Safety and tolerability of elubaquine (bulaquine, CDRI 80/53) for treatment of Plasmidium vivax malaria in Thailand

Abstract

We conducted a study to compare the safety and tolerability of anti-relapse drugs elubaquine and primaquine against Plasmodium vivax malaria. After standard therapy with chloroquine, 30 mg/kg given over 3 days, 141 patients with P. vivax infection were randomized to receive primaquine or elubaquine. The 2 treatment regimens were primaquine 30 mg once daily for 7 days (group A, n = 71), and elubaquine 25 mg once daily for 7 days (group B, n = 70). All patients cleared parasitemia within 7 days after chloroquine treatment. Among patients treated with primaquine, one patient relapsed on day 26; no relapse occurred with elubaquine treatement. Both drugs were well tolerated. Adverse effects occurred only in patients with G6PD deficiency who were treated with primaquine (group A, n = 4), whose mean hematocrit fell significantly on days 7, 8 and 9 (P = 0.015, 0.027, and 0.048, respectively). No significant change in hematocrit was observed in patients with G6PD deficiency who were treated with elubaquine (group B, n = 3) or in patients with normal G6PD. In conclusion, elubaquine, as anti-relapse therapy for P. vivax malaria, was as safe and well tolerated as primaquine and did not cause clinically significant hemolysis.

Full text

INTRODUCTION
Plasmodium vivax causes an acute, debilitating
febrile illness in which the primary infection may be
followed by relapses originating from hypnozoites,
dormant liver stages of the parasite (Baird and
Hoffman, 2004). Each year, an estimated 80 million
cases of P. vivax malaria develop, predominantly in
Latin America, the Middle East, the Western Pacific
and in Asia (Mendis et al., 2001). In Thailand 3
decades ago, P. vivax caused only about 20% of malar-
ia infections and P. falciparum 80%, but by 1998 these
proportions had become approximately equal
(Chareonviriyaphap et al., 2000). Currently the stan-
dard treatment for P. vivax malaria is a 3-day course of
chloroquine in a total dose of 1,500 mg followed by
primaquine, 15 mg a day for 14 days. This regimen
generally produces resolution of acute symptoms and
clearing of parasitemia although a substantial number
of relapses subsequently develop (Bunnag et al., 1994;
Looareesuwan et al., 1997; Wilairatana et al., 1999). In
recent years, chloroquine-resistant strains have been
Safety and tolerability of elubaquine (bulaquine,
CDRI 80/53) for treatment of Plasmodium vivax
malaria in Thailand
Srivicha KRUDSOOD
1)
, Polrat WILAIRATANA
1)
*, Noppadon TANGPUKDEE
1)
, Kobsiri CHALERMRUT
1)
,
Siripun SRIVILAIRIT
1)
, Vipa THANACHARTWET
1)
, Sant MUANGNOICHAROEN
1)
,
Natthanej LUPLERTLOP
1)
, Gary M. BRITTENHAM
2)
and Sornchai LOOAREESUWAN
1)
1)
Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand,
2)
Department of Pediatrics and Medicine, Columbia University, College of Physicians and Surgeons, New York City, USA
Abstract: We conducted a study to compare the safety and tolerability of anti-relapse drugs elubaquine and pri-
maquine against Plasmodium vivax malaria. After standard therapy with chloroquine, 30 mg/kg given over 3 days,
141 patients with P. vivax infection were randomized to receive primaquine or elubaquine. The 2 treatment regimens
were primaquine 30 mg once daily for 7 days (group A, n = 71), and elubaquine 25 mg once daily for 7 days (group B,
n = 70). All patients cleared parasitemia within 7 days after chloroquine treatment. Among patients treated with pri-
maquine, one patient relapsed on day 26; no relapse occurred with elubaquine treatement. Both drugs were well tol-
erated. Adverse effects occurred only in patients with G6PD deficiency who were treated with primaquine (group A, n
= 4), whose mean hematocrit fell significantly on days 7, 8 and 9 (P = 0.015, 0.027, and 0.048, respectively). No sig-
nificant change in hematocrit was observed in patients with G6PD deficiency who were treated with elubaquine
(group B, n = 3) or in patients with normal G6PD. In conclusion, elubaquine, as anti-relapse therapy for P. vivax
malaria, was as safe and well tolerated as primaquine and did not cause clinically significant hemolysis.
Key words: Plasmodium vivax, vivax malaria, elubaquine, bulaquine, safety, tolerability, Thailand
Korean Journal of Parasitology
Vol. 44, No. 3: 221-228, September 2006
�Received 8 March, 2006, accepted after revision 14 July,
2006.
*Corresponding author (e-mail: tmpwl@mahidol.ac.t)

reported from other regions of the world (Baird and
Hoffman, 2004), but in Thailand, virtually all acute P.
vivax infections can be successfully treated with
chloroquine (Looareesuwan et al., 1999).
Elubaquine [N-(3-acetyl-4-5-dihydro-2-furanyl)-N-
(6-methoxy-8-quinolinyl)1,4-pentanediamine; com-
pound CDRI (Central Drug Research Institute) Code
80/53; bulaquine] is an 8-aminoquinoline analogue of
primaquine which has shown anti-relapse activity
against established sporozoite induced infections with
P. cynomolgi in rhesus monkeys (Dutta et al., 1989;
Puri and Dutta, 1990; Dutta et al., 1994). Initial labora-
tory, animal and clinical studies have suggested that
elubaquine may be less toxic than primaquine.
Limited studies in vitro in G6PD deficient red cells
found that elubaquine produced less damage than
primaquine to both normal and G6PD-deficient red
cells (Anklesaria et al., 1994). In mice, elubaquine
inhibited hepatic anti-oxidant enzymes less than pri-
maquine (Srivastava et al., 1993). In beagle dogs, the
magnitude of elubaquine-induced methemoglobine-
mia was 3-4 fold less than that with primaquine (Puri
et al., 1989). In patients, a comparison between pri-
maquine and elubaquine after 7 days administration
has shown that primaquine increased methemoglobin
levels significantly from about 4% to 16%. By contrast,
with elubaquine, the change from about 2-3% was
insignificant (Valecha et al, 2001). Elubaquine has
completed Phase II/III clinical trials and is now mar-
keted in India for use (25 mg/day for 5 days) for pre-
vention of relapse in P. vivax relapsed malaria
(Valecha et al., 2001; Adak et al., 2001).
The primary objective of our study was to deter-
mine the safety and tolerability of elubaquine in com-
parison with primaquine, when administered for 7
days after chloroquine treatment of P. vivax. Our sec-
ondary objective was to determine if elubaquine
antagonizes the activity of chloroquine against blood-
stage schizonts of P. vivax. This is the first clinical
study of elubaquine outside the Indian subcontinent.
PATIENTS AND METHODS
Study design
This was a randomized, open-label, prospective
study of elubaquine to assess its safety and tolerability
in comparison to primaquine in patients with P. vivax
malaria with and without deficiency of G6PD. The
study protocol was approved by the Ethics
Committee of Faculty of Tropical Medicine, Mahidol
University, Bangkok, Thailand.
Study site and participants
Patients admitted to the Bangkok Hospital for
Tropical Diseases between January 2004 and July 2005
were included in this study, if they were diagnosed as
having malaria caused by P. vivax. P. vivax infection
was defined by the presence of P. vivax asexual stage
parasites on a thin blood smear. Patients enrolled in
the study were 16-51 years old, weighed 40-65 kg, had
the ability to take oral medications, gave informed
consent, and agreed to remain in the hospital in
Bangkok for a total of 28 days. The Bangkok metro-
politan area has no known malaria transmission.
Exclusion criteria for the study included pregnancy,
lactation, concomitant infection with P. falciparum at
presentation, hematocrit of < 25%, protracted vomit-
ing, oliguria, a systolic blood pressure of < 90 mmHg,
concomitant systemic disease, a history of antimalarial
ingestion in previous 2 weeks, a history of allergy to
primaquine or elubaquine, and a history of dark urine
or significant hemoglobinuria during the course of
previous malarial attack.
Interventions
All patients received 1,500 mg of chloroquine over 3
days to achieve clearance of blood-stage parasites and
were then randomized to 1 of 2 treatment groups after
completing chloroquine treatment, as follows: group
A; primaquine 30 mg once daily for 7 days (n = 71),
and group B; elubaquine 25 mg once daily for 7 days
(n = 70). On the day that chloroquine therapy was
completed, parasitemia clearance was documented by
2 consecutive negative results of blood smears.
Primaquine and elubaquine were administered within
222 Korean J. Parasitol. Vol. 44, No. 3: 221-228, September 2006

1 hr of a meal under direct observation. The duration
of follow-up was 28 days. Out of total 141 patients,
132 (93.6%) completed 28 days’ follow-up in the hos-
pital. All patients showed negative parasitemia by 7
days after chloroquine treatment.
Procedures
Oral temperature, pulse, and respiratory rates were
measured every 4 hr and blood pressure was mea-
sured once a day. Monitoring for signs and symptoms
of malaria was performed daily for the first 7 days of
admission and weekly thereafter. All of these patients
were closely monitored for evidence of intravascular
hemolysis and hemoglobinuria.
Pretreatment investigations included a complete
blood count (RBC count, hemoglobin, hematocrit,
total WBC count, differential count, and platelet
count), serum electrolytes, total and direct bilirubin,
alkaline phosphatase, blood urea nitrogen, creatinine,
albumin, globulin, aspartate and alanine aminotrans-
ferases, and urinalysis. These tests were repeated on
days 7, 14, 21, and 28. A screening test for G6PD defi-
ciency was performed on admission. Thick and thin
blood films were examined before treatment and
every 12 hr for malaria parasites until negative, and
then thick films were examined daily until discharge.
In patients with G6PD deficiency, hematocrit mea-
surements were performed on days 0 to 10, 14, 21, and
28 to detect changes in hematocrit with treatment.
Microscopic examination of blood smears was con-
ducted using our standard operating procedure
whereby 200 oil-immersion fields (magnification, x
1,000) are read on Field’s stained thick blood smears.
The identification of ≥ 1 asexual P. vivax parasite was
recorded as a positive smear result. Blood films were
considered negative if no parasites were seen in 200
oil-immersion fields in a thick blood film.
Fever clearance time (FCT) was defined as the time
from the start of treatment until the oral temperature
decreased to 37.0°C and remained below this for the
next 48 hr. Parasite clearance time (PCT) was defined
as the time from the start of treatment until the blood
film was negative and remained negative for the next
24 hr.
Outcome measurements
Safety and tolerability. Patients were assessed
daily during chloroquine and anti-relapse treatments.
Assessments included a review of symptoms for
adverse events, a clinical evaluation and a blood
smear examination for malarial parasites. After com-
pletion of antimalarial drug therapy, evaluations were
conducted each week to day 28. A complete blood
count was determined and standard hepatic and renal
function tests were conducted on admission, days 7,
14, 21 and 28. Reported adverse events in the treat-
ment groups were compared in terms of the propor-
tion of all randomized subjects with each adverse
event.
Patients with reappearance of parasitemia after
therapy with either regimen were treated with stan-
dard regimens in our hospital of chloroquine (30
mg/kg) and primaquine (15 mg a day for 14 days in
patients with normal G6PD), or of chloroquine (30
mg/kg) and primaquine (30 mg once a week for 6
weeks in patients with G6PD deficiency).
Efficacy. The primary efficacy end point in our
study was the efficacy of chloroquine against acute
attacks of P. vivax malaria when combined with pri-
maquine or elubaquine. The response to treatment
was defined according to Baird et al (1997).
Statistical methods. Groups of patients were com-
pared using the unpaired Student’s t-tests for continu-
ous variables with a Gaussian distribution, the Mann-
Whitney test for nonparametric tests of continuous
variables without a Gaussian distribution, and
Fisher’s exact test for proportions. All statistical tests
were 2-tailed and a significance level of 0.05 was used.
RESULTS
A total of 141 patients were enrolled in this study,
71 in group A and 70 in group B. Demographic data
and pretreatment characteristics are shown in Table 1.
Both groups were comparable with respect to clinical
and laboratory characteristics. The majority of the
patients had contracted the infection at the Thailand-
Myanmar border.
Following treatment, 7 patients, i.e., 3 (4.3%) in
Krudsood et al.: Safety of elubaquine for vivax malaria treatment 223

group A and 4 (5.7%) in group B, left the hospital
before completing 28 days of follow-up (dropped out)
(Table 2) due to social reasons unrelated to drug treat-
ment or side effects. All were asymptomatic and nega-
tive for asexual forms before discharge from the hos-
pital.
The FCT and PCT of both groups are shown in
Table 2 and Fig. 1; there were no significant differ-
ences in either FCT or PCT. One patient with normal
G6PD (1.5%) in group A had reappearance of P. vivax
on day 26 and was retreated with chloroquine (30
mg/kg) and primaquine (15 mg/day for 14 days). The
difference in the cure rates at 28 days (group A: 98.5%,
group B: 100%) was not significant. There was no
appearance of P. falciparum, P. ovale, or P. malariae in
either group after treatment.
Neither group of patients with normal G6PD levels
(n = 67 in each group) showed a significant reduction
of hematocrit after treatment (Fig. 2). By contrast, in
patients with G6PD deficiency who were treated with
primaquine (group A, n = 4), the mean hematocrit
was significantly reduced on days 7, 8 and 9 (P =
0.015, 0.027, and 0.048 respectively) (Fig. 3.) compared
to the mean hematocrit in patients with G6PD defi-
ciency treated with elubaquine (group B, n = 3).
Subsequently, the hematocrit in these 4 patients in
group A increased without blood transfusion. No sig-
nificant change in hematocrit occurred during the
study in the group of patients with G6PD deficiency
who were treated with elubaquine (group B, n = 3).
224 Korean J. Parasitol. Vol. 44, No. 3: 221-228, September 2006
Table 1. Clinical and laboratory characteristics of study groups on admission before treatment
Group A Group B P-value
(n = 71) (n = 70)
Gender (Male/Female) 0053/18 054/16 0.729
Age (yr)
Mean (±SD) 0025.03 0(6.68) 026.76 00(7.98) 0.165
Range 0016-50 016-51
Height (cm)
Mean (±SD) 0160.80 0(6.63) 160.30 00(5.38) 0.613
Weight (kg)
Mean (±SD) 0053.50 0(6.59) 052.95 00(6.47) 0.617
Fever [mean (±SD)]
Highest fever before treatment (°C) 0037.59 0(0.97) 037.48 00(0.84) 0.447
No. of patients with (%)
Splenomegaly 0003 000.(4.2) 001 0000.(1.4) 0.317
Hepatomegaly 0016 00.(22.5) 014 0.00(20.0) 0.713
G6PD deficiency 0004 00.0(5.6) 003 0000.(4.3) 0.713
Geometric mean parasites count (/
µ
l) 4,786 5,245 0.974
Range 23~42,640 118~61,160
Laboratory data [mean (±SD)]
Packed cell volume (%) 035.77 0(5.77) 037.39 00(6.13) 0.109
Platelet count (/
µ
l) 109.96 (82.94) 093.200 (56.33) 0.163
White blood cell (x 10
3
/
µ
l) 006.14 0(1.92) 005.83 00(2.04) 0.335
Blood urea (mg/dl) 015.26 0(5.25) 013.90 00(5.28) 0.127
Creatinine (mg/dl) 000.917 (0.285) 000.845 0(0.186) 0.079
Direct bilirubin (mg/dl) 000.501 (0.381) 000.554 0(0.480) 0.471
Total bilirubin (mg/dl) 001.48 0(0.84) 001.48 00(0.88) 0.968
Albumin (g/dl) 003.76 0(0.48) 003.92 00(0.49) 0.053
Alkaline phosphatase (U/L) 096.23 (43.64) 085.47 0(36.29) 0.114
Aspartate aminotransferases (U/L) 029.76 (21.20) 028.930 (18.06) 0.802
Alamine aminotransferases (U/L) 031.94 (28.17) 032.11 0(29.93) 0.972

All adverse events listed in Table 3 occurred during
the first 3 days of administration of study drugs.
These symptoms then resolved during the first week
of treatment. No emesis occurred after taking the
study drugs. Serious adverse effects such as cyanosis,
abdominal cramp, hypertension, arrythmias, central
nervous system symptoms, granulocytopenia, agranu-
locytosis, leucopenia, or leukocytosis were not found
in patients given primaquine or elubaquine treatment.
During the 28-day follow-up period, both primaquine
and elubaqine were well tolerated.
Krudsood et al.: Safety of elubaquine for vivax malaria treatment 225
0
20
40
60
80
100
120
0 12243648
Times after treatment (hr)
Malaria reduction (%)
Group
A
Group B
15.00
20.00
25.00
30.00
35.00
40.00
45.00
12345678910142128
Day after treatment
Heamatocrit (%)
G6PD deficiency patients (Group A; n=4)
G6PD deficiency patients (Group B; n=3)
P-v a l u e = 0.015
P-v a l u e = 0.027
P-v a l u e = 0.048
*
*
**
**
***
***
Fig. 3. Hematocrit in patients with deficient levels of
G6PD during the study period.
35.00
36.00
37.00
38.00
39.00
40.00
12345678910142128
Day after treatment
Heamatocrit (%)
G6PD normal patients (Group A; n=67)
G6PD normal patients (Group B; n=67)
Fig. 2. Hematocrit in patients with normal levels of G6PD
during the study period.
Table 2. Therapeutic responses
Group A Group B P-value
(n = 71) (n = 70)
No. (%) of patients withdrawal 03 (4.3%) 4 (5.7%) -
(day at withdrawal) 22, 22, 22 14, 14, 22, 28
No. (%) of patients with 28-day follow-up 68 (95.7%) 64 (94.3%) -
(evaluable patients)
No. (%) of patients with P. vivax reappearance 1 (1.5%) 000000. -
Day of reappearance of parasitemia 26000000.. 00000.0
No. (%) of patient cured at day 28 67/68 (98.5%) 64/64 (100%) 0.565
Fever clearance time (hr)
Mean (± SD) 18.65 (13.65) 22.74 (17.62) 0.125
Range 4~70 4~90
Parasite clearance time (hr)
Mean (± SD) 43.68 (17.29) 44.07 (19.02) 0.897
Range 14~88 20~106
Fig. 1. Reduction in the pertentage of malaria parasites
during treatment.

DISCUSSION
The treatment of malaria caused by P. vivax has 2
objectives: to cure acute clinical symptoms and to pre-
vent relapses. For the first objective, chloroquine has
been the standard treatment for the last 50 years.
Although chloroquine-resistant strains have appeared
in recent years (Baird, 2004), P. vivax in Thailand has
remained sensitive (Looareesuwan et al., 1999). After
the 3-day regimen of chloroquine (30 mg/day) used
in our study, blood levels of chloroquine remain
above the minimal effective concentration for sensi-
tive P. vivax for as long as 35 days (Baird, 2004). As a
consequence, our study with 28 days of follow-up
does not permit evaluation of elubaquine as an anti-
relapse treatment for P. vivax. Nonetheless, our results
show that elubaquine does not abrogate or antagonize
the antimalarial efficacy of chloroquine.
Primaquine has been used predominantly for pre-
venting relapse originating from dormant P. vivax
hypnozoites in the liver. The conventional dose is 15
mg/day for 14 days. In an earlier study in Thailand,
this regimen was associated with a 28% relapse rate
during a 6-month period of observation (Bunnag et
al., 1994). A higher dose (30 mg/day for 14 days) is
now recommended in patients who are not G6PD
deficient (Silachamroon et al., 2003; Baird and
Hoffman, 2004). In India, the National Anti-Malaria
Program has recommended 15 mg of primaquine for
only 5 days as anti-relapse treatment (Adak et al.,
2001). A recent study in India has found that this pri-
maquine regimen (15 mg/day for 5 days) was associ-
ated with a 27% relapse rate during one year of fol-
low-up (Adak et al., 2001). In this same study,
elubaquine (25 mg/day for 5 days) was associated
with a similar overall relapse rate of about 30% at one
year. Neither primaquine nor elubaquine produced a
significant reduction in the overall, 1-year relapse rate,
when compared to the rate of 40% observed in a
group treated with placebo. In a subanalysis in this
same study, a comparison of effects on relapse occur-
ring between 7 and 12 mon after treatment found that,
with respect to the rate observed in the placebo group
(21%), significantly lower rates of relapse were found
after treatment with either primaquine (10%) or
elubaquine (14%) (Adak et al., 2001).
In our study, to provide more comparability with
previous clinical studies (Valecha et al, 2001; Adak et
al., 2001), we used a similar dose of elubaquine, 25
mg/day, administered once daily over a 7-day period.
Given our past experience in Thailand, we selected a
higher dose of primaquine (30 mg/day) for study,
also administered once daily over a 7-day period. P.
vivax parasitemia reappeared in only a single study
patient, who had been treated with primaquine
(group A), and was observed on Day 26. Because
malarial transmission has not been reported in
Bangkok, the reappearance of parasitemia was almost
certainly not reinfection. In this study, we could not
distinguish recrudescence from relapse by a chloro-
quine-resistant parasite (Baird et al., 1997).
The principal potential advantage of elubaquine as
an anti-relapse agent is that this drug might have less
oxidative toxicity than primaquine, diminishing or
eliminating methemoglobinemia and hemolysis in
patients with G6PD and related erythrocytic enzyme
deficiencies. Although we did not measure methemo-
globin levels, and the number of patients with G6PD
deficiency included in our study was small, changes
in hematocrit shown in Fig. 3 support this possibility.
The 4 patients with G6PD deficiency treated with pri-
maquine had a clinically significant fall in hematocrit,
while the 3 patients with G6PD deficiency treated
with elubaquine did not.
Despite the limitations of our study, the results sug-
gest that elubaquine deserves further evaluation of
both (i) safety and tolerability in patients at increased
risk of oxidative toxicity, and (ii) efficacy as an anti-
relapse treatment for P. vivax malaria. Studies of safe-
226 Korean J. Parasitol. Vol. 44, No. 3: 221-228, September 2006
Table 3. Adverse events during study period
Group A Group B
Headache (%) 4 (5.6) 3 (4.3)
Abdominal pain (%) 1 (1.4) 0 (0)0.
Dizziness (%) 6 (8.5) 4 (8.5)
Nausea without vomiting (%) 5 (7.0) 3 (4.3)
Nausea with vomiting (%) 2 (2.8) 0 (0)0.
Pruritus (%) 1 (1.4) 0 (0)0.

ty and tolerability should focus first on individuals
with well-characterized types of G6PD deficiency to
determine the extent to which use elubaquine might
decrease the extent of hemolysis. Studies of efficacy
will need to take account of the fact that the response
of malaria parasites to drugs depends not only on the
species but also on the strains within the same species.
Some strains have an inherent degree of drug toler-
ance and treatment requires a much higher dosage of
an antimalarial agent than other strains. In this regard,
a number of studies have shown heterogeneity in
strains and geographic isolates of P. vivax by a vari-
ability of doses of 8-aminoquinolines required to pre-
vent relapse (Baird and Hoffman, 2004). Thus, further
studies with different P. vivax strains and geographic
isolates and with greater numbers of patients with
various types of G6PD deficiency with longer periods
of follow-up are needed to assess the safety, tolerabili-
ty and efficacy of elubaquine in general use.
ACKNOWLEDGMENTS
The authors are grateful to the staff and nurses of
the Hospital for Tropical Diseases for their help. We
also thank J. Kevin Baird for his helpful comments
and suggestions. This study was partly supported by
Mahidol University Research Grants.
REFERENCES
Adak T, Valecha N, Sharma VP (2001) Plasmodium vivax
polymorphism in a clinical drug trial. Clin Diagn Lab
Immunol 8: 891-894.
Anklesaria PS, Ashar VJ, Kshirsagar NA, Gupta KC (1994)
Comparison of the effect of compound CDRI 80/53 [N1-
(3 acetyl-4-5-dihydro-2 furanyl)-N4-(6-methoxy-8-
quinolinyl)1,4-pentanediamine] with primaquine on
human erythrocytes in vitro. In Tropical Diseases:
Molecular Biology and Control Strategies, Kumar S, Sen
AK, Dutta GP, Sharma RN (eds.). p 256-261, Publication
and Information Directorate, Council of Scientific and
Industrial Research, New Delhi, India.
Baird JK (2004) Chloroquine resistance in Plasmodium vivax.
Antimicrob Agents Chemother 48: 4075-4083.
Baird JK, Hoffman SL (2004) Primaquine therapy for malar-
ia. Clin Infect Dis 39: 1336-1345.
Baird JK, Leksana B, Masbar S, Fryauff DJ, Sutanihardja
MA, Suradi, Wignall FS, Hoffman SL (1997) Diagnosis
of resistance to chloroquine by Plasmodium vivax: timing
of recurrence and whole blood chloroquine levels. Am J
Trop Med Hyg 56: 621-626.
Bunnag D, Karbwang J, Thanavibul A, Chittamas S,
Ratanapongse Y, Chalermrut K, Bangchang KN,
Harinasuta T (1994) High dose of primaquine in pri-
maquine-resistant vivax malaria. Trans R Soc Trop Med
Hyg 88: 218-219.
Chareonviriyaphap T, Bangs MJ, Ratanatham S (2000) Status
of malaria in Thailand. Southeast Asian J Trop Med Public
Health 31: 225-237.
Dutta GP, Puri SK, Bhaduri AP, Seth M (1989) Radical cura-
tive activity of a new 8-aminoquinoline derivative
(CDRI 80/53) against Plasmodium cynomolgi B in mon-
keys. Am J Trop Med Hyg 41: 635-637.
Dutta GP, Puri SK, Pandey VC, Seth M, Bhaduri AP,
Chatterjee SK, Asthana OP, Gupta KC (1994) New
potential anti-malarials: anti-relapse compound CDRI
80/53. In Tropical Diseases: Molecular Biology and
Control Strategies, Kumar S, Sen AK, Dutta GP, Sharma
RN (eds.). p 276-285, Publication and Information
Directorate, Council of Scientific and Industrial
Research, New Delhi, India.
Looareesuwan S, Buchachart K, Wilairatana P, Chalermrut
K, Rattanapong Y, Amradee S, Siripiphat S,
Chullawichit S, Thimasan K, Ittiverakul M, Triampon A,
Walsh DS (1997) Primaquine-tolerant vivax malaria in
Thailand. Ann Trop Med Parasitol 91: 939-943.
Looareesuwan S, Wilairatana P, Krudsood S, Treeprasertsuk
S, Singhasivanon P, Bussaratid V, Chokjindachai W,
Viriyavejakul P, Chalermrut K, Walsh DS, White J
(1999) Chloroquine sensitivity of Plasmodium vivax in
Thailand. Ann Trop Med Parasitol 93: 225-230.
Mendis K, Sina BJ, Marchesini P, Carter R (2001) The
neglected burden of Plasmodium vivax malaria. Am J
Trop Med Hyg 64: 97-106.
Puri SK, Dutta GP (1990) Causal prophylactic activity of a
new 8-aminoquinoline derivative against Plasmodium
cynomolgi B in rhesus monkeys. Indian J Med Res 91: 197-
199.
Puri SK, Srivastava R, Pandey VC, Sethi N, Dutta GP (1989)
Methemoglobin toxicity and hematological studies on
malaria anti-relapse compound CDRI 80/53 in dogs.
Am J Trop Med Hyg 41: 638-642.
Silachamroon U, Krudsood S, Treeprasertsuk S, Wilairatana
P, Chalearmrult K, Mint HY, Maneekan P, White NJ,
Krudsood et al.: Safety of elubaquine for vivax malaria treatment 227

Gourdeuk VR, Brittenham GM, Looareesuwan S (2003)
Clinical trial of oral artesunate with or without high-
dose primaquine for the treatment of vivax malaria in
Thailand. Am J Trop Med Hyg 69: 14-18.
Srivastava P, Puri SK, Dutta GP, Pandey VC (1993) Effect of
the anti-malarial agents primaquine and (N1-3-acetyl-4-
5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl)1,4-
pentanediamine on oxidative stress and anti-oxidant
defences in mice. Biochem Pharmacol 46: 1859-1860.
Valecha N, Adak T, Bagga AK, Asthana OP, Srivastava JS,
Joshi H, Sharma VP (2001) Comparative anti-relapse
efficacy of CDRI compound 80/53 (bulaquine) vs pri-
maquine in double blind clinical trial. Curr Sci 80: 561-
563.
Wilairatana P, Silachamroon U, Krudsood S, Singhasivanon
P, Treeprasertsuk S, Bussaratid V, Phumratanaprapin
W, Srivilirit S, Looareesuwan S (1999) Efficacy of pri-
maquine regimens for primaquine-resistant Plasmodium
vivax malaria in Thailand. Am J Trop Med Hyg 61: 973-
977.
228 Korean J. Parasitol. Vol. 44, No. 3: 221-228, September 2006