Drug Development

• Foxgloves – Digitalis purpurea
• The leaves are poisonous when eaten by humans and animals.
• They have a string bitter taste as a warning.
• Symptoms of poisoning:
o Dizziness
o Vomiting
o Diarrhoea
o Hallucinations
o Heart failure – irregular heart beat rate
• This effect on heart beat rate meant that it was use in moderation as a remedy for dropsy.
• The accumulation of fluid in the bodies tissues.
• A painful condition that can result in a slow death.
• Caused by heart and kidney problems it results in an increased blood pressure.
• This means tissue fluid fails to return to the capillaries and so builds up in patients feet, legs and organs.
• Eventually the patient dies by drowning due to fluid accumulation on the lung.
• William Withering had heard of foxgloves curative properties for dropsy, but here was no evidence to prove this until he began his investigations into the plants medicinal properties after meeting a wise woman called Mrs Hutton.
• Mrs Hutton used foxglove as one ingredient in her “special tea” which seemed to treat the symptoms of dropsy.
• Withering proposed that it was the foxglove which contained the active ingredient.
• He began making his own version of the tea which proved successful in treating one patient but
nearly killed another and so he gave up.
• Withering move to Birmingham hospital which saw a great number of dropsy cases and Withering was persuaded to restart his investigations.
• Discovering and recording the side-effects of the digitalis.
• Withering discovered that the dosage was vitally important in the success of the medicine.

• He would administer the patient with increasing amounts until diarrhoea and vomiting was induced and then reduce the dosage slightly from that point, this enabled him to find the correct dosage for each patient.
• After 10 years of studying the medicinal properties of the digitals Withering wrote a book.
• Withering helped to change the face of the medical practice for ever.
• We now know the active ingredient in the foxglove to be a chemical called digitalin.
• Withering found Digitalis
• Now the active ingredient in drug mixtures to treat Dropsy
• When the heart is too weak to circulate blood effectively now known to be the cause of limb swelling
• Digitalis is not now accepted for treatment of heart disease
• Digitoxin used as treatment to slow muscular dystrophy and to reduce pressure in the eye of Glaucoma victims
• An overdose of Foxglove is fatal
• He gave more and more to his patients until they either:
o showed signs of recovery
o died
• 1 patient almost died of a heart attack
• On average it takes 10 -12 years and £550 million to develop a new drug.
• New drugs go through a rigorous round of testing.
• A new drug has to be effective, safe, stable, easily absorbed and removed from the body and easily manufactured on a large scale.
• Potential new substances are analysed and the active ingredient identified and copied so that it can be manufactured synthetically.
• Slight variations to the chemical structure are made to see if increases the medicinal effect.
• Nowadays many new drugs are discovered through computer modelling chemical structures.
• Once a compound has been identified a series of trials begin.
• There are five stages:
• First is preclinical testing
• Followed by three phases of clinical trials
• Then a final after licensing trial.

Animal and laboratory studies on cells and tissues so assess safety and effectiveness of the compound
Small group of volunteers normally healthy are given the drug to see if it is absorbed, distributed and excreted by the body by the predicted mechanisms.
A small group of people with the disease are treated to look at drugs effectiveness.
Large group of patients is used split into two groups one given a placebo and the others given the active drug. This is done as a double-blind randomised controlled trail, neither the patients nor the doctors know who has been given what. If statistically significant results come back showing the drug has worked. If all goes well the drug can then be licensed and marketed.
Trials continue collecting data on the effectiveness and safety.