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Medicinal Plants: From Farm To Pharmacy

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This book offers a fresh look on a variety of issues concerning herbal medicine - the methods of growing and harvesting various medicinal plants; their phytochemical content; medicinal usage; regulatory issues; and mechanism of action against myriad of human and animal ailments. ‘Medicinal Plants: From Farm to Pharmacy’ comprises chapters authored by renowned experts from academics and industry from all over the world. It provides timely, in-depth study/analysis of medicinal plants that are already available in the market as supplements or drug components, while also introducing several traditional herbs with potential medicinal applications from various regions of the world. The book caters to the needs of a diverse group of readers: plant growers, who are looking for ways to enhance the value of their crops by increasing phytochemical content of plant products; biomedical scientists who are studying newer applications for crude herbal extracts or isolated phytochemicals; clinicians and pharmacologists who are studying interactions of herbal compounds with conventional treatment modalities; entrepreneurs who are navigating ways to bring novel herbal supplements to the market; and finally, natural medicine enthusiasts and end-users who want to learn how herbal compounds are produced in nature, how do they work and how are they used in traditional or modern medicine for various disease indications.
Godina:
2019
Izdavač:
Springer
Jezik:
english
Strane:
445
ISBN 10:
3030312682
ISBN 13:
9783030312695
Fajl:
PDF, 13,03 MB
Preuzeti (pdf, 13,03 MB)

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Nirmal Joshee
Sadanand A. Dhekney
Prahlad Parajuli Editors

Medicinal
Plants
From Farm to Pharmacy

Medicinal Plants

Nirmal Joshee • Sadanand A. Dhekney
Prahlad Parajuli
Editors

Medicinal Plants
From Farm to Pharmacy

Editors
Nirmal Joshee
Agricultural Research Station
Fort Valley State University
Fort Valley, GA, USA
Prahlad Parajuli
Department of Neurosurgery
Wayne State University
Detroit, MI, USA

Sadanand A. Dhekney
Department of Agriculture, Food
and Resource Sciences
University of Maryland Eastern Shore
Princess Anne, MD, USA

ISBN 978-3-030-31268-8    ISBN 978-3-030-31269-5
https://doi.org/10.1007/978-3-030-31269-5

(eBook)

© Springer Nature Switzerland AG 2019
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewe; rbestrasse 11, 6330 Cham, Switzerland

Foreword

Plants have been used to satisfy a wide variety of human needs since the dawn of
civilization, especially those that contribute towards meeting the increasing demand
for food. A number of plant species that provide health benefits in addition to meeting the dietary needs have been discovered and used for the prevention and treatment of ailments. While such plant species were primarily collected from the wild,
processed locally, and used in conjunction with local traditions, there has been an
increasing trend in the commercial cultivation of medicinal and aromatic plants,
large-scale extraction of the active compounds, along with their processing and
marketing as dietary supplements. Furthermore, several chemical compounds with
specific mode of action in the human body have been discovered, tested, and produced as drugs. This trend has been catalyzed by sharing of information across the
globe, providing impetus to research towards discovering potential life-saving
drugs. This has also facilitated regulations to ensure generation of accurate, science-­
based information that can be disseminated in an unbiased manner for the benefit of
humankind.
The book Medicinal Plants: Farm to Pharmacy, edited by Drs. N. Joshee,
S. Dhekney, and P. Parajuli, is an important treatise that covers topics providing an
excellent, in-depth review of the pipeline starting from the production, mechanistic
studies, and efficacy testing, up to the time a plant-based product reaches the ­market.
v

vi

Foreword

The editors have assembled experts in the field of medicinal plants cultivation,
chemistry, and biomedical research to effectively highlight the production, testing,
and development of plant-based medicines. I am confident that the book will be
very useful to researchers and readers interested in the areas related to medicinal
plants cultivation and processing. It will also be useful to students at both the undergraduate and graduate level who wish to pursue a career in the field of medicinal
plant chemistry and cultivation. The book comes at a time when interest in the use
of herbal medicines is growing at a rate that has never been witnessed before. The
contributing authors are spread across several countries, which testifies global recognition of research and regulatory framework on medicinal and aromatic plants. I
believe the authors have addressed an area that covers a vast amount of knowledge
in a very effective manner through the selection of relevant topics. I commend the
editors and authors for their efforts in this excellent compilation and am confident
that the book will be useful to a wide spectrum of people in the research community
as well as the general population interested in knowing more about the effects of
plants on human health and well-being.
Biotech Park
Lucknow, India

Pramod Tandon

Preface

This book is an extension of the idea that was presented as a workshop “From Farm
to Pharmacy” during the American Society for Horticultural Sciences annual meeting, August 8–11, 2016, Atlanta, Georgia. The session was conceived by Dr.
Changbin Chen, University of Minnesota, and Dr. Hideka Kobayashi, Kentucky
State University; and Dr. Nirmal Joshee served as the moderator.
Having spent some momentous years of life in the Indian and Nepal Himalayas
where a vast majority of the world’s medicinal herbs are found, the three editors of
this book share personal connections with traditional medicinal plants. This book
was motivated by a shared love and respect for medicinal herbs. The editors have
tremendous amount of shared expertise on a number of plant species with medicinal
properties, commercial or otherwise, and this experience led them to compile information on the usages of various plants in alternative and complementary medicinal
practices. They are also driven by a deep desire to generate awareness and dissipate
knowledge about the agricultural/harvesting practice and current research on biological activities and medical usages of some popular and some relatively unknown
traditional herbs from different parts of the world. Overall, this book is a celebration
of the vast plant wealth around us and their tremendous benefit to both humans and
animals.
An increasing interest in plants as a source of medicine along with an awareness
of the side effects of synthetic drugs has led to a rapid increase in the utilization of
several plant species for medicinal purposes. Several medicinal plants are grown
commercially to meet the demand for supplemental plant products. This book provides timely information on the techniques for cultivation of plants with medicinal
properties, in vitro studies detailing the effect of bioactive molecules from various
plant species using human/animal cell culture system as well as in vivo disease
models and the processing of various plant parts for formulation into medicines.
We expect this book will attract attention of a large cross section of people who
are interested in plants and their healing properties. This book can be read on two
different levels. First, it may be read by ordinary people with a limited scientific
background. Most chapters of the book have been written with this audience in
mind. The book offers initial few chapters that provide a rich heritage and practice
vii

viii

Preface

of ethnobotanical systems still adopted in different parts of the world. There are
other chapters that deal with specific crops, their commercial potential, agronomic
practices, distribution in different ecological conditions, and molecular mechanisms
of bioactive compounds present therein. Some chapters may contain somewhat
overwhelming Latin names, while some chapters, especially the ones detailing the
mechanisms of action, may include intimidating chemical names and busy schemes.
These scientific details are meant for the scholarly readers and can be avoided by
others without diluting the overall message. Nonetheless, the scientific evidence
supported by citations from original documents and the inferences as well as recommendations made can be easily comprehended by readers from all background. This
book will be particularly useful for people seeking to optimize production and post-­
harvest practices for medicinal and aromatic plants, students and researchers interested in elucidating the effects of plant metabolites on cell/animal disease models,
and individuals in the private sector/industry who utilize plants for the development
of herbal medicines/supplements.
There are 17 chapters in the book. It opens with a commentary on the increasing
role of medicinal plants as a reservoir of many bioactive compounds from a practicing physician’s perspective. The book is broadly categorized in sections that briefly
talk about the use of plants for drug discovery and development, cultivation/production practices for medicinal plants, studies detailing the effects of plant extracts and
phytochemicals on in vitro/in vivo disease models, and the various bioactive molecules used for the development of plant-based medicines.
There is a need to conduct systematic research on numerous plants that have
been used in traditional medical systems—to scientifically test their efficacy against
various diseases and to isolate and characterize therapeutically active molecules.
The book strives to drive the point that a lot of fruits, vegetables, ornamental plants,
and other herbs that are part of our daily consumption come with beneficial medicinal properties. In our daily life, plants are often content being in the background. It
is about time that we appreciate them, treat them with proper respect, and spread
awareness with thorough conservation programs. We hope this book will instigate
some level of consciousness, enthusiasm, and gratitude towards the tremendous
health benefits that are hidden in the flora surrounding us.
Fort Valley, GA, USA
Princess Anne, MD, USA 
Detroit, MI, USA 

Nirmal Joshee
Sadanand A. Dhekney
Prahlad Parajuli

Contents

1	The Evolution of Modern Medicine: Garden to Pill Box ��������������������    1
Tejas S. Athni and Sudhir S. Athni
2	Bioprospecting for Pharmaceuticals: An Overview and Vision
for Future Access and Benefit Sharing��������������������������������������������������   17
Danielle Cicka and Cassandra Quave
3	Nepal: A Global Hotspot for Medicinal Orchids����������������������������������   35
Brajesh Nanda Vaidya
4	Current Status and Future Prospects for Select Underutilized
Medicinally Valuable Plants of Puerto Rico: A Case Study ����������������   81
Prachi Tripathi, Lubana Shahin, Ankush Sangra, Richa Bajaj,
Alok Arun, and Juan A. Negron Berrios
5	Black Pepper: Health Benefits, In Vitro Multiplication,
and Commercial Cultivation������������������������������������������������������������������ 111
Virendra M. Verma
6	Prospects for Goji Berry (Lycium barbarum L.) Production
in North America�������������������������������������������������������������������������������������� 129
Sadanand A. Dhekney and M. R. Baldwin
7	Skullcaps (Scutellaria spp.): Ethnobotany and Current Research������ 141
Lani Irvin, Carissa Jackson, Aisha L. Hill, Richa Bajaj,
Chonour Mahmoudi, Brajesh N. Vaidya, and Nirmal Joshee
8	Cultivating Research Grade Cannabis for the Development
of Phytopharmaceuticals ������������������������������������������������������������������������ 169
Hemant Lata, Suman Chandra, Esther E. Uchendu, Ikhlas A. Khan,
and Mahmoud A. ElSohly

ix

x

Contents

9	Natural Products as Possible Vaccine Adjuvants for Infectious
Diseases and Cancer�������������������������������������������������������������������������������� 187
Anna-Mari Reid and Namrita Lall
10	In Vitro Plant Cell Cultures: A Route to Production of Natural
Molecules and Systematic In Vitro Assays for their Biological
Properties�������������������������������������������������������������������������������������������������� 215
Peeyushi Verma and Rakhi Chaturvedi
11	Antioxidant, Antimicrobial, Analgesic, Anti-inflammatory
and Antipyretic Effects of Bioactive Compounds from
Passiflora Species ������������������������������������������������������������������������������������ 243
Narendra Narain, Saravanan Shanmugam,
and Adriano Antunes de Souza Araújo
12	Modulation of Tumor Immunity by Medicinal Plant
or Functional Food-­Derived Compounds���������������������������������������������� 275
Robert E. Wright III, Nirmal Joshee, and Prahlad Parajuli
13	Dietary Brown Seaweed Extract Supplementation
in Small Ruminants��������������������������������������������������������������������������������� 291
Govind Kannan, Thomas H. Terrill, Brou Kouakou, and Jung H. Lee
14	Discovery of Green Tea Polyphenol-Based Antitumor Drugs:
Mechanisms of Action and Clinical Implications���������������������������������� 313
Reda Saber Ibrahim Ahmed, Claire Soave, Tracey Guerin Edbauer,
Kush Rohit Patel, Yasmine Elghoul, Antonio Vinicius Pazetti de Oliveira,
Andrea Renzetti, Robert Foldes, Tak-Hang Chan,
and Q. Ping Dou
15	Therapeutic and Medicinal Uses of Terpenes���������������������������������������� 333
Destinney Cox-Georgian, Niveditha Ramadoss, Chathu Dona,
and Chhandak Basu
16	Unexplored Medicinal Flora Hidden Within South Africa’s
Wetlands���������������������������������������������������������������������������������������������������� 361
Karina Mariam Szuman, Namrita Lall, and Bonani Madikizela
17	Sea Buckthorn: A Multipurpose Medicinal Plant
from Upper Himalayas���������������������������������������������������������������������������� 399
Ashish Yadav, Tsering Stobdan, O. P. Chauhan, S. K. Dwivedi,
and O. P. Chaurasia
Index������������������������������������������������������������������������������������������������������������������ 427

Chapter 1

The Evolution of Modern Medicine:
Garden to Pill Box
Tejas S. Athni and Sudhir S. Athni

1.1

Introduction

To first explore how natural substances have been used to treat humans, one can
look to Colombia and Peru over 8,000 years ago. Historical evidence suggests that
these ancient foraging societies chewed on the leaves of the cocoa tree to keep
warm, to battle altitude sickness, and to provide a quick source of instant energy
(Mortimer 1974). As history progressed, the cocoa leaf became an integral panacea
medicine for nearly all illnesses and diseases in Andean Incan society. This is the
first documented example of the utilization of biologically-active, plant-derived
substances—referred to as phytochemicals—to treat human ailments. Over the last
few millennia, thousands of other herbal substances have been used by various cultures to combat a myriad of sicknesses. Human society has consistently been able to
harness the power of phytochemicals, even though at times the exact mechanisms of
action were not well understood. In the contemporary age, naturally derived medicine has allowed society to tackle diseases in numerous areas of healthcare. Although
there are too many such drugs to discuss in this chapter, a few medications in
select healthcare categories will be highlighted.
From an economic standpoint, the medicinal plant industry has been equally
productive. Global imports and exports (2000–2008) of medicinal plants were
worth USD $1.59 and $1.14 billion/year, respectively, with a >40% growth rate
per annum (Rajeshwara Rao and Rajput 2010). As is evident in this statistic, the
medicinal plant industry is growing at an ever-increasing rate. However, it is important to note that out of the 3000 medicinal plants traded internationally, only 900 are

T. S. Athni
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
S. S. Athni (*)
Neurology of Central Georgia, Macon, GA, USA
e-mail: md@athni.com
© Springer Nature Switzerland AG 2019
N. Joshee et al. (eds.), Medicinal Plants,
https://doi.org/10.1007/978-3-030-31269-5_1

1

2

T. S. Athni and S. S. Athni

under cultivation, and the vast majority of exported biomass is harvested from
the wild (Rajeshwara Rao and Rajput 2010). Hence, this implies that more than
two-­thirds of the medicinal plants currently exported have yet to be cultivated
commercially, signaling an area of huge economic potential.

1.2

Types of Drugs

In medicine, drugs are often classified based on their functional use in the human
body. In this chapter, four major categories of drugs are explored: cardiovascular,
oncologic, neurologic, and pain-suppressants. Pertinent plant-derived medications,
including their history, botanical origins, chemical properties, and mechanism of
action, will be discussed in each category.

1.2.1

Cardiovascular Drugs

1.2.1.1

Atropine

Imagine a patient feeling lightheaded and confused Drugs, experiencing symptoms Cardiovascular drugs such as fainting and shortness of breath. After visiting
the clinician, the patient finds out that he or she has been diagnosed with bradycardia, a medical condition where the electrical impulses in the heart don’t fire as
normally as they should, resulting in an abnormally low heart rate (Kounis and
Chopra 1974). A medication that is used every day in the hospital to revive a
patient’s abnormally slow heart rate and to treat conditions such as bradycardia is
a drug known as atropine (Kounis and Chopra 1974).
Before delving into the specifics of this medication, some foundational
human physiology will first be discussed. The human nervous system is broken
down into the central nervous system (CNS) and the peripheral nervous system
(PNS). The CNS includes the brain and the spinal cord. The PNS contains all other
nerves outside of the CNS. More specifically, the PNS can be categorized into the
somatic nervous system and the autonomic nervous system. The somatic nervous
system controls voluntary muscle movements (e.g., raising an arm, moving a leg),
and the autonomic nervous system is in charge of functions that are not consciously
controlled (e.g., breathing, heart beat). Within the classification of the autonomic
system, there are two main types of nerves which work antagonistically with each
other: the sympathetic and parasympathetic nerves (Langley 1921). In simple terms,
the sympathetic nerves are activated during times of stress (“fight” response), causing an increase in heart rate and rise in blood pressure (Jänig 2006). The parasympathetic nerves slow down the heart rate and lower the blood pressure (“flight”
response). There is a push-pull balance between these nerves to maintain
homeostasis.

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The Evolution of Modern Medicine: Garden to Pill Box

3

Atropine works as an anticholinergic or anti-parasympathetic medication through
competitive inhibition (Satake et al. 1992), causing decreased activity of the parasympathetic nerves and leading to an increase in sympathetic nerve activity. In the
clinical setting, an increase in sympathetic activity coupled with a decrease in parasympathetic activity leads to an elevation in heart rate and a rise in blood pressure
(Jänig 2006). For critically ill hospitalized patients, atropine is used to chemically
stimulate the heart when the heart rate drops significantly, such as in cases of poisoning (McDonough and Shih 2007). This medication is a crucial aspect of all crash
carts in the hospital and ICU settings. Atropine is even on the World Health
Organization’s List of Essential Medicines, which is a comprehensive compilation
of the most safe and effective medicines (WHO 2011).
While atropine is a critical, lifesaving medication, its origins are quite humble.
The drug is naturally derived from various plants found in nature, such as the deadly
nightshade (Atropa belladonna, found mainly in Europe, North Africa, and Western
Asia), henbane (Hyoscyamus niger, found mainly in Eurasia), thorn apple (Datura
stramonium, found mainly in Central America), and mandrake (Mandragora officinarum, found mainly around the Mediterranean coast) (West and Mika 1957). The
medicinal properties of the mandrake plant were first described in fourth century
B.C. by Theophrastus, a Greek plant biologist, who described the chemical as an
ideal treatment for wounds, sleeplessness, and love (Hamilton and Baskett 2000).
Extracts from the henbane plant were used in the last century B.C. by Queen
Cleopatra of the Ptolemaic Kingdom of Egypt as a pupil dilation agent to appear
more alluring (Hocking 1947). During the Renaissance period of Europe, many
women also used the juice of the deadly nightshade plant in order to enlarge their
pupils.
These plants contain both hyoscyamine and hyoscine, which are two closely
related alkaloid compounds (Pearse 1876). Specifically, atropine is a mixture of two
different forms of the hyoscyamine alkaloid. As technology advanced, atropine itself
was isolated in the year 1833 (West and Mika 1957). Since that point, through extensive research and scientific testing, atropine is now one of the most widely available
generic medicines found in hospitals around the world, with a price tag less than USD
$0.50 for 1 mg vials. Derived from plants and first used over 6,000 years ago, atropine
has sealed its place as a crucial drug in the modern medical system.
1.2.1.2

Digoxin

There are other cardiac arrhythmias (i.e., abnormal cardiac rhythms) and heart
conditions (e.g., congestive heart failure) which can be disabling and sometimes
fatal (Domanski et al. 1994). Some of these arrhythmias include atrial fibrillation
and atrial flutter. For these conditions, the plant-derived drug digoxin can help
regulate the heart rhythm and improve cardiac function during heart failure
(Hollman 1996). Digoxin’s ability to inhibit the sodium potassium adenosine
triphosphatase enzyme (Na/K pump), mainly in the myocardium, helps the heart
to beat more regularly and with stronger force (Schwartz et al. 1968).

4

T. S. Athni and S. S. Athni

Like atropine, digoxin is on the World Health Organization’s List of Essential
Medicines (WHO 2011). Unlike intravenous atropine used in the hospital setting,
however, digoxin is used as a cardiac medication consumed daily in the form of a
tablet. As of 2019, monthly prescription of digoxin costs less than USD $10.
Digoxin was first derived from the foxglove plant, also known as Digitalis lanata
(Hollman 1996). Digoxin has also been extracted from other plants from the same
genus Digitalis. The foxglove plant is part of the plantain family, originally coming
from the continent of Europe. However, as colonization occurred, the plant was
domesticated and brought to North America. The slightly acidic soils of the continent helped foster an environment suitable for optimal plant growth (Allen 1987).
The foxglove plant can be found in a wide variety of geographic locations, ranging
from woods and cliffs to grassy meadows and wastelands.
In 1785, the English physician William Withering first described the medicinal
practicalities of Digitalis derivatives in his book, “An Account of the Foxglove and
Some of its Medical Uses with Practical Remarks on Dropsy and Other Diseases”
(Withering 2014). In his descriptions, Withering talks about Digitalis extract’s ability to fight dropsy, which is the former name for congestive heart failure and the
associated edema (i.e., abnormal accumulation of fluid within certain tissues of the
body) (Withering 2014). Based on these accounts, digoxin and digoxin-related substances have been used to treat congestive heart failure for almost 250 years.
1.2.1.3

Warfarin

Warfarin is one of the most popular anticoagulants (i.e., blood thinners) available on
the drug market (Pollock 1955). Today, warfarin is commonly used to treat conditions such as blood clots and deep vein thrombosis (i.e., a blood clot in a deep vein,
usually within the legs), as well as to prevent strokes in people who have artificial
heart valves, atrial fibrillation (i.e., irregular heart rhythm), and valvular heart disease (i.e., damage or defect in one or more of the four heart valves) (Pollock 1955).
Warfarin can also help prevent future blood clots and embolism, a condition in
which a blood clot migrates through vasculature and physically blocks blood supply
to vital organs or tissue.
This drug’s origins can be traced back to a very unusual disease that afflicted
cattle in the 1920s—one that resulted in sudden and fatal bleeding after minor injuries. Investigation of this mysterious illness concluded that these cattle had consumed a plant known as the sweet clover (Melilotus alba and M. officinalis) (Kresge
et al. 2005). The sweet clover, part of the family Fabaceae, is a part of the common
grassland plants and often known as the “weed of cultivated ground.” These plants
originally are from Asia and Europe, but they are now found all throughout the
world. Intrigued by this plant, scientists found that it contained a hemorrhagic factor
that reduced the activity of prothrombin, a protein present in the plasma of blood.
Researchers were determined to find the identity of this unknown hemorrhagic
­factor, and eventually identified the active compound as coumarin. These coumarin
compounds can also be found in other plants, most notably the sweet-scented bedstraw

1

The Evolution of Modern Medicine: Garden to Pill Box

5

(Galium odoratum, family Rubiaceae) and lavender (Lavandula angustifolia)
(Pollock 1955). However, the coumarin compounds themselves do not exert any
effect on clotting. Rather, they must be metabolized into compounds such as
4-hydroxycoumarin by various fungi, and then into a compound called dicoumarol,
which is the actual active component (Bye and King 1970).
Physiologically, dicoumarol works as an anticoagulant by acting as a vitamin K
depleter, functioning to reduce the metabolism of vitamin K in the blood and effectively reduce the clotting of blood cells (Bye and King 1970). Mechanistically,
dicoumarol acts to competitively inhibit vitamin K epoxide reductase,
the enzyme responsible for vitamin K recycling (Patel et al. 2019). After extensive
research into these naturally derived compounds and their medicinal properties,
Karl Link and fellow scientists at the University of Wisconsin decided to produce
the pharmaceutical drug known today as warfarin (a name which is the combination
of the acronym WARF, which stands for the Wisconsin Alumni Research Foundation,
and the suffix “-arin” from its coumarin components). Today, warfarin is on the
World Health Organization’s List of Essential Medicines, yet interestingly, was first
approved as a rat poison before its use on humans (WHO 2011).

1.2.2

Oncologic Drugs

1.2.2.1

Paclitaxel

Breast cancer is the second most common type of cancer in the United States (second only to skin cancer). Each year, approximately 266,000 women are diagnosed
with invasive breast cancer and an additional 65,000 women are diagnosed with
noninvasive breast cancer in situ (Levi et al. 2002). Research into finding effective
treatment options for breast cancer has been unrelenting. Currently, treatment
options include surgical resection, chemotherapy, radiation therapy, immunotherapy, and hormonal therapy (Levi et al. 2002). One of the more effective chemotherapy options is a medication known as paclitaxel, another member of the World
Health Organization’s List of Essential Medicines (WHO 2011).
Paclitaxel is a microtubule-stabilizing drug which interferes with the arrangement of microtubules during the process of mitotic cell division, ultimately impeding the proliferation of cancer cells and inducing cell death (Long and Fairchild
1994). As the most well-known naturally derived antitumor drug in the United
States, paclitaxel’s history is quite unique. In 1962, samples of the Pacific yew tree,
also known as Taxus brevifolia, were sent by the US Department of Agriculture to
the National Cancer Institute (NCI) to aid in their objective of finding natural products that could potentially help treat and cure cancer (Stierle et al. 1994). Scientists
from the Research Triangle Institute in North Carolina soon discovered that extracts
from the bark actually caused cytotoxic activity on cancer cells (Stierle et al. 1994).
Following this stunning discovery, additional samples of bark were collected and
extracts produced for further testing to identify the most bioactive component within

6

T. S. Athni and S. S. Athni

the samples (Stierle and Stierle 2000). After several years, paclitaxel in its pure form
was finally discovered as the main bioactive constituent within the Pacific yew tree’s
bark. Then began the process of testing paclitaxel’s biological mechanisms. In-vitro
biological mechanistic studies eventually led to in-vivo trials against the mouse
melanoma B16 model (Holmes et al. 1991). Finally, paclitaxel was selected to be
further developed in the clinical pipeline after extensive testing, both in-vitro and
in-vivo.
The wealth of compounds found in an extract such as the bark of the Pacific yew
is quite remarkable. Before the evolution of modern paclitaxel, native peoples in
North America used the needles and twigs of the tree in order to brew homeopathic
teas for various ailments (Wilson and Hooser 2012). However, many traditional
shamans were careful in using the tree’s medicinal properties, as an excess
amount could lead to devastating toxico logical consequences for the human body,
including yew poisoning. Interestingly, the yew tree was known as the “tree of
death,” whose extracts were used to murder ancient kings such as Catuvolcus, the
king of the Gallic-Germanic tribe known as the Eburones (Panzeri et al. 2010).
1.2.2.2

Vinblastine

Although some chemotherapeutic agents are used to treat one specific type of cancer, other agents have been used for the treatment of many. An exemplar drug is
vinblastine, a common chemotherapeutic used in the field of oncology. Typically
utilized as an adjuvant treatment in conjunction with other medications, vinblastine
is effective in treating various forms of cancer. For example, the drug is known for
its ability to fight non-small cell lung cancer, brain cancer, testicular cancer, melanoma, bladder cancer, and most notably Hodgkin’s lymphoma (Ratain et al. 1987).
Vinblastine is also used to treat non-malignant conditions, such as histiocytosis and
other blood disorders (Tennant Jr 1969).
Currently, vinblastine is on the World Health Organization’s List of Essential
Medicines and has been recognized as one of the most effective chemotherapeutic
substances (WHO 2011). Chemically, vinblastine is an alkaloid compound. It works
to inhibit cancer growth by specifically targeting metaphase in the mitotic process.
Normally during metaphase, each chromosome lines up in the center of the cell,
with every sister chromatid being attached to a respective spindle fiber. Vinblastine
binds to tubulin—the protein which is the main constituent of cellular microtubules—in order to prevent the cell from creating spindle fibers in the first place
(Jordan et al. 1992). This ultimately interferes with the cell division process and
inhibits tumor cell growth by stopping proper mitosis. Vinblastine is similar to
paclitaxel in that it interferes with tumor cells during the cell cycle. However, while
paclitaxel targets the arrangement of microtubules, vinblastine targets the creation
of microtubules altogether (Long and Fairchild 1994).
With all of its intricacies and molecular charm, vinblastine derives its origins
from a simple plant known as the Madagascar periwinkle (Catharanthus roseus),
which is in the dogbane family Apocynaceae (Iskandar and Iriawati 2016). Also

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The Evolution of Modern Medicine: Garden to Pill Box

7

called the “old maid” and the “Cape periwinkle,” this plant is native and endemic to
Madagascar. However, the periwinkle is grown in various places around the world
as a medicinal and ornamental plant. For example, the extract of the roots and shoots
of Madagascar periwinkle has been used for numerous centuries as an Ayurvedic
(i.e., traditional Indian medicine) agent against several diseases (Iskandar and
Iriawati 2016). In traditional Chinese medicine, the plant was used to battle various
other diseases ranging from malaria to diabetes.
Having such an extensive history of use among various cultures, it was only
recently that drug development of vinblastine took place. In 1958, Robert Noble and
Charles Thomas Beer at the University of Western Ontario isolated the vinca alkaloid vinblastine from the periwinkle plant (Ratain et al. 1987). Shortly thereafter,
vinblastine’s potential use as a chemotherapeutic agent was advanced after a successful decrease in infected rabbits’ white blood cell count—an indication of the
effectiveness of the compound.
1.2.2.3

Etoposide

Besides paclitaxel and vinblastine, another common chemotherapeutic agent is etoposide. Primarily used to treat testicular cancer, leukemia, neuroblastoma, ovarian
cancer, lymphoma, and lung cancer, etoposide can either be ingested orally or be
injected directly into the bloodstream through an intravenous injection (Van Maanen
et al. 1988). The drug is also on the World Health Organization’s List of Essential
Medicines (WHO 2011).
The mechanism of action of etoposide is very different from other chemotherapeutic substances of its sort. Instead of inhibiting the microtubule processes during
mitotic cell division like paclitaxel and vinblastine, etoposide targets the actual
DNA strands of the tumor cell. The drug forms a ternary complex with the topoisomerase II enzyme on the DNA (Hande 1998). Topoisomerase II is a protein which
helps with DNA unwinding and is crucial for cancer cell function since tumor cells
divide so rapidly. When etoposide latches onto the topoisomerase II enzyme, it prevents the DNA strands from religating, ultimately causing errors in DNA synthesis
and causing the DNA strands to break (Van Maanen et al. 1988).
While etoposide was approved for medical use in the United States in 1983 and
eventually received a designation on the World Health Organization’s List of
Essential Medicines (WHO 2011), the plant the compound is derived from, known
as the wild mandrake (Podophyllum peltatum), has a long and extensive history of
medicinal use (Hande 1998). Also known as the mayapple, the wild mandrake is
a herbaceous perennial plant in the family Berberidaceae, first described as a
genus by the Swedish botanist Carl Linnaeus in 1753 (Springob and Kutchan
2009). The wild mandrake is found all across the eastern United States and southeastern Canada. Interestingly, every single part of the plant is poisonous, including
its green fruit.
The plant has been used for many centuries by American Indians as an emetic
(i.e., vomit inducing), antihelminthic (i.e., expelling parasitic worms), and cathartic

8

T. S. Athni and S. S. Athni

(i.e., psychological relief) agent (Hamilton and Baskett 2000). By boiling the
poisonous roots of the wild mandrake, the Native Americans were able to create a
natural tonic water in order to treat stomach aches and other gastrointestinal problems. As further research was done into the plant, historians found that the rhizome
of the plant was used by settlers in the New World to treat ailments. Creating a
semisynthetic derivative of a compound known as podophyllotoxin from the rhizome of the wild mandrake, scientists were able to produce the chemotherapeutic
drug known today as etoposide (Hande 1998).

1.2.3

Neurologic Drugs

1.2.3.1

Scopolamine

The brain is regarded as the control center for volitional activities. The brain is also
the command module for involuntary activities, such as breathing, heartbeat, bowel
and bladder activities, and much more. A critical neurotransmitter, acetylcholine, is
involved with the transmission of the brain’s signals to the various muscles of
the body, both voluntary and involuntary (Perry et al. 1999).
The type of receptor on which acetylcholine interacts is labeled as either muscarinic or nicotinic (Leprince 1986). Nicotinic receptors are usually found on muscles
over which the body has volitional control. Muscarinic receptors typically control
involuntary function. Chemicals or medications which block the muscarinic receptors prevent acetylcholine from reaching its post-synaptic target site which, in
essence, cause malfunction of the end organ (Perry et al. 1999). These chemicals are
said to have anticholinergic properties. When one consumes medications or substances with such properties, numerous effects are observed, such as dry mouth,
constipation, urine retention, and sleepiness, to name a few.
One commonly used anticholinergic chemical is scopolamine, which is derived
from various genuses in the Solanaceae (nightshade) plant family, most notably
Scopolia and Hyoscyamus (Phillipson and Handa 1975). Scopolamine is also found
in the secondary metabolites of other plants, such as jimson weed (Datura stramonium) and corkwood (Duboisia myoporoides) (Phillipson and Handa 1975). For
many centuries, the effects of scopolamine were observed and used for various
medicinal and divine purposes. Starting from the Neolithic period (from 10,200 to
2,000 BCE), the henbane plant (Hyoscyamus niger) has been harnessed for human
benefit (Hocking 1947). The ancient Egyptians, Celts, Germans, and Greeks all
sought use of the plant as a sacred healing agent as well as an alcoholic enhancer.
For example, the Oracle of Delphi inhaled the burning smoke of the henbane plant
before forecasting prophecies and divinations (Hocking 1947). After a short period
of disappearance from historical records, the drug reappeared during the Middle
Ages (4,000–1,400 CE) as a topical ointment. Since strong doses of the medication
caused hallucinations and delirium, many regarded topical henbane ointment as the
“witch’s herb” (Müller 1998).

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The Evolution of Modern Medicine: Garden to Pill Box

9

In the modern era, scopolamine is a common medication in the antimuscarinic
family. Used to treat conditions including postoperative nausea, vomiting, motion
sickness, and intestinal and bladder cramps, scopolamine can help alleviate the
spasmodic pain that is associated with such problems (Hardy and Wakely 1962).
Scopolamine is also known for its effects targeting other gastrointestinal problems such as irritable bowel syndrome and diverticular disease. The drug works
by blocking the effects of acetylcholine, ultimately reducing the spasmodic contractions of the smooth muscles in the walls of the gastrointestinal tract (Hardy
and Wakely 1962).
Interestingly, scopolamine was initially used in conjunction with opioids such as
morphine and oxycodone in order to put mothers in labor to a deep sleep (Phillipson
and Handa 1975). Scopolamine’s analgesic properties when combined with opioids
are strong enough to be used as a form of anesthesia. Since scopolamine was first
isolated and tested, extensive research has been done on the specific properties of
the drug. It is now a key member of the World Health Organization’s List of Essential
Medicines (WHO 2011).
1.2.3.2

Levodopa (l-Dopa)

Another neurotransmitter, dopamine, is a critical chemical used in the control of
body movements, along with many other functions (Hornykiewicz 2010). When
there is a loss of dopamine activity in parts of the brain known as the substantia
nigra and the basal ganglia, a condition known as Parkinson’s Disease (PD) ensues
due to impaired neuron-to-neuron communication and firing (Hornykiewicz 2010).
This neurodegenerative disorder can be quite disabling without treatment.
A phytochemical compound, levodopa (also known as l-dopa), was first isolated
in the years 1910–1913 using the seeds of the broad bean plant (Vicia faba) (Tomita-­
Yokotani et al. 2004). Functionally an amino acid, levodopa is a precursor to dopamine but is not an active compound itself. A few years after the initial discovery of
l-dopa, however, scientists discovered in 1938 that an enzyme called dopa-­
decarboxylase was able to enzymatically convert l-dopa into the neurotransmitter dopamine (Blaschko 1942). This finding set the basis for further research into
dopamine replacement therapy, a type of treatment which increases levels of dopamine in affected brain regions to optimal levels for proper neuronal functioning
(Kebabian and Calne 1979).
A member of the World Health Organization’s List of Essential Medicines
(WHO 2011), l-dopa is now a critical component of the modern health system’s
toolkit to battle CNS diseases including PD (Rodnitzky 1992). In 1967, a levodopa
drug regimen was introduced to help treat PD and has been used extensively ever
since. Mechanistically, l-dopa crosses the blood-brain barrier—a highly selective
and semi-permeable border that serves to separate circulating intravascular blood
from cerebrospinal fluid—and is enzymatically decarboxylated into dopamine. The
blood-brain barrier is comprised of a close packaging of endothelial cells that line
the blood vessels of the CNS, astrocyte end-feet, and pericytes and their basal

10

T. S. Athni and S. S. Athni

l­amina (Daneman and Prat 2015). It is also comprised of tight junctions of protein
complexes, which serve to bolt the endothelial cells together and restrict movement
of ions, molecules, and cells into and out of the CNS (Luissint el al. 2012). Since
dopamine itself is too large to cross the blood-brain barrier, levodopa is a smaller,
more permeable molecule that is an ideal alternative to get dopamine into the
brain (Hornykiewicz 2010). Physiologically, this levodopa-induced spike in dopamine concentrations helps to fight many of the motor symptoms caused by PD, such
as bradykinesia, tremors, and impaired gait (Zach et al. 2017).
Historically, levodopa has been used for thousands of years in order to treat
PD-like symptoms. For example, ancient civilizations in India used extracts of a
therapeutic legume known as the velvet bean (Mucuna pruriens) as a psycho-­
spiritual and purifying herb in Ayurvedic medicine (Tomita-Yokotani et al.
2004). More specifically, the velvet bean is an annual climbing shrub that is of the
family Fabaceae and can grow to over 50 feet in length. Interestingly, in addition to
its use as a treatment for neurological diseases, the plant also was used as an antagonist to fight the toxins of various snake bites (Tomita-Yokotani et al. 2004). Other
than the velvet bean, l-dopa can also be derived from natural sources such as the
broad bean (Vicia faba) and plants in the Cassia, Dalbergia, Piliostigma, Phanera,
and Canavalia genera.

1.2.4

Pain Suppressants

1.2.4.1

Aspirin

Fever? Headache? Reach for the aspirin: one of the most widely used medications
found in households all over the world (Miners 1989). For everyday aches, aspirin
has consistently been the go-to pharmaceutical agent of the past century. A member
of the World Health Organization’s List of Essential Medicines, aspirin acts
in numerous pain suppressant roles and is used immediately after a heart attack in
order to reduce the risk of death post-cardiac arrest (WHO 2011). The medication is
also used as a preventative medication for ischemic strokes, heart attacks, and blood
clotting (Reed 1914). Mechanistically, aspirin inhibits the activity of cyclooxygenase (COX), an enzyme which functions to produce prostaglandins—a specific group
of lipids. Physiologically, when aspirin is specifically used as a pain reliever, COX
inhibition reduces swelling, inflammation, and pain.
Before the development of the pharmaceutical drug aspirin, its precursor was the
medicinal usage of bark from various species of the willow tree family, such as the
white willow (Salix alba), the black willow (Salix nigra), the weeping willow (Salix
babylonica), and the crack willow (Salix fragilis) (Norn et al. 2009). These trees are
native to Asia, Europe, and some parts of North America. Since 2,000 B.C., the
­willow bark’s medicinal potential has been recognized and widely used for its anti-­
inflammatory effects and ability to treat conditions such as headaches, muscle pains,
menstrual pains, and arthritis (März and Kemper 2002). For example, about

1

The Evolution of Modern Medicine: Garden to Pill Box

11

4,000 years ago, the Sumerian culture described the pain-relieving properties of
willow bark on clay tablets (Norn et al. 2009). Ancient Mesopotamian civilizations
utilized this willow bark’s extracts to treat the daily pains and inflammations of citizens. For more than 2,000 years, traditional Chinese medicine has also made use of
willow bark and the bark of the poplar tree in order to help treat colds, goiter, and
fever. Additionally, around 400 B.C., during the time of the Greek physician and
ancient founder of medicine Hippocrates, citizens were advised to chew on the bark
of the willow tree and drink teas derived from the willow tree to relieve fever and pain
(Norn et al. 2009).
Despite such long historical usage of the willow bark, it wasn’t until 1763 that
Edward Stone, member of the Royal Society of London, conducted the first clinical
study using an extract of the willow bark on patients affected with ague (i.e., a fever
which many believed to be caused by malarial agents) (Stone 1763). By the nineteenth century, many chemists and pharmacists were experimenting with various
chemicals found in the willow bark extract. In 1829, a French pharmacist by the
name of Henry Leroux isolated a pure crystalline form of a compound known as
salicin—one of the primary active components in the willow bark (Norn et al. 2009).
After identifying this salicin compound, in 1853, a French chemist by the name
of Frederic Gerhardt combined sodium salicylate (i.e., a sodium salt of salicin) with
acetyl chloride to produce the novel compound of acetylsalicylic acid (Norn et al.
2009). Over the next few decades, various chemists worked to determine the exact
chemical structure and properties behind this molecule. Eventually, in 1899, scientists at the Bayer company manufactured the drug known as aspirin derived
from acetylsalicylic acid (Sneader 2000).
1.2.4.2

Morphine

Morphine is one of the most popular and most commonly used pain medications in
the world. Classified as an opiate, morphine works to decrease the feeling of pain by
acting directly on the CNS. The drug can be taken for both chronic and acute pain,
with morphine being used to treat pain from conditions such as bone fractures,
cancer-associated pain, and postsurgical pain (Hamilton and Baskett 2000).
Mechanistically, morphine works by binding to μ-opioid receptors in the
CNS. The G-protein in the opioid signaling chain increases the conductivity of
potassium channels and inhibits adenylyl cyclase (i.e., the enzyme which synthesizes cyclic AMP from ATP) (Brook et al. 2017). Together, all of these biochemical changes dampen the effect of the nervous system signaling systems which
transmit pain.
Morphine is derived from a plant called Papaver somniferum, commonly known
as the opium or breadseed poppy, which is a species of flowering plant in the family Papaveraceae (Miller et al. 1973). The plant was traditionally grown in the
eastern Mediterranean, but is now found all over the world. Primarily, morphine is
isolated from the poppy straw portion of the opium poppy. First isolated by the
German pharmacist Friedrich Serturner in 1804 (Lockermann 1951), the alkaloid

12

T. S. Athni and S. S. Athni

compound was named after Morpheus, the Greek god of dreams, because of its
tendency to cause sleep (Hensel and Zotterman 1951). Before the actual isolation
of the compound, the opium plant has had a long and extensive history of use.
Traditionally, an opium-based elixir was brewed by alchemists in the Byzantine era
as a potent painkiller. In the year 1522, the Swiss physician and astrologer
Paracelsus referenced an opium-based pain medication called laudanum (from the
Latin “laudare,” to praise) in his texts, but stated that it should only be used sparingly (Miller et al. 1973). In the late eighteenth century, laudanum reappeared and
became popular among the East India Trading Company, which had a direct interest in the opium trade in India. Fast forward to the nineteenth century—a few years
after Friedrich Serturner’s isolation of the alkaloid compound of morphine in
1804—the pharmaceutical company Merck began marketing morphine commercially (Brook et al. 2017). Within a few decades, pharmaceutical production of
morphine and other opioid-based medications had become a huge industry.
Currently, morphine is classified as a schedule II drug in the United States and is
on the World Health Organization’s List of Essential Medicines (WHO 2011).
However, unfortunately, the abuse of and addiction to prescription opioids such as
morphine is one of the most rampant drug epidemics that the United States and
other countries have ever seen (Brook et al. 2017).
1.2.4.3

Menthol

Cough drops. Soothing tea. Chapstick. What key ingredient do all three of these
day-to-day, winter-time items have in common? The answer is menthol, a drug produced from the mint plant that provides a cooling sensation when ingested or
applied. Besides helping to relieve sore throats and chapped lips, menthol is also
used to treat minor pains and aches of muscles and joints (Hensel and Zotterman
1951). For example, menthol is commonly used to treat conditions such as arthritis,
backache, and sprains.
How exactly does menthol work? The drug has a natural analgesic (i.e., pain
relieving) property. Mechanistically, the menthol compound acts as a ligand and
binds to the κ-opioid receptor, effectively producing a numbing effect in the target
location (Hensel and Zotterman 1951). Additionally, when menthol is applied onto
a sore or an aching muscle, the blood vessels in that location are dilated, increasing
blood flow to the area and bringing necessary nutrients faster (Hensel and Zotterman
1951). Menthol also acts by stimulating thermoreceptors within the skin cells themselves, tricking the brain into thinking that the temperature in that area has decreased
drastically (a process known as counterirritation) (Yosipovitch et al. 1996). In reality, this sense of cooling distracts the brain from the uncomfortable, hot pain at the
inflammation site.
For its vast plethora of properties, menthol is derived from a very simple plant:
the wild mint, a group of 15-20 species found in the Mentha genus (Iqbal et al.
2013). These plants are part of the family Lamiaceae and are found in nature as

1

The Evolution of Modern Medicine: Garden to Pill Box

13

perennial herbs. Having originated in the Mediterranean region and Asia, the plant
has been known to possess beneficial medicinal effects throughout history. For
example, the ancient Greeks added mint into their baths to help stimulate their bodies, and the ancient Romans included mint in certain sauces as a digestive aid and
mouth freshener (Iqbal et al. 2013).
Medieval monks also used the mint plant, especially in their cooking, in order to
help ward off illnesses. In the seventeenth century, an English traveler by the name
of John Josselyn chronicled in his writings that the pilgrims brought mint to the
New World and included botanical information on the plant (Josselyn and
Tuckerman 1865). Currently, mint has a wide distribution all around the world,
including in five continents.

1.3

Conclusion

Although this chapter details just a few of the countless naturally-derived drugs
used to treat human ailments, the full list of medications is far more extensive.
Mankind has harnessed thousands of compounds, but the wealth of undiscovered
medicinal gems in nature is unfathomable. The focus of modern pharmaceutical research has been toward the direction of lab-synthesized drugs and compounds,
yet many of these molecules unfortunately have undesirable side effects. Rather,
society should look to discover the true potential of phytochemicals in nature—an
option that is both scientifically and economically rewarding. Medicinal plants also
provide an opportunity to train young minds in the fields of botany, plant conservation,
and
natural
product
chemistry
(https://www.youtube.com/
watch?v=0YqEPDAYsWQ). Time after time, nature has shown to be the master
craftsman in creating an inexhaustible array of therapeutic molecules, and carries
infinite potential for future drug discovery and treatment of human diseases.

References
Allen DE (1987) William withering and the foxglove. Med Hist 31:375
Blaschko H (1942) The activity of l(-)-dopa decarboxylase. J Physiol 101:337–349
Brook K, Bennett J, Desai SP (2017) The chemical history of morphine: an 8000-year journey,
from resin to de-novo synthesis. J Anesth Hist 3:50–55
Bye A, King HK (1970) The biosynthesis of 4-hydroxycoumarin and dicoumarol by aspergillus
fumigatus Fresenius. Biochem J 117:237–245
Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7:a020412
Domanski MJ, Garg R, Yusuf S (1994) Prognosis in congestive heart failure. In: Hosenpud JD,
Greenberg BH (eds) Congestive heart failure: pathophysiology, diagnosis, and comprehensive
approach to management. Springer, New York, pp 622–627
Hamilton GR, Baskett TF (2000) Mandrake to morphine: anodynes of antiquity. Bull Anesth Hist
18:20–22

14

T. S. Athni and S. S. Athni

Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur
J Cancer 34:1514–1521
Hardy TK, Wakely D (1962) The amnesic properties of hyoscine and atropine in pre-anaesthetic
medication. Anaesthesia 17:331–336
Hensel H, Zotterman Y (1951) The effect of menthol on the thermoreceptors. Acta Physiol
24:27–34
Hocking GM (1947) Henbane—healing herb of hercules and of apollo. Econ Bot 1:306
Hollman A (1996) Drugs for atrial fibrillation Digoxin comes from Digitalis lanata. BMJ 312:912
Holmes FA et al (1991) Phase II trial of taxol, an active drug in the treatment of metastatic breast
cancer. J Natl Cancer Inst 83:1797–1805
Hornykiewicz O (2010) A brief history of levodopa. J Neurol 257:S249–S252
Iqbal T, Hussain AI, Chatha SAS, Naqvi SAR, Bokhari TH (2013) Antioxidant activity and volatile
and phenolic profiles of essential oil and different extracts of wild mint (Mentha longifolia)
from the Pakistani Flora. J Anal Methods Chem 2013:536490
Iskandar NN, Iriawati P (2016) Vinblastine and vincristine production on madagascar periwinkle
(catharanthus roseus (L.) G. Don) callus culture treated with polyethylene glycol. MAKARA
J Sci 20(1):7–16
Jänig W (2006) The peripheral sympathetic and parasympathetic pathways. In: Jänig W (ed)
Integrative action of the autonomic nervous system. Cambridge University Press, Cambridge,
pp 106–167
Jordan MA, Thrower D, Wilson L (1992) Effects of vinblastine, podophyllotoxin and nocodazole
on mitotic spindles. Implications for the role of microtubule dynamics in mitosis. J Cell Sci
102(Pt 3):401–416
Josselyn J, Tuckerman E (1865) New-England’s rarities discovered in birds, beasts, fishes, serpents, and plants of that country./By John Josselyn, gent.; With an introduction and notes by
Edward Tuckerman, M.A. William Veazie, Washington, DC
Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96
Kounis NG, Chopra RKL (1974) Atropine and bradycardia after myocardial infarction. Ann Intern
Med 81:117–118
Kresge N, Simoni RD, Hill RL (2005) Hemorrhagic sweet clover disease, Dicumarol, and warfarin: the work of Karl Paul link. J Biol Chem 280:e5–e5
Langley JN (1921) The autonomic nervous system. W. Heffer, Dublin
Leprince P (1986) Studies on the nicotinic cholinergic receptor of sympathetic neurons. In:
Maelicke A (ed) Nicotinic acetylcholine receptor. Springer, Berlin, Heidelberg, pp 333–344
Levi F, Randimbison L, Te V-C, La Vecchia C (2002) Long-term mortality of women with a diagnosis of breast cancer. Oncology 63:266–269
Lockermann G (1951) Friedrich Wilhelm Serturner, the discoverer of morphine. J Chem Educ
28:277
Long BH, Fairchild CR (1994) Paclitaxel inhibits progression of mitotic cells to G1 phase by interference with spindle formation without affecting other microtubule functions during anaphase
and telephase. Cancer Res 54:4355–4361
Luissint A-C, Artus C, Glacial F, Ganeshamoorthy K, Couraud P-O (2012) Tight junctions at the
blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids
Barriers CNS 9:23
März RW, Kemper F (2002) Willow bark extract--effects and effectiveness. Status of current
knowledge regarding pharmacology, toxicology and clinical aspects. Wien Med Wochenschr
152:354–359
McDonough JH, Shih T-M (2007) Atropine and other anticholinergic drugs. In: Marrs TC,
Maynard RL, Sidell FR (eds) Chemical warfare agents. Wiley, Hoboken, NJ, pp 287–303
Miller RJ, Jolles C, Rapoport H (1973) Morphine metabolism and normorphine in Papaver somniferum. Phytochemistry 12:597–603
Miners JO (1989) Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid. Clin
Pharmacokinet 17:327–344

1

The Evolution of Modern Medicine: Garden to Pill Box

15

Mortimer WG (1974) History of coca: ‘The Divine Plant’ of the incas. And/Or Press, Berkeley, CA
Müller JL (1998) Love potions and the ointment of witches: historical aspects of the nightshade
alkaloids. J Toxicol Clin Toxicol 36:617–627
Norn S, Permin H, Kruse PR, Kruse E (2009) From willow bark to acetylsalicylic acid. Dan
Medicinhist Arbog 37:79–98
Patel S, Preuss CV, Singh R, Patel N (2019) Warfarin. In: StatPearls. StatPearls Publishing,
Treasure Island (FL)
Panzeri C, Bacis G, Ferri F, Rinaldi G, Persico A, Uberti F, Restani P (2010) Extracorporeal life
support in a severe Taxus baccata poisoning. Clin Toxicol 48:463–465
Pearse JS (1876) On the action of HYOSCYAMINE and its resemblance to atropine. Lancet
108:319–320
Perry E, Walker M, Grace J, Perry R (1999) Acetylcholine in mind: a neurotransmitter correlate of
consciousness? Trends Neurosci 22:273–280
Phillipson JD, Handa SS (1975) N-oxides of hyoscyamine and hyoscine in the Solanaceae.
Phytochemistry 14:999–1003
Pollock BE (1955) Clinical experience with warfarin (Coumadin) sodium, a new anticoagulant.
J Am Med Assoc 159:1094–1097
Rajeswara Rao BR, Rajput DK (2010) Global scenario of medicinal plants. National Conference
on Conservation of Medicinal Plants, Banglore
Ratain MJ, Vogelzang NJ, Bodey GP (1987) Periwinkle alkaloids I: vinblastine and vindesine. In:
Lokich JJ (ed) Cancer chemotherapy by infusion. Springer, Netherlands, pp 167–180
Reed EN (1914) Idiosyncrasy to aspirin (Acetylsalicylic Acid). JAMA LXII:773–773
Rodnitzky RL (1992) The use of Sinemet CR in the management of mild to moderate Parkinson’s
disease. Neurology 42:44–50; discussion 57–60
Schwartz A, Matsui H, Laughter AH (1968) Tritiated digoxin binding to (Na+ + K+)-activated
adenosine triphosphatase: possible allosteric site. Science 160:323–325
Springob K, Kutchan TM (2009) Introduction to the different classes of natural products. In:
Osbourn AE, Lanzotti V (eds) Plant-derived natural products: synthesis, function, and application. Springer, New York, pp 3–50
Satake N, Kiyoto S, Shibata S, Gandhi V, Jones DJ, Morikawa M (1992) Possible mechanisms
of inhibition with atropine against noradrenaline-induced contraction in the rabbit aorta. Br J
Pharmacol 107:553–558
Sneader W (2000) The discovery of aspirin: a reappraisal. BMJ 321:1591–1594
Stierle AA, Stierle DB (2000) Bioactive compounds from four endophytic Penicillium sp.
of a Northwest Pacific yew tree. In: Bioactive Natural Products (Part E), vol 24. Elsevier,
Amsterdam, pp 933–977
Stierle A, Stierle D, Strobel G, Bignami G, Grothaus P (1994) Bioactive metabolites of the endophytic fungi of pacific yew, Taxus brevifolia. In: Taxane Anticancer Agents, vol 583. American
Chemical Society, Washington, pp 81–97
Stone E (1763) XXXII. An account of the success of the bark of the willow in the cure of agues.
In a letter to the Right Honourable George Earl of Macclesfield, President of RS from the Rev.
Mr. Edward Stone, of chipping-Norton in Oxfordshire. Philos Trans 53:195–200
Tennant FS Jr (1969) Vinblastine for adult histiocytosis X. JAMA 210:2284
Tomita-Yokotani K, Hashimoto H, Fujii Y, Nakamura T, Yamashita M (2004) Distribution of
L-DOPA in the root of velvet bean plant (Mucuna pruriens L.) and gravity. Biol Sci Space
18:165–166
Van Maanen J, Retel J, De Vries J, Pinedo HM (1988) Mechanism of action of antitumor drug
etoposide: a review. JNCI 80:1526–1533
West FR, Mika ES (1957) Synthesis of atropine by isolated roots and root-callus cultures of
belladonna. Bot Gaz 119:50–54
WHO (2011) WHO model list of essential medicines: 17th list, March 2011
Wilson CR, Hooser SB (2012) Chapter 82: Toxicity of yew (Taxus spp.) alkaloids. In: Gupta RC
(ed) Veterinary toxicology (Second Edition). Academic Press, Cambridge, pp 1121–1127

16

T. S. Athni and S. S. Athni

Withering W (2014) An account of the foxglove, and some of its medical uses. Cambridge
University Press, Cambridge
Yosipovitch G, Szolar C, Hui XY, Maibach H (1996) Effect of topically applied menthol on
thermal, pain and itch sensations and biophysical properties of the skin. Arch Dermatol Res
288:245–248
Zach H, Dirkx M, Pasman JW, Bloem BR, Helmich RC (2017) The patient’s perspective: The effect
of levodopa on Parkinson symptoms. Parkinsonism Relat Disord 35:48–54

Chapter 2

Bioprospecting for Pharmaceuticals:
An Overview and Vision for Future Access
and Benefit Sharing
Danielle Cicka and Cassandra Quave

2.1

Introduction

Before the advent of synthetic chemistry, plants were well known as a primary
source of medicine. Still today, medicinal plants are used for healing around the
world; in some regions, up to 80% of the population relies on plants as primary
sources of medicine (WHO 2002). Conservative estimates show that at least 28,187
plant species are currently recorded as being of medicinal use (RBGK 2017).
Though drug discovery has tended toward synthetic compounds, almost half of the
drugs approved since 1994 are based on natural products (Harvey 2008). These
medicines include some of the world’s most essential medicines including acetylsalicylic acid, dihydroartemisinin, pilocarpine, and warfarin (WHO 2017). With the
increase of microbial resistance, chronic disease, and heavy burden of communicable disease, new medications are in high demand. Plants can help meet this
demand by their unparalleled array of untapped complex chemical diversity.
This chapter gives an overview of the role of bioprospecting in the drug discovery process, the unique regulatory environment for such drugs, challenges in bioprospecting, and a vision for navigating these processes for future discovery.

2.2

Plants in Drug Discovery

Plants play several critical roles in the development of pharmaceuticals. Their
unique chemical compounds may be developed into novel drugs as well as become
the basis for novel drug classes. Further, the accessibility of plants throughout

D. Cicka · C. Quave (*)
Emory University, Atlanta, GA, USA
e-mail: cassandra.leah.quave@emory.edu
© Springer Nature Switzerland AG 2019
N. Joshee et al. (eds.), Medicinal Plants,
https://doi.org/10.1007/978-3-030-31269-5_2

17

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D. Cicka and C. Quave

h­ istory has allowed for much investigation by local communities and this knowledge can be used to assist targeted drug development.

2.2.1

The Story of Paclitaxel

The discovery of bioactive compounds from natural products has had important
contributions in several aspects of drug development. The story of the discovery of
the natural product paclitaxel, a widely used cancer chemotherapy, exemplifies the
contribution of natural product research throughout the drug discovery process.
In 1962, the National Cancer Institute and the United States Department of
Agriculture conducted a collection of plants for screening. Through this untargeted
mass screening of plant extracts for bioactivity, 4% of extracts were found to have
anticancer activity (Suffness and Douros 1982). The Pacific yew (Taxus brevifolia
Nutt., Taxaceae) was found to have cytotoxic effects. The compound paclitaxel was
eventually isolated from the Pacific yew via bioassay-guided fractionation and
underwent clinical trials for ovarian cancer (McGuire et al. 1989) and breast cancer
(Holmes et al. 1991). Paclitaxel stabilizes microtubules, preventing their disassembly during cell division and is used especially for ovarian tumors, representing a
novel mechanism of action at the time (BMS 2011; Schiff et al. 1979).
However, T. brevifolia yields a small quantity of paclitaxel, just 0.02% from the
bark (Wani et al. 1971). Further, stripping the bark for collection of paclitaxel is
detrimental to the survival of the tree and therefore is not a sustainable resource for
anticancer treatment. The structure of paclitaxel is so complex that the process of
total synthesis is neither time nor cost efficient. To preserve the species, structure-­
activity relationship (SAR) studies were undertaken to determine the active structural components of paclitaxel necessary for the preservation of therapeutic effect.
A related species, English yew (Taxus baccata L., Taxaceae) was screened for its
microtubule effects (Guenard et al. 1993). A compound in the species, baccatin, was
found to be a precursor of paclitaxel, but did not exhibit the anticancer properties.
The difference between baccatin and paclitaxel resides in a specific side chain,
which was then deemed essential for paclitaxel’s bioactivity. Baccatin as well as
10-deacetylbaccatin III is found in higher quantities than paclitaxel in T. baccata;
10-deacetylbaccatin III can then be synthesized into paclitaxel (Fig. 2.1). These
compounds are found in high quantities in the needles of the tree, providing a
renewable resource (van Rozendaal et al. 2000). Paclitaxel can also be more sustainably synthesized from plant cell cultures (Malik et al. 2011) or from fungal endophytes (Stierle et al. 1993). These options allow the sustainable production of
paclitaxel in higher quantities.
Paclitaxel is just one example of a lifesaving, natural product pharmaceutical.
The structural complexity and diversity of natural products derived over years of
selective pressure of plant defenses can not only offer novel treatments, but also add
to the repertoire of chemical structures from which drugs can be modeled.

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Bioprospecting for Pharmaceuticals: An Overview and Vision for Future Access…

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Fig. 2.1 Structure of paclitaxel and its precursors. (a) Paclitaxel. (b) Baccatin III. (c)
Deacetylbaccatin III

2.2.2

Structure-Activity Relationship Studies

Bioactive compounds from plants can be used as scaffolds for structure-activity
relationship (SAR) studies. These analyses identify the active groups of the compound to determine how modifications can maximize the effect of the compound.
As discussed previously, SAR studies were crucial for the discovery of a sustainable
source of Taxol.
As natural compounds have greater complexity and diversity than synthesized
libraries, the potential for novel structures is great (Camp et al. 2012). There has

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D. Cicka and C. Quave

been continued use in recent years of SAR studies of natural products in search for
treatments for diseases such as malaria, breast cancer, and Alzheimer’s (Aratikatla
et al. 2017; Lee et al. 2017; Robles et al. 2017). The more natural product structures
that are elucidated, the more SAR studies can be completed by comparing the activity of various molecules. Screening large natural product libraries has many challenges compared to synthetic compounds; however, natural products likely already
have bioactivity for the plant, and thus may have a high likelihood to be active in
other biological systems (Atanasov et al. 2015; Hunter 2008).

2.2.3

Ethnobotanical Approach to Drug Discovery

An ethnobotanical approach to drug discovery is one in which the traditional uses
of a plant are taken into consideration when looking for potential therapies in nature.
In fact, natural products are more likely to be bioactive when based on ethnomedical
data rather than random screens (Elvin-Lewis 2011). Though random screens such
as the National Cancer Institute’s search for anticancer compounds had viable
yields, a more strategic approach can increase prospects of finding bioactive
compounds.
The discovery of artemisinin particularly exemplifies this strategy and its necessity for effective drug discovery. Dr. Youyou Tu is credited with the discovery of
artemisinin from sweet wormwood (Artemisia annua L., Asteraceae). This compound and its derivatives have been widely used as an antimalarial drug, rendering
Dr. Tu a winner of the 2015 Nobel Prize in Physiology or Medicine. Artemisia was
screened for antimalarial properties in the 1960s as part of a study of traditional
Chinese medicine (TCM), but was found to have fluctuating effects on the parasitic
infection. However, when an extraction method was developed that incorporated its
traditional preparation, the active compound was isolated (DeNicola et al. 2011).
Artemisinin-based combination therapies are now recommended for treatment of
Plasmodium falciparum infections worldwide (WHO 2016).

2.3

Framework for Managing Intellectual Property

Given the successes of bioprospecting, it is essential to preserve natural biodiversity
and the capacity of corporations and local communities to continue to develop the
potential of natural resources. Care must be taken to ensure the protection of knowledge and maintenance of ethical standards to avoid exploitation of natural products
and traditional knowledge while recognizing the financial incentive for companies
and local communities to develop lucrative pharmaceuticals. Though this section is
not all encompassing, discussion of the regulatory environment is necessary to paint
a picture of the hurdles and protections involved in bioprospecting. Even though a

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Bioprospecting for Pharmaceuticals: An Overview and Vision for Future Access…

21

framework exists for navigating the regulatory environment, there is a lack of clarity
for its implementation. It is a problem for all parties involved when intellectual
property is not protected. This is especially clear when natural products and their
indications for use are traditionally used by local communities.

2.3.1

 rotecting Intellectual Property of Researchers:
P
Patenting of Natural Products

The process of drug discovery is long and arduous; however, as stated at the start of
this chapter, patience is rewarded as there have been many invaluable medicinal
discoveries from natural resources. To market active compounds as pharmaceuticals
in the United States, the product must meet standards for approval by the Food and
Drug Administration as a pharmaceutical. While drugs are being developed and
undergoing clinical trials, protection of the investigators’ rights to the compound
must be maintained. Investigators may seek to secure patents on the active compound while bringing the use of the natural product to commercialization to the
public domain. The FDA also grants market exclusivity separately from patents that
may have a different time course than the patent for certain pharmaceuticals (FDA
1999). Without patents, discoveries would become public knowledge much sooner,
which may inhibit a discoverer from recouping discovery costs as soon as another
party is able to market and sell the compound.
There are specific patenting issues to address when working with natural products. Patent laws differ by country and a product can be patented in multiple countries (Worthen 2004). Focusing on the United States in this chapter, patenting natural
products has recently been put into the spotlight. In 2013, the United States Supreme
Court ruled against patenting of naturally occurring entities such as genes in
Association for Molecular Pathology vs. Myriad Genetics Inc. Due to this case and
others before it, the court issued a memorandum on patent eligibility for natural
products (Wong and Chen 2014). This document states that a patentable product
must be significantly different from its naturally occurring form (Hirshfeld 2014).
Therefore, a biologically active natural product likely will have to be modified if it
is to be patentable. This lends to the following possibilities for patentable entities.
One could possibly patent the altered product itself, the method of production, or a
novel use of the product. If the constituents of the product cannot be fully determined, a product-by-process patent may be considered. This does not include products synthesized from a new process that are identical to a naturally occurring
product. For one to patent the method of production, the method cannot simply be
common knowledge or a general application of the product. The specific dosage,
regime, and disease target must be stated (Hirshfeld 2014; Wong and Chen 2014).
Though the barriers to patenting drugs may be stringent, they provide some hope for
stability and protection in a competitive market in which investment of time and
capital is extraordinary.

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2.3.2

D. Cicka and C. Quave

 rotecting Intellectual Property of Local Communities
P
and Biodiversity

Exploitation of natural resources and their guardians is a concern in the pursuit of
lifesaving medications. In 1993, the Convention on Biological Diversity (CBD)
established rules regarding the protection of biodiversity. This agreement laid the
groundwork for fundamental principles of intellectual property rights to protect
both economic incentives and maintain biodiversity. The convention established
that prior informed consent must be obtained from informants and mutually agreed
terms determined in order to achieve adequate benefit sharing (UN 1992). Around
the same time, in 1991, the International Cooperative Biodiversity Groups Program
(ICBG) was established and provided for benefit-sharing projects. The CBD was an
important step; however, it was criticized for its lack of specific requirements, leaving interpretation to individual countries. Thus, the 1995 Agreement on Trade-­
Related Aspects of Intellectual Property (TRIPS), for members of the World Trade
Organization, attempted to fill some of the gaps left by the CBD, particularly by
requiring minimum patent laws of member nations (WTO 1995).
Further, the Nagoya Protocol, implemented in 2014, was developed as a supplement to the CBD. Its aim is to ensure benefit sharing when using genetic resources
(CBD 2011). It currently has 93 member parties. Most members of the UN have
ratified the Nagoya Protocol, the notable exception being the United States (CBD
2017). The Nagoya Protocol aimed to address specific benefit-sharing goals not
explicitly addressed by the CBD including promotion of the role of women as stakeholders of traditional knowledge and necessity of explicit capacity-building agreements with developing countries.
The Nagoya Protocol and the TRIPS agreement, though both aimed at the protection of knowledge, highlight different aspects of the protection. TRIPS does not
state the importance of benefit sharing, but rather focuses on the importance of
maintaining intellectual property rights, often in the form of patents. The Nagoya
Protocol focuses more on access and benefit and places intellectual property rights
as one of the possible benefits. Various other legal documents to clarify access and
benefit sharing have been developed, though mostly by developing nations
(Medaglia and Silva 2007). However, these major legislative pieces highlight the
different aspects of post-CBD agreements between researchers and local communities. Implementation of the Nagoya Protocol and CBD may be improved by having
an overarching regulatory body to help navigate adherence to the protocol.

2.3.3

Organizational Regulations

Various international professional societies have delineated standards for members’
publications which help to accomplish the goals of the international regulations.
These standards include obtainment of informed consent and engagement of

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23

c­ ommunities throughout the process. For example, the Society for Economic Botany
adheres to the International Society of Ethnobiology Code of Ethics (ISE 2006),
which expects its members to uphold communities’ rights as historical protectors of
the genetic resources and requires informed consent. The American Society of
Pharmacognosy also mandates its members to try to protect communities and obtain
prior informed consent (Flamini et al. 2002). Though these statements err on the
side of vagueness, this may allow each agreement to be shaped to fit the needs of the
project and the parties involved.

2.3.4

Managing Expectations

Ethical standards are critical; however, those standards can only be maintained if
both parties agree that the standards have been met. Managing expectations of the
outcome of bioprospecting endeavors is vital to this mutual understanding of realistic results. With the hope of a blockbuster drug on the horizon, source countries
may have unreasonable expectations about the financial gains of partnering with a
drug discovery team. Expectations on both sides need to be transparently outlined
initially. A typical marketable drug costs $2.558 billion to develop (DiMasi et al.
2016) and can take at least 10 years (NCCIH 2015). Local communities and partnering countries need to be aware that there is no guarantee that a blockbuster drug
will be discovered from the partnership. On the other hand, researchers face expectations for publication and revenue generation from their employers. Provisions
for conservation and benefit sharing at the initiation of the project can protect
against pressure-­
causing parties to default on vague promises or act on
unfounded fears.
Disparities in expectations can arise from differences in the information to which
each party has access. Countries supplying natural products may not know how
much the products are worth and overestimate their value. They also may not be
able to follow the product throughout the research process and therefore enact stringent access regulations. Researchers may distrust their in-country partners since the
quality of the natural products may not be transparent and they may not know how
their benefits are being utilized (Richerzhagen 2011). Maintaining realistic expectations is difficult but necessary in a field of uncertainty and diversely specialized
players.

2.4

Challenges in Bioprospecting

Though there is much promise in bioprospecting for the discovery of novel compounds and uses, there are significant hurdles to overcome in the process. Strides
have been made toward improving access and benefit sharing, but the potential ben-

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D. Cicka and C. Quave

efit of these agreements is still greatly untapped. An interdisciplinary approach may
be necessary to harness the potential of these regulatory environments to better
serve all parties.

2.4.1

Biopiracy

The fine line between bioprospecting and biopiracy has been a constant debate
despite regulations (Rose et al. 2012). The term “biopiracy” is credited to the Rural
Advancement Foundation International (RAFI) and generally refers to the use of
intellectual property systems to legitimize the exclusive ownership over biological
resources and processes that have been historically used in nonindustrialized nations
(RAFI 1993).
International cooperative biodiversity groups (ICBGs) were developed in 1991
to be the model for cooperation between drug discovery and protection of knowledge. They supported the ideals of prior informed consent, benefit sharing, local
infrastructure development, and biodiversity management (Rosenthal 1997). RAFI’s
critiques, along with protests from COMPITCH, the State Council of Organizations
of Indigenous Traditional Healers and Midwives, against ICBG-Maya caused the
project to fold in 2001 (ETC 2001). Critiques also came from the International
Society of Ethnobiology for failure to achieve adequate consent and debate ensued
over the criteria of such consent. The conflict that arose over ICBG Maya reveals the
complexities of remaining an unbiased researcher while navigating a the historical
and political landscape as well as managing external pressures and competing
voices (Hayden 2003). This case highlights how the very fine line between biopiracy and bioprospecting is subject to interpretation by different participating
members.
Biopiracy is still a major concern, though. At a 2002 meeting in Cancun, 17 member nations of Like-Minded Megadiverse Countries made it a priority to ensure the
careful protection of Latin America’s and South America’s unparalleled diversity of
plants. Commenting on the status of bioprospecting in this region, Fernando
Quezada, Consultant of the Sustainable Development and Human Settlements
Division of the Economic Commission for Latin America and the Caribbean,
acknowledged that the megadiverse countries have a fear of being taken advantage
of and this has resulted in a hindrance to drug development (Quezada 2007).
Stringent legislation regarding bioprospecting stems partly from fear of biopiracy and exploitation of endangered species. This fear is not unfounded for cases
such as Brazil where the illegal trade of wildlife is a massively profitable and rampant industry (Rocha 2003). The illegal trade is detrimental to biodiversity and to
indigenous communities as protocols for benefit sharing and conservation are not
adhered to.
Though the CBD established states’ control over access to their genetic resources,
these agreements will require careful planning (UN 1992). The Nagoya Protocol
combats this problem of biopiracy by providing more specific international require-

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Bioprospecting for Pharmaceuticals: An Overview and Vision for Future Access…

25

ments for research endeavors. Promoting transparency, ensuring accountability, and
establishing legal frameworks will need to occur in order for adherence to this protocol (Kursar 2011).

2.4.2

Conservation

The Nagoya Protocol encourages conservation efforts when bioprospecting.
Enforcement of these measures is crucial as nonadherence can have devastating
effects. For instance, it was found that parts of Bushman’s hat (Hoodia gordonii
(Masson) Sweet ex Decne., Apocynaceae) have dramatic appetite-suppressant
effects. The San people, an indigenous group in South Africa, used the plant to suppress appetite while hunting. Phytopharm filed for patents on H. gordonii active
components; however, this was done without prior informed consent or benefit sharing with the San people. The South African Council for Scientific and Industrial
Research intervened to establish an agreement between the two parties (Robinson
2010). Though it is not currently marketed as a pharmaceutical, the publicity generated led to its collection and marketing as a health food supplement by other companies not a part of the agreement (Wynberg et al. 2009). Now, H. gordonii is
included in Appendix II of the Convention on International Trade and Endangered
Species of Wild Fauna and Flora to protect it from unsustainable collection (CITES
n.d.). This case highlights the importance of up-front consent and benefit sharing
and the importance of ensuring biodiversity within those agreements.
Furthermore, the World Health Organization issued regulations on the collection
of medicinal plants for the safety of the species and the users. The regulations prevent overharvesting by prohibiting collection of plants that are scarce and mandating that the source country ensure that the plants do not become endangered. Further,
these regulations ensure that plants are identified correctly and are not exposed to
large amounts of pesticides or chemicals (WHO 2003). Adherence to the Nagoya
Protocol and WHO policies is one step toward the prevention of the detrimental
effects of the commercialization of medicinal plants, as seen with the collection of
H. gordonii.

2.4.3

Sharing of Intellectual Property

There are two intellectual property components at stake—the property of the local
communities that provide ethnobotanical knowledge and the property of the
researchers that develop the plant extracts into single-compound pharmaceuticals or
refined formulations of botanical drugs. Without protected intellectual property, the
economic incentive for developing pharmaceuticals could diminish for all parties
involved. However, the intellectual property used in the discovery process must be
shared respectively among all parties involved in the development of the pharma-

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D. Cicka and C. Quave

ceutical and contracts must be negotiated fairly and clearly across national and
political boundaries. Tangible benefits of sharing intellectual property can take various forms and will be discussed in the future direction portion of this chapter.
There are inherent general challenges when sharing intellectual property. First,
determination of who is the rightful owner of the ethnobotanical knowledge can be
difficult. Different communities may have similar ethnobotanical knowledge of how
to use a plant for medicinal purposes. Determining who should be given benefits
and a share in the intellectual property is challenging and is best determined early
on in the process of bioprospecting. Researchers have used a variety of definitions
to guide them. In ICBG-Peru, it was discussed that all Aguaruna communities
would receive long-term benefits and those directly involved with research would
receive more immediate benefits. Sometimes, royalties are shared among all communities a company has worked with, a stance taken by Shaman Pharmaceuticals
(King 1994; Rosenthal 1997). Naming individuals on patents is a more guaranteed
way to ensure that benefits are distributed to locals, but such individual inventors
must be defined (USPAT 2015).

2.4.4

Access to Resources

Before the bioprospecting research even begins, there are hurdles to overcome, specifically in obtaining permits to access the plants of interest. Access permits are
administered by each individual country. These permits are difficult to obtain in
certain countries, to the extent that researchers have been dissuaded from collecting
in some regions. For example, Brazil has a multitude of agencies with the power to
approve a permit (Silva and Espindola 2011), rendering the permit process unclear
and decentralized (Danley 2011). Additional permits may also be needed after
access is granted. Permits may be needed to export materials from the country and
for additional uses than originally intended (Medaglia and Silva 2007; Silva and
Espindola 2011).

2.5

Future Directions in Bioprospecting

The future of bioprospecting will necessitate addressing some of the challenges
associated with bioprospecting, especially regarding adequate access and benefit-­
sharing agreements. To accomplish this, several models of access and benefit sharing have been employed around the world. However, there is no streamlined process
for formulating these complex agreements. Ensuring that interdisciplinary players
and representatives of all parties are party to forming these agreements can help
mitigate some of the difficulties of bioprospecting.

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Bioprospecting for Pharmaceuticals: An Overview and Vision for Future Access…

2.5.1

27

Access and Benefit Sharing

A practical way to ensure protection of intellectual property of host countries is
through adequate access and benefit sharing. Though access and benefit sharing
have been required by the Nagoya Protocol, there is much room for interpretation.
The benefits have taken a variety of forms suited to the project’s capabilities and the
communities’ needs.
Benefit sharing can take two forms: monetary or nonmonetary. For monetary
benefit sharing, different payment schedules can be devised, including payments for
the plants collected, research using the plants, and royalties from any product developed. Advance payments can also be used, as in the form of trust funds, which can
help communities up front during the long drug discovery process (Guerin-­
McManus et al. 2002; Rosenthal 1997). Patents may provide some monetary benefits, but are generally not considered the best mechanism for benefit sharing with
local communities (Greaves 1994) and require that all parties to receive monetary
benefit be individually named on the patent for effective distribution of monetary
compensation (Rose et al. 2012).
Access and benefit sharing do not solely imply monetary compensation for gains
from a blockbuster drug. Monetary compensation may never be a reality as many
potential pharmaceuticals fail clinical trials, and many products collected and tested
never make it past the laboratory bench. Access and benefit sharing require open
communication with the host country and groups throughout the process.
Perhaps equally constructive for local communities are nonmonetary benefits.
Maintaining close connections with the host country and the local communities may
help mitigate some of uncertainty of loose ties between parties in the lengthy
research and development process. These benefits may be in the form of training for
the project, capacity building, commitment to research local diseases, or provision for conservation needs. Several ICBGs enacted advance payments for conservation and development projects. In fact, each ICBG had elements of capacity
building in the form of community health clinics, herbaria, or equipment for research
(Rosenthal 1997).
Collaborations with host country universities can support worldwide research
connections. For example, the National Cancer Institute established a partnership
with a Panamanian research institute to build local capacity and relations (Rose
et al. 2012). Additionally, researchers can assist in the preservation of knowledge by
reporting back collected data in a manner that is accessible to the local communities. For instance, books in the local language recording uses of local plants can be
gifted to the community. Lastly, there is an untapped market for the pharmaceutical
industry to contribute to combating diseases that primarily affect the source countries of their partnerships (Rose et al. 2012). Encouraging pharmaceutical companies to invest in those disease areas could increase the industry’s involvement in the
neglected disease sector.
Outside organizations such as governmental institutions or NGOs may be necessary to ensure conservation of natural resources long term. Benefits may be given to

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D. Cicka and C. Quave

the government or NGO as well as in the case of Suriname ICBG and the African
ICBG, respectively (Rosenthal 1997). To further ensure adequate benefit sharing,
local organizations can empower local communities to become knowledgeable
about the contracts they are signing.
Benefit sharing is often undefined, causing remunerations to be forgotten or lost
in the discovery process. Because research is often not carried out by the same
people for the entirety of the project, original informants or terms of agreement may
be ignored (Rose et al. 2012). Further, as stated earlier, determining the recipient of
such benefits is important and can take several forms.

2.5.2

The Role of Ethnobotanists

Ethnobotanists provide a crucial link between the protection of indigenous knowledge and the advancement of scientific discoveries due to their close relationship
with communities and their knowledge of botany. Ethnobotanists are those generally equipped with botanical and anthropological knowledge, though there are few
degree-awarding programs in ethnobotany. While ethnobotanists may seem like the
perfect marriage of anthropology and botany, they are still an underutilized source
for medicinal plant collections. In a 2010 editorial, the Journal of Ethnopharmacology
highlighted the underutilization of interdisciplinary research, though it is a popular
buzzword (Heinrich 2001).
Ethnobotanists have the skillset to address the social aspect as well as the botanical aspect of bioprospecting. For example, it is important to address the distribution
of botanical knowledge and whether the knowledge differs between lay person and
healer in order to correctly choose informants for the project. Knowledge of techniques such as cultural consensus analysis, an anthropological technique to determine the accurate descriptions of local knowledge, can be employed in determining
the trustworthiness of information from single informants. Further, a researcher
who knows how to correctly collect anthropological data will be better suited to
classify illnesses where terminology may differ from Western medicine (Reyes-­
García 2010).
Botanical knowledge of an ethnobotanist is vital as well since the researcher
must have the skills to correctly prepare a botanical voucher and obtain the necessary information on how a plant is prepared for usage (Elvin-Lewis 2011). The
ability to integrate anthropological and botanical knowledge will not only provide a
robust study of medicinal plants, but also build strong relationships with the
community.
Furthermore, registering knowledge in a database may be useful for communities who wish to provide regulated access to their knowledge for data mining of the
information collected by researchers (Ningthoujam et al. 2012). Ethnobotanists
would be a vital asset in helping to set up such databases in a fashion suited for the
community. Countries have already begun to establish databases, but some have
expressed concerns about their release until there is a system of international

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29

p­ rotection for the information (Elvin-Lewis 2007). The regulation of such databases
will be further discussed in the following section.

2.5.3

A Vision for an Interdisciplinary Bioprospecting Strategy

The crux of successful bioprospecting hinges on access and benefit sharing between
all parties involved. Partnerships between industrialized and developing nations
through bioprospecting have the potential to play a vital role in fostering trust and
teamwork. Bioprospectors and local communities both recognize the value in the
natural world and can unite around their common respect for nature and its potential
to fight illness. Few areas of science incorporate both the traditional and modern
views of healing and this can be a major point of dialogue.
These terms of benefit sharing must be clearly delineated before research has
begun. While there may not be a standard template for all bioprospecting endeavors,
flexibility will allow each project to reach terms that are mutually agreeable to the
parties involved. The terms must include provisions for plasticity if needed
(Rosenthal 1997). This may necessitate the involvement of an unbiased third party
to negotiate the terms. Ethnobotanists could be an important part of that team since
they are familiar with the challenges of obtaining knowledge and protecting it.
Public registration of traditional knowledge in databases would allow for large
searches for information; however, this would strip the knowledge of some ability
to generate revenue. If the knowledge is available to all, it also becomes prior art and
cannot be patented according to US law (35 U.S.C. § 102). However, much of the
medicinal plant knowledge today is already public. On the other hand, databases
with selective access may allow communities to generate revenue from access fees
imposed on knowledge for research (Elvin-Lewis 2007). Additionally, knowledge
from multiple communities could be registered in a database in which communities
only have access to their own information. When there is a question as to whether
certain information is unique to a community, software may be used to search the
whole database for similar information (Sampath 2005). Elvin-Lewis describes the
complexities of establishing databases and defining ownership (Elvin-Lewis 2007).
In an ideal world, a third-party or academic organization would establish an
independent organization that could negotiate between local communities, their
databases, researchers, and governments (Fig. 2.2). This would ensure adequate
benefit sharing, minimizing lawsuits post-discovery. This organization would compile a regulatory board of reviewers for each bioprospecting venture. The board
could be based on permanent or long-term representatives from academia representing the areas of anthropology, ethnobotany, law, and basic science. Academics are
in a unique position to help subdue biases of supplier countries and researchers,
with their general commitment to furthering of scientific knowledge and access to
disciplines that work closely with local communities. Others on the board would
change for each case, with the minimum following categories being represented: a
pharmaceutical company representative, a source country governmental

30

D. Cicka and C. Quave

Anthropologist

Patent Lawyer

Ethnobotanist

Basic Scientist

Regulatory
Board
Local
Community
Representative

Certificates of Compliance
NGO
Representative

Source Country
Government
Representative

Access and Benefit Sharing Agreements

Ethnobotanical Databases

Pharmaceutical
Company
Representative

Fig. 2.2 Model for a third-party regulatory board. The board would serve to check the interests
and biases of other board members while taking into account each member’s expertise. Issues and
pressures would be brought to the board to protect the active participants in the agreements. Green
squares: long-term members. Blue circles: project-specific members

r­epresentative, and a local community representative. NGOs supporting the rights
of local communities may be involved as well. The long-term members should be
trained in the intricacies of bioprospecting negotiations.
Importantly, this third-party organization could supply certificates of compliance
(Richerzhagen 2011) to each party, certifying that each has met the standards of the
CBD and Nagoya Protocol. This international indicator of compliance would diminish some of the mistrust and increase transparency in negotiations between parties
involved.
Ethnobotanists on the team could assist communities in establishing databases of
their traditional knowledge since there is danger of its loss through generations
(Benz et al. 2000; Krauss 1992; Ramirez 2007; Reyes-García et al. 2013). They
would also be in a position to encourage governments to conserve their biodiversity.
When negotiations are made, benefits could be given to the local people and to the
governments, to avoid dissemination of benefits through corrupt governmental
infrastructure.
The organization could be the mediator between researchers and local databases
of knowledge so that local people can effectively capitalize on their knowledge
while avoiding pressures from large pharmaceutical companies. It is imperative that
local communities and their advocates be vital members of any discussions.
A third party would allow for centralization of negotiations. Many projects have
received criticism for failing to interact with communities or provide adequate benefits. Further, researchers have become leery of the difficult legal processes involved
in each country. This would take some burden off the researchers and communities
and allow centralization of regulatory processes.

2

Bioprospecting for Pharmaceuticals: An Overview and Vision for Future Access…

2.6

31

Conclusion

If bioprospecting practices are not established in an easy-to-navigate and enforceable format, they will continue to be circumvented for exploitation of local communities and the environment. Ethical players will be discouraged from entering the
bioprospecting business.
Though there is much room for improvement, it is clear that nature’s chemistry
is complex and rich in diversity and should be utilized to maximize its benefits,
especially for those that already use natural products for treatment. This area of
scientific endeavor has the opportunity to unite efforts across economic borders if
this turbulent area of work can be navigated and result in the centralization of negotiations of individualized agreements that adhere to the ethical and equitable principles of the Convention on Biological Diversity and Nagoya Protocol.

References
Aratikatla EK, Valkute TR, Puri SK, Srivastava K, Bhattacharya AK (2017) Norepinephrine alkaloids as antiplasmodial agents: synthesis of syncarpamide and insight into the structure-­activity
relationships of its analogues as antiplasmodial agents. Eur J Med Chem 138:1089–1105.
https://doi.org/10.1016/j.ejmech.2017.07.052
Atanasov AG et al (2015) Discovery and resupply of pharmacologically active plant-derived
natural products: a review. Biotechnol Adv 33:1582–1614. https://doi.org/10.1016/j.
biotechadv.2015.08.001
Benz BF, Cevallos J, Santana F, Rosales J, Graf S (2000) Losing knowledge about plant use in the
Sierra de Manantlan biosphere reserve, Mexico. Econ Bot 54:183–191
BMS (2011) TAXOL (paclitaxel) injection
Camp D, Davis RA, Campitelli M, Ebdon J, Quinn RJ (2012) Drug-like properties: guiding principles for the design of natural product libraries. J Nat Prod 75:72–81. https://doi.org/10.1021/
np200687v
CBD (2011) Nagoya protocol on access to genetic resources and the fair and equitable sharing of
benefits arising from their utilization to the convention on biological diversity. United Nations,
Montreal
CBD (2017) Parties to the Nagoya protocol. Convention on Biological Diversity. https://www.cbd.
int/abs/nagoya-protocol/signatories/default.shtml
CITES (n.d.) Convention on international trade in endangered species of wild fauna and flora
appendices I, II, III
Danley V (2011) Biopiracy in the Brazilian Amazon: learning from International and comparative
law successes and shortcomings to help promote biodiversity conservation in Brazil. Florida A
& M Univ Law Rev 7:291
DeNicola GM et al (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and
tumorigenesis. Nature 475:106–109. https://doi.org/10.1038/nature10189
DiMasi JA, Grabowski HG, Hansen RW (2016) Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 4