Drug and Chemical Toxicology
ISSN: 0148-0545 (Print) 1525-6014 (Online) Journal homepage: http://www.tandfonline.com/loi/idct20
Partitioning of Oxamniquine into Brain Tissue Following Intravenous Administration to Female Wistar Rats Gilbert O. Kokwaro & Glyn Taylor To cite this article: Gilbert O. Kokwaro & Glyn Taylor (1990) Partitioning of Oxamniquine into Brain Tissue Following Intravenous Administration to Female Wistar Rats, Drug and Chemical Toxicology, 13:4, 347-354, DOI: 10.3109/01480549009032291 To link to this article: http://dx.doi.org/10.3109/01480549009032291
Published online: 27 Sep 2008.
Submit your article to this journal
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Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idct20 Download by: [NUS National University of Singapore]
Date: 06 November 2015, At: 07:49
DRUG AND CHEMICAL TOXICOLOGY, 1 3 ( 4 ) , 3 4 7 - 3 5 4 ( 1 9 9 0 )
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
PARTITIONING OF OXAMNIQUINE INTO BRAIN TISSUE FOLLOWING INTRAVENOUS ADMINISTRATION TO FEMALE WISTAR RATS Gilbert 0. Kokwarol
and
Glyn Taylor',
Welsh School of
Pharmacy, University of Wales College of Cardiff,
P.O. Box 13,
Cardiff CF1 3XF. Great Britain.
'Present
address: Department of Pharmacy, University of Nairobi,
P.O.Box I9 b7&, Nairobi, Kenya. 2Correspondence.
ABSTRACT Brain
and
plasma
concentrations
of
oxamniquine
were
determined following intravenous dosing (15 mg kg-l) i n female Wistar rats.
Maximum brain concentrations were achieved one
hour a f t e r dosing and at a l l sampling times oxamniquine levels were higher i n brain
tissues
compared t o t h e
corresponding
plasma samples. It
is
concluded
that
the
reported
adverse
neurological
effects associated with t h e clinical u s e of oxamniquine i n man may be due t o t h e passage of s u f f i c i e n t l y large q u a n t i t i e s of t h i s drug i n t o t h e CNS. 34 7 Copyright 0 1990 by Marcel Dekker, Inc
348
KOKWARO AND TAYLOR INTRODUCTION
Oxamniquine
(6-hydroxymethyl-2-isoproplyaminomethyl-7-
nitro-1,2, 3,4-tetrahydroquinoline) is the drug of choice in the
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
treatment
of
Schistosoma
mansonil,
a
disease
is
which
widespread in t h e tropics2.
The common side effects associated
with
oxamniquine
the
clinical
use
of
include
CNS
effects,
including dizziness, headache, nausea and d r o w ~ i n e s s ~ >A~ .few cases of
seizures following treatment with oxamniquine have
also been r e p ~ r t e d ~ - ~ . Toxicity laboratory
of
oxamniquine
animals.
oxamniquine
produced
repeated doses9.
has
also
Pre-clinical CNS
effects
been
testing in
dogs
reported showed
given
in that
high
or
Because of t h e increasing concern about t h e
neurotoxicity of oxamniquine, it has recently been suggested t h a t oxamniquine should no longer be considered a s t h e drug of choice in t h e treatment of Schistosoma mansoni infections". In v i t r o work has shown t h a t oxamniquine is lipophilic and t h u s may be able t o penetrate into the CNS.
This has led t o the
suggestion t h a t t h e CNS-related side effects observed following administration of oxamniquine a r e probably due t o t h e presence of sufficiently large amounts of oxamniquine in t h e CNS".
The
aim of t h e present study was t o use t h e r a t a s an animal model t o evaluate t h e extent of in-vivo brain uptake of oxamniquine. MATERIALS AND METHODS Oxamniquine powder (Pfizer Limited, Sandwich, Kent) was dissolved
in
citrate-phosphate
mg m l - 1 solution.
buffer, pH
5.0, t o give
a
20
349
CONCENTRATIONS OF OXAMNIQUINE
Treatment of R a t s . Groups of 3 or 4 female Wistar r a t s (209 - 344 g) were used. Each rat w a s anaesthetised with sodium pentobarbitone (40 mg
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
kg-l) and tracheostomised.
Surgical anaesthesia was maintained
with pentobarbitone throughout the period of experimentation. The right jugular vein was cannulated f o r administration of oxamniquine (15 mg kg-l).
Rats w e r e killed with an overdose of
pentobarbitone a t 0.5 h r (4 r a t s ) , 1 h r (4 rats), 2 h r (3 r a t s ) and 3 h r (3 rats) post drug administration, and whole brain tissue
was excised and placed in a previously weighed glass tube. Prior t o killing t h e r a t , a blood sample (3 m l ) was obtained by cardiac puncture and centrifuged t o obtain plasma.
Treatment of brain tissue and plasma. After recording the weight of the wet brain tissue, 5ml of cold citrate-phosphate
buffer, pH 5.0, was added followed by
homogenization (microultrasonic cell disrupter, Kontes Ltd., New Jersey) f o r 20 minutes. acid
solution
(protein
Following addition of 0.5 m l perchloric precipitant,
20%
v/v
in
water)
the
homogenate was centrifuged (3,000rpm f o r 15 minutes) and t h e clear supernatant separated.
To 1.0 m l of t h e supernatant was
added 0.1 m l of internal standard solution (containing 1.0 pg of quinine), followed by addition of 2 m l of 1 M sodium hydroxide solution.
The
alkalized
solution
was
then
extracted
by
vortexing with two portions (3 m l each) of chloroform f o r 10 minutes.
The combined chloroform extracts w e r e evaporated
3 50
KOKWARO AND TAYLOR
over a w a t e r b a t h (50'C) residue
was
(phosphate
reconstituted
under in
buffer/acetonitrile
a stream of 0.03ml
70/30)
of
nitrogen.
the and
mobile
The phase
analysed
for
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
oxamniquine according t o a previously described HPLC method12.
A
calibration
curve
was
constructed
by
spiking
citrate-
phosphate with known amounts of oxamniquine and extracting a s described above, For analysis of plasma samples, t h e procedure described previously12 w a s followed, except t h a t quinine was used a s t h e i n t e r n a l standard.
RESULTS Levels of oxamniquine (mean ? s.d.) in plasma (pg ml- 1) and
in brain t i s s u e (pg g-l) a r e summarised i n t h e t a b l e below.
TABLE 1. Plasma and Brain Levels of Oxamniquine Following Intravenous Administration ( 1 5 m g kg-l) t o t h e Rat.
Time
(h)
No. of Rats
Brain weight (g)
Bolus
Oxamniquine Levels Plasma Whole Brain (pg m1-l) (pg g - 9
0.5
4
1.35 ? 0.22
1.64 5 0.76
6.08 2 3.3
1.0
4
1.28 2 0.16
1.63 t 0.52
7.49 4 1.47
2.0
3
1.36 2 0.12
0.85 t 0.06
5.47 f 1.03
3.0
3
1.40 2 0.07
0.67 ? 0.06
3.67 ? 0.48
351
CONCENTRATIONS OF OXAMNIQUINE
Significant
amounts
of
oxamniquine
brain t i s s u e with peak amounts of
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
detectable
approximately
found 1 h o u r p o s t drug administration. were approximately
were
f i v e times higher
decline i n pal-allel with, plasma levels.
7.5
in
pg g-'
Thereafter brain levels than,
and appeared
to
Throughout t h e sampling
period of 0.5 - 3 h r , brain levels of oxamniquine w e r e higher than corresponding plasma levels.
D I S C U S S I O N AND C O N C L U S I O N S
The above r e s u l t s show t h a t oxamniquine readily passes i n t o rat brain t i s s u e following intravenous administration.
(log P, a measure of t h e
estimated hydrophobicity parameter lipophilicity
of
a
compound)
The
for
oxamniquine
has
been
This is t h e optimum log P
r e p o r t e d l l t o be approximately 2.0.
exhibited by compounds previously shown13 t o be capable of penetrating
into
brain
tissue.
For
a
lipophilic
compound,
distribution i n t o brain t i s s u e would be expected because of t h e high lipid content of t h e brain14. The rat w a s chosen f o r s t u d y since it h a s been successfully used
as
a
model
for
studying
pharmacokinetic
and
pharmacodynamic f a c t o r s a f f e c t i n g t h e neurotoxicity
(seizures
and convulsions) associated with theophylline I5li6.
Although
s l i g h t q u a n t i t a t i v e differences amounts
of
oxamniquine
can
passing
be
into
expected
between
rat
human
and
the
brain
t i s s u e s , t h e present r e s u l t s using rat brain t i s s u e appear t o s u p p o r t t h e theory t h a t t h e presence of significant amounts of
352
KOKWARO AND TAYLOR
oxamniquine
in
the
CNS
is
the
basis
for
the
reported
neurological side-effects associated with the clinical use of this This conclusion is supported by previous findings which
drug.
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
indicated
that
seizures and
associated with
other
related
CNS-
the clinical use of
side-effects
oxamniquine occurred a t
times when peak blood levels of oxamniquine would be expected, following present
oral
administration of
findings
together
this
with
the
drug5.
Further,
reported
finding
the that
oxamniquine blocks autonomic t r a n s m i ~ s i o n may ~ ~ explain the basis f o r t h e reported neurological
side effects.
The exact
mechanism has not been elucidated but it may be s i m i l a r t o t h a t proposed t o explain t h e neurotoxicity of local anaesthetics.
The
most serious toxic effects of local anaesthetics on the CNS are generalized
convulsions,
resembling
accompanied by EEG changes18. reported
with
the
clinical
epileptic
seizures,
Similar side effects have been use
of
oxamniquine.
Like
oxamniquine, local anaesthetics are lipophilic weak bases (pK, It is known t h a t whilst t h e uncharged free base form of
7-9).
local anaesthetics penetrate t h e diffusion barrier of the nerve, it is the cationic form which which is active in producing nerve block19.
I t has been postulated t h a t t h e cationic species is also
responsible for the CNS side effects18. I t is therefore possible t h a t a similar mechanism m a y also account for t h e CNS toxicity of oxamniquine, although t h i s needs t o be verified. It
is
concluded
that
the
lipophilicity
of
oxamniquine
facilitates entry into brain tissue in quantities t h a t may be sufficient t o cause neurological side effects.
353
CONCENTRATIONS OF OXAMNIQUINE
ACKNOWLEDGEMENTS
is a grateful recipient o f a studentship f r o m the
G.O.K.
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
A s s o c i a t i o n of C o m m o n w e a l t h U n i v e r s i t i e s (U.K.).
REFERENCES 1.
T.G.Nash, Med.
2.
E.A.Ottensen and J.A.Cook, Ann. Int.
A.W.Cheever,
97,
740 (1982).
P.J.Kumar
i n " C l i n i c a l Medicine", B a i l l i e r e
and M.L.Clark,
T i n d a l l , L o n d o n , 1987, p.90. 3.
E.A.H.Friedheirn,
in
of
"Chemotherapy
R . C a v i e r and F.Hawkin, eds.
Schistosomiasis",
P e r g a m o n P r e s s , O x f o r d , 1973,
p.29. 4.
N.Katz,
E.Grinbaum,
A.Chaves,
Rev. Inst. Med. T r o p . S. P a u l o ,
5. 6.
J.S.Keystone, Am. J. T r o p . Med. Hyg., S.Krayden, Hyg.,
7.
F.Zicker
18,371
S.A.de
J.S.Keystone
32, 1344
and
J.Pellegrino,
(1976).
21,
and C.Glenn,
360 (1978). Am. J. T r o p . Med.
(1988).
C a r v a l h o , M.A.Shikanai-Yasuda,
and F.J.C.Lucas,
Rev.
V.A.Neto,
MShiromo
Inst. Med. T r o p . S . P a u l o ,
21,
132
(1985). 8.
H.Stokvis,
A.G.C.Bauer,
D.Overbosch, 9.
R.Foster, (1973).
P.C.Stuiver,
Am. J. T r o p . Med. Hyg.
A.D.Malcolm
35, 330
Rev. Inst. Med. T r o p . S. P a u l o ,
and
(1986).
15, ( s u p p l .
l), 1
KOKWARO AND TAYLOR
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3 54
32,
10.
M.Katz, D r u g s
11.
W.M.Kofi-Tsekpo,
D r u g s E x p t l . Clin. Res.
12.
W.M.Kofi-Tsekpo,
M.Mugambi, O.Were and M.E.Ochieng, P r o c .
358 (1986).
6,
421 (1980).
3rd KEMRI Scientific C o n f e r e n c e , N a i r o b i , 1983, p.237.
13.
C.Hansch,
in
"Structure
-
Activity
Relationships"
C.J.Cavalito, ed., P e r g a m o n P r e s s , O x f o r d , 1973, Chap.3. 14.
D.A.Eigenberg, Dispos.,
15.
T.L.Pazdernik
11,366
1.M.Ramzan
and
J.Doul1,
Drug
Metab.
(1983).
and G.Levy, J. P h a r m a c o l . Exp. T h e r .
236,
708
and G.Levy, J. P h a r m a c o l . Exp. T h e r .
240,
584
(1986). 16.
I.M.Ramzan (1987).
17.
C.O.Adewumni and J.A.O.Ojewole, Meth. Find. Exp. C l i n . Pharmacol.
18.
2,
79 (1987).
S . E n g l e s s o n and S. G r e v s t e n , A c t a A n a e s t h . Scand.
18,88
(1974). 19.
J.M.Ritchie, B. R i t c h i e and P. G r e e n g a r d , J. P h a r m a c o l . Exp. Ther.
150 152
(1965).
ISSN: 0148-0545 (Print) 1525-6014 (Online) Journal homepage: http://www.tandfonline.com/loi/idct20
Partitioning of Oxamniquine into Brain Tissue Following Intravenous Administration to Female Wistar Rats Gilbert O. Kokwaro & Glyn Taylor To cite this article: Gilbert O. Kokwaro & Glyn Taylor (1990) Partitioning of Oxamniquine into Brain Tissue Following Intravenous Administration to Female Wistar Rats, Drug and Chemical Toxicology, 13:4, 347-354, DOI: 10.3109/01480549009032291 To link to this article: http://dx.doi.org/10.3109/01480549009032291
Published online: 27 Sep 2008.
Submit your article to this journal
Article views: 11
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idct20 Download by: [NUS National University of Singapore]
Date: 06 November 2015, At: 07:49
DRUG AND CHEMICAL TOXICOLOGY, 1 3 ( 4 ) , 3 4 7 - 3 5 4 ( 1 9 9 0 )
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
PARTITIONING OF OXAMNIQUINE INTO BRAIN TISSUE FOLLOWING INTRAVENOUS ADMINISTRATION TO FEMALE WISTAR RATS Gilbert 0. Kokwarol
and
Glyn Taylor',
Welsh School of
Pharmacy, University of Wales College of Cardiff,
P.O. Box 13,
Cardiff CF1 3XF. Great Britain.
'Present
address: Department of Pharmacy, University of Nairobi,
P.O.Box I9 b7&, Nairobi, Kenya. 2Correspondence.
ABSTRACT Brain
and
plasma
concentrations
of
oxamniquine
were
determined following intravenous dosing (15 mg kg-l) i n female Wistar rats.
Maximum brain concentrations were achieved one
hour a f t e r dosing and at a l l sampling times oxamniquine levels were higher i n brain
tissues
compared t o t h e
corresponding
plasma samples. It
is
concluded
that
the
reported
adverse
neurological
effects associated with t h e clinical u s e of oxamniquine i n man may be due t o t h e passage of s u f f i c i e n t l y large q u a n t i t i e s of t h i s drug i n t o t h e CNS. 34 7 Copyright 0 1990 by Marcel Dekker, Inc
348
KOKWARO AND TAYLOR INTRODUCTION
Oxamniquine
(6-hydroxymethyl-2-isoproplyaminomethyl-7-
nitro-1,2, 3,4-tetrahydroquinoline) is the drug of choice in the
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
treatment
of
Schistosoma
mansonil,
a
disease
is
which
widespread in t h e tropics2.
The common side effects associated
with
oxamniquine
the
clinical
use
of
include
CNS
effects,
including dizziness, headache, nausea and d r o w ~ i n e s s ~ >A~ .few cases of
seizures following treatment with oxamniquine have
also been r e p ~ r t e d ~ - ~ . Toxicity laboratory
of
oxamniquine
animals.
oxamniquine
produced
repeated doses9.
has
also
Pre-clinical CNS
effects
been
testing in
dogs
reported showed
given
in that
high
or
Because of t h e increasing concern about t h e
neurotoxicity of oxamniquine, it has recently been suggested t h a t oxamniquine should no longer be considered a s t h e drug of choice in t h e treatment of Schistosoma mansoni infections". In v i t r o work has shown t h a t oxamniquine is lipophilic and t h u s may be able t o penetrate into the CNS.
This has led t o the
suggestion t h a t t h e CNS-related side effects observed following administration of oxamniquine a r e probably due t o t h e presence of sufficiently large amounts of oxamniquine in t h e CNS".
The
aim of t h e present study was t o use t h e r a t a s an animal model t o evaluate t h e extent of in-vivo brain uptake of oxamniquine. MATERIALS AND METHODS Oxamniquine powder (Pfizer Limited, Sandwich, Kent) was dissolved
in
citrate-phosphate
mg m l - 1 solution.
buffer, pH
5.0, t o give
a
20
349
CONCENTRATIONS OF OXAMNIQUINE
Treatment of R a t s . Groups of 3 or 4 female Wistar r a t s (209 - 344 g) were used. Each rat w a s anaesthetised with sodium pentobarbitone (40 mg
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
kg-l) and tracheostomised.
Surgical anaesthesia was maintained
with pentobarbitone throughout the period of experimentation. The right jugular vein was cannulated f o r administration of oxamniquine (15 mg kg-l).
Rats w e r e killed with an overdose of
pentobarbitone a t 0.5 h r (4 r a t s ) , 1 h r (4 rats), 2 h r (3 r a t s ) and 3 h r (3 rats) post drug administration, and whole brain tissue
was excised and placed in a previously weighed glass tube. Prior t o killing t h e r a t , a blood sample (3 m l ) was obtained by cardiac puncture and centrifuged t o obtain plasma.
Treatment of brain tissue and plasma. After recording the weight of the wet brain tissue, 5ml of cold citrate-phosphate
buffer, pH 5.0, was added followed by
homogenization (microultrasonic cell disrupter, Kontes Ltd., New Jersey) f o r 20 minutes. acid
solution
(protein
Following addition of 0.5 m l perchloric precipitant,
20%
v/v
in
water)
the
homogenate was centrifuged (3,000rpm f o r 15 minutes) and t h e clear supernatant separated.
To 1.0 m l of t h e supernatant was
added 0.1 m l of internal standard solution (containing 1.0 pg of quinine), followed by addition of 2 m l of 1 M sodium hydroxide solution.
The
alkalized
solution
was
then
extracted
by
vortexing with two portions (3 m l each) of chloroform f o r 10 minutes.
The combined chloroform extracts w e r e evaporated
3 50
KOKWARO AND TAYLOR
over a w a t e r b a t h (50'C) residue
was
(phosphate
reconstituted
under in
buffer/acetonitrile
a stream of 0.03ml
70/30)
of
nitrogen.
the and
mobile
The phase
analysed
for
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
oxamniquine according t o a previously described HPLC method12.
A
calibration
curve
was
constructed
by
spiking
citrate-
phosphate with known amounts of oxamniquine and extracting a s described above, For analysis of plasma samples, t h e procedure described previously12 w a s followed, except t h a t quinine was used a s t h e i n t e r n a l standard.
RESULTS Levels of oxamniquine (mean ? s.d.) in plasma (pg ml- 1) and
in brain t i s s u e (pg g-l) a r e summarised i n t h e t a b l e below.
TABLE 1. Plasma and Brain Levels of Oxamniquine Following Intravenous Administration ( 1 5 m g kg-l) t o t h e Rat.
Time
(h)
No. of Rats
Brain weight (g)
Bolus
Oxamniquine Levels Plasma Whole Brain (pg m1-l) (pg g - 9
0.5
4
1.35 ? 0.22
1.64 5 0.76
6.08 2 3.3
1.0
4
1.28 2 0.16
1.63 t 0.52
7.49 4 1.47
2.0
3
1.36 2 0.12
0.85 t 0.06
5.47 f 1.03
3.0
3
1.40 2 0.07
0.67 ? 0.06
3.67 ? 0.48
351
CONCENTRATIONS OF OXAMNIQUINE
Significant
amounts
of
oxamniquine
brain t i s s u e with peak amounts of
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
detectable
approximately
found 1 h o u r p o s t drug administration. were approximately
were
f i v e times higher
decline i n pal-allel with, plasma levels.
7.5
in
pg g-'
Thereafter brain levels than,
and appeared
to
Throughout t h e sampling
period of 0.5 - 3 h r , brain levels of oxamniquine w e r e higher than corresponding plasma levels.
D I S C U S S I O N AND C O N C L U S I O N S
The above r e s u l t s show t h a t oxamniquine readily passes i n t o rat brain t i s s u e following intravenous administration.
(log P, a measure of t h e
estimated hydrophobicity parameter lipophilicity
of
a
compound)
The
for
oxamniquine
has
been
This is t h e optimum log P
r e p o r t e d l l t o be approximately 2.0.
exhibited by compounds previously shown13 t o be capable of penetrating
into
brain
tissue.
For
a
lipophilic
compound,
distribution i n t o brain t i s s u e would be expected because of t h e high lipid content of t h e brain14. The rat w a s chosen f o r s t u d y since it h a s been successfully used
as
a
model
for
studying
pharmacokinetic
and
pharmacodynamic f a c t o r s a f f e c t i n g t h e neurotoxicity
(seizures
and convulsions) associated with theophylline I5li6.
Although
s l i g h t q u a n t i t a t i v e differences amounts
of
oxamniquine
can
passing
be
into
expected
between
rat
human
and
the
brain
t i s s u e s , t h e present r e s u l t s using rat brain t i s s u e appear t o s u p p o r t t h e theory t h a t t h e presence of significant amounts of
352
KOKWARO AND TAYLOR
oxamniquine
in
the
CNS
is
the
basis
for
the
reported
neurological side-effects associated with the clinical use of this This conclusion is supported by previous findings which
drug.
Downloaded by [NUS National University of Singapore] at 07:49 06 November 2015
indicated
that
seizures and
associated with
other
related
CNS-
the clinical use of
side-effects
oxamniquine occurred a t
times when peak blood levels of oxamniquine would be expected, following present
oral
administration of
findings
together
this
with
the
drug5.
Further,
reported
finding
the that
oxamniquine blocks autonomic t r a n s m i ~ s i o n may ~ ~ explain the basis f o r t h e reported neurological
side effects.
The exact
mechanism has not been elucidated but it may be s i m i l a r t o t h a t proposed t o explain t h e neurotoxicity of local anaesthetics.
The
most serious toxic effects of local anaesthetics on the CNS are generalized
convulsions,
resembling
accompanied by EEG changes18. reported
with
the
clinical
epileptic
seizures,
Similar side effects have been use
of
oxamniquine.
Like
oxamniquine, local anaesthetics are lipophilic weak bases (pK, It is known t h a t whilst t h e uncharged free base form of
7-9).
local anaesthetics penetrate t h e diffusion barrier of the nerve, it is the cationic form which which is active in producing nerve block19.
I t has been postulated t h a t t h e cationic species is also
responsible for the CNS side effects18. I t is therefore possible t h a t a similar mechanism m a y also account for t h e CNS toxicity of oxamniquine, although t h i s needs t o be verified. It
is
concluded
that
the
lipophilicity
of
oxamniquine
facilitates entry into brain tissue in quantities t h a t may be sufficient t o cause neurological side effects.
353
CONCENTRATIONS OF OXAMNIQUINE
ACKNOWLEDGEMENTS
is a grateful recipient o f a studentship f r o m the
G.O.K.
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A s s o c i a t i o n of C o m m o n w e a l t h U n i v e r s i t i e s (U.K.).
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