Download PDF - Blood Journal

From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
B L 00
FEBRUARY,
D
The Journal
1959
The
Heinolytic
Effect
of
By
Primaquine
ERNEST
in
amino
detail
unless
the
red
cells
are
group
defect
States,
of the
that
Israel
Army
been
published
Italian.78
in
been
possible
Penitentiary,
the
antimalarial
revealed
deficiency
an
in some
way,
of drugs.
harmless
anemia
hemolytic
when
Illinois,
drug,
have
communication
of this red
been
entirely
which
the
Army
undertook
primaquine
carried
out
to in18- ( 4
Some
of
possible
recently
the
vitro
the
the
administratests
for
in the
portions
sensitivity
been
of
that
studies
laboratories
also
the
study
investigations
subsequent
in many
has
intrinsic
harmless
extensive
of the earlier
on primaquine
work
of
by
in
to review
defect
and
and Italy.
A brief
review
malaria
research
project
English.49
usually
simple
made
cell
new
type
apparently
is
most
Relatively
abnormality
have
and distribution.
is the purpose
of this
led to the elucidation
United
work
Related
certain,
ordinarily
an acute
hemolytic
to a drug-induced
previously
anemia
enzyme
red cell
genetics
of the
that
when
individuals
sensitivity
had
challenged
of a large
detection
of this
its biochemistry,
2
)-6-methoxyquinoline].
of this hemolytic
abnormality,
an
of one
It
have
than
at Stateville
effect
of
1-methylbutylamino
Study
red
cell
tion
greater
Research
Unit
the
hemolytic
and
NO.
BEUTLER
HAS
LONG
BEEN
KNOWN
drugs
are administered
to some
results.
An opportunity
arose
to study
Malaria
vestigate
XIV,
a Review
T
anemia
VOL.
,
Compounds:
I
of Hematology
of
the
has
reviewed
in
HIsT0RIcAL#{176}
In
1926,
when
plasmochin
stated
“that
themselves
erroneous
From
the
the
not
and
through
was
the
its
soon
only
of
by
use
the
often
rapid
use in cases
to be
Argonne
University
Submitted
June
Cancer
of
25,
on
page
Research
Chicago,
corrected.
1958;
accepted
Hospital,
of
the
naturally
effect
on
of acute
hemolytic
anemia
caused
In a preliminary
report,
he referred
The
#{176}Seefootnote
to me
treatment
but also
conclusion
the first cases
by Cordes.32
(leScril)ed
in the treatment
has
110
damaging
is suggested
globin
during
splenomegalv
cine,
M#{252}hlens#{176}7
first
(pamaquine)
plasmochin
8-aminoquinoline,
acquired
the
red
significant
increase
and
significant
of blackwater
It was
and
The
in
same
were
of acute
I)epartment
he
cells
hemo-
regression
fever
in the
by pamaquine
to 4 cases
USAEC,
malaria,
blood
year
of
This
that
described
hemolytic
of
Medi-
Illinois.
for
publication
August
10,
1958.
104.
103ThiB
One
IIIIIIIIIIIIIII1II\IIIUI1IIIIII\II11
LQHX-CEW
1NRN
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
104
ERNEST
anemia
occurrmg
reported
in
in some
72
Negro
detail.
patients
These,
receiving
and
two
250 were
presented
in greater
detail
smears
from
one of his patients
were
who
observed
marked
oligocytosis,
normoblasts
and some
polychromatophilia.
organs
of one patient
cells in the endothelial
Brosius2#{176}and
who
died
leukocytes
MansonBahrs
cases
carried
normal,
out
osmotic
except
that
fragility
in two
per cent
saline.
No controls
by Palma’#{176}#{176}
of a probable
pamaquine
Palma’s
1928
treatment,
observations
tests.
of the
with
of
formed
primaquine
Between
the
test
the
basis
that
the
results
tion of pamaquine
milder
hemolytic
purely
of theoretical
Since
1940, there
#{176}While it
has
closely
hemolytic
each
other
by
with
other
drugs
torical
the
are
portion
induced
by
In
1933,
clinical
some
reports
review
is
been
anemia
at
of
415
were
quite
to be
somewhat
be
.38
considered
of
of
papers
October,
had
from
hematologic
arbitrary
4
appeared
of
malaria
in
be
separated
clearly
limitations
is less
of
hemolytic
of
reports
induced
and
this
kind
of
from
separation
cells
following
were
evaluation
its
of
clear
space,
indiwhen
the
his-
anemias
omitted
to
receiving
often
of
some
The
medication
the
from
have
inadequate.
of
to
possibility
inadvertently
reported
were
introduction
pamaquine.
been
patients
presented
the
of
the
years
have
the
and
data
he
the
primaquine
prototype
The
and
almost
and
may
agents,
red
regarding
may
Many
literature
that was
a
compounds.
1930,
hemolysis
evident.
and
drug
caused
by Blackie18
anemia
of
daily.
of
pamaquine
in pamaquine
normal
consideration
detection
Donath-Lansteiner
earlier
effect
may
with
8-aminoquinoline
by
by
to the
reported
the
primaquine
because
the
hemolysis
the
variety
individuals
mg.
for
were
normal.
Immersing
hemolysis.
Readministra-
hemolytic
large
individuals
to
suffering
The
may
and
and
interest
that
very
this,
8-aminoquine
therefore
8-aminoquinolines.
necessary
least
of
until
interest
is a report
occurring
during
caused
exposure
cases were
of
a
limited
other
that
30
from
of
and
range
abnormality
in the
This
observation
some
of the
as a rare toxic
nonsensitive
is
noted
original
possible
reviewed
anemia
of
review
tests
apparent
and
Because
this
Dixon47
this
the
by
defect
primaquine
that
to
cell
used.
of
medicine,
hemolytic
red
cases
cases
begin
of pamaquine
clotting
times
any further
a resurgence
administration
this
during
the
not
method
hemolysis
a case
fragility
increasingly
Sensitive
within
did
in vitro
of
and
elicit
8-aminoquinolines
reaction.
viduals
osmotic
individuals
related
first
reports
bleeding
did not
interest.
has been
become
were
Of particular
hemolytic
anemia
reported
Strauss”9
hemolytic
“pnmaquine-sensitive
other
the
26 clays after
episode.
Additional
and Dixon.47
In 1939,
stated
that he regarded
in
for
more
of
were
normal
and that
patient
in cold water
results
anemia
many
additional
observed
three
tile appearance
of this
receiving
primaquine.”
Ficacci’
found
was
totaling
the appearance
of Heinz
bodies
in the red cells.
escaped
our notice
and that
of most
other
investi-
sensitivity.’3
1930 and
1940
were
hemolytic
years
Seno103
hemolysis
were
reported.
case
of mild
gators.
WTe noted
independently
red
cells
of sensitive
individuals
subsequently
The
patients,
case
a series
other
things,
many
red
1927, Eiselberg,5#{176} Menk,8#{176}
of acute
few
and
in
publications.3335
Blood
Professor
Victor
Schilling,
and
poikilocytosis,
many
B. Mallory
examined
the
and
found,
among
of the spleen.
In
reported
One
cases
in subsequent
examined
by
anisocvtosis,
Dr. F.
pamaquine
administration.
In the
next
were
reported.5’21’’76’83’92’#{176}”#{176}#{176}’”Roskott
and
pamaquine.
additional
BEUTLER
developed
in
It
cases
addition
has
reviewed.
thus
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF
PRIMAQUINE
AND
RELATED
105
COMPOUNDS
newer
8-aminoquinolines
due to the requirements
of two
tempts
were
made
to determine
the mechanism
of hemolysis.
described
the presence
of a nonspecific
hemagglutinin
in
patient
and
conjectured,
sponsible
for
reported
finding
one
that
incorrectly,
hemolysis.
autoagglutinins
going
hemolysis
25
caused
cases
intradermal
of
by
to
In
pamaquine
and
were
al.52
Feldman
et
and
normal,
and
the
patient
who
amounts
red
cells
the
authors
patient’s
had
were
cells
recently
agglutinins,
sensitive
correlation
and
and
autoagglutinins,
nonsensitive
between
plasma
cluded
that
“pamaquine
as a precipitating
factor
disposing
factors
posing
factors”
et al.,71 examined
and
osmotic
are
likely,
one
of producing
called
to the
attention
observed
mistakenly
readministration
We
now
marked
anemia
concluded
of
recognize
plasma
They
failed,
of
obtained
and
were
familial
in
to
such
in vitro
by
plasma
from
which
a
varying
incubating
Earle
and
the
his
mechanical
cold
hem-
its metabolic
products,
hemolysis
when
certain
to elucidate
normal
results.
the
of Negroes.
Negro
for
Zylmann,147
acts
pre“predisJones
sickling
Birnbaum
et
in vitro
hemolytic
effect
of pamaquine
of hemolysis.
Hockwald
et al.69 studied
nature
of
anemia
nine
temporary
of pamaquine
two
subjects
was
days
a
and
established
that
these
paperformed
sickling
and osmotic
found
no correlation
between
hemolysis.
Further
clinical
also published.19’3031’65’7381’32’137
one
that
the
primaquine
that
obgiven
three
studies
were
cell fragility
pamaquine
for
hemolysins,
however,
number
of patients
sensitive
to primaquine
tients
were
also sensitive
to pamaquine.
They
fragility
tests,
obtaining
normal
results.
They
formation
studies,
patients
studies
group
hemolysis
with
its
without
detecting
any
difference
between
subjects.
They
also
noted
that
there
was
no
pamaquine
levels
and
hemolysis.
They
con-
al.9#{176}
studied
the
the mechanism
methemoglobin
any experimental
on
to their
ambitious
had been
added,
or by
with
the
patient’s
plasma.
or, more
capable
and
the
observations
in that
they noted
the susceptibility
red cells of one primaquine-sensitive
fragility
al.17 and
Mer
et
without
elucidating
McMartin4#{176}
studied
Feldman’s
plasma,
receiving
isoagglutinins,
found
under-
11 Negro
patients
drug
again
after
to reproduce
pamaquine,
of patients
red cells,
present.”
except
the
and
was observed.
Special
hemolytic
episode.
Red
homologous
received
al.48
only
Bayliss12’
a patient
pamaquine
The most
et
re
later
They
some
among
given
the
unable
with
of pamaquine
hydrochloride
from
a control
patient
associates
studied
the blood
and osmotic
fragility
of the
Earle
anemia
was
were
et a!.48
pamaquine;
and
in
Dimson
made
of
anemia.
and a second
hemolytic
episode
out in one patient
during
the
incubating
Earle
receiving
Swantz
results
1946,
also
by
served
2 cases
of acute
hemolytic
pamaquine.
One
of these
patients
was
factors
that
hemoglobinuria.
Readministration
hemolytic
months,
carried
patients
pamaquine.
in vitro
hemolytic
activity.
after
30 days
caused
recurrent
by
plasma
respect,
anemia.
In 1945,
test gave
negative
pamaquine-induced
response
made
abnormal
in this
in three
developed
a hemolytic
the Donath-Landsteiner
reported
that
It is of interest,
wars.
Several
atIn 1943, Mann85
the blood
of one
not
later
insensitivity
sensitivity.
receiving
caused
failed
without
TurchettP32
Gennis
primaquine.
by
to
to
reports,
the
et al.5#{176}
They
the drug
because
cause
recurrence.
hemolytic
effect
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
106
ERNEST
of primaquine
subject
(vide
is characteristic
infra).
RACIAL
A very
great
Negroes
to
the
few
past
anemia
no
of assessing
way
the
hemolysis
to the
Dimson
and
Dixon47
600
in
weight
indicate
no
Strauss
that
among
100
Gennis,’2
no
and
99
no
163
acute
This
was
by
studied
case
Caucasians
treated
of
Caucasian
364
other
than
Bedouins
hemoglobinuria
daily.
crises
hemolysis
Loeb8’
merely
among
200,
\Varthin
160
et al.’34
pamaquine,
pentaquine.
575 Caucasians
al.5#{176}
observed
among
et
receiving
reported
severe
Indians
with
three
and
among
300
was observed
in 2 Jews,
The anemia
during
curred
in an Italian
in an Italian
striking
cause
attributed
subjects
cases
cases
and
Caucasians
among
anemia
1 white
of
in
icterus
15
no
mg.
anemia
Alving’
receiving
60
Caucasians
1 of
171
Rhodesian,
as well
or
acute
refers
more
observed.
among
reported
mg.
of
receiving
Caucasians
1 case
of
and Smith’8
reported.
three
were
of hemolytic
quinine.
500
been
for
pentaonly
receiv-
hemolysis
to cases
as in 7 Indians.
pamaquine
administration
reported
by Atchley
male.
Motulsky96
has observed
primaquine-induced
et al.4 ochemol-
patient.
Negroes:
given
pamaquine
not tolerate
as
susceptibility
1 Greek,
has
pamaquine
ing pentaquine.
Coatney
et al.3#{176}
have
reported
occurring
in a Jewish
male
receiving
pentaquine,
groes
could
The
given
Gennis
susceptible
of the Conall cases
of
receiving
anemia
more
Hawking,#{176}7 Monk93
Caucasians
daily.
Marino”2
reported
10 possible
of Sardinia
given
pamaquine
2 acute
hemolytic
quine
daily.
No
American
and
less
et al.#{176}4
and
49
the
is
of positive
troops.
respectively
hemolytic
carefully
sex
of
sex
since
there
2).
Smith,”8
were
Caucasians
among
primaquine
in
Reitler7
Missiroli
and
1043 inhabitants
ysis
and
Reports
Most
and
cases
of
hemolvsis
of hemolysis
race
Indian
occurred
pamaquine.
regarding
In tile Proceedings
was made
that
Burmese.
years
hemolytic
males,
but
plantations,
troops
were
in
surprising
first twenty
reports
of
were
and
British
individuals.
hemolysis
American
conclusions
by
appreciated.
tile observation
and
demonstrated
daily.
However,
mg.
valid
than
and
no
hemolysis
of primaquine
30
been
the
most
reported
that
of these
receiving
among
One
in
of
incidence
pamaquine
a sensitive
it is somewhat
installations
The
Indians
et al.29 reported
30 to 240 mg.
hemolysis
any
cases
McMartin,4
troops
and
Clayman
receiving
draw
factor.
of
body
British
observed
days.
and
action
occurred
lower
and
that
generally
nature
military
difference
was not always
of Medical
Specialists,3’
ference
has
in
1)
Caucasians
primaquine
more
The
of the
sex
( Table
of
is so striking
from
the
hemolytic
of this
of
to
Most
episode
for sensitivity
is considered
separately
(table
It wa
observed
by Manifold,84
Amy3
and
by
recently
susceptibility
recognized
compounds.
impossible
a hemolytic
TO HENIOLYsI5
the
difference
originated
in vitro tests
Caucasians:
Kligler
The
it
often
and
activity
of sensitivity.
reports
to
hemolytic
been
these
makes
incidence
in
years.
not
of
SUSCEPTIBILITY
difference
the
that
it had
clinical
use
following
BEUTLER
Cordes35
in
much
of
observed
1928,
and
pamaquine
a relatively
6 cases
of hemolysis
Menk8#{176}suggested
as other
racial
high
proportion
among
250
Ne-
that
Haitian
Negroes
groups.
However,
the
of
American
Negroes
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
to
EFFECT
the
OF
hemolytic
Swantz
PRIMAQUINE
effect
and
of
Bayliss12’
following
pamaquine
3,000
individuals
receiving
Earle
et al.48
jects.”
Five
was
reported
one
in the
case
among
et
al.7’
primaquine.
administered
developed
African
the
observed
Of
199
30
of
of
8-aminoquinolines
terest
is the
daily
14 days
for
to
elicit
“untoward
symptoms”
West
African
natives
were
given
references
receiving
to
native.
Mann85
Other
Chinese
refers
Racial
patients
to
primaquine
and
Earle
Smits.5
Chinese
subject
symptoms
et
al.’3’
cient
15
*In
reviewing
reactions.
change
blood
hemolytic
that
several
urine,
but
the
records
as
men
hemoglobin
Readministration
men
were
level
of
Indies
each
of
an
No
Negroes
East
hemolysis
pamaquine.
reported
African
daily.
Although
by
many
2 of 38
A case
Baermann
hemolysis
in
in
this
Thaeler
Indians
dose
sensitive
is
who
not
subjects,#{176}
would
reported
a
fever-
Formosa.
Miskito
were
performed
Brosius2’
has
in
black-water
pamaquine
Nicaraguan
in
children),
African
observed
200
hemolysis
mg.
subjects.
in
observed
given
among
for
and
was
have
subjects
of
in-
symptoms
among
42
There
are, however,
given
Namikawa”8
25
effect
Of particular
villagers
30
doses
observed
natives
Keng73
regarding
sensitive
a Basuto
a Javanese
in
and
cent,
a Bantu.
Seno1oa
9 East
primaquine
of
had
was
an
considerable
of the
Hockwald’s
developing
not
recognized
14
(lays
subsequent
a
early
sharp
to
these
fall
sensitive
of
drug
men
in
has
been
actually
as
suffithe
re-
have
been
hemogiobinuria
in
the
the
revealed
review
that
of
the
that
the
they
study
suf-
the
day
were
as
natural
associated
of
drug
“sensitive.”42
of
the
hemolytic
because
used
original
level
14th
several
acute
was
hemoglobin
by
that
original
administration
a
occurred
found
underwent
demonstrated
one,”
had
it
anemia”
studies
self-limited
recovery
drug
patients
“mild
after
\Vhen
reaction
that
and
in
have
11 per
patient.
destruction.
the
of
1
signs
originally
These
in
Roskott
examinations
that
detection
of sensitivity.
Rican
regarded
mg.
in
anemia
in
occurring
hemolysis
clinical
hematologic
to permit
in a Costa
of
20
to cause
peated
ficient
17
to
case
3 of
no
lower
cases
al.’
et
hemolytic
Negroes.
Sudanese
hemolytic
to
pamaquine.
among
observed
received
one
al.48
given
the
acute
daily.*
information
to
episodes
of
refers
of
receiving
Dern
observed.
Rice’4
noted
no
20 mg. of pamaquine
daily.
hemolysis
et
available
correspondingly
occurrence
Groups:
and in
whom
there
be-
confirmed
approximately
American
gave
160
hemolytic
Smith”8
of probable
like
the
pamaquine.
(or
severe
or
Negroes
for
who
later
Negroes
14
to
less
African
than
is the case
by Henderson8
sufficient
isolated
of
was
among
22,
sub-
observed
5 cases
rng.
of primaquine
30
the
Subsequently
76 “pigmented
Negroes
volunteers,
daily,
ob-
of
Of 81 Caucasians,
This
striking
difference
who
hemolysis
anemia.
is considerably
sensitivity
report
of pamaquine
of
Negro
when
they
although
among
al.”
1945
that
Caucasians.
Chinese.
given
primaquine
acute
hemolytic
Negroes:
There
incidence
a dose
mg.
were
et
until
Negroes,
anemia.”
Hockwald
case
in
American
volunteers
1
hemolysis
reactions
and
consecutive
noted
of
one
hemolytic
Negro
not
most
Negroes,
by
was
cases
were
drug
Caucasians
105
10
hemolytic
developing
of primaquine
hemolysis
Jones
the
were
of
all
107
COMPOUNDS
compounds
treatment
men
“slowly
susceptibility
RELATED
that
6 acute
these
tween
these
reported
served
of
AND
an
the
index
course
data
of
revealed
with
administration.
dark
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
108
ERNEST
1.-Racial
TABLE
Incidence
of
8-aminoquinoline-induced
Author
Drug
Race
Corde&4
Pamaquine
Negro
Henderson”
Pamaquine
Negro
Hemolytic
(Sudanese
Anemia
No. of
Subjects
Developing
Hemolytic
Anemia
No.
of
Subjects
Surveyed
BEUTLER
Approximate
Developing
Hemolytic
Anemia
%
250
6
2
160
0
0
villagers)
Feldman
et
Earle
et
Hockwald
et
Jones
et
Dern
aU
al.4
al.”’
al.7’
et al.43
Kligler
and
Reitler7#{176}
Pamaquine
Negro
Pamaquine
“Pigmented
Primaquine
Negro
ii
2
18
76
6
8
105
5
subjects”
Primaquine
Negro
14
Primaquine
Negro
199
20
Pamaquine
Caucasian
364
1-4
7
1
11
.3-1.1
(Bedouins)
Manifold54
Pamaquine
Caucasian
(British
Manifold54
Pamaquine
Caucasian
(Indian
Dixon47
Pamaquine
and
Marino’2
Caucasian
Pamaquine
2*
.15”
1915
5*
.26*
Troops)
(British
Missiroli
1298
Troops)
600
0
0
1043
10
1
0
0
Troops)
Caucasian
(Sardinia)
Most
et al.’
Pamaquine
Caucasian
Pamaquine
Caucasian
Pamaquine
Caucasian
Pamaquine
Caucasian
0
0
Alving’
Pentaquine
Caucasian
800
2
0.25
Loebsi
Pentaquine
Caucasian
181
1
0.6
Pentaquine
Caucasian
116
1
0.9
Primaquine
Caucasian
575
0
0
Primaquine
Caucasian
99
0
0
Primaquine
Mongolian
38
2
5.3
Pamaquine
Mongolian
25
3
12
1
11
Warthin
et
Dimson
al.’24
and
McMartin”'
100
251
22,000
200
0.11
27
13.5
(Punjabis)
Earle
et
al.4’
Atchley
et
Clayman
Gennis
al.4
et
et
Roskott
al.”
al.5’
and
Seno”
81
(Chinese)
Namikawa”
(Formosan)
Roskott
and
Thaeler
et al)2’
Seno’’7
Pamaquine
East
Primaquine
Indian
Indies
natives
9
200
0
0
(Nicaraguan
Mishito)
Alving
et
al.2
Primaquine
*Frank
jaundice.
fFrank
hemoglobinurla.
CLINICAL
When
no
a primaquine-sensitive
evidence
In contrast
administration
After
two
tient
COURSE
may
of
occurs
might
be
of primaquine
or three
days
observe
tile patient
feels
become
icteric
no
(females)
69
6
8.7
Negro
(males)
72
8
11.1
OF
THE
individual
hemolysis
to what
Negro
other
the
HEMOLYTIC
is given
30 mg. of primaquine
daily,
3 days
after
the first dose
of drug.
in immunologic
sensitivity,
subsequent
until
2 or
expected
does
not shorten
urine
begins
to
abnormality.
weak
and complains
and
the
urine
may
REACTION
When
of abdominal
be nearly
this latent
darken.
In
hemolysis
and
black.
back
The
period.
mild
cases
is
more
pain,
the
hemoglobin,
the
pa-
severe
sclerae
red
blood
count
and hematocrit
fall rapidly,
and a reticulocytosis
begins
to develop.4’
Heinz
bodies
appear
in many
of the red cells,’1
but no alteration
in
fragility
or shape
of the cells
is observed.
The
Coombs’
test is negative”44
Even
if primaquine
administration
is continued,
however,
this “acute
hemolytic
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
phase”
OF
terminates
phase”
PRIMAQUINE
spontaneously
begins.
The
patient
normal,
the hemoglobin,
the reticulocyte
count
with
Heinz
AND
bodies
RELATED
in
feels
about
better,
one
the
color
no longer
seen,
and
tile
week,
and
of the
red count
and hematocrit
remains
high
at first,
it
are
109
COMPOUNDS
urine
begin
to rise,
begins
to
Coombs’
Red cell fragility
remains
essentially
unaltered.
picture
returns
entirely
to normal
and the patient
spite
of continued
administration
of primaquine.4’
the
“recovery
rapidly
becomes
and,
although
decline.
test
Red
remains
Finally,
tile peripheral
blood
is entirely
asymptomatic
in
This
apparent
tolerance
to primaquine
lasts for only a few weeks
after
withdrawal
of the
ever,
since
re-administration
of primaquine
always
causes
an acute
reaction.
There
is no tendency
for successive
attacks
to become
the
intervals
between
Although
there
sensitivity
administration
is some
to 30 mg.
teers,
is essentially
in regard
to the
been
carried
proximately
are
in the
of primaquine
per
an all-or-none
survival
of labeled
sufficiently
intensity
day,
as observed
phenomenon.
erythrocytes.
hemolytic
no
the
have
been
reaction
hemolysis,
the
quine,
acetanilid,
evidence
While
carried
course
of events
sulfanilamide
When
gradual57
extensive
out
in patients
response,
male
This is true both
Red cell survival
is quite
similar
or nitrofurantoin
phenylhydrazine
and in favism,
hemolytic
in healthy
volun-
clinically
studies
gradually
administration
of accelerated
observations
wilatsoever
most
drug,
howhemolytic
milder
if
great.4’
of the
out on several
subjects
whose
hemoglobin
2 Gm. per 100 cc. of blood
during
tile
quine.
There
was
in these
studies.43
tered.41’43
is more
of drug
variability
cells
negative.”
and
ilave
declined
apof prima-
red cell destruction
on the course
of the
with
primaquine-induced
when
drugs
(Furadantin)
is given,
however,
onset
is more
sudden
such
as panlaare adminis-
the onset
of
than
is tile
hemolysis
case
with
primaquine.82
METHEMOGLOBINEMIA
It
is not
our
purpose
8-aminoquinolines.
the
relationship
brief
symptom
in
of
most
of
tile
Sioli”7
cyanosis
Fisher
of
dusky
reports
dealing
to
with
tile
assuming
Weise55
that
demonstrated
of patients
8-aminoquinolines
not prove
any
have
implicitly
exists.
For example,
action
of phenylhydrazine,
it was
tilat
both,
this does
many
authors
section
has
been
as
use
an
of
eliminated
the
causal
relationship
or
most
outstanding
to
explicitly
disturb-
was
Although
methemoglobin
the
cause
pamaquine
forma-
between
assumed
other
to clinical
that
it was
circulatory
and
Gillman,6#{176} in
“Methemoglobin-containing
recent
toxic
and
pamaquine
the fact
methemoglobin
received
pamaquine.
cause
hemolysis
or
Goodman
stated
from
due
of
concerning
this subject
pamaquine
and M#{252}hlens,”7 in introducing
but failed
initially
to recognize
apparently
are more
vulnerable
to physiological
the reticulo-endotheiial
system.
The
result
is
cytes.”#{176} We know
of no experimental
support
*This
properties
confusion
hemoiysis,
and
mucil
is mentioned
who
may
relationship
hemolytic
been
formation
Cyanosis
color
other
tion,
or
However,
and
HEMOLYSIS
methemoglobin-fornling
has
methemoglobin
to methemoglobinemia,
ances.
and
the
there
consideration.
8-aminoquinolines.
medicine,
noted
tile
review
Nevertheless
deserves
due
to
AND
the
that
reviewing
two.
such
a
the
cells
stress
and to destruction
by
the disintegration
of erythrofor such
a view,
and,
on the
edition.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
110
contrary,
in dogs.
Clark
and
Morrisey28
However,
as recently
between
methemoglobin
having
rel)orted
the
report
nature
of
formation
one
these
of
toxic
production
administration
sodium
or
failed
cause
failed
tile
course
in
although
sensitive
PRLMAQUINE
Tile
exposed
is no
SENSITIVITY
AS AN
tion of abnormal
extracorpuscular
istration
of prin1qui11e
or as
of
susceptible
labeled
Cr51
given
nonsensitive
quine
and
was
given
of primaquine
to
sensitivity
to primaquine
was
ment
of abnormal
Having
The
tilat
studies
defect
globin
was identical
syndromes,
of
2).
OF
THE
Tilese
They
RED
CELL
out
nonsensitive
hemoglobin
during
saponin
red cells were
electrophoresis,
in vivo
and
in
and taurocholate
compared
mechanical
by
in
produc-
1953
of tile
adminof
erytilrocyteS
red
that
from
prima-
the
of the drug
individuals.
sub-
cells
and
localized
establisiled
were
were
individuals,
studies
tile
sen-
that
individuals
Cr31-labeled
defect
sensitivity
or
develop-
an
intrinsic
DEFECT
was
to
iue
to
determine
whether
this
as tile abnormal
hemogiobinuria
a previously
to
a variety
and osmotic
vitro
exposure
to primaquine
hemolysis
with
and
without
when
the
who
with
or a variant
of defects
such
thalassemia,
paroxysmal
nocturnal
genital
ilemolytic
anemia,
or whether
it represented
red cell abnormality.
Tile
latter
alternative
proved
and
ing
of
recipiellts
to primaquine
carried
ERYTHROCYTE
anemia
sensitive
degradation
by sensitive
sensitivity
were
THE
basis
the
sensitive
erythrocyte.
Negroes
marked
forma-
in response
to the
unique
susceptibility
Conversely,
into
meas-
hemolytic
nonsensitive
to abnormal
mecilanislils
NATURE
OF
Ofl
from
(fig.
to the
erythrocytes,
of
1).
hemolytic
Negroes.
et al.44la
established
intrinsic
abnormality
transfused
demonstrated
defect
developed!
into
recipients
potently
Spectrophotometric
acute
a
drugs,14#{176}
to
as phenyihydrazine,
nonsensitive
an
erythrocytes
(fig.
Some
of
has
and
nonsensitive
formation
is more
that
methemoglobin
either
manifestation
transfused
not clue
immune
THE
develop
explained
which
due
such
and
in
the
prima-
amount
of methemoby administration
ABNORMALITY
factors
were
the
rare,
than
INTRINSIC
a
primaquine
individuals
is
Dern,
\Veinstein
was clue to an
subjects.
with
sequently
by
(3)
(4)
of
blue,
sensitive,
in sensitive
methemoglobin
greater
finding
that some
individuals
to primaquine
could
be
erytilrocyte.
Studies
sitivity
to primaquine
are
by
hemolysis
rnetilemoglobin
formation.43’54
hemolysis
Negroes
of
cells
any
the
formed
of hemolysis.4””
these
considerations:
induced
metilylene
of
reduction
or no methemoglobin
Caucasians,41
that
actually
independent
following
cause
altilougll
of
Administration
to which
Hansen#{176}4 as
when
essentially
tile
to
cells,
urement
of methemoglobin
formation
and in Caucasians
has indicated
that
tion
from
excess
the
misquoting
of methemoglobinemia
has
in
in effecting
to influence
little
evident
red!
greatly
derivatives
by
is not the case
the confusion
in a Caucasian,
Tile
degrees
nitrite
(2)
influence
aniline
is
nonsensitive
was
hemolysis
methemoglobinemia.
effects
8-aminoquinolines.41
has
and
hemolysis
of marked
of
quine-sensitive
globin
formed!
marked
have
demonstrated
that
this
as 1955,
\Vilcocks’#{176}1 illustrated
primaquille-indilced
was
( 1 ) The
ill
BEUTLER
ERNEST
be
hemoor con-
undescribed
correct.
Sensitive
of techniques,
includfragility
before
and
and
other
acceleration
agents,
with
and
naph-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYT1C
EFFECT
OF PRIMAQUINE
AND
RELATED
111
COMPOUNDS
U)
Id
U
a
Id
Id
1
Id
0
-j
Ut1)
U)-
Ui.)
L.
‘‘0
“1
Z
0
wp..
ZId
U
Z
M.
5
10
15
25
20
DAYS
PRIMAQUPNE,3OMG.MSE,DAy
FIG.
1.-Chromium51-labelled
red
a primaquine-sensitive
One
(open
circles)
Rapid
destruction
noted.
(From
thalene
was
of
Dern
and
measured.
to
donor.
et
hemolysis
did
It
is possible
oxidation
coupled
drug.
survival
studies
red
The
cells
others
red
J.
The
Lab.
carried
were
were
cells
& Clin.
was
carried
out.
nonsensitive
No
that
when
including
any
cells.’3
substances,
that
of the
red
oxidation
The
cause
and
they
cell
with
manner
may
first
component;
hemoglobin.
or,
difference
in pattern
liable
differentiation
of Heinz
of sensitive
body
from
published
et aL’3
or more
by Beutler
Five
these
of
from
daily.
primaquine
primaquine
sensitive
for
be
is
cells
protein
It was
presence
these
cell
bepossible
of oxygen
hvdroxylamine,
compounds,
components
in
alternatively,
vivo
that
of a test
Heinz
was
developed
a consistently
particles135)
formation
oxidized
formation,
nonsensitive
cells
susceptibility
demonstrated
means.
in which
Details
recipients.
of
could
of
of red
become
cells
four
a test
incubated
in the
acetyiphenylllydrazine,
oxidation
red
into
receiving
content
and
ascorbic
acid,
sensitive
of Heinz
body
(denatured
nonsensitive
mg.
with
Med.)
difference
by
30
recipients
determined,
cells
out
transfused
given
in
methemoglohin
pattern
however,
of substances,
phenylhydrazine
different
pattern
reducing
no
courtesy
was
and
to demonstrate,
with a variety
are
al.,44
antigenic
sensitive
than
given
cell
sensitive
primaquine-sensitive
primaquine.
The
acid
tween
The
and
they
were
clear.
then
cause
may
procedure
undergo
utilizing
which
makes
individuals,
bodies
which
is not
found
possible
have
this
rebeen
invariably
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
112
ERNEST
BEUTLER
1.00
0.80
-
o060
-
_____
z
-
D.J.
#{149}-
0.10.
J.K.
0.08
O-
0.06
DONOR:W.P.
I
o
z
_____
“
(CONTROL)
NOPRIMAOUINE
u
H.F.CONTROU
0.04
D.J.
20
1
10
5
I
15
I
25
20
DAYS
Fic.
a
2.-Chroniium5-labelled
red
primaquine-nonsensitive
J. K. was
a Caucasian,
sensitive
Negro
was
given
rot
destroyed
cated
not
donor.
in
presumably
recipients.
no
when
B,
destroying
As
and
the
l).J.
shown
primaquine
the
survival
in
was
primaquine
cells
part
given
A of
the
administered,
normal
carried
were
cells.
30
and
H.F.
of
primaquine
the
in
a
Dern
from
recipients.
primaquine
daily.
red
sensitive
al.,44
cells
were
nonsensitive
his
et
red
three
mg.
hemolyzed
(From
with
into
D.J.
graph,
even
recipient
out
transfused
recipient.
were
sensitive
transfused
studies
normal
nonsensitive,
J.K.
primaquine.
part
cell
The
recipient.
own
red
H.F.
cells
As
indi-
cells,
while
J. Lab.
courtesy
were
& Clin.
Med.)
in
more
of red
under
40 per
cent
blood
had
been
acetylphenylhydrazine.
of the
erythrocytes
of
incubated
in a phosphate
With
few exceptions,
than
heparinized
cose and
cells
from
nonsensitive
identical
conditions’3
by
Kimbro
by
Sansone,’#{176}T
by
Larrizza
Josephson
firm
the
two
Heinz
et
al.,74
studied
studying
et
et
who
al.72
finding
bodies
cells
state
in
most
when
cells
from
studying
al.,78
that
subjects
(fig.
3).
the
a recent
red
incubated
after
glucent
contained
5 or more
Heinz
bodies
These
findings
were
later
confirmed
from
patients
subjects
red
paper
cells
sensitive
subjects
buffer
containing
less than
30 per
with
cells
of
that
they
sensitive
to
naphthalene
favism.
have
from
normal
subjects
with
acetylphenylhydrazine,
nitrofurantoin,
sensitivity
On
the
been
unable
form
and
other
hand,
to
only
as
one
in
con-
or
this
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
Fic.
EFFECT
3.-Heinz
body
erythrocytes
after
as
by
described
x 1300.
test.
(From
Their
OF PRIMAQUINE
formation
incubation
Beutler
Beutler
failure
anticoagulant
no glucose
was
tive to changes
et
to
instead
in
with
et
AND
al.’3
sensitive
100
Wet
(upper
J. Lab.
do
so
& Clin.
in the
tension
field)
and
nonsensitive
(lower
acetylphenylhydrazine
stained
with
crystal
for
violet.
field)
4
hours
Magnification
Med.)
is probably
of heparin
113
COMPOUNDS
buffered
preparations
al.,1’
included
in oxygen
mg.%
RELATED
due
as originally
incubation
and to
to
their
use
described
medium.
The
changes
in the
of
and
oxalate
to
the
as
fact
the
that
test is quite
sensihematocrit
and has
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
114
BEUTLER
ERNEST
therefore
been
found
to be somewhat
less satisfactory
under
field
than
when
carried
out on healthy
volunteers.8”46
Flanagan
et al.57
posed
the
correction
of the
test.
Biochemical
that
examinations
primaquine
activity,
hematocrit
of
sensitivity
in carbonic
to normal
anhydrase
of nonsensitive
groups)
caused
with
to
body
caused
by
in
cholinesterase
or
demonstrated
tended
to
Heinz
iodoacetate
react
like
and
Chari-Bitrou’23
have
reported
(iod!ometric
titration)
GSSG
of
Beutler8
they
cells
erythrocytes
suggested
in catalase
sensitive
that
be
(which
in vitro
of
crises
when
observed
when
thoquinone’4’
using
and
that
of tile
binds
with
of
sulfhydryl
respect
red
to
et
associates
al.,78
using
found
iodometric
and
men
were
there
was a marked
fall in the
in normal
cells.
Similar
destruction
GSH
from
K
GSSG
primaquine-sensitive
phenylhydrazine,
vitamin
his
have
have
method
nonspecific
and
decreased
with
favism.
were
used.
Subsequently,
nitrofurantoin,74
a and
certain
also
findings
during
cells
primaquine,
their
relatively
Larizza
GSSG,
report
in subjects
cells
but
ascorbic
acid,
similar
results
/3 naphthol,’#{176}7’14’
derivatives.’07”25’14’
of
analine
have
been
rea and
/3 naph-
Naphthalene
has
ineffective.’4’
The
finding
that
the GSH
of sensitive
red cells
is
destruction
forms
the basis
for a means
of differentiating
sensitive
cells
in
vitro,
the
“glutathione
to the
red
cells
plied
by
Beutler
jects,
the
GSH
of
while
that
of
the
to
a random
application
of 159
seen.
subjects,
All of the
from
Negro
after
racial
Caucasian.7
nonsensitive
subjects
population,
were
found
acetylphenylhydrazine
In
final
GSH
et al.57
pointed
out
of primaquine
mixture
this
test
to have
with
these
subjects,
to
that
the
in
Appropriate
the
incidence
It
sample.’
blood
corrections
certain
A
had
of
was
review
been
are
of the
GSH,
the
GSH
positive
tests
that
of
these
in
this
cases
from
the
data
in
revealed
mg.%,
the
first
blood
in
35
to
each
case.8*
the
to
that
of
several
hospital,
were
presented
in
2.
be
de-
known
a high
another
table
mg.%
found
means
than
due
were
samples
concentration
the
lower
be
its
127
was
16 mg.%
might
44
In
than
GSH
was
sub-
responses
greater
the
modifications
obtained
made
distinct
121
ap-
male
on
and
below
proposed
out
Two
Negro,
falling
proposed
sensitivity.
whose
all
mg.%.
carried
to
non-
originally
above
12
being
6 subjects,
concentration
have
than
was
stable
When
remained
less
sensitive
from
7 nonsensitive
subjects
fell
uniquely
sensitive
test.”8
and
127 Negroes
and 32 Caucasians.
samples
from
Caucasian
donors
cases.
was
Negro
the
of
Flanagan
*11
of
sensitive
donors
the
cidence
all
stability
of 5 sensitive
incubation
each
unstable,
of
How-
content
poisoning
sensitive
Flanagan
normal.
with
acetylphenylhydrazine,
4). No such
fall occurred
and
hydroxylamine
ported
by others
in
cells.’4
glutathione
Furthermore,
(GSSG),
employed.
to
determination
hemolytic
reported
incubated
level
(fig.
been
that
sensitive
for the
following
was
of
in glycolysis,
of
or arsenite
sensitive
cells
content
of oxidized
glutathione
by Flanagan
et al.57 because
GSH
to performance
formation.
Szeinberg
titration
shortly
a defect
that
the reduced
be below
normal.
a decreased
been disputed
tile
prior
primaquine-sensitive
is not
ever,
Beutler
et al.’4
sensitive
erythrocytes
cells
thenl
values
conditions
have
pro-
indegree
allegedly
actually
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF PRIMAQUINE
AND
RELATED
115
COMPOUNDS
U
-j
0
0
LU
0.
I
I,)
0
0
2
HOURS
Fic.
4.-The
male
GSH
subjects
Beutler,”
termining
and
GSH.
GSH
original
and
have
While
these
with
In
for
to use
is less
males.
cells
it has
have
reliable
Some
in
predicting
females
with
Szeinberg
the
et al. have
more
routine
clear
addition
and
five
per
cell
has
sensitive
ml.
the
(From
some
glucose
that
cases
was
(final
the
to
hemolysis
GSH
found
the
stability
own
by
test,
laboratory.
with
acetylseveral
in-
female
display
relatives
of
an intermediate
also observed
data
which
intermediate
found
while
GSH
to incubation
confirmed
sometimes
precision
have
in our
GSH
been
We have
presented
or
of the
found
sensitivity
glucose
of
increase
modification
GSH
normal
detected
when
well
purposes
been
unstable
tion with acetylphenylhydrazine
were
in vivo when
exposed
to primaquine,
made
the
it without
addition,
red
nonsensitive
may
bimodal
response
of red
in random
populations
whose
seven
acetylphenylhydrazine
modifications
degree
of instability.27’63’78”#{176}9”#{176}”22
our laboratory.7
Alving
et al.2 have
test
from
5 mg.
investigators27’#{176}3’74’78’’99”#{176}9”22”43
satisfactory
continued
vestigators.27’122
subjects
cells
incubation
other
to be
The essentially
phenylhydrazine
blood
red
INCUBATION
& Clin. Med.)
estimation,
method
we
of
after
J. Lab.
courtesy
of the
content
before
OF
one such
case in
indicate
that
this
in
females
values
than
after
in
incuba-
to have red cells which
hemolyzed
some
had red cells which
did not.
in which
added,
and
concentration,
the
these
results
of the
authors
400
test
were
recommend
mg.%)
to
each
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
116
ENEST
tube.1-2”-’
blood
glucose
While
sample
does
jects,7’88”22”27
citrate-dextrose
makes
we
and
tile
( ACD
the
blood
necessity
samples
are
and
of
nonsensitive
of
30
to
an
suggestion
is probably
) solution
as
for
instance
in
which
a fresh
of glucose,
the addition
red
cells
from
sensitive
a sound
anticoagulant,
concern
about
performing
using
found
the
tllat
“nonsensitive”
infants,
75
encountered
required
addition
GSH
stability
of
one. We
rather
than
now use
heparin.
level
of
a short
the blood
time
after
the glucose
the test within
of
subacidThis
and
the
drawn.
Extensive
studies
infants.
It has been
“sensitive”
not
adult
the
the
unnecessary
obviates
have
from
an
not affect
BEUTLER
hours,
GSFI
stability
test
the GSH
concentration
is somewhat
it is stable
however,
stable,6263124’125”41”43
glucose-6-phosphate
infants
*
to
the
have
acetyl
red
in spite of the
dehydrogenase
been
of cord
carried
blood
elevated,
and
in the
phenylhydrazine.’25
cell
GSH
fact that
(G-6-P.D.)
of
the
all
out in
of both
At
infants
case
the
age
becomes
concentration
and glutathione
un-
of the enzymes
reductase
are
not diminished.62”25”43
In nonsensitive
infants,
this instability
can be corrected
with glucose
or inosine.’25”43
The effect
is apparently
due to low blood
sugar
levels
and extraordinarily
rapid
utilization
of glucose
by the infant’s
red cells,
which
is accentuated
has
shown
In
sensitive
cannot
that
in
infants,
be
the
a marked
G-6-P.D.
sensitive
are again
of
acetylphenylhydrazine.’43
in glucose
correction
made.’25
obtained
from
sensitive
infants
hydrazine.62”25”4’
presence
decrease
of
GSII
deficiency
level
instability
has
infants.39”25
able
to
the
with
also
Red
protect
Zinkham
precedes
been
fall
glucose
detected
in GSH.
or
inosine
in cord
blood
cells
from
eight-day-old
nontheir
GSH
against
acetylphenyl-
The GSH
stability
test has been
found
to be normal
in subjects
with
acute
leukemia,
polycythemia
vera, myeloid
metaplasia,
symptomatic
acquired
hemolytic anemia,
disseminated
lupus
erythematosus,
reticulum
cell sarcoma,
lymphosarcoma,
macroglobulinemia
of \Valdenstr#{246}m,
diabetes
mellitus,
hyperthyroidism,
leprosy,7
iron-deficiency
fetalis,
glycogen
storage
disease,
tosis88
obtained
will
after
splenectomy
in nonspherocytic
Heparinized
blood
give
satisfactory
cubated
with
fore
initiation
that
the
stored
of
and
crease
three
in
the
terms
refer
to
sensitive,
have
the
of
demonstrated
exposed
to drug
erythroblastosis
agranulocy-
in labor.’25”27
Positive
hemolytic
anemia.99”44
as long
as four
with
the GSH
10 per
cent
Studies
of banked
GSH
but not
stability
glucose
stability
for
test
solution
blood
test
test has provided
GSH
destruction
glutathione
“sensitive”
presence
in women
congenital
galactosemia,
mesantoin-induced
are
tests
for
if
been
seven
days
at 4 C.
if the blood
is inone-half
hour
solution
indicated
in ACD
valid
have
the
blood
has
bebeen
weeks.88”27
oxidized
the
as
been
of
of
test.7
or four
GSH
stability
mechanism
‘The
to
parts
of tile
results
for
The
the
.05
stored
results
anemia,7’88
plumbism,
and
or
sensitive
“nonsensitive”
absence
by
of
a means
for
and
protection
in
in vivo,
of
vitro
will
the
test,
red
be
red
cells
used
cell
defect
whether
or
further
in
in
the
which
not
the
in
vitro
cells.
red
was
found
remainder
makes
subject
to
occur
this
paper
subject
drug-
of
the
or
studies
An in-
his
red
cells
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
as the
GSH
OF
PRIMAQUINE
disappeared.15
AND
RELATED
Zinkham’41
has
demonstrated
that
of normal
infant
red cells
tion of glucose
subsequently
fell, following
depletion
of
resulted
in a rise in GSH.
onstrated
that
phenythydrazine
destruction
occurred
of the CSH
only when
When
dioxide
carbon
suspension
prior
plete
inhibition
with
or
carbon
acetylphenylhydrazine
of sensitive
tile red cell
monoxide
to incubation
of the destruction
with
alone
that
the
through
destruction
the
action
solutions
prepared
phenylhydrazine
by carbon
description
this
was
monoxide.
The
of the enzyme
enzyme
could
in
phosphate
buffer
hydrazine.
When
again
rate,
malate
5). Szeinberg
cose
for
Beutler
hydrazine
their
was
cell
differences
Glucose
6-phosphate,
fective
red
against
in
GSH
against
the
against
cells
also
be
by
effect
with
acetylnot modified
a hemoglobinin a saline-
of acetylphenyl-
however,
but
mediated
identified.’5
Recent
Mills9’
suggests
that
red
cell
ribose,
pyruvate,
for GSH
for the
protection
presence
and
in
by
nonsensitive
substances
such
ribose-5-phosphate
destruction
(fig.
glu-
of
with
acetylphenylsubstrates
revealed
of sensitive
but
GSH
fuma-
Studies
incubated
of various
cells
but
Hemoglobin
acetylphenylhydrazine.
red
cell
or comof GSH
level,
suspended
the
system,
substrate,
6-diphosphate,
GSH
might
substrates
necessity
the
red
GSH
oxyhemoglobin.
effect,
of hemolysates
in the presence
an ineffective
fructose-i,
in protecting
the
a similar
between
was
the
of GSII
GSH
present
had
et al.15 of the capacity
to protect
their
GSH
dividuals.
in
Ilas not been
in red cells by
washed
lactate
were
ineffective
al.’3#{176}
have
confirmed
red
the
marked
Incubation
system
in moderately
high
place.
Carboxyhemoglobin,
led Beutler
et al.’5 to sug-
destruction
that
Inosine
protecting
fall
cells
on
oxidative
protect
glucose
and
et
no consistent
sitive
explain
dilute
the
not
protected.
red
with
acetyl
oxygenated.
cells
w’hich
had
been
incubated
to destroy
GSH.
Their
activity
was
demonstrated
did
no
to the
took
findings
active
compound
GSH peroxidase
mediate
compound.
et al.’5
when
through
resulted
in sensitive
GSH
addidem-
passed
phenyiilydrazme,
was observed.
acetylphenylhydrazine
from
red
were
shown
peroxide
Beutler
was
of GSH
of
the
the blood
sugar,
Beutler
et al.8’15
cells incubated
suspension
was
acetyl
of GSH
if a solution
of oxyhemoglobin
was addled
concentrations,
rapid
destruction
of GSH
however,
was inert
in this respect.’5
These
gest
117
COMPOUNDS
or inosine
hemoiysates
in-
as glucosewere
from
ef-
both
sen-
and
nonsensitive
cells.
However,
Carson
et al.,24
in an attempt
to
the abnormalities
of GSH
levels
in drug-sensitive
cells,
used
a more
system
and succeeded
in demonstrating
that
hemolysates
from
sensi-
tive subjects
present,
but
could
reduce
GSSG
when
that when
glucose-6-phosphate
reduction
was
deficiency
in
markedly
impaired.
glucose-6-phosphate
sensitive
permitted
cells. This deficiency
to incubate
with
sensitive
different
cells.25
assay
siderably
in red
jects
or
with
favism.
their
Several
procedures,
cells
addition,
These
TPNH
or phosphogiuconate
was used
as the substrate,
important
dehydrogenase
was best
a nondialyzable
findings
indicated
(G-6-P.D.)
demonstrated
stromal
when
factor
was
GSSG
that
existed
with
positive
GSH
drug-induced
Wailer
et
stability
tests,
hemoiytic
al.,’33
misinterpreting
a
in
the
the hemolysate
present
in normal
was
or
groups
of investigators,40’63’78’#{176}9”#{176}7’127”29’142
have
confirmed
that
G-6-P.D.
is decreased
with
families
In
either
in red
anemias
cells
and
Carson’s
using
con-
from
in
sub-
subjects
findings,
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
i18
ERNEST
80
_____________________
GLUCOSE
70
&
METHYLENE
GLUCOSE
60
BEUTLER
BLUE
50
40
U
D
30
-
20
-
LACTATE
4IlIMALATE
PYRUVATE
\FUMARATE
\\\X
0
0
10
-
Id
RIBOSE
NO SUBSTRATE
(CONTROL)
““u’
8
.
-
I
(1)
C)6
C)
4
3
2
0
2
OF INCUBATION
HOURS
Fic.
5.-The
effect
erythrocytes
from
buffer,
pH
glucose
0.02
0.04
M;
7.0.
M
malate
were effective
J. Clin. Invest.)
of
substrate
The
final
have
reported
intermittent
methylene
0.04
NI;
total
blue
fumarate
for
absence
clinical
GSH
genase
of three
activity
and positive
Caucasian
children
nonsensitive
phosphate
by
the
and
laboratory
instability,
a
been
GSH
were
stability
ribose
0.02
in the
red
patient
authors,
this
cells
seems
of an
quite
confirmed
using
Heinz
congenital
in three
other
patients
cells.
It
has
i-carbon
of glucose,7#{176} and
methylene
blue4#{176}
is impaired
been
shown
produce
that
that
decreased
methemoglobin
in these
cells.
LeRoy
cells
with
patient
in
an
view
Bass99
have
dehydro-
bodies,
in
hemoiytic
the
blood
anemia.
Zinkham.’44
30 days
in ACD
of either
sensitive
deficient
quantities
of
reduction
in the
et al.8#{176}
have
of
as having
unlikely
by
inosine
courtesy
Iranian
findings
presented.
Newton
and
total
absence
of glucose-6-phosphate
in vitro
tests,
with nonspherocytic
M;
pyruvate
and
al.,”
on
.02
NI;
glucose
et
regarded
to Szeinberg
et al.’28 storage
of blood
for
not affect
appreciably
the G-6-P.D.
content
dehydrogenase
0.04
the
Beutler
out
phosphate
glucose
lactate
Only
was
saline
were:
NI;
NI.
(From
carried
in
used
0.02
GSH.
their
test
suspended
substrates
inosine
of
of G-6-P.D.
anemia
have
the
and
the
cells
M;
Although
of the
reported
results
of
0.00005
NI;
of
red
protection
jaundice.
hemolytic
According
tion
does
result
The
0.04
the
active
These
the
sul)ject.
concentrations
with
substrates
with
on
a nonsensitive
CO2
found
soluor
glucose-6from
presence
decreased
the
of
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF PRIMAQUINE
AND
Sit.
RELATED
119
COMPOUNDS
of
ceUs
tabolic
of sensitive
proposed
b
Careen .t al#{149}
Glucose
#{163}TP
it
TPII
“I
-6-posp1*te
Tm
inosins
2 ksto-6-phoepIogluccnat.
AT?
‘I,
AD?
Fructose
1,
6,
diphoephate
boos-1.pbosphate
I
/
‘If
14’
SF111
I
‘Vt’
#{149}
posanthine
SF11
lactate
Fic.
eral
6.-Carbohydrate
sources.
duction
thione
Invest.)
deficiency
of TPN.
(GSSG)
utilization
tive
metabolism
A
of
Reduced
TPN
in the red cell
of the
in
the
red
cell:
glucose-6-phosphate
1-carbon
acts as
(not
an
abbreviated
scheme
dehydrogenase
in
on
sev-
impaired
re-
donor for the reduction
of oxidized
gluta(From
Beutler
et al.,”
courtesy
of J. of Clin.
hydrogen
shown).
of glucose
based
results
administrated
intravenously
to two
sensi-
subjects.
Studies
of other
enzyme
been carried
out. Although
GSH
reductase
activity
viduals,
subsequent
more
a slight
the
increase
activity
sensitive
suggested
enzymatic
sine
lactic
dehydrogenase
suggest
acids
the
red
genase
cleotide).
enzyme
was
reported
to
actually
be
present.
increased
cells
the
cell.
would
This,
elevation
hydrolyzed
no
been
dehydrogenase,
of
dehydrogenase
6-phosphogluconic
in
the
red
cells
of
revealed
sensitive
illustrates
been
cells
have
et al.24 suggested
in
Data
as
by Larizza
well
and aldolase.
Gross
et al.63
dehydrogenase
and
of purine
of sensitive
subjects.
Examination
hemoglobin
from
sensitive
Similarly,
primaquine-
isomerase
presented
dehydrogenase
indithat
as has
been
for its primary
levels
of adeno-
phosphohexose
cells.
lactic
also
that
the red cells
of sensitive
by Schrier
et al.”4
showed
in G-6-P.D.-deficient
a slight
phosphorylase
It has
of this
has
primaquine-sensitive
report
by Carson
normal
in
studies
phosphogluconic
ceraldahyde-phosphate
mal
levels
of
a!.123
activity
in
cells.78”3
These
changes
might
well
be considered,
by Schnier,”3
attempts
of the red cell to compensate
defect.
Johnson
and Marks7#{176}have
reported
normal
al.78
amino
systems
original
might
be
quantitative
aldolase
triphosphate,
and
et
in the
of
the
cells
by
as
of
gly-
found
nornucleoside
of the
Szeinberg
et
abnormality.
pointed
out
is probably
expected
It is
result
by
Beutier
that
apparent
in impaired
in turn,
et al.15
that
the
GSH
a result
of their
deficiency
effect
of this enzymatic
defect
would
the
defect
reduction
impair
in
of
reduction
instability
glucose-6-phosphate
TPN
of
of drug-
in G-6-P.D.
Figure
in the metabolism
dehydro-
(tri-phosphopyridine
GSH,
which
6
of
nu-
is generally
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
120
ERNEST
believed
presented
to occur
recently
in a TPN-linked
system,”3
although
that
in a hemolysate,
di-phosphopyridine
for
On the
impaired
other
hand,
as a result
reductase
activity
Thus,
dehydrogenase
bcth
have
relation
it should
be evident
that
of other
metabolic
lesions,
or
defects
the
result
been
activity
carried
is quite
in the
of the
GSH
discrepancies
also
been
reduced
GSH
when
the
to
level
assay
dissociation
observed.
have
have
also be
in GSH
transport
of glu-
of glucose-6-phosphate
of
A few
unstable
been
subjects
GSH,’29
found
results
to
has
been
ob-
was
discussed
above,
may
Other,
less well
explained,
with
and
have
normal
a few
normal
enzyme
subjects
or
only
with
slightly
stability.78’143
OF
were
made
drug
is administered
measuring
stability
could
as a decrease
and/or
and
red
cell GSH,
as
cell G-6-P.D.#{176}2’63”25
KINETICS
Studies
test
although
been
found
enzyme
GSH
such
phosphorylation
stability
good,63’78”29
have
have
decreased
been
may
do not have identical
meanings.
In point
of fact, where
out on the red cells
of a single
individual,
the cor-
served.
Infants
with
unstable
have
normal
or elevated
red
levels
evidence
has
nucleotide
TPN.26
substitute
cose.
BEUTLEB
the
to
survival
THE
HEMOLYTIC
determine
why
to sensitive
of Cr5’-labeled
REACTION
“tolerance”
to
primaquine
individuals
red
cell
for
develops
several
populations,
weeks.
Dern
et
By
al.41
de-
termined!
that (1) a sensitive
individual
who had developed
such “tolerance”
to
primaquine
retains
an undiminished
capacity
to destroy
transfused
sensitive
red cells
and
(2)
the red cells
of a sensitive
individual
who
had
developed
such
“tolerance”
were
not sensitive
to primaquine,
even
in a recipient
who
had never
previously
been
given
the drug.
“Tolerance”
is therefore
not due
to
altered
metabolism
population
of
sensitive
and
That
the red
strated
one-half
the
only
those
and
have
been
proportion
a clinically
This
half
hemolytic
destroyed
in
destroyed
produced
becomes
imperceptible
cells
about
The
the
60 days
old.
If
these
cells
would
be
is destroyed
phase”
of
by
Dern
labeling
(fig. 7).
primaquine
acute
also
remain.
As
phase
action
over
a period
of several
susceptible
to destruction
event.
a segment
of
a period
of about
At the end of this
age,
they
exceeding
by the bone
are
of
weeks,
daily,
are
de-
the normal
marrow
to
insensitive
administration
is
to age sufficiently
the
is
is administered
these
not
hemolytic
through
cell
may
be explained
half of the red cell
rapidly
over
et al.41).
60 days
at a rate
new cells produced
primaquine
be expected
red
one-half
Fe59. Beutler
et al.12 demonto the hemolytic
action
of
highly
sensitive
observed
when
insensitive
but for
destruction.
to
demonstrated
the
about
of primaquine.
for a prolonged
period
of time
is first administered,
the older
younger,
stroyed
gradually,
rate of red cell
too,
are
60 days,
ones are
the events
individual
primaquine
time,
was
that
that
action
the
while
older
on this finding,
case
appears
hemolytic
of narrow
age range
with
blood
cells
are insensitive
is sensitive.
(the
“acute
be
to the
is actually
population
one week
they
small
insensitive
it
population
young
red
to a sensitive
readily.
When
sensitive
Rather,
is heterogeneous,
cell
that
Based
they,
over
primaquine.
individual
this
primaquine,
replace
of
a sensitive
until
continued
for
to become
primaquine.
however,
and
this
Since
only
a
would
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF
PRIMAQUINE
AND
RELATED
121
COMPOUNDS
I)
U
VS
I
WV)
0
NW
DAYS
SMAOtD
Fic.
tion
7.-The
with
effect
of
8
to
Fifty-five
primaquine
The
21
age.
the
(From
changes
No
same
shaded
et
were
rapidly
al.,”
courtesy
occur
cells
are
observed,
then
even
in red
hours.57
Similar
This is in contrast
was
seen.’5
Flanagan
destruction
GSSG
of glutathione
occurs
a question
requires
stability
tests
GSH
does
GSSG
Fe5’-labelled
the
cells
were
course
adminisby
of
while
GSH
occurred.
cells
and
that
fall
in
GSH,
no
examined
This
the
rise
every
in
two
been
made
by Larizza
et al.78 in
in vitro,
in which
a transient
rise
that
the
failure
is not converted
to
not
seem
entirely
pool
in erythrocytes
out
took
Med.)
primaquine
new
GSSG
on three
of GSSG
levels
GSSG
during
drug
warranted
since
it
is strictly
limited
is formed
as to what
is the final
further
study.
Flanagan
carried
in
cells
have
been
investigated
there
was rapid
destruction
administration,
but that
the
whenever
popula-
another
& Clin.
during
cell
contained
young
when
Lab.
During
conclude
was
these
destroyed
J.
red
Fe”
of
samples
have
findings
et al.57
and
However,
it does raise
sitive cells. This problem
blood
observations
with
our
an
period
a rise in the
the
susceptible
destroyed.’5
when
BASE PER DAY)
(3Om
destruction
of hemolysis
occurred,
GSH
is destroyed
in
means
that
This
conclusion
the size of the
sults
cells
that
upon
first
perceptible
Beutler
to rise perceptibly
administration.
is possible
that
that
the
sensitive
and
nonsensitive
subjects
and associates.56’57
They
found
that
GSH
during
the first few days
of drug
was
in GSSG
later
OF PRIMAOUINE
administration
During
of
COURSES
to
GSH-depleted
to four
favism.
days
given.
the major
portion
may
indicate
that
GSSG
range.
days
was
TWO SIX-CAY
primaquine
age
biochemical
tration
Flanagan
red cell
REPRESENT
of
a narrow
erythrocytes
place.
AREAS
normal
from
fate of GSH
et al.57 report
and
four
GSH.
of senthe re-
sensitive
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
122
ERNEST
subjects,
that
before,
no
a slight
and
during
significant
change
increase
in
GSH
after
primaquine
in GSH
stability
stability
in
administration.
occurred.
all
four
mediately
following
several
months
the hemolytic
naphthalene-induced
later.
episodes
It is likely
induced
et
hemolysis,
administered
ing red
cells
levels
remained
slight
for
increase
G-6-P.D.
in
a sufficiently
activity
enzyme
soon
support
the
they
ported
concept
tilat
contain
more
by the report
young
than
activity
period
instability
to
the
low
to further
hemolysis.57
et al.78 in favism.
\Vhile
cells
young
so
with
original
are
more
that
cells
cells.
some
other
and
The
that
assay
the
difference
procedure
red
deficiency)
nism)
wears
THE
patilway,
more
levels,
cell
may
out,
and
a leaky
not
the
RELATIONSHIP
boat
quinolines
It was
recognized
to primaquine
PRIMAQUINE
by
are
extended
to other
molecule
that
by
The
not
just
hemolytic
one
also
Similar
observations
these
observations
but
the
do
to hemolysis
have
not
because
by
large
Marks
and
in
Flanagan
measured
the
the reduction
in young
may be
old
cells.
a pump.
pump
TO
The
It
may
de-
between
leak
(G-6-P.D.
(compensatory
nn
cells
found
mecha-
HEMOLYTIC
EFFECT
COMPOUNDS
and
co-workers#{176}9 that
derivatives
the
than
with
if the
to pamaquine.
for
young
in prima-
by
Flanagan
has
measured
directly
SENSITIVITY
Hockwald
sensitive
is responsible
but
OTHER
aminoquinoline
The investigations
ber of aminoquinoline
It has been possible
while
even
when
glucose-6-phosphate
one
might
draw
an analogy
equipped
enlarge
in size,
boat will sink.
OF
Amino
in
damage,
Thus
OF
A.
a
but
even
is particularly
used
available
young
cells
to resist
activity
is reduced.
a sensitive
remain-
dehydrogenase
individuals,
of TPN.
If a higher
glucose-6-phospilate
dehydrogenase
level
is not tile cause
of their
resistance
to hemolysis,
the explanation
enable
the
hydrogenase
the
for
had
reticulocytosis,
resistant
et al differ;
tiiis may
explain
the discrepancy.
rate of reduction
of GSSG,
while
Marks87
has
in
observed
the in vitro
test
after
the drug
of time
observed
the
to the fact that
are more
severe
Glucose-6-phosphate
individuals.
In sensitive
was
of
and
Larizza
et al.78
fava
bean-induced
stable
GSH
im-
with
that
even
was
two
G-6-P.D.
than
do older
cells,
such
a supposition
is supby Johnson
and Marks7#{176}that G-6-P.D.
activity
is higher
in
in older
quine-sensitive
long
sensitive.
normal
returned
patient
remained
refractory
been
reported
by Larizza
in
that this discrepancy
is due
by fava beans
or naphthalene
were
no longer
unchanged
in
there
and
al.’22
after
relatively
than
those
observed
when
primaquine
is given.
The
data
presented
by Flanagan
et al. reveal
sensitivity,
using
Heinz
bodies,
remained
positive
been
It is concluded
Nonetheless,
sensitive
three
nonsensitive
subjects.
However,
Szeinberg
have
reported
transient
loss
of GSH
instability
hemolysis.
Dawson
et al.4#{176}
have
also
observed
BEUTLER
hemolytic
These
individuals
observations
to determine
properties
the
of these
sensitive
have
portion
been
of the
compounds.
have
been
limited
necessarily
by the relatively
small
numderivatives
that
may
be administered
safely
to man.
to conclude,
however,
that hemolytic
potency
is influenced
rather
potencies
by
a considerable
of five
6-methoxy
number
of structural
8-amino-quinoiines,
alterations.
differing
only
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
in
tile
EFFECT
OF
structure
PRIMAQUINE
the
of
side
AND
chain
RELATED
at the
8-amino
differ
greatly.
4-Amino-1-methylbutylamino,
amino
and
5-isopropylaminoamylamino
pamaquine
and pentaquine,
respectively,
in doses
side
of 30 mg.
chain,
daily.
forming
requiring
three
to
position,
3883
six
times
have
been
found
to
4-diethylamino-1-methylbutylchains,
forming
primaquine,
compounds
highly
hemolytic
side
formed
A 4-aminobutylamino
S.N.
123
COMPOUNDS
or 2-amino-1-methylethylamino
and
C.N.
1110,
the
dose
of
respectively,
primaquine
formed
compounds
cause
comparable
to
1043
Alteration
of the
influences
60 mg./day
the
the
6-methoxy
was
B.
administered.
group,
500
mg.
per
Extension
primaquine
(S.N.
day
was
15,324,
acid,
of these
(fig.
8)
zine,
Gm.
present
had
almost
3294,
the
S.N.
chloroquine,
the
another
daily
aniline
that
acetylsalicylic
the
destroys
compounds
in the
they
These
group
All
the
amino
With
had
on
no
when
except
for
methoxy
group
If, instead
of
the
quinoline
hemolytic
in
the
nucleus,
potency,
even
4-amino
isomer
of pamaquine,
4-amino
quinoline.’#{176}’43
of
2.0
Gm.
3.0
or 300
related
acid,
in
8.0
Gm.
mg.
The
Gm.
reached
the
“recovery
indicate
that
that
elicits
compounds
tested
that
compounds.
the availability
cells
300
of in vitro
phase,”
means
for
to
the
be
that
very
Sulfadia-
was
similar
hemolysis
detection
were
of drug
it has become
possible
for physicians
to test blood
of patients
of drug-induced
hemolytic
anemia
to determine
whether
stability
or G-6-P.D.
deficiency
is present.
Kimbro
and associates
induced
clinically
including
of the
volunteers
occurred.42
one member
in sensitive
hemolytic
were
forma-
hemolytic.43
nonsensitive
individuals,
administration
to these
further
is merely
reaction
found
not
in
reaction
was
no
diphenyl(Pyribenza-
in vitro,8
was
acute
hemolysis
hemoiytic
primaquine
a hemolytic
mg.
5 Gm.
quinine
and
Daraprinl,
in vitro
Heinz
body
volunteers
were
3.6
para-aminobenzoic
Pronestyl,
when
primaquine
was given
to these
recovery
that
occurs
during
continued
when
primaquine
was administered
observations
of compounds
to
also
sulfanilamide,
of tripelennamine
compounds,
which
induces
sensitive
Gm.
chloramphenicol,
Antistine,
indicated.
tested
3.6
less
closely
cells
are
300 mg. sulfoxone
(Diasone)
and
sulfanilimide,
5.0 Gm.
sulfacetamide
30 mg. aniline,
100 mg. para-amino-
GSH
in sensitive
caused
significant
dosage
compounds
to that occurring
the spontaneous
drugs.
Furthermore,
after
mg.
or sulfathiazole
mine).
The
more
distantly
not hemolytic.’#{176}’42’43 Ascorbic
by
to pentaquine
(Tralgon),
acid,
400
sulfamerizine,
tion and which
None
of these
markedly
hemolysis
derivatives
related
primaquine-sensitive
administration
para-hydroxyacetanilid
(Benadryl),
individuals
identical
was
studies
to
demonstrated
to
3.6 Gm.
3.6
nucleus
derivatives
sensitive
hydramine
quinoiine
considerable
group
Gm.
acetanilid,
30 mg. phenylhydrazine,
3.6 Gm. Phenacetin,
5.0 Gm.
N4 acetyl
and 6.0 Gm. thiazolsulfone,
but not to
phenol,
the
caused
15,305)
given.
as was
aniline
uniquely
S.N.
a 7-methyl
compound
nonhemolytic
Other
in
Pentaquine
in the latter
a hydroxy
group
has replaced
the
of the quinoline
nucleus,
was less hemolytic.
resulting
whell
substituent
potency.
was
fact that
6-position
the
6-position
hemolytic
of a large
individuals.
aromatic
sensitivity
with
a history
glutathione
inhave
demon-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
124
ERNEST
BEUTLER
.
0”
Is
.
35
SO
,j40
S
S
.
.
.
.
30
.
.
S
01c2
00
cP
10
0
S
-ooWboO
0.030MM.
PNENYLHYDIAZSNE
ACETANILID
36 GM.
3.6 GM.
SUIIANILAMIDI
PRIMAOUNII
DAILY Dii
DOS
CH3
,
2N CH2)3N
NH
5NHS
$OCHS
CH3O1II1Z)
102NH2
‘
Z
hO
0
-
60
4
So
u,
z
:
30
,
120
I
#
#{149}
.#{149}.
.
DAILY
DOSI
.
pop
0cp0
DRUG
PHENACETIN
3.6 GM.
IULFOXONE (DIASONI)
0.3 GM.
SYDSOXY ACETANID
3.6 GM.
AC
‘AMINOSINZ#{212}IC
6.0 GM.
NHCN2SO2Na
c
c
NH2
c;OCH3
Fic.
of
8.-The
hemolytic
a primaquine
sensitive
sents
the
sensitive
per
cent
cells
effect
and
hemolysis
of
12
priniaquine
and
nonsensitive
labelled
cells
seven
volunteers.
of transfused,
Nonsensitive
(5).
OH
0C2H5
?CN2SO2NA
(o).
aniline
In
cells
(From
each
from
Dern
COOH
derivatives
column,
a different
et
al.,4’
on
each
donor.
courtesy
red
point
cells
repre-
Primaquine-
J. Lab.
& Clin.
Med.)
strated
glutathione
developed
(Furadantin).
a hemolytic
They
who
developed
and
the
probenecid.
red
cell
Furadantin-induced
instability
of
anemia
also found
following
glutathione
hemolytic
anemia
the
red
when
cells
the
exposed
A patient
with
gantnisin-induced
defect.74
West
and
Zimmerma&8
hemolysis
in
a Negro
of
two
subjects
who
had
administration
of nitrofurantoin
instability
of red cells in subjects
to
antipyrine,
pancytopenia
have
reported
subject
of the type
of hemolysis
observed
in individuals
cells,
However,
no studies
have
been
carried!
dividual.9
Naphthalene,
which
has been
known
hemolytic
anemia,
particularly
in Negro
children
which
was
phenacetin
did
a
quite
not have
case
of
typical
with
primaquine-sensitive
out
on red
cells
of this
infor many
years
to cause
a
who
have
ingested
naptha-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF
lene
moth
balls,’45
will
cause
hemolysis
PRIMAQUINE
has
also
in
AND
been
shown
sensitive
et al.,#{176}3
McGovern
was
found
to
et al.,88
be
et al.39
the
have
the
observed
cell
occurs
In
defect
of
primaquine
sensitivity
in normal
newborns.’41’143
1948,
Turchetti132
called
tween
favism
and
suggested
carrying
sensitivity
on red
findings
or
attention
to
plasmoquine-induced
out
cells
of Sansone
the
and
to
certain
with
Segni’#{176}8and
in
Szeinberg
GSH
pain
instability
superficial
vitro
a history
these
anemia
sub-
which
similarities
anemia.
developed
subjects
G-6-P.D.
of
after
the
ingestion
of
been
suggested
that
the
may be related
to the
the
hemolytic
newly
from
cells
hemolytic
jects
red
found
Negro
patients
by Zuelzer,’45
Sansone.107
red
with
a positive
glutathione
stability
test
Superanahist
and possibly
after
Orinase.
It has also
hemolytic
effect
of vitamin
K derivatives
on newborns
which
Childs’4’
of four
confirmed
et al.38”#{176}and
in
compounds
and
erythrocytes
results
were
markedly
Dawson
among
Zinkham
Dawson
decreased
tients.38’39’40’63’88”#{176}7
to be
in the
These
125
COMPOUNDS
individuals.
positive
glutathione
stability
tests
with this type of hemolytic
anemia.
Gross
RELATED
In
tests
1956,
for
of favism.
primaquine
The
et al.’23”3#{176}that
be-
Crosby3#{176}
independent
the
glutathione
content
of red cells
of patients
with
a history
of favism
was
low gave
the
first experimental
evidence
linking
these
disorders.
Subsequently
these
authors
have
applied
the glutathione
stability
test to the red cells of subjects
with
a
history
also
of favism
assayed
and
the
concentration
et
Carcassi
of
statistical
for
found
the
but because
positive
and
GSH
of red
their
results
they
a marked
results
have
Pujatti,’#{176}’ Gross
concluded
et
cells
did
that
is clearly
unwarranted.
is the fall of GSH
results’#{176}#{176}”22;
they
found
The
and
significance,
Such
a conclusion
induced
hemolysis
obtained
G-6-P.D.
enzyme.”29
Panizon
et al.23 also
to be low,
favism
of
al.,142
always
cells
this
of
Zinkham
have
red
been
in
the
confirmed
al.#{176}3
and
by
Larizza
from
subjects
not reach
an
this
Further
observed
have
decrease
et
al.78
with
a history
adequate
level
difference
was
not
real.
similarity
to primaquinein the early
phase
of
the
clinical
episode,78”22
the
similar
hereditary
pattern63’78”09’112”42
and
the
susceptibility
of the red cells to in vitro
Heinz
body
formation.78”#{176}2”#{176}6Thus
it would
appear
that
subjects
susceptible
to the hemolytic
effect
of the fava
bean
have
are
sensitive
been
with
an
erythrocytic
to
obtained
primaquine
favism.
involved
It
the
by
defect
hemolytic
Larriza
et
in a subject
is probable
in the response
that
to
Szeinberg
et al.’25”26
have
known
to have this red cell
Aside
from
with
primaquine.
al.79 who
produced
with
a history
other
factors,
fava
bean
that
susceptibility
that
primaquine-sensitive
of infection.
We have
with
this
cell
is identical
of
of
that
a typical
and
the
possibly
eventuates
defect
in
with
there
Jews,
who
do
not
have
this
defect.’26
subjects
is reason
to
sup-
under
the
in a subject
welchii
following
a septic
abortion.7
Szeinberg
et al. have
called
attention
fact
that
the
incidence
of hemolytic
anemia
following
influenza
higher
in Sephardic
Jews,
who have
a high
incidence
of this defect,
Ashkenazy
has
are
also
Indeed,
which
impunity.
and
who
this
episode
stigma
of
immunologic,
in hemolysis.
may
hemolyze
more
readily
a severe
hemolytic
anemia
Clostridium
of
hemolytic
red cell
cells
observed
developed
beans,
subjects
proof
to drugs
who
fava
of
Final
referred
to several
instances
defect
have eaten
fava beans
pose
stress
red
that
effect
septicemia
is
to the
much
than
in
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
126
ERNEST
__
I
uls
__
BEUTLER
#{149}1O
th
FAMILY
2
#{149}
MI.
FAMILY
FAM.4#{149}I4OC. FAMILY
3,BU.
m
8
9
II
FAMILY
12
3
I,MA.
FAMIO,BE.
j!I
FAMILY
6,LE.
FAMILY
7,AS.
,w
FAMILY
Au
‘
SM.
4
8,IIOL.
____
I
______
“
______
4
FAMILY
4516
FAMILY
71$
I3#{149}HU
S
I
II,HA.
10
FAMILY
__
II
12
13
I2,LA.
__
__
23
FAMILY
I4,MAR.
6
FAMILY
FAMILY
Fic.
test.
9.-Pedigrees
Black
females
of
circles
whose
Those
marked
Bull.
and
Johns
red
cells
with
an
Hopkins
families
in
squares
gave
X are
assumed
early
abnormality
with
transmitted.8’13’37
quine
al.,2
members
divided
appeared
detected
by
who
et
were
by
The
with
not
tested.
the
glutathione
partially
the
stability
black
glutathione
(From
Sansone
INCIDENCE
study
OF
availability
THE
circles
stability
Childs
et
al.,’7
are
test.
courtesy
DEFECT
of primaquine
vitro
methods
studies
aL,’22”26
red
in
sensitivity
et al.78
cell defect
However,
reactor
and
values
intermediate
and
and
is greater
the most
defect
have been
done
applied
the
glutathione
(fig. 9). They
found
group
for
the
have
all
cell
detection
of
transAlving
observed
that
in families
of its carriers
than
definitive
studies
of the genetic
Childs,
stability
that
while
Browne
et al.22’27 These
test
to an impressive
male
relatives
could
be
groups,
family
was
a red
genetically
of pana-
of its genetic
Gross
et al.,63
Beutler7
by
nonreactor
among
that
incidence
would
be
the familial
nature
made
possible
extensive
Segni,’#{176}9 Szeinberg
et
al.,4#{176}
Larizza
into
an
AND
in the
glutathione
that
tested
reaction
of
of the
have
families
clearly
reactors.
The
has
and
Dawson
incubation
intermediate
were
male
in racial
emphasized
the incidence
of the
in the population-at-large.
transmission
investigators
number
of
an
members
and
marked
difference
Turchetti’32
had
sensitivity.
this
abnormality
mission.
Sansone
et
female
16.JO.
Hosp.)
GENETICS
It was
which
are
7
I5,HAW.
the
females
present.
Segni,’#{176}4”#{176}7”#{176}”1
Szeinberg
distribution
was
This
group
et al.,’26
of
post-
continuous.
has
Larizza
also
It
been
et al.78
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF
and
et
who
Gross
al.63
PRIMAQUINE
used
G-6-P.D.
Gross
et al.63
values
in the intermediate
appeared
in
that
the
findings
degrees
and
as
this
could
stability
test
17 mothers
been
reported
much
limited
this
marked
red
the
with
Childs’
loss
cells.
of Gross
female
the
a recipient
has
al.22’27
cidence
latter
phenotype
on
penetrance.
basis
gene
test,
for
are
G-6-P.D.
of the
the
results
quite
possibly
by
vivo
ilemizygote
glutathione
of expresnormality
occur
is suggested
abnormal
glutathione
heterozygous
by tile
normal
activity
by
is
sexgene
in
female
observa-
sons
and that
had
normal
mode
of inof red cells
vitro
testing
of
approximately
equal
number
Such
a finding
is, of course,
proposed
by Browne,
Childs
if the
were
further
in
male
complete
given
have
autosomal
that
the
to support
this
in vivo hemolysis
test,
female
obtained
convincing,
and
indicated.
The
application
made
available
stability
in the
4 fathers
results
distribution
The
does
that
apparent
only
with
an
appear
with
he reports
an
and females.
of inheritance
GSH
expected
While
stability
assay
the
than
was
peculiar
to apparent
tend
actual
the
intermediate
not in males
Similar
mother
had four
reduced
enzyme
other
investigators
pointed
out that
et al.27
from
to cause
marked
show
all degrees
subjects
that
one such
with
markedly
that
but
detected,
of heterozygote
some
Childs
It
trait.27
expressivity.
stability
for
or a sex-linked
gene.
whom
the glutathione
This
expected
might
type
that
is a different
of the
the
al.63
variable
the red cells.
Using
this method,
of positive
reactors
among
males
not incompatible
with
the mode
et
gene
upon
a sex-linked
gene
than
studies
it would
therefore
would
be
heterozygote
assay
evident
than
males,
in females
randomly
et
the
by
was
have
normal
parents.
That
the
of G-6-P.D.
activity
is demonstrated
et al.,63
offspring
by
It
dominance.
of
Gross
with
males)
loss
Studies
Alving2
were
evidence
and
suggested
recessive.
autosomal
25 mothers
of glutathione
That
it was
who
test
23 of 24 subjects
with
G-6-P.D.
Because
the affected
individuals
autosomal
and
observation27’63”26
fathers.
heritance.
in
Lanizza78
is sex-linked
stability
(always
may
show
marked
tion
some
and
some
female
homozygote
while
the female
from
of the
by
by
defect
simple
done
indicated
more
consistent
gene.
From
and the
instability,
sion
been
stability
less “reactor”
females
stabilities
were
present
be
127
COMPOUNDS
GSH
than
either
a sex-limited
of 18 fathers
and
had
but
rather
not
was
that
the
generations,
dominant
that
there
were
of gluthathione
that
both
RELATED
example,
found
that
range
were women.
three
as
was
that
the gene
It was found
for
for
many
gene
AND
two
equally
Childs
et
genetic
al.,27
studies
challenge
of
times
higher
balanced
using
using
the
by
red
inlower
the
this
cells
GSH
test,
with
an
drug
are
defect.
Such
THE
of
further
data
WITHOUT
show
volunteers
some
no
of primaquine
evidence
summarized
OF
OCCURRENCE
Male
response:
are
the GSH
stability
data
regarding
DRUG-INDUCED
30
HEMOLYTIC
DEFECTS
to
It
120
assays
and
for G-6-P.D.
distribution
of
have
this
2.
mg. of primaquine
develop
an acute
of hemolysis.
is increased
test
and
incidence
in table
DEMONSTRABLE
given
individuals
the
OF
ANEMIA
THEIR
IN
RED
INDIVIDUALS
CELLS
daily
manifest
an
hemolytic
anemia,
has
been
reported,
mg.
some
individuals
that
who
if the
were
all-or-none
all others
daily
dose
classified
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
128
ERNEST
2.-Incidence
TABLE
of
Positive
Sensitivity
in
in
Vitro
Various
Tests
for
Racial
Red
Cell
Groups,
Defect
Random
BEUTLER
Associated
Drug
with
Surveys
%
Author
Method
Detection
of
Beutler’,’,”
Glutathione
stability
Group
Surveyed
test
No.
of
Subjects
males
34
8.8
91.2
0
Negro
females
73
5.5
94.5
0
98.0
0
Oriental
males
51
2.0
Oriental
females
40
0
100
0
30
0
100
0
100
males
Caucasian
et aL’7
Glutathione
stability
test
females
Negro
males
Negro
females
Caucasan
Szeinberg
et
al.”,”
Glutathione
females
Ashkenazic
stability
test
% Neg.
Pos.
Negro
Caucasian
Childs
%
Intermediate
20-35
mg.%
20
0
144
14.58
83.34
2.08t
184
1.63
93.48
4.89t
0
2.Ot
51
0
0
Jewish
males
203
Ashkenazic
0
100
0
100
*
Jewish
females
85
Non-Ashkenazic
Jewish
males-total
267
11.2
88.8
23.6
76.4
*
Subgroups
iraq
89
Yemen
62
8.1
91.9
43
2.3
97.7
North
Africa
Persia
9
0
Egypt
19
0
100
India
1
0
100
Turkey
22
Bulgaria
Others
and
unknown
*
100
9.1
*
*
90.9
*
9
0
100
*
2
0
100
*
Non-Ashkenazic
Jewish
females
260
13.4
86.6
*
Subgroups
Iraq
91
Yemen
North
et a).”
G-6-P.D.
et
al.’
stability
‘Not
t23-40
test
94.0
*
2.5
97.5
*
44.4
55.6
Egypt
19
0
Turkey
22
4.5
95.5
Bulgaria
11
9.1
90.9
and
American
Glutathione
24.1
9
unknown
1
Negroes
Caucasians
Alving
*
6.0
40
Persia
Others
Gross
75.9
50
Africa
100
*
*
100
0
*
152
7.2
92.8
153
1.3
98.7
*
Negro
males
130
6.9
86.9
6.2
Negro
females
186
2.7
92.5
4.8
given.
mg.%.
as “nonsensitive”
develop
mild
on the
basis
of their
response
to 30 mg.
of primaquine
would
hemolysis.42
It is perfectly
clear,
however,
that nonsensitive
cells do not have
the same
degree
of resistance
to the hemolytic
action
of some
of the other
compounds
studied.
For
example,
although
30 mg.
of phenylhydrazine
administered
daily
caused
little
that
larger
doses
recipients.
Flanagan
phenylhydrazine-induced
et
known
or
no
sensitive
individuals
tion. Severe
hemolysis
by
administration
Gm.
of 3.6
hemolysis
of
in
nonsensitive
phenylhydrazine
al.57 have
hemolysis
individuals,42
cause
pointed
out
certain
in normal
individuals
primaquine,
sulfanilamide
has been
produced
in normal
of acetanilid
acute
and
90 mg.
it
hemolysis
is
well
in
all
differences
between
and
hemolysis
in
and acetanilid
individuals
of primaquine,
by
administracombined
and
gradual
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
OF PBIMAQUINE
AND
mild
hemolysis
has
been
produced
acetanilid
alone.42
It appears,
then,
hemolysis
In the case
induced
by
of phenyihydrazine,
to
hemolysis
of
of
hemolysis
of
While
normal
probably
There
in the
are
may
hemolytic
it is possible
differ
from
true
that
many
derivatives
red cells,
surely
or
that
this
different
recipients,
sensitive
cells
76 per
individual
of
most
a
hemolyzed
Gm.
of thiazolsulfone
toms,
failed
that
during
of
cells
studied
varies.
basic
mechanism
primaquine-induced
cases
the
hemolyze
any
perhaps
of
primaquine-
varied
from
thiazolsulfone-induced
in a
abdominal
administration.
another
and
that
this is so was
to thiazoisulfone.
In
destroyed
normal
pain,
While
primaquine-sensitive
daily,
during
are in patients
to be the case
percentage
were
greatest
hemolysis
absorption
Evidence
response
that
occurred
of
reported
assumed
in the
that
the
drug
transfused
to
found
donor
cells
methemoglobinemia,
anemia
sively
same
observed
marked
slight
of
been
be
differences
al.42
et
the
primaquine-sensitive
veloped
and
Dern
from
It was
cent.
tion
that
have
cannot
metabolism
of some
of these
compounds.
by detailed
studies
of the
erratic
obtained
compounds
that the
Gm.
cells.
administration
of analine
with
primaquine-sensitive
always.
129
COMPOUNDS
by the
administration
of 3.6
that the resistance
of “nonsensitive”
different
at least,
cells
sensitive
it is
the
RELATED
recipient,
who
primaquine-sensitive
destruc-
recipient
nausea,
this
cells
0 to
who
deheadache
recipient
when
exten-
given
developed
no
cells
when
even
Only
toxic
3
sympgiven
18
Gm. of thiazolsulfone
daily.
Similar
observations
were
occurrence
of hemolysis
in a nonsensitive
individual
3.6 Gm. acetanilid
daily.
It is beyond
the scope
of
made
with respect
to the
after
administration
of
this review
to discuss
in
detail
of
hemolytic
mechanisms
in equivocal
in
results,
other
drugs.
hemolytic
Most
mechanisms
described
pointed
that
has
in
out,
part
intrinsic
factors
in
the
“Historical”
that
excellent
drug-induced
basis.66
of drug-induced
red
cell
defect
may
in some
in
section
hemolytic
While
the
instances
of
the
discovery
sensitive
of
to
cluding
such
be
a
and
that
the
the
older
the
of
members
administration
hemoglobin
other
of
and/or
the
to
stroma
tilat
should
by
by
produced
suggests
with
that
8-aminoquinoline
individuals,
but
until
remained
of primaquine
cell
cell
obscure.
The
sensitivity
defect.
of
be
Harris
Fuadin,
that
the
the
cells,
same
other
of
the
with
amino
compounds
recently
the
use
has
of modern
resulted
in
this
defect
are
compounds,
in-
derivatives.
subjects
population.
drug
Cells
aromatic
sensitive
a hemolytic
the
It
presented
are associated
primaquine-sensitive
8-aminoquinoline
red
paper.
evidence
by
SUMMARY
number
primaquine
of
AND
red
a large
anemia
drug-induced
as has been
responsible.
has
study
intrinsic
by
primaquine
Administration
of
new
hemolysis
this
been
anemia,
available
a long
time
in certain
sensitivity
for the
technics
of
has
hemolytic
anemias
as is present
in
It has been
recognized
for
may
cause
hemolytic
anemia
hematologic
induction
evidence
DISCUSSION
mechanism
the
demonstrate
immune
ended
in failure
or
however,
at least
one
an immunologic
majority
involved
efforts
to
anemias
have
results
Available
causes
sensitive
oxidative
cell.
in
evidence
damage
Heinz
destruction
suggests
to
bodies
either
are
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
130
ERNEST
visible
manifestation
from
the
of
such
by
in
circulation
endothelial
Red cell
system.
glutathione
has
damage.
vivo
been
to these
compounds
: ( 1 ) the
lower
than
that
of nonsensitive
of red
respect
found
occurs
in vivo
when
damaged
(2
cells
primaquine
cells
are
removed
by
the
reticulo-
related
in some
way
to sensitivity
level of sensitive
cells is consistently
) poisoning
of the sulfhydryl
groups
to react
) a rapid
(3
red
presumably
to be
glutatilione
cells;
cells causes
nonsensitive
to Heinz
body
formation;
level
The
mechanisms,
BEUTLER
like sensitive
fall in the
is administered
cells in vitro
with
red cell glutathione
to sensitive
individuals
but not to nonsensitive
ones;
and
(4)
a rapid
fall in GSH
level
occurs
in
sensitive
but not in nonsensitive
cells
when
they
are incubated
with
acetyl
phenylhydrazine
and
many
other
compounds.
These
observations
indicate
that
there
is a mechanism
sensitive
inosine.
cells.
This
In sensitive
older
cells
that
is destroyed.
The
to be exerted
through
Primaquine-sensitive
6-phosphate
involved
stability
not
GSH
GSH
depletion
GSH
in the
hemolysis
plays
been
cell
in many
effect
entirely
of G-6-P.D.,
different
obtained
role
merely
actually
in cell
and
only
other
in the
by
red
to hemolysis.
If the
to
one
sidered,
therefore,
hemolysis,
in sensitive
that
cells
may
not
be
significance.
Primaquine-sensitive
effect
drugs
of many
commonly
drugs
can
are
sensitive
in
GSH
to
on
occasion
to the
fava
stability
and
GSH
and
that
result
of
in
glucose-
in
the
is
Thus,
defective
GSH
in-
indicator
of
or whether
hemolysis.
GSH
which
level
GSH
The
role
depletion
may
be
grossly
possible
of
leads
to
injurious
that
another
leads
to cell damage
might,
for example,
cause
have
also
alone
mild
According
case.
The
defects
are
G-6-P.D.
expect
changes
associated
cells
of
might
this
bean
at least,
dehydrogenase
reduction.’#{176}3
established
that
either
red! cells is the primary
only
other
compounds,
used
in medicine.
also
deficient
It is entirely
hemoiysis.
is not the
red
in
or
the
in some
interfere
cell.77
cell’s
mild
susceptibility
by Alving
et al.,2
be
as a convenient
lead to cell death
means
to susceptability
in
not
in vitro,
could
explanation
death
ways.51’751”’
clearly
of these
result
reported
to
evidence
It cannot
even
be considered
stability
or G-6-P.D.
deficiency
resistance
but
presence
of glucose
and
the GSH
of
cells.
such
as TPNH
deprivation,
way.
Inability
to reduce
TPN
syntilesis
nonsensitive
appears
found
dehydrogenase
serve
as an
is unknown,
has
red
the
effect
been
GSH
serves
the cell tilat
a primary
cell
to the
lipid
red
whether
within
red
in
to require
is defective
destructive
oxyhemogiobin.
cells
have
glucose-6-phosphate
and may
therefore
clear
changes
GSH
was found
mechanism
activity.
Glucose-6-phosphate
TPN
is a coenzyme
for
of drug-sensitive
It is
important
with
the
red
dehydrogenase
in TPN
reduction.45
a deficiency
in
GSH
reduction
protects
mechanism
cells,
this
but
rather
uniquely
the
defect
GSH
inleading
governs
enzyme
the
to preliminary
possibility
must
even
the
than
of
sensitive
red
deficiency
to
data
con-
be
G-6-P.D.
changes
primary
etiologic
to
the
hemolytic
including
acetanilid,
Furadantin
and other
Yet, it would
appear
that
many
of these
hemolysis
also
glucose-6-phosphate
of normal
been
shown
red
cells.
to have
dehydrogenase
Subjects
who
the
same
defect
as
primaquine-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
sensitive
OF
individuals
factors
would
The
cell
to be
defect
It has
thus
been
been
of
shown
out
so
a similar
here
with
Es
that
discoperta
effectively
depost
de
es sensibile
incluse
le
nunc
un
nove
mente
in
Heinz
essite
maniera
glutathiona
un
quando
tos.
Iste
iste
del
resultate
con
aromatic
in
iste
le
defecto
amino-compositos,
sensibile
resulta
in le destrucerythrocytos.
Le datos
usque
de
de
le
tin
droga
stroma
visible
per
glutathiona
Le
hemolytic
del
de
tal
causa
cellulas
sensibile.
damnos.
mechanismos
Le
in vivo,
non-sensibiie
de corpores
in cellulas
con
que
es defective
afficite
probabile-
plus
non
ii existe
in cellulas
de glucosa
de
pare-al
plus
quando
primaquina
administrate
de glutathiona
in cellulas
mechanismo
vetule
cellulas
rapide
illo es
nivellos
non
altere
que
cellulas
es
sensibile
protege
GSH
que iste
sensibile,
es destruite.
in vitro-esser
a
composi-
sensibile.
Esseva
trovate
o de inosina.
In cellulas
minus
de
como
le
reduction
e multe
un
un
nivello
de
que
in le
sulfhydrylic
in vitro
(3)
Un
in vivo
in
Le
basse
gruppos
quando
rapide
del
sed
relationate
(1)
non
sensibile
e le GSH
GSH
es
occurre
acetyl-phenylhydrazina
indica
de
del
a reager
de Heinz.
sensibiie
sed
(4) Un diminution
occurre
destruction
erythrocytic
a iste
compositos.
es uniformemente
invenenamento
non sensibile
sed non
require
le presentia
mechanismo
effecto
ha
le
8-aminoquinolina.
e/o
erythrocytic
es incubate
observationes
in cellulas
mechanismo
de
sensibilitate
sensibile
glutathiona
(GSH)
illos
has
es capace
Celhulas
de
a subjectos
population
manifestation
(2)
a individuos
non sensible.
reducite
8-aminoquinolina
primaquina
le administration
que
altere
al
le cellulas
induce
cellulas
quanto
al formation
de
as
sensitivities
reticulo-endothelial.
erythrocytos
sensibile
nivellos
drug
sed usque
recentemente
Le uso de moderne
technicas
numero
ab le circulation
non-sensibile.
administrate
individuos
related
possible,
other
erythrocytic.
grande
que
es
a
hemoglobina
cellulas
del
is intimately
is entirely
de
individuos,
obscur.
defecto
un
le
constatate
o un
in
transmitted,
that
compositos
derivatos
es eliminate
in le systema
Ha
per
suggere
de
erythrocytos
genetically
INTERLINGUA
sensibilitate
de primaquina
membros
del
oxydative
Corpores
IN
que
intrinsec
e altere
accumulate
damnos
is
It
Motulsky,95
in certe
remaneva
de
a hemolyse
administration
del plus vetule
tion
predisposing
reaction
deficiency.
by
longo
studio
primaquina
Le
unknown,
penetrance.
a drug-sensitivity
enzyme
anemia
hemoiytic
de ille sensibiiitate
in
yet
basis.
cognoscite
hematologic
as
intermediate
SUMMARIO
a producer
mechanismo
other,
primaquine-sensitivity
gene
transmitted
pointed
have
but
131
COMPOUNDS
involved.
as a sex-linked
to a genetically
RELATED
AND
display,
seem
red
probably
may
PRIMAQUINE
exercite
Le
per
le
oxyhemoglobina.
Ha
del
essite
activitate
constatate
que
de dishydrogenase
glucosa-6-phosphato
phopyridina
(NTP).
deficientia
de
cellulas
de
es interessate
NTP
es un
dishydrogenase
de
sensibile
a primaquina
glucosa-6-phosphato.
in le
co-enzyma
ha un deficientia
Dishydrogenase
de
reduction
de nucleotido
in le reduction
de
glucosa-6-phosphato
resultarea
de
GSH.
in
triphosAssi, un
le
defec-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
132
ERNEST
tive reduction
pharmaco-sensibile.
Ii non
tiones
de
es clar
intra
GSlI
si GSH
le cellula
e explicarea
le instabilitate
es solmente
tin
Ic quales
GSH
ha un rob
primari
dIC GSH
in Ic erythrocyto
resulta
in hemolyse
duce
indicio
essite
del
effectuate
6-phosphato-per
exemplo
ceilula
de
in un
11 es
erythrocytos
governava
que
es Ic defecto
hemolysate.
Ic resistentia
un
leve
de
contra
resultarea
enzyma
sed
que
mesmo
es defectos
non
solmente
le aiterationes
del
associate
Erythrocytos
plus
sensibile
effecto
hemolytic
de
tino,
e altere
drogas
br
de
que
tin
del
leve
de
altere
commun
es
etiam
de
so!
on
expectarea
susceptibilitate
de
per Alving
et
esser
prendite
GSII
de
in-
susceptibilitate
hemolytic,
in
le
glucosa-6-phosphato
le effecto
factores
que
glucosa-6-phosphato
preliminari
reportate
le possibilitate
debe
a primaquina
numerose
de uso
establite
de
le alterationes
le incapaci-
in le erythrocyto.
explica
dishydrogenase
tosto
es possibilerespectos.
Ii
de glucosa-
exemplo,
clarmente
que
del
esser
hemolysate.
Secundo
le datos
isto non es le caso.
Per consequente,
consideration
Per
lipidic
dishydrogenase
erythrocytic
deficientia
que
de
function
de GSH
in le damnification
dishydrogenase
1)rimari
Si le nivello
medios
NTPH-resulta
como
de
aitera-
o si le depletion
in multe
altere
de dishydrogenase
le synthese
considerar
o Ic deficientia
per
differente.
obstruer
possible
GSH
de
completemente
poterea
mesmo
ie
in iste
esser
NTP
non
stabilitate
deprivation
maniera
reducer
erythrocytos
importante
cellula
solmente
injuriose
pro le erythrocyto
possihile
que un altere
effecto
tate
de
in
cellula
e in le hemolyse.
Le
e le prova
que le depletion
mente
grossiermente
es conipletemente
del
GSH
patente
al morte
in le morte
del
es incognoscite,
ha
de
BEUTLER
in
cellulas
sensibile
glucosa-6-phosphato
primari
al,2
in
in illos
signification
etiologic.
distinctivemente
sensibile
compositos,
incluse
acetanilido,
in Ic practica
medical.
Tamen,
al
Furadanii pare
q
multes
inter
iste drogas
es etiam
capace,
in certe
casos,
a causar
le hemolyse de erythrocytos
normal.
Subjectos
qui
es sensibile
a Vicia
fava
ha manifestate
Ic mesme
defecto
in le stahilitate
de GSH
e in dishydrogenase
de
glucosa-6-phosphato
como
individuos
sensibile
a primaquina,
sed ii pare
que
in tal casos altere
e DOll ancora
cognoscite
factores
Le
defecto
erythrocytic
del
sensibilitate
a
geneticamente,
probabilemente
como
gen
predisponitori
primaquina
a ligation
sexual
es
es interessate.
transmittite
con
penetrantia
intermediari.
Assi
ii ha
essite
intimemente
monstrate
relationate
Ii es completemente
mente-que
que
con
tin
un
possibile-como
altere
reaction
deficientia
de
Motulsky95
sensibilitates
drogal
pharmaco-sensibilitate
enzymatic
ha
de
lo ha
bases
del
es
transmission
signalate
mesme
genetic.
si plausibile-
genere.
REFERENCES
1.
Alving,
A.
Pentaquine
agents
effective
Fourth
International
2.
248,
Amy,
M.
in
R.
aspects
(SN-13,276)
reducing
of
\V.,
and
relapse
Congress
Kellermeyer,
,
genetic
3.
S.:
on
Tarlov,
rate
Tropical
A.,
Schrier,
primaquine-sensitive
isopentaquine
in
(SN-13,274),
vivax
malaria.
Medicine
and
S.
hemolytic
L.
and
therapeutic
Washington,
Malaria.
Carson,
anemia.
May
P.:
Ann.
D.C.,
10-18,
Proc.
1948.
Biochemical
mt.
Med.
and
49:240-
1958.
A.
Corps
C.:
Hemoglobinuria:
62:178-191,
a new
269-278,
problem
318-329,
on
1934.
the
Indian
frontier.
J.
Roy.
Army
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
4. Atchley,
OF
PRIMAQUINE
J. A., Yount,
berger,
L. :
E. H., Husted,
Reactions
with quinacnne
J. Nat. Mal. Soc.
5.
Baermann,
G.
Hygiene
AND
during
(Atabrine)
and
T. N., Alving,
treatment
metachloridine
7:118-124,
133
COMPOUNDS
J. R., Pullman,
observed
A. S. and
with
pentaquine,
1,437
) and
( SN-i
Eichel-
administered
with
sulfadiazine.
1948.
Smits,
33:24-37,
RELATED
E.:
tYber
II.
Plasmochin.
Mitt.
f.
Arch.
Schiffs-u.
Tropen-
1929.
6. Benesch,
R. E. and Benesch,
R. : Relation
between
Arch. Biochem.
48:38-42,
1954.
7. Beutler,
E. : Unpublished
observations.
8. -:
mn vitro studies
of the
stability
of red
sensitivity.
J. Clin. Invest.
( abstract
) 35:690-691
erythrocyte
integrity
and
sulfhydryl
a
test
groups.
The
-:
glutathione
in vitro
9.
cinal
11.
and
sensitive
-,
and
age
to
sensitivity
14.
-,
16.
Robson,
M.
and protection
J. Clin. Invest.
and Yeh,
Bimbaum,
and
in
the
for
the
1957.
anemia
Chem.
induced
Soc.
III. A
44:177-184,
1954.
of
primaquine.
by
of Medi-
Div.
of
A.
S.:
The
primaquine-
relationship
of
1954.
prirtiaquine.
Lab.
of
study
IV.
44:439-442,
J.
Alving,
hemolytic
Am.
primaquine.
VI.
& Clin.
The
drug-sensitive
Buttenwie’er,
An
Med.
in
vitro
test
45:40-50,
hemolytic
for
1955.
effect
of
primaquine.
Lab.
&
Clin.
J.
erythrocytes.
E.:
The
and
drug-sensitive
36:617-628,
mechanism
of
non-sensitive
glutathione
erythrocytes.
Med.
destruction
In
vitro
studies.
1957.
M.:
The incidence
of the erythrocyte
oriental
subjects.
(To
be published.)
Goldblum,
N. and Kligler,
I. J.: Further
D.,
of
Blackie,
and
of
method
defect
associated
with
drug-
among
fragility
18.
L.
studies
new
49:84-95,
1954.
Med.
effect
a
Med.
at
effect
primaquine.
drug-
1955.
sensitivity
17.
to
for
1957.
of
Presented
& Clin.
cells:
& Clin.
Studies
hemolytic
C.
Biochemical
-,
-
The
erythrocytes
45:286-295,
S.:
hemolytic
J. Lab.
Flanagan,
-,
VII.
15.
The
-:
of
A.
new
1956.
red
J. Lab.
New York, N.Y., Sept.
15,
The hernolytic
effect
of
J. Lab. & Clin. Med.
-:
and
-,
drug-sensitive
compounds.
hemolysis.
glutathione:
,
164:1381-1382,
Alving,
related
erythrocytes.
-
cell
of
sensitivity.
J.A.M.A.
and
Chemistry,
and -:
,
drug
anemia.
R. J.
Dern,
,
primaquine
13.
of
Hemolytic
-:
10.
12.
instability
detection
cell
W.
red
K.:
cells
in
A fatal
malaria
case
patients.
Acta.
of plasnioquine
observations
med.
Orient.
poisoning.
on the enhanced
5:177-184,
South
1948.
African
J.
M.
9:147-148,
1935.
19.
Braun,
K.
and
anaemia.
20.
Brosius,
0.
Dept.),
21.
Plasmochin
-:
51-70,
A.:
Eugene,
cell
predisposing
The
to
101:115,
P.
-,
E.,
S.
human
-,
27.
Childs,
and
B.,
study
of
-
of
Clark,
L.
Annual
Report,
Report,
the
cause
of
United
Fruit
United
and
Flanagan,
and
and
Contu,
It.
C.
Ickes,
L.,
Alving,
C.
Fed.
a defect
B.
of
an
intrinsic
hemolytic
Arch.
acute
haemolytic
Fruit
Co.
Co.
(Med.
(Med.
of the
abnormality
anemia.
L.:
Sc.
Med.
C.
L.:
Proc.
\V.,
in
Ii
Bull.
Glutatione
Trop.
E.
John
Dept.),
red
Hopkins
S.:
blood
Hosp.
Alving,
Inactivation
Med.
Use
I)PNH
as
(abstract)
Browne,
E.
glutathione
Enzymatic
deficiency
glucose-6-phosphate
(abstract)
dehydro-
48:794-795,
for
1956.
glutathione
reductase
1957.
Kimbro,
metabolism
S.:
Favismo
1957.
1956.
coenzyme
16:19-20,
A.,
A.
of
& Clin.
nel
38:335-348,
124:484-485,
J. Lab.
of
Eritrocitario
Parass.
and
Science
A.
erythrocytes.
Zinkham,
102:21-37,
B.
16th
Annual
erythrocytes.
hemolyzates.
Hosp.
28.
17th
inheritance
L.
Flanagan,
in
26.
as
1957.
Lenzenni,
Schrier,
genase
malaria.
drug-induced
in primaquine-sensitive
25.
in
in malaria.
A.:
U.,
Carson,
quinine
1927.
Ittero-Emoglobinurico.
24.
and
1944.
1928.
Browne,
Carcassi,
Plasmochin
27:219-221,
26-53,
(abstract)
23.
Vries,
Plasmochin
T.:
pp.
pp.
22.
de
Harefua
E.
L.
and
of
the
erythrocyte.
of
nicthemoglobin
J.
Torbert,
Bull.
V.:
Johns
A
genetic
Hopkins
1958.
Morrissey,
R.
W.:
Relation
to
hemolysis.
Blood
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
134
ERNEST
6:532-543,
29.
1951.
Clayinan,
C.
Status
B.,
of
G. R.,
Coatney,
H.
J.
32.
Nat.
Mal.
of
42:406-409,
\V. :
35.
-:
death
in
Crosby,
Dameshek,
38.
Dawson,
\V.
of
the
(
and
W.
149:
J.A.M.A.
B.,
White,
on
Chesson
strain
W.
C.
the
use
vivax
North-Westem
and
of
malaria.
Army
Proceedings,
Punjab,
and
1944.
fever
),
of
62-67,
pp.
66-71,
undergoing
Fruit
effect
( preliminary
malaria
Dept.
United
pp.
der
in
Med.
malarial
toxic
Dept.),
H.:
Favism
of
the
Trop.
Dis.
reports).
treatment
plasmochin.
15th
1926.
( Med.
Co.
with
),
Dept.
16th
plasmochin
pp.
Annual
72-73,
1926.
Report,
United
1927.
Plasmochinbehandlung.
in
and
Arch.
Thayer,
-,
-
thalene
the
W.
and
\V.
the disease.
Dern,
R. J.,
The natural
Schiffs
f.
-
J.
Lab.
and
-:
u.
Tropen.
Hyg.
cases,
in
(abstract)
patients
with
6:11-12,
1958.
communication.
in
with
anemia
Res.
Personal
anemia
two
E.
and
Alving,
of
the
hemolytic
A.
the
newborn
infant
investigation
The
into
due
the
to
naph-
mechanism
of
effect
the
of
mechanism
primaquine.
of
II.
its
self-limited
Med.
45:30-39,
1954.
effect
multiple
hemolytic
and
44:171-176,
hemolytic
a
S.:
anemia
Med.
The
of
hemolytic
Clin.
F.:
1956.
1955.
1958.
& Cliii.
a manifestation
induced
J.
11:91-92,
18:315-325,
involved.
of
13:1113,
Blood
Med.
I)rug
hemolytic
Report
course
F.:
Desforges,
Acute
Beutler,
character.
J.
and
Blood
J.
Am.
mechanisms
-:
poisoning.
(newsletter).
anemia.
Desforges,
into
-,
Sardinia
Heinolytic
P.
40.
as
J. H.:
Edgcomb,
Observations
of
Officer,
plasmochin
Co.
Report,
bei
W.:
J.
-,
and
1928.
39.
42.
case
Annual
(Med.
investigations
41.
Culwell,
XXVII.
Command
with
on
32:143-148,
36.
E.,
treatment
Medical
Fruit
a
15th
Co.
and
Civil
United
Zwischenfiille
37.
H.
Caucasians.
1944.
Observations
Fruit
E.
in
1950.
Experiences
Report,
A
the
D.
malaria.
Central
with
compound.
-:
Young,
priinaquine
Eyles,
9:222-232,
Specialists
Bull.
Cordes,
34.
of
human
prevention
Soc.
Meeting
C.,
in
the
Med.
Joint
-:
R. S.,
Toxicity
W.
Studies
in
Annual
33.
Cooper,
A. :
pentaquine
Conf.
III.
1952.
Lints,
31.
J., Hockwaldl,
Arnold,
primaquinc.
1563-1568,
30.
BEUTLER
of
primaquine.
V.
Primaquine
& Clin.
J. Lab.
drug-sensitivity.
sensitivity
1955.
43.
-,
44.
-,
and
-
I.
hemolytic
effect
defect
45.
46.
in
Dickens,
Metabolic
haven
National
Dixon,
and
48.
Earle,
of
The
Major
Dimson,
cells
Editorial:
50.
Eiselberg,
observations.
LeRoy,
C.
priniaquine.
S.
U.
S.
Laboratory,
and
Talmage,
The
the
p.
R.
B.:
and
the
& Clin.
pathway
for
Energy
Upton,
McMartin,
W.
of
J. Lab.
direct
Atomic
I).
localization
individuals.
of
Fuels.
B.
V.,
I.
significance
Comm.
134-161,
Alving,
Med.
S.:
The
hemolytic
43:303-309,
glucose
1954.
oxidation.
BNL-206,
New
(September),
The
In
York,
Brook-
1952.
haemoglobinuria.
Pamaquine
A.
drug-induced
Quart.
J. Med.
1946.
H.
B.
F.:
D.
A
J.
quinine.
P.,
of
report
Roy.
Jr.,
of
J.
man.
on
Army
F.
the
Clin.
S.,
human
Zubrod,
Poisoning
of
C.
malaria
treated
C.
and
Kane.
of
Effect
J.A.M.A.
(plasmochin):
2
C.
A.:
plasinoquine
Studies
on
pamaquine
27:121-129,
anemia.
with
1933.
IX.
(Supplement).
hemolytic
P.:
cases
60:431-439,
malarias.
Invest.
Drug-induced
K.
six-hundred
NI. Corps
Bigelow,
chemotherapy
49.
M.,
primaqume-sensitive
F.:
15:25-46,
47.
Unpublished
-:
Weinstein,
on
the
the
blood
1948.
158:310,
cases.
Wien.
1955.
klin.
Wchnschr.
40:525,
1927.
51.
Fegler,
C.:
Relationship
haemolysis
52.
Feldman,
thoate
53.
in shed
Ficacci,
H.
A.,
Packer,
as
a prophylactic
L.:
Etnoglobinuria
between
reduced
Nature
170:624-625,
blood.
H.,
Murphy,
for
da
malarial
plasmochina.
F.
glutathione
content
and
spontaneous
1952.
D.
and
Watson,
J.
infections.
II
Clin.
Policlinoco
R.
Invest.
B.:
Pamaquine
26:77-86,
42:136-139,
naph1947.
1935.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
54.
EFFECT
Finch,
OF
C. A.
Fisher,
AND
: Methemoglobinemia
239:470-479,
55.
PRIMAQUINE
RELATED
and
135
COMPOUNDS
sulfhemoglobincmia.
New
J. Med.
England
1948.
0.
and
Weise,
W. : Ueber
bei der Behandlung
Wirkungen
der menschuichen
und
Nebenwirkungen
Malaria.
Deutsch.
des
med.
Plasmochins
Wchnschr.
53:1380-
1382, 1927.
56.
Flanagan,
C.
L.,
erythrocytes
( abstract
57.
58.
)
E.,
S.
quine.
VIII.
sitivity.
J.
Freiman,
Carson,
P.
effect
Lab.
of
& Clin.
M. : Plasmoquine
Ped.
Res.,
the
28th
63.
-,
in
Clin.
Med.
Alving,
NI.
S. : The
on
hemolytic
effect
parameters
of
in
treatment
of
prima-
primaquine
sen-
1958.
compound
and
Klein,
veterans.
Am.
the
of
malaria.
A.:
The
B. : The
use
J. Med.
of
primaquine
17:223-228,
Pharmacological
for
the
1954.
Basis
of
Therapeutics.
Lon-
1150.
Hurwitz,
R.
in
E.:
J.
Beasley,
drug
and
Sui,
induced
M.:
Studies
hemolytic
on
the
anemias.
Soc.
1958.
The
between
E.,
certain
Meeting,
R.
A.
pentose
the
phosphate
age
of
the
pathway
subject
in
and
human
enzyme
erythrocytes:
activity.
Pediatrics
1958.
and
-
certain
Beasley,
drug
-‘
changes
&
J. Lab.
1929.
Korean
Annual
relationship
and
plasmoquine
defect
Hurwitz,
22:435-460,
S. : Biochemical
derivatives.
administration
Kenney,
in
enzymatic
and
-
A.
aniline
51:600-608,
and
60. Goodman,
L. S. and Giliman,
don, MacMillan,
1941,
p.
61. Gross, R. T., Marks, P. A.,
62.
Alving,
by
32:165-169,
malaria
hereditary
E.
drug
Med.
J. Trop.
Med.
& Hyg.
59. Gennis,
J., Straus,
B.,
of
J. and
R.
induced
1955.
L.,
The
treatment
Dern,
hemolysis
46:814,
Schrier,
-,
Beutler,
during
and
-
olism:
J.:
induced
Further
studies
hemolytic
Marks,
P.
in
anemias.
A.:
An
glucose-6-phosphate
the
Clin.
hereditary
hereditary
Res.
enzymatic
dehydrogenase
biochemical
(abstract)
defect
J.
deficiency.
lesion
6:73-74,
in
Clin.
in
1958.
erythrocyte
Invest.
metab-
37:1176-1184,
1958.
64.
J.
Hansen,
E.,
Cleve,
primaquine
quine.
65.
66.
Int.
Lab.
Hawking,
68.
Henderson,
the
69.
70.
W.:
Hockwald,
Toxicity
Johnson,
A.
normal
Res.
71.
Jones,
72.
and
M.,
of
J.
73.
Keng,
mie),
74.
Kimbro,
Kho
anemia
and
L.,
induced
Ibid.,
P.
Lab.
C.
A.:
Bull.
N.
C.
geval
Sachs,
by
Johns
treated
with
to
prima-
analysis
of
258
cases.
a
drug-induced
hemolytic
J.
anemia.
42:254,
1945.
in
Sudan
the
Trop.
Med.
and
Alving,
B.
J.A.M.A.
Glucose
with
& Hyg.
A.
special
S.:
Status
149:1568-1570,
metabolism
to
1934.
of
primaquine.
1952.
and
deficient
reference
28:157-164,
oxygen
consumption
human
in
erythrocytes.
Clin.
1958.
and
A.,
Alving,
in
M.,
bodies
door
Jr.,
malaria
due
toxicity:
dehydrogenase
& Clin.
Een
vivax
Marx,
A.
doses
R.
S.:
L.,
Korean
from
to
10
Levy,
B.
Kenny,
E.
vivax
malaria.
III.
Curative
daily.
Am.
30
mg.
L.,
J.
C.,
Trop.
1953.
Shapiro,
waarschijnlijk
E.
Soc.
Negroes.
primaquine
Heinz
Lien:
Bull.
Roy.
in
2:977-982,
A.
of
malaria
Clayman,
M.
of
of
(methemoglobinemia)
Plasmochin
L. S., DiLorenzo,
toxicity
production
syndromes.
J.,
Johnston,
& Hyg.
Josephson,
Dis.
of
6:187-188,
M.,
Med.
Trop.
Marks,
Jackson,
Relapse
1956.
primaquine
and
L.:
mechanism
glucose-6-phosphate
Jr.,
effect
the
Trans.
Arnold,
(abstract)
Gilbert,
on
note.
B.
W.:
cyanosis
1954.
I.
47:760-775,
Prophylaxis
of
F.
of
1946.
H.:
S.,
and
R.
227:9-12,
plasmoquine.
R.
IV.
case
Editor’s
L.
of
Pruitt,
one
25:103-112,
Med.
F.:
and
of
Applebaum,
Studies
& Clin.
use
Sc.
and
Med.
J.
Harris,
67.
M.
M.
A.
report
J.
Am.
Hardgrove,
Ann.
E.
and
Rozengvaig,
in
various
Med.
51:736-744,
van
zwartwaterkoorts
plasmochine.
M.
nitrofurantoin
Hopkins
V.
Torbert,
(Furadantin).
Hosp.
Singer,
K.:
The
and
experimental
the
thalassemic
1958.
Med.
and
and
S.
hemoglobinopathies
101:245-257,
met
cyanose
Maandblad
J.
V.,
Fed.
(niethaemoglobinae-
1:342-347,
Jr.:
Mechanism
Proc.
(abstract)
1957.
1948.
of hemolytic
16:312,
1957,
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
136
75.
Kiebanoff,
77.
in
Kligler,
in
J.
I.
Langdon,
P.,
81.
Loeb,
R. : Studies
Riv.
: The
P.,
V.,
R.
Okita,
Manai,
84.
Manifold,
A.:
W.
N.:
Soc.
F.
and
reduction
of
gluta-
Prophylactic
use
of
plasmochin
1929.
acids
in
rat
J. Biol.
liver.
Chem.
226:615-
Ventura,
S. : L’Individualita
Anomalie
Bio-Enzimatica
biochimiche
e nei
loro
ed
familiari.
enzimatiche
delle
Haematologica
43:205-
a
communication.
E.
new
C.:
Personal
communication.
antimalarial
Board
for
agent,
Coordination
( SN
pentaquine
of
Malarial
13,276)
Studies.
singular disease affecting chiefly red blood
Plasmochina.
Policlinico
on
a
trial
malaria.
J.
Roy
Med.
of
(sez.
M.
state-
132:
J.A.M.A.
the
37:151-155,
P.:
The
action
of
Red
cell
glucose-6-phosphate
quinine
1929.
in
56:321-338,
20:
cells. Medicine
36:1215-1217,
and
Corps
following
& Hyg.
prot.)
plasmoquine
Army
Haemoglobinuria
Manson-Bahr,
the
treatment
of
1931.
administration
of
plasmoquine.
Trans.
1943.
plasmochin
on
malaria.
Proc.
Roy.
Soc.
Med.
20:919-
1927.
Marks,
P. A.:
phosphorylase.
J. J.,
McGovern,
the
\V.:
16th
dehydrogenases
and
1958.
J.
P.
of
C.,
Birnbaum,
salts.
C.
D.
189-197,
and
red
and
Grossman,
blood
NI.
cells.
plasmnochin
United
Kligler,
Roy.
Soc.
Hemoglobin
which
and
Report,
Trans.
C.:
zyme
quinine
Annual
bile
Soc.
S.:
Observations
Ped.
Res.,
on
28th
Ann.
J.:
I.
Med.
Co.
Lysis
& Hyg.
catabolism.
protects
I.
hemoglobin
treatment
Fruit
of
Dept.),
blood
of
34:373-378,
malaria
malaria
Haitian
1928.
patients
peroxidase,
oxidative
in
78-81,
bile
by
1941.
Glutathione
from
for
(Med.
an
J.
breakdown.
erythrocyte
Biol.
en-
229:
Chem.
1957.
Missiroli,
A.
Arch.
and
f. Sch.
J.
Monk,
Rose,
stability
Combined
Negroes.
Mills,
K.,
(GSH)
6-phosphogluconic
127:1338,
1958.
Menk,
Mer,
and
Science
Isselbacher,
glutathione
Meeting,
93.
Personal
Report
Trop.
nucleoside
92.
fatty
IV.
8:28-33,
favismo
Tocus,
the
da
A.:
tertain
925,
91.
-:
of
by
Ittero
J.
Mann,
or
of
and
1957.
1946.
Roy.
90.
da
F. : Activity
benign
89.
malaria.
Alcune
affetti
C.,
approved
83.
88.
Sopra
and
-
C.
82. Luisada, L.: Favism:
229-250, 1941.
87.
oxidation
1958.
321-323,
86.
The
65:423-430,
malariol.
Grignani,
“Fabico”
pazienti
-,
ment
85.
in
di
biosynthesis
Brunetti,
nei
250,
LeRoy,
Reitler,
C.
2.
J.
Biochem.
population.
‘Eritrocito
emazie
80.
and
R.
dell
-,
metabolism.
erythrocytes.
1957.
Larizza,
79.
: Glutathione
intact
a Bedouin
629,
78.
J.
S.
thione
76.
BEUTLER
ERNEST
Marino,
P.:
Anwendung
u. Tropenhyg.
F.:
Modern
38:1-16,
therapy
of
des
Chinoplasmin
zur
Malariasanierung.
1934.
benign
tertian
malaria.
Bnt.
J.
1:1221-1225,
F.
and
Med.
1948.
94.
Most,
J.
H.,
Kane,
NI.,
relapse
95.
C.
Combined
rate.
Am.
Motuisky,
A.
835-837,
C.:
96.
-:
M#{252}hlens,
Personal
l)ie
H.:
W.
hemolytic
Panizon,
genitori
London,
I.
NI.
Sc.
212:550-560,
reactions,
NI.,
Schroeder,
treatment
of
E.
vivax
malaria:
Hayman,
effect
on
1946.
enzymes,
and
biochemical
genetics.
165:
J.A.M.A.
Behandlung
der
natiirlichen
Symptoms
A.,
Jr.
anemia.
NI.
menschlichen
14:1162-1166,
of
poisoning
in
Malaria-infektion
mit
1926.
the
treatment
of
malaria.
Taiwan
Igakkai
1928.
D.:
44:753-756,
101.
J.
Drug
284:75,
Newton,
Palma,
H.,
Naturwissenschaften
Namikawa,
Zasshi
100.
P.
quinine-plasmnochin
communication.
P.:
Plasmochin.
99.
Lavietes,
1957.
97.
98.
A.,
Jr.:
and
Bass,
Soc.
Ped.
Considerazioni
J.
Res.,
sulla
C.:
Glutathione
28th
sensitive
Annual
Meeting,
chronic
non-spherocytic
1958.
plasmochinaterapia
della
malaria.
Riforma
Med.
favismo
e
1928.
F.
and
Pujatti,
dei fabici.
C.: La Glutationemia
St. Sass. 35:346,
1957.
nella
(Cited
crisi
by
emolitica
Larizza
et
da
al.”)
nei
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
EFFECT
and
-
71,
102.
( Cited
and
da
St.
104.
Chem. 194:119-130,
Rice,
J. B. : Experiments
W.
and
Negroes
Med.
Roskott,
R.
A.
106.
Sansone,
L.
107.
Seno,
and
A.
di
Heinz
Larizza
durante
et
11:
Latina
la
crisi
emolitica
al.7s)
reductase
as
Costalis
of
a
animal
prophylactic
infected
J. Biol.
tissues.
among
with
West
subtertian
African
malaria.
Ann.
1932.
R. : Ervaringen
tossica
Emolitica
del
met
favismo
Acuta
latina
Segni,
Favismo.
Paed.
Plasniochin.
Gennesk.
Tijkdschr.
v.
1928.
Haernatologica
-
Acta
del
alterata
morfologia
eritrocitaria.
Mm.
1957.
L’Anemia
-:
bino.
108.
and
68:80-98,
48:3317,
corpi
by
plasmoquine
of
26:555-576,
C. : Patogenesi
Med.
di
( Cited
L. : Glutathione
on
bites
& Parasitol.
E.
favismo.
1952.
to
Nederl.-Indie
presenza
1957.
A.
nd
al.7)
sulla
35:105,
137
COMPOUNDS
eritrocitario
et
Lehninger,
exposed
Trop.
RELATED
glutatione
rilievi
Rall,
AND
Larrizza
Sass.
103.
105.
sul
by
Primi
-:
favismo.
T.
PRIMAQUINE
Studio
-:
1958.
-
OF
C.:
Prime
Bollettino
de
(in
Ingestione
Accidentale
Determinazione
Della
di
Naftalina
nel
Barn-
press).
Societa
del
Italiana
Glutatione
di
(GSH)
Biologia
Ernatico
Sperimentale.
Ne!
32:456-458,
1956.
109.
and
-
di
110.
-
111.
-
di
un
Biol.
Test
and
Italiana
di
Biol.
broad
beans.
dell
della
una
Cenetico.
Lancet
‘alterato
nel
2:295,
Favismo.
Boll.
Utilizza-
della
Soc.
Ital.
1957.
Biochimismo
Glucoso-6-P
35:327-329,
per
(GSH)
degli
di
Eritrociti
Deidrogenasi.
Boll.
Favici:
della
Societa’
1958.
teoria
genetica
del
favismo.
Acta
paediat.
Latina
10:505-
1957.
Schrier,
S. and
Kellermeyer,
-,
R.
W.:
J. Clin.
Investigation
Carson,
P. E. and
erythrocytes.
114.
Sper.
Ernatico
Problenia
1957.
Completa
E. :Elementi
517,
to
Aspetti
Pressoche’
112. Sartori,
al
33:1057-1060,
Neuvi
-:
Clutatione
Introduzione
Sensitivity
-:
and
del
Selettivo.
Sperimentale
Assenza
113.
L’Instabilita’
-:
zione
-,
prirnaquine-sensitive
Compensatory
mechanisms
(abstract):
Alving,
J.
erythrocytes.
in
928-929,
A.
Lab.
primaquine-sensitive
1958.
S.:
A
&
Clin.
second
Med.
enzyme
S.:
The
hemolytic
abnormality
(abstract)
in
50:951-952,
1957.
114a.
-,
-,
IX.
Med.
115.
Sein,
M.:
Sheets,
by
of
F.,
F.:
Smith,
Note
H.:
Strauss,
B.
Swantz,
in
122.
H.
-,
of
J.
primaquine.
Lab
&
Clin.
by
and
plasmochin,
taken
as
prophylactic
of
human
against
1937.
DeGowin,
E.
L.:
Hemolysis
acid.
Proc.
Soc.
erythrocytes
Exp.
Biol.
& Med.
and
J.:
Radical
Y.
with
and
Chari-Bitrou,
Paralytiker.
Naturwissen-
M.:
and
past
Adam,
A.
relapsing
vivax
War
malaria.
C.:
of
Studies
favism
CSH
Acta
Sheba,
of
und
des
on
or
plasmochmn.
Atebrins
Arch.
of
ten
Med.
cases
glutathione
after
incorporation
of
7:104-107,
pentaquineits
occurrence
1945.
stability
sulfa-drug-induced
18:229-233,
The
with
1950.
concentration
Hemat.
C.:
malaria
33:1413-1422,
report
Blood
and
of
NIed.
from
Sheba,
sulphonamides.
Plasmochins
Hemoglobinuria:
history
A.:
des
Int.
administration
1943.
1939.
cure
Ann.
the
37:155-156,
55-73,
convalescence
Asher,
faba or
Ramot, B.,
43:19-32,
Bayliss,
1958.
der
following
& Hyg.
study.
during
cases
Inipfmalaria
Nebenwirkungen
Hyg.
Gennis,
E.
der
hemoglobinuria
Med.
Klinischen
and
bei
1926.
u.Trop.
A.,
of
vicia
E.
Plasmochins
Trop.
13:348-358,
-
effect
erythrocytes.
p-chloromercimribenzoic
a controlled
Szeinberg,
to
124.
Die
Negroes
cytes
123.
des
Soc.
-
quinine:
121.
H.
regarding
Roy.
f. Schiffe
120.
caused
inhibitor,
14:1160-1162,
S.:
Stauss,
A.
primaquine-sensitive
Gaz. 72:86-87,
Hamilton,
Prufung
Trans.
119.
Alving,
in
1956.
schaften
118.
Med.
a sulihydryl
Sioli,
and
hernoglobinuria
Indian
91:423-427,
117.
E.
1958.
Case
R.
C.
abnormalities
52:109-117,
malaria.
116.
Ickes,
-,
Enzymatic
in
hemolysis.
hernolytic
erythroBlood
anemia
due
glycine
into
1957.
of labeled
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
138
ERNEST
glutathione
-,
-,
erythrocytes
infant.
Sheba,
-,
Rabau,
with
and -:
Soc. Ped. Res.,
-
born
125.
of
-,
E. :
C.,
28th
Adam,
Glutathione
glutathione
metabolism
Ann.
A.,
( To
instability.
Glutathione
in
NIeeting,
I.,
in
be published.)
cord
blood
and
in
the
new-
1958.
Halbrecht,
metabolism
BEUTLER
cord
Rikover,
and
M.,
Vishniewsky,
newborn
infant
of
glutathione
S.
blood.
and
(To
be
published.)
126.
Sheba,
-,
red
127.
C.
blood
-,
and
Adam,
corpuscles
and
-
of
-:
A. :
the
Selective
various
occurrence
Jewish
Storage
stability
of
Blood
glutathione
tribes.
Blood
blood
with
13:
1043,
instability
in
1958.
instable
glutathione.
(To
be
published.)
128.
-,
and
-
patients.
129.
-‘
-,
vicia
of
haemolytic
Bull.
Thaeler,
A.
D.,
Trop.
Med.
J.
Turchetti,
A.:
malarica.
133.
H.
J.
frequenti
W.
cyten)
134.
Warthin,
T.
with
J.
135.
KIm.
in
Wchnschr.
A.,
Med.
S.
(SN
238:467-469,
Webster,
S. H.:
S.:
A
the
emoglobmnuna
on
erythrocytes
in
p-amino-salicylic
cases
with
past
12:603-613,
history
of
1957.
of
clinical
study
Miskito
Indians
primaquine
of
Nicaragua.
da
farmaci
in
corso
di
infezione
1948.
Tabatabai,
M.:
Hamolyse
Blutzellen
und
(Eine
Fehlen
von
Fermentanomalie
Glucose-6der
Erythro-
1957.
and
A.
sen-
1958.
1953.
Roten
7618)
population
and
Blood
among
35:1022-1027,
Levine,
chloroquine
A.
malaria
di
and
Phosphatdehydrogenase
studies
in
anemia.
2:989-999,
62:325-328,
a
181:1256,
suiphonamides
erythrocytes
Alving,
of
of
Nature
1957.
on
and
poco
in splenectomized
erythrocytes
Chemical
faba,
hemolytic
med.
L#{246}hr,G.
E.:
6E:115-118,
treatment
stability
its
anemia.
vicia
Studies
& Hyg.
Forme
D.,
to
Israel
Arnold,
Riforma
\Valler,
Bodony,
due
-:
the
in
hemolytic
acute
Jr.,
in
and
abnormality
and
drug-induced
13272)
level
1958.
induced
N.
and
and
(S.N.
132.
drug
Council
-
favism
Am.
or
anaemia
Res.
-,
24),
Enzymatic
faba
Hirschorn,
acid.
131.
(May
-:
to
-,
cases
-,
1134
and
-
sitive
130.
-:
Lancet,
Evans,
and
R.
Malaria;
A.:
combined
quinine
observations
and
on treatment
plasmochin.
New
England
1948.
Heinz
body
phenomenon
in
erythrocytes-a
review.
Blood
4:479-497,
1949.
136.
Weinstein,
I.
hemolysis
137.
West,
No.
138.
West,
J.
NI.,
in
B.
82,
Dem,
and
and
1944,
Wilcocks,
A.
B.:
J.:
H.
J.A.M.A.
C.:
Talmage,
D.
J.
Plasmochin
W.:
Studies
Clin.
on
Invest.
the
mechanism
(abstract)
intoxication.
Bull.
of
32:609,
U.S.A.
1953.
Med.
Dept.
p. 87.
Zimmerman,
(Furadantin).
139.
and
Negroes.
Henderson,
(Nov.)
Ni.
J.
R.
primaquine-sensitive
Hemolytic
anemia
162:637-639,
Summary
of
recent
in
patient
receiving
nitrofurantoin
1956.
abstracts.
Malaria,
III.
Trop.
Dis.
Bull.
an
antidote
52:317-328,
1955.
140.
J.
Williams,
poisoning.
and
R.
Case
19:166-171,
141.
Zinkham,
naphthalene
and
with
142.
and
B.:
hemolytic
anemia.
Effect
Methylene
blue
as
experimental
of
36:938-939,
A
-:
R.
102:169-175,
of
vitamin
J.
A.M.A.
naphthalene
with
for
J. Lab.
study.
anilin
dye
& Clin.
Med.
K and
from
normal
Dis.
Child.
derivatives
napththalene
and
(abstract)
on
naphthalene
metabolites
newborns
patients
94:420-423,
glutathione
hemolytic
on
with
1957.
metabolism
J.
anemia.
C!in.
of
Invest.
1957.
defect
of
induced
activity
Effect
erythrocytes
patients
a naphthalene
drogenase
Hosp.
Childs,
of
Lenhard,
-,
E.:
confirmatory
metabolism
from
(abstract)
and
H.
-:
erythrocytes
-
F.
with
1933.
W.
glutathione
-
Challis,
report
E.,
Jr.
in
glutathione
and
erythrocytes
1958.
metabolism
heniolytic
Childs,
anemia.
B.:
from
A
in
Pediatrics
22:461-471,
of
deficiency
patients
with
erythrocytes
from
glucose-6-phosphate
Favism.
Bull.
patients
1958.
dehyJohns
Hopkins
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HEMOLYTIC
143.
-:
EFFECT
PRIMAQUINE
An in vitro abnormality
newborns:
mechanism
and
Personal
communication.
144.
-:
145.
Zuelzer,
W.
J.A.M.A.
146.
OF
W.
and
Discussion
-:
Apt,
141:185-190,
AND
of glutathione
metabolism
clinical significance.
(To
L.:
Acute
139
COMPOUNDS
RELATED
hemolytic
anemia
in erythrocytes
be
due
from
normal
published.)
to
naphthalene
poisoning.
1949.
of paper
by
Zinkham
and
Childs.
A.
M.
A.
J.
Dis.
Child.
94:421-422,
1957.
147.
Zylmann,
der
C.:
Synthetischen
In
vitro
und
in
Malariamittel.
vivo
Versuche
Deut.
#{252}berdie
Tropenmed.
haemolytischen
Ztschr.
48:7-18,
Eigenschaften
1944.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1959 14: 103-139
The Hemolytic Effect of Primaquine and Related Compounds: a Review
ERNEST BEUTLER
Updated information and services can be found at:
http://www.bloodjournal.org/content/14/2/103.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.