WEEK 5.1- Drug Development: History, Discovery, and Regulation

Course Scope and Regulation in Australia

• From Drug discovery through testing, regulation and marketing.

• Key stages include: drug discovery, drug design, in vitro & in vivo testing, clinical trials, regulation of therapeutic goods in Australia (the TGA), and access and availability of therapeutic goods in Australia (the PBAC; the PBS).

• 

History of Medicinal Plants

• Sumerian clay slab from Nagpur — $5000\,\text{years ago}$

• 12 recipes for drug preparation referring to over $250\,\text{plants}$ including poppy, henbane & mandrake

• Pen T\'Sao written by Emperor Shen Nung $c\,2500\text{ BC}$ — 365 drugs; dried parts of medicinal plants including ginseng, cinnamon bark, camphor

• Ebers papyrus $c\,1550\text{ BC}$ — collection of $800\text{ prescriptions}$ referring to $700\text{ plant species}$ and drugs used for therapy including aloe, senna, garlic, willow, juniper

• Homer\'s epics — $c\,800\text{ BC}$ — 63 plant species used in pharmacotherapy from Minoan, Mycenaean, and Egyptian/Assyrian contexts

• Hippocrates (459-370 BC) — about $300\,\text{medicinal plants}$ classified by physiological action

• Narcotics: opium, henbane, deadly nightshade & mandrake

• Emetics: hellebore & hazel wort

• Diuretics: celery, parsley, asparagus, garlic

19th Century Advances

• Isolation of alkaloids from:

  • poppy ($1804-1806$)

  • ipecacuanha ($1817$)

  • Strychnos ($1817$)

  • Quinine ($1820$)

• Isolation of glycosides

• Use of Digitalis purpurea extract to treat heart conditions first described in English medical literature in $1785$

• As chemistry advanced, other active substances from medicinal plants were discovered

Opium Poppy Constituents

• The opium poppy contains a variety of compounds:

  • Codeine

  • Thebaine

  • Morphine (main active ingredient)

  • 

Morphine: History and Pharmacology

• Morphine used as a narcotic in Sumerian cultures in Asia as early as $4000\,\text{BC}$

• Isolated from dried poppy resin by Friedrich W. Sert\u00fcrner in the early $1800s$; named \"morphium\" after Morpheus, the Greek god of dreams

• In $1925$, Sir Robert Robinson proposed the correct structure of morphine

• Morphine is particularly effective in relieving severe, continuous pain such as that experienced by patients with terminal cancer — without loss of consciousness where other analgesics fail

• Side effects: severe constipation, respiratory depression, drowsiness, vomiting, loss of appetite, etc.; highly addictive and induces tolerance

Heroin: Origin and Marketing

• Heroine (diacetylmorphine) was invented by mistake

• It was used in cough mixtures, especially for children

• Advertised by Bayer in the early days as a cough remedy with preparations like heroin hydrochloride; claimed to be an efficient cough suppressant with small effective doses

• The product was marketed as a sedative/antitussive, not primarily as an analgesic

Morphine vs Heroin pharmacokinetics

• Morphine binds more tightly than heroin to opioid receptors in the brain, so one might expect morphine to give a stronger high

• In reality, heroin is more potent and addictive because the two acetyl groups render it more lipid-soluble, allowing faster diffusion through the blood–brain barrier

• Thus, heroin reaches the brain more rapidly than morphine, contributing to its higher perceived potency

Quinine: History, Isolation and Synthesis

• Quinine derived from powdered dried bark of the cinchona tree, native to South America; used by Quechua Indians of Peru to treat fevers

• Jesuit priests carried cinchona bark to Europe in the $1620s-1632$ to treat malaria

• Quinine isolated in $1820$ by Pierre Joseph Pelletier and Joseph Caventou

• First total synthesis achieved by $RB\ Woodward$ and $WE\ von Doering$ in $1943$

• Quinine kills the parasites causing malaria; mode of action is complex and not fully understood

Willow Bark and Salicylic Acid

• Doctrine of Signatures: belief that the plant resembling a body part can cure related ailments; willow bark was used for fevers

• Rev Edward Stone investigated willow bark on the ground near rivers and noted its fever-reducing effects

• Willow bark contains salicin, which is metabolized in vivo to the active agent salicylic acid

• Salicylic acid led to the development of acetylsalicylic acid (aspirin) in the late 19th century; mechanism of action not discovered until the 1970s

Willow Bark: Timeline

• 1763: Rev. Edward Stone described willow bark experiments for treating ague (intermittent fever, pain, chills, fatigue)

• 1820s-1830s: isolation of salicylic acid

• 1897: Bayer developed acetylsalicylic acid (aspirin)

• 1915: aspirin approved as an OTC medication in tablet form

Serendipity in Drug Discovery

• Serendipity: discoveries made by accident and sagacity

• Term coined by Horace Walpole in 1754

• Sagacity: penetrating intelligence, keen perception, and sound judgment

Pasteur\'s Maxim on Observation

• A famous adage: in the field of observation, chance favors only the prepared mind

Penicillin

• Alexander Fleming, 1928

• During influenza research, a mould contaminant on a Staphylococcus culture plate created a bacteria-free zone

• Isolation of the mould revealed a substance with powerful activity against many bacteria affecting humans

• Fleming\'s reflection: he did not plan to revolutionize medicine, but his observations changed everything

Cisplatin

• Barnett Rosenberg, 1965, studying effects of electric fields on E. coli growth

• Bacteria increased in size but ceased to divide when exposed to an electric field; a platinum compound released from platinum plates was implicated

• Hypothesized that if this compound could inhibit bacterial cell division, it might stop tumor growth

• Human trials conducted in $1972$; FDA approval in $1978$

LSD Discovery and Hofmann

• Hofmann synthesized Lysergic acid diethylamide (LSD-25) and, in 1943, reported a novel psychoactive experience

• Described experiences of intense, kaleidoscopic imagery and color changes while working with LSD

Existing Drugs with New Uses: Mechlorethamine (Mustine)

• Mechlorethamine was used as a chemical warfare agent (mustard gas) during WWI

• Approved for medical use in the US in $1949$

• Used to treat Hodgkin\'s lymphoma, some non-Hodgkin\'s lymphomas, various leukemias

Existing Drugs with New Uses: Aspirin (Acetylsalicylic Acid)

• Analgesic, antipyretic, anti-inflammatory

• 1988: FDA proposed new uses for aspirin to reduce risk of recurrent myocardial infarction and to prevent first myocardial infarction in patients with unstable angina

• Aspirin has also been studied for cancer risk reduction in recent years

The ASPREE Study (Aspirin in Reducing Events in the Elderly)

• March 2010 – January 2018: international clinical trial

• Design: randomized, double-blind, placebo-controlled trial of daily low-dose aspirin ($100\text{ mg}$)

• Population: healthy older people without prior cardiovascular disease, dementia, or significant physical disability

• Enrollment: $19{,}114$ participants

• Results (average follow-up $4.7\ ext{years}$): aspirin did not prolong disability-free survival or dementia

• Cardiovascular endpoints not significantly reduced; major bleeding risk higher in aspirin group

• Trial characterized as the gold-standard for evaluating aspirin in the elderly

Thalidomide

• Initially used as a sedative, hypnotic, and antiemetic

• Currently approved to treat: erythema nodosum leprosum (in US/AU) and multiple myeloma (US/AU/EU)

Is Serendipity a Thing of the Past?

• Several anti-serendipity factors identified:

  • Move toward rational drug design based on translational research

  • Reduction in the amount of time clinicians have to observe patients

  • Greater reliance on double-blind placebo-controlled designs to demonstrate efficacy

Historical references and further reading

• Historical review of medicinal plants\' usage: B. Petrovska. Pharmacogn. Rev. 6, 1-5 (2012).

• Nitrogen mustard: origin of chemotherapy for cancer. J. Einhorn. Int. J. Radiation Oncol. Biol. Phys., 11, 1375-1378.

• Chance favours the prepared mind – from serendipity to rational drug design. H. Kubinyi. J. Receptors and Signal Transduction, 19, 15-39.