Drug Discovery and Ethnopharmacology - Comprehensive Notes

01 INTRODUCTION

  • Course outcomes: Demonstrate knowledge on drug discovery and development overview, ethnopharmacology, natural product research and basic biology of disease.

  • Outline of the course content: 1.1 Overview of Drug Discovery and Development; 1.2 Ethnopharmacology and Natural Product Research; 1.3 Understanding the Pathophysiology of the Disease.

1.1 Overview of Drug Discovery and Development

  • Ancient Times context

    • Treatments often discovered by chance or from observing nature.

    • Ingredients typically extracted from plants and animals.

    • Used for physical remedies and spiritual healing.

  • Modern Drug Discovery (began around the early 1900s)

    • Modern understanding emphasizes pure chemical entities.

    • Local and traditional knowledge remains an essential starting point for research and development (R&D).

    • Reference: Singh N, Vayer P, Tanwar S, Poyet J-L, Tsaioun K and Villoutreix BO (2023).
      Drug discovery and development: introduction to the general public and patient groups. Front. Drug Discov. 3:1201419.

  • DRUG DEVELOPMENT: overview

    • Basic Research focus: identify macromolecules (genes, proteins), dysfunctional signaling pathways, or molecular mechanisms linked to disease.

  • PRE-DISCOVERY STAGE

    • Emphasizes target discovery and initial biological understanding prior to drug candidate identification.

    • Reference: Singh et al. (2023).

  • CHALLENGES in drug discovery

    • Finding the right target is extremely challenging.

    • Effective drugs must interact specifically with the intended therapeutic target and avoid unintended targets.

  • VALIDATION

    • Scientists must find therapeutic agents that modify the function of the perturbed target to restore health or alleviate symptoms.

  • HIT IDENTIFICATION

    • High-throughput screening (HTS) and other methods identify potential therapeutic compounds.

  • PRECLINICAL PHASE

    • Potential drugs are tested in animal models to demonstrate safety and select candidates.

    • Novel strategies to avoid animal testing are being developed.

  • PHASES OF CLINICAL TRIALS

    • Phase I: Tests safety and dosage in a small group of healthy volunteers.

    • Phase II: Evaluates efficacy and side effects in a larger group of patients.

    • Phase III: Confirms efficacy and monitors adverse reactions in a large patient population.

    • Phase IV: Post-marketing surveillance to monitor long-term safety and efficacy in the general population (pharmacovigilance).

  • REGULATORY REVIEW AND APPROVAL

    • Studies are submitted to regulatory agencies (e.g., FDA) for review.

    • Agencies review documents and decide on market approval.

    • If approved, the drug can be marketed and administered to patients.

  • References: Singh N, Vayer P, Tanwar S, Poyet J-L, Tsaioun K and Villoutreix BO (2023). Front. Drug Discov. 3:1201419.

1.2 Ethnopharmacology and Natural Product Research

  • Definition and scope

    • Ethnopharmacology is the study or comparison of traditional medicine based on bioactive compounds in plants and animals, practiced by various ethnic groups (e.g., indigenous peoples).

    • Emphasizes knowledge-based drug discovery.

    • Reference: Acharya, D., & Shrivastava, A. (2008).

  • Ethnopharmacology as a bridge to natural product research

    • Traditional healing practices; traditional knowledge informs drug discovery.

  • OLD DRUGS – NEW MEDICINE (historical perspective)

    • Beginning of modern pharmacology with natural products entering Western medicine.

  • THE LATE EIGHTEENTH AND THE NINETEENTH CENTURY

    • Curare and other plant-derived toxins played a pivotal role in anesthesia and neuromuscular research.

    • Notable historical notes and quotes (from Alexander von Humboldt and others) illustrate the ethnobotanical context and challenges of botanical identification in early exploration.

  • Claude Bernard and curare

    • Claude Bernard studied pharmacological effects of curare and noted it blocks conduction of nerve impulse; toxicity was lower in the gastrointestinal tract, explaining traditional stomach uses.

  • THE 400 LONG HISTORY of ethnopharmacology

    • Key figures and milestones in curare research include early clinical uses and later isolation and standardization efforts (e.g., d-tubocurarine).

    • Representative timeline: 1940s – development of neuromuscular blockers; 1935–1942 – discovery and clinical adoption.

  • Early isolated compounds (early 19th century examples)

    • Morphine from Papaver somniferum (Opium Poppy): 1804 identified; alkaloid characterized 1817; structure elucidated in 1923.

    • Emetine from Ipecacuanha: 1817 fully characterized (structure elucidation by 1948).

    • Quinine from Red Cinchona: 1820 isolation; structure elucidated in 1880s.

    • Caffeine from Coffea arabica: 1821 isolation; structure elucidated 1882.

    • Coniine from Conium maculatum (Hemlock): 1826 isolation; first alkaloid structure elucidated (1870).

    • Atropine from Atropa belladonna: 1833 isolation; used for asthma historically.

    • Capsaicin from Capsicum frutescens: 1846 isolation; partly elucidated 1919.

  • 1945–1990s: compounds with CNS effects

    • Galantamine: discovered in the early 1950s from snowdrop; researched for CNS effects; acetylcholinesterase inhibitor; used in myasthenia gravis and cognitive disorders.

    • Ginkgo biloba, St. John’s Wort (Hypericum), Devil’s Claw (Harpagophytum procumbens), Kava-Kava (Piper methysticum) as ethnopharmacologic agents with various CNS or other effects.

    • Hoodia (Hoodia pilifera, Hoodia gordonii) as appetite suppressants; contentious regulatory status.

    • Galega officinalis (Goat's Rue) linked historically to metformin development.

  • Anticancer agents developed between 1950 and 1980

    • Podophyllotoxin derivatives: Etoposide (Vepesid) and Teniposide (VM-26).

    • Vinca alkaloids: Vinblastine, Vincristine, and Navelbine (vinorelbine).

    • Paclitaxel (Taxol) from Taxus brevifolia (Pacific Yew).

    • Betulinic acid from Corylus avellana (European Hazel).

    • Camptotheca acuminata (Happy Tree): Camptothecin as an anticancer agent.

    • Mechanisms include microtubule stabilization and inhibition of DNA topoisomerases.

  • The Revolution of the Molecular Biology: 1990s to today

    • Anticancer and antiviral agents arising from molecular biology advances; examples include artemisinin and related antimalarials repurposed for anticancer research; neem-derived compounds studied for anticancer potential; multiple natural products studied for anti-inflammatory or anti-cancer effects.

    • Artemisinin (Artemisia annua): antimalarial origin; research on anticancer properties.

    • Azadirachtin and Nimbin (Neem tree): insecticidal and potential anticancer effects under study.

    • Euphorbia peplus and Tripterygium wilfordii as anti-inflammatory and immunomodulatory compounds.

    • Capsaicin, resiniferatoxin (RTX) as modulators of pain and inflammation via TRPV1 receptor interactions.

    • Hoodia and Galega again referenced in the context of metabolic disease drug development (anti-obesity/anti-diabetes).

  • The Changing Legal Framework: CBD and biodiversity

    • Convention on Biological Diversity (CBD, 1992): international framework governing conservation and sustainable use of biological resources and fair sharing of benefits.

    • Rep. Act No. 9147 (Philippines, 2001): wildlife conservation and protection act; regulates wildlife resources, permits, and trade; sets penalties and administrative structures.

    • Key sections in RA 9147 include: Scope, Jurisdiction of DENR and DA, Definition of terms, Bioprospecting, Scientific research, Biosafety, Commercial breeding/propagation, Economically important species, Management and scientific authorities, Permits and penalties, and other purposes.

    • Definitions (Section 5) include bioprospecting, by-products, captive-breeding, collection, conservation, export/import/reexport permits, indigenous wildlife, and more.

    • Permits and processes (Section 19-20): management by PAWB (DENR) for terrestrial and BFAR (DA) for aquatic resources; various permits with validity periods; renewal conditions and guidelines; intolerance toward illegal collection and trade.

    • Additional notes include forfeiture of wildlife and derivatives; deportation for aliens; inflation-adjusted fines every three years.

  • Ethnopharmacological information today

    • Today’s information landscape is scattered across languages and sources; major ethnobotanical knowledge exists but is not always accessible in English.

    • Notable resources: NAPRALERT database; Indian National Institute of Science Communication and Information Resources (NISCAIR) in New Delhi, India.

    • Ethnobotanical studies underpin drug discovery but are often distinct from typical drug development goals.

  • TODAY’S CORE CHALLENGES

    • Stakeholders include traditional knowledge holders and neglected diseases communities.

    • Debates about whether extracts can be medicines; balancing traditional use with modern pharmacology; broader questions about food as medicine and medicine as food.

1.3 Pathophysiology of the Disease

  • Understanding health and disease dynamics

    • Homeostasis: maintaining stable internal conditions.

    • Pathology vs pathophysiology: Pathos = feeling/suffering; Physis = nature/origin (physiology).

  • Etiology and Pathogenesis

    • Etiology: the cause of a disease; Pathogen = disease-causing agent.

    • Etiology terms: Multifactorial (many factors), Nosocomial (healthcare-associated), Iatrogenic (medical treatment-induced), Idiopathic (unknown cause).

    • Pathogenesis: evolution of disease through stages: Stage of Susceptibility → Stage of Subclinical Disease → Stage of Clinical Disease → Stage of Recovery, Disability, or Death; includes exposure, pathologic changes, onset of symptoms, and usual time of diagnosis.

  • Signs vs Symptoms

    • Signs: objective, measurable phenomena observed by others (e.g., fever, rash).

    • Symptoms: subjective experiences reported by the patient (e.g., pain, fatigue).

  • Clinical manifestation terms

    • Local vs Systemic; Acute vs Chronic; Insidious (gradual onset); Exacerbation (worsening symptoms); Subacute (between acute and chronic); Remission (symptom-free period); Asymptomatic (no noticeable symptoms).

  • Diagnosis and prognosis

    • Diagnosis: labeling a disease; Prognosis: forecasting outcomes; Morbidity: disease rate; Mortality: death rate.

  • Population health and epidemiology

    • Epidemiology: study of diseases within populations.

    • Key terms:

    • Incidence: number of new cases in a specific period per population.

    • Prevalence: total number of existing cases at a given time.

    • Endemic: disease regularly found in a geographic area.

    • Epidemic: sudden increase in cases above normal expectation in an area.

    • Pandemic: epidemic spread across regions/countries globally.

  • Health-to-death continuum

    • Conceptual view of health status and disease progression; public health interventions and clinical treatment influence transitions along the continuum.

    • a) Effective public health interventions maintain health.

    • b) Lack of interventions allows disease initiation.

    • c) Effective diagnosis and treatment enable recovery to a healthy state.

    • d) Lack of treatment or ineffective treatment leads to disability or death.

  • Pathophysiology and drug development

    • Re-emphasizes unmet clinical needs; deeper understanding improves drug target identification and potential treatment modalities.

  • Cross-cutting connections

    • Ethnopharmacology informs target discovery and potential therapeutic modalities.

    • Regulatory and ethical frameworks (CBD, RA 9147) shape how ethnopharmacological resources can be studied and used.

REFERENCES AND SOURCES (selected from slides)

  • Singh N, Vayer P, Tanwar S, Poyet J-L, Tsaioun K and Villoutreix BO (2023). Front. Drug Discov. 3:1201419.

  • Acharya, D., & Shrivastava, A. (2008). Indigenous herbal medicines: Tribal formulations and traditional herbal practices. Jaipur: Aavishkar Publishers.

  • Schultes, R. E. (2022). Teonanácatl, the Sacred Mushroom [Video]. YouTube.

  • Griffith HR. The evolution of the use of curare in anesthesiology. Annals of the New York Academy of Science, 54:493-97, 1951.

  • Fleming, D. A., & Moyer, V. A. (2023). Acute bronchitis: Clinical presentation, diagnosis, and treatment. Medscape.

  • Convention on Biological Diversity. (1992). Estudos Avançados, 6(15), 193–233. https://doi.org/10.1590/s0103-40141992000200015

  • Republic Act No. 9147 (2001). An Act Providing for the Conservation and Protection of Wildlife Resources and their Habitats, Appropriating Funds Therefore and for Other Purposes. Official Gazette of the Republic of the Philippines.

  • Szklo, M., & Nieto, F. J. (2014). Epidemiology: Beyond the basics (3rd ed.). Jones & Bartlett Learning.

  • Lee MR. Curare: The South American Arrow Poison. The Journal of the Royal College of Physicians of Edinburgh 2005;35(i):83-92.

  • Mcintyre AR. Curare: Its History, Nature and Clinical Use. Chicago: University of Chicago Press, 1947.

  • Napralert database (www.napralert.org) and NISCAIR (CSIR) resources for ethnopharmacology/current ethnopharmacological information.