1 Ultraviolet–Visible Spectroscopy 36217.4.2 Infrared Spectroscopy 36317.4.3 Nuclear Magnetic Resonance Spectroscopy 36317.4.4 Mass Spectrometry 36317.5 Types of Natural Phytotoxins 36317.5.1 Aquatic Biotoxins 36317.5.2 Glycosides 36417.5.3 Other Common Phytotoxins 36417.6 Conclusion 365References 36518 In Silico Modeling as a Tool to Predict and Characterize Plant Toxicity 367Charles Oluwaseun Adetunji, William Peter Mitembo, Chukwuebuka Egbuna, and G.M. Narasimha Rao18.1 Introduction 36818.2 Components of In Silico Toxicity Methods 36818.2.1 Databases 36918.2.2 Molecular Descriptors 36918.2.3 Toxicity Models and Modeling Software 36918.2.4 Simulation Packages 36918.3 Modeling Methods 37118.4 Structural Alerts/Rule Based 37118.5 Statistical Structure-Based Activity Relationship Models 37318.5.1 Read-Across 37318.6 Conclusion 374References 375Index 379

ANDREW G. MTEWA trained in Medicinal Chemistry for his PhD under the WCAIR at the University of Dundee in Scotland and also at the Mbarara University of Science and Technology in Uganda. He teaches Chemistry at the Malawi University of Science and Technology in Malawi. CHUKWUEBUKA EGBUNA, MICCON, AMRSC, is a chartered chemist, a chemical analyst, and an academic researcher. He obtained his BSc and MSc degrees in Biochemistry at Chukwuemeka Odumegwu Ojukwu University, Anambra State, Nigeria. He is a PhD fellow in Nutritional Biochemistry/Toxicology with the World Bank Africa Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port-Harcourt, Rivers State, Nigeria. DR. G. M. NARASIMHA RAO is an Associate Professor of Botany at Andhra University, where he also obtained his MSc in Botany and M.Phil in Marine Algal Ecology.

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• List of Contributors xviiList of Figures xxiList of Tables xxiiiPreface xxvEditors xxvii1 Historical Use of Toxic Plants 1Godwin Anywar1.1 Introduction to Toxic Plants 11.2 Poisonous Plants as Sources of Traditional and Modern Medicines 21.3 Toxic Plants and Justice 41.3.1 Toxic Plants in Capital Punishment 41.3.2 Trial by Ordeal 41.4 Toxic Plants in Poisoned Weapons 61.4.1 Arrow Poisons 61.5 Plant Fishing Poisons/Piscicides/Ichthyotoxins 61.6 Poisonous Plants as Food 71.7 Poisonous Plants as Biopesticides 91.8 Toxic Psychoactive Plants for Recreational and Religious Purposes 91.9 Poisonous Plants in Warfare and Bioterrorism 101.10 Poisonous Plants as Carcinogens and Teratogens 111.11 Conclusion 12References 122 Classification of Phytotoxins and their Mechanisms of Action 19Andrew G. Mtewa, Chukwuebuka Egbuna, Kennedy J. Ngwira, Fanuel Lampiao, Umang Shah, and Thokozani Kachulu Mtewa2.1 Introduction 202.1.1 Endophytic Phytotoxins 202.1.2 Secondary Metabolites 212.2 Possible Categorization 212.2.1 Biological Characteristics 212.2.2 Chemical Characteristics 222.3 Currently Available Classification Tools 242.4 Role of Phytotoxin Classification 252.4.1 Drug Discovery 252.4.2 Environmental Monitoring 252.4.3 Phytotoxins, Aquatic Life, and Water Quality 262.4.4 Air Contamination 262.4.5 Food Contamination 262.4.6 Security and Safety Services 272.4.7 Agricultural 272.5 Brief Mechanisms of Action 272.6 Conclusion 28References 283 Poisonous Plants as Sources of Anticancer and Other Drugs 31Félicien Mushagalusa Kasali, Andrew G. Mtewa, and Gaétan Tabakam3.1 Introduction 313.2 Poisonous Plants in the Treatment of Cancer and Other Diseases 323.3 Poisonous Plant-Based Anticancer Drugs that are on the Market 333.4 Poisonous Plant-Based Drugs Against Other Diseases that are on the Market 333.5 Conclusion 33References 754 Drugs in Clinical Practice from Toxic Plants and Phytochemicals 79Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo4.1 Introduction 804.2 Drugs in Clinical Practice from Toxic Plants 814.2.1 Curare 814.2.2 Drugs Acting on the Central Nervous System 814.2.2.1 Morphine 814.2.2.2 Cocaine 824.2.2.3 Ergot Alkaloids 834.2.3 Atropine, Scopolamine, and Hyoscyamine 844.2.4 Physostigmine and Other Acetylcholinesterase Inhibitors 854.2.5 Antitumor Agents 854.2.5.1 Podophyllotoxin and Etoposide 854.2.5.2 Taxanes 864.2.5.3 Vincristine and Vinblastine 874.2.6 Other Drugs 884.2.6.1 Cardiac Glycosides 884.2.6.2 Colchicine 894.2.6.3 Coumarins 894.2.6.4 Nicotine and the Neonicotinoids 90References 905 Toxicology and Health Benefits of Plant Alkaloids 95Ibrahim Chikowe, Andrew G. Mtewa, and Duncan C. Sesaazi5.1 Introduction 955.2 Pharmacological Properties of Alkaloids 975.3 Toxicological Properties of Alkaloids 1005.4 Acute and Chronic Toxicities 1005.4.1 Genotoxicity and Tumorigenicity 1015.4.2 Lung Toxicity, Neurotoxicity, and Teratogenicity 1025.5 Factors that Influence the Toxicological Profile of Alkaloids 1025.6 Conclusion 103References 1036 Chemical and Pharmacological Mechanisms of Plant-Derived Neurotoxins 109Amanjot Annu, Reuben S. Maghembe, Andrew G. Mtewa, and G.M. Narasimha Rao6.1 Introduction 1106.2 Nerve Agents 1106.3 Chemical Mechanisms of Neurotoxicity Induced by Organophosphate Nerve Agents 1116.4 Mustards 1126.4.1 Effect of HD on Skin 1136.4.2 Effect of HD on Other Organs 1136.4.3 The Activation of HD 1146.4.4 Mechanism of Action 1156.5 Plant Natural Neurotoxins 1166.6 Plant Glycosides 1186.7 Conclusion 119References 1197 Phytosedatives for Drug Discovery 123Shahira M. Ezzat, Ahmed Zayed, and Mohamed A. Salem7.1 Introduction 1237.2 Treatment of Neuropsychological Disorders: The Current Scenario 1247.3 Phytosedatives: Desirable Alternatives to Synthesized Drugs 1257.4 Different Classes of Phytosedatives 1257.4.1 Flavonoids 1267.4.2 Alkaloids 1287.4.3 Essential Oils 1297.4.4 Other Classes of Phytosedatives 1307.5 Plants with Reported Sedative Actions 1307.6 Conclusion 152References 1528 Mushroom Species and Classification: Bioactives in Poisonous and Edible Mushrooms 163Sadia Zafar, Farhat Jabeen, Muhammad Akram, Zarfishan Riaz, and Naveed Munir8.1 Introduction 1638.2 Classification of Mushrooms 1648.2.1 Edible Mushrooms 1658.2.2 Non-Edible Mushrooms 1658.3 Bioactive Agents in Mushroom Species 1658.4 Bioactive Agents in Non-Edible Mushroom Species 1668.4.1 Polysaccharides 1668.4.2 Glucans 1668.4.3 Polysaccharide–Protein Complexes 1748.4.4 Terpenes 1748.4.5 Phenolic Compounds 1758.4.6 Peptides and Proteins 1768.5 Other Bioactive Compounds of Mushroom Species 1768.6 Conclusion 176References 1779 Toxicity Protocols for Natural Products in the Drug Development Process 189Tamirat Bekele Beressa, Amanjot Annu, and Andrew G. Mtewa9.1 Introduction 1909.2 In Vitro Toxicity Testing for Natural Products 1909.2.1 Cell Culture Method for Toxicity Testing 1919.2.2 Cell Culture for Acute Toxicology Testing 1929.3 Methods Used for In Vitro Toxicity Studies 1939.3.1 MTT Assay 1939.3.2 Neutral Red Uptake Assay 1939.3.3 Lactate Dehydrogenase Assay 1949.4 In Vitro Models for Liver Toxicity 1949.5 In Vitro Models for Nephrotoxicity Studies 1949.6 In Vitro Model for Dermal Toxicity Testing 1959.7 Mutagenicity Testing In Vitro 1959.7.1 Bacterial Cell System 1969.8 Reproductive and Teratogenicity Studies In Vitro 1969.8.1 H295R Steroidogenesis Assay 1979.8.2 Embryonic Stem Cell Test 1979.8.3 Whole Rat Embryo Cultures 1979.9 In Vivo Toxicity Testing of Natural Products 1989.9.1 Acute Toxicity Testing 1989.9.2 Subchronic Toxicity Testing 2009.9.3 Chronic Toxicity Testing 2019.9.4 Dermal and Ocular Toxicity 2039.9.5 Toxicity Testing for Fertility and Reproduction 2049.9.6 Combined Repeated Dose Toxicity Study with Reproduction/Developmental Testing 2069.9.7 In Vivo Carcinogenicity Testing 2079.10 Conclusion 208References 20810 Quality Control for the Safety of Natural Products 213Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo10.1 Introduction 21410.2 Quality Assurance of Herbal Products 21510.3 Methods of Quality Control for Herbal Products 21610.3.1 DNA-Based Technologies 21610.3.2 Good Practice Guidelines 21610.3.3 Chemoprofiling 21710.3.4 Toxicology 21710.3.5 Monographs and Pharmacopeias 21710.3.6 Preclinical Evidence of Safety and Efficacy 21710.3.7 Systems Biology 21810.3.8 Animal Experimentation 21810.3.9 Clinical Evidence of Safety and Efficacy 21810.4 WHO Guidelines for Quality Standardization of Herbal Formulations 21910.4.1 Quality Control of Crude Material 21910.4.2 Identity of Plant Material 21910.4.3 Safety Assessment and Documentation 22010.5 Concept of Validation in Herbal Products 22010.6 Challenges Related to Quality Control and Monitoring the Safety of Herbal Products 221References 22211 Secondary Metabolites and Toxins of Microbial Origin for the Treatment of Diseases 225Dharmandra Baria, Umang Shah, Chukwuebuka Egbuna, and Andrew G. Mtewa11.1 Introduction 22611.2 Antimicrobial Agents from Microbial Sources 22711.3 Antifungal Agents from Microbial Sources 22911.4 Anticancer Agents from Microbial Sources 23011.5 Hypocholesterolemic Agents from Microbial Sources 23511.6 Immunosuppressants from Microbial Sources 23711.7 Enzyme Inhibitors from Microbial Sources 23911.8 Antiparasitic Agents from Microbial Sources 24011.9 Recent Advances in Drug Discovery from Microbial Sources 241References 24312 Development of Phyto-Antidotes Against Adverse Chemical Agents 249Roman Lysiuk, Petro Oliynyk, Halyna Antonyak, and Dmytro Voronenko12.1 Introduction 24912.2 Heavy Metals and their Effects on the Body 25112.3 Detoxification Properties of Biologically Active Substances of Plant-Based Foods 25312.3.1 Pectins 25312.3.2 Phytin 25412.3.3 Betalains 25512.3.4 Phytochelatins 25612.3.5 Ellagic Acid 25712.3.6 Miscellaneous 25812.4 Current State of Clinical Application of Phyto-Antidotes 25912.5 Further Prospects in the Search for Promising Phyto-Antidotes 26012.6 Conclusions 261References 26213 Nanoformulated Herbal Drug Delivery as Efficient Antidotes Against Systemic Poisons 269Prabir Kumar Kulabhusan, Shailaja Agrawal, Jaison Jeevanandam, and Michael K. Danquah13.1 Introduction 26913.2 Herbal Phytochemicals as Antidotes for Systemic Poisons 27113.2.1 Herbal Phytochemicals as Antidotes for Heavy Metal Poisoning 27213.2.2 Herbal Phytochemicals as Antidotes for Snake Venom Poisoning 27513.3 Nanoformulated Herbal Phytochemicals as Antidotes 27613.3.1 Inorganic Nanoparticles 27813.3.2 Micelles and Liposomes 27913.3.3 Polymeric Nanoparticles 28113.4 Mechanism of Nanoformulated Herbal Phytochemicals against Systemic Poisoning 28113.5 Future Perspectives 28313.6 Conclusion 285References 28514 Phytochemical-Based Nanoparticles as Foes and Friends 295Charles Oluwaseun Adetunji, Oluwaseyi Olaniyan, Juliana Bunmi Adetunji, and Itoan Roli14.1 Introduction 29514.2 Phytochemicals Used in the Synthesis of Nanoparticles 29714.3 Anti-Inflammatory Effects of Nanoparticles 29714.4 Wound-Healing Effects of Nanoparticles 29914.5 Antiparasitic, Antifungal, and Antibacterial Activities of Nanoparticles 30014.6 Neuroprotective Effects of Nanoparticles 30414.7 Cardioprotective Effects of Nanoparticles 30714.8 Anticancer Effects of Nanoparticles 30814.9 Advantages of Nanoparticles 31114.10 Disadvantages of Nanoparticles 31114.11 Conclusion and Future Directions 312References 31315 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 323Mohamed A. Salem, Ahmed Zayed, and Shahira M. Ezzat15.1 Introduction 32415.2 Traditional Use of Medicinal Plants 32515.3 Natural Products: Safety and Toxicity 32815.3.1 Safety 32815.3.2 Toxicity and Natural Killers 32915.4 Biological Systems in Phytochemical Poisoning and Remediation 33015.5 Metabolomics: An Important Functional Genomics Tool 33215.5.1 Essential Components of a Metabolomics Workflow 33315.5.2 Sample Preparation 33415.5.3 Analytical Methods in Metabolomics 33415.5.4 Metabolite Identification 33515.5.5 Data Processing and Analysis 33515.5.6 Pathway Analysis 33515.6 Assessment of Toxicity of Herbal Medicines Using Metabolomics 33515.7 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 33615.7.1 Hepatotoxicity of Triptolide 33715.7.2 Hepatotoxicity of Noscapine 33715.8 Conclusion 338References 33816 Methods for the Detection and Identification of Phytotoxins 349Senyo Botchie and Andrew G. Mtewa16.1 Introduction 35016.2 Phytotoxins 35016.2.1 Importance of Toxins 35116.3 Methods Generally Used for Phytotoxin Detection 35216.3.1 Biological Method Review of Detecting Phytotoxins 35216.3.2 Chemical and Microbiological Reagents 35216.4 Protease Inhibition Detection Protocol 35416.4.1 Exposure of the Protease Detection Plate to a Protease Inhibitor or Bacterial Growth (Step 1) 35416.4.2 Exposure to a Protease-Containing Solution (Step 2) 35516.4.3 Detecting Zones of Protease Inhibition (Step 3) 35516.5 Isolation of Phytotoxins from Microorganisms 35516.5.1 Detection of Phytotoxins Isolated from Fungi 35616.5.2 Purification of the Extracted Phytotoxins 35616.6 Conclusion 356References 35717 Categorization, Management, and Regulation of Potentially Weaponizable Toxic Plants 359Muhammad Akram and Rabia Zahid17.1 Introduction 35917.2 Management of Weaponized Natural Food Agents 36017.3 Techniques Used for Extraction, Segregation, and Decontamination of Phytochemicals 36117.3.1 Solvent-Based Extraction of Phenolic Compounds 36117.3.2 Microwave-Associated Extraction 36117.3.3 Ultrasound-Assisted Extraction 36217.4 Techniques for Identification of Bioactive Compounds 36217.4.1 Ultraviolet–Visible Spectroscopy 36217.4.2 Infrared Spectroscopy 36317.4.3 Nuclear Magnetic Resonance Spectroscopy 36317.4.4 Mass Spectrometry 36317.5 Types of Natural Phytotoxins 36317.5.1 Aquatic Biotoxins 36317.5.2 Glycosides 36417.5.3 Other Common Phytotoxins 36417.6 Conclusion 365References 36518 In Silico Modeling as a Tool to Predict and Characterize Plant Toxicity 367Charles Oluwaseun Adetunji, William Peter Mitembo, Chukwuebuka Egbuna, and G.M. Narasimha Rao18.1 Introduction 36818.2 Components of In Silico Toxicity Methods 36818.2.1 Databases 36918.2.2 Molecular Descriptors 36918.2.3 Toxicity Models and Modeling Software 36918.2.4 Simulation Packages 36918.3 Modeling Methods 37118.4 Structural Alerts/Rule Based 37118.5 Statistical Structure-Based Activity Relationship Models 37318.5.1 Read-Across 37318.6 Conclusion 374References 375Index 379

ANDREW G. MTEWA trained in Medicinal Chemistry for his PhD under the WCAIR at the University of Dundee in Scotland and also at the Mbarara University of Science and Technology in Uganda. He teaches Chemistry at the Malawi University of Science and Technology in Malawi. CHUKWUEBUKA EGBUNA, MICCON, AMRSC, is a chartered chemist, a chemical analyst, and an academic researcher. He obtained his BSc and MSc degrees in Biochemistry at Chukwuemeka Odumegwu Ojukwu University, Anambra State, Nigeria. He is a PhD fellow in Nutritional Biochemistry/Toxicology with the World Bank Africa Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port-Harcourt, Rivers State, Nigeria. DR. G. M. NARASIMHA RAO is an Associate Professor of Botany at Andhra University, where he also obtained his MSc in Botany and M.Phil in Marine Algal Ecology.

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• List of Contributors xviiList of Figures xxiList of Tables xxiiiPreface xxvEditors xxvii1 Historical Use of Toxic Plants 1Godwin Anywar1.1 Introduction to Toxic Plants 11.2 Poisonous Plants as Sources of Traditional and Modern Medicines 21.3 Toxic Plants and Justice 41.3.1 Toxic Plants in Capital Punishment 41.3.2 Trial by Ordeal 41.4 Toxic Plants in Poisoned Weapons 61.4.1 Arrow Poisons 61.5 Plant Fishing Poisons/Piscicides/Ichthyotoxins 61.6 Poisonous Plants as Food 71.7 Poisonous Plants as Biopesticides 91.8 Toxic Psychoactive Plants for Recreational and Religious Purposes 91.9 Poisonous Plants in Warfare and Bioterrorism 101.10 Poisonous Plants as Carcinogens and Teratogens 111.11 Conclusion 12References 122 Classification of Phytotoxins and their Mechanisms of Action 19Andrew G. Mtewa, Chukwuebuka Egbuna, Kennedy J. Ngwira, Fanuel Lampiao, Umang Shah, and Thokozani Kachulu Mtewa2.1 Introduction 202.1.1 Endophytic Phytotoxins 202.1.2 Secondary Metabolites 212.2 Possible Categorization 212.2.1 Biological Characteristics 212.2.2 Chemical Characteristics 222.3 Currently Available Classification Tools 242.4 Role of Phytotoxin Classification 252.4.1 Drug Discovery 252.4.2 Environmental Monitoring 252.4.3 Phytotoxins, Aquatic Life, and Water Quality 262.4.4 Air Contamination 262.4.5 Food Contamination 262.4.6 Security and Safety Services 272.4.7 Agricultural 272.5 Brief Mechanisms of Action 272.6 Conclusion 28References 283 Poisonous Plants as Sources of Anticancer and Other Drugs 31Félicien Mushagalusa Kasali, Andrew G. Mtewa, and Gaétan Tabakam3.1 Introduction 313.2 Poisonous Plants in the Treatment of Cancer and Other Diseases 323.3 Poisonous Plant-Based Anticancer Drugs that are on the Market 333.4 Poisonous Plant-Based Drugs Against Other Diseases that are on the Market 333.5 Conclusion 33References 754 Drugs in Clinical Practice from Toxic Plants and Phytochemicals 79Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo4.1 Introduction 804.2 Drugs in Clinical Practice from Toxic Plants 814.2.1 Curare 814.2.2 Drugs Acting on the Central Nervous System 814.2.2.1 Morphine 814.2.2.2 Cocaine 824.2.2.3 Ergot Alkaloids 834.2.3 Atropine, Scopolamine, and Hyoscyamine 844.2.4 Physostigmine and Other Acetylcholinesterase Inhibitors 854.2.5 Antitumor Agents 854.2.5.1 Podophyllotoxin and Etoposide 854.2.5.2 Taxanes 864.2.5.3 Vincristine and Vinblastine 874.2.6 Other Drugs 884.2.6.1 Cardiac Glycosides 884.2.6.2 Colchicine 894.2.6.3 Coumarins 894.2.6.4 Nicotine and the Neonicotinoids 90References 905 Toxicology and Health Benefits of Plant Alkaloids 95Ibrahim Chikowe, Andrew G. Mtewa, and Duncan C. Sesaazi5.1 Introduction 955.2 Pharmacological Properties of Alkaloids 975.3 Toxicological Properties of Alkaloids 1005.4 Acute and Chronic Toxicities 1005.4.1 Genotoxicity and Tumorigenicity 1015.4.2 Lung Toxicity, Neurotoxicity, and Teratogenicity 1025.5 Factors that Influence the Toxicological Profile of Alkaloids 1025.6 Conclusion 103References 1036 Chemical and Pharmacological Mechanisms of Plant-Derived Neurotoxins 109Amanjot Annu, Reuben S. Maghembe, Andrew G. Mtewa, and G.M. Narasimha Rao6.1 Introduction 1106.2 Nerve Agents 1106.3 Chemical Mechanisms of Neurotoxicity Induced by Organophosphate Nerve Agents 1116.4 Mustards 1126.4.1 Effect of HD on Skin 1136.4.2 Effect of HD on Other Organs 1136.4.3 The Activation of HD 1146.4.4 Mechanism of Action 1156.5 Plant Natural Neurotoxins 1166.6 Plant Glycosides 1186.7 Conclusion 119References 1197 Phytosedatives for Drug Discovery 123Shahira M. Ezzat, Ahmed Zayed, and Mohamed A. Salem7.1 Introduction 1237.2 Treatment of Neuropsychological Disorders: The Current Scenario 1247.3 Phytosedatives: Desirable Alternatives to Synthesized Drugs 1257.4 Different Classes of Phytosedatives 1257.4.1 Flavonoids 1267.4.2 Alkaloids 1287.4.3 Essential Oils 1297.4.4 Other Classes of Phytosedatives 1307.5 Plants with Reported Sedative Actions 1307.6 Conclusion 152References 1528 Mushroom Species and Classification: Bioactives in Poisonous and Edible Mushrooms 163Sadia Zafar, Farhat Jabeen, Muhammad Akram, Zarfishan Riaz, and Naveed Munir8.1 Introduction 1638.2 Classification of Mushrooms 1648.2.1 Edible Mushrooms 1658.2.2 Non-Edible Mushrooms 1658.3 Bioactive Agents in Mushroom Species 1658.4 Bioactive Agents in Non-Edible Mushroom Species 1668.4.1 Polysaccharides 1668.4.2 Glucans 1668.4.3 Polysaccharide–Protein Complexes 1748.4.4 Terpenes 1748.4.5 Phenolic Compounds 1758.4.6 Peptides and Proteins 1768.5 Other Bioactive Compounds of Mushroom Species 1768.6 Conclusion 176References 1779 Toxicity Protocols for Natural Products in the Drug Development Process 189Tamirat Bekele Beressa, Amanjot Annu, and Andrew G. Mtewa9.1 Introduction 1909.2 In Vitro Toxicity Testing for Natural Products 1909.2.1 Cell Culture Method for Toxicity Testing 1919.2.2 Cell Culture for Acute Toxicology Testing 1929.3 Methods Used for In Vitro Toxicity Studies 1939.3.1 MTT Assay 1939.3.2 Neutral Red Uptake Assay 1939.3.3 Lactate Dehydrogenase Assay 1949.4 In Vitro Models for Liver Toxicity 1949.5 In Vitro Models for Nephrotoxicity Studies 1949.6 In Vitro Model for Dermal Toxicity Testing 1959.7 Mutagenicity Testing In Vitro 1959.7.1 Bacterial Cell System 1969.8 Reproductive and Teratogenicity Studies In Vitro 1969.8.1 H295R Steroidogenesis Assay 1979.8.2 Embryonic Stem Cell Test 1979.8.3 Whole Rat Embryo Cultures 1979.9 In Vivo Toxicity Testing of Natural Products 1989.9.1 Acute Toxicity Testing 1989.9.2 Subchronic Toxicity Testing 2009.9.3 Chronic Toxicity Testing 2019.9.4 Dermal and Ocular Toxicity 2039.9.5 Toxicity Testing for Fertility and Reproduction 2049.9.6 Combined Repeated Dose Toxicity Study with Reproduction/Developmental Testing 2069.9.7 In Vivo Carcinogenicity Testing 2079.10 Conclusion 208References 20810 Quality Control for the Safety of Natural Products 213Tadele Mekuriya Yadesa, Patrick Engeu Ogwang, and Casim Umba Tolo10.1 Introduction 21410.2 Quality Assurance of Herbal Products 21510.3 Methods of Quality Control for Herbal Products 21610.3.1 DNA-Based Technologies 21610.3.2 Good Practice Guidelines 21610.3.3 Chemoprofiling 21710.3.4 Toxicology 21710.3.5 Monographs and Pharmacopeias 21710.3.6 Preclinical Evidence of Safety and Efficacy 21710.3.7 Systems Biology 21810.3.8 Animal Experimentation 21810.3.9 Clinical Evidence of Safety and Efficacy 21810.4 WHO Guidelines for Quality Standardization of Herbal Formulations 21910.4.1 Quality Control of Crude Material 21910.4.2 Identity of Plant Material 21910.4.3 Safety Assessment and Documentation 22010.5 Concept of Validation in Herbal Products 22010.6 Challenges Related to Quality Control and Monitoring the Safety of Herbal Products 221References 22211 Secondary Metabolites and Toxins of Microbial Origin for the Treatment of Diseases 225Dharmandra Baria, Umang Shah, Chukwuebuka Egbuna, and Andrew G. Mtewa11.1 Introduction 22611.2 Antimicrobial Agents from Microbial Sources 22711.3 Antifungal Agents from Microbial Sources 22911.4 Anticancer Agents from Microbial Sources 23011.5 Hypocholesterolemic Agents from Microbial Sources 23511.6 Immunosuppressants from Microbial Sources 23711.7 Enzyme Inhibitors from Microbial Sources 23911.8 Antiparasitic Agents from Microbial Sources 24011.9 Recent Advances in Drug Discovery from Microbial Sources 241References 24312 Development of Phyto-Antidotes Against Adverse Chemical Agents 249Roman Lysiuk, Petro Oliynyk, Halyna Antonyak, and Dmytro Voronenko12.1 Introduction 24912.2 Heavy Metals and their Effects on the Body 25112.3 Detoxification Properties of Biologically Active Substances of Plant-Based Foods 25312.3.1 Pectins 25312.3.2 Phytin 25412.3.3 Betalains 25512.3.4 Phytochelatins 25612.3.5 Ellagic Acid 25712.3.6 Miscellaneous 25812.4 Current State of Clinical Application of Phyto-Antidotes 25912.5 Further Prospects in the Search for Promising Phyto-Antidotes 26012.6 Conclusions 261References 26213 Nanoformulated Herbal Drug Delivery as Efficient Antidotes Against Systemic Poisons 269Prabir Kumar Kulabhusan, Shailaja Agrawal, Jaison Jeevanandam, and Michael K. Danquah13.1 Introduction 26913.2 Herbal Phytochemicals as Antidotes for Systemic Poisons 27113.2.1 Herbal Phytochemicals as Antidotes for Heavy Metal Poisoning 27213.2.2 Herbal Phytochemicals as Antidotes for Snake Venom Poisoning 27513.3 Nanoformulated Herbal Phytochemicals as Antidotes 27613.3.1 Inorganic Nanoparticles 27813.3.2 Micelles and Liposomes 27913.3.3 Polymeric Nanoparticles 28113.4 Mechanism of Nanoformulated Herbal Phytochemicals against Systemic Poisoning 28113.5 Future Perspectives 28313.6 Conclusion 285References 28514 Phytochemical-Based Nanoparticles as Foes and Friends 295Charles Oluwaseun Adetunji, Oluwaseyi Olaniyan, Juliana Bunmi Adetunji, and Itoan Roli14.1 Introduction 29514.2 Phytochemicals Used in the Synthesis of Nanoparticles 29714.3 Anti-Inflammatory Effects of Nanoparticles 29714.4 Wound-Healing Effects of Nanoparticles 29914.5 Antiparasitic, Antifungal, and Antibacterial Activities of Nanoparticles 30014.6 Neuroprotective Effects of Nanoparticles 30414.7 Cardioprotective Effects of Nanoparticles 30714.8 Anticancer Effects of Nanoparticles 30814.9 Advantages of Nanoparticles 31114.10 Disadvantages of Nanoparticles 31114.11 Conclusion and Future Directions 312References 31315 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 323Mohamed A. Salem, Ahmed Zayed, and Shahira M. Ezzat15.1 Introduction 32415.2 Traditional Use of Medicinal Plants 32515.3 Natural Products: Safety and Toxicity 32815.3.1 Safety 32815.3.2 Toxicity and Natural Killers 32915.4 Biological Systems in Phytochemical Poisoning and Remediation 33015.5 Metabolomics: An Important Functional Genomics Tool 33215.5.1 Essential Components of a Metabolomics Workflow 33315.5.2 Sample Preparation 33415.5.3 Analytical Methods in Metabolomics 33415.5.4 Metabolite Identification 33515.5.5 Data Processing and Analysis 33515.5.6 Pathway Analysis 33515.6 Assessment of Toxicity of Herbal Medicines Using Metabolomics 33515.7 Application of Metabolomics in Emergency Phytochemical Poisoning and Remediation 33615.7.1 Hepatotoxicity of Triptolide 33715.7.2 Hepatotoxicity of Noscapine 33715.8 Conclusion 338References 33816 Methods for the Detection and Identification of Phytotoxins 349Senyo Botchie and Andrew G. Mtewa16.1 Introduction 35016.2 Phytotoxins 35016.2.1 Importance of Toxins 35116.3 Methods Generally Used for Phytotoxin Detection 35216.3.1 Biological Method Review of Detecting Phytotoxins 35216.3.2 Chemical and Microbiological Reagents 35216.4 Protease Inhibition Detection Protocol 35416.4.1 Exposure of the Protease Detection Plate to a Protease Inhibitor or Bacterial Growth (Step 1) 35416.4.2 Exposure to a Protease-Containing Solution (Step 2) 35516.4.3 Detecting Zones of Protease Inhibition (Step 3) 35516.5 Isolation of Phytotoxins from Microorganisms 35516.5.1 Detection of Phytotoxins Isolated from Fungi 35616.5.2 Purification of the Extracted Phytotoxins 35616.6 Conclusion 356References 35717 Categorization, Management, and Regulation of Potentially Weaponizable Toxic Plants 359Muhammad Akram and Rabia Zahid17.1 Introduction 35917.2 Management of Weaponized Natural Food Agents 36017.3 Techniques Used for Extraction, Segregation, and Decontamination of Phytochemicals 36117.3.1 Solvent-Based Extraction of Phenolic Compounds 36117.3.2 Microwave-Associated Extraction 36117.3.3 Ultrasound-Assisted Extraction 36217.4 Techniques for Identification of Bioactive Compounds 36217.4.1 Ultraviolet–Visible Spectroscopy 36217.4.2 Infrared Spectroscopy 36317.4.3 Nuclear Magnetic Resonance Spectroscopy 36317.4.4 Mass Spectrometry 36317.5 Types of Natural Phytotoxins 36317.5.1 Aquatic Biotoxins 36317.5.2 Glycosides 36417.5.3 Other Common Phytotoxins 36417.6 Conclusion 365References 36518 In Silico Modeling as a Tool to Predict and Characterize Plant Toxicity 367Charles Oluwaseun Adetunji, William Peter Mitembo, Chukwuebuka Egbuna, and G.M. Narasimha Rao18.1 Introduction 36818.2 Components of In Silico Toxicity Methods 36818.2.1 Databases 36918.2.2 Molecular Descriptors 36918.2.3 Toxicity Models and Modeling Software 36918.2.4 Simulation Packages 36918.3 Modeling Methods 37118.4 Structural Alerts/Rule Based 37118.5 Statistical Structure-Based Activity Relationship Models 37318.5.1 Read-Across 37318.6 Conclusion 374References 375Index 379