Tinospora crispa (L.) Hook. f. & Thomson

Last updated: 09 Aug 2016

Scientific Name

Tinospora crispa (L.) Hook. f. & Thomson

Synonyms

Menispermum crispum L., Tinospora gibbericaulis Hand.-Mazz., Tinospora mastersii Diels, Tinospora thorelii Gagnep. [1]

Vernacular Name

Malaysia Akar putarwali, bertangwali, daun akar wali, patau wali, petawali, putawali [2]
English Heavenly elixir [3]
China Bo ye qing niu dan [2], bo ye qing niu dan, fa leng teng [3]
India Giloya [3]
Indonesia Daun gadel (Jawa); andawali (Sunda); kebut, lalang (Madura); halalang, tingen (Kalimantan) [4]; bratawali [5]
Thailand Bo-ra-pet, bora phed, boraphet, chettamuun naam, hang nuun, khruea khao ho, thao hua duan, tua chettamuun yaan, wan kab hoi yai [2], bora phet, chung ching, kuakhohoo (don daeng) [3]
Laos Khua kao ho [2]
Philippines Makabuhai, makabuhay, taganagtagwag (Tagalog); paliaban, paliahan, panauan, pañgiauan, pañgiauban, taganagtagua, tagua (Bisaya) [3]
Cambodia Bandaul pech [2]
Vietnam Day coc [6]
France Liane-quinine [3].

Geographical Distributions

No documentation.

Botanical Description

Tinospora crispa is a member of the Menispermaceae family. It is a climbing shrub with glabrous young shoots while the older ones are with warted barks. [7][8]

The leaves are membranous, glabrous, ovate-cordate, entire or repand, and sometime subsagittate. The length of the blade is 5-15 cm long, breath is 2.5-10 cm and the petiole measures 2.5-7.5 cm long. The racemes is 10-20 cm on the old wood, solitary or fascicled. [7][8]

There are 2-3 flowers in the axils of ovate bracts 3 mm long, campanulate and green. The stamens are adnate to the base of the petals and anthers are quadrate. The drupe are elliptic-oblong in shape, pale yellow in colour measuring about 3 inch long or less. [7][8]

Cultivation

No documentation.

Chemical Constituent

The cis clerodane-type furanoditerpenoids include, (2R,5R,6R,8S,9S,10S,12S)-15,16-epoxy-2-hydroxy-6-O-{β-D-glucopyranosyl-(1→6)-α-Dxylopyranosyl}-cleroda-3,13(16),14-trien-17,12-olid-18-oic acid methyl ester, (2R,5R,6R,8R,9S,10S,12S)-15,16-epoxy-2-hydroxy-6-O-(β-D-glucopyranosyl)-cleroda-3,13(16),14-trien 17,12-olid-18-oic acid methyl ester, (5R,6R,8S,9R,10R,12S)-15,16-epoxy-2-oxo-6-O-(β-D glucopyranosyl)-cleroda-3,13(16),14-trien-17,12-olid-18-oic acid methyl ester, methyl (2R,7S,8S)-8[(2S)-2-(3,4-dihydroxy-2,5-dimethoxytetrahydro-3-furanyl)-2-hydroxyethyl]-2,8-dimethyl-10-oxo-11-oxatricyclo[7.2.1.0]dodec-3-ene-3-carboxylate, (5R,6R,8S,9R,10S,12S)-15,16-epoxy-2-oxo-6-O-(β D-glucopyranosyl)-cleroda-3,13(16),14-trien-17,12-olid-18-oic acid methylester, (2R,5R,6S,9S,10S,12S)-15,16-epoxy-2-hydroxy-6-O-(β-D-glucopyranosyl)-cleroda-3,7,13(16),14-tetraen 17,12-olid-18-oic acid methyl ester, (5R,6S,9S,10S,12S)-15,16-epoxy-2-oxo-6-O-(β-D glucopyranosyl)-cleroda-3,7,13(16),14-tetraen-17,12-olid-18-oic acid methyl ester, (3R,4R,5R,6S,8R,9S,10S,12S)-15,16-epoxy-3,4-epoxy-6-O-(β-D-glucopyranosyl)-cleroda-3,13(16),14 trien-17,12-olid-18-oic acid methyl ester and (1R,4S,5R,8S,9R,10S,12S)-15,16-epoxy-4-O-(β-D glucopyranosyl)-cleroda-2,13(16),14-triene-17(12),18(1)-diolide. [9]

The stems also contained five flavone glycosides identified as luteolin 4’-methyl ether 7-glucoside, genkwanin 7-glucoside, luteolin 4’-methyl ether 3’-glucoside, diosmetin and genkwanin. [10]   

The stems contained aporphine alkaloid, N-formylasimilobine 2-O-β-D-glucopyranoside, N-formylasimilobine 2-O-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside (tinoscorside A), N-formylanonaine, N-formyldehydroanonaine, N-formylnomuciferine, N-demethyl-N-formyldehydronornuciferine, magnoflorine, paprazine, N-transferuloyltyramine and cytidine. [11][12]

The dichloromethane extract showed presence of vanillin, syringin, N formylannonain, N-formylnornuciferin, borapetosides B, C and F, N-cis-feruloyltyramine, N-trans feruloyltyramine and secoisolariciresinol. [13]

The chloroform extracts of the dried stems showed presence of cycloeucalenol and cycloeucalenone. [14]

The n-butanol extract of the stems was found to contain salsolinol, adenosine, uridine, tyramine, higenamine, syringing, borapetoside A, B, D and E, adenine and litcubinine. [15]

The ethanolic extract showed presence of 2-O-lactoylborapetoside B, 6’-O lactoylborapetoside B, tinocrispol A, borapetosides A-F, borapetols A and B and columbin. [16]

Plant Part Used

Dried stem [4]

Traditional Use

T. crispa is traditionally used for indigestion, stomachache, jaundice [17], small pox, and rheumatism [18]. The plant has been advocated in the treatment of various forms of fever including those associated with jaundice or liver.  It is externally used in treatment of syphilis, sore eyes, itchiness, wounds, and mosquito bites [18]. This plant has been promoted for the treatment diabetes and hypertension and is being sold in markets in Penang, Kuala Lumpur, Kota Kinabalu and Sandakan. Similar use has been documented in Brunei [19].

The decoction of T. tuberculata is considered an emetic and at the same time an appetite stimulant based on the concentration of the decoction given. High doses acts as emetic while low doses can act as a bitter appetite stimulant. The same decoction is applied as a vermifuge. An infusion of the whole plant is used in the treatment of cholera. [18]

Infusion of T. crispa stem is traditionally useful as vermifuge [18][19]. As a febrifuge a decoction of the stem is prepared and given to the patient to drink. It is also used in the treatment of malaria. In India it is considered as a powerful febrifuge.  The boiled dried stem is used to treat rheumatism and to treat different inflammatory conditions like ophthalmia, syphilis, gonorrhea, small pox and venomous bites including snakebites. In various skin afflictions, a decoction of the stem is used as a wound cleanser and had been shown to effectively initiate healing of syphilitic ulcers, sores, smallpox and infected wounds [4][18][20][21][22][23]

A lotion of the T. tuberculata  stem applied on the body acts as a vermifuge and prevents mosquitoes from biting. Necklace made of bits of the stem is supposed to cure jaundice by the Indians while the same is used to remove worms amongst the Malays. A little of the juice is applied to the nipples as an act of weaning of a child. [18]

Preclinical Data

Pharmacology

Antioxidant activity 

N-cis-feruloyltyramine, N-trans-feruloyltyramine and secoisolariciresinol isolated from CH2Cl2 extract of T. cripa exhibited antioxidant and radical scavenging activities towards β-carotene and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. They prove to be more active than the synthetic antioxidant butylhydroxytoluene. [24]

Aqueous extract of T. crispa stem (dose) scavenged DPPH free radicals (86.51 ±0.07%) and inhibited oxidation of ferric ions (0.89 ±0.07 mmol/L, p < 0.05) compared to vitamin C (96.36 ±0.90%, 1.05 ±0.00 mmol/L) and BHT (96.51 ±0.95%, 1.03 ±0.03 mmol/L) controls. This extract also inhibited lipid peroxidation (39.2 ±5.14%) by using thiobarbituric acid assay compared to vitamin C (73.2 ±5.14%) and BHT (75.8 ±6.08%) controls. The extract contained flavonoids (1.58 µg/mg of catechin, 0.85 µg/mg of luteolin, 1.44 µg/mg of morin and 1.38 µg/mg rutin) and phenolic (0.29 ±0.01 mg gallic acid equivalent/100 g of fresh sample). [25]

Methanol, chloroform, and water extracts of T. crispa stem showed significant total phenolic content (79.00-255.33 mg gallic acid equivalents/g extract, p < 0.05) by using Folin-Ciocalteu method and flavonoid content (2.67-9.53 mg quercetin equivalents/g extract, p < 0.05) by using Dowd method. Only methanol extract inhibited the scavenging activity of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals with IC50 value of 12 µg/mL compared to vitamin C control by using DPPH free radical scavenging assay. [26]  

Aqueous extract of T. crispa dried stem was prepared through different temperatures with respective time length, i.e. 20°C/24h, 40°C/12h, 60°C/6h, 80°C/3h, and 100°C/15 min. The extract at 60°C/6h significantly inhibited DPPH free radicals with 85.95 ±0.52% inhibition (p<0.05) compared to 20°C/24h (66.86 ±0.55%) and also inhibited thiobarbituric acid (TBA) (39.20 ±2.97%). [26]

Cardiotonic activity 

Triterpenes namely cycloeucalenol and cycloeucalenone isolated from crude chloroform extract of T. crispa dried stem (5.6x10-5 M for each triterpene) showed mild cardiotonic effects on isolated rat’s right and left atria (male Wistar rats weighed 250-300 g) compared to ethanol (80%v/v) control. The former showed slight increase in the right atrial contraction force where it showed an initial reduction followed by sustained reduction of about 10% on the left atria of the rat in vitro. Cycloeucalenone on the other hand showed only slight change from the control of right and left atrial contraction force [14]. In a preliminary screening of the chloroform extract of T. crispa it was demonstrated that it has potent cardiovascular activity [27]

Antibacterial activity

Aqueous, ethanol, and chloroform extracts of T. crispa dried stem (25, 50, 75, and 100% concentration/strength) showed antibacterial activities against several Gram positive (Bacillus cereus, Staphylococcus aureus, Listeria monocytogenes, Stretococcus pneumoniae and Clostridium diphtheriae) and Gram negative (Shigella flexneri, Salmonella typhi, Klebsiella pneumoniae, Proteus vulgaris and Escherichia coli) bacteria using in vitro disc diffusion methods. The results showed that the aqueous extracts at all concentrations was active against S. pneumoniae and C. diphtheriae but show an activity against E. coli at the concentrations of 50% and above. The ethanol extract was active against S. aureus, S. pneumoniae, C. diphtheriae andS. flexneri at all concentrations while the chloroform extracts was able to inhibit the growth of E. coli at concentrations above 50%. [28] 

Ethanol (95%v/v) extract of T. crispa dried stem inhibited the growth of eight methicilin-resistant Staphylococcus aureusisolated strains with minimum inhibitory concentrations (MIC) of 0.40-0.78 mg/mL and minimum bacterial counts (MBC) of 0.78-1.56 mg/mL by using checkerboard assay. [29]

Antiplasmodial activity

Ethanol (95% v/v) extract of T. crispa stem administered intraperitoneally (20, 40, and 80 mg/kg/day) to female ICR mice (pre-inoculated with Plasmodium yoelii, aged 6 weeks) for 20 days exhibited antiplasmodial activity in a dose-dependent manner with lower percentage of P. yoelii (18.12 ±2.24%) compared to ethanol (30%v/v) control (45.45 ±3.67%) on day 8. A pre-inoculated mouse given 80 mg/kg/day extract was alive without P. yoelii anymore in its blood stream on day 20. [30]

In a study to evaluate the efficacy of traditional remedies for malaria in the French Guiana it was confirmed that the one containing T. crispa was able to inhibit more than 50% of the parasitic growth in vivo. [31] 

Antifilarial activity

Aqueous extract of T. crispa (10 mg/mL) against Dirofilaria immitis with mean relative movability (RM) value of 30.15% after 24 hours treatment (p < 0.05) compared to DMSO control (100%). [32]

Aqueous extract of T. crispa stem (0.5, 1.0, 5.0, and 10.0 mg/mL) exhibited antifilarial activity against adults worms ofBrugia malayi (harvested from 4-6 weeks old male cat infected with L3-stage larvae from Aedes togoi) with the mean relative movability (RM) values of adults worms ranging between 0-100, in a dose-dependent manner, after 24 hours incubation compared to RPMI1640 culture medium as control (mean RM value of 100). [33]

Antiproliferative activity

Methanol, chloroform, and water extracts of T. crispa stem inhibited the growth of MCF-7 (IC50 = 33.75-42.75 µg/mL), MDA-MB-231 (IC50 = 44.83-51.25 µg/mL), HeLa (IC50 = 46.13-53.83 µg/mL), and 3T3 (IC50 = 52.58-65.50 µg/mL) cancer cell lines, in a dose-dependent manner compared to tamoxifen control by using MTT assay. [26]

Aqueous extract of T. crispa dried stem inhibited the growth of Caov-3 (IC50 = 80 µg/mL compared to cisplatin control), HepG2 (IC50 = 60 µg/mL compared to cisplatin control), MCF-7 (IC50 = 60 µg/mL compared to tamoxifen control), and HeLa (IC50 = 79 µg/mL compared to tamoxifen control) cancer cell lines on day 3 by using MTT assay. [34]

Anti-inflammatory activity 

Various extracts of T. crispa has shown inhibitory effects on inflammation induced by carragineen on rat’s foot pad. The most effective extract was the n-butanol soluble fraction given orally. Similar effects were also illicited when the extract was give subcutaneously and intraperitoneally. When given intravenously it also reduced LPS-induced fever in rabbits. [35]

Ethanol extract of T. crispa dried stem administered intraperitoneally in a single dose (30, 100, and 300 mg/kg body weight) to Sprague Dawley rats (aged 8-10 weeks) significantly exhibited anti-inflammatory activity in a dose-dependent manner with the means of paw edema ranging between 0.11-0.41 mL/h (p ≤ 0.05) compared to saline control (0.57 ±0.05) at 1 hour by using carrageenan-induced paw edema test. [36]

Antidiabetic activity 

Water extracts of the T. crispa stem exhibited hypoglycaemic properties by stimulating the release of insulin from the beta cells of the islets of Langerhans. [37][38]

The probable mechanism T. crispa extract’s insulinotropic activityis because the extract sensitizes the b-cel to extracellular Ca2+ and promotes intracellular Ca2+ accumulation which in turns causes increased insulin release. This increase of intracellular Ca2+ is due to stimulation of Ca2+ uptake from extracellular medicu and inhibition of Ca2+ efflux from the cytosol. This physiological effect suggests that the extract contains an insulin scretagogues with potential of being developed into an oral hypoglycaemic agent for treatment of Type 2 Diabetes. [39]

Further research was done to seek other pharmacological characterization of the antihyperglycaemic properties of T. cripa extract. The result showed that the hypoglycaemic effects was not due to its interference in intestinal glucose absorption or uptake of sugar into peripheral cells. [39]

The effects of aqueous extracts of T. crispa on glucose transport activity in skeletal muscle was found that the extract enhances glucose transport of L6 myotubes in an insulin-independent pathway in a time and dose dependent manner. [40]

Water-ethanol extract of T. crispa stem (400 µg/mL) significantly increased 2-deoxy-D-glucose uptake (214.49 ±9.00% above basal, p < 0.01) in isolated rat’s L6 skeletal muscle cells after 24 hours incubation compared to metformin (205.80 ±6.28% above basal). However, this extract-stimulated glucose uptake may adversely be inhibited by 3.5 µM cycloheximide (glucose uptake < 100%) compared to partially inhibited metformin-stimulated glucose uptake (< 150%). This extract also significantly increased AMPKα1 (2.10 ±0.38 fold above basal, p < 0.05) and PPARγ (6.73 ±0.88 fold above basal, p < 0.05) mRNA levels after 15 minutes treatment while significantly increased GLUT1 mRNA level (1.29 ±0.38, p < 0.05) after 4 hours compared to control. [25]

Antinociceptive activity

Ethanol extract of T. crispa dried stem administered intraperitoneally in a single dose (30, 100, and 300 mg/kg body weight) to male Balb-C mice (aged 5-7 weeks) significantly exhibited antinociceptive activity in a dose-dependent manner with writhing response values of 3-15 (p ≤ 0.05) compared to saline control (36 ±1.45) by using acetic acid-induced writhing test and latency of discomfort of 10.84-13.16 seconds (p ≤ 0.05) compared to saline control (8.12 ±0.71) at 240 minutes by using hot plate test. [41]

Antihypercholesterolemic activity

Aqueous extract of T. crispa stem (450 mg/kg/day body weight) given to male New Zealand white rabbits fed with high cholesterol diet for 10 weeks significantly increased the levels of glutathione peroxidase (494.32 ±96.72 U/L) and high density lipoprotein (HDL) (9.23 ±1.36 mmol/L) (p <0.05) compared to untreated high cholesterol diet rabbits (220.41 ±19.69 U/L , 0.86 ±0.11 mmol/L). This extract also significantly decreased the levels of triglycerides and low density lipoprotein (LDL) (8.38 ±0.99 mmol/L) (p < 0.05) compared to untreated high cholesterol diet rabbits (16.46 ±1.60 mmol/L). No foam cell formation was observed in the aorta of rabbits. [42]

Cytochrome inhibitory activity

Methanol and ethanol-soluble fractions from aqueous extract of T. crispa stem (1.65 mg/mL) respectively inhibited activity of drug metabolizing enzymes from human liver microsomes, i.e. CYP3A4 (>70% inhibition; <30% inhibition) compared to ketoconazole control and CYP2D6 (>70% inhibition; <30% inhibition) compared to quinidine control. [43]                                    

Methanol extract of T. crispa stem (0.5 mg/mL) inhibited the activity of drug metabolizing enzymes from human liver microsomes, i.e. CYP3A4 (>30% inhibition) compared to troleandomycin control (37.9% inhibition) and CYP2D6 (<30% inhibition) compared to paroxetine control (60.7% inhibition). [44]

Cytotoxic activity

Methanol and water crude extract of T. crispa dried stem (5-500 µg/mL) showed less cytotoxicity effect (IC50 value > 500 µg/mL) on HL-60, MCF-7 and HepG2 cancer cell lines by using MTT assay. [45]

Toxicity

Acute toxicity

Oral single dose acute toxicity study using aqueous mixture of dried powder of T. crispa stem on female Sprague Dawley rats (aged between 8 and 12 weeks old) showed no toxic effect on the parameters observed which includes behaviors, body weight, food and water intakes. All rats were observed for 14 days prior to necropsy. No death was found throughout the study period. Necropsy revealed no significant abnormality (LD50 > 2,000 mg/kg). [46]

Ethanol (95%v/v) extract of T. crispa stem (1, 2, and 4 g/kg body weight) given single dose orally to ICR mice (25±2 g body weight) showed no sign of toxicity after seven days observation. [47]

Chronic toxicity

Ethanol (95%v/v) extract of T. crispa stem (0.02, 0.16, and 1.28 g/kg/day) given orally to Wistar rats (200-230 g body weight) for 180 days showed no effect on hematological parameters (hematocrit, white blood cells, platelet, neutrophil, eosinophil, lymphocyte, monocyte). The extract at the concentration of 1.28 g/kg/day significantly decreased creatinine and potassium levels, reduced rats’ body weight (p<0.05, both genders) and showed morphological changes (bile duct proliferation and focal liver cell hyperplasia) on male rats’ liver compared to control. [48]

Clinical Data

Clinical findings

A randomized double blind placebo controlled trial to study the hypoglycemic effect of T. crispa was conducted involving 40 patients (included dropouts of six patients) with type 2 diabetes mellitus and glycosylated hemoglobin more than 8.5%, aged above 35 years old, who consumed adequate dose of oral hypoglycemic drug for at least two months, and refused insulin injection. These patients were divided evenly into two groups, i.e. a group given 1 g of T. crispa powder capsule and another given placebo, thrice daily for six months period. Fasting plasma glucose, glycosylated hemoglobin, and insulin levels in treatment group were not significantly different (p ≥ 0.0.5) compared to baseline and placebo. Body weight of treatment group decreased significantly but cholesterol increased significantly (p ≤ 0.05). Changes of liver enzymes profile were not observed. [49]

A randomized double-blind placebo-controlled crossover trial to study the hypoglycemic effect of T. crispa was conducted involving 36 patients who met the metabolic syndrome criteria by National Cholesterol Education Program Adult Treatment Panel III and did not consume any oral hypoglycemic drug. These patients were divided into two groups, i.e. a group given 250 mg T. crispa dry extract powder capsule (consists of 0.98% dry weight marker substance A) and another given placebo, at 30 minutes before meal twice daily for two months period. After two months, each group of patients received the other treatment. The fasting blood glucose (112.06 ± 13.98 mg/dL) and triglyceride (135.78 ± 65.59 mg/dL) levels in treatment group were significantly decreased (p < 0.05) and the HDL level (48.03 ±9.95 mg/dL) was significantly increased (p < 0.05) while total cholesterol (189.31 ±33.91 mg/dL) and LDL (114.11 ±30.82 mg/dL) levels were not significantly changed (p>0.05), respectively compared to baseline. No significant difference in above measured parameters, calorie intakes, and body weights between treatment and placebo groups during the treatment period. 91.6% of total patients adhered to T. crispa (assessed by capsule count method). The extract increased level of liver enzymes (AST and ALT) more than three times the baseline levels. [48]

Precautions

Extract-thioacetamide treated rats showed significant increase in the levels of liver enzymes and liver body weight ratios. Histological examination revealed hepatocytes degeneration, centrilobular necrosis of hepatocytes, and inflammatory cell infiltration containing lymphocytes and mononuclear cells on liver of the rats. [50]

250 mg T. crispa dry extract powder capsule (consists of 0.98% dry weight marker substance A) given to diabetic patients, at 30 minutes before meal twice daily for two months period, increased the level of liver enzymes (AST and ALT) more than three times the baseline levels. This extract may be a risk factor to elevated liver enzymes. [48]

Side effects

No documentation.

Pregnancy/Breast Feeding

No documentation.

Age limitation

No documentation.

Adverse reaction

T. crispa may result in an increase risk of hepatic dysfunction due to marked increase in liver enzymes as evidenced amongst patients in one clinical trial to test its efficacy as an adjuvant to diabetic therapy. This is however reversible upon discontinuation of the drug. [51]

Diabetic patient may experience increased appetite, flatulence and dizziness while receiving 250 mg T. crispa dry extract powder capsule (consists of 0.98% dry weight marker substance A). [48]

Interaction & Depletion

No documentation.

Contraindications

No documentation.

Dosage

No documentation.

Poisonous Management

No documentation.

Line drawing

No documentation.

References

  1. The Plant List. Ver1.1. Tinospora crispa (L.) Hook. f. & Thomson [homepage on the Internet]. c2013 [updated 2012 Apr 18; cited 2016 Aug 09]. Available from: http://www.theplantlist.org/tpl1.1/record/tro-50053822
  2. Quattrocchi U. CRC world dictionary of medicinal and poisonous plants: Common names, scientific names, eponyms, synonyms, and etymology. Volume V R-Z. Boca Raton, Florida: CRC Press, 2012; p.578
  3. Philippine Medicinal Plants. Makabuhay. Tinospora crispa (L.) Hook.f. & Thomson [homepage on the Internet]. No date [updated 2015 Sep; cited 2016 Aug 09] Available from: http://www.stuartxchange.com/Makabuhay.html
  4. Dalimartha S. Atlas tumbuhan obat Indonesia Jilid 5. Jakarta: Pustaka Bunda, 2008; p. 10-12.
  5. Stevens AM, Schmidgall Tellings AE. A comprehensive Indonesian-English dictionary. Athens: Ohio Universitiy Press, 2004; p. 153.
  6. Nguyen-Pouplin J, Tran H, Tran H, et al. Antimalarial and cytotoxic activities of ethnopharmacologically selected medicinal plants from South Vietnam. J Ethnopharmacol. 2007;109(3):417-427.
  7. Ridley HN. The flora of the Malay Peninsula. Volume 1: Polypetale. London: L. Reeve & Co., 1922; p.103.
  8. Hooker JD. The flora of British India. Volume 1. London: L. Reeve & Co., 1875; p. 96-97.
  9. Choudhary MI, Ismail M, Shaari K, Abbaskhan A, Sattar SA, Lajis NH. Cis-Clerodane-type furanoditerpenoids from Tinospora crispa. J Nat Prod. 2010;73(4):541–547.
  10. Umi Kalsom Y, Noor H. Flavone O-glycosides from Tinospora crispa. Fitoterapia. 1995;66(3):280.
  11. Imphanban K, Kongkathip N, Dhumma-upakorn P, Mesripong R, Kongkathip B. Synthesis of N-formylnornuciferine with cardiotonic activity. Nat Sci. 2009;43(4):738–744.
  12. Choudhary MI, Ismail M, Ali Z, Shaari K, Lajis NH. Alkaloidal constituents of Tinospora crispa. Nat Prod Com. 2010;5(11):1747–1750.
  13. Cavin A, Hostettmann K, Dyatmyko W, Potterat O. Antioxidant and lipophilic constituents of Tinosproa crispa. Planta Med. 1998;64(5):393–396.
  14. Kongkathip N, Dhumma-upakorn P, Kongkathip B, Chawananoraset K, Sangchomkaeo P, Hatthakitpanichakul S. Study on cardiac contractility of cycloeucalenol and cycloeucalenone isolated from Tinospora crispa. J Ethnopharmacol. 2002;83(1-2):95–99.
  15. Praman S, Mulvany MJ, Williams DE, Andersen RJ, Jansakul C. Hypotensive and cardiochronotropic constituents of Tinospora crispa and mechanisms of action on the cardiovascular system in anesthetized rats. J Ethnopharmacol. 2012;140:166–178.
  16. Lam SH, Ruan CT, Hsieh PH, Su MJ, Lee SS. Hypoglycemic diterpenoids from Tinospora crispa. J Nat Prod. 2012; 5(2);153–159.
  17. Perry LM. Medicinal plants of East and Southeast Asia. Massachusetts: MIT Press. 1980;p.268.
  18. Burkill IH. A dictionary of the economic products of the Malay Peninsula. Volume 2. London: Published on behalf of the governments of the Straits settlements and Federated Malay states by the Crown agents for the colonies, 1935; p. 2164-2165
  19. Samy J, Sugumaran M, Lee KLW. Herbs of Malaysia: An Introduction to the medicinal, culinary, aromatic and cosmetic use of herbs. Kuala Lumpur: Federal Publications Sdn. Bhd., 2005; p. 219.
  20. Gosling DL. Religion and ecology in India and Southeast Asia. London: Routledge; 2001.
  21. Johnson T. CRC ethnobotany desk reference. Boca Raton, Florida: CRC Press, 1999; p. 838.
  22. Djing OG. Terapi mata dengan pijat dan ramuan. Jakarta: Niaga Swadaya, 2006; p. 29.
  23. Vardhana R. Floristic plants of the world. New Delhi: Sarup & Sons, 2006; p. 869.
  24. Cavin A, Hostettmann K, Dyatmyko W, Potterat O. Antioxidant and lipophilic constituents of Tinospora crispa. Planta Med. 1998;64(5):393-396.
  25. Zulkhairi A, Hasnah B, Sakinah I, Nur Amalina I, Zamree MS, Mohd Shahidan A. Nutritional composition, antioxidant ability and flavonoid content of Tinospora crispa stem. Adv Nat App Sci. 2009;3(1):88-94.
  26. Ibrahim MJ, Wan-Nor I’zzah WMZ, Narimah AHH, Nurul Asyikin Z, Siti-Nur Shafinas SAR, Froemming GA. Anti-proliperative and antioxidant effects of Tinospora crispa (batawali). Biomed Res. 2011;22(1):57-62.
  27. Bakhari NA, Sadikun A, Choon TS, Ying TS, Asmawi MZ. Aporphine alkaloids isolated from the cardiovascular active fraction of Tinospora crispa. Malays J Sci. 2005:24(1);161-165.
  28. Zakaria ZA, Mat Jais AM, Somchit MN, Sulaiman MR, Faizal FO. The in vitro antibacterial activity of Tinospora crispa extracts. J Bio Sci. 2006;6(2):398-401.
  29. Al-Alusi NT, Kadir FA, Ismail S, Abdullah MA. In vitro Interaction of combined plants Tinospora crispa and Swietenia mahagoni against methicillin-resistant Staphylococcus aureus. Afr J Microbiol Res. 2010;4(21):2309-2312.
  30. Rungruang T, Boonmars T. In vivo antiparasitic activity of the Thai traditional medicine plant Tinospora crispa against Plasmodium yoelli. Southeast Asian J Trop Med Public Health. 2009;40(5):898-900.
  31. Bertani S, Bourdy G, Landau I, Robinson JC, Esterre P, Deharo E. Evaluation of French Guiana traditional antimalarial remedies. J Ethnopharmacol. 2005;98(1-2):45-54.
  32. Merawin LT, Arifah AK, Sani RA, et al. Screening of microfilaricidal effects of plant extracts against Dirofilaria immitis. Res Vet Sci. 2010;88(1):142–147.
  33. Zaridah MZ, Idid SZ, Omar AW, Khozirah S. In vitro antifilarial effects of three plants species against adult worms of subperiodic Brugia malayi. J Ethnopharmacol. 2001;78(1):79-84.
  34. Zulkhairi A, Abdah MA, M Kamal NH, et al. Biological properties of Tinospora crispa (akar patawali) and its antiproliferative activities on selected human cancer cell lines. Malays J Nutr. 2008;14(2):173-187.
  35. Higashino H, Suzuki A, Tanaka Y, Pootakham K. Inhibitory effects of Siamese Tinospora crispa extracts on the carrageenin-induced foot pad edema in rats (the 1st report)]. Nippon Yakurigaku Zasshi. 1992;100(4):339-344. Japanese.
  36. Noipha K, Ninla-aesong P. The activation of GLUT1, AMPKα and PPARγ by Tinospora crispa in L6 myotubes. Spatula DD. 2011;1(4):245–249.
  37. Noor H, Hammonds P, Sutton R, Ashcroft SJ. The hypoglycaemic and insulinotropic activity of Tinospora crispa: Studies with human and rat islet and HIT-T15 B cells. Diabetologia. 1989;32(6):354-359.
  38. Noor H, Ashcroft SJ. Antidiabetic effects of Tinospora crispa in rats. J Ethnopharmacol. 1989;27(1-2):149-161
  39. Noor H, Ashcroft SJ. Pharmacological characterisation of the antihyperglycaemic properties of Tinospora crispa extract. J Ethnopharmacol. 1998;62(1):7-13.
  40. Noipha K, Purintrapiban J, Herunsalee A, Ratanachaiyavong S. In vitro glucose uptake activity of Tinospora crispa in skeletal muscle cells. Asian Biomed. 2008;2(5):415-420.
  41. Sulaiman MR, Zakaria ZA, Lihan R. Antinociceptive and anti-inflammatory activities of Tinospora crispa in various animal models. Int J Trop Med. 2008;3(3):66-69.
  42. Zulkhairi A, Hasnah B, Zamree MS, et al. Potential of Tinospora crispa as a hypocholesterolemic agent in rabbits. Malays J Med Health Sci. 2009;5(2):1-10.
  43. Usia T, Iwata H, Hiratsuka A, Watabe T, Kadota S, Tezuka Y. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants. Phytomedicine. 2006;13(1-2):67–73.
  44. Subehan, Usia T, Iwata H, Kadota S, Tezuka Y. Mechanism-based inhibition of CYP3A4 and CYP2D6 of Indonesian medicinal plants. J Ethnopharmacol. 2006;105(3):449–455.
  45. Tungpradit R, Sinchaikul S, Phutrakul S, Wongkham W, Chen ST. Anti-cancer compound screening and isolation: Coscinium fenestratumTinospora crispa and Tinospora cordifolia. J Sci Faculty of Chiang Mai University. 2010;37(3):476-488.
  46. Teh BP, Hamzah NF, Rosli SNS, Yahaya MAF, Zakiah I, Murizal Z. Acute oral toxicity study of selected malaysian medicinal herbs on Sprague Dawley rats. Institute for Medical Research, Ministry of Health; 2012. Report No.: HMRC 11-045/01/TT/S/P.
  47. Pranee C, Aimmanus A, Anchalee C, Pranee C. Toxicological study of crude extract of Tinospora crispa Mier ex Hook F. & Thoms. Thai J Pharm Sci. 1997;21(4):199-210.
  48. Sriyapai C, Dhumma-upakorn R, Sangwatanaroj S, Kongkathip N, Krittiyanunt S. Hypoglycemic effect ofTinospora crispa dry powder in outpatients with metabolic syndrome at King Chulalongkorn Memorial Hospital. J Health Res. 2009;23(3):125-133.
  49. Sangsuwan C, Udompanthurak S, Vannasaeng S, Thamlikitkul V. Randomized controlled trial of Tinospora crispa for additional therapy in patients with type 2 diabetes mellitus. J Med Assoc Thai.2004;87(5):543-546
  50. Farkaad AK, Faizah O, Mahmmod AA, Farida H, Pouya H. Effect of Tinospora crispa on thioacetamide-induced liver cirrhosis in rats. Ind J Pharm. 2011;43(1):64-68.
  51. Koh HL, Kian CT, Tan KH. A guide to medicinal plants: An illustrated, scientific and medicinal approach. Singapore: World Scientific Publishing Co. Pte. Ltd, 2009; p. 152.