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Paediatrica Indonesiana

VOLUME 53 November ‡ NUMBER 6

Original Article

Methisoprinol for children with


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

D
Abstract engue fever remains a serious public
Background Dengue fever is associated with many health health concern in tropical regions as it
complications and medical costs. Furthermore, there is currently continues to claim many lives year after
no approved dengue antiviral medication or vaccine. Empiric year. The Philippines is known to be
evidence has suggested that patients who received supplemental
methisoprinol therapy had faster recovery times and fewer
endemic for the four antigenic subtypes of dengue
complications. viruses, with no locality or social stratum spared from
Objective To determine the effects of oral methisoprinol on the LW 'HQJXH PRUWDOLW\ LQ WKH FRXQWU\ QXPEHUHG 
clinical course and laboratory findings of children with early phase RXWRIWKHUHSRUWHGFDVHV FDVHIDWDOLW\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
VXEMHFWVWRUHFHLYHHLWKHURUDOPHWKLVRSULQRO PJNJ%: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' YV 6' 
[/3 @,QDGGLWLRQWKHPHDQGHFUHDVHLQSODWHOHWFRXQW
practitioners and even physicians who claim their
ZDVOHVVLQSDWLHQWVRQPHWKLVRSULQRO> 6' YV 6' effectiveness based on practice-based evidence. These
 [/3 @1RVLJQLILFDQWGLIIHUHQFHVEHWZHHQWKH include homeopathic remedies and trial-stage antiviral
WZRJURXSVZHUHIRXQGIRU)&7 3  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+HDUW 6/8+6+ 3KLOLSSLQHV
[Paediatr Indones. 2013;53:320-7.].
Reprint requests to: Melissa G. Ompico, Department of Pediatrics, Saint
/RXLV8QLYHUVLW\+RVSLWDORIWKH6DFUHG+HDUW 6/8+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 assessed to have severe dengue infection, critical
as a direct-acting antiviral for the systemic treatment or in the recovery phase of dengue fever, previously
RI YLUDO LQIHFWLRQV DQG DV DQ LPPXQRVWLPXODQWLP- diagnosed with bleeding diathesis, platelet disorder
munomodulator.6 Methisoprinol has already been or immunodeficiency disorder, previously ingested
proven effective in human and animal models either aspirin, ibuprofen or other antithrombotic medication
singly or in combination for many viral diseases. ZLWKLQWKHSUHYLRXVKRXUVSUHJQDQWRUODFWDWLQJ
It is marketed in the Philippines for the following unable to swallow oral medications (non per orem
indications: subacute sclerosing panencephalitis RUGHU  PDOQRXULVKHG  6' ZHLJKWIRUKHLJKW
663(  YDULFHOOD PXPSV UKLQRYLUXV LQIOXHQ]D $ RU %0, IRU DJH  RU LI FRQVHQW ZDV XQREWDLQDEOH
measles, encephalitis, herpes zoster, herpes simplex 3HUPLVVLRQ IURP SDWLHQWV· DWWHQGLQJ SK\VLFLDQV ZDV
labialis, hepatitis A, acute viral B hepatitis, herpes also secured verbally or in writing. Patients and their
genitalis, as well as immunorestoration in conditions SDUHQWVJXDUGLDQVZHUHLQIRUPHGRIWKHQDWXUHRIWKH
such as pre-acquired immune deficiency syndrome planned intervention, that placebo would be used
$,'6 SHUVLVWHQWJHQHUDOL]HGO\PSKDGHQRSDWK\DQG and that improvement would be monitored through
AIDS-related complex, neoplastic disease, anergy and several laboratory tests. The medical risks associated
K\SRHUJ\SULRUWRPDMRUVXUJHU\DQGVHYHUHEXUQV.5 with taking the medication were explained. A consent
0HWKLVRSULQROZDVILUVWSRVWXODWHGDVDQDGMXYDQW IRUP ZDV ILOOHG LQ GXSOLFDWH E\ WKH SDWLHQW DQGRU
for dengue fever in Thailand, but no other studies SDUHQWVJXDUGLDQV 7KH FRQVHQW IRUP ZDV DYDLODEOH
have confirmed nor refuted its claims. We aimed to in English, Filipino, and Iluko. It was explained to
determine the effects of oral methisoprinol treatment them in the vernacular on the occasion that a patient
on the clinical course of early phase dengue infection could not understand these. The consent forms and
in pediatric patients and specifically, to establish the research proposal were submitted and approved by the
HIIHFW RI PHWKLVRSULQRO RQ GHQJXH SDWLHQWV· IHYHU 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\WRSHQLD QDGLUSODWHOHWFRXQWV 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+HDUW 6/8+6+ %DJXLR&LW\3KLOLSSLQHV GRVHV KRXUVRIPHGLFDWLRQ ZHUHFRPSOHWHGZKLFK
for early dengue fever. Patients were eligible if they also corresponded to the maximal period of viremia.
ZHUH DJHG  WR  \HDUV  PRQWKV ZLWK FOLQLFDO Research assistants were responsible to administer,
symptoms suggestive of dengue fever, as defined by or supervise the administration of the correct
WKH:+2'HQJXH*XLGHOLQHV and laboratory intervention. A checklist for scheduling of dosages
confirmation of very early or early acute infection, via ZDVDOVRSODFHGDWWKHEHGVLGHIRUWKHSDWLHQWJXDUGLDQ
Dengue Duo Pack® (SD Bioline: Standard Diagnostics 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\RWKHUDGMXYDQWV SURELRWLFV Supposing that half of these were in the early phase
YLWDPLQVXSSOHPHQWVRUKHUEDOUHPHGLHV GXULQJWKH of dengue infection, then the ideal sample would be
observation. SDWLHQWV
Patient profiles, diagnoses, classification, date Data remained blinded until the database was
and time of admission and discharge, vital signs finalized and ready for analysis. Statistical analysis was
and laboratory results were recorded in case record performed with SPSS Version 2.0. A two-sided P value
forms. Clinical history and significant examination ”ZDVFRQVLGHUHGWREHVLJQLILFDQWIRUDOOSDUDP-
findings were also recorded. Daily vital signs including eters. The null hypothesis was that isoprinosine had
temperature, obtained by aural digital thermometer 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, )LVKHU·VH[DFWWHVW &KLVTXDUHZKHQDSSOLFDEOH DQG
and platelet counts were done as clinically indicated, T-test were used to compare values between groups.
DFFRUGLQJ WR WKH DWWHQGLQJ SK\VLFLDQ·V GLVFUHWLRQ There were some patients who had existing comor-
Inpatient laboratory determinations were done in the bidities while they were treated in the hospital, such
SLU-HSH Laboratory. Extent of hemoconcentration as pneumonia, typhoid, and acute tonsillopharyngitis.
and thrombocytopenia variation was compared to Likewise, pre-admission anemia, baseline laboratory
normal values for age and sex. Fever clearance time, determination variability, and obesity may have also
and duration of confinement, progression to dengue 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
GHILQHGDVWKHORZHVW QDGLU SODWHOHWFRXQW PD[L- DQG FRQVHQWLQJ WR SDUWLFLSDWH  SDWLHQWV ZHUH
mum hemoconcentration calculated as [(maximum LGHQWLILHG DV SRWHQWLDO VXEMHFWV RI ZKLFK  KDG
KHPDWRFULWUHFRUGHGGXULQJLQSDWLHQWSHULRG ² PHDQ 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\DFTXLUHGSQHXPRQLD FODVV%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
7KHPHDQORZHVW QDGLU :%&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
7KHPHDQORZHVW QDGLU SODWHOHWFRXQWREWDLQHG WKHWZRJURXSV 3  6FDWWHUSORWDQGWUHQGLQJ
during confinement was also recorded and compared analysis in Figure 2 supports this lack of hematocrit
to baseline values at admission. A smaller drop in difference between groups. Since R values in both
platelet count was observed in the methisoprinol DUPV RI WUHDWPHQW ZHUH  WKHUH ZDV YHU\ OLWWOH
group than in the placebo group. Hence, methiso- consistent, predictable and significant relationship
prinol reduced the anticipated thrombocytopenia by between medicating with either methisoprinol and
[/RU hemoconcentration.

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


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

All admitted patients were on IV fluid therapy complement surface markers. It increases cytokine
and their treatment was according to protocols for ,/ SURGXFWLRQ DQG HQKDQFHV ,/ SURG XFW LRQ
dengue infection management. In addition, we also XSUHJXODWLQJ WKH H[SUHVVLRQ RI WKH ,/ UHFHSWRU LQ
compared complications in the two groups. The vitro. It significantly increases endogenous IFN-
outcomes are shown in Table 2. 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 ZKLOHLQKLELWLQJYLUDOULERQXFOHLFDFLG 51$ V\QWKHVLV
WBC count decrease in the placebo group. Hence, achieved by yet to be clarified degrees of incorporation
if the theorized effect of methisoprinol were true, of inosine-mediated orotic acid into polyribosomes.
its immunostimulant role may have produced an It also inhibits of polyadenylic acid attachment to
increase in the overall WBC count, and effectively viral messenger RNA and engages in molecular
arrested or lessened the leukopenia and severity of reorganization of lymphocyte intramembrane plasma
GHQJXHLQIHFWLRQ0HWKLVRSULQRO·VLPPXQRPRGXODWRU\ particles that result in a nearly threefold increase in
effect can probably be explained based on its ability density. The effect of the test drug on platelet
to normalize deficient or dysfunctional cell-mediated counts, on the other hand, was unexpected and
LPPXQLW\ E\ HYRNLQJ D 7KW\SH UHVSRQVH ZKLFK the exact mechanism of methisoprinol action on
in turn, initiates T-lymphocyte maturation and the platelets cannot be explained by the existing
differentiation as well as potentiation of induced literature.
lymphoproliferative responses in mitogen- or The paucity of severe dengue complications is
antigen-activated cells. Similarly, the drug has been consistent with the anticipated absence of antibody-
shown to modulate T-lymphocyte and natural killer dependent enhancement in primary infections. 
FHOO F\WRWR[LFLW\ 7 VXSSUHVVRU DQG 7 KHOSHU FHOO Since the population under study had mostly primary
functions, and also to increase the number of IgG and 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 103&  3KLOLSSLQHV IRU SURYLGLQJ ERWK WKH PHGLFDWLRQ DQG
and more severe dengue cases was not assessed. placebo preparations, as well as financial support to partially
Methisoprinol was hypothesized to decrease fund this research.
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 References
results. This may be explained by the fact that the
number of hours of confinement is only, at best, an  :RUOG+HDOWK2UJDQL]DWLRQ:HVWHUQ3DFLILF5HJLRQ(PHUJLQJ
approximate reflection of the time of improvement disease surveillance and response-Dengue Situation Updates.
or recovery of a dengue patient. Patients are not  >FLWHG )HE @ $YDLODEOH IURP KWWSZZZZSUR
necessarily discharged at the time-point of clinical ZKRLQWHPHUJLQJBGLVHDVHV'HQJXH6LWXDWLRQ8SGDWHVHQ
recovery. Patients may also be discharged earlier than index.html.
others, based on the anticipated level of parental care  'HSDUWPHQWRI+HDOWK1DWLRQDO(SLGHPLRORJ\&HQWHU3XEOLF
and supervision at home or the amenability to follow- Health Surveillance and informatics division. Republic of the
up. In our study, patients were not monitored after 3KLOLSSLQHV'HSDUWPHQWRI+HDOWK:HEVLWH>FLWHG)HE
confinement, and no attempt was made to determine if @$YDLODEOHIURPKWWSZZZGRKJRYSKVLWHVGHIDXOW
or when laboratory parameters resumed to normal. ILOHV'HQ:05SGI
It is recommended that further studies be made  :RUOG +HDOWK 2UJDQL]DWLRQ  >FLWHG )HE @
in a hospital setting with more patient admissions, Available from: KWWSZZZZKRLQWPHGLDFHQWUHIDFWVKHHWV
i.e., public hospitals in known dengue hotspots in the IVHQ
country and other Asian locales. We should allow for  $\DKDR)'0DQLOD%XOOHWLQ2QOLQH>FLWHG0D\@
UHFUXLWPHQWRIRXWSDWLHQWVXEMHFWVEXWZLWKDVVLJQHG Available from: KWWSZZZPEFRPSKDUWLFOHV
dedicated research assistants to help monitor home- reality-bites#.USCtIGdNsxM.
bound patients. Trials using different strengths (dosag- 5. Newport Pharmaceuticals. Methisoprinol [Package Insert].
LQJ IUHTXHQF\DQGGXUDWLRQVIRUWKHWHVWPHGLFDWLRQ 'HF
are also recommended, as well as using in vitro studies 6. MIMS Online Team. MIMS Philippines Online. [cited
WR LQYHVWLJDWH WKH DQWLYLUDOLPPXQRPRGXODWRU\ DQG 'HFHPEHU@$YDLODEOHIURPKWWSZZZPLPVFRPSK
antithrombocytopenic effects of the medication on the 3KLOLSSLQHVGUXJLQIR,VRSULQRVLQH,VRSULQRVLQH"W\SH IXOO
dengue virus in a local setting. 7. Limson B. Methisoprinol in the treatment of non-bacterial
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reduce fever clearance time or length of hospital stay, Griseofulvin-methisoprinol combination in the treatment
nor do it diminish or prevent hemoconcentration or RIKHUSHV]RVWHU3KDUPDFRO5HV&RPPXQ
the development of complications in children with  )HPLDQR)*RPERV)6FXOO\&2UDOSUROLIHUDWLYHYHUUXFRXV
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  $\GLQ 2 6HQELO 1 .X\XFX 1 *UHU <. &RPELQHG
fluid and antipyretic therapy for dengue treatment. 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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hemorrhagic fever and other cellular infections with emphasis E. Inosine pranobex in the treatment of HIV infection: a
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rat liver. Its relation to host defense against virus infection. ELRORJ\6FLHQFH

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