1A. Drug Discover and Development

drug

is a chemical or biological substance that has a physiological or biochemical effect once ingested or introduced into the body

drug

it may be a single compound or a mixture of different compounds.

drug

Its effects are intended to be beneficial but can cause harmful side effects in some people.

stimulating or blocking

Drug works either by ___or ___ the activity of their targets.

therapeutic effect

All drugs interact with specific ‘targets’ in the body, with the aim of modifying their activity and often resulting in a ___. For example, pain relief.

-usually proteins

-small regions of dna or rna

Drug targets are usually ___ but are, in some cases, small regions of __ or _

herbs and potions

early 19th century, medicines consisted mainly of ___ and __

pure chemicals

mid-19th century, the start of isolating and purifying the “active principles” of those remedies (i.e. the ___responsible for the medicinal properties).

pharmaceutical companies

The success of these efforts led to the birth of many of the__we know today.

NATURAL PRODUCT SPIKE OFF

Since then, many naturally occurring drugs have been obtained and their structures determined.

“lead compound”

drug discovery and drug development also evolved; drug research was then very much focused on what is known as the___

cellular and molecular

rise of medicinal chemistry on the_ and_ level

structure and function

rise of medicinal chemistry

As a result, identifying a suitable target in the body and designing a drug to interact with that target

__ of the target, as well as the mechanism by which it interacts with potential drugs, is crucial to this approach

1. Drug Discovery

2. Drug Rational Design

3. Drug Development

Drug discovery , Design, development, this led to the identification of 3 major stages:

trial and error

Ancient times: The use of natural extracts for medicinal purposes goes back thousands of years. Most likely discovered through a combination of __, early medicines often had as much religious and spiritual significance as they did healing importance.

plants

What were the basis of the ancient medicines, and were complemented with minerals and animal substances. Often the same plants and herbs times were used for similar diseases among different civilizations, even though they were discovered separately.

heretics

5th-15th centurey: Treatment of disease through development of new herbal remedies may have been very difficult in an environment where the prevailing attitude is that disease is God's punishment for sin. Practitioners of herbal remedies would often be seen as __. Medical progress is very weak due to the prevailing unscientific opinion.

pharmacopeias

14th-17th century: During the Renaissance, the development of medicinal remedies in Europe is reborn. __are established in multiple cities.

Rudolf Buchheim

Oswald Schmiedeberg

Paul Ehrlich

Henry Dale

The subject of pharmacology (Materia Medica) is established as a scientific discipline late in the century, by people such as ___.

Oswald Schmiedeberg

Until the late 1800s, most drugs are based on herbs or extraction of ingredients from botanical sources. __ (1838-1921) is generally recognized as the founder of modern pharmacology.

active ingredients

20th century: In the 1930s, drug discovery starts concentrating on screening natural products and isolating the active ingredients for treating diseases. The ___ are normally the synthetic version of the natural products.

penicillin

The introduction of __in the 1940s starts the era of antibiotics, which are recognized as one of the greatest advances in therapeutic medicine.

Watson and Crick

A great milestone that 20th century would boost the era of DNA and medicine is the elucidation of the double-helical structure of DNA by ___in 1953.

vancomycin

In the 1950s __is discovered.

biotechnology industry

In the late 1970s, recombinant DNA products utilizing knowledge of cellular and molecular biology starts development, and the __launches!

combinatorial chemistry, high-throughput screening, molecular modeling and bioinformatics are already contributing to the discovery

By the 1990s, __of newer generation drugs based on genomics and proteomics.!)

21th century

In the current century, more pharmaceutical advances are made possible thanks to a number of advanced disciplines. Along with cellular biology, chemical biology and microbiology, state-of-the art research includes enzyme-based molecular synthesis, recombinant biomolecules and stem cell research.®

In the last years, hundreds of pharmaceutical companies have more than 7,000 century medicines in development around the world, with about half of those new drugs undergoing development in the United States.

It seems likely that the next stage of advances in drug discovery will be result of integrating sophisticated new computational, bioinformatics, pharmacogenomics, engineering, and/or nanotechnology methods. "

10,000 compounds

how many compounds in drug discovery timeline?

250 compounds

how many compounds in preclinical timeline?

3 compounds

how many compounds in clinical timeline?

1

how many compound/drug can be approved by fda?

6.5 years

years for drug discovery -preclinical?

7 years

years for drug clinical trials?

1.5 years

years for fda review?

forward pharmacology approach

-functional activity in vivo or in vitro (e.g. of ectracts or natural products)

-lead compounds

-target identification

reverse pharmacology approach

-identification of promising target proteins

-screening for compounds interacting with the target protein

-functional activity in vivo

➢ development of traditional medical systems incorporating plants as a means of therapy can be traced back only as far as recorded documents of their likeness.

➢ anthropologic or archeologic fact

➢ their value is as a methodology of medicinal agents, which, according to the World Health Organization (WHO), almost 65% of the world’s population have incorporated into their primary modality of healthcare

Fossil records date human use of plants as medicines, at least to the Middle Paleolithic age some 60,000 years ago. The value of plants used in traditional medicine for drug discovery led to the following:

a) to isolate bioactive compounds for direct use as drugs

b) to produce bioactive compounds of novel or known structures as lead compounds for semi-synthesis to produce patentable entities of higher activity and/or lower toxicity

c) to use agents as pharmacologic tools d) to use the whole plant or part of it as a herbal remedy

The goals of using plants as sources of therapeutic agents are:

6% have been screened for biologic activity

15% have been evaluated phytochemically

The number of higher plant species (angiosperms and gymnosperms) on this planet is estimated at 250,000… Of these, only about __

ethnobotanic medicine

study of relationship between people & of plants used as medicines & alternative method for healing or curing

traditional medicine

a broad term used to define non Western health practices, approaches, knowledge, and beliefs incorporating plant, animal, and mineral-based medicines, spiritual therapies, manual techniques, and exercises, applied singularly or combined to treat, diagnose and prevent illnesses or maintain wellbeing.

ethnopharmacology

a highly diversified approach that contribute to the discovery of natural products with biologic activity

from ethobotanic medicine-traditional medicine-ethnopharmacology

how ethnopharmacology came to be?

✓ botanist

✓ ethnobotanist

✓ ethnopharmacologist or

✓ plant ecologist

The process of drug development from Ethnomedicine & Ethnopharmacology typically begins with a:

- collects and identifies plants of interest

ethnopharmacology

the interdisciplinary scientific study of materials used by ethnic and cultural groups, their health, and how it relates to their physical habits and methodology in creating and using as medicines

ethnopharmacology

a branch of Ethnobotany; the study of the use of plants, minerals & animal substances used to affect health other than orthodox medicines

ethnopharmacology

mainly concerned with “the observation, description, and experimental investigation of biological activity and the bioactive substance of plants and animals seeking a rationale for use of traditional medicine handed down from generation to generation

ethnopharmacology

considered as a “traditional medicine” approach

“Hallucinogens: Ethnopharmacological Search for Psychoactive Drugs”

term “ethnopharmacology” -- 1st time used or introduced in 1967 during an international symposium on “Traditional Medicine of Psychoactive drugs” as the title of a book on__; presented during the symposium

race or culture

prefix “ethno” is a word-forming element meaning "__" from Greek word “ethnos” meaning "people, nation, class, caste, tribe; a number of people accustomed to living together

ethnos

word “__” meaning "people, nation, class, caste, tribe; a number of people accustomed to living together"

➢ used to form modern compounds in the social sciences

ethnopharmacology

However, in Ayurvedic medicine, it means “preventive & therapeutic modalities other than the Western medicine”

ethnopharmacology

In 1981, the term was re-defined as “the inter-disciplinary scientific exploration of biologically active agents traditionally employed or observed by man”

Dorland's Medical Dictionary for Health Consumers. © 2007

ethnopharmacology /eth·no·phar·ma·col·o·gy - the systematic study of the use of medicinal plants by specific cultural groups. -

ethnopharmacology

is the interdisciplinary scientific exploration of the biologically active agents that are traditionally employed.

medicinal plants

are an important element of Indigenous medical systems in many parts of the world, and these resources are usually regarded as part of the traditional knowledge of culture; thus, any study that focuses on the documentation and systematic study of local and traditional uses of a plant or a group of plants can be considered to have ethnopharmacological relevance

preclinical and clinical studies

Moreover, the biological activity potential of natural medicines has been investigated in many __, revealing diverse biological effects of a wide range of plant-derived compounds in various classes of chemical group

Enlightenment in Europe

The beginning of Old drugs - New Medicines:

In the early 19th century - drug development and discovery as we know it today is an outcome of the __and the rapid expansion of pharmaceutical industries, which started in the second half of the nineteenth century. Until this point, medical treatment strictly relied on crude materials obtained from nature and their extracts that were processed and formulated into medicines.

pure chemical entities

The beginning of Old drugs - New Medicines: researchers began characterizing __ in medically used or toxic plants and other organisms.

The beginning of Old drugs - New Medicines

The study of the botanical origin of the arrow poison curare, its physiological (as well as toxic) effects, and the compound responsible for these provides a fascinating example of an early ethnopharmacological approach.

curare

__ was used by ‘certain wild tribes in South America for poisoning their arrows’. Many early explorers documented this usage.

Alexander von Humboldt

Particularly well-known are the detailed descriptions of the process used by __ in 1800 to prepare poisoned arrows in Esmeralda, Venezuela, on the Orinoco River

Chondrodendron tomentosum Ruiz et Pavon

Later, the botanical source of curare was identified as __, which produces the so-called tube curare (named because of the bamboo tubes used as storage containers).

Menispermaceae (Chondrodendron spp., Curarea spp., and Abuta spp.)

and species of the Loganiaceae (Strychnos spp.)

Other species of the ___are also used in the production of curares.

Claude Bernard

The first systematic studies on the pharmacologic studies of the pharmacological effects were conducted by the French physiologist _ (1813–78).

curare

The discovery and study of the pharmacological effects of in some detail became very significant until today of understanding how it is use and the proven effects of __.

written (printed) records

Little is known about popular traditions in medieval and early modern Europe. Our knowledge starts with the availability of __on medicinal plant use by common people.

Foxglove (Digitalis purpurea L., Scrophulariaceae)

Another typical case of ethnopharmacological approach is the discovery of __,reportedly used by an English housewife to treat dropsy, and then more systematically by the physician William Withering (1741-99)

nineteenth century

There have been numerous natural products first identified during the early years of the __. All there activities were automatically based on the common medical use of these species. Today, they would thus be considered ethnopharmacologically driven.

opium poppy (Papaver somniferum L., Papaveraceae

-F. W. Serturner

1804 – Morphine from the ) was first identified by (Germany). It took until 1817 for it to be chemically characterized as an alkaloid. Its structure was established in 1923 by J. M. Gulland and R. Robinson England

emetine

from ipecacuanha (Cephaelis ipecacuanha (Brot.) A. Rich., Rubiaceae) was fully characterized as late as 1948 and used as an emetic as well as in cough medications.

strychnine

from Strychnos spp., Loganiaceae, was used as a tonic and stimulant.

quinine

(2) was first isolated from Cinchona spp. (Rubiaceae) by Pierre Joseph Pelletier and Joseph Bienaime Caventou of France: the structure was elucidated in the 1880s by various laboratories. Used as an anti-malarial drug and to prevent muscle cramps

caffeine

(3) from the coffee tree (Coffea arabica L. and C. canephora Pierre ex. Froehn, Rubiaceae); its structure was elucidated in 1882. and proven to be an effective neuro-stimulant.

coniine

a highly poisonous natural product, was first isolated from hemlock (Conium maculatum L., Apiaceae).

socrates

connine: Its properties had been known for years (__was sentenced to death by drinking a mixture containing poison hemlock).

coniine

It was the first alkaloid to have its structure elucidated (1870). Some years later, it was synthesized (1889)

atropine

from belladonna (Atropa belladonna L., Solanaceae) was used at the time for asthma; today, the compound is still used in ophthalmology for pupil dilation.

capsaicin

: L. Thresh isolated __from Capsicum frutescens L., s.l. Its structure was partly elucidated in 1919 by E.K. Nelson (modified after Heinrich et al. based on Sneader and others)

antiobiotics

The First Half of the Twentieth Century: ___as a new model. Howard Florey and Ernst Chain further developed penicillin in the late 1930s.

benzylpenicillin

One of the most important events that influenced the use of ethnopharmacology driven drug development in the last century was the serendipitous discovery of the antibacterial properties of fungal metabolites such as __ by Alexander Fleming in 1928 at St. Mary’s Hospital (London, Paddington).

The First Half of the Twentieth Century

These natural products changed forever the perception and use of plant-derived metabolites as medicines by both scientists and the lay public.

anti-infective agents

The First Half of the Twentieth Century:

From this point onward, in terms of drug discovery, plant-derived drug leads, generally based on local and traditional knowledge, competed with the chemosystematic diversity of microorganisms. This diversity resulted in tremendous discoveries, most importantly as __. Clearly, and with only a few exceptions, microorganism-based drug discovery cannot be ethnopharmacologically driven.

methylene blue

Another important development came with the advent of synthetic chemistry in the field of pharmacy. The first successful use of a synthetic compound, __, as a chemotherapeutic agent was achieved by Paul Ehrlich in Germany (1854–1915). Unfortunately, this finding could not be extended to the more severe forms of malaria common in the tropics.

The First Half of the Twentieth Century

led to further studies on the therapeutic properties of dyes and other synthetic compounds followed.

secondary natural products

The later twentieth century also saw a rapid expansion in the knowledge of __, their biosynthesis, and their biological and pharmacological effects.

The First Half of the Twentieth Century

During this period, alternative strategies offered novel ways to discover and develop new drugs and drug leads. Serendipity and more random approaches ultimately led to a strategy where the essential goal was an increase in the total number of samples to be screened, resulting in high-throughput technologies.

scope of ethnopharmacology

a multidisciplinary field involving various professionals such as botanists, pharmacologists, pharmacognosists, chemists, physiologists, pathologists, toxicologists, pharmacists &medical doctors

▪ Western/botanical and ethno-taxonomic classifications

▪ Assessments of how plants are perceived and used in varied sociocultural contexts

▪ Constituent analyses and investigations of pharmacological activities

▪ Examinations of the physiological or clinical impact of plant use on human health

multidisciplinary study that encompasses:

❖To rescue and document important cultural heritage before it is lost

❖To establish a realistic approach to traditional medicine by investigating and evaluating agents (bioactive compounds) employed to promote and further contribute to modern medical practice

❖To explore the resources of traditional medicine in the light of modern science with a view to rationalizing the most effective and useful techniques while discouraging dangerous practices

❖To promote the integration of sound knowledge and experimentation techniques both in traditional and modern medicine

❖To encourage collaboration amongst researchers worldwide in determining the effectiveness of plants and their medical utilization.

OBJECTIVES of Ethnopharmacology

does not evaluate the non- tangible components of traditional medical practice

LIMITATION of Ethnopharmacology

tangible

non-tangible

components of traditional medicine

tangible

plants, minerals and animal materials for the prevention and treatment of disease

tangible

the practice of some surgical procedures such as circumcision, bone setting, TBA’s e.t.c.

non-tangible

Spiritism, incantations, shamanism, and rituals

▪The Stakeholders --- Who?? ▪Neglected People and Diseases --- Why??

▪Extracts as Medicines --- How??

Challenges of Ethnopharmacology

✓scientists generally in large scientific research institutions

✓the pharmaceutical industry ✓university-based researchers ✓medical doctors

✓legal representatives

✓indigenous groups

✓provider countries

✓NGOs

the main stakeholders are:

Neglected people and diseases --- Why??

➢ diseases with NO industrial R&D activities exist; however, there is no standard global definition of neglected diseases.

➢ The key elements are diseases affecting principally poor people in poor countries, for which health interventions – and R&D – are seen as inadequate.

Leishmaniasis, Schistosomiasis, Onchocerciasis, Lymphatic filariasis, Chagas disease, Malaria, Leprosy, African trypanosomiasis, Tuberculosis (TB), and Dengue.

Here are examples of neglected (‘tropical’) diseases have been listed by the World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO/TDR).: