TheHerbal ExtractCompany of AustraliaVersion: mar1s6/01

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FamilyCaricaceae.

A small family having four genera in the world. The genus Carica is represented by four species of which Carica papaya is the most widely cultivated and best-known species.1,2

Parts UsedLeaf

DescriptionOriginating from Central and South America, paw paw is a tree-like herbaceous plant that bears highly nutritious, and delicious, fruit and is also a source of papain, a protease used for centuries to tenderise meat. Due to its edible fruits paw paw is widely cultivated in several tropical, sub-tropical and temperate regions including Australia, Brazil, China, Hawaii, Malaysia and India. Paw paw fruit is one of the most commonly consumed throughout the world constituting a rich nutritional source of fi bre, minerals and antioxidant nutrients. Paw paw trees can grow fi ve to 10 metres tall, with large leaves 50 to 70 cm in diameter and fruits 15 to 45 cm long and 10 to 30 cm in diameter. The plants are usually short-lived but can produce fruit for more than 20 years. The tree is frost sensitive and fast growing, producing fruits within two to three years. Paw paw has a straight trunk and lush, dark green, long, drooping leaves

that turn golden brown during autumn. Flowers emerge before the leaves in mid spring

on the previous year’s wood and may reach up to fi ve

centimetres in diameter. The fl owers form into large oval fruits that have orange or pink aromatic fl esh and many small black seeds. The paw paw has a rather complicated means of reproduction. The plants are male, hermaphrodite or female. The male trees are uncommon but sometimes occur when homeowners collect their own seeds. Hermaphrodite trees (fl owers with male and female parts) are the commercial standard, producing a pear shaped fruit. These plants are self pollinated. Paw paw plants produce natural compounds (annonaceous acetogenins) in leaf, bark and twig tissues that possess both highly anti-tumour and pesticidal properties. The high level of natural self-defence compounds in the tree makes it highly resistant to insect and disease infestation. Diff erent parts of the plant (fruits, leaves, barks, roots, fl owers, seeds and latex) as well as some of their extracts have been traditionally used worldwide in folk medicine to treat a wide range of ailments in humans. Indeed, nowadays paw paw is considered a nutraceutical plant due to its various medicinal properties.3.4.5

Traditional and Empirical UsePaw paw is also known as papaya, or papaw, and when fi rst encountered by Europeans it was nicknamed ‘tree melon’. In traditional Ayurvedic literature paw paw leaves were used for asthma, beri beri, fever, abortion, dressing wounds (fresh leaves), antibacterial activity, jaundice, gonorrhoea, urinary complaints and as a vermifuge.6

Paw paw leaves have been used to treat malaria, yellow fever, oral candidosis, dengue and anaemia. Fresh, green paw paw leaf is an antiseptic. It cleans the intestines of bacteria (only a healthy intestine is able to absorb vitamin and minerals, especially vitamin B12). Green paw paw leaf tea promotes digestion and aids in the treatment of ailments such as chronic indigestion, obesity, arteriosclerosis, high blood pressure and weakening of the heart. In some parts of Asia, the young leaves of the paw paw are steamed and eaten like spinach. The brown, dried paw paw leaf is best as a tonic and blood purifi er. The fruit, as well as all other parts of the plant, contain a milky juice in which active principles known as papain and chymopapain are present. Papain has also been used commercially in many applications including to clarify beer and de-hair animal hides before tanning. The seed is used for intestinal worms when chewed. The root is chewed and the juice swallowed for cough, bronchitis and other respiratory diseases. The unripe fruit is used as a remedy for ulcer and impotence. Chewing the seeds of ripe pawpaw fruit also helps to clear nasal congestion. The latex sap of the plant has been used

Paw Paw(Carica papaya Linn.)

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Paw Paw (Carica papaya) full monograph

on warts, freckles, boils and other skin overgrowths. The plant also has a reputation against cancer and infection in some countries.7,8,9,10

Paw paw was mentioned in the classic 1930s book A Modern Herbal, the fi rst comprehensive encyclopaedia of herbs to appear since the days of Culpeper (1600s). The author Maude Grieve said an infusion of the leaves and fruit makes the toughest meat tender when rubbed with it or cooked in the leaves. If chicken and pigs are fed the leaves it will make their fl esh tender. She said the leaves have also been used as a substitute for soap. The fresh leaves were used to dress foul wounds.11

ConstituentsEnzyme (papain), volatile oil, terpenoids, folic acid, vitamins B1, B2, B12, A, C and E, alkaloids (carpaine and pseudocarpaine), saponins, tannins, anthraquinones, cardiac glycosides, glucosinolate (benzylglucosinolate), choline, fl avonoids and the minerals calcium, magnesium, sodium, potassium, manganese and iron.12,13,14,15

ActionsAnthelmintic, antiparasitic, antibacterial, antiviral, antifungal, anti-infl ammatory, digestive stimulant, antihypertensive.

Pharmacological ActivityAnthelmintic and antiparasitic activityDaily consumption of paw paw leaves as greens, and as a herbal infusion, is common in some parts of Indonesia as a means for preventing malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. Antiplasmodial (inhibits the growth and pathogenicity of the plasmodium. Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria) activity of the leaf extracts, and of the main alkaloid carpaine, were confi rmed in a 2014 study. A quantitative assay for determination of carpaine in paw paw leaves was developed and validated. A total of 29 paw paw leaf samples were analysed and carpaine concentration in dry leaves was found to range from 0.02 to 0.31%. No obvious dependence on geographic origin and leaf maturity was observed. The study found that the antiplasmodial activity of paw paw leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo mouse model. Further investigations are needed to clarify the divergence between the negative in vivo results for carpaine and previous reports of in vivo activity with paw paw leaf extracts.16,17

A recent study has found that the leaf and stem of paw paw has signifi cant anthelmintic activity and could

be a potent drug due to cost benefi ts and easy availability. The research was

conducted using the

Indian adult earth worm (Pheretima posthuma) as a test worm. Various concentrations (5%, 2.5%, 1%) were in vitro tested using diff erent extracts (eg. hydroalcoholic, chloroform) and the results of time for paralysis, and time of death, were recorded. The shortest time for paralysis was in 5% concentration while the time for paralysis and death increased by 2.5% and 1% respectively compared to standard drug Albendazole.18

Antiviral and antibacterial Dengue is a viral disease that today aff ects a vast number of people in more than 125 countries and is responsible for a sizable number of deaths. In the absence of an eff ective antiviral drug to treat the disease various treatments are being investigated. Studies have indicated that the juice of the leaves of the paw paw plant could help to increase the platelet levels in these patients. A 2014 review describes some of the published studies on this topic. The authors concluded that from the various reports published in scientifi c literature, it appears that paw paw leaf extract does have benefi cial properties in dengue. It has been shown to bring about a rapid increase in platelet count. This could be possibly attributed to its membrane-stabilising property. The fl avonoids and other phenols present in the extract have been suggested to provide the benefi cial eff ects.19 One study found that the leaves of paw paw are rich in several minerals. The researchers suggested that these minerals may balance the mineral defi ciency caused by the virus and strengthen the immune cells against it. In addition to its eff ect against the virus, paw paw also appears to be eff ective against the Aedes mosquito. Thus, if proved to be eff ective, this plant could control dengue at two levels, at the level of transmission as well at the host level. Paw paw extract no doubt off ers a cheap and possibly eff ective treatment for dengue however, currently, it is also necessary not to rely entirely on the leaf extract and ignore standard treatment for dengue until the benefi ts are established. Large scale randomised clinical trials in dengue-confi rmed patients is necessary to establish their usefulness.20

Paw paw possibly brings about its eff ect in dengue by treating the thrombocytopenia associated with the condition. A 2012 study has reported membrane stabilising properties of paw paw leaf extracts in in vitro studies. The study found that paw paw leaf extracts inhibited heat-induced and hypotonicity-induced hemolysis of erythrocytes obtained from both healthy individuals and individuals with dengue infection; the eff ect was observed at the lower concentrations of the extracts. Thus, the extracts are likely to possess membrane-stabilising properties and protect blood cells against stress-induced destruction. This property may be useful in patients with dengue infection where the leaf extracts could possibly prevent platelet lysis. The authors postulate that this eff ect could be due to the presence of fl avonoids and other phenolic compounds in the paw paw leaves.21

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Paw Paw (Carica papaya) full monograph

Mature leaves of paw paw are widely used to treat malaria in several African countries. A study examined the antiplasmodial activity of paw paw leaf extract and/or artesunic acid (from Artemisia species) in Plasmodium berghei-infected mice. The combination of 50 mg/kg of paw paw extract and 15 mg/kg of artesunic acid produced a signifi cant reduction of parasitemia (81.25%), compared to 50 mg/kg paw paw extract alone (37.7%). Although pawpaw alone was found to have a very good activity, its combination with artesunic acid is antagonistic. Combinations of artemisinins and paw paw show promise for combination therapy development.22

A study examined the properties of paw paw leaf extract and the bacterial insecticide, spinosad, on larvicidal and pupicidal activity against the Aedes aegypti (a species of mosquito), which transmits the Chikungunya virus. The plant extract showed larvicidal and pupicidal eff ects after 24 hours of exposure, however, the highest larval and pupal mortality was found in the leaf extract of methanol paw paw. No mortality was observed in the control. The results show that the leaf extract of paw paw and bacterial insecticide, spinosad, display promising larvicidal and pupicidal properties.23

Methanol extracts of plant parts commonly used in Cameroon for the treatment of typhoid fever were tested for antibacterial activity against diff erent Salmonella species. The formulations included three with paw paw extracts. Formulation A comprised Cymbogogon citratus leaves, paw paw leaves and Zea mays silk. Formulation B comprised paw paw roots, Mangifera indica leaves, Citrus limon fruit and Carica citratus leaves. Paw paw leaves on their own were also examined. Antimicrobial activity was tested and, generally, Formulation A elicited inhibitory activity at a lower range of 0.02 to 0.06 mg/ml. Similarly, Formulation B elicited bacterial activity at the lowest range of 0.06 to 0.25 mg/ml. Salmonella paratyphi was most sensitive to the formulations while Salmonella typhimurium was the least sensitive.24

Another study found that ripe and unripe paw paw fruits and seeds exhibited signifi cant antibacterial activity against Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa and Shigella. However in this study the leaves produced very little antibacterial activity.25

Antifungal activityThe bioactive compounds from paw paw leaves and seeds of discarded ripe and unripe fruit were examined for antifungal activities. Analysis of the leaf extract with phytochemical tests showed the presence of alkaloids, fl avonoids and terpenes. Antifungal eff ectiveness was determined by challenging the extracts against three

phytopathogenic fungi: Rhizopus stolonifer, Fusarium spp. and Colletotrichum gloeosporioides. The

leaf extract exhibited the broadest action and showed good antifungal

properties.26

Digestive activityPaw paw leaves contain carpaine, a substance which kills microorganisms that often interfere with the digestive function.27

Anti-infl ammatory activityThe anti-infl ammatory activity of an ethanolic extract of paw paw leaves was investigated in rats and compared to a control group receiving indomethacin. The ulcerogenic activity of the extract was also investigated. The results show that the extracts signifi cantly reduced paw oedema and the amount of granuloma formed. Likewise, in the formaldehyde arthritis model, the extracts signifi cantly reduced the persistent oedema from the fourth day to the 10th day of the investigation. The results confi rmed the anti-infl ammatory actions of paw paw. The extracts produced slight mucosal irritation at high doses.28

Haematological activityThe seed, leaf and pulp extracts of paw paw were examined for bioactive compounds and also to investigate their eff ect on the haematology in rats. Results show that the phytochemicals found in seed, leaf and pulp were almost the same but in varying proportions. The study also revealed that there were signifi cant eff ects of the extracts on the haematology of the treated rats specifi cally through enhancing the production of selected blood parameters in a dose dependent fashion.29

Paw paw and Parquetina nigrescens have been used traditionally for the management of sickle cell anemia. A study was carried out to screen the leaf extracts of these herbs for possible antioxidant phytochemicals, nutrient content and amino acid composition. The screening confi rmed the presence of folic acid, vitamin B12, alkaloids, saponins, glycosides, tannins and anthraquinones. Some of the previously established anti-sickling amino acids were also present in the plants. Cyanogenic glycosides were absent from both plant extracts, indicative of the non-toxic eff ects of these plants when taken orally. The results suggest that the previously reported anti-sickling properties of these herbs may be due to antioxidant and nutrient composition.30

Antioxidant activityThe ethanol extract of paw paw showed strong antioxidant properties against both hydrogen peroxide and superoxide anion in a 2014 study investigating the antioxidant capacities and anti-infl ammatory activities of ethanol extracts of leaves of Cassia alata, Eleusine indica, Carica papaya, Eremomastax speciosa and the stem bark of Polyscias fulva, collected in Cameroon. The authors concluded that these properties may contribute to the value of these plants in traditional medicine, and in general medical practice.31

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The eff ects of aqueous extracts of paw paw leaf were examined in alcohol induced acute gastric damage and the immediate blood oxidative stress level in rats. The results showed that gastric ulcer index was signifi cantly reduced in rats pre-treated with paw paw leaf extract as compared with alcohol treated controls and another assay showed strong antioxidant actions. The acute alcohol induced damage was refl ected in the alterations of blood oxidative indices and the paw paw extract off ered some protection via reduced plasma lipid peroxidation level and increased erythrocyte glutathione peroxidase activity. Paw paw leaf may potentially serve as a good therapeutic agent for protection against gastric ulcer and oxidative stress.32

Antidiabetic activityA study examined the antidiabetic eff ect of the ethanol extracts of paw paw on streptozotocin-induced diabetic mice. While there was no signifi cant diff erence in the body weight of the treated groups when compared to diabetic control, there was signifi cant decrease in the blood glucose level of the plant-treated groups. Histologically the pancreas of the treated groups indicated signifi cant regeneration of the β-cells when compared to the diabetic control. The liver and kidney tissues of the treated groups also showed benefi cial eff ects.33

The ethanolic leaf extract of paw paw at the dose 5.0 mg/kg produced signifi cant blood sugar level reduction with no signifi cant eff ects at the higher dose of 10mg/kg. The extract delayed the onset of hypoglycemic activity of glimepiride and increased the hypoglycemic eff ect of metformin with the variables interacting diff erently for each drug-extract combinations.34

Anticancer activityIncreasing anecdotal reports of paw paw’s eff ects in cancer treatment and prevention, with many successful cases, have warranted that these pharmacological properties be scientifi cally validated. A 2014 study found that no clinical or animal cancer studies were identifi ed and only seven in vitro cell-culture-based studies were reported; these indicate that paw paw extracts may alter the growth of several types of cancer cell lines. Many studies focused on specifi c compounds in paw paw and reported bioactivity including anticancer eff ects.35

There have been anecdotes of patients with advanced cancers achieving remission following consumption of tea extract made from paw paw leaves. However the precise cellular mechanism of action of paw paw tea extracts remains unclear. Since paw paw leaf extract can mediate a T helper cell 1 type shift in the human immune system, a recent in vitro study suggested that it may potentially

provide the means for the treatment and prevention of selected human diseases such as cancer, various

allergic disorders and may also serve as an immunoadjuvant for vaccine

therapy. The eff ects of aqueous-extracted paw paw leaf fraction on the growth of various tumour cell lines and on the anti-tumour eff ect of human lymphocytes was examined. Signifi cant growth inhibitory activity of the extract was shown on tumour cell lines. The production of interleukins IL-2 and IL-4 was reduced following the addition of paw paw extract, whereas that of IL-12p40, IL-12p70, interferon and tumor necrosis factor-alpha was enhanced without growth inhibition. Moreover, the expression of 23 immunomodulatory genes was enhanced by the addition of paw paw extract and may serve as index markers of the immunomodulatory eff ects of paw paw extract.36

Antihypertensive activityThe positive results of a 2014 study are the fi rst step into the development of a new phytotherapeutic product which could be used in the treatment of hypertension. The aims of this study were to evaluate the antihypertensive eff ects of the standardised methanolic extract of paw paw, its angiotensin converting enzyme inhibitory eff ects in vivo, its eff ect on the barorefl ex and serum angiotensin converting enzyme activity, and its chemical composition. The methanolic extract of paw paw elicited angiotensin converting enzyme inhibitory activity. The antihypertensive eff ects elicited were similar to those of enalapril, and the barorefl ex sensitivity was normalised in treated spontaneously hypertensive rats. Plasma angiotensin converting enzyme activity and cardiac hypertrophy were also reduced to levels comparable to the enalapril-treated group.37

Indications• Viral, bacterial and fungal infections• Wounds and skin infections, acne • Poor digestion• Possible use in diabetes, hypertension and cancers

ToxicityNone known.

Use in PregnancySafety during pregnancy and lactation has not been established. In the absence of suffi cient data, the use during pregnancy and lactation is not recommended. Consumption of the ripe fruit is safe. The unripe fruit, and an infusion of the leaves, was traditionally used as an abortifacient, or contraceptive, in parts of the Indian continent.39

ContraindicationsAllergies and reactions to the plant pollen can occur rarely and the latex sap from the fresh plant may cause irritation on sensitive skins.

Drug InteractionsControlled studies are not available.

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Administration and DosageLiquid extract 1:1 30% alcohol: 15 to 30 mL weekly 40

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3. Ayoola PB, Adeyeye A. Phytochemical and Nutrient Evaluation of Carica Papaya (Pawpaw) Leaves. IJRRAS. 2010 Dec; 5(3): 325-8.

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5. Rodrigues M, Alves G, Francisco J, Fortuna A, Falcão A. Herb-drug pharmacokinetic interaction between carica papaya extract and amiodarone in rats. J Pharm Pharm Sci. 2014;17(3):302-15.

6. Vij T, Prashar Y. A review on medicinal properties of Carica papaya Linn. Asian Pacifi c Journal of Tropical Disease. 2015 Jan; 5(1):1–6. DOI: 10.1016/S2222-1808(14)60617-4

7. Sagnia B, Fedeli D, Casetti R, Montesano C, Falcioni G, Colizzi V. Antioxidant and anti-infl ammatory activities of extracts from Cassia alata, Eleusine indica, Eremomastax speciosa, Carica papaya and Polyscias fulva medicinal plants collected in Cameroon. PLoS One. 2014 Aug 4;9(8):e103999. doi: 10.1371/journal.pone.0103999. eCollection 2014.

8. Ayoola PB, Adeyeye A. Phytochemical and Nutrient Evaluation of Carica Papaya (Pawpaw) Leaves. IJRRAS. 2010 Dec; 5(3): 325-8.

9. Aravind G, Debjit B, Duraivel S, Harish, G Traditional and Medicinal Uses of Carica papaya. Journal of Medicinal Plants Studies. 2013;1(1):7-15.

10. Morton JF. Papaya. In: Fruits of warm climates. Miami: Julia F. Morton; 1987. p.336–346.

11. Grieve MA. Modern Herbal. Surrey: Merchant; 1973. p. 608.12. Ogan AU. The basic constituents of the leaves of Carica papaya.

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Oyeniyi B, Dokai PN, et al. Phytochemical and antioxidant nutrient constituents of Carica papaya and Parquetina nigrescens extracts. Scientifi c Research and Essays. 2010 Aug;5(16):2201-2205.

14. Ayoola PB, Adeyeye A. Phytochemical and Nutrient Evaluation of Carica Papaya (Pawpaw) Leaves. IJRRAS. 2010 Dec; 5(3): 325-8.

15. Seigler DS, Pauli GF, Nahrstedt A, Leen R. Cyanogenic allosides and glucosides from Passifl ora edulis and Carica papaya. Phytochemistry. 2002 Aug;60(8):873-82.

16. Julianti T, Oufi r M, Hamburger M. Quantifi cation of the antiplasmodial alkaloid carpaine in papaya (Carica papaya) leaves. Planta Med. 2014 Aug;80(13):1138-42. doi: 10.1055/s-0034-1382948. Epub 2014 Aug 25.

17. Julianti T, De Mieri M, Zimmermann S, Ebrahimi SN, Kaiser M, Neuburger M, et al. HPLC-based activity profi ling for antiplasmodial compounds in the traditional Indonesian medicinal plant Carica papaya L. J Ethnopharmacol. 2014 Aug 8;155(1):426-34. doi: 10.1016/j.jep.2014.05.050. Epub 2014 Jun 2.

18. Deb Roy S, Goswami R, Das S, Shil D, Baniya R, Haldar S. Pharmacognostic Evaluation and Anthelmintic Activity of Leaf and Stem Extract of Carica papaya. Journal of Pharmacy Research 2012;5(9):4763-4766.

19. Senthilvel P, Lavanya P, Kumar KM, Swetha R, Anitha P, Bag S, et al. Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly. Bioinformation. 2013 Nov 11;9(18):889-95. doi: 10.6026/97320630009889. eCollection 2013.

20. Sarala N, Paknikar S. Papaya extract to treat dengue: a novel therapeutic option? Ann Med Health Sci Res. 2014 May;4(3):320-4.

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21. Ranasinghe P, Ranasinghe P, Abeysekera WP, Premakumara GA, Perera YS, Gurugama P, et al. In vitro erythrocyte membrane stabilization properties of Carica papaya L. leaf extracts. Pharmacognosy Res. 2012 Oct;4(4):196-202. doi: 10.4103/0974-8490.102261.

22. Onaku LO, Attama AA, Okore VC, Tijani AY, Ngene AA, Esimone CO. Antagonistic antimalarial properties of pawpaw leaf aqueous extract in combination with artesunic acid in Plasmodium berghei-infected mice. J Vector Borne Dis. 2011 Jun;48(2):96-100.

23. Kovendan K, Murugan K, Naresh Kumar A, Vincent S, Hwang JS. Bioeffi cacy of larvicdial and pupicidal properties of Carica papaya (Caricaceae) leaf extract and bacterial insecticide, spinosad, against chikungunya vector, Aedes aegypti (Diptera: Culicidae).Parasitol Res. 2012 Feb;110(2):669-78. doi: 10.1007/s00436-011-2540-z. Epub 2011 Jul 13.

24. Nkuo-Akenji T, Ndip R, McThomas A, Fru EC. Anti-Salmonella activity of medicinal plants from Cameroon. Cent Afr J Med. 2001 Jun;47(6):155-8.

25. Emeruwa AC. Antibacterial substance from Carica papaya fruit extract. J Nat Prod. 1982 Mar-Apr;45(2):123-7.

26. Chávez-Quintal P, González-Flores T, Rodríguez-Buenfi l I, Gallegos-Tintoré S. Antifungal Activity in Ethanolic Extracts of Carica papaya L. cv. Maradol Leaves and Seeds. Indian J Microbiol. 2011 Jan;51(1):54-60.

27. Aravind G, Debjit B, Duraivel S, Harish, G Traditional and Medicinal Uses of Carica papaya. Journal of Medicinal Plants Studies. 2013;1(1):7-15.

28. Owoyele BV, Adebukola OM, Funmilayo AA, Soladoye AO. Anti-infl ammatory activities of ethanolic extract of Carica papaya leaves. Infl ammopharmacology. 2008 Aug;16(4):168-73.

29. Ikpeme EV, Ekaluo UB, Kooff reh ME, Udensi O. Phytochemistry and heamatological potential of ethanol seed leaf and pulp extracts of Carica papaya (Linn.). Pak J Biol Sci. 2011 Mar 15;14(6):408-11.

30. Imaga NA, Gbenle GO, Okochi VI, Tomi Duro-Emmanuel SA, Oyeniyi B, Dokai PN, et al. Phytochemical and antioxidant nutrient constituents of Carica papaya and Parquetina nigrescens extracts. Scientifi c Research and Essays. 2010 Aug;5(16):2201-2205.

31. Sagnia B, Fedeli D, Casetti R, Montesano C, Falcioni G, Colizzi V. Antioxidant and anti-infl ammatory activities of extracts from Cassia alata, Eleusine indica, Eremomastax speciosa, Carica papaya and Polyscias fulva medicinal plants collected in Cameroon. PLoS One. 2014 Aug 4;9(8):e103999. doi: 10.1371/journal.pone.0103999. eCollection 2014.

32. Indran M, Mahmood AA, Kuppusamy UR. Protective eff ect of Carica papaya L leaf extract against alcohol induced acute gastric damage and blood oxidative stress in rats. West Indian Med J. 2008 Sep;57(4):323-6.

33. Sasidharan S, Sumathi V, Jegathambigai NR, Latha LY. Antihyperglycaemic eff ects of ethanol extracts of Carica papaya and Pandanus amaryfollius leaf in streptozotocin-induced diabetic mice. Nat Prod Res. 2011 Dec;25(20):1982-7. doi: 10.1080/14786419.2010.523703. Epub 2011 Jun 27.

34. Fekeye TO, Oladipupo T, Showande O, Ogunremi Y. Eff ects of co-adminstration of extract of Carica papaya on activity of two oral hypoglycemic agents. Trop J Pharm Res 2007;6(1):671-678

35. Nguyen TT, Shaw PN, Parat MO, Hewavitharana AK. Anticancer activity of Carica papaya: a review. Mol Nutr Food Res. 2013 Jan;57(1):153-64. doi: 10.1002/mnfr.201200388. Epub 2012 Dec 5.

36. Otsuki N, Dang NH, Kumagai E, Kondo A, Iwata S, Morimoto C. Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory eff ects. J Ethnopharmacol. 2010 Feb 17;127(3):760-7. doi: 10.1016/j.jep.2009.11.024. Epub 2009 Dec 2.

37. Brasil GA, Ronchi SN, do Nascimento AM, de Lima EM, Romão W, da Costa HB, et al. Antihypertensive eff ect of Carica papaya via a reduction in ACE activity and improved barorefl ex. Planta Med. 2014 Nov;80(17):1580-7. doi: 10.1055/s-0034-1383122. Epub 2014 Oct 8.

38. Halim S, Abdullah N, Afzan A, Abdul Rashid B A, Jantan I, Ismail Z. Acute toxicity study of Carica papaya leaf extract in Sprague Dawley rats. Journal of Medicinal Plants Research. 2011 Apr; 5:1867-1872.

39. Morton, JF. Papaya. In: Fruits of warm climates. Julia F. Morton, Miami, FL 1987. p. 336–346.

40. British Parmaceutical Codex. 1934. p. 702