pilocarpine (2.2), used in the treatment of glaucoma, can be applied in a steady-release
ocularinsert that lasts for a week. The intrauterine release of progesterone (3.38) as a con-
traceptive has also been achieved, with a single insert lasting a year. The great advantage
of this is that the constant release rate of 65 μg/day means that much less drug is released
than with the use of oral contraceptive tablets. The transdermal delivery of scopolamine as
an antiemetic for motion sickness represents another successful application of microporous
membrane technology. Here the drug is applied in a plastic strip similar to a “Band-Aid,”
usually behind the ear. Low-density lipoproteins and liposomes (drug-filled lipid–cholesterol
vesicles measuring a fraction of a micrometer) are also being used to protect drugs from
enzymatic destruction during transport in the bloodstream.
Osmotic minipumps — cylinders measuring about 25 ×5 mm — are widely used to
deliver constant amounts of drug solutions to experimental animals. They require sur-
gical implantation. The osmotic compartment swells in contact with tissue fluid and
squeezes the drug reservoir, displacing the drug solution in a continuous flow. The rate
of delivery is specified by the size of the opening in the container and the swelling rate
of the osmotic “syringe.”
The great advantage of these systems is the uniform drug delivery they permit, as
opposed to the enormous drug level fluctuations inherent with the traditional oral or
injected parenteral modes of drug administration. Patient compliance and convenience
of use are also ensured. Although these interesting developments in bioengineering are
not, strictly speaking, in the realm of drug design or even medicinal chemistry, they can
nevertheless contribute substantially to the success of drug therapy.
3.6 FROM LEAD DISCOVERY TO CLINICAL TRIALS:
THE CONCEPT OF A “USEFUL DRUG”
The ultimate long-term goal of medicinal chemistry is to design a “useful drug”. A use-
ful drug is more than a molecule that is safe and efficacious. It is more than a compound
that produces papers in scholarly journals. A useful drug is a drug molecule that is not
only safe and efficacious, but also one that can pass government regulations, pass
through multiple levels of human clinical trials, be economically produced in large
quantities, be successfully marketed, and can ultimately help people with disease.
Successfully treating humans with disease is the “bottom line” in drug design.
Perhaps the greatest hurdle along the pathway of a molecule becoming a useful
drug is the need to sequentially pass clinical trials. However, before a drug can be
evaluated in human clinical trials, it must first successfully negotiate preclinical test-
ing.This frequently involves five or six types of test, and is completed in non-human
animals:
- Acute toxicity — acute dose that is lethal in 50% of animals; usually two species,
usually two routes of administration - Subacute toxicity — physiology, histology, autopsy studies; two species, sometimes
with dosings over a 6 month time period - Chronic toxicity — detailed organ evaluation; two species, sometimes studied
for 1–2 years
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 159