Phytochemistry and Pharmacology of Ichnocarpus Frutescens

Chinese Journal of Natural Chinese Journal of Natural Medicines 2012, 10(4): 0241−0246 Medicines

doi: 10.3724/SP.J.1009.2012.00241

Phytochemistry and pharmacology of Ichnocarpus frutescens

Narendra Kumar Singh*, V. P. Singh

Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India Available online 20 July 2012

[ABSTRACT] Ichnocarpus frutescens R. Br. (Apocynaceae), is a woody climbing shrub, found almost in all parts of India. In India, tribes used this plant as a substitute of Indian Sarsaparilla (Hemidesmus indicus) for the treatment of atrophy, convulsions, cough, delirium, dysentery, measles, splenomegaly, tuberculosis, tumor, diabetes as a lactogogue, antipyretic, demulcent, diaphoretic and in skin diseases. Phytochemical investigations indicate that 28 compounds reported from the plant belong to various chemical category viz. phytosterol, triterpenes, flavonoids and various other phenolic compounds. Pharmacological activities of different parts of the plant reported include antiurolithiatic, hepatoprotective, antioxidant, analgesic, antipyretic, anti-inflammatory, antidiabetic, antihyperlipidemic and antitumor activity. In the present review the literature data on the phytochemical and biological investigations on the I. frutescens are summarized up to March 2011. [KEY WORDS] Ichnocarpus frutescens; Antitumor; Anti-inflammatory; Hepatoprotective [CLC Number] R93, R965 [Document code] A [Article ID] 1672-3651(2012)04-0241-06

1 Introduction linear lobes, longer than the hairy ovary. Follicles 10−15 cm. by 4 mm, straigit or slightly curved, very slender, cylindric, Ichnocarpus frutescens R. Br. (Apocynaceae), commonly rusty pubescent at first, afterwards glabrous. Seeds 1.3−2 cm known as Krishna Sariva, is a red woody climber, found al- long, linear, black, not beaked, coma as long as the seed, most in all parts of India, ascending to an altitude of 4 000 scanty and white[2]. ft[1]. Leaves of the plant are characterized by 4.5−7.5 by 2.0−3.8 cm, elliptic–oblong, acute or acuminate, glabrous 2 Ethnopharmacology above, glabrous or slightly pubescent and pale beneath, base Because of its good fragrance, it is known as Sugandha. usually rounded, main nerve 5−7 pairs with finely reticulate This plant is used by tribes as a substitute of Indian Sarsapa- venation, petiole 3−6 mm long. Flowers are greenish white, rilla (Hemidesmus indicus), for the treatment of atrophy, numerous, in axillary and terminal rusty-pubescent trichoto- convulsions, cough, delirium, dysentery, measles, splenome- mous pedunculate cymes, pedicles 3−4 mm long, often tree galy and tuberculosis. It is also used in the abdominal and together, rusty pubescent. Calyx fulvous–hairy, divided glandular tumors and its roots are used as alterative, anti- 1/2-way down, lobes ovate, acute, without glands inside. dysentric, antipyretic, demulcent, diaphoretic and hypogly- Corolla-tube is 2.5−3.0 mm long with a narrow portion below cemic[3-5]. Four different plant materials viz. Decalepis ham- about 0.85 mm long, the middle portion of the tube is much iltonii, Cryptolepis buchananii, Ichnocarpus frutescens and inflated (almost globular) over the stamens; the upper portion Hemidesmus indicus are indiscriminately sold in the local is constricted below the lobes, lobes 5 mm long pubescent on crude drug market under the name Sariva. Sariva is tradition- the upper side with white hairs, broad and oblong at the base, ally being given to pregnant women who have a tendency of produced at the apex into a long falcate slender twisted acu- abortion as this help to secure their fetal growth with advan- men which is deflexed in bud and flower. Disks of 5 erect tage. I. frutescens is used in the indigenous system of medicine in the treatment of fever, gout, rheumatism, arthritis, [6-7] [Received on] 30-June-2011 epilepsy, venereal diseases, herpes and skin diseases . [8] [*Corresponding author] Narendra Kumar Singh: M. Pharm., Tel: The roots of I. frutescens are given to treat rheumatic pain . [9] 91-9956749674, E-mail: narendra_ [email protected] Decoction of roots is used as blood purifier . The Gond These authors have no any conflict of interest to declare. tribes use the roots as remedy for jaundice[10]. The roots of I.

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Narendra Kumar Singh, et al. /Chinese Journal of Natural Medicines 2012, 10(4): 241−246 frutescens along with roots of Cissampelos pareira, Bauhinia isolation of α-L-sarbopyranoside (1)[20], α-L-ramnopyra- vahlii and Ardisia solanacea are processed together and giv- nosyl-(1→4)-β-D-glucopyranosyl-(1→3)-α-amyrin (2)[21], 6, en orally to cure stomach cancer[11]. Dried root powder of I. 8, 8, trimethylpentacosan-7-one (3), α-amyrin (4a) and its frutescens is used as lactogogue and is administered about 10 acetates (4b), lupeol (5a) and its acetates (5b), friedelin (6), g twice a day with a glass of fresh water after the meals[12]. epi-friedelinol (7) β-sitosterol (8)[22], n-butyl oleate (9), The leaf is given to treat fever[13] and root paste is applied in n-octyl tetracontane (10), tetratriacontadiene (11), the rat bites and skin diseases[14]. The roots of the plant are n-nonadecanyl benzoate (12) and benzocosanyl arachidate used as diuretic and diaphoretic[15]. The stalks and leaves are (13) from its stem[23]. used in the treatment of skin eruptions and fever[16]. The Leaves of the plant reported to contain apigenin (14), tribal’s of Madhya Pradesh and Siddis of Uttara Kannada luteolin (14b), vanillic acid, syringic acid, protocatechuic district of Karnataka use the roots and flowers as a cure for acid, sinapic acid[24], ursolic acid acetate (15a), kaempferol diabetes[17-18]. Leaf of the plant is used by the tribes of Chi- (16a), kaempferol-3-galactoside (17) and mannitol[25]. Flow- trakoot, Madhya Pradesh on cuts to stop bleeding[19]. ers of I. frutescens contain quercetin ( 16b ) and quercetin-3-O-β-D-glucopyranoside (18)[26]. Only one com- 3 Phytochemistry pound ursolic acid (15b) reported from the roots of the Phytochemical investigation on I. frutescens led to the plants[27].

roots of I. frutescens on nephrolithiasis induced in the rats 4 Pharmacology was investigated. Nephrolithiasis in the rats were induced by 4.1 Antiurolithiatic activity the administration of aqueous solution of ethylene glycol The inhibitory effect of the ethyl acetate extract of the (0.75%) for 28 d. Ethylene glycol feeding resulted in hyper-

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Narendra Kumar Singh, et al. /Chinese Journal of Natural Medicines 2012, 10(4): 241−246 oxaluria as well as increased renal excretion of calcium and nolic extract of leaves of I. frutescens in a dose of 200 phosphate. Urinary excretion of oxalate, calcium and phos- mg·kg−1 to carbon tetrachloride and tamoxifen-intoxicated phate are significantly increased in calculi-induced rats [(2.10 rats produced significant increment in the reduced glu- ± 0.08), (8.15 ± 0.33) and (7.2 ± 0.06) mg·dL−1, respectively] tathione levels with significant decrement in malondialde- as compared with normal control (saline) rats [(0.34 ± 0.02), hyde and lever transaminases levels. Histopathological (2.916 ± 0.17) and (3.64 ± 0.04) mg·dL−1, respectively]. changes of liver sections showed that prophylactic and cura- When standard drug (Cystone 750 mg·kg−1 p.o.) administered tive treatments with polyphenolic extract resulted in a rela- to calculi-induced rats, the excretion levels of oxalate, cal- tively good protection against both carbon tetrachloride and cium and phosphate were significantly decreased to (1.00 ± tamoxifen intoxicated rats. The extract inhibits CYP 0.05), (3.916 ± 0.25) and (3.18 ± 0.09) mg·dL−1 respectively. monooxygenase aminopyrine-N-demethylase and aniline Ethyl acetate extracts of the roots of I. frutescens were used hydroxylase, suggesting a plausible hepatoprotective mecha- −1 nism. The normalization of phenobarbitone induced sleeping in three different concentrations 250, 500 and 1 000 mg·kg time suggests the restoration of liver CYP enzymes. The p.o. on calculi-induced rats to determine the efficacy of the study shows that hepatoprotective effect of polyphenolic test drugs. It was observed that all the three concentrations of extract is by regulating the level of hepatic microsomal drug ethyl acetate extracts of I. frutescens decreased excretion metabolizing enzymes[29]. levels of oxalate and calcium significantly as compared to In another experiment chloroform and methanolic extract standard drugs, whereas excretion level of phosphate was of entire part of I. frutescens were conducted for their hepa- significantly less at the dose of 250 and 500 mg·kg−1 p.o. but toprotective effect on paracetamol (750 mg·kg−1)-induced almost equal to standard drug at the dose of 1 000 mg·kg−1 acute liver damage on Wister albino rats. The degree of pro- p.o. The deposition of crystalline components in the renal tection was measured using biochemical parameters such as tissues, namely oxalate, calcium and phosphate were in- serum glutamate oxalate transaminase (SGOT), serum glu- creased in calculi-induced rats [(1.650 ± 0.06), (5.216 ± 0.14) tamate pyruvate transaminase (SGPT), alkaline phosphatase −1 and (3.74 ± 0.10) mg·dL , respectively] as compared to (ALP), bilirubin and total protein. Chloroform and methanol normal (Saline) rats [(0.191 ± 0.02), (4.783 ± 0.38) and (2.35 extracts at a dose of 250 and 500 mg·kg−1 produce significant −1 ± 0.03) mg·dL , respectively]. The deposition levels of ox- hepatoprotection by decreasing the activity of serum enzymes alate, calcium and phosphate were significantly decreased and bilirubin but methanolic extract at the same dose showed [(0.500 ± 0.05), (3.633 ± 0.15) and (2.52 ± 0.07) mg·dL−1, better effect than chloroform extract. The effects of chloro- respectively] in standard group. Administration of 250 form and methanol extract of the plant were comparable to mg·kg−1 p.o. of ethyl acetate extract of I. frutescens signifi- those of standard drug silymarin[30]. cantly lowered the deposition of oxalate, calcium and phos- 4. 3 Antioxidant activity phate [(0.233 ± 0.03), (2.588 ± 0.23) and (2.08 ± 0.10), re- In vitro antioxidant activity of methanolic extract of spectively]. Serum uric acid and blood urea nitrogen re- roots of I. frutescens was performed. Methanolic extract of markably increased in calculi-induced rats [(7.866 ± 0.25) the plant exhibited strong scavenging effects on 2, and (25.09 ± 0.24)], while serum creatinine is slightly ele- 2-diphenyl-2-picryl hydroxyl (DPPH) free radicals, nitric vated in calculi-induced rats (0.855 ± 0.01). When standard oxide, super oxide anion, hydroxyl radicals and lipid peroxi- drug (Cystone 750 mg·kg−1 p.o.) was used in calculi-induced dation with IC50 were (17.4 ± 0.75), (172.8 ± 1.95), (37.4 ± −1 rats, the levels of uric acid, blood urea nitrogen and creatinine 0.34), (49.2 ± 0.64) and (130.7 ± 2.50) µg·mL , respec- [31] were significantly decreased [(5.033 ± 0.08), (21.398 ± 0.39) tively . In vitro antioxidant activity of petroleum ether, chloro- and (0.981 ± 0.006) mg·dL−1, respectively]. Administration of form, ethyl acetate and alcoholic extracts of flowers and fla- ethyl acetate extract of I. frutescens at 250 mg·kg−1 p.o. sig- vanoid isolated from thin layer chromatography from the nificantly reduced the levels of uric acid, blood urea nitrogen ethyl acetate extract of flowers of I. frutescens were per- and creatinine [(1.533 ± 0.14), (33.431 ± 0.73) and (1.146 ± formed. The percentage of free radical scavenging activity by −1 [28] 0.01) mg·dL , respectively] . DPPH assay and scavenging capacity for hydroxyl radicals of 4.2 Hepatoprotective activity different extracts and isolated flavanoid were performed. Protective and curative effect of polyphenolic extract of I. Isolated flavanoid showed more free radicals and hydroxyl frutescens against carbon tetrachloride and tamoxifen-in- radicals scavenging activity with IC50 was 33.89 and 19.83 duced hepatotoxicity in rats was examined. Carbon tetra- respectively than different extracts of the flowers of I. frutes- −1 −1 chloride (1 mL·kg ) and tamoxifen (45 mg·kg ) given cens[32]. through intraperitonial route caused liver damage in rats 4.4 Analgesic activity manifested by significant rise in serum enzymes levels, de- Analgesic effects of 70% alcoholic extract of leaves, clines in reduced glutathione level and elevations in stem and roots of I. frutescens were performed in Wistar rats malondialdehyde levels. The oral administration of polyphe- of either sex by hot plate and tail immersion methods. Alco-

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Narendra Kumar Singh, et al. /Chinese Journal of Natural Medicines 2012, 10(4): 241−246 holic extract of stem at a dose of 500 mg·kg−1 showed higher frutescens (250 and 500 mg·kg−1, p.o.) induced significant latency of percentage protection (hot plate, 154.12% and tail reduction (P < 0.05) of fasting blood glucose levels in strep- immersion 221.33%) in comparison with alcoholic extract of tozotocin−nicotinamide-induced type-II diabetic rats on 10th leaf (hot plate, 122.42% and tail immersion 195%) and root and 15th days. In the oral glucose tolerance test, the extract (hot plate, 138.66% and tail immersion 214.67%)[33]. increased the glucose tolerance[35]. 4.5 Antipyretic activity α-Glucosidase inhibitory activity of alcohol–water Methanolic extract of the roots of I. frutescens R. Br. extract (AWE) of Ichnocarpus frutescens leaves was studied was evaluated for its antipyretic potential on normal body in the rats. AWE exhibited the rat intestinal α-glucosidase, temperature and yeast-induced pyrexia in albino rats. Yeast sucrase, isomaltase, and maltase activities. Sucrose was suspension (10 mg·kg−1) increased rectal temperature 19 h administered orally with or without extract to rats at a dose of after subcutaneous injection. Methanolic extract of the root of 1 000 mg·kg−1, p.o. The postprandial elevation in the blood plant at doses of 100, 200 and 300 mg·kg−1, p.o. produced glucose level after the administration of sucrose with the significant reduction in normal temperature and yeast in- extract was significantly suppressed when compared with the duced elevated temperature in a dose-dependent manner. The control[36]. effect extended up to 5 h after the drug administration. The Insulin secretagogue effect of Ichnocarpus frutescens antipyretic effect of methanolic extract of root of I. frutescens leaf extracts were performed in the glucose-fed diabetic rats was found comparable to that of standard drug paracetamol and streptozotocin-induced diabetic rats. Methanolic extract (150 mg·kg−1, p.o.)[34]. of the leaf of I. frutescens was tested against different types 4.6 Anti-inflammatory activity of glycemia (normal, glucose–fed hyperglycemic and strep- The anti-inflammatory activity of the methanolic extract tozotocin-induced diabetic rats) for their potential to induce of the root of I. frutescens was evaluated by cara- insulin secretion and cellular insulin responses. Fasting plas- geenan-induced paw edema and cotton pellet-induced granu- ma glucose levels were determined at different doses and loma tests to determine its effects on acute and chronic phase times following treatment with methanolic extract of the leaf of inflammation models in rats. Methanolic extract of the root of I. frutescens or with vehicle in normal, glucose of I. frutescens showed maximum inhibition (54.63%) at a fed-hyperglycemic and diabetic rats. Oral administration of dose of 100 mg·kg−1 b.w. after 3 h of drug administration in the methanolic extract of the leaf of I. frutescens led to a carageenan-induced paw edema, whereas indomethacin pro- significant blood glucose-lowering effect in glucose–fed duced 57.65% of inhibition. In the chronic model 300 hyperglycemic and diabetic rats. The hypoglycemic effect −1 −1 was observed at doses of 100 and 200 mg·kg after 2 and 6 h mg·kg b.w. of methanolic extract like indomethacin and administration respectively in glucose–fed hyperglycemic dexomethasone standard drug decreased formation of granu- rats. The maximum effect of the methanolic extract of the loma tissue by 22.64%, 29.63% and 34.84% respectively[31]. leaf of I. frutescens was detected at 2 h with 200 mg·kg−1 in Anti-inflammatory activities of 70% alcoholic extract of leaf, diabetic animals and this profile was maintained for the next stem and roots of I. frutescens were analyzed by cara- 6 h (37.23%) but increased after that at 24 h. Oral administra- geenan-induced paw edema. Anti-inflammatory activity of tion of the methanolic extract of the leaf of I. frutescens daily ethanolic extract of stem at a dose of 500 mg·kg−1 showed for 45 d to diabetic rats significantly reduced the fasting higher percentage of inhibition (29%) at 180 min to reduce plasma glucose (54.5%) to near normal. After 7 d of strepto- inflammation in comparison to leaf and root extract (24% and zotocin administration plasma insulin decreased in diabetic 25% respectively) at the same dose[33]. controls compared to normal controls. Treatment with the 4.7 Antidiabetic activity methanolic extract of the leaf of I. frutescens significantly Antidiabetic activity of aqueous extract of roots of I. prevented the decrease in plasma insulin levels from day 0 to frutescens was estimated in streptozotocin–nicotinamide 45 in comparison to diabetic controls. Oral administration of -induced type-II diabetic rats. Type-II diabetic rats were ad- n-hexane fraction led to a significant glucose-lowering effect −1 ministered aqueous root extract (250 and 500 mg·kg , p.o.) in diabetic rats (54.50%). Histopathological examination of the plant drug or vehicle (gum acacia solution) or standard showed that methanolic extract of the leaf of I. frutescens −1 drug glibenclamide (0.25 mg·kg ) for 15 d. Blood samples extract protected the pancreatic tissue from streptozoto- were collected by retro-orbital puncture and were analyzed cin-induced damage enormously. Oral administration of for serum glucose level on days 0, 5, 10 and 15 using glucose methanolic extract and n-hexane extract of the leaf of I. fru- oxidase-peroxidase reactive strips and glucometer. For oral tescens to normal and streptozotocin-induced diabetic rats glucose tolerance tests glucose (2 g·kg−1, p.o.) was adminis- decreased plasma glucose levels without hypoglycemic ef- tered to nondiabetic control rats treated with glibenclamide fect[37]. (10 mg·kg−1, p.o.) and aqueous root extract of I. frutescens. The effects of polyphenol extract of I. frutescens in the The serum glucose levels were analyzed at 0, 30, 60 and 120 progression of nephropathy due to oxidative stress in strep- min. after drug administration. The aqueous root extract of I. tozotocin-induced diabetic rats were studied. Intraperitoneal

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Narendra Kumar Singh, et al. /Chinese Journal of Natural Medicines 2012, 10(4): 241−246 glucose tolerance test revealed a significant decrease in blood 5 Conclusion glucose levels at 180 min after glucose loading in rats fed The phytochemical investigations of I. frutescens reveal with polyphenol extract of I. frutescens. During the eight the occurrence of 28 chemical compounds belong to phytos- weeks of experimental period, diabetic rats exhibited wide terol, triterpenes, flavonoids and other phenolics. Out of 28 range of symptoms, including loss of body weight, hypergly- compounds only one compound ursolic acid was reported cemia, polyuria, proteinuria, renal enlargement, and total from the root of the plant. Extracts and fractions of the plant renal dysfunction. A significant increase in TBARS possess antiurolithiatic, hepatoprotective, antioxidant, anal- (Thio-Barbituric acid reactive substances) level was observed gesic, antipyretic, anti-inflammatory, antidiabetic, antihyper- in diabetic kidney, which was accompanied by a significant lipidemic and antitumor activity. Pharmacological investiga- decrease in enzymatic and non-enzymatic antioxidant levels. tions of the plant reveal that no biological activity has been After eight weeks, polyphenol extract of I. frutescens treated reported for isolated compound. groups showed a lower level of blood glucose compared with non-treated streptozotocin-induced diabetic rats. The in- Acknowledgements creases in urinary albumin and protein after eight weeks of Authors are thankful to Mr. Ashok Gupta, Department of treatment were significantly inhibited by prolonged treatment Pharmacology, IMS, BHU, for providing literature data for with polyphenol extract of I. frutescens. In addition, poly- this review. phenol extract of I. frutescens attenuates the adverse effects on hepatic biomarkers[38]. References 4.8 Antihyperlipidemic activity Antihyperlipidemic effects of the polyphenolic extract of [1] Medicinal plants of India (Vol. 2) [M]. New Delhi: Indian Council of Medical Research, 1987, 62-64. I. frutescens leaves was evaluated in alloxan-induced diabetic [2] Kirtikar KR, Basu BD. Indian medicinal plants [M]. New rats. Diabetes was induced by single intraperitoneal injection Delhi: Lalit Mohan Basu publications Allahabad. 1998, −1 of alloxan (150 mg·kg ). Administration of polyphenolic 1590-1592. extract of the plant (300 mg·kg−1 for 21 d) showed significant [3] Chatterjee A, Prakashi S. The treatise of Indian medicinal decrease in hepatic HMG-CoA reductase activity of alloxan plants (Vol. 4) [M]. New Delhi: NISCAIR, 2003, 110-112. [4] Anonymous: A dictionary of Indian raw materials and indus- diabetic rats. No significant effects were found in the normo- trial products (Vol. 3) [M]. New Delhi: NISCOM, 2002, 330. glycemic rats. Polyphenolic extract exhibited significant [5] Ambasta SP. Useful plants of India [M]. New Delhi: NISCOM, hypolipidemic effect as evident from correction of hyperlipi- 1999, 283. demic indicators (TC, TGs, VLDL, HDL and LDL). Oral [6] Anonymous: The wealth of India: A dictionary of Indian raw administration of polyphenolic extract (100 mg·kg−1) signifi- materials and industrial products (Vol. V) [M]. New Delhi: cantly enhanced the release of lipoprotein lipase enzyme CSIR 1959, 162-163. [7] Nandkarni KM. The Indian material medica [M]. New Delhi: significantly. The histopathological studies of aorta in poly- Bombay popular prakashan, 1982, 674. phenolic extract treated alloxan-rats revealed almost recovery [8] Singh V, Pandey RP. Medicinal plant-lore of the tribal’s of [39] to normal appearance . eastern Rajasthan (India) [J]. J Econ Tax Bot, 1980, 1:137-147. 4.9 Antitumor activity [9] Goel AK, Mudgal V. A survey of medicinal plants used by the In vivo antitumor activity of polyphenolic extract of tribals of Santal Pargana (Bihar) [J]. J Econ Tax Bot, 1988, 12: leaves of I. frutescens was evaluated on Murine Ehrlich As- 329-335. [10] Rai MK. Ehtnomedicinal survey of Patalkot and Tamiya (Dis- cites Carcinoma (EAC) model. In vitro cytotoxicity study trict Chhindwara) Plants used against skin diseases and liver was performed in monocytoid leukemia (U-937) and disorders [J]. J Econ Tax Bot, 1988, 12(92): 337-339. erythroleukemia (K-562) cell lines. In vivo study showed a [11] Hembrom PP. Tribal medicine in Chotanagpur and Santhal significant decrease in tumor volume, viable tumor cell count Parganas of Bihar, India [J]. Ethnobotany, 1991, 3: 97-99. and a significant increase of life span in the polyphenolic [12] Singh AK, Raghubanshi AS, Singh JS. Medical ethnobotany of extract treated group compared to the untreated one. The life the tribal’s of Sonaghati of Sonbhadra district, Uttar Pradesh, span of polyphenolic extract treated animals increased by India [J]. Ethnopharmacology, 2002, 81(1):31-41. −1 −1 [13] Rajendran K, Rengamani SK. Medicinal plants and their utili- 53.41% (50 mg·kg ) and 73.95% (100 mg·kg ). The result zation by villagers in southern districts of Tamilnadu [J]. J was found comparable with standard drug 5-fluorouracil Econ Tax Bot, 2006, 30: 208-216. (86.97%) at a dose of 20 mg·kg−1. In vitro study indicates that [14] Malabadi RB, Mulgund GS, Nataraja K. Ethanobotanical sur- polyphenolic extract of the leaves of the plant at doses of 5, vey of medicinal plants from Belgaum district, Karnataka [J]. 10 and 20 µg·mL−1 effectively inhibits proliferation of U-937 India J Med Arom Plant Sci, 2007, 29: 70-77. [15] Nandkarni AK, Ichnocarpus frutescens. In: The Indian material and K-562 cell lines and result was found comparable with medica (Vol. 1) [M]. New Delhi: Bombay popular prakashan standard drug cytarabine arabinoside at a dose of 20 2002, 674. µg·mL−1[40-41]. [16] Yoganarasimhan SN, Togunashi VS, Keshavamurthy KR, et al.

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