Introduction - Uppsala Monitoring Centre

used in 1779 with reference to tobacco. The first use of the adjective ‘addict’ (with
the meaning of ‘delivered, devoted’) was in 1529 and comes from Latin addictus, pp.
of addicere (‘deliver, yield, devote,’ from ad-, ‘to’ + dicere, say). WHO defines ‘drug
abuse’ as persistent or sporadic excessive drug use inconsistent with or unrelated to
acceptable medical practice (WHO, 2002).
Lactic acidosis: Buformin and Phenformin.
This is a biguanide class effect which is shared with metformin, but which has a
much lower incidence and has not been withdrawn (Enia et al., 1997). There were
two earlier diguanides which produced lactic acidosis: phenethyldiguanide in 1958
(Walker & Linton, 1959) and Compound 2254RP (para-aminobenzene
sulphonamide-isopropyl thiadazol) which was originally used for typhoid fever, but
was found to cause fatal hypoglycaemia. This should have been a warning for future
diguanides.
Hepatotoxicity: cincophen, sulfathiazole, diamthazole, oxyphenisatin, iproniazid
and nialamide
Since most cases of hepatotoxicity, if caught in time, are reversible they do not have
the same consequences as blood dyscrasias or neurological ADRs. ‘in many cases a
compound found to be hepatotoxic in an animal species will be tested in man for
definite assessment of its hepatotoxic potential.’ (Ballet, 1997). Type ‘B’ liver reactions
are relatively rare and therefore are not picked up until many patients have been
treated. ‘given that the idiosyncratic risk for liver damage lies between 1/10,000 and
1/100,000 exposures for most drugs.’ (Andrade & Lucena, 2001).
Neurotoxicity: thalidomide, bismuth, clioquinol, piperazine, Stalinon and
diamthazole. Neurological adverse effects may well not be reversible on stopping
the drug.
Drugs whose manufacturers were found culpable: thalidomide, Coralgil,
clioquinol, Stalinon and triparanol.
Actions taken by a regulatory authority will depend on:
The level of suspicion
The severity of the reaction
Other ADRs attributed to the drug
The severity of the disease for which the drug is used
The availability of alternative drugs
The incidence of the reaction
The overall cost/benefit ratio
The possibility to detect who is predisposed (Westerholm, 1980).
There are also other courses open to a regulator other than allow on the
market or remove from the market:
Restrict the indications, e.g. chloramphenicol (resistant infections); butazolidines
(acute rheumatism, ankylosing spondylitis and acute gout)
Warnings of adverse effects (Black box warnings). An American study found that