A REPORT ON CARICA PAPAYA

Submitted in partial fulfillment for award of the degree of

BACHELOR OF PHARMACY

SUBMITTED BY

ADITYA NARAYAN SAMAL

Regd No: 2003251029

Under the guidance of

MR. NILURAM PARIDA
Asst. Professor, Dept. of Chemistry

KANAK MANJARI INSTITUTE OF PHARMACEUTICAL SCIENCES, CHHEND,

ROURKELA

AFFILIATED TO

BIJU PATNAIK UNIVERSITY OF TECHNOLOGY, ROURKELA, ODISHA

KANAK MANJARI INSTITUTE OF PHARMACEUTICAL SCIENCES,ROURKELA,
ODISHA

CERTIFICATE

This is to certify that the project entitled “CARICA PAPAYA” is a bonafide research done by
“ADITYA NARAYAN SAMAL”, Regd. No- 2003251029, B.Pharm, 7th Sem in a partial
fulfillment for the award of degree of “Bachelor of Pharmacy” . The work has been carried out at
KANAK MANJARI INSTITUTE OF PHARMACEUTICAL SCIENCES ,RORKELA, ODISHA
under the guidance of Mr. NILURAM PARIDA Asst. Prof, Department of Chemistry, Kanak
Manjari Institute of Pharmaceutical Sciences, Rourkela.

Prof. (Dr.) Biswaranjan Behera

Principal
Kanak Manjari Institute of
Pharmaceutical Sciences, Rourkela

DATE:
PLACE: ROURKELA
 KANAK MANJARI INSTITUTE OF PHARMACEUTICAL SCIENCES, CHHEND,
ROURKELA

CERTIFICATE

This project work entitled “CARICA PAPAYA” is a bonafide research done by “ADITYA
NARAYAN SAMAL”, Regd. No- 2003251029, B.Pharm, 7th Sem in a partial fulfillment for
the award of degree of “Bachelor of Pharmacy” . The work has been carried out at KANAK
MANJARI INSTITUTE OF PHARMACEUTICAL SCIENCES ,RORKELA, ODISHA under the
guidance of Mr. NILURAM PARIDA Asst. Prof, Department of Chemistry, Kanak Manjari
Institute of Pharmaceutical Sciences, Rourkela

MR. NILURAM PARIDA

Asst. Professor Department of Chemistry

Kanak Manjari Institute of Pharmaceutical Sciences,

Rourkela

DATE:

Place: Rourkela
 KANAK MANJARI INSTITUTE OF PHARMACEUTICAL SCIENCES,
ROURKELA,ODISHA

DECLARATION

I hereby declare that the project work entitled “CARICA PAPAYA” is a bonafide research
work done by ADITYA NARAYAN SAMAL in partial fulfillment for the award of
degree of “Bachelor of Pharmacy”. The work has been carried out KANAK MANJARI
INSTITUTE OF PHARMACEUTICAL SCIENCES, ROURKELA,ODISHA under the
noble guidance of Mr. NILURAM PARIDA, Asst. Prof, Department of Chemistry,
Kanak Manjari Institute of Pharmaceutical Sciences, Rourkela.

ADITYA NARAYAN SAMAL

Regd. No. 2003251029

Kanak Manjari Institute of

Pharmacutical Sciences,Rourkela
 ACKNOWLEDGEMENT

I wish to place my record my indebtedness to Mr. Nilaram Parida Asst. Prof. Department Of
Chemistry, KMIPS Rourkela for her sustained co-operation, interest and encouragement
throughout this project work

I express my deep sense of gratitude and indebtedness to our Principal Prof. (Dr.) Biswa
Ranjan Behera, KMIPS Rourkela for his kind support and facilities in the for the literature
review on carica papaya

I express my sincere thanks to other faculty members of KMIPS, Rourkela for their continuous
encouragement, interest and valuable discussion during the period of project work.

I am indebted to my parents for their moral support and personal sacrifice to see mee through the
project work

Sincerely I express my deep feelings to all my friends who rendered a helping hand in the hour
of need.

I owe my soulful thanks to almighty for endowing his immense blessings that helped me to
wards the successful completion of my literature Review work

ADITYA NARAYAN SAMAL

Regd. No. 2003251029
 CONTENT

 ABSTRACT

 INTRODUCTION

 LITERATURE REVIEW

 PHYSIOLOGICAL DISORDER

 PHARMACOLOGICAL ACTIVITY

 REFERENCE
ABSTRACT

The Carica papaya L. leaf is gaining interest is a potential therapeutic agent for alleviating
dengue- and non-dengue-associated thrombocytopenia. In that regard, safety considerations are
as important as efficacy potential. The safety evaluation of botanical products for human use is
complicated by variable formulations, complex phytochemical composition, and extrinsic
toxicants. This review aimed to systematically collate related safety clinical and preclinical data,
as well as reports on herb-drug interactions of C papaya leaf consumption. Methods. A
systematic search using predetermined keywords on electronic databases (MEDLINE, Cochrane
Library Central, LILACS, and Web of Science) and grey literature was conducted. Relevant
clinical and preclinical studies were identified, screened, and analysed to present an overall
safety profile of C papava leaf consumption. Results. A total of 41 articles were included (23
clinical, 5 ongoing trials, and 13 preclinical) for descriptive analysis on study characteristics,
adverse reactions, toxicity findings, and herb-drug interactions, from which 13 randomised
controlled and quasi experimental trials were further assessed for risk of bias and reporting
quality. Overall, C. papaya leaf consumption (in the form of juice and standardised aqueous
extract) was well tolerated by adult humans for short durations (<five days) while one
randomised controlled trial reported safe consumption of C papaya leaf standardised aqueous
extract in children (aged 1-12 years), Minor gastrointestinal side effects were most commonly
reported. There are concerns about hepatotoxicity and reproductive toxicity in long-term use,
supported by animal studies Unfavourable herb-drug interactions with metformin, glimepiride,
digoxin, ciprofloxacin, and artemisinin were accounted. Conclusion. C. papaya leaf
consumption in adults is generally safe for short-term use though cautioned in pregnancy and
people with liver impairment. It has potential herb-drug interactions with oral hypoglycaemic
agents, p-glycoprotein substrates, and antibiotics with cation chelating properties.
INTRODUCTION

Carica papaya L. is a common medicinal plant used in folk medicine. Traditionally, the leaves of
C papa, in decoction or infusion form, are consumed orally to reduce blood pressure and sugar
levels. The juice of C. papaya leaf is used for irregular menstruation while infusion of young leaf
is used for fever. There is long standing interest in the use of C. papaya leaf as an adjunctive
treatment to the standard care for improving platelet counts, especially in cases of dengue fever,
or more recently, in cancer treatments. Among the most important clinical findings on the
efficacy of C papaya leaf is its use in thrombocytopaenia management during dengue infection, a
common and potentially life-threatening complication during the course of infection Such
clinical benefits and potential mechanisms of action have also been investigated and backed by
preclinical data Other efficacy evidence of C. papaya leaf includes hypoglycaemic.
hypolipidaemic, gastroprotective, antimicrobial, antimalarial, and wound healing properties C
papaya leaf has been reported to contain several important phytochemical compounds including
flavonoids, alkaloids, tannins, quinones, and steroids which may collectively contribute towards
its biological activities. In addition to the abundance of phenolic compounds with antioxidant
properties identified in a methanol extract of C. papaya leaf the alkaloid carpaine was reported to
be a major contributor towards the leaf's antithrombocytopenic properties:

Apart from being efficacious, the safety assurance of a medicinal herb and its formulation are
important considerations. The World Health Organization (WHO) Global Report on Traditional
and Complementary Medicine (2019) outlined that the safety of herbal medicines is often
required to be assessed thoroughly, in most countries, under processes similar to those for
conventional medicine, including post marketing surveillance. Herbal medicines for traditional
use are also subjected to specialised regulatory requirements taking into consideration
documented scientific research on similar products that are already marketed. In general, the
toxicity of herbs is broadly categorised as intrinsic or extrinsic. Intrinsic toxicity takes into
account adverse reactions inherent to the pharmacological nature and bioactive phytochemicals
of herbs, while extrinsic toxicity refers to impurities and potential toxicants introduced externally
through agricultural practices or processing, for example, heavy-metal and pesticide
contamination. General and specific animal toxicity studies of various durations conducted with
adherence to Good Laboratory Practice are often required by regulatory agencies when
registering a herbal formulation for medicinal use. Herb-drug interaction studies, though
challenging to conduct and interpret, are also crucial components of a herb's safety profile.

As C papaya leaf consumption increasingly gains attention for therapeutic uses, it is important to
thoroughly assess its safety data, including potential herb-drug interactions. At present, there are
still insufficient focused-systematic collection and in-depth analysis on all available safety and
toxicity data pertaining to consumption of C. papaya leaf. Two systematic reviews on the clinical
efficacy and safety of C. popaya leaf were published separately in 2016 and 2019. However,
those two reviews were more focused on the meta-analysis of efficacy, accounting for the use of
C papaya leaf in dengue patients only. Furthermore, only reported adverse effects during the
trials" duration were taken into consideration. Therefore, this review aimed to systematically
search, identify, and collate all safety-related clinical data and animal toxicity studies, as well as
reports on herb-drug interactions of orally administered of C papaya leaf. Based on the findings
of two previously published systematic reviews, it was also observed that diverse formulation of
C papaya leaf were investigated. Hence, the construction of a well-rounded safety profile of C
papaya leaf, through the methodological framework of a scoping study to account for the variety
of data and flexible information sources, is most suited here. To the best of our knowledge, this
is one of the available systematically conducted comprehensive reviews on clinical safety,
toxicity and herb interaction of C.papaya leaf consumption according for both published articles
and grey literature
LITERATURE REVIEW

Maximising the potential health properties of papaya fruit and leaf eaten as a food. Abstract
presented (Oral presentation) 46th Annual AIFST Convention Yesterday, Today Tomorrow,
Brisbane, QLD, Australia, July 14-16, 2013, Program & Abstracts 42 Ikram EH. Netzel M.
Fanning K. Stanley R (2013) Phytochemicals in Australian papaya cultivars: the effect of
maturity and cooking. Abstract presented (Oral presentation) 37th Annual Scientific Meeting of
the Nutrition Society of Australia in conjunction with the Nutrition Society of New Zealand.
Brisbane, QLD, Australia, December 4-6, 2013, Australasian Medical Journal 2013, 6, 11: 605

Ikram et al. (2014) Carotenoid and polyphenol content of Carica papaya Linn cultivars, Abstract
presented (Oral presentation) AIFST Food Science Summer School 2014, St. Leo's College, The
University of Queensland, St. Lucia, QLD, Australia, February 5-7, 2014, Program & Abstracts
Ikram EH, Netzel M, Fanning K, Stanley R (2014) Phytochemicals in different plant parts of
Australian papaya cultivars. Abstract presented (Oral presentation) 29th International
Horticultural Congress, Brisbane, QLD, Australia, September 17-22, 2014, Abstract: 01452.
Ikram EH, Stanley R, Netzel M. Fanning K (2014) Maximising the potential health properties of
papaya fruit and leaf eaten as a food. Abstract presented (poster presentation finalist) at World
Food Day Poster Competition. Global Change Institute Atrium, Liniversity of Queensland, St
Lucia, Brisbane, Australia. 16 October 2014, Abstract collection. Ikram EH, Stanley R, Netzel
M. Fanning K (2014) Getting your fruits and greens from the one tree. Abstract presented (Poster
presentation) at QAAFI Annual Research Meeting (ARM), Brisbane Convention Centre,
Brisbane, Australia, 25-26 November 2014, Abstract collection

Ikram EH et al.(2016). Innovation of Nutrient dense Papaya Gummies Gold Award.

Barger et al. [1937) investigated various degradation of carpine and isolated carpamic acid
[CHNO] and the structure formula carpine [CHO] was proposed as a lactone containing 7
methyletic groups attached to a pyrrolidine nucleus.

Rapoport et al. [1953), reinvestigated this structure of carpaine and found that it has a piperidine
structure instead of the pyrrolidine.
Burdick et al. [1971]. Coke and rice accomplished the "absolute configuration of carpaine."

Eungate et al. 2010, Rivera-Pastrana et al. 2010. Yadava et al. 1990). Pred dry p reduce crop
output (Almeida. Bemards Susza Marin & Grips, 2003) Papaya is grown in y all countries of the
tropical Americas (Central and South America and the state of Healt also cultivated in India. Sri
Lanka, various Asian countries, as well as the Amilles and tropical Africa (Chan & Paull, 2008)

Brazil stands out as the world's biggest producer, supplying 25% of the world demand. foment
by Mexico at 14%, Nigeria at 11 India and Indonesia at 10% other papaya growing a include
Venezuela, China, Peru, Congo, and Ethiopis, all of which contribute less than 3% of the papaya
supply (Benassi 2010) Brazil is the world's third biggest exporter of the papsos (FAOSTAT
2010) and the principal markets for consumption are the USA and Europe . Papaya crops require
year-round labor, which has made it an excellent choice from socio-economic perspective in
countries that produce it. However, the quality of the papayas grown ca be compromised by
conditions and practices adopted during commercialization (anes stal 2010). Physiological
disorders or disturbances can at times result in restrictions against exportation of this fruit in
nature and cause production losses and, in turn, a negative financial Impact throughout the chain
of papaya production (Campostrini, Pommer, & Yemanishi. 2019% In Brazil the principal
commercial papaya varieties belong to two large groups: Solo and Teise CTrindade, Dantas,
Almeida, & Maia, 2001) The Solo varieties present a pear-shaped or oval appearance and are
characterized by their small size franging between 400 and 600 g) (Expe Yamanishi, 2001). As
the name suggests, a Solo papaya is about the right amount of fre one person. The Taiwan
varieties are plants that produce a pear oblong-shaped fruit that is larger in size (weighing
between 800 and 2000 g), with higher sugar levels, and an increased resistance during transport
(Costa & Pasova 20033 There are another genotypes of papaya with importance in the world
such as 'Maradol, originates from Coba and very cultivated in Mexico, the "Sekak (also known
as "Hong Kong) and 'Eksotika" cultivated in Malaysia, and "Khack Dum cativated in Thailand
(Chan & Paull, 2008)

Ripening of papaya fruit affects sensurial, pharmacological and nutritional quality and some
problems in pre or postharvest can be identified during ripening stage. This maniscript highlights
some important factors in the growth of this fruit and describes the principal physiological
disorders that can compromise the production and quality of the fruit.
Papaya composition: nutritional characteristics pharmacological properties and volatile
compounds

Papaya is a climacteric fruit, which grows year-round, is an elongated berry of various sizes with
a smooth thin skin and a greenish-yellow color (Calegario et al. 1992. Fagundes and Yamanisht
2001, Euggats. al. 2010). Its flesh is thick with a color ranging from yellow to red and offers a
pleasant, sweet, mellow flavor (Devitt et al. 2006. Euggate et al. 2010). The papaya tree and
green fruits produce latex, which remains isolated in lactiferous cells. When these cells rupture
coagulation occurs, and this represents an important defense mechanism of the plant against
pathogens and other harmful attacks. The latex contains a mixture of endopeptidases rich in
cysteine: papain (Mitchel Chaiken & Smith, 1970), chymopapain A and B (Watson Yamaguchi,
& Lann, 1990), endopeptidase papain III and IV (Barret and Battle, 1985. B ala 1989). Recently,
Paull et al. (2018) described the genes for these proteinases Papain, whose proteolytic action is
similar to that of pepsin and trypsin, is employed as a meat tenderizer is cooking and in
applications in the food industry (in cheeses and beers, as well as in the textile pharmaceutical,
and cosmetic industries (Su Nie. Zhu, & Chen, 2009)

The seeds of the papaya also contain a substance that reduces male fertility Monkeys, rabbies,
and rats treated with a water- or chloroform-based extract of papaya seeds exited reversible
azoospermia and reduced spermatozoid mobility symptoms, causing brief periods of sterility.
This effect is post-testicular, altering the functional capacity of the spermatozoid without
affecting the libido. This substance is non-toxic. It has been suggested that the compound
responsible for this contraceptive effect could be an alkaloid.
PHYSIOLOGICAL DISORDER

Physiological disorders of the most varied causes are common many true species (Chatenet al.
2000. Paull and Reyes 1996 Roper, 1999), and the papaya is not an exception (Kaiser et al. 1996.
Oliveira et al. 2010. Reyes et al. 1994, Schripsema et al., 2010. These disturbances are almost
always related to environmental factors (Campostrini et al. 2010, is stal 2005: Oliveira et al.,
2004, Oliveira.st.al. 2002) which, in certain cases are difficult for growers to prevent

Among the most important physiological disorders of the papaya are skin freckles pulp
Translucency, pulp softening, and hard lumps in the pulp. All of these disorders appear
seasonally whereby peak occurrences are followed by periods when the disorder is not observed,
suggesting an influence of climactic factors on their presence

Papaya skin freckles

Skin freckles are a disorder of an inorganic nature that occurs most intensely on fruit directly
exposed to solar radiation. Their case is not well-understood despise documentation of this
disorder in commercial crops since the 1960s (ishii & Holtzmann 1963). Blemishes are visible in
both unripe and ripe fruit, the freckles develop during the later stages of fruit maturation and not
seen in young fruit. This disorder occurs with minor incidence on cv. Golden of the solo group.
This disturbance appears as superficial dark brown spots on the skin of the fruit Fequently these
spots increase in size and may engulf several smaller spots forming large circular areas with a
corky aspect on the fruit skin, thus causing it to be called "frog skin or kin freckles These
discolorations are concentrated on the parts of the fruit most directly exposed to direct sunlight
and are most frequently found in the midface of the fruit.
showing standard symptoms of skin freckles. A-Photo shows the fruit surface that was directly
exposed to the sun, exhibiting an increased presence of blemishes. shows the other side of the
same fruit, which was not exposed to the sun, featuring reduced blemish incidence

Papaya pulp flesh translucency

Another disturbance known as pulp flesh translucency is characterized by a translucency of "jelly

like appearance of the mesocarp (Campostrini et al., 2010, Oliveira et al. 2004. Oliveira el al
2002. Oliveira et al. 2010. Scbriosema et al. 2010) Symptoms gradually spread from the
endocarp to the exocorp, yet show no visible outward signs of their presence. The fruit becomes
denser due to the accumulation of low quantities of water in the seed cavities, which makes the
disorder's identification easier in the packing house wash tank. Papaya pulp flesh translucency
appears from color breakers stage, until the later stages of from development while it stay in tree
and not seen in mature green fruit. Another typical characteristic of pulp flesh translucency fruit
is a kind of "detachment" of the skin and outer layer mesocarp from the rest of the pulp making it
possible to remove the skin by hand, not unlike peeling a banana. Currently, it is believed that
only cv, Golden of the Solo variety presents the pulp flesh translucency disorder.
Golden papaya fruit with symptoms of pulp flesh translucency (B) compared with a healthy fruit
(A). Lower photo shows the outer appearance of the fruit with no symptoms that distinguish it
from healthy fruit (C) and from those with flesh translucency (D).

Golden papaya fruit with pulp flesh translucency symptoms. It is possible to observe that the skin
of the fruit detaches easily from the pulp, a condition not typically found in healthy fruits
PHARMACOLOGICAL ACTIVITIES

C papaya is tremendously efficient in different types of ailment cure due to availabilty of wide
varieties of phytoconstituents in almost all parts of plant

Antioxidant activity

Free radical causes many chronic health problems. Antioxidants can help us by preventing the
formation of free radicals. Research is going on to find new sources of antioxidants of natural
origin which are safe and economically viable, According to a study hexane fraction of C
papoyar male flower shows a good antioxidant activity (IC5D-100.81 1.180). Low IC value
reflects a high antioxidant activity of fractions (Chakraborty et al., 2015, Koleva et al., 2002),
The antioxidant capacity of fruit extract in the ripening stage was determined by different
methods (Ferric reducing antioxidant power, 2.2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-
arinobis-3- ethylbenzothiazoline-6-sulfonic acid) and result showed that the antioxidant activity
papaya fruit increased in the ripening stage (Zuhair et al, 2013), Oloyede et al. (2016) reported
that the ethyl acetate extract of unripe fruit containing beta sitosterol and quercetin are
responsible for the antioxidant properties, Silver nanoparticles (Ag-NPs) synthesized from C
papaya peel extract (CPPE), and was tested for their antioxidant activity. The result revealed that
56% average inhibition for synthesized Ag-NPs and 38% for CPPE at different concentrations
and the activity is concentrations dependent on Ag-NPs (Kokila et al., 2016). One recent
research investigation reported that the antioxidant activity of methanolic extract of seeds was
determined by DPPH free radical scavenging activity (Singh et al, 2020a, Singh et al., 2020b.
Singh et al., 2020e). In another study, papaya seed extracts were used to examine the antioxidant
activity and results revealed that the highest DPPH free radical scavenging ability was found in
hexane extract and the least activity in the aqueous extract (Agada et al, 2020). Nisa et al. (2019)
study the antioxidant activity of papaya leaves with different varieties, maturity, and solvent. The
solvents used for extraction were water, methanol, and ethanol 70%. Results showed that mature
leaves extracted with water exhibited the highest antioxidant activity higher than others.
According to Shen et al. (2018), the enzyme PaMsrB3 (Plant methionine sulfoxide reductase B1)
from papaya was examined with Escherichia coli which contain MBP (Maltose binding protein)
its N at terminal protease activity helps in the digestion of MBP-tag and leads to the isolation of
recombinant PaMsB1. The purified recombinant protein PaMarB1 showed the reductase activity
against methionine sulfoxide (MetSO), Dabsyl MetSO in the presence of dithiothreitol. Various
proteins that interact with PaMari1 were obtained and identified by affinity chromatography and
LC-MS/MS. These results provide a platform to understand the defense mechanism of PaMsrB
against anti-oxidative stress Further, details of the antioxidant activities of C. papaya is
summarized in.

Insecticidal and repellent responses

The seed extract of C papaya (petroleum-ether, benzene, ethyl acetate, chloroform: methanol
(1:1 v/v) and crude extract can be useful for their larvicidal, pupicidal, adulticidal, repellent
effects and smoke toxicity against Culex quinquefasciatus, malaria and Anopheles stephensi,
respectively. The mortality rate of A. stephensi and C. quinquefascianer at 0.5% concentration is
more effective. It was found that the repellant effect against both female mosquitoes with
protection percentages 78 and 92 respectively, Protection time against biting was 4 h for C
quinquefasciates and 5 h for A. stephensi. One research study showed toxic smoke test, 186
mosquitoes of An. stephensi and 190 mosquitoes of C. quinquefasciatus, out of 200 mosquitoes,
died after 5 h of smoke, IR study provides information about the nature of the active component,
polyhydroxy aliphatic amide. One research study showed that peel and seed aqueous extract of
papaya has a larvicidal activity for delet egypt it was also found that seed extract has higher
larvicidal activity in comparison to peel extract. Perhaps, due to the presence of phytochemicals
in extract such as flavonoids tannins, and alkaloids Another study showed that leaf, bark, root,
and seeds possess insect repellent activity against Aedes aegypti. It was also found that crude
ethanol extract was much effective in controlling the vector as compared to aqueous extract
(Malathi and Va 2015). Also, it was found that puppy leaf extract has the potential to develop as
a source of natural insecticide against chikungunya (Kovendan et al. 2012a, Kovendan d 2012b).
Tilaria (Rawani et al. 2009) and malaria vector mosquito (Sesanti et al. 2014, Kovenda et al.,
2012a, Kovendan et al., 2012b). Leaf extract of papaya in ethanol has the potential to act natural
insecticides to control the population of German cockroaches which are known to resistant
against synthetic insecticides (Rahayu et al., 2020), Anaher research study revealed the toxic
effect of leaf extract against Mustard aphid which is an important insect pest of various mustard
species (Ujan et al. 2014) Papain (enzyme) found in papaya has also been reported for its
insecticidal activity (Konno et al., 2004).

Antibacterial activity

Published reports are available which showed that the various parts of papaya have significant
antimicrobial activity. Oleic acid isolated from the seed and was tested for its chemo- preventive
action on live fish which was infected with pathogenic bacteria named Klebsiella PKBSG14 and
a was found that drug bioavailability increases with an increase in oleic acid (Ghosh et al., 2017),
Research investigation was carried out to check the antimicrobial activity of fresh and dried
leaves extracts (acetone, aqueous, and ethanol) of papaya by disc diffusion method. Results
exhibited that aqueous extracts were less effective as compared to organic extracts. It was also
found that a fresh sample was more efficient against Gram-negative bacteria and the dry sample
showed great efficiency against both Gram-positive and Gram- negative bacteria (Alabi et al.,
2012), Research investigation reported that ethyl acetate chloroform, hexane, methanol, acetone,
hot water, ethanol and petroleum ether leaf extracts of papaya extract exhibited antibacterial
activity (Baskaran et al., 2012). Adejuwon et al (2011) also reported antimicrobial activity of that
methanolic and aqueous root extract papaya against seven were bacteria and four were fungi.
Anibijuwon and Udeze (2009) reported that papaya leaf extract showed antimicrobial activity
against Pseudomonas aeruginosa. The leaf extract showed superior effects against all Gram-
positive bacteria as compared to Gram-negative bacteria.

Callixte et al. (2020) also reported the antibacterial activity of papaya leaf aqueous and
methanolic extracts against Escherichia coli, Staphlyococcus aureus, and Candida albicans The
antibacterial activity of the methanolic extract was significant compared to aqueous extract.
Another report showed that methanolic seed extract was examined for the antibacterial activity
by using Agar well diffusion method. This activity was tested against S. aureus, Bacillus
subutilis E. coli, and P aeruginosa (Sahni, 2020). The maximum zone of inhibition was against
Sore 16 mm followed by aeruginosa 14 mm. Recent research investigation reported that
methanolic extract of papaya seed was tested for its antibacterial activity against E. coli,
Klebsiella pneumonia, and Pseudomonas vulgaris by using the Agar disc diffusion method. The
extract showed antimicrobial activity in the following order E coli P vulgaris K. pneumonia
(Singh et al., 2020a, Singh et al., 20206, Singh et al., 2020e). NPs prepared different plant parts
have also shown antimicrobial activity for example silver nanoparticles (Ag-NPs) were obtained
fruit extract exhibited a dose-dependent manner antibacterial activity against P. aeruginosa and S
durer (Sasirekha et al., 2018). Renganathan et al. (2019) used leaf extract for the synthesis of Ap-
NPs and these NPs performed excellent antimicrobial activity against P. aeruginosu and E coll.
Ag-NPs prepared from the peel of C papaya were tested for antimicrobial activity against two
bacterial strains E. coli and S. aureur. The zone of inhibition was greater for Gram-negative
(bacteria in comparison to Gram-positive bacteria (Balavijayalakshmi and Ramalakshmi, 2017).
Ag-NPs were fabricated from leaf extract showed antibacterial activity (Banala et al, 2015),
Kalpana et al. (2018) have also synthesized Ag NPs from leaf extract and reported their
antimicrobial activity against 5 aureus and P. aeruginosa (Kalpana et al. 2018), Jain et al. (2009)
used green un-ripened papaya fruit extract for Ag-NPs and these NPs showed antibacterial
activity against E. coli and P aeruginosa, 5.4. Antidiarrheal responses Prabhu et al. (2017)
reported that the chloroform extract (25 mg/ml.) of raw pay and acetone extract (25-0.39 mg/ml.)
of ripe C papaya had essential antidiarrheal activity against the gut pathogens. The antidiarrheal
activity of ripe C papaya extract was extensively seen against plesiomonas shigelloides with
ranges from 50 mg/ml, 0.39 mg/ml.Alkindele .et.al.(2011) reported that DAS-77 (herbal mixture
prepared dried root of with young hark of Mangifera indica) effective in the treatment of
diarrhoea. DAS-77 was tested on mice and the result showed that DAS-77 possesses
antidiarrhoeal activity In another study antafartheal activity of leaf aqueous extract of C papaya
was tested in rats model and found that extrict has good antidiarrheal activity and the extract was
observed to be safe at 200 mg/kg in the case of rats model (Zanna et al., 2017).

Wound-healing activity

Various skin disorders as well as wounds can be cured by papaya. The ethanolic papaya seed
extract was tested in Sprague-Dawley rats, for its wound-healing activity. Results showed that
the seed extract assists wound healing in rats (Nayak et al. 2012), papa loaded PVA/Gelatin
nanofibrous was prepared from leaves of C va by electrospinning process. The fabricated
nanofibers were hydrophilic and showed wound healing activity. It also exhibited strong
antibacterial activity against both S. aureus (Gram-positive) and call (Gram-negative) (Ahlawat
et al., 2019). In a research investigation, the effect of aqueous extract of the mot of C papaya on
wound healing in albino rats was checked and root extract showed wound healing activity. It was
concluded that the extract-treated wound shows remarkable wound healing activity like standard
FSC (Framycetin sulphate cream). In comparison with control (80.38%), tested animals reveal
89.40% reduction in wound part after treated by latex of C papaya (Tiwari et al., 2011). In one
research study, C. papaya stem was analyzed for its wound healing property in albino rats. Ten
albino rats were used as experimental animals in two groups. The first group of five animals was
treated with an antiseptic named Betadine, whereas other groups of five animals were treated
with ointment obtained from C. papaya. Initial and mean size of the wound every two days
interval showed no major effect. The final wound size in millimeters after fifteen days showed a
major effect. This result suggested the wound healing activity of C. papaya in albino rats
(Ancheta and Acero, 2016).

Anticancer activity

In vitro investigation of C. papaya suggested that it has anti-cancer properties. The plant contains
an enzyme, namely papain which is a constituent of papaya and very helpful in cancer treatment.
Eibrin breaks down by papain which coats the tumor cells into amino acid. The pigment copene
is found inside the papain which is highly reactive towards free radical and oxygen. Papaya also
contains isothyocynate which protects the breast, prostate, pancreas, lung. leukemia, and colon
cancer (Fauziya and Krishnamurthy, 2013). In a research study, it was revealed that the leaf
extract of C. papaya can prevent the progression of cancerous cells. Various markers such as
CA15-3 and LDH are the important biochemical parameter for the detection of cancerous cells;
and it was found that the leaf extract in a dose of 200 mg/kg body weight has a significant effect
to decrease both markers in the treatment of cancer (Gurudatta et al. 2015), Petroleum ether,
ethyl acetate, chloroform, and methanol (80%) extracts of aerial parts C. papaya were analyzed
for their anticancer effect against three types of cancer cells such as UACC62 (melanoma) TK10
(renal) and MCF7 (breast) cancer cells. It was concluded that the petroleum extract of papaya
aerial parts had a significant effect on MCF7 (breast) cancer cells (Khaled and Gerda, 2013).
One research report concluded that black seed from yellow ripe papaya has a direct effect to
reduce the growth of prostate cancer cells. Methanolic extract of black seed (ripe papaya) and
white seed (unripe papaya) was tested against the prostate cancer cell line. It has been reported
that the black seed extract is effective against prostate cancer cells whereas the white seed shows
a stimulating effect on pre-existing prostate cancer cells (Alotaibi et al., 2017). Another research
study reported that papaya leaf juice has also an anti-proliferative

BENEFICIAL ROLE OF CARICA PAPAYA

Unripe papaya has been used as a folk medicine, eg, to relieve menstrual pain, improve
ingestion, wound healing, and heart disease. An in vitro study showed that unripe Carica papaya
fruit inhibited a-amylase and a-glucosidase enzymes. In addition, the fruit extract protected Beta-
cell against oxidative stress in streptozotocin induced diabetes rats. The phytochemical analysis
of Carica papaya fruits revealed the presence of phytochemicals, including kaempferul
quercetin, and caffeic acid.

An in vivo study suggested that chloroform extract of Carica papaya leaves protected B-cells of
islet of Langerhans from oxidative stress-induced damage and promoted pancreatic (-cell
regeneration at a dose of 31 mg/kg, leading to an increase in insulin production. In addition.
Juarez-Rojop and colleagues reported that Carica papaya leaf extract stimulated the healthy -
cells to release more insulin in vivo, At concentrations of 0.75 and 1.5 g/100 ml, Carica papaya
leaf aqueous extract also demonstrated antioxidant properties vin increasing NO production,
consequently lowering ROS production, and diminishing diabetes-induced oxidative stress. As a
result, this mechanism delayed or prevented the progression to diabetic complications such as
neuropathy and nephropathy.
REFERENCES

1. G. Aravind. D. Bhowmik. S. Duraivel, and G. Harish, "Traditional and medicinal uses of

Carica papaya," Journal of Medicinal Plants Studies, vol. 1, pp. 7-15, 2013.

2. H. C. Ong, R. M. Zaki, and P. Milow, "Traditional knowledge of medicinal plants among the
Malay villagers in Kampung Mak Kemas. Terengganu, Malaysia." Studies on Ethno- Medicine,
vol. 5, no. 3, pp. 175-185, 2011.

3. H. C. Ong and J. Norzalina, "Malay berbal medicine in Gemencheh, Negri Sembilan,

Malaysia." Foterapia, vol. 70, no. 1, pp. 10-14, 1999.

4. N. Sarala and S. Paknikar, "Papaya extract to treat dengue: a novel therapeutic option Annals
of Medical and Health Sciences Research, vol. 4, no. 3, pp. 320-324. 2014.

5. D. Sundarmurthy, R. Jayanthi, and 1 Kumtegowdanahalli, "Effect of Carica papaya lear

extract on platelet count in chemotherapy-induced thrombocytopenic patients: a preliminary
study," National Journal of Physiology, Pharmacy and Pharmacology, vol. 7. P. 1, 2017.

6. S. Subenthiran, T. C. Choon, K. C. Cheong et al., "Carica papaya leaves juice significantly

accelerates the rate of increase in platelet count among patients with Dengue fever and Dengue
haemorrhagic fever," Evidence Based Complementary and Alternative Medicine, vol. 2013,
Article ID 616737, 2013 vol. 11, no. 3, pp. 480-496, 1998

7.D.J.Gubler,”Dengue and Dengue hemorrhagic fever” ,”Clinical Microbiology Reviews”, vol.3,

pp.480-496,1998,
8. V. Anjum. P. Arota, S. H. Ansari A K. Najmi, and S. Ahmad. "Antitrombocytopenic and
immunomodulatory potential of metabolically characterized aqueous extract of Corson papaya
leaves." Pharmaceutical Biology, vol. 55, no. 1, pp. 2043-2056, 2017.

9. S. Chinnappan. V.S. R. K. Tamilarasu, U. M. Krishnan, A. K. B. Pillai and S. Rajendran,

"Inhibition of platelet aggregation by the leaf extract of Carica papaya during Dengue infection:
an in vitro study, Viral Immunology, vol. 29, no. 3, pp. 164-168, 2016.

10. N. Sharma, K. P. Mishra, S. Chanda et al, Evaluation of anti-dengue activity of Carica papa
aqueous leaf extract and its role in platelet augmentation." Archives of Virology, vol. 164, no. 4,
pp. 1095-1110, 2019.

11. K. Sobia, M. Javaid, M. Ahmad et al. "Assessments of phytochemicals and hypoglycemic

activity of leaves extrates of Carica papaya in diabetic mice." International Journal of
Pharmaceutical Sciences, vol. 7, pp. 1000-1008, 2016.

12. V.Sheneni and P. Idakwoji, "In-vivo biological effects of Carica papaya leaf extracts on P-
407-induced hyperlipidemia in albino Wistar rats," Journal of Medical Sciences, vol. 6. pp.
1243-1249, 2018

13. M. Indran, A. A. Mahmood, and UR. Kuppusamy, "Protective effect of Carica papaya L leaf
extract against alcohol induced acute gastric damage and blood oxidative stress in rats," West
Indian Medical Journal, vol. 57, no. 4, pp. 323-326, 2008.

14. C. Baskaran, V. R. Bai, S. Velu, and K. Kumaran, "The efficacy of Carica papaya leaf extract
on some bacterial and a fungal strain by well diffusion method." Asian Pacific Journal of
Tropical Disease, vol. 2, pp. 8658-8662, 2012.

15. W.C. Teng, W. Chan, R. Suwanarusk et al., "In vitro antimalarial evaluations and
cytotoxicity investigations of Carica papaya leaves and carpaine, Natural Product
Communications, vol. 14, no. 1, p. 1934578X19014001 10, 2019.

16. M. Abdulla, K. Sidik, and S. Ismail, "Wound healing activity of Carica papayo L. aqueous
leaf extract in rats. International Journal of Molecular Medicine and Advance Sciences, vol. 1,
2005.
17.1.E. Juárez-Rojop, C. A. Tevilla-Zárate, D. E. Aguilar-Dominguez et al., "Phytochemical
screening and hypoglycemic activity of Carica papaya leaf in streptozotocin-induced diabetic
rats." Revista Brasileira de Farmacognosia, vol. 24, pp. 341-347, 2014.

18. N. Gogna, N. Hamid, and K. Doral, "Metabolomic profiling of the phytomedicinal

constituents of Carica papaya L. leaves and seeds by IH NMR spectroscopy and multivariate
statistical analysis," Journal of Pharmaceutical and Biomedical Analysis, vol 115, pp. 74-85,
2015.

19. A. Canini, D. Alesiani, G. D'Arcangel, and P. Tagliatesta, "Gas chromatography-mass

spectrometry analysis of phenolic compounds from Carica papovo L leaf," Journal of Food
Composition and Analysis, vol. 20, no. 7, pp. 584-590, 2007.

20. V. Zanjur, R. P. Dash, M. Jivrajani, B. Trivedi, and M. Nivsarkar, "Antithrombocytopenic

activity of carpaine and alkaloidal extract of Carica papaya Linn. leaves in busulfan induced
thrombocytopenic Wistar rats," Journal of Ethnopharmacology, vol. 181, pp. 20- 25, 2016,

21. World Health Organisation (WHO), Global Report on Traditional and Campics Medcine
2019, WHO, Geneva. Szerland, 2019.

22. Jayasinghe, Y De Mel, S. Perera, and P. Ratnaweera. Novel insights of toxicological

evaluation of herbal medicine: human-based toxicological assays" AJPP, vol. 3. PP.

23.-S. P. Bone, D. P. Singh, and M. Nivsarkar. Linderstanding the relevance of herb-drug

interaction studies with special Eseus on interplays a prerequisite for integrative medicine, Port
Biomedical Journal, vol. 4, no. 2, p. e15, 2019.

24. J. Charan, D. Saxena, J. P. Goyal, and S. Yasobant. Efficacy and safety of Carica papaya leaf
extract in the dengue: a systematic review and meta-analysis. International Journal of Applied
and Basic Medical Research, vol. 6, no. 4. pp.

25. S. Rajapakse, N. L. De Silva, P. Weeratunga, C. Rodrigo, C. Sigera, and S. D. Fernando,

"Carica pipay extract in Dengue: a systematic review and meta-analysis. BMC Complementary
and Alternative Medicine, vol. 19, no. 1, p. 265, 2019.

26. H. Arksey and L. O'Malley, Scoping studies: towards methodological framework"

International Journal of Social Research Methodology, vol. 8, m. 1, pp. 19 32, 2005,
27. D. Levac, H. Colquhoun, and K. K. O'Brien, "Scoping studies advancing the methodology,"
Implementation Science, vol. 5, no. 1, p. 69, 2010.

28. National Institute for Health Research, PROSPERO International Prospective Register of
Systematic Reviews, National Institute for Health Research, Bethesda, MD, USA. 2016 29. J. J.
Gagnier, H. Boon, P. Rochon, D. Moher, J. Barnes, and C. Bombardier, "Recommendations for
reporting randomized controlled trials of herbal interventions explanation and elaboration,
Journal of Clinical Epidemiology, vol 59, no. 11, pp. 1134-1149,2006.

View at:

30. Bahagian Dasar dan Perancangan Strategik Farmasi Kementerian Kesihatan Malaysin. "Garis
panduan menjalankan penyelidikan di bawah program perkhidmatan farmasi kementerian
Kesihatan Malaysia,"2018.

View at:

31. A. C. Tricco, E. Lillie, W. Zarin et al., "PRISMA extension for scoping reviews (PRISMA-
SCR): checklist and explanation, Annals of Internal Medicine, vol. 169, no. 7, pp. 467-473,
2018.

32. S. Hettige, "Salutary effects of Carica papaya leaf extract in Dengue fever patients-a

33. N. Ahmad, H. Fazal, M..Ayar, B. H. Abbasi, I. Mohammad, and L. Fazal, "Dengue fever
treatment with Carica papaya leaves extracts," Asian Pacific Journal of Tropical Biomedicine,
vol. 1, no. 4, pp. 330-333, 2011.

34. M. Z. K. Assir, H. Mansoor, T. Waseem, H. Ahmed, S. Bukhari, and J. Akram, "Effect of

Papaya leaf extract on platelet count in dengue fever a randomised controll trial(PLEAD Trial),
International Journal of Infectious Diseases, vol. 16, p e473, 2012.

35. C. P. Kala, "Leaf juice of Carica papaya L: a remedy of Dengue fever," Medicinal &
Aromatic Plants, vol. 1, pp. 1-2, 2012.