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International Journal of Health Sciences and Research

www.ijhsr.org ISSN: 2249-9571

Review Article

Dengue Fever: Role of Carica Papaya L.


Mrinal Saraf1, Bhushan Kavimandan2
1
Research Scholar, 2Assistant Professor,
Department of Biochemistry, Moolji Jaitha College, Jalgaon (MS) - 425001
Corresponding Author: Bhushan Kavimandan

ABSTRACT

Dengue is spreading in urban area with the lightning speed. Dengue is now endemic in more than 100
countries. Dengue disease creates highly complex patho-physiological, economic and ecologic
conditions. Approximately 2.5 billion people live in dengue-risk regions with about 100 million new
cases each year worldwide. Dengue is a public health issue with an economic burden that is currently
challenged for any substantial medicine or vaccination. Considering, the possible positive effects of
papaya leaves in thrombocytopenia occurring in dengue fever, this review highlights the
understanding of dengue and remedy for it.

Key words: Dengue, thrombocytopenia, Carica papaya L., alkaloids, Aedes aegypti.

INTRODUCTION vector of dengue (Aedes aegypti) has


Dengue: adapted well to the urban environment and
The name dengue originated from always breeds in stagnant containers. Eggs
the Swahili word for “bone-breaking fever” need moist conditions, and mature in 24–72
or the word for “the walk of a dandie” in h. Mosquito bites are the only route of virus
Spanish. The first probable case of dengue spread. The transmission of virus is often
fever (DF) was recorded during the Jin from human to human through domestic
Dynasty (265–420 AD) in China. The first mosquitoes. An outbreak starts after a
recognized epidemics occurred almost mosquito sucks the blood of a patient with
simultaneously in Asia, Africa and North dengue fever/ dengue hemorrhagic fever.
America in the 1780s, shortly after the After being transmitted to a new human host
identification and naming of the disease in by infected mosquitoes, the virus replicates
1779 by Benjamin Rosh (Cecilia D 2014). in the lymph nodes and spreads through the
Dengue is an acute viral infection lymph and blood to other tissues. All four
with potential fatal complications. Dengue serotypes can cause full spectrum of disease
viruses (DV) belong to family Flaviviridae from a subclinical infection to a mild self-
and there are four serotypes of the virus limiting disease. The dengue fever (DF) is a
(Benazir, 2015; Soonwera M 2015). It is severe disease that may be fatal due to
transmitted mainly by Aedes aegypti and dengue hemorrhagic fever or dengue shock
Aedes Albopictus mosquito. Aedes syndrome. According to WHO (1997)
mosquitoes are small and black with white classification dengue was divided into
markings on the body and legs. Female undifferentiated fever, dengue fever (DF),
mosquitoes need blood from biting humans and dengue hemorrhagic fever. The WHO
or animals to produce live eggs. It takes 2–3 2009 classification divides dengue fever
days for egg development. The principal into two groups: uncomplicated and severe,

International Journal of Health Sciences & Research (www.ijhsr.org) 249


Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

yet the 1997 WHO classification is still approximately 11 kb in length, has a single
widely used. open reading frame. Reading frame codes
Virology: for three structural and seven structural
Dengue virus (DENV) is a positive- proteins. Structural proteins are capsid,
strand RNA virus of the family Flaviviridae, membrane and envelope glycoproteins.
genus Flavivirus. It exists as four closely Non-structural proteins are NS1, NS2A,
related but anti-genitically distinct serotypes NS2B, NS3, NS4A, NS4B and NS5.
(DENV-1, -2, -3, and -4), all of which have Important biological properties of dengue
Aedes aegypti mosquitoes as their primary viruses, including receptor binding,
vector, with A. albopictus as a secondary haemagglutination of erythrocytes and the
vector. induction of neutralizing antibodies and the
The virion comprises a spherical protective immune response, are associated
particle, 40–50 nm in diameter, with a with the E glycoprotein (Lalla J K 2014).
lipopolysaccharide envelope. The positive
single-strand RNA genome, which is

Life cycle Aedes Albopictus mosquito:

(Source:http://www.biogents.com/cms/website.php?id=/en/traps/mosquitoes/tiger_mosquitoe s.htm)

Pathophysiology of dengue fever:


Dengue infection is caused by bites bloodstream and, if left untreated, can
of the female Aedes aegypti mosquito damage blood vessels and lymph nodes
carrying Flavivirus. After a person is bitten, resulting in dengue hemorrhagic fever with
the virus incubation period varies between 3 symptoms such as bleeding from the nose,
and 14 days, after which the person may gums or under the skin. Dengue
experience early symptoms such as fever, hemorrhagic fever patients also have
headache, rash, nausea, and joint and difficulty in breathing and severe
musculoskeletal pain. This classic DF development can lead to dengue shock
records temperatures between 39 and 400C syndrome. Dengue shock syndrome can
and usually last for 5–7 days. During this result in death if proper treatment is not
period, the virus may get into the peripheral

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Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

provided (Behram M et al, 2015; Bajaj shown a steady rise with every passing year,
A2015; Dengue national guide lines 2015). the mortality has reduced. The overall
World-wide frequency: mortality rate of 1.2% in 2007 dropped to
Some 1.8 billion people are at risk 0.25% in 2013. Compared with the rest of
for dengue worldwide which accounts at South-East Asia, the number of dengue
more than 70%.An estimated 50 million shock syndrome (DSS) cases in India is low
dengue infections occur worldwide (Cecilia D 2014).
annually. An estimated 50,00,00 people Treatment:
with DHF require hospitalization each year. Allopathy- benefits and hazards:
A very large proportion (approximately There is no specific therapy for dengue
90%) of them are children aged less than infections. Good supportive care may be
five years, and about 2.5% of those affected life-saving, but ultimately initiatives aimed
die. Dengue and DHF is endemic in more at vector control and prevention of mosquito
than 100 countries in the WHO regions of bites may provide the greatest benefit
Africa, the Americas, the Eastern (Singhi S et al 2007).
Mediterranean, South-East Asia and the Management of dengue fever is
Western Pacific. The South-East Asia and symptomatic and supportive. Bed rest is
Western Pacific regions are the most advisable during the acute phase. Use
seriously affected. Epidemics of dengue are cold/tepid sponging to keep temperature
increasing in frequency. During epidemics, below 38.5° C. Antipyretics may be used to
infection rates among those who have not lower the body temperature.
been previously exposed to the virus are Aspirin/NSAIDS like Ibuprofen, etc should
often 40% to 50% but can also reach 80% to be avoided since it may cause gastritis,
90%.Seasonal variation is also observed. vomiting, acidosis, platelet dysfunction and
Aedes(Stegomyia) aegypti is the primary severe bleeding.
epidemic vector. Primarily an urban disease, Oral fluid and electrolyte therapy is
dengue and DHF are now spreading to rural recommended for patients with excessive
areas worldwide. Imported cases are sweating or vomiting. Patients should be
common. Co-circulation of multiple monitored for 24 to 48 hours after they
serotypes/genotypes is evident. (WHO become a febrile for development of
2011, 2014) complications (Dengue national guide lines
Status in India: 2015).
When dengue first emerged in India Till now there is no licensed vaccine
during 1950–60s, the disease was mild available against dengue viral infection.
despite circulation of all four serotypes. The Several trials are ongoing in the world for
disease profile changed and greater severity the development of tetravalent dengue
was reported from the late 1980s.The vaccine. So far phase III trials of a
history of dengue outbreaks in India has recombinant, live attenuated tetravalent
been studied. More recent and systematic dengue vaccine (CYD-TDV) has completed
statistics was given by NVBDCP (National in Five Asian countries in children which
vector borne disease control program). Data may be promising in preventing dengue
had shown that dengue has been endemic in infection in near future (Dengue national
16 states since the beginning: Maharashtra, guide lines 2015).
Punjab, Rajasthan, Pondicherry, Kerala, Effective vector control measures
Madhya Pradesh, Delhi, Gujarat, Haryana, are critical to achieve and sustain reduction
Andhra Pradesh, Karnataka, Uttar Pradesh, of morbidity attributable to dengue.
West Bengal, Chandigarh, Goa and Tamil Preventive and vector control interventions
Nadu. During 2010–2012, dengue aim to reduce dengue transmission, thereby
encroached into the remaining states. Even decreasing the incidence of the infection and
though the number of dengue cases has preventing outbreaks of the disease. Attempt

International Journal of Health Sciences & Research (www.ijhsr.org) 251


Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

to identify potential antiviral for the The in vitro and in vivo inhibitory
treatment of dengue is a global challenge as potential of aqueous extract of Azidarachta
all four serotypes are frequently undergoing indica (neem) leaves on the replication of
mutations (WHO 2012). virus was evaluated by Parida et al2002.
Studies on herbal medicinal products Turmerone obtained from volatile oil
for platelet augmentation are consistently of Curcuma longa give 100% mosquitocidal
increasing due to the limited supportive activity against Aedes aegypti(Roth et
treatments available for thrombocytopenic al1998).
disorders. The water decoction of leaves from
Plants species traditionally used to treat Euphorbia hirta, locally known as gatas–
dengue fever: gatas, is used in the Philippines as a folk
According to a World Health medicine to treat DF.
Organization (WHO) 80 % of the Efficacy of these species is in
population in some Asian and African following order: P. longum> P.
countries depends on traditional medicine as armentosum Roxb> P ribesoides Wall. This
their primary health care due to economic study conclude that Pepper plant possess
and geographical constraints. Natural activity against Aedes aegypti (U Chaithong
products have become the main source of et al2006).
test material in the development of antiviral Psidium guava is an evergreen shrub
drugs based on traditional medical practices. or small tree indigenous to Mexico, the
Traditional medicinal plants have been Caribbean and Central and South America,
reported to have antiviral activity, and some has been tested in vitro and showed to
have been used to treat viral infections in inhibit the growth of dengue- virus. Water
animals and humans. In the Philippines, boiled with guava leaves has been used to
Euphorbia hirta, known locally as tawa- avoid bleeding in dengue hemorrhagic
tawa, is used in folk medicine to cure fever, and to elevate platelet counts. P.
dengue fever by people in rural areas guava ripe fruit or juice has healing
(Naresh Kumar et al 2015) Andropogon properties in cases of DF by improving the
citratum oil is put in candles and lanterns declining levels of platelets (Abouthealt-
that can be burnt to repel mosquitoes. Its h.com/dengue-fever-medicine 2011).
mosquito repellent qualities have been Carica papaya, Ipomea batatas
verified by research, including effectiveness green and violet variety, Alternanthera
in repelling Aedes aegypti (Gadhwal A et al Sessilis, and Euphorbia hirta have
2016; Ibrahim Jet al,1998). Also there are significant platelet augmentation activity.
many undocumented uses of Euphorbia This is suggestive these plants extracts can
hirta for platelet augmentation probably be used as supportive treatment for
owing to its current prominence in the thrombocytopenic disorders and dengue
Philippines as an alternative supportive hemorrhagic fever which may be an
treatment for dengue hemorrhagic fever. alternative to platelet transfusions (Allorado
This claim is verified by the published et al2010).The investigation on these plant
report (Johnson et al2010) which showed 93.1777% increase in platelet count
demonstrated that there is a significant which corroborated the previous
increase in platelet counts and a decrease in investigation on its effect on blood
bleeding and clotting times in ethanol- components. It is recommended that more
induced thrombocytopenic rats after investigations can be conducted on Ipomea
administration of Euphorbia hirta decoction batatas and Alternanthera Sessilis to further
for 14 days. These folkure medicines need a support the cause (Johnson et al2010).
careful review of other evidences regarding Several Ayurvedic herbs have been
the use of Euphorbia hirta. shown to be effective in treatment of dengue
fever.

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Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

They include: folk treatment, papaya has shown


Amaltas: Amaltas is the root of the cassia remarkably admirable results in many
tree. It is used as a tonic for reducing fever diseases and disorders. The plant is weak,
in dengue infection. usually un-branched and having soft stem
Chirayata: Chirayata is very effective for and can grow up to 20m high. Carica
reduction of fevers. It is useful for treating papayaL plant bears cluster of large and
convulsions that occur with fever in dengue. long stalked leaves (V. Yogiraj2014).
Datura: Datura leaves are effective in Papaya is known as "A powerhouse of
reducing the fever in dengue infection. It nutrients" and was reputably called the "The
helps to reduce the seriousness of fever in fruit of Angels" by Christopher Columbus
dengue infection. in the 20th century.
Hara dhania: Coriander leaves taken as a
Botanical classification of papaya plant: (USDA)
tonic can reduce fever in dengue. Kingdom : Plantae
Hermal: Powdered Hermal seeds taken Subkingdom : Tracheobionta
Super division : Spermatophyta
either as an infusion or as a decoction can Division : Magnoliophyta
help to treat intermittent and recurrent Class : Magnoliopsida
fevers in dengue. (Lalla JK2014) Subclass : Dilleniidae
Order : Violales
Kanghi: An infusion of kanghi can help to Family : Caricaceae
reduce fever in dengue. Genus : Carica L.
Species : papaya L.
Giloy or Amrita: It is an anti-inflammatory
(that reduces inflammation) and antipyretic Part of plant and its constituents: (The wealth of India
(that reduce fever) herb. This herb, which 1992; Kirtikar KR 1998; Indian Medicinal Plants 2005;
has been used in Ayurvedic Rasayanas since Krishna KL 2008):
Part Constituent
centuries, is very helpful in building up the
Fruit Protein, fat, fibre, carbohydrates, minerals(calcium,
immune system and the body's defense phosphorous, iron), Vitamin (vitamin C, thiamine,
against infecting organisms. (Lalla riboflavin, niacin, and carotene), amino acids, citric
and malic acids (green fruits), volatile compounds
JK2014)In a scientific study conducted (linalool, benzyl iso-thiocyanate, cis and trans 2, 6-
using human WBC (white blood dimethyl-3,6 epoxy-7 octen-2-ol), Alkaloid (carpaine,
benzyl- β -D glucoside, 2-phenylethyl -β-D-glucoside,
corpuscles), the Ayurvedic herb helps in 4-hydroxy- phenyl-2 ethyl-β-D-glucoside and four
enhancing the killing ability of macrophages isomeric malonated benzyl-β-D-glucosides).
Juice N-butyric, n-hexanoic and n-octanoic acids, lipids;
(the resistant cells which are responsible for myristic, palmitic, stearic, linoleic, linolenic and cis -
fighting foreign bodies as well as vaccenic and oleic acids.
microorganisms). Bark Β-Sitosterol, glucose, fructose, sucrose, galactose and
xylitol
Some other herbs that are effective in the Seed Fatty acids, crude protein, crude fibres, papaya oil,
treatment of fever in dengue include methi, alkaloid Carpaine, some volatile componds benzyl
iso-thiocyanate, benzyl glucosinolate,
punarnava, rojmari, tulsi leaves (Lalla glucotropacolin, benzyl thiourea, hentriacontane, β-
JK2014). sitosterol, caricin and myrosin
Root Carposide and an enzyme myrosin
Carica papaya Leaf Alkaloids carpain, pseudocarpain and
India is a country having a wide dehydrocarpaine I and II, choline, carposide,vitamin C
medicinal history as “Ayurveda”. Many and E
Latex Proteolytic enzymes, papain and chemopapain,
plants and their parts have been explored glutamine cyclotransferase, chymopapains A, B and
and exploited for their medicinal C, peptidase A and B
importance. Since then man has been
showing interest in the medicinal use of The screening of leaves at all three
plants. As new discovery and inventions stages (green, yellow and brown) show
came up, technology grew up to explore the richness in vitamins like thiamine,
old ideas in a new way. riboflavin, ascorbic acid. Similarly minerals
Carica papayaL is not an exception. like calcium, magnesium, sodium,
Its leaf extract is now-a-days gaining potassium, manganese and iron were also
popularity in many aspects. Considering the detected at considerable amount. The

International Journal of Health Sciences & Research (www.ijhsr.org) 253


Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

Phytochemical analysis of the leaves hematocrit, Red blood cells, thrombocytes


showed that the leaves contained saponins, and total protein contents (Halim et al2011.)
cardiac glycosides, and alkaloids (Ayoola A study has reported membrane
PB 2010). Carica papaya leaves contain stabilizing properties of Carica papayaL.
various phyto-constituents like saponins, leaf extracts even in lower concentration in
tannins, cardiac glycosides and alkaloids. vitro studies by inhibiting heat-induced and
The alkaloids present include carpaine, hypotonicity-induced hemolysis of
pseudo-carpaine and dehydro-carpaine I and erythrocytes obtained from both healthy
II (Patil S 2013). The fruit, seed and leaf individuals and individuals with dengue
were found to be rich in proteins. All the infection. Thus, the extracts are likely to
three parts were rich not only in minerals possess membrane-stabilizing properties
(calcium, magnesium, phosphorous, and and protect blood cells against stress-
iron) but also vitamins (vitamin C, niacin, induced destruction. This property may be
thiamine, riboflavin, and beta-carotene) useful in patients with dengue infection
(Godson EN2012). where the leaf extracts could possibly
Proximate analysis of the plants prevent platelet lysis. The theory postulates
showed that all the macronutrients were that this effect could be due to the presence
present, with carbohydrate being the most of flavonoids and other phenolic compounds
abundant in Carica papaya. Vitamins A, C, in the papaya leaves (Mathews A
B12 and Folic acid were present but are 2016).Papaya leaf extracts possess
void of Vitamin E. Papaya leaf extract biological membrane stabilization properties
contained only magnesium, the other metals preventing stress-induced destruction of the
tested were not detected (Begum M plasma membrane. Flavonoids and other
2014).The study of the Carica papaya phenolic compounds present in papaya leaf
leaves of semi-arid zone of Kutch region extracts were responsible for the observed
showed that it is rich in elements like membrane stabilizing property and thereby
calcium, magnesium, sodium, potassium, prevent the internal bleeding in the blood
chlorine, and lithium with comparison to vessels (Ranasinghe et al 2012).
other reported analysis of other regions. Vinca-alkaloids have been proven
This is in contradiction to above analysis effective against anti-platelet macrophages
due to nature of soil here (Vyas S 2014). in patients suffering from Idiopathic
Carica papaya leaf has been used Thrombocytopenic Purpura (ITP) (Ahn Y et
traditionally in the treatment of Dengue. al1998). Vitamin C may act as anti-oxidant
The leaf has been investigated for its to scavenge the oxygen radical (superoxide,
potential against DF. Anti-dengue virus hydroxyl, peroxyl) sulphur radicals and
activity, papaya leaf extract being a strong nitrogen - oxygen radicals (Sebastian et
stimulant of IL-6 and SCF might help to al2003). Magnesium ions in papaya leaves
improve thrombocytopenic conditions of the are found to improve erythrocyte hydration.
infected patients. Papaya leaves extract, rich Sodium ions help in maintaining electrolyte
in papain, was shown to improve balance and prevent hypo-natremia during
thrombocyte (platelet) count in dengue dengue infection (Jutrat et al2005). Calcium
patients (Aziz Jet al, 2015). The qualitative ions helps in the proliferation of lymphocyte
phytochemical analysis reveals that except cells, play key role in platelet aggregation
steroids and tannins all the phytochemical when combine with Vitamin D and prevents
including glycosides, alkaloids, saponins, thrombocytopenia (Cabrera-Cortina et al,
flavonoids, proteins are present in leaf of 2008). Vitamin B12 helps in maintaining the
papaya (Sherwani SK 2014). Papaya leaf normal count of thrombocytes and helps to
contains anti-oxidant vitamins and minerals fight against thrombocytopenia (Betty et al,
which may help to increase the hemoglobin, 2009). A recent study showed that
flavonoids, present in Carica papaya

International Journal of Health Sciences & Research (www.ijhsr.org) 254


Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

inhibits NS2B-NS3 protease and thereby suitable platelet count in mammals, in


prevent the DEN-2 Virus assembly particular during chemotherapy
(Senthilvel et al 2013; Subenthiran S et al, (http://www.google.com/patents/WO201102
2013 investigated the platelet increasing 8098A1). Enzyme papain and chymo-
property of Carica papaya leaves juice papain activate enzyme caspase (protease),
(CPLJ) in patients with dengue fever (DF). which in turn regulates pro-platelet, thus
This was clearly demonstrated by the this protein digestion increases platelet
significant increase in the mean platelet count. Tannins are large poly-phenolic
count after 40 hours and 48 hours of juice compounds containing sufficient hydroxyls
consumption. A suspension of powdered and other groups (such as carboxyl) to form
crude Carica papaya leaves in palm oil strong complexes with proteins and other
when administered to experimental animal macromolecules. On retraction events to
show the consistent rise of the thrombocyte release individual pro-platelets. The
counts in the treated group. The effect of complex – forming properties of tannins
papaya leaf formulations was higher and may contribute to the positive effects on
significant indicating a potential in the platelet count in blood. Papaya leaf juice
treatment of thrombocytopenic purpura prevents reversible thrombocytopenia
(Kathiresan et al 2009). The results of induced by carboplatin in a dose dependent
experiments of Zunjar V et al, 2016 manner. There is no difference between
suggested that Carica papaya leaves male and female plants in this respect (Tahir
decoction has very good anti- N et al2014).
thrombocytopenic properties. It is predicted The RNA was extracted from the
in the study that anti-thrombocytopenic blood of the experimental patients and gene
property of Carica papaya leaves may be expression of two genes, namely, the ALOX
due to carpaine. Additionally, no visible 12 and the PTAFR were conducted. There
toxicity or any adverse effect was observed was a 15-fold increase in the ALOX 12 gene
in animals treated with carpaine. activity among the patients which is known
The study reiterated that the mature to be associated with increased
leaf Carica papaya concentrate (MLCC), megakaryocyte production. Also ALOX 12
irrespective of whether obtained from is linked with conversion of the
mature or immature leaves of Carica megakaryocyte to platelets through 12-
papaya, has the potential to be developed as HETE mediated pathway which in turn
a plant based therapeutic agent for leads to increased platelet production. The
thrombocytopenia. It was also observed that alkaloids present include carpaine, pseudo-
the MLCC prepared by the mature leaves of carpaine and dehydro-carpaine I and II.
Carica papaya can be orally administered, These constituents can act on the bone
is safe (non-toxic) for a period of 3 days and marrow, prevent its destruction and enhance
is orally active, effectively increasing its ability to produce platelets. Moreover, it
platelet, WBC and RBC counts in normal can also prevent platelet destruction in the
(non-thrombocytopenic) and blood and thereby increase the life of the
thrombocytopenic rats (Gamulle A 2012). platelet in circulation. (Patil S, 2013).
Multiple mechanisms mediated by
many active principles in papaya leaf juice CONCLUSION
may be responsible for increasing the blood Papaya leaf has a great potential to
cell counts. Papaya leaves contain active fight against dengue. The review implies
compounds papain, chymopapain, alkaloids, that major research is done on crude extract
flavonoids, benzyl-glucos-inolate and of various solvents basically water and
tannins. These compounds stimulate and / or methanol. Various researches suggest
improve the megakaryocytes to produce various components in the papaya leaf that
sufficient numbers of platelets to maintain a promote the rise of platelet count. The

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Vol.8; Issue: 1; January 2018
Mrinal Saraf et al. Dengue Fever: Role of Carica Papaya L.

probable active components include  Global strategy for dengue prevention and
enzymes such aspapain, chymopapain, control(WHO2012)
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carpaine and dehydro-carpaine I and II, and chikungunya in India. WHO South-East
flavonoids, benzyl-glucos-inolate and Asia J Public Health; 3(1): 22–27.
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Yet no firm composition responsible to
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exact composition of bio-components pharmacological properties of papaya
responsible to raise the platelet count and (Carica papaya Linn.), Natural Product
counter act dengue. Radiance, Vol 7 (4), pp.364-373.
The isolation and purification of the  Patil S, Shetty S, Bhide R and Narayanan S
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in disease such as dengue. There is also a murine model Asian Pacific Journal of
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How to cite this article: Saraf M, Kavimandan B. Dengue fever: role of carica papaya L. Int J
Health Sci Res. 2018; 8(1):249-258.

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