Contributions of various scientists in Pharmacology

Dr. Harmanjit Singh Department of Pharmacology

GMC, Patiala

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INTRODUCTION & HISTORICAL DEVELOPMENT

SOME HISTORICAL LANDMARKS

GREAT SCIENTISTS & THEIR CONTRIBUTIONS

PIONEERS OF PHARMACOLOGY

NOBEL LAUREATES IN PHARMACOLOGY

SERENDIPITY IN PHARMACOLOGY

A Brief History Of Pharmacology

Pharmacology is the science of drugs (Greek pharmakos, medicine

or drug; and logos, study).

It is the study of substances that interact with living systems through chemical processes, especially through binding to regulatory molecules and activating or inhibiting normal body processes.

History of Pharmacology, Knowledge of drugs and their use in disease is as old as history of mankind

But as a science Pharmacology is quite a young one

The birth date of pharmacology is not as clear-cut 3

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Primitive men gathered the knowledge of healing and medicine by observing the nature, noticing animals while ill and by personal experiences after consuming certain herbs and berries as remedies

Hippocrates (460B.C.-377B.C. “The Father of Medicine” was the first to attempt to separate the practice of medicine from religion and superstition , developed his pledge of proper conduct for doctors

“I will use treatment to help the sick according to my ability and judgment, but never with the view to injury and wrong doing…Into whatsoever houses I enter, I will enter to help the sick”

Ebers papyrus describes more than 700 drugs in extensive pharmacopeia of that civilization. Included in this are: beer, turpentine, berries, poppy, lead, salt and crushed precious stones etc.(Egyptian remedies)

Dhanvantari : an early Indian medical practitioner and one of the world’s first surgeons., regarded as the source of Ayurveda. He perfected many herbal based cures and natural remedies and was credited with the discovery of the antiseptic properties of turmeric and the preservative properties of salt which he incorporated in his cures.

Susruta Ancient Hindu Medical Text Describes 760 herbs Charka Samhita describes more thnn 65O drugs of animal,

plant and mineral origins are used.

Chinese remedies

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o Paracelsus (1493-1541) :pioneered the use of

chemicals and minerals (zinc) in medicine. vigorously opposed polypharmacy , or the prescription of multiple ingredients in a single medicine.

o willow bark was used to treat fever and pains

Extract of foxglove plant, used to treat dropsy (congestive heart failure) in 1785. Contains digitoxin and digoxin; today called digitalis

William Withering( 1741-1799) discovered digitalis Synthetic organic chemistry was born in 1828, when

Friedrich Wohler synthesized urea from inorganic substances and thus demolished the vital force theory.

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Some Historical landmarks

Morphine : Friedrich Serturner (1805) Atropine : Grieger & Hessie (1833) Histamine : Vogt (1907) Sulfanilamide : P. Gleno (1908) Oxytocin : Abel (1919) Insulin: Banting & Best (1922) Penicillins : A. Flemming (1928) Sulfonamides : Domagk (1932) Cortisone: Edward C.Kendall Streptomycin : Waksman (1944) Chloramphenicol : Bartz (1948) Tetracycline: Duggar (1948) Lithium : Cade (1950)

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40 - 90-AD

Pedanius Dioscorides, a Greek physician,

He personally researched each plant and its uses. About 65 AD, he wrote De Materia Medica, "Regarding Medical Matters",on the "preparation, properties, and testing of drugs."  

 five volume book on the uses of over 1,000 plants and minerals.

For nearly 1500 years, De Materia Medica was the supreme authority on medicine and pharmacology in western civilization.

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FRANÇOIS MAGENDIE

  A French physiologist, considered a pioneer of experimental physiology.

He is known for describing the foramen of Magendie.

There is also a Magendie sign, a downward and inward rotation of the eye due to a lesion in the cerebellum

Studied the action of nux vomica (a strychnine-containing plant drug) on dogs, and showed that the spinal cord was the site of its convulsant action.

His work was presented to the Paris Academy in 1809.

(1783 – 1855)

François Magendie

Established the idea of experimental physiology (an idea further popularized by Claude Bernard)

He described in detail the effects of strychnine injections on animal subjects--and also proved that the poison reached the animal's spinal cord by the blood stream and not (as was then commonly believed) by the lymphatic system.

Because of such experiments, Magendie was able to introduce into French medicine a variety of new drugs, including morphine, codeine, quinine and, strychnine.

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Claude Bernard  

A French Physiologist

Further expanded work of Francois Megendie In 1842, Claude Bernard discovered that the

arrow poison curare acts at the neuromuscular junction to interrupt the stimulation of muscle by nerve impulses.

Also k/a Father of Modern Experimental Medicine

Bernard's experiments changed medicine

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(1813-1878)

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Claude Bernard’s Contributions

The discovery of the role of the pancreatic secretion in the digestion of fats (1848).

The discovery of a new function of the liver--the "internal secretion" of glucose into the blood (1848).

The production of sugar by washed excised liver (1855) and the isolation of glycogen (1857).

The demonstration that curare specifically blocks motor nerve endings (1856).

He also established the existence of Vasomotor system and observed Vasodilatation & Vasoconstriction

Pharmacology was held to have emerged as a separate science only when the first university chair was established.

This occurred in 1847, when Rudolf Buchheim (a German pharmacologist) , was appointed professor of pharmacology at the University of Dorpat in Estonia .

Today at the University of Giessen is the Rudolf Buchheim Institute for Pharmacology.

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Rudolf Buchheim(1820 – 1879)

R.Buchheim

Lacking outside funding, Buchheim built the world’s 1st

pharmacology laboratory at his own expense in the basement of his home

Buchheim is remembered for his pioneer work in experimental pharmacology.

He introduced the bioassay to pharmacology,

His reputation is overshadowed by that of his student, Oswald Schmiedeberg

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Oswald Schmiedeberg

Generally recognized as the founder of modern pharmacology

Schmiedeberg obtained his medical doctorate in 1866 with a thesis on the measurement of chloroform in blood

In 1872, he became professor of pharmacology at the University of Strassburg

In 1878, he published a classic text, Outline of Pharmacology

In 1885, he introduced urethane as hypnotic 15

1838–1921)

In his 46 years at Strasburg, Schmiedeberg trained most of the men who became professors at other German universities and in several foreign countries

He was largely responsible for the preeminence of the German

pharmaceutical industry up to World War II.

In the United States, the first chair in pharmacology was established at the University of Michigan in 1890 under John Jacob Abel, an American who had trained under Schmiedeberg.

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Schmiedeberg

John Jacob Abel

An American Pharmacologist, ph.D from the university of Michigan and trained under Schmiedeberg.

In the United States, the first chair in pharmacology was established at the University of Michigan in 1890 under John Jacob Abel.

In 1893, Abel went to Johns Hopkins University in Baltimore, where he had a long and brilliant career.

Also k/a FATHER OF AMERICAN PHARMACOLOGY 17

1857- 1938

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John Jacob Abel’s Contributions

Gave the name Pharmacology as a subject (earlier k/a Materia Medica)

He was second to isolate epinephrine (1897–1898) from adrenal gland extracts (first was Napoleon Cybulski in 1895)

Isolated amino acids from the blood (1914) Isolation of histamine from pituitary extract

(1919) Preparation of pure crystalline insulin (1926). His student Reid Hunt discovered acetylcholine

in adrenal extracts in 1906.

Friedrich Serturner, the German pharmacist who isolated the first alkaloid from opium in 1805, administered a very large dose (100 mg) to himself and three friends

All experienced the symptoms of severe opium poisoning for several days. The alkaloid was named morphine, for Morpheus, the Greek god of sleep.

Although humans are no longer used as laboratory animals, they are essential in clinical pharmacology

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OTTO LOEWI

1873 - 1961

A German Pharmacologist, brilliantly obtained his doctor’s degree with a thesis about “techniques of isolations of frog’s heart

1902 In London, in Starling’s laboratory, he met for the first time Henri Hallet Dale, who was to become a lifelong friend.1909 He was appointed to the Chair of Pharmaco logy in Graz.

1921 He proved, the chemical transmission of the nerve impulses& in 1936 He received the Nobel price, with Henri Dale.

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OTTO LOEWI CONTRIBUTIONS

He designed his most famous experiment, which provided the first evidence for the existence of chemical transmission in a synapse.

The legend tells that he had the idea of the experiment in a dream and that he ran to the lab in the middle of the night.

The experiment was very simple and became a prototype for all investigations of chemical factors in the nervous system.

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OTTO LOEWI

He cut out two hearts from frogs and perfused them with a warm physiological solution (Ringer).

He then stimulated the vagus nerve to one of the hearts. As a consequence, there was a strong inhibition in this

heart beats (R). The second heart was unaffected However, when he perfused the second heart with the

outflow of the perfusion of the first one, he achieved exactly the same effect (D).

It was therefore concluded that some substance produced at the parasympathetic synapse level in heart R, was able to induce a similar response in the muscles of heart D (acetylcholine)

SIR HENRY HALLET DALE

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An English Pharmacologist Received his M.D. from Cambridge in 1909.

Worked under John Langle & Paul Ehrlich , also a Fast friend of Otto Loewi.

Dale became the Director of the Deptt of Biochemistry and Pharmacology at the National Institute for Medical Research in London in 1914.

Also served asPresident of the Royal Society from 1940 to 1945

1875 - 1968

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SIR HENRY HALLET DALE CONTRIBUTIONS IN PHARMACOLOGY Distinguished Muscarinic &Nicotinic receptors in 1914

First identified acetylcholine in 1914 as a possible neurotransmitter, Loewi showed its importance in the nervous system. (shared the 1936 Nobel Prize for Physiology or Medicine.)

  Dale's principle ( Dale's Law). This principle states that each neuron releases only one type of neurotransmitter.

Dale’s Vasomotor Reversal Phenomenon : only fall in BP occurs when an alpha blocker is given before injecting adrenaline .He demonstrated this in cat & used Ergot alkaloids as alpha blocker

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Colonel Ram Nath Chopra

k/a FATHER OF INDIAN PHARMACOLOGY

Obtained MD degree from Cambridge University in 1908

In 1921 : Appointed as the first professor of pharmacology in newly established Calcutta School of Tropical Medicine and parallely headed the Department of pharmacology at he Calcutta medical college

From 1941 to 1957: he was Director of the Drug Research Lab at Srinagar

1882-1973

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Colonel Ram Nath Chopra CONTRIBUTIONS :

He 1st introduced and done systematic study

of Rauwolfia serpentina

Had a major contribution in establishing the 1st National Drug Research Institute of India, Lucknow ( presently known as Central Drug Research Institute, CDRI)

He pioneered research on herbal drugs in India

Indian Posts & Telegraph department has issued a commemorative stamp in his honor.

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Paul Ehrlich (1854-1915)  German scientist in the fields of hematology, 

immunology, and chemotherapy He is noted for curing syphilis and for his research in autoimmunity

He coined the term chemotherapy and popularized the concept of a  

magic bullet. Also coined the term Receptor (earlier called as receptive substance

by Langley) Ehrlich skillfully transformed diphtheria antitoxin along with

Emil Adolf von Behring, into an effective preparation, his first world renown achievement

However, von Behring cheated Ehrlich out of both recognition and financial reward. Only von Behring received the first Nobel Prize in Medicine, in 1901,

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Paul Ehrlich

In 1906 he discovered the structural formula of atoxyl, a chemical compound which had been shown to be able to treat sleeping sickness

  In1908, Ehrlich was awarded the Nobel Prize in Medicine

In 1909 he and his student Sahachiro Hata developed Salvarsan

, a treatment effective against syphilis.

 Salvarsan became the most widely prescribed drug in the world, most effective drug for treating syphilis until penicillin became available in the 1940s

Known as FATHER OF CHEMOTHERAPY

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Alexander Fleming (1881-1955)

Scottish biologist and pharmacologist. His best-known discoveries are the - discovery of the enzyme lysozyme in 1923-  antibiotic  penicillin from the mold Penicillium notatum in 1928

which was a discovery by chance.  On 3 September 1928, Fleming returned to his lab. after vacation. Before leaving, he had stacked all his cultures of staphylococci on a bench in a corner of his laboratory.

- On returning, Fleming noticed that one culture was contaminated with a fungus, and that the colonies of staphylococci that had immediately surrounded it had been destroyed, whereas other colonies farther away were normal

He shared the Nobel Prize in Physiology or Medicine in 1945 with Howard Florey and Ernst Chain who purified penicillin

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Sir Frederick Banting & Charles Best

Sir Frederick Grant Banting,  (1891 –1941) was

a Canadian medical scientist & doctor Charles Best February (1899 – 1978)was his

assistant Known for  the discovery of the e insulin—one

of the most significant advances in medicine, enabling an effective treatment for diabetes.

 In 1921, Banting traveled to Toronto to visit J.J.R. Macleod at  University of Toronto, where he used his lab for this discovery.

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Banting & Best

He also supplied Banting with ten dogs to experiment on, and two medical students, Best and Clark Noble, to use as lab assistants.

Since Banting only required one lab assistant, Best and Noble flipped a coin & Best won the coin toss, and took the first shift as Banting's assistant.

 Loss of the coin toss was very unfortunate for Noble as Best worked with Banting for the entire summer (and eventually shared half his Nobel Prize money and a large part of the credit for the discovery of insulin with the winner of the toss)

In 1923, the Nobel Banting and J.J.R. Macleod won the Nobel Prize in Medicine for the discovery of insulin, & Nobel prize committee ignored Best. This incensed Banting, who voluntarily shared half of his award money with Best.

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Gerhard Domagk (1895-1964)

a German pathologist and bacteriologist  Done extensive work on infections & antibiotics

Credited with the discovery of Sulfonamidochrysoidine (KI-730) – the first commercially available antibiotic (marketed under the brand name Prontosil)

 He found the sulfonamide Prontosil to be effective against streptococcus, and treated his own daughter with it, saving her the amputation of an arm.

In 1939, Domagk received the Nobel Prize in Physiology or Medicine for this discovery, the first drug effective against bacterial infections

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Daniel Bovet

1907 - 1992

Swiss born Italian pharmacologist

In the early 1930’s Bovet and his coworkers conducted a series of experiments on Prontosil & they concluded that Prontosil derived its therapeutic powers due to the presence of sulphanilamide

In 1937 Bovet and his research student Anne Marie Staub succeeded in synthesizing the first antihistaminic Thymoxidiethylamine.

Thymoxidiethylamine. was too toxic to be used so he continued with hundreds of experiments to find a more human body friendly antihistamine.

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Daniel Bovet

After years of research he succeeded in discovering Pyrilamine (mepyramine) a very important histamine.

In 1947 he discovered gallamine when he was looking for a synthetic substitute for curare

Isolated succinylcholine, a muscle relaxant now used in conjunction with anesthesia during certain surgical procedures. 

In 1957 he was awarded the Nobel Prize in Physiology or medicine for his discoveries.

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Louis Lasagna : Father of Clinical Pharmacology

Famous American Clinical Pharmacologist Medical degree from Columbia University in 1947. Lasagna joined the faculty of Johns HopkinsUniversity in 1954,

where he established the first ever clinical pharmacology department.

In 1964, Lasagna revised the Hippocratic Oath Conceptualize controlled clinical trials and the placebo effect Lasagna's work led to the improvement of controlled clinical trials

to test drug effectiveness, and improved the regulation of drugs for effectiveness and safety.

Lasagna's Law : The incidence of patient availability sharply decreases when a clinical trial begins and returns to its original level as soon as the trial is completed.

1923-2003

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Sir James Black A Scottish Pharmacologist Studied Medicine at Univ. of St. Andrew. in 1950, he joined the University of Glasgow

He was interested in the effect of  adrenaline on the human heart.

Joined  ICI Pharmaceuticals in 1958

1n 1964 he joined Smith, Kline and French for

whom he worked for nine years until 1973

He was awarded the Nobel Prize for Medicine in 1988 for his work.

1924- 2010

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Sir James Black : Major Contributions

He established the Physiology Department at Univ of Glasgow He developed Propranolol while working for ICI , which later

became the world's best-selling drug.

Black was developing a similar method of treatment for stomach ulcers, but ICI did not wish to pursue the idea so Black resigned in 1964 and joined Smith, Kline and French 

 While there, Black developed his second major drug, cimetidine (brand name Tagamet ) in 1975 and soon outsold propranolol to become the world's 1st billion dollar drug.

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Louis J. Ignarro, Robert Furchgott  and

 Ferid Murad

Louis J. Ignarro (born May 31, 1941) is an Italian American pharmacologist

Robert Francis Furchgott ( 1916 – 2009) was a n  American biochemist.

Ferid Murad (born September 14, 1936) is an Albanian-American physician and pharmacologist

Their main contribution is the Discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system

Co-winners of the 1998 Nobel Prize in Physiology or Medicine.

L.Ignaro

R. Furchgott

Ferid Murad

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Other Scientists & Their Contributions

Thomas Renton Elliott: Elaboration of the Concept of Chemical Neurotransmission

John Langley (1878) : Receptor concept (called it Receptive substance

William Henry Howell & Jay McLean (1916) : Discovered Heparin from

Canine Liver

Raymond Ahlquist (1948) : Existence of two types of adrenergic receptors i.e. Alpha & Beta Receptors

G.Brotzu (1948) : discovered Cephalosporins

Selman Waksman : discovered streptomycin: the first antibiotic effective against tuberculosis - Nobel Prize (1952)

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Other Scientists & Their Contributions

Ulf von Euler, Julius Axelrod, and Sir Bernard Katz: the processes involved with the biosynthesis, release, actions,and inactivation of neurotransmitters (Nobel Prize 1970)

Earl Wilbur Sutherland Jr. : He discovered cAMP as 2nd messenger concerning the mechanisms of the action of hormones," especially epinephrine ( Nobel Prize in in 1971)

Sir John Robert Vane:  worked on aspirin  & discovered that it inhibits  prostaglandin biosynthesis ( Nobel Prize 1982)

Martin Rodbell & Alfred G. Gilman: Known for their discovery of G-proteins and the role of these proteins in signal transduction in cells (Nobel Prize 1994)

Some Scientists in History of Anesthetics

Nitrous oxide : Synthesized by Priestley in 1774, 1st clinically used by Humphery Davy who used it on himself for toothache and called it as Laughing gas

Horace Wells : used N2O for tooth extraction & patient cried in pain. He became very frustrated and chloroform addict n committed suicide by cutting his femoral artery.

Ether: prepared by Valeus Cordus and was k/a ‘sweet oil of vitroil’.First public demonstration was given by W.T.G Morton on 16th October 1846 (World Anesthesia Day)

Chloroform: first use was done by Simpson but John Snow popularized it by using it successfully in 4,000 patients (also used on Queen Victoria for birth of her 8th child)

Cocaine was 1st used by Carl koller for anesthetizing cornea41

Pioneers of Pharmacology

Hippocrates: Father of Modern Medicine Claude Bernard: Father of Modern Experimental

Pharmacology Oswald Schmiedberg: Father of Modern

Pharmacology Paul Ehrlich: Father of Modern Chemotherapy John Jacob Abel: Father of American

Pharmacology Ram Nath Chopra: Father of Indian

Pharmacology Louis Lasagna: Father of Clinical Pharmacology 42

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Nobel Laureates In Pharmacology

1908: Elie Metchnikoff, Paul Ehrlich: First antimicrobial drugs (“magic bullet”)

1923: Frederick Banting, John Macleod: Isolation and discovery of insulin and its application in the treatment

of diabetes 1936: Sir Henry Dale, Otto Loewi: Chemical transmission of

nerve impulses 1945: Ernst Chain, Sir Alexander Fleming, Sir Howard

Florey : Discovery of penicillin and its curative effect in various infectious diseases

1950: Edward Kendall, Tadeus Reichstein, Philip S. Hench : Hormones of the adrenal cortex, their structure and biological effects

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Nobel Laureates In Pharmacology

1957: Daniel Bovet: Antagonists that block biologically active amines, including the first antihistaminic

1970: Julius Axelrod, Sir Bernard Katz, Ulf von Euler: Transmitters in the nerve terminals and the mech. For storage, release, and inactivation

1971: Earl Sutherland Jr. : Mechanisms of the action of hormones with regard to inhibition and stimulation of cyclic AMP

1982: Sune Bergström, Bengt Samuelsson, John R. Vane: Discovery of prostaglandins and the mechanism of action of aspirin which inhibits prostaglandin synthesis

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Nobel Laureates In Pharmacology

1988: Sir James W. Black, Gertrude B. Elion, George H. Hitchings: Development of the fi rst beta-blocker, propranolol, and anticancer agents that block nucleic acid synthesis

1994: Alfred Gilman, Martin Rodbell: Discovery of G proteins and the role of these proteins in signal transduction in cells

1998: Robert Furchgott, Louis Ignarro, Ferid Murad: Role of NO as a signaling molecule in the cardiovascular system

2000: Arvid Carlsson, Paul Greengard, Eric Kandel: Role of dopamine in schizophrenia and signal transduction in the nervous system leading to long-term potentiation

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Serendipity in Pharmacology

Penicillin by Alexander Fleming. He failed to disinfect cultures of bacteria when leaving for his vacations, only to find them contaminated with Penicillium molds, which killed the bacteria.

5-fluorouracil's therapeutic action on actinic keratosis, was initially investigated for its anti-cancer actions

Minoxidil's action on baldness; originally it was an oral agent for treating hypertension. It was observed that bald patients treated with it grew hair too.

Viagra (sildenafil citrate), an anti-impotence drug. It was initially studied for use in hypertension and angina pectoris. Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.

The libido-enhancing effect of LEVODOPA The first anti-psychotic drug, chlorpromazine, was discovered by

French pharmacologist Henri Laborit. He wanted to add an anti-histaminic to prevent surgical shock and noticed that patients treated with it were unusually calm before the operation.

The first antidepressants, imipramine and iproniazid were 1st used in schizophrenics (imipramine) & in the t/t of TB (iproniazid).

The psychedelic effects of LSD by Albert Hofmann, he unintentionally absorbed a small amount of it upon investigating its properties, and had the first acid trip in history, while cycling to his home in Switzerland; this is commemorated among LSD users annually as Bicycle Day.

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SERENDIPITY

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 Mustine – a derivative of mustard gas (a chemical weapon). In 1943, physicians noted that the white cell counts of US soldiers, accidentally exposed mustard gas shells were decreased, and mustard gas was investigated as a therapy for Hodgkin's lymphoma.

The anesthetic nitrous oxide (laughing gas). its properties were discovered when British chemist Humphry Davy tested the gas on himself and some of his friends, and soon realised that nitrous oxide considerably dulled the sensation of pain, even if the inhaler was still semi-conscious

SERENDIPITY

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REFERENCES

Goodman and Gilman’s :The Pharmacological Basis of Therapeutics : 12th edition

Clinical Pharmacology : Bennett and Brown 10th editionBasic and clinical pharmacology : Katzung,Masters and

Trevor: 11th edition A Brief History of Great Discoveries in Pharmacology.

Rubin PR. Pharmacol Rev 2007; 59: 289–359. "All Nobel Prizes in Physiology or Medicine".

Nobelprize.org.

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"I have been trying to point out that in our lives chance may have an astonishing influence and, if I may offer advice to the young laboratory worker, it would be this - never to neglect an extraordinary appearance or happening.”

Alexander Fleming

THANK YOU

Some Pharmacologists in History

• William Withering, 1741-1799 (digitalis)• Claude Bernard 1813-1878 (d-tubo curare)• Friedrich Sertürner 1783--1841 (morphine) • Rudolf Buchheim 1820-1879 (1st Pharmacology

Laboratory, University of Dorpat (now Tartu, Estonia)

• Oswald Schmiedeberg 1838-1921 (Strassburg, now Strasbourg, trained many pharmacologists)

• John Langley 1852--1926 (Receptor concept)• Paul Ehrlich 1854-1915 (Receptor concept)• Otto Loewi, Henry Dale (Neurotransmission)