Introduction - Uppsala Monitoring Centre

of benefit to me.’ The first rules for the testing of drugs were given by Avicenna in
980 AD when he said that the drug must be free from any extraneous accidental
quality. That it must be used on a simple, not a composite, disease and the drug
must be tested with two contrary types of diseases, because sometimes a drug
cures one disease by its essential qualities and another by its accidental ones. His
next rule was that the quality of the drug must correspond to the strength of the
disease, by which he presumably meant that the cost-benefit ratio must be
favourable. The problem of distinguishing the disease from the action of the drugs
was summed as ‘the time of action must be observed, so that essence and action
are not confused.’ He was well aware of the risks of anecdotal reports when he
said ‘The effect of the drug must be seen to occur constantly or in many cases, for
if this did not happen, then it only constitutes an accidental effect.’ It was in
Holland in 1662 that the first randomised clinical trial was proposed based on the
occurrence of adverse events whilst comparing two drugs–‘see how many funerals
both us shall have.’ The first mention of training physicians in regard to
pharmacovigilance comes in 1800 when Lucas, writing on education of surgeonapothecaries,
says ‘A practitioner versed in chemistry, may not only be better
apprised of the noxious effects of some remedies, but be more quick-sighted in
opportunely counteracting their pernicious effects.’
Carus had, many years before in 49 BC, pointed out a problem with relying on
the results from testing in animals when he said ‘fierce poison is the Hellebore to us,
but puts the fat on goats and quails’ and Avicenna had added that experimentation
must be done with the human body, for testing a drug on a lion or a horse might not
prove anything about its effect on man. Similarly Woodville in 1790 said ‘Henbane is
poisonous to birds and dogs; but horses, cows, goats and swine it does not affect.’
This truth was rammed home with thalidomide. It is quite common even these days
that drugs go on the market with too high a dose (Bashaw, 1992). Yet, in 1689 Wills
gave the general rule, particularly where active medicines are employed to begin
with small doses and gradually increase them to the extent the constitution will bear.
Several writers have suggested predisposing factors in addition to dose: Moyse in
1676 pointed out that with mercury it sometimes excites the salivation in delicate
persons indicating that he realised that different constitutions required different
treatment. Pechey was more precise when he wrote in 1694 concerning Hellebore
‘the root ought not be given to old men, women, or children, or to such as are
weakly, and costive in the body.’; echoing Pliny in 77AD,Discorides in 78 AD and
later repeated by Berenguier in 1874. Continued use of a drug may cause delayed
effects. In 1752 James said of mercury ‘For the miners and others employed about
it, though of the strongest constitutions imaginable, seldom remain four years in that
state, but are seized with trembles and palsies and die miserable’. On the other
hand 40 years earlier Pomet had written of morphia ‘Custom will bring people to
bear great doses of it, but at first every one must begin with very small ones’