Paediatrica Indonesiana

VOLUME 53 November ‡ NUMBER 6

Original Article

Methisoprinol for children with

early phase dengue infection: a pilot study
Melissa G. Ompico

Abstract
Background Dengue fever is associated with many health
complications and medical costs. Furthermore, there is currently
no approved dengue antiviral medication or vaccine. Empiric
evidence has suggested that patients who received supplemental
methisoprinol therapy had faster recovery times and fewer
complications.
Objective To determine the effects of oral methisoprinol on the
clinical course and laboratory findings of children with early phase
D
engue fever remains a serious public
health concern in tropical regions as it
continues to claim many lives year after
year. The Philippines is known to be
endemic for the four antigenic subtypes of dengue
viruses, with no locality or social stratum spared from
LW 'HQJXH PRUWDOLW\ LQ WKH FRXQWU\ QXPEHUHG 
RXWRIWKHUHSRUWHGFDVHVFDVHIDWDOLW\UDWH
dengue infection. &)57KHPDMRULW\EHORQJWRWKH
Methods We conducted a randomized, double-blind study from years age group. The World Health Organization
-XQHWR6HSWHPEHURQFKLOGUHQDJHG\HDUVZLWK
ODERUDWRU\FRQILUPHG HDUO\ GHQJXH LQIHFWLRQ 6XEMHFWV KDG QRW :+2HVWLPDWHVWKHUHWREH²PLOOLRQGHQJXH
previously received antithrombotic agents, nor did they have LQIHFWLRQVZRUOGZLGHHYHU\\HDUDQGRYHUELOOLRQ
bleeding disorders or immunodeficiency. We randomized the SHRSOH  RI WKH ZRUOG·V SRSXODWLRQ DUH QRZ DW
VXEMHFWVWRUHFHLYHHLWKHURUDOPHWKLVRSULQROPJNJ%:GD\ risk from dengue.3 Presently though, there is still
GLYLGHGLQWRIRXUGRVHVRUSODFHERIRUKRXUVZLWKVXEMHFWV
SHUJURXS7KHSULPDU\HQGSRLQWZDVIHYHUFOHDUDQFHWLPH)&7
no approved antiviral treatment for dengue. While
and secondary endpoints were platelet nadir, white blood cell there are protocols for effective standard supportive
:%&QDGLUPD[LPXPKHPRFRQFHQWUDWLRQOHQJWKRIKRVSLWDO treatment with fluids and transfusions, the ‘race for
stay, and development of complications. WKHFXUH·LVVWLOOLQSURJUHVVLQFOXGLQJVXSSOHPHQWDO
Results The mean decrease in WBC count was less with therapeutic modalities used by several health
PHWKLVRSULQROWKDQZLWKSODFHER>6'YV6'
[/3 @,QDGGLWLRQWKHPHDQGHFUHDVHLQSODWHOHWFRXQW
practitioners and even physicians who claim their
ZDVOHVVLQSDWLHQWVRQPHWKLVRSULQRO>6'YV6' effectiveness based on practice-based evidence. These
[/3 @1RVLJQLILFDQWGLIIHUHQFHVEHWZHHQWKH include homeopathic remedies and trial-stage antiviral
WZRJURXSVZHUHIRXQGIRU)&73 OHQJWKRIKRVSLWDOVWD\ products, among others. Off-label use of methisoprinol
3 KHPRFRQFHQWUDWLRQRUGHQJXHFRPSOLFDWLRQV
Conclusion Methisoprinol initiated at an early phase in dengue
infection reduced the anticipated leukopenia by 56% and
WKURPERF\WRSHQLD E\  +HQFH LW FDQ EH XVHG DORQJ ZLWK )URPWKH'HSDUWPHQWRI&KLOG+HDOWK6DLQW/RXLV8QLYHUVLW\+RVSLWDO
standard approved fluid and antipyretic therapy. RIWKH6DFUHG+HDUW6/8+6+3KLOLSSLQHV
[Paediatr Indones. 2013;53:320-7.].
Reprint requests to: Melissa G. Ompico, Department of Pediatrics, Saint
/RXLV8QLYHUVLW\+RVSLWDORIWKH6DFUHG+HDUW6/8+6+$VVXPSWLRQ
Keywords: Dengue, leukopenia, methisoprinol, 5RDG%DJXLR&LW\3KLOLSSLQHV7HO
thrombocytopenia )D[(PDLORPSLFR#\DKRRFRP

320‡Paediatr Indones, Vol. 53, No. 6, November 2013

 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

for supplementary dengue treatment in the Philippines for the study. The additional serology results
has only been testimonial in nature.4 LPPXQRJOREXOLQ ,J * DQG ,J0 ZHUH XVHG WR
Methisoprinol is a synthetic complex of inosine distinguish primary from secondary infection.
and dimethylaminoisopropanol (as p-acetamidoben- 3DWLHQWV ZHUH H[FOXGHG LI WKH\ ZHUH 16QHJDWLYH
]RDWH5 It belongs to the class of other antivirals, used
as a direct-acting antiviral for the systemic treatment
RI YLUDO LQIHFWLRQV DQG DV DQ LPPXQRVWLPXODQWLP-
munomodulator.6 Methisoprinol has already been
proven effective in human and animal models either
singly or in combination for many viral diseases.
It is marketed in the Philippines for the following
assessed to have severe dengue infection, critical
or in the recovery phase of dengue fever, previously
diagnosed with bleeding diathesis, platelet disorder
or immunodeficiency disorder, previously ingested
aspirin, ibuprofen or other antithrombotic medication
ZLWKLQWKHSUHYLRXVKRXUVSUHJQDQWRUODFWDWLQJ
unable to swallow oral medications (non per orem
indications: subacute sclerosing panencephalitis RUGHU PDOQRXULVKHG  6' ZHLJKWIRUKHLJKW
663( YDULFHOOD PXPSV UKLQRYLUXV LQIOXHQ]D $
measles, encephalitis, herpes zoster, herpes simplex
labialis, hepatitis A, acute viral B hepatitis, herpes
genitalis, as well as immunorestoration in conditions
such as pre-acquired immune deficiency syndrome
RU %0, IRU DJH RU LI FRQVHQW ZDV XQREWDLQDEOH
3HUPLVVLRQ IURP SDWLHQWV· DWWHQGLQJ SK\VLFLDQV ZDV
also secured verbally or in writing. Patients and their
SDUHQWVJXDUGLDQVZHUHLQIRUPHGRIWKHQDWXUHRIWKH
planned intervention, that placebo would be used
$,'6SHUVLVWHQWJHQHUDOL]HGO\PSKDGHQRSDWK\DQG
AIDS-related complex, neoplastic disease, anergy and
K\SRHUJ\SULRUWRPDMRUVXUJHU\DQGVHYHUHEXUQV.5
0HWKLVRSULQROZDVILUVWSRVWXODWHGDVDQDGMXYDQW
for dengue fever in Thailand, but no other studies
have confirmed nor refuted its claims. We aimed to
determine the effects of oral methisoprinol treatment
on the clinical course of early phase dengue infection
in pediatric patients and specifically, to establish the
HIIHFW RI PHWKLVRSULQRO RQ GHQJXH SDWLHQWV· IHYHU
and that improvement would be monitored through
several laboratory tests. The medical risks associated
with taking the medication were explained. A consent
IRUP ZDV ILOOHG LQ GXSOLFDWH E\ WKH SDWLHQW DQGRU
SDUHQWVJXDUGLDQV 7KH FRQVHQW IRUP ZDV DYDLODEOH
in English, Filipino, and Iluko. It was explained to
them in the vernacular on the occasion that a patient
could not understand these. The consent forms and
research proposal were submitted and approved by the
Bioethics Committee of the Saint Louis University
FOHDUDQFH WLPH )&7 WKUHVKROG RI OHXNRSHQLD Hospital of the Sacred Heart.
QDGLU ZKLWH EORRG FHOO:%& FRXQWV WKUHVKROG RI Patients were randomly assigned to either the
WKURPERF\WRSHQLDQDGLUSODWHOHWFRXQWVPD[LPXP methisoprinol group (syrup provided at a therapeutic
hemoconcentration, duration of confinement, and GRVH RI PJNJGD\ RU WKH SODFHER JURXS %RWK
prevention of dengue complications. the actual medication and placebo preparations had
identical presentation without distinctive marks
except for a letter coding (the identity of the products
Methods ZDVRQO\UHYHDOHGDIWHUGDWDFROOHFWLRQZDVFRPSOHWH
Assignment of treatment was done randomly with
:H SHUIRUPHG D UDQGRPL]HG DOORFDWLRQ UDWLR  Random Allocation Software® ver 1.0LQEORFNVRI
GRXEOHEOLQG SLORW JURXS VWXG\ RI  FKLOGUHQ patients. The intervention was started immediately
hospitalized in Saint Louis Hospital, University of the after laboratory confirmation of early dengue. Twelve
6DFUHG+HDUW6/8+6+%DJXLR&LW\3KLOLSSLQHV
for early dengue fever. Patients were eligible if they
ZHUH DJHG  WR  \HDUV  PRQWKV ZLWK FOLQLFDO
symptoms suggestive of dengue fever, as defined by
WKH:+2'HQJXH*XLGHOLQHV and laboratory
confirmation of very early or early acute infection, via
Dengue Duo Pack® (SD Bioline: Standard Diagnostics
GRVHVKRXUVRIPHGLFDWLRQZHUHFRPSOHWHGZKLFK
also corresponded to the maximal period of viremia.
Research assistants were responsible to administer,
or supervise the administration of the correct
intervention. A checklist for scheduling of dosages
ZDVDOVRSODFHGDWWKHEHGVLGHIRUWKHSDWLHQWJXDUGLDQ
to fill. Clinical care, including other treatment such
Inc, KoreaDWWKHWLPHRIDGPLVVLRQ3DWLHQWVPXVW as intravenous fluids were at the discretion of the
EH 16 SRVLWLYH DQG LQ WKH IHEULOH SKDVH WR TXDOLI\ DWWHQGLQJ SK\VLFLDQ IROORZLQJ :+2'HSDUWPHQW

Paediatr Indones, Vol. 53, No. 6, November 2013‡321

 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

RI +HDOWK '2+ 3KLOLSSLQH 3HGLDWULF 6RFLHW\ IRU  FRQILGHQFH LQWHUYDO DW  PDUJLQ RI HUURU
336 'HQJXH *XLGHOLQHV  6WXG\ VXEMHFWV ZHUH WKHHVWLPDWHGFDQGLGDWHSRSXODWLRQZDVSDWLHQWV
QRWDOORZHGWRWDNHDQ\RWKHUDGMXYDQWVSURELRWLFV Supposing that half of these were in the early phase
YLWDPLQVXSSOHPHQWVRUKHUEDOUHPHGLHVGXULQJWKH
observation.
Patient profiles, diagnoses, classification, date
and time of admission and discharge, vital signs
and laboratory results were recorded in case record
forms. Clinical history and significant examination
findings were also recorded. Daily vital signs including
temperature, obtained by aural digital thermometer
of dengue infection, then the ideal sample would be
SDWLHQWV
Data remained blinded until the database was
finalized and ready for analysis. Statistical analysis was
performed with SPSS Version 2.0. A two-sided P value
”ZDVFRQVLGHUHGWREHVLJQLILFDQWIRUDOOSDUDP-
eters. The null hypothesis was that isoprinosine had
no effect on fever clearance, maximum hemoconcen-
DIWHUHDUFDQDOSDWHQF\ZDVHQVXUHGDQGODERUDWRU\ tration, leukopenia, thrombocytopenia, confinement
results were logged on a daily basis. Laboratory duration, and development of dengue complications.
determinations for serial hemoglobin, hematocrit,
and platelet counts were done as clinically indicated,
DFFRUGLQJ WR WKH DWWHQGLQJ SK\VLFLDQ·V GLVFUHWLRQ
Inpatient laboratory determinations were done in the
SLU-HSH Laboratory. Extent of hemoconcentration
and thrombocytopenia variation was compared to
normal values for age and sex. Fever clearance time,
and duration of confinement, progression to dengue
)LVKHU·VH[DFWWHVW&KLVTXDUHZKHQDSSOLFDEOHDQG
T-test were used to compare values between groups.
There were some patients who had existing comor-
bidities while they were treated in the hospital, such
as pneumonia, typhoid, and acute tonsillopharyngitis.
Likewise, pre-admission anemia, baseline laboratory
determination variability, and obesity may have also
been present. These covariates thought to influence
VKRFNV\QGURPH'66QHHGIRULQWHQVLYHFDUHXQLW the time to resolution of fever, recovery, and laboratory
,&8FDUHQHHGIRUEORRGWUDQVIXVLRQDQGPRUWDOLW\ results, were accounted for in the final model.
were noted accordingly.
The primary endpoint of the study was FCT,
defined as the time from fever onset to the start of Results
WKHILUVWKRXUSHULRGGXULQJZKLFKWKHWHPSHUD-
WXUHUHPDLQHGEHORZoC. Secondary endpoints 'XULQJ WKH VWXG\ SHULRG WKHUH ZHUH D WRWDO RI 
ZHUHOHXNRSHQLDWKUHVKROGGHILQHGDVWKHORZHVW children with dengue infection admitted to SLU
QDGLU:%&FRXQWWKURPERF\WRSHQLDWKUHVKROG Hospital. Having met the clinical inclusion criteria
GHILQHGDVWKHORZHVWQDGLUSODWHOHWFRXQWPD[L- DQG FRQVHQWLQJ WR SDUWLFLSDWH  SDWLHQWV ZHUH
mum hemoconcentration calculated as [(maximum LGHQWLILHG DV SRWHQWLDO VXEMHFWV RI ZKLFK  KDG
KHPDWRFULWUHFRUGHGGXULQJLQSDWLHQWSHULRG²PHDQ QHJDWLYH16DQGZHUHVXEVHTXHQWO\H[FOXGHG7KUHH
normal hematocrit of age- and sex-matched popula- patients refused admission, one patient withdrew
WLRQ YDOXH@PHDQ QRUPDO KHPDWRFULW RI DJH DQG FRQVHQWRQHSDWLHQWZDVUHMHFWHGGXHWRLQFRPSOHWH
VH[PDWFKHG SRSXODWLRQ YDOXH [ @  GXUDWLRQ monitoring, and two patients did not meet the age
RIFRQILQHPHQWDQGQXPEHURISDWLHQWVZKRGH- FULWHULD+HQFHFKLOGUHQZHUHUDQGRPO\DVVLJQHG
veloped DSS, were admitted to the ICU, transfused to either the methisoprinol group or the placebo group
with blood products, and other complications such VXEMHFWVSHUJURXSFigure 1
as bradyarrythmia or carditis, effusions, hepatitis or $OPRVWDOOVXEMHFWVKDGSULPDU\LQIHFWLRQV,J*
encephalitis. QHJDWLYH2QO\RQHVXEMHFWKDGDVHFRQGDU\LQIHFWLRQ
%DVHGRQWKHH[LVWLQJKRVSLWDOFHQVXVIRU and belonged to the placebo group. Prior to admission,
there were 46 patients with dengue infection admitted WKHPRVWFRPPRQSUHVHQWLQJV\PSWRPVRIWKHVXEMHFWV
EHWZHHQWKH-XQHWR$XJXVWSHULRGWKHPRQWKVZKLFK ZHUHP\DOJLDERG\DFKHVDQGSDLQVDQRUH[LD
are considered to be high-risk by the Department of QDXVHDDQGDEGRPLQDOSDLQ:KLOH
Health. Ninety-six percent of cases treated were WKHUH ZHUH  REHVH SDWLHQWV LQ WKH SODFHER JURXS
classified as uncomplicated dengue infection (all cases there was no observed significant difference to the
RIGHQJXHH[FHSW'66VWDJHVDQG&RPSXWLQJ methisoprinol group with normal BMIs. Fourteen of

322‡Paediatr Indones, Vol. 53, No. 6, November 2013

 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

131 children admitted with dengue

42 children met inclusion criteria and

willing to participate
Excluded (n=20):
15 had negative NS1
Enrolled in the study (n=22) 3 refused admission
1 withdrew consent
1 incomplete monitoring

Methisoprinol group (n=11) Placebo group (n=11)

Analyzed (n=11) Analyzed (n=11)

Figure 15VWF[ƀQYEJCTV

6TGPFUQH'HHGEV+PVGTXGPVKQPQP*GOQEQPEGPVTCVKQP
30
Placebo
Percentage of Drop in hematocrit from Reference

25
Methisoprinol
20 Linear (Placebo)
Values by Age and Gender

15 R2= 0.2698

10
Linear (Methisoprinol)
R2= 0.0029
5

-5

-10

-15

Figure 2. Scatterplot and linear regression of the effects of intervention on hemo-

concentration in %. Each plot in the graph shows the percentage change in hema-
tocrit level from reference values for age and gender of each of the patients with
UGTKCN JGOCVQETKV FGVGTOKPCVKQPU FWTKPI EQPſPGOGPV YKVJ OGVJKUQRTKPQN
„) and
placebo (‹) treatment.

VXEMHFWVPDQLIHVWHGWZRRUIHZHUNH\FRPSODLQWV :HDOVRIRXQGWKDWVXEMHFWVZHUHOHXNRSHQLF
suggesting that reliance on clinical symptoms coupled DW DGPLVVLRQ  1RQH RI WKH VXEMHFWV VKRZHG WKH
with timely laboratory determination are important FODVVLF•LQFUHDVHLQKHPDWRFULWFRQFHQWUDWLRQ
to catch patients at the early stage of the disease. KHPRFRQFHQWUDWLRQEDVHGRQUHIHUHQFHYDOXHVIRU
Three patients had pre-existing or concurrently age and gender, nor at admission baseline levels.
treated comorbidities. Two patients had acute upper %DVHOLQH SODWHOHW VWDWXV ZDV QRUPDO LQ WKH PDMRULW\
respiratory tract infections and one patient had  %DVHOLQH FKDUDFWHULVWLFV RI WKH WZR JURXSV
SHGLDWULFFRPPXQLW\DFTXLUHGSQHXPRQLDFODVV%² are summarized in Table 1.
PLQLPDOULVN7KHVHFRQGLWLRQVGLGQRWVLJQLILFDQWO\ :HIRXQGWKDWVXEMHFWVZHUHIHEULOHDWWKHWLPH
alter the results. RIDGPLVVLRQVXEMHFWVZHUHDIHEULOHDWDGPLVVLRQEXW

Paediatr Indones, Vol. 53, No. 6, November 2013‡323

 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

Table 1. Baseline characteristics of subjects

Characteristics Methisoprinol group Placebo group
(n=11) (n=11)
Mean age, years (SD) 10.72 (4.71) 10.3 (4.52)
Gender, n
Male 4 3
Female 7 8
BMI, n
Normal 11 9
Overweight 0 2
5GTQNQIKEUWDENCUUKſECVKQPP
Early to late acute (NS1+,IgM+) 2 4
Very early acute (NS1+, IgM-) 9 7
%NKPKECNENCUUKſECVKQP
Dengue without warning signs 7 6
Dengue with warning signs 4 5
Mean onset of fever prior to admission, hours (SD) 68.82 (27.21) 58.55 (38.13)
Key symptoms prior to admission
Anorexia/nausea 4 7
Rash 4 3
Myalgia, body aches and pains 6 9
Abdominal pain 4 5
Tourniquet test positive 4 1
Fluid accumulation 0 2
Lethargy 1 1
Mucosal bleeding 1 1
Number of key symptoms
2 or fewer 8 6
More than 2 3 5
Mean WBC count on admission, x 109/L (SD) 3.68 (1.25) 4.59 (3.45)
Normal for age 2 2
Low for age 9 9
Mean platelet count on admission, x 109/L (SD) 216.27 (30.19) 190.91 (91.52)
Normal 11 8
Low 0 3
Mean hematocrit at admission, % (SD) 40.76 (3.46) 39.52 (3.20)
*WBC: white blood cell

developed fever afterwards during confinement, and Patients in the placebo group were hospitalized
VXEMHFWVGLGQRWGHYHORSPRUHIHYHUDWDOOGXULQJ longer than the methisoprinol group, but this
confinement after a history of reported fever at home difference was not statistically significant.
shortly before admission. Fevers seemed to clear faster The mean highest hematocrit level recorded
in the placebo group than in the methisoprinol group, GXULQJ FRQILQHPHQW H[FOXGLQJ DGPLVVLRQ LQ WKH
but this result was not statistically significant. methisoprinol group was higher than that of the
7KHPHDQORZHVWQDGLU:%&FRXQWVREWDLQHG placebo group. With regards to mean maximum
during confinement while medicating was recorded hemoconcentration based on age-matched reference
and compared to baseline values at the time of values, and baseline admission hematocrit level,
admission. The methisoprinol group had significantly WKH\ ZHUH QRW VWDWLVWLFDOO\ GLIIHUHQW 3  DQG
lesser magnitude of WBC drop compared to the 3  6LPLODUO\ WKH ´GLVFKDUJH KHPDWRFULWµ
placebo group. Hence, methisoprinol reduced the or the last hematocrit taken after the patient was
DQWLFLSDWHGOHXNRSHQLDE\[/RU considered to be stable was not different between
7KHPHDQORZHVWQDGLUSODWHOHWFRXQWREWDLQHG
during confinement was also recorded and compared
to baseline values at admission. A smaller drop in
platelet count was observed in the methisoprinol
group than in the placebo group. Hence, methiso-
prinol reduced the anticipated thrombocytopenia by
[/RU
324‡Paediatr Indones, Vol. 53, No. 6, November 2013
WKHWZRJURXSV3 6FDWWHUSORWDQGWUHQGLQJ
analysis in Figure 2 supports this lack of hematocrit
difference between groups. Since R values in both
DUPV RI WUHDWPHQW ZHUH  WKHUH ZDV YHU\ OLWWOH
consistent, predictable and significant relationship
between medicating with either methisoprinol and
hemoconcentration.
 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

All admitted patients were on IV fluid therapy
and their treatment was according to protocols for
dengue infection management. In addition, we also
compared complications in the two groups. The
outcomes are shown in Table 2.
complement surface markers. It increases cytokine
,/ SURGXFWLRQ DQG HQKDQFHV ,/ SURG XFW LRQ
XSUHJXODWLQJ WKH H[SUHVVLRQ RI WKH ,/ UHFHSWRU LQ
vitro. It significantly increases endogenous IFN-
gamma secretion and decreases IL-4 production in

Table 2. Treatment outcomes between the methisoprinol and placebo groups

Parameters Methisoprinol group Placebo group
P value
(n=11) (n=11)
Mean fever clearance time (SD), hours 109.07 (22.87) 89.47 (34.00) 0.158
Mean lowest WBC count during study (SD), x 109/L 2.33 (0.58) 2.37 (0.93) 0.906
Mean decrease in WBC count (SD), x 109/L 1.14 (0.84) 2.60 (3.12) 0.004
Mean lowest platelet count during study (SD), x 109/L 177.91 (21.20) 140.45 (18.21) 0.195
Mean decrease in platelet count (SD), x 109/L 38.36 (58.3) 50.46 (73.42) 0.046
Mean length of stay (SD), hours 84.33 (23.86) 90.68 (20.53) 0.511
Mean highest hematocrit level during study (SD), % 41.88 (4.92) 40.34 (3.21) 0.393
Mortality, n - -
Complications, n
Required fresh frozen plasma 2 - *
Experienced bradycardia/carditis 1 3 0.586
2NGWTCNGHHWUKQP
TCFKQNQIKEEQPſTOGF - 1 *
Transferred to ICU - -
Encephalitis - -
*GRCVKVKU - -
Epistaxis 2 1 0.476
Allergic reaction - -
*P value could not be computed because of a zero value in one of the groups.

Discussion vivo.5 It has been shown to potentiate neutrophil,

monocyte and macrophage chemotaxis and phago-
Leukopenia usually precedes the onset of the critical cytosis. As an antiviral, in vivo, methisoprinol
phase of dengue and has been associated with severe enhances potentiation of depressed lymphocytic
disease. In our study, the WBC decrease in the mRNA protein synthesis and translational ability,
methisoprinol group was 56% less than the anticipated
WBC count decrease in the placebo group. Hence,
if the theorized effect of methisoprinol were true,
its immunostimulant role may have produced an
increase in the overall WBC count, and effectively
arrested or lessened the leukopenia and severity of
GHQJXHLQIHFWLRQ0HWKLVRSULQRO·VLPPXQRPRGXODWRU\
effect can probably be explained based on its ability
to normalize deficient or dysfunctional cell-mediated
LPPXQLW\ E\ HYRNLQJ D 7KW\SH UHVSRQVH ZKLFK
in turn, initiates T-lymphocyte maturation and
differentiation as well as potentiation of induced
lymphoproliferative responses in mitogen- or
antigen-activated cells. Similarly, the drug has been
shown to modulate T-lymphocyte and natural killer
FHOO F\WRWR[LFLW\ 7 VXSSUHVVRU DQG 7 KHOSHU FHOO
functions, and also to increase the number of IgG and
ZKLOHLQKLELWLQJYLUDOULERQXFOHLFDFLG51$V\QWKHVLV
achieved by yet to be clarified degrees of incorporation
of inosine-mediated orotic acid into polyribosomes.
It also inhibits of polyadenylic acid attachment to
viral messenger RNA and engages in molecular
reorganization of lymphocyte intramembrane plasma
particles that result in a nearly threefold increase in
density. The effect of the test drug on platelet
counts, on the other hand, was unexpected and
the exact mechanism of methisoprinol action on
the platelets cannot be explained by the existing
literature.
The paucity of severe dengue complications is
consistent with the anticipated absence of antibody-
dependent enhancement in primary infections. 
Since the population under study had mostly primary
dengue infections, this scenario was anticipated. It is
Paediatr Indones, Vol. 53, No. 6, November 2013‡325
 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

important to note, however, that our study is limited to the residents, interns, and nurses who served as research assistants,
the effects of methisoprinol in early dengue infection as well as to the New Marketlink Pharmaceutical Corporation
alone, and the full spectrum of its effect on later stages
and more severe dengue cases was not assessed.
Methisoprinol was hypothesized to decrease
fever duration, but this was not observed in our
study. There were also no significant decreases in
the recovery period or admission duration in our
results. This may be explained by the fact that the
number of hours of confinement is only, at best, an
approximate reflection of the time of improvement
or recovery of a dengue patient. Patients are not
necessarily discharged at the time-point of clinical
recovery. Patients may also be discharged earlier than
others, based on the anticipated level of parental care
and supervision at home or the amenability to follow-
up. In our study, patients were not monitored after
confinement, and no attempt was made to determine if
or when laboratory parameters resumed to normal.
It is recommended that further studies be made
in a hospital setting with more patient admissions,
i.e., public hospitals in known dengue hotspots in the
country and other Asian locales. We should allow for
UHFUXLWPHQWRIRXWSDWLHQWVXEMHFWVEXWZLWKDVVLJQHG
dedicated research assistants to help monitor home-
bound patients. Trials using different strengths (dosag-
103& 3KLOLSSLQHV IRU SURYLGLQJ ERWK WKH PHGLFDWLRQ DQG
placebo preparations, as well as financial support to partially
fund this research.
References
 :RUOG+HDOWK2UJDQL]DWLRQ:HVWHUQ3DFLILF5HJLRQ(PHUJLQJ
disease surveillance and response-Dengue Situation Updates.
 >FLWHG )HE @ $YDLODEOH IURP KWWSZZZZSUR
ZKRLQWHPHUJLQJBGLVHDVHV'HQJXH6LWXDWLRQ8SGDWHVHQ
index.html.
 'HSDUWPHQWRI+HDOWK1DWLRQDO(SLGHPLRORJ\&HQWHU3XEOLF
Health Surveillance and informatics division. Republic of the
3KLOLSSLQHV'HSDUWPHQWRI+HDOWK:HEVLWH>FLWHG)HE
@$YDLODEOHIURPKWWSZZZGRKJRYSKVLWHVGHIDXOW
ILOHV'HQ:05SGI
 :RUOG +HDOWK 2UJDQL]DWLRQ  >FLWHG )HE @
Available from: KWWSZZZZKRLQWPHGLDFHQWUHIDFWVKHHWV
IVHQ
 $\DKDR)'0DQLOD%XOOHWLQ2QOLQH>FLWHG0D\@
Available from: KWWSZZZPEFRPSKDUWLFOHV
reality-bites#.USCtIGdNsxM.
5. Newport Pharmaceuticals. Methisoprinol [Package Insert].
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are also recommended, as well as using in vitro studies
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antithrombocytopenic effects of the medication on the
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reduce fever clearance time or length of hospital stay,
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the development of complications in children with
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uncomplicated acute primary dengue infection. How- OHXNRSODNLD 39/ RSHQ WULDO RI VXUJHU\ FRPSDUHG ZLWK
ever, methisoprinol is observed to reduce leukopenia combined therapy using surgery and methisoprinol in
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prinol could be used along with the standard, approved
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Acknowledgments

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treatment with subcutaneous interferon-alpha, oral
isoprinosine, and lamivudine for subacute sclerosing
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Thanks to Dr. Catherine Gomez, Dr. Elizabeth Gallardo and Dr. RIUKDEGRYLUXVHVLVRODWHGIURPFDUS&\SULQXVFDUSLRDQG
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326‡Paediatr Indones, Vol. 53, No. 6, November 2013

 Melissa G. Ompico: Methisoprinol for children with early phase dengue infection

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Paediatr Indones, Vol. 53, No. 6, November 2013‡327