Carica papaya L. - GlobinMed

Home > Medicinal Herbs and Plant Database > Malaysian Herbal Monograph > Carica papaya L.

Malaysian Herbal Monograph

Betik Leaves

Carica papaya L.

Caricaceae

Figure 1 : Carica papaya. (a) Tree; (b) stem with leaves scar; (c) adaxial leaf; (d) abaxial leaf; (e) hermaphrodite flower; (f) male flowers; (g) female flower with showy stigma; (h) unripe fruits. (Photos courtesy of Institute for Medical Research, 2016)

DEFINITION

Betik leaves consist of the powder of dried leaves of Carica papaya L. (Caricaceae).

SYNONYM

Carica citriformis J.Jacq. ex Spreng., Carica hermaphrodita Blanco, Carica mamaya Vell., Carica peltata Hook. & Arn., Carica posopora L., Papaya carica Gaertn., Papaya citriformis (Jacq.) A. DC. [ 1 ].

VERNACULAR NAMES

Pawpaw, papaya (English); Betek, betik, gedang (Malay); Fan mu gua (Chinese); Pappali, pappalippal (Tamil) [ 2 ].

CHARACTER

Colour	Green to dark green [ 3 ]
Odour	Characteristic [ 3 ]
Taste	Bitter [ 3 ]

IDENTIFICATION

Plant Morphology

C. papaya is trees or shrubs, 2–10 m tall, containing white milky-juice in all parts. Stem cylindrical, usually unbranched, sometimes branched due to injury, hollow with prominent leaf scars and spongy-fibrous tissue, 10–30 cm in diameter. Leaves simple,spirally arranged, clustered near apex of trunk, with leaf blade orbicular, 25-75 cm in diameter, palmately and deeply 7-11-lobed, glabrous, prominently veined; petiole hollow, greenish or purplish-green, 40–100 cm long, 1–3 cm in diameter. Flowers male, female or hermaphrodite, axillary, and can be found on separate trees. Male flowers in panicles, 25-100 cm long, sessile; calyx cup-shaped, small ca. 2 mm long, 5-lobed; corolla tube creamy yellow, 3-6 cm long, 5-lobed, lanceolate, ca. 1.8 cm long, 0.45 cm wide; stamens 10, in 2 whorls alternating with the petal lobes with 5 longer and 5 shorter, shorter ones almost without filaments; filaments white, ca. 1.5 mm long, papilose; anthers 1.5–2 mm long, 2-celled dehiscing longitudinally, basifixed. Female flowers usually solitary or aggregated in few-flowered cymes, 3.5–5 cm long; pedicel short or nearly absent; calyx cup-shaped, 3–4 mm long, yellow green in colour; corolla of 5 almost free petals, creamy yellow, oblong or lanceolate, 5–6.2 long, 1.2–2 cm wide; ovary ovoid, 2–3 cm long, with numerous ovules; stigmas 5, fan-shaped, sessile, ca. 6 mm long. Hermaphrodite flowers of 2 main types: elongata type with short-peduncle clusters, petals 5 with partially united, stigmas fan-shaped, ovary elongate, stamens 10 in 2 clusters; pentandria type with short-peduncle clusters, petals 5 with almost free all along their length, stigmas fan-shaped, ovary ovoid oblong, stamens 5 attached by long filaments near base of ovary. Fruits fleshy berry, ovoid-oblong to nearly spherical, 10–30 cm long, yellowish or orange at maturity. Seeds numerous, wrinkled, globose, 5 mm in diameter, each enclosed in gelatinous membrane, black or greyish at maturity [ 3 , 4 , 5 , 6 ].

Microscopy

Powdered material consists of fragments of fibre; fragment of the parenchyma cells of the leaves, in surface view or elongated parenchyma showing some cells containing druses of calcium oxalate crystals; lower epidermis with stomata surrounded by anisocytic and actinocytic stomata; fragment of lamina, in transverse view, showing upper epidermis with spongy mesophyll cells; fragments of annular vessels [ 3 , 7 , 8 , 9 ].

Figure 2 : Microscopic characters of Carica papaya leaves powder of 0.355 mm size. (a) Fibre (magnification 20x); (b) elongated parenchyma cells showing druse calcium oxalate crystals (DC) (magnification 40x); (c) parenchyma cells (magnification 40x); (d) lower epidermis with anisocytic stomata (AN) and actinocytic stomata (AC) (magnification 100x); (e) fragment of mesophyll cells (M) (magnification 40x); (f) annular vessels (magnification 20x). [Scale bars: a = 100 µm; b = 50 µm; c = 10 µm; d = 50 µm; e = 50 µm; f = 20 µm]

Colour Tests

Observe colour of solution after treatment with various reagents:

Sodium chloride (10%) and ferric chloride (5%)

Green for phenolics

Thin Layer Chromatography (TLC)

Figure 3 : TLC chromatogram of rutin (S), ethanol extract of Carica papaya dried leaves powder (L) observed under (a) UV at 366 nm after derivatisation.

Test Solutions	Weigh about 5.0 g of C. papaya dried leaves powder of 0.355 mm size in a vial and add 15 mL of ethanol. Sonicate the mixture for 30 min at room temperature. Filter the solution with a filter paper and use as test solution.
Standard solution	Dissolve rutin standard (CAS no.:153-18-4) in ethanol to produce a standard concentration 0.1 mg/mL.
Stationary Phase	HPTLC Glass Silica Gel 60 F_254, 10 x 10 cm
Mobile phase	Ethyl acetate : water : formic acid : acetic acid; (50 : 13 : 5.5 : 5.5) (v/v/v/v)
Application	Rutin standard (S); 5 µL, as a band Ethanol extract of C. papaya dried leaves powder (L); 5 µL, as a band
Development distance	8 cm
Drying	Air drying
Detection	After heating at 100°C for 5 min followed by spraying with natural product reagent and polyethylene glycol 400 reagent and observe under (a) UV at 366 nm Natural Product Reagent Dissolve 1.0 g of 2-aminoethyldiphenylborinate in 200 mL of ethyl acetate Polyethylene glycol 400 (PEG 400) Dilute 10.0 g of PEG 400 in 200 mL of ethanol

High Performance Liquid Chromatography (HPLC)

Test solution

Weigh about 5.0 g of C. papaya dried leaves powder of 0.355 mm size in a vial and add 15 mL of ethanol. Sonicate the mixture for 30 min at room temperature. Filter the solution with a 0.45 µm syringe filter and use as test solution.

Standard solution

Dissolve rutin standard (CAS no.:153-18-4) in ethanol to produce a standard concentration 0.1 mg/mL.

Chromatographic system

Detector: UV 354 nm

Column: Symmetry, C18 column (5 µm, 100 Å, 3.9 x 150 mm)

Column oven temperature: 30°C

Flow rate: 1.0 mL/min

Injection volume: 10 µL

Mobile Phase (gradient mode)

Run Time (min)	A – Formic acid in water (0.1%) (%)	B – Formic acid in acetonitrile (0.1%) (%)
0	90	10
5	90	10
20	70	30
21	5	95
24	5	95
26	90	10
30	90	10

System suitability requirement

Perform at least five replicate injections of rutin solutions (0.1 mg/mL). The requirements of the system suitability parameters as follow:

Symmetry factor (A_s) is not more than 1.5.
Percentage of relative standard deviation (RSD) of the retention time (t_r) for rutin standard is not more than 2.0%.

Acceptance criteria

Retention time (t_r) of rutin in the test solution is similar to the t_r of the standard solution.
The ultraviolet (UV) spectrum of rutin in the test solution is similar to the standard solution (optional supportive data).

(a)

(b)

Figure 4 : Whole HPLC chromatogram of (a) rutin standard solution (0.1 mg/mL) at t_r= 13.416 min and (b) ethanol extract of Carica papaya dried leaves powder showing peak corresponding to rutin standard solution at t_r= 13.402 min.

(a)

(b)

Figure 5 : HPLC chromatogram highlighting the elution region of rutin in (a) rutin standard solution (0.1 mg/mL) and (b) ethanol extract of Carica papaya dried leaves powder showing peak corresponding to rutin standard solution at t_r= 13.402 min.

Figure 6 : UV spectrum of rutin standard solution (0.1 mg/mL) and ethanol extract of Carica papaya dried leaves powder.

PURITY TESTS

The purity tests are based on C. papaya dried leaves powder of 0.355 mm particle size.

Foreign Matter

Not more than 2%

Ash Contents
Total ash	Not more than 15%
Acid-insoluble ash	Not more than 2%

Loss on Drying

Not more than 8%

Extractive Values
*Water-soluble extracts*
Hot method	Not less than 33%
Cold method	Not less than 6%
*Ethanol-soluble extracts*
Hot method	Not less than 10%
Cold method	Not less than 5%

SAFETY TESTS

The safety tests are based on C. papaya dried leaves powder of 0.355 mm particle size.

Heavy Metals
Arsenic	Not more than 5.0 mg/kg
Mercury	Not more than 0.5 mg/kg
Lead	Not more than 10.0 mg/kg
Cadmium	Not more than 0.3 mg/kg

*Microbial Limits*
Total bacterial count	Not more than 10⁵ cfu/g
Total yeast and mould count	Not more than 10⁴ cfu/g
Bile-tolerant gram negative	Not more than 10⁴ cfu/g

*Specific Pathogens*
Salmonella spp.	Absent in 25 g
Escherichia coli	Absent in 1 g
Staphylococcus aureus	Absent in 1 g
Pseudomonas aeruginosa	Absent in 1 g

CHEMICAL CONSTITUENTS

Water extract of the C. papaya leaves was found to contain alkaloid carpaine [ 10 ].

Aqueous methanol extract of the C. papaya leaves was found to contain flavonoids (e.g. quercetin-3-O-rutinoside, quercetin-3-O-glucopyranuronide, quercetin-3-O-α-¹C₄-rhamnopyranoside, kaempferol, quercetin, apigenin), phenolic acids (e.g., protocatechuic acid, p-coumaric acid, 5,7-dimethoxycoumarin, caffeic acid, chlorogenic acid) and a cyanogenic glucoside [e.g. (R)-2-(β-D-glucopyranosyloxy)-2-phenylacetonitrile (prunasin)] [ 11 , 12 , 13 , 14 , 15 ].

Aqueous ethanol extract of the C. papaya leaves was found to contain alkaloids (e.g. carpaine, dehydrocarpaine I, dehydrocarpaine II) [ 16 ].

Methanol extract of the C. papaya leaves was found to contain alkaloids (e.g. choline, carpamic acid, methyl carpamate, carpaine, 6-(8-methoxy-8-oxooctyl)-2-methylpiperidin-3-yl-8-(5-hydroxy-6-methylpiperidin-2-yl)octonoate, 13,26-dimethyl-2,15-dioxa-12,25-diazatricyclo[22.2.2.211,14]triacontane-3,16-dione), flavonoids (e.g. hesperidin, rutin, naringenin kaempferol, apigenin, manghaslin, clitorin, rutin, nicotifluorin), phenolic acids (e.g. chlorogenic acid, naringenin, caffeic acid, cinnamic acid, protocatechuic acid, vanillic acid, coumaric acid), amino acids (e.g. leucine, valine, alanine, glutamic acid, glutamine, aspartic acid, cysteine, phenylalanine, serine, tyrosine, histidine, tryptophan, GABA) carbohydrates (e.g. raffinose, α-glucose, β-glucose, sucrose), organic acids (e.g. propionic acid, lactic acid, quinic acid, acetic acid, malic acid, citric acid, succinic acid, fumaric acid) and others (e.g. creatine, choline, trigonelline) [ 17 , 18 , 19 ].

Chloroform extract of the C. papaya leaves was found to contain alkaloid (e.g. carpaine) [ 17 ].

The juice of the C. papaya leaves was found to contain alkaloid (e.g. carpaine), flavonoids (e.g. manghaslin, clitorin, rutin, nicotiflorin) and organic acids (e.g. quinic acid, malic acid and malic acid derivatives caffeoyl malate, p-coumaroyl malate and feruloyl malate) [ 20 ].

The fresh leaves of C. papaya was found to contain vitamins (e.g. ascorbic acid, thiamine, riboflavin) [ 21 ].

Lyophilized of the C. papaya leaves was found to contain phenolic acid (e.g. chlorogenic acid, caffeic acid, ferulic acid), vitamin (e.g. ascorbic acid) and a carotenoid (e.g. β-carotene) [ 12 ].

C. papaya leaves was found to contain minerals (e.g. calcium, magnesium, manganese, iron, potassium, sodium) [ 21 ].

MEDICINAL USES

Uses described in folk medicine, not supported by experimental or clinical data

C. papaya leaves in decoction or infusion is consumed orally to reduce blood pressure, blood sugar level and body fat [ 22 , 23 ]. The juice of C. papaya leaves is used for irregular menstruation while infusion of young leaves is used for fever [ 24 ].

Biological and pharmacological activities supported by experimental data

Antidiabetic activity

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) administered orally to streptozotocin-induced diabetic male Wistar rats (250 – 300 g, 10-11 weeks old) for duration of 30 days significantly (p < 0.05) decreased the serum glucose level to 305.4 ± 9.68 mg/dL, 306.5 ± 8.8 mg/dL and 250 ± 10.2 mg/dL respectively compared to untreated diabetic rats (434 ± 7.49 mg/dL) [ 25 ].

Alcohol (30%) extract of C. papaya leaves (100, 200 and 400 mg/kg) was administered orally to alloxan-induced diabetic male and female Wistar albino rats (150 – 200 g) with blood glucose level more than 250 mg/dL for a duration of 21 days. The extract significantly (p < 0.01) reduced serum glucose level to 269.3 ± 4.9 mg/dL, 221.4 ± 4.3 mg/dL and 151.6 ± 2.6 mg/dL at respective concentration compared to glibenclamide (0.1 mg/kg) treated group (95.5 ± 1.4 mg/dL) [ 26 ].

Hypolipidemic activity

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) administered orally to streptozotocin-induced diabetic male Wistar rats (250 – 300 g, 10-11 weeks old) for duration of 30 days significantly (p < 0.05) decreased serum cholesterol level to 70.32 ± 3.27 mg/dL, 88.11 ± 4.56 mg/dL and 57.37 ± 2.9 mg/dL at respective concentration compared to untreated diabetic control group (75.62 ± 2.9 mg/dL) [ 25 ].

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) also significantly (p < 0.05) decreased triglyceride level to 146.5 ± 8.9 mg/dL, 144.5 ± 11.6 mg/dL and 93.71 ± 17.2 mg/dL at respective concentration compared to untreated diabetic control (232.1 ± 17.3 mg/dL) [ 25 ].

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) also showed significant (p < 0.05) decrease in liver cholesterol level to 11.23 ± 1.04 mg/g tissue, 10.54 ± 1.11 mg/g tissue and 9.49 ± 0.82 mg/g tissue at respective concentration compared to untreated diabetic control (10.78 ± 1.06 mg/g tissue) [ 25 ].

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) also showed significant (p < 0.05) decrease in liver triglyceride level to 55.40 ± 4.64 mg/g tissue, 59.07 ± 6.48 mg/g tissue and 56.47 ± 2.43 mg/g tissue at respective concentration compared to untreated diabetic control group (69.71 ± 5.00 mg/g tissue) [ 25 ].

Alcohol (30%) extract of C. papaya leaves (400 mg/kg) administered orally to alloxan-induced diabetic male and female Wistar albino rats (150 – 200 g) for duration of 21 days significantly (p < 0.05) reduced cholesterol level (135.32 ± 4.04 mg/dL) compared to untreated diabetic control group (153.88 ± 4.19 mg/dL). The extract also significantly (p < 0.05) reduced triglyceride level (145.18 ± 3.67 mg/dL) compared to untreated diabetic control (189.86 ± 1.74 mg/dL) [ 26 ].

Antioxidant activity

Aqueous methanol (80%) extract of C. papaya leaves showed antioxidant activity with 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity (IC₅₀ of 80 µg/mL) compared to L-ascorbic acid (IC₅₀of 4.4 µg/mL) using DPPH scavenging assay and ethylenediaminetetraacetic acid (IC₅₀of 9.6 µg/mL) using metal chelating assay and reducing power assay
[ 27 ].

Methanol extract of C. papaya leaves (2.00 mg/mL) showed antioxidant activity with hydroxyl scavenging activity (88%), hydrogen peroxide scavenging activity (45%), metal chelating activity (38%) and reducing ability (95%) compared to ascorbic acid (0.5 mg/mL) (hydroxyl scavenging activity: 90%, hydrogen peroxide scavenging activity: 50%, metal chelating activity: 60%, reducing ability: 97%) [ 28 ].

The extract (0.25, 0.50, 1.00 and 2.00 mg/mL) also inhibited erythrocyte haemolysis with IC₅₀ of 7.90 ± 0.06 mg/mL, 8.45 ± 0.23 mg/mL, 9.18 ± 0.17 mg/mL and 15.70 ± 0.53 mg/mL at respective concentration compared to ascorbic acid (estimated IC₅₀= 1.87 mg/mL). The extract (0.25, 0.50, 1.00 and 2.00 mg/mL) also inhibited erythrocyte lipid peroxidation with IC₅₀ of 10.95 ± 1.16 mg/mL, 24.54 ± 1.47 mg/mL, 36.87 ± 0.66 mg/mL and 58.99 ± 0.34 mg/mL at respective concentration compared to ascorbic acid (estimated IC₅₀= 0.43 mg/mL) [ 28 ].

Fractions (petroleum ether, ethyl acetate, n-butanol and water) of ethanolic extract of C. papaya leaf (3 – 50 µg/mL) showed reactive oxygen species (ROS) scavenging activity using Dichloro-dihydro-fluorescein assay. Petroleum ether fraction (25 µg/mL) showed highest lactate dehydrogenase (LDH) leakage protection (90%) in comparison to tert-butyl hydroperoxide-treated group using LDH leakage assay. Petroleum ether fraction (25 µg/mL) showed higher reduction (47%) of ROS when compared with α-tocopherol (17%) [ 29 ].

Gastroprotective activity

Aqueous extract of C. papaya leaves (500 mg/kg) was administered orally to adult male Sprague Dawley rats (180 – 220 g) 30 min before induction of gastric ulcer using ethanol. The extract significantly (p < 0.05) increased glutathione peroxidase level (GPx: 2.475 ± 0.214 U/mg protein) compared to ethanol-induced untreated control group (GPx: 2.229 ± 0.281 U/mg protein). The extract reduced mean ulcer index of 993.6 ± 141.384 mm² compared to ethanol-induced untreated control group (mean ulcer index = 6235.2 ± 386.33 mm²) [ 30 ].

Antimutagenic activity

Ethanol (96%) extract of C. papaya leaves (500 mg/kg) administered orally to female Wistar-Kyoto rats (100 – 250 g, four months old) for duration of 24 hr significantly (p < 0.05) decreased micronucleated polychromatic erythrocytes rate (MN-PCE: 1.6 ± 0.5) compared to cyclophosphamide (40 mg/kg) treated control group (MN-PCE: 20 ± 4.9) [ 31 ].

Antisickling activity

Methanol extract (75%) of C. papaya leaves (5 mg/mL) was administered to sickle erythrocytes before induction of sickling using sodium metabisulphite (2%). The extract inhibited formation of sickle cells (SS) with 0 – 2% sickle cells formation at 40 min compared to untreated SS cells (60% sickle cells formation). The extract (3 mg/mL in 0.25% sodium chloride) decreased the percentage haemolysis of SS cells to 5% compared to untreated SS cells (50%) [ 32 ].

Wound healing activity

Aqueous extract of C. papaya leaves (50 mg/g Vaseline and 100 mg/g Vaseline) was applied topically twice a day on dorsal neck excised wound of adult male Sprague Dawley rats (180 – 200 g). The extract showed significant (p < 0.05) decrease in healing time 12.83 ± 0.31 days and 12.33 ± 0.42 days respectively compared to 100% pure Vaseline treated control group (17.33 ± 0.67 days) [ 33 ].

Antibacterial activity

Ethanol extract of C. papaya leaves (100 g/100 mL) showed inhibited growth of Escherichia coli (inhibition zone = 8.30 ± 0.26 mm), Micrococcus luteus (8.23 ± 0.25 mm), Pseudomonas aeruginosa (8.23 ± 0.21 mm), Bacillus cereus (9.20 ± 0.26 mm), Klebsiella pneumonia (6.17 ± 0.15 mm) and Staphylococcus aureus (8.20 ± 0.20 mm) compared to ciprofloxacin (10 µg/mL) (E. coli = 23.50 ± 0.50 mm, M. luteus = 16.97 ± 0.45 mm, P. aeruginosa (25.0 ± 0.50 mm), B. cereus (21.83 ± 0.29 mm), K. pneumonia (14.83 ± 0.29 mm) and S. aureus (29.83 ± 0.76 mm) using well diffusion method [ 34 ].

Antifungal activity

Ethanol extract of C. papaya leaves (100 g/100 mL) showed inhibited growth of Aspergillus niger (inhibition zone = 7.07 ± 0.12 mm), Aspergillus flavus (6.20 ± 0.20 mm), Candida albicans (8.23 ± 0.25 mm), Candida tropicalis (10.0 ± 0.20 mm), Cryptococcus neoformans (7.0 ± 0.20 mm) and Candida kefyr (6.0 ± 0.00 mm) compared to ketoconazole (10 µg/mL) (A. niger = 7.40 ± 0.53 mm, A. flavus = 8.23 ± 0.25 mm, C. albicans = 8.83 ± 0.29 mm, C. tropicalis = 10.10 ± 0.36 mm, C. neoformans = 13.17 ± 0.29 mm and C. kefyr = 11.17 ± 0.29 mm) using well diffusion method [ 34 ].

Antimalarial activity

Methanol (70%) extract of C. papaya leaves (200 mg/kg) was administered to adult Swiss albino mice (20 g) for a duration of five days after 72 hr malaria-induction using Plasmodium berghei. The extract showed a significant (p < 0.05) reduction in parasitemia level from Day-1 post treatment (66%) to Day-5 post treatment (12%) compared to untreated control (Day-1 post treatment: 66%, Day-5 post treatment: 80%). The extract also significantly (p < 0.05) increase the percentage of chemo suppression (0.78 ± 0.04% – 82.22 ± 2.51%) compared to artesunate (3.43 ± 0.21% – 96.60 ± 2.77%) and Alstonia broonai (1.25 ± 0.09% – 53.73 ± 2.13%) [ 35 ].

Antiplasmodial activity

Ethanol extract of C. papaya leaves (25, 50, 100 and 150 µg/mL) showed antiplasmodial activity against chloroquine (CQ) sensitive strain of Plasmodium falciparum with IC₅₀ of 40.8 ± 3.6%, 36.5 ± 3.6%, 25.3 ± 1.0% and 18.0 ± 1.7% at respective concentration compared to chloroquine control group (IC₅₀ = 1.0 ± 0.3%) [ 36 ].

Ethanol extract of C. papaya leaves (25, 50, 100 and 150 µg/mL) also inhibited the growth of CQ – resistant strain of P. falciparum with IC₅₀of 50.2 ± 1.0%, 32.5 ± 2.0%, 21.4 ± 2.6% and 23.1 ± 2.6% at respective concentration compared to chloroquine control group (IC₅₀ = 5.0 ± 0.8%) using in-vitro antiplasmodial assay [ 36 ].

Platelet enhancing activity

Aqueous extract of C. papaya leaves (400 and 800 mg/kg) was administered to cyclophosphamide-induced thrombocytopenic male and female Wistar rats (100 – 125 g) for a duration of 15 days. The extract significantly (p < 0.001) increased the platelet count (400 mg/kg: 556833 ± 30414 cells/mm³, 800 mg/kg: 831000 ± 16118 cells/mm³) compared to cyclophosphamide (50 mg/kg) treated control for a duration of three days (164500 ± 13304 cells/mm³) [ 37 ].

Petroleum extract (200 mg/kg), ethyl acetate extract (200 mg/kg) and alkaloid fraction (carpaine) (2 mg/kg) of C. papaya leaves were administered subcutaneously to bulsufan-induced thrombocytopenia male Wistar rats (200 – 250 g) for a duration of 20 days increased platelet count to 662.25 ± 33.12 x 10⁹/L, 584.02 ± 29.20 x 10⁹/L and 555.5 ± 27.77 x 10⁹/L respectively compared to non-treated control group (78.00x 10⁹ /L) [ 10 ].

Anti-inflammatory activity

Juice extract of C. papaya leaves (0.36 mL/100g and 0.72 mL/100g) was administered to male and female adult Wistar rats with hydroxyurea induced thrombocytopenia one hr before induction of paw edema into the sub-plantar surface of the right hind paw using carrageenan. At four hr of post-injection, the extract significantly inhibited paw edema swelling (p < 0.05) (43%) and (p < 0.01) (37%) at respective concentration, compared to distilled water treated control group (62%) [ 38 ].

Trypanostatic activity

Aqueous extract of C. papaya leaves (0.078 – 10 mg/mL) significantly (p < 0.05) reduced Trypanosoma brucei parasite count minutes post inoculation from 0.61 ± 0.04 x 10⁶ (at lowest concentration) to 0 (at highest concentration) compared to phosphate buffered glucose solution treated control group (1.89 ± 0.06 x 10⁶)at 30 min [ 39 ].

Aqueous extract of C. papaya leaves (0.078 – 2.5 mg/mL) significantly (p < 0.05) increased Trypanosoma brucei percentage inhibition minutes post inoculation from 67.66 ± 2.88% (at lowest concentration) to 99.22 ± 1.22% (at highest concentration) compared to control phosphate buffered glucose solution (0%) at 30 min [ 39 ].

Clinical studies

Platelet enhancing activity

A case report to study effect of C. papaya leaves extracts as compared to broad spectrum antibiotics and antimalarial drugs for five days was carried out. This case report involved a 45-year old male patient diagnosed with dengue fever with symptoms of body ache, breathing problem, shivering, vomiting and hypertension. The patient was administered with grinded C. papaya leaves mixed with some sucrose administered orally (25 mL) twice daily for five consecutive days. The observations were made on the patient’s platelet count every 24 hr before and after extract administration. Results showed recovery of platelet counts, white blood cells and neutrophils to its normal levels [ 40 ].

A pilot study on the beneficial effects of C. papaya leaf extract in combination with antiemetic, paracetamol and antibiotics on 12 patients (adult and children below 10 years old) with strong clinical suspicion of dengue, more than 3 days fever, more than 5 years of age and platelet count of above 130000 per cu.mm. The patients were administered orally with C. papaya leaf extract crushed into juice form at 8-hr interval for adults (two 5 mL doses) and children (two 2.5 mL doses) for nine consecutive days. The observations were made by taking blood sample every 24 hr to determine platelet count and other parameters. Results showed that platelet counts and total white cells increased within 24 hr of C. papaya leaf extract administration [ 41 ].

A randomized controlled trial involving 80 subjects was conducted to study the effects of C. papaya leaves extract capsules (CPC) (550 mg) to dengue fever patient. The intervention group was given additional two CPC three times daily while the control group received standard treatment. Blood samples were obtained twice daily and the platelet count and hematocrit level were determined. The result showed that CPC had significantly (p < 0.05) increased the platelet count to 200 x 10³ /µL on the 9^th examination compared to control group (117.48 10³ /µL). No side effect was observed. Changes in haematocrit level were not significant between intervention and control group [ 42 ].

An open labeled randomized controlled trial to study the platelet increasing effect of C. papaya leaves juice was conducted involving 290 patients (including dropouts of 62 patients) who were diagnosed with Dengue fever or Dengue haemorrhagic fever Grade I and II with platelet count of ≤ 100,000/µL. These patients were divided into two groups: one group was given standard management according to National Clinical Practice Guidelines for the Management of Dengue (control group) and another group was given fresh juice of C. papaya leaves (50 mg) concurrently with standard management (intervention group). Intervention group was treated orally at 15 min after breakfast once daily for three consecutive days. At 48^th hr, the mean platelets count (MPT) significantly (p < 0.05) increased in the intervention group (mean difference of -16.76) compared to MPT at 8^th hr [ 43 ].

A non-randomized trial to study the platelet enhancing activity of C. papaya leaves was conducted involving 9 patients infected with dengue. These patients were orally given 5 mL of papaya leaf extract (3 doses daily at a 6 hr interval) for five consecutive days. No dropout was reported. The mean platelet count significantly (p < 0.05) increased from 0.618 ± 0.087 on Day 1 to 1.330 ± 0.110 on Day 6 [ 44 ].

Immunomodulatory activity

A non-randomized trial to study the immunomodulatory activity of C. papaya leaves was conducted involving 9 patients infected with dengue. These patients were orally given 5 mL of papaya leaf extract (3 doses daily at a 6 hr interval) for five consecutive days. No dropout was reported. The mean total white blood cell count significantly (p < 0.05) increased from 4911.110 ± 869.298 on Day 1 to 13100.000 ± 2000.000 on Day 6 [ 44 ].

SAFETY INFORMATION

Preclinical studies (Toxicology studies)

24-hours toxicity study

Aqueous extract of C. papaya leaves (100 – 5000 mg/kg) given orally to male Sprague-Dawley rats (180 – 250 g) for 24 hr showed no signs of toxicity at LD₅₀ > 5000 mg/kg [ 45 ].

Aqueous extract of C. papaya leaves (100 – 800 mg/kg) given intraperitoneally to albino rats for 24 hr showed clinical signs of sluggishness, awkward posture, loss of appetite, starry hair coat and terminal death at median LD₅₀ > 600 mg/kg [ 39 ].

14-days toxicity study

Aqueous extract of C. papaya dried leaf (2000 mg/kg) was administered orally as a single dose to female Sprague Dawley rats (aged between 6 to 7 weeks old). There was no toxicity effect observed for a period of 14 days (LD₅₀ > 2000 mg/kg) [ 40 ].

Aqueous extract of C. papaya leaves (10 – 500 mg/kg) given orally to male Sprague-Dawley rats (180 – 250 g) for 14 days showed dose-dependent increase in levels of alkaline phosphatase (AP), gamma glutamyl transferase (GGT) and bilirubin (BIL) suggesting toxicity to the hepato-billiary system [ 45 ].

Aqueous extract of C. papaya leaves (10 – 500 mg/kg) given orally to male Sprague-Dawley rats (170 – 190 g) g) for 14 days showed significant reduction in sperm count, sperm motility (conc: 500 mg/kg; p < 0.01), sperm viability (conc: 100 – 500 mg/kg; p < 0.001) and testosterone (conc: 100 – 500 mg/kg; p < 0.01) [ 45 ].

Oral single dose acute toxicity study on female Sprague Dawley rats ( aged between 8 and 12 weeks old) using aqueous extract of C. papaya leaves showed no toxic effect on the parameters observed, including behavior, body weight food and water intake. All rats were observed for 14 days prior to necropsy. No death was found throughout the study period. Necropsy revealed no significant abnormality. No observed -adverse effect level (NOAEL) is 2,000 mg/kg body weight [ 47 ].

28-days toxicity study

Aqueous extract of C. papaya leaf powdered (2000 mg/kg) was administered orally to both male and female Sprague Dawley rats (aged between six to seven weeks) once daily for 28 days. The extract did not cause any mortality and abnormalities on the behavior or physical changes as well as hematological parameters and serum biochemistry [ 20 ].

13-weeks toxicity study

Aqueous extract of C. papaya leaf (2000 mg/kg) was administered orally by oral gavage to both male and female Sprague Dawley rats (aged between six to seven weeks) for duration of 13 weeks. The extract did not cause any mortality and abnormalities of behavior or changes in body weight as well as food and water intake. However, significant (p < 0.05) differences was observed for biochemistry values (LDH, creatinine, total protein and albumin) which require further hepatotoxicity study. The No Observed Adverse Effect Level (NOAEL) was 2000 mg/kg [ 46 ].

Others (Adverse reaction, contraindication, side effect, warning, precaution)

Information and data have not been established.

DOSAGE

Information and data have not been established.

STORAGE

Store below 30^°C. Protect from light and moisture.

REFERENCES

The Plant List [Internet]. Carica papaya L.; 2013 [cited on 4th November 2014]. Available from: http://www.theplantlist.org/tpl1.1/record/kew-2700919.

Multilingual Multiscript Plant Name Database [Internet]. Carica papaya L.; 2012 [cited on 4^th November 2014]. Available from: http://www.plantnames.unimelb.edu.au/Sorting/Carica.html#papaya.

Anjum V, Ansari SH, Naquvi KJ, Arora P, Ahmad A. Development of quality standards of Carica papaya Linn. leaves. Scholars Research Library. 2013; 5(2):370-376.

Jimenez VM, Mora-Newcomer E, Gutierrez-Soto MV. Biology of the papaya plant. In: Ming R, Moore PH, editors. Genetics and genomics of papaya. New York: Springer Science; 2014. p. 17-33.

Flora of Pakistan. [Internet] Carica papaya Linn. [cited on 5^th November 2014]. Available from: http://www.efloras.org/florataxon.aspx?flora_id=5&taxon_id=200014477.

Villegas VN. Carica papaya L. In: Verheij EWM, Coronel RE, editors. Plant Resources of South-East Asia No. 2: Edible fruits and nuts. Pudoc, Wageningen, The Netherlands; 1991. p. 108-112.

Zunjar V, Mammen D, Trivedi BM, Daniel M. Pharmacognostic, physicochemical and phytochemical studies on Carica papaya Linn. leaves. Pharmacognosy Journal. 2011; 20(3): 5-8.

Lalla JK, Ogale S. Pharmacognostic evaluation of leaves of Carica papaya Linn. World Journal of Pharmacy and Pharmaceutical Sciences. 2015;8(4):1066-1081.

Verma D, Vaidya M. Macroscopic and microscopic evaluation of Carica papaya L. leaves with reference to sexual dimorphism. Journal of the Indian Botanical Society. 2015;1&2(94):145-148.

Zunjar V, Dash RP, Jivrajani M, Trivedi B, Nivsarkar M. Antithrombocytopenic activity of carpaine and alkaloidal extract of Carica papaya Linn. leaves in busulfan induced thrombocytopenic Winstar rats. Journal of Ethnopharmacology. 2016; 181: 20-25.

Andarwulan N, Batari R, Sandrasari DA, Bolling B, Wijaya H. Flavonoid content and antioxidant activity of vegetables from Indonesia. Food Chemistry. 2010; 121: 1231-1235.

Andarwulan N, Kurniasih D, Apriady RA, Rahmat H, Roto AV, Bolling BW. Polyphenols, carotenoids and ascorbic acid in underuitilized medicinal vegetables. Journal of Functional Foods. 2012; 4: 339-347.

Canini A, Alesiani D, D’Arcangelo G, Tangliatesta P. Gas chromatographty-mass spectrometry analysis of phenolic compounds from Carica papaya L. leaf. Journal of Food Composition and Analysis. 2007; 20: 584-590.

Olafsdottir ES, Jørgensen LB, Jaroszewski JW. Cyanogenesis in glucosinolate-producing plants: Carica papaya and Carica quercifolia. Phytochemistry. 2002; 60: 269-273.

El-Mesallamy AMD, Hussein SAM, Abd El-Azim MHM, El-Gerby M. Phenolic composition and biological activities of methanolic extract of Carica papaya. Natural Products: An Indian Journal. 2014; 10(4): 91-98.

Tang CS. New macrocylic ∆¹-piperideine alkaloids from papaya leaves: dehydrocarpaine I and II. Phytochemistry. 1979; 18: 651-652.

Ogan AU. The basic constituents of the leaves of Carica papaya. Phytochemistry. 1971; 10: 2544-2547.

Julianti T, Maria MD, Zimmermann S, Ebrahimi SN, Kaiser M, Neuburger M, Raith M, Brun R, Hamburger M. HPLC-based activity profiling for antiplasmodial compounds in the traditional Indonesian medicinal plant Carica papaya L. Journal of Ethnopharmacology. 2014; 155: 426-434.

Gogna N, Hamid N, Dorai K. Metabolomic profiling of the phytomedicinal constituents of Carica papaya L. leaves and seeds by 1H NMR spectroscopy and multivariate statiscal analysis. Journal of Pharmaceutical and Biomedical Analysis. 2015; 115: 74-85.

Afzan A, Abdullah NR, Halim SZ, Rashid BA, Raja Semail RH, Abdullah N, Jantan I, Muhammad H and Ismail Z. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats. Molecules. 2012;17:4326-42

Ayoola PB, Adeyeye A. Phytochemical and nutrient evaluation Carica papaya (pawpaw) leaves. International Journal of Recent Research and Applied Studies. 2010; 5(3): 325-328.

Ong HC, Ruzaila BN, Milow P. Traditional knowledge of medicinal plants among the Malay villagers in Kampung Tanjung Sabtu, Terengganu, Malaysia. Indian Journal of Traditional Knowledge. 2011;10(3):460-465.

Ong HC, Norzalina J. Malay herbal medicine in Gemencheh, Negri Sembilan, Malaysia. Fitoterapia. 1999;70:10-14.

Ong HC, Rosnaini MZ, Milow P. Traditional knowledge of medicinal plants among the Malay villagers in Kampung Mak Kemas, Terengganu, Malaysia. Journalof Ethnobiology and Ethnomedicine. 2011;5(3):175-185.

Isela EJ-R, Juan CD-Z, Jorge LB-C, Pedro HM-O, Andrés EC-R, Carlos AT-Z, Arturo R-H, Hidemi A-M, Teresa R-F, Deysi YB-O. Hypoglycemic effect of Carica papaya leaves in streptozotocin-induced diabetic rats. BMC Complementary and Alternative Medicine. 2012;12:236.

Yasmeen M, Prabhu B. Antihyperglycemic and hypolipidemic activities of aqueous extract of Carica papaya Linn. leaves in alloxan-induced diabetic rats. Journal of Ayurveda and Integrated Medicine. 2012;3(2):70 -74.

Tan S-A, Ramos S, Martin MA, Mateos R, Harvey M, Ramanathan S, Najimudin N, Alam M, Bravo L, Goya L. Protective effects of papaya extracts on tert-butyl hydroperoxide mediated oxidative injury to human liver cells (An in-vitro study). Free Radicals and Antioxidants. 2012;2(3):10-9.

Okoko T, Ere D. Reduction of hydrogen peroxide-induced erythrocyte damage by Carica papaya leaf extract. Asian Pacific Journal of Tropical Biomedicine. 2012: 449-453.

Tan S-A, Goya L, Ramanathan S, Sulaiman SF, Alam M, Navaratnam V. Chemopreventive effects of standardized papaya leaf fraction on oxidatively stress human liver cells. Food Research International. 2014;64: 387-395.

Indran M, Mahmood AA, Kuppusamy UR. Protective effect of Carica papaya L. leaf extract against alcohol induced acute gastric damage and blood oxidative stress in rats. West Indian Medical Journal. 2008;57(4):323.

Kalil IC, Gibson BAV, Ribeiro CA, Beninca LS, Brasil GA, Andrade TU, Batitucci MCP, Endringer DC. Antimutagenic activity of Carica papaya L. assayed in vivo by micronucleus test. Journal of Basic and Applied Pharmaceutical Sciences. 2011;32(3):419-423.

Imaga NOA, Gbenle GO, Okochi VI, Akanbi SO, Edeoghon SO, Oigbochie V, Kehinde MO, Bamiro SB. Antisickling property of Carica papaya leaf extract. African Journal of Biochemistry Research. 2009;3(4):102-106.

Mahmood AA, Sidik K, Salmah I. Wound healing activity of Carica papaya L. aqueous leaf extract in rats. International Journal of Molecular Medicine and Advance Sciences. 2005;1(4):398-401.

Baskaran C, Bai VR, Velu S, Kumaran K. The efficacy of Carica papaya leaf extract on some bacterial and a fungal strain by well diffusion method. Asian Pacific Journal of Tropical Disease. 2012;2:S658-S62.

Arise RO, Malomo SO, Lawal MM. Comparative antimalarial and toxicological effects of artemisinin with methanolic extract of Carica papaya leaves and bark of Alstoniabroonai in animal models. Advances in Natural and Applied Sciences. 2012;6(2):116-23.

Kovendan K, Murugan K, Panneerselvam C, Aarthi N, Kumar PM, Subramaniam J, Amerasan D, Kalimuthu K, Vincent S. Antimalarial activity of Carica papaya (Family: Caricaceae) leaf extract against Plasmodium falciparum. Asian Pacific Journal of Tropical Disease. 2012;2:S306-S11.

Patil S, Shetty S, Bhide R, Narayanan S. Evaluation of platelet augmentation activity of Carica papaya leaf aqueous extract in rats. Journal of Pharmacognosy and Phytochemistry. 2013;1(5):57-60.

Gammulle A, Ratnasooriya WD, Jayakody JRAC, Fernando C, Kanatiwela C, Udagama PV. Thrombocytosis and anti-inflammatory properties, and toxicological evaluation of Carica papaya mature leaf concentrate in a murine model. International Journal of Medicinal Plants Research. 2012;1(2):21-30

Biu AA, Buratai LB, Ahmad AA, Hambali IU, Ngulde SI, Zakariah M and Lawal JR. Phytochemistry, toxicity and efficacy of crude aqueous extract of Carica papaya leaf against trypanosoma brucei. Bangladesh Journal of Veterinary Medicine. 2016;14(1): 99-102

Ahmad N, Fazal H, Ayaz M, Abbasi BH, Mohammad I, Fazal L. Dengue fever treatment with Carica papaya leaves extracts. Asian Pacific Journal of Tropical Biomedicine. 2011:330-333

Hettige S. Salutary effects of Carica papaya leaf extract in dengue fever patients – a pilot study. Sri Lankan Family Physician. 2008;29:17-19

Yunita F, Hanani E, Kristianto J. The effect of Carica papaya L. leaves extract capsules on platelets count and hematocrit level in dengue fever patient. International Journal of Medicinal and Aromatic Plants. 2012;2(4):6

Subenthiran S, Choon TC, Cheong KC, Thayan R, Teck MB, Muniandy PK, Afzan A, Abdullah NR, Ismail Z. 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. 2013:1-7

Kumar CVM Naresh, Taranath V, Venkatamuni A, Vardhan R Vishnu, Prasad Y Siva, Ravi U, Gopal D V R Sai. Therapeutic potential of Carica Papaya L. leaf extract in treatment of dengue patients. International Journal of Applied Biology and Pharmaceutical Technology. 2015 Jul-Sept; 6(3): 93-98

Ansah C, Appiah JA, Mensah KB, Mante PK. Aqueous leaf extract of Carica papaya (Caricaceae) Linn. causes liver injury and reduced fertility in rats. International Journal of Pharmacy and Pharmaceutical Sciences. 2016; 8(2):261-265

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

Teh BP, Jumriani AA, Noorashikin AH, Lalitha Suganthi S. Acute oral toxicity study of selected Malaysian medicinal herbs on Sprague Dawley rats. Institute for Medical Research, Ministry of Health; 2019. Report no.: NON-GLP/2019/01/01.

QUICK LINKS

Contact Information

GlobinMed Secretariat,
Integrative Health Information Unit
(Unit Informasi Kesihatan Integratif),

Herbal Medicine Research Center,

Institute for Medical Research,

Block C, National Institutes of Health (NIH),

No.1, Jalan Setia Murni u13/52,

Seksyen U13, Bandar Setia Alam,

40170 Shah Alam, Selangor

Tel: +603-33627657
Email: [email protected]

Disclaimer

The Government of Malaysia and Institute for Medical Research (IMR) shall not be liable for any loss or damage caused by the usage of any information obtained from this web site.