differences in medical practice. The type and
frequency of adverse reactions observed during
clinical trials was generally lower in Japanese sub-
jects, although there was no correlation between
reduced adverse reactions and lower doses.
Cultural attitudes relating to the use of preferred
terms, different assessment methods and reporting
differences were provided as explanations for the
lower incidence of Japanese adverse reactions.
More Western subjects were included in trials for
a given indication than Japanese subjects, and
Japanese dose-ranging trials were frequently of
an open design. Phase III trials were controlled,
although regional differences in the numbers of
subjects and the use of placebos and reference
drugs were observed, placebo controls being
more frequent in the United States.
The only apparent difference in clinical effec-
tiveness between the West and Japan was not con-
sidered to be significant, for all 21 compounds
displayed no geographic differences in risk–benefit
assessment (for further details, see Harvey and
Walker, 1993).
Other ethnic factors with pharmacologic
implications
Differences seen across regions and nations, both
in reports of efficacy and incidence of adverse
reactions, are much greater than can be accounted
for by ethnic variations of PK and PD. Other
objective differences are now discussed.
Alcohol
Even modest amounts of alcohol may induce
enzyme activity of many hepatic-metabolized
drugs; thus, it is conceivable that data derived
from a French, Italian or Spanish European popu-
lation, who regard wine or beer as a ‘digestive’ and
part of the daily diet, might enhance, albeit slightly,
a higher metabolism of some drugs, thus requiring
higher dosages to achieve efficacy. Contrast this
with the same drug developed in a Moslem or
Mormon society, or in populations who have less
tolerance of alcohol, because of poor metabolism
due to a reduction or absence of either aldehyde
dehydrogese or gastric alcoholic dehydrogenase
(Agarwal, 1990). This reduction or absence of
enzyme occurs in Japanese (44%), Eskimos
(43%) or South American Indians (41–43%) and
to a much lesser degree in other ethnic groups
(Mendoza, 1991). Initially, this reduced enzyme
might exaggerate possible adverse events with
drugs competing for the same metabolic pathway.Other influences on drug differencesSome curiosities, such as prolongation of ductus
arteriosus closure in the neonate at high altitudes
and its resistance to indomethacin closure, are inter-
estingbuthardlyrelevanttomostpopulations.Of
greater impact is the effect of ultraviolet light on
skin. Black pigment gives about 30% protection
from sunburn, but Caucasian populations living
intropical areas not only suffer exaggeratedsunburn
and photosensitivity when ingesting some classes of
drugs, for example, tetracyclines and quinolones,
but also develop a higher incidence of skin cancers.
Concurrent presence of diseases dominating in a
region, for example, chronic hepatitis B, which is
endemic in Asia and may affect up to 30% of the
population, might distort laboratory normals of
liver enzyme responses to drugs and population
baseline measurements. Heterozygous sickle cell
anemia gene confers immunity against falciparum
malaria to Africans (Medawar, 1961), but this ben-
efit is unneeded in African-Americans in malaria-
free United States, and homozygous genes (two
sets) confer illness and sickle cell anemia episodes
may confuse drug assessment. Indeed, drugs such
as chloroquine give rise to occasional fulmanent
hepatitis in these patients and diltiazam has been
shown to produce greater sensitization of the PR
interval in sickle cell C and S patients (Weintraub
and Rubio, 1992).
Although nutritional status is good in Japan,
much of Asia lives on less than optimal nutrition,
and it might be argued that the United States and
Europe suffer from nutritional excess, with about
30% of their populations overweight. Either status
has implications regarding lipophilic drug storage,
metabolism and tissue distribution.18.3 OBJECTIVE DIFFERENCES 237