E-DRUG: Norgestrel and combined contraceptive pills (cont'd)

[John Urquhart <urquhart@netcom.com>]

E-drug: Norgestrel and combined contraceptive pills (cont'd)
---------------------------------------------

I would concur with Offerhaus's comment that isomers deemed 'inactive'
can sometimes be responsible for untoward effects. It serves as a
reminder that Mother Nature does not issue Certificates of
Risklessness, based on general pharmacological principles, e.g.,
"racemic mixtures have one active and one inactive isomer", "it's better
to give the active isomer in pure form than to have the impure racemic
mixture".  

Such principles are simply not robust enough to exempt each new
pharmaceutical development program from the need for careful
experimental toxicology and pre- and post-marketing surveillance of
patients receiving the new product. 

Another such principle often invoked as a claim for risklessness is
"new form of an old, well-understood drug"; it, too, is sullied by facts
which also served to remind us that "old" and "well-understood" are
more often than not contradictory, because the standards of evidence
that brought old drugs into the market are grossly inadequate by
today's standards, and post-marketing surveillance, though far
stronger than in prior decades, still leaves a good deal to be desired. 

A further point about norgestrel ... the single isomer, levonorgestrel,
is used in NORPLANT, which is the 5-year subcutaneous implant
contraceptive that has the lowest conception rate of any of the
steroidal contraceptives, including the most widely-used combination
estrogen/progestagen oral contraceptives. In the U.S. market, the older
oral contraceptive products use the racemic mixture, whereas the
newer ones use the single isomer. 

Patent considerations involving the separation or synthesis techniques
have undoubtedly played a role in this change. Of course patent
protection has no commercial value unless people are convinced that
the patented entity, in this case, levonorgestrel, has some added value
over the racemic mixture. That consideration brings us back to the
original premise, with its implication that Mother Nature has issued a
Certificate of Purity and Risklessness for the single isomer. If you
believe that, then you have the opportunity to pay a premium price
for the added value that you perceive is there, but which may or may
not be demonstrable by experimental means. 

John Urquhart
Prof. of Pharmaco-epidemiology
Maastricht University
Maastricht NL
urquhart@netcom.com
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