[PHARM 5] DDD Module 1

black bile yellow bile blood phlegm

- framework of health and disease

Lind 1973

Control of scurvy

Jenner 1798

Vaccination

Semmelweis 1861

Surgical infections using aseptic techniques

1864

British Pharmacopeia

Rudolf Virchow

Cell theory

Rudolf Buccheim

Birth of Pharmacology as a scientific discipline

Magendie and Claude

Therapeutics

Louis Pasteur

- Germ theory of disease
- Airborne infection was the underlying cause
- Immunization procedures

Paul Ehrlich

Chemotherapy
- "Vital staining"
- Receptor and Magic bullet
- Antitoxin and bacteria

Diethyl ether 1950

Sweet oil of vitriol

Nitrous oxide

* Stupefying agent
* Anesthetic

Amyl nitrite

* 1st therapeutic drug to come from synthetic chemistry (Gunthrie, 1859)
* Vasodilating effects (Brunton, 1864)

Aniline

* Precursor of mauvein
* Accidental discovery by Perkin for supposedly Quinine, 1865

kekule 1865

benzene

morphine

first alkaloid

merck

* first local apothecary in 1827

Scheringer and Boehringer

* 19th century

squibb

ether (main product in 1858)

Parke Davis and Eli lilly

* manufacturing chemists, purified Adrenaline

Bayer Hoechst Agfa Sandoz Geigy

* dyestuff manufacturers

Chloral hydrate

* first non-volatile CNS depressant

Barbitone

* by Von Mering

procaine

* by Einthorn; first local anesthetic drug

Cocaine

* local anesthetic action in the eye; Simund Freud

synthetic chemistry

* Became the established model in the early part of the 20th century
* Key discipline in drug discovery; prevailed for 50 years ·
* Research management was largely at hand of the chemists

benozdiazepines tranquilizers antiepileptic drugs antihypertensive antipshychotics

drugs produced

natural product chemistry

* Pharmaceutical companies on "love-hate" relationship
* Pharmaceutical industry has difficulty in synthesizing structures.
* Natural products remain significant source of drugs.

penicillin

1929

chloramphenicol

1947

tetracycline

1948

streptomycin

1949

vincristine and vinblastine

1958

paclitaxel

1971

ciclosporin

1972

tacrolimus

1993

mevastatin

1976

target-driven drug discovery

* Concept of Chemotherapy
* Paul Ehrlich is the first "modernist" who defined the principles of drug specificity in terms of specific interaction between a drug molecule and a target molecule.
* "Corpora non agunt nisi fixata"
* Chemistry remained empiric for many years.
* "Magic bullet"

IG Farbenindustrie

* interest in preparing antimicrobial drugs

Prontosil

* saved life of Domagk's daughter

antimetabolite principles

* By Hitching and Elions in 1944
* Interest in the synthesis of folic acid, purines and pyrimidines as chemotherapeutic agents
* Identified dihydrofolate reductase which is necessary for DNA synthesis.
* Pyrimidine analogues inhibited the enzyme
* Emergent drugs include: Pyrimethamine, Trimethoprim, 6- mercaptopurine, Azathioprine, Aciclovir, Zidovudine

ligand-receptor interaction

* Drug antagonism
* Classes of receptors have varied effects

pronethalol

1960 toxic

propranolol

1964

burimamide

1972

digitalis

treating dropsy

quinine

antidysrhythmic

amphetamine

adhd

phenothiazine

laborit's discovery

promethazine

sedation

1900

* System of "prescription only" medicines
* What info should be on the label; system of "what cures"
* Controlling of addictive substances

1937

* Diethylene glycol caused death; demonstrated the need for safety

1960

* Thalidomide disaster
* Chemie Grunenthal
* UK began to follow US regulatory laws in safety; urgent reappraisal because of the incident

1963

* Etablishment of Commission on the Safety of Drugs o
* All new drugs has to be submitted for approval before clinical trials and market release
* Medicines Act (closed the loophole) - added efficacy

Warfarin

- Anticoagulant
- Synthetic compound from dicoumarol
- Found in spoiled sweet clover

Heparin

- Anticoagulant
- Occurring naturally in mammalian tissues

Hirudin

- Anticoagulant from leech
- Now produced by genetic engineering

Opiates

- Analgesic compounds from poppies

Methylxanthines

- Caffeine and Theophylline
- Phosphodiesterase inhibitors and adenosine receptor antagonists
- Produced by tea, coffee, coca plants

Statins

- HMG CoA reductase inhibitors used to reduce plasma cholesterol
- Lovastatin is a fungal metabolite
- Later compounds (mevastatin, pravastatin) synthesized from lovastatin

Cromoglycate

- Asthma prophylaxis
- Synthetic compound based on khellin, plant for herbal medicine

Vinca alkaloids

- Vincristine and Vinblastine
- Anticancer drugs produced by plants of the periwinkle family

Paclitaxel

- Anticancer drug from yew tree

Etoposide

- Anticancer drug synthesized from podophyllotoxin, produced by mandrake plant, used in folk medicine

Artemether

- Antimalarial drug
- Semisynthetic derivative of artemisinin, a chinese herb

Ivermectin

- Antihelminthic drug
- Semisynthetic derivative of avermectin, a fungal metabolite

Antibiotics

- Too numerous to list
- Majority of current antibiotics are derived from fungal metabolites

Disease genes

* Gene mutations of which cause or predispose to the development of human disease.
* Concept of "inborn errors of metabolism"
* This class of disease genes does not seem to include many obvious drug targets.

disease-modifying genes

* These are non-mutated genes that are directly involved in the pathophysiological pathway leading to the disease phenotype.
* The phenotype may be associated with over or underactivity of the gene product detectable by expression profiling.
* This is the most important category in relation to drug targets as therapeutic drug action generally occurs by changing the activity of functional proteins, whether or not disease alters their expression level

gene expression profiling

* Principle: development of any disease phenotype involves changes in gene expression in cells and tissues involved.
* "Critical path genes" may represent potential drug targets, some are "bystander genes" How to identify using this method: group genes into functional classes, then determine plausibility criterion in causing a disease; identify genes which are co-regulated and might point to a biochemical signaling

comprehensive gene knockout screening

* Elimination or inactivation of the gene

druggable genes

* For a gene product to serve as drug target, it must possess a recognition site capable of binding small molecules.
* They likely to possess a binding site irrespective of whether such interaction will have a therapeutic value

combine druggability with disease modifying properties

goal for genes

target validation

* It refers to the experimental approaches by which a potential drug target can be tested and given further credibility.
* Main approaches are pharmacologic and genetic
* Lack of efficacy causes abandonment of roughly 1/3 of drugs in Phase II, reflecting unreliability of the earlier evidence for target validity

Pharmacologic criterion

* Whether drugs that influence potential drug target actually produce the expected effects on cells, tissues or whole animals.

Genetic criterion

* Whether genes are critical to the disease process

phase 1

safety

phase 2

efficacy

phase 3

safety and efficacy in a population

phase 4

post-marketing surveillance