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Clausena excavata Burm. (Rutaceae)

Synonyms

Clausena lanulata Hayata, Clausena moningerae Merr., Clausena tetramera Hayata.

Vernacular Names:

Malaysia: Pokok Kemantu, Pokok Cerek
English: Clausena
Australia: Whample [1]
Chinese: Jia Huang Pi, Ye Huang Pi.
Indonesia: Bagal Tikus (Java), Chamar, Daun Sicerek [2]

General Information

Clausena excavata is a wild shrub which grows up to 1.5m high and is extensively distributed in Southeast Asia.  It is found in India (from the Coromandel and northern districts to Bhutan), Burma, Thailand, southern China, Vietnam, Laos, Cambodia, the Malay Peninsula, Sumatra, Java, Borneo, Philippines and New Guinea. [3]

Description

The trees or shrubs are without spines. The leaves are odd-pinnate, leaflets alternate, usually 3-7 sometimes 19-32. The rachis usually not winged. The inflorescences terminal or axillary, paniculate or laxly racemose, flowers often in cymose clusters, flower buds small, subglobose or short-oval or oblong, never long-cylindric. The flowers small, calyx 4-5 lobed. The sepals fused into a cup below. The petals free, 4 or 5 imbricate in the bud, usually elliptical; stamens 10, in 2 whorls, the outer row opposite, the sepals usually longer, filaments more or less dilated or flattened below, often geniculate where the filiform apical portion joins the flattened and expanded basal portion, anthers ovate or elliptical, rarely short and subglobose. The gynophore well developed, usually a perfectly glabrous hourglass-shaped column resting on an annular nectary below and supporting (sometimes clasping). The base of the ovary above; ovary with 2-5 locules, often pubescent or glandular, ovules 2 in each locule (rarely 1). The style deciduous, often shorter than the ovary or equaling it in length (rarely longer), thick, sometimes merging gradually into the ovary, often sharply delimited and narrowed where it joins the ovary. The stigma is inconspicuous, sometimes subcapitate after the style shrivels. The fruits are small, subglobose or ovate, with 2-5 segments, sometimes only 1 seed maturing and all flower parts are usually showing many (not all) cells strongly impregnated with tannin residues. [3]

C. excavata has a distinctive gynophore which is full, smooth, hourglass-shaped and is completely glabrous supporting a strongly hirsute ovary.  It arises from the annular nectary below and, after contracting, again expands and may even be slightly flaring where it joins the ovary.  The ovary, which is 5-locular, tapers gradually into the thick style without any clear line of demarcation, the style is not narrowed where it joins the tip of the ovary. [3]

Plant Part Used

Stems,woods, leaves. [11][16]

Chemical Constituents

The acetone extract of the root bark of C. excavata contained carbazole alkaloids; clausine-M, -N, -O, -P, -Q, -R, -S, -U, -V and clausenatine-A, 2-hydroxy-3-formyl-7-methoxycarbazole, glycozolidal, heptaphylline, murrayafoline-A, 3-methylcarbazole, girinimbine, mukonal, mukonidine, mukonine, methyl carbazole-3-carboxylate, murrayanine, 3-formylcarbazole, clausine-C, -E, -F, -K, -T, -W, furoclausine-A, -B, clausevatine-D, -E, -F, -G, clausamine-A, carbazomarine-A and 2,7-dihydroxy-3-formyl-1-(3′-methyl-2′-butenyl) carbazole; the coumarins; claucavatin-A, claucavatin-B, kinocoumarin, clausenidin, clausarin, nordentatin, xanthoxyletin, xanthyletin, osthol, and cedrelopsin; and flavonoids, isoliquiritigenin and 4′,7-dihydroxyflavanone. [4][5] Other compounds were carbazole alkaloids; lansine, heptaphylline, heptazoline, methyl carbazole-3-carboxylate, murrayanine (2-hydroxy-3-methylcarbazole, clausine-D; a coumarin, scopoletin; phenols, methyl p-hydroxycinnamate and syringaldehyde; tetranortriterpenoids, zapoterin and O-methylclausenolide and a carbazoquinone, clausenaquinone-A. [6][7][8]

The methanol extract of the stem bark of C. excavata contained clausines A, C, G and J which were identified as 3-formyl-2-hydroxy-8-methoxycarbazole 3-carbomethoxy-7-methoxycarbazole, 3-carbomethoxy-l-hydroxy-6-methoxycarbazole and 3-formyi-1, 7-dihydroxy-6-methoxycarbazole, respectively. [9]

A binary carbazole alkaloid, clausenamine-A, and a carbazolepyranocoumarin were isolated from the stem bark and root bark extract of C. excavate. [10]   The rhizomes and roots of C. excavata contained O-methylmukonal, 3-formyl-2,7-dimethoxycarbazole and clauszoline J. [8]

Clausine-L, a carbazole alkaloid and 11 known compounds, safrole, glutinol, 132-hydroxy( 132-R)-pheophytin-a, methyl pheophobide-a, scopoletin, steroidal glycoside [b-sitosteryl glucoside + stigmasteryl glucoside], 2-methoxy-4-(2-propenyl)phenyl-/3-D-glucoside, 2,6-dimethoxy-4-(2-propenyl)phenyl-b-D-glucoside, p-hydroxybenzoic acid, rutin and nicotiflorin were isolated from the leaves of C. excavate. [11]

Other compounds isolated from C. excavata were the coumarins, dentatin, nordentatin, clausenidin and xanthoxyletin [12]; excavatins A-M [13] and carbazole derivatives, 3-formylcarbazole, mukonal, 3-methoxycarbonylcarbazole, murrayanine, 2-hydroxy-3-formyl-7-methoxycarbazole and clauszoline J. [12] Clauslactone-N, clauslactone-O, clauslactone-P and clauslactone-Q were isolated from the leaves and twigs of C. excavata collected in Indonesia. [14]

Traditional Use:

C. excavata is used in folk medicine to treat snake-bites, abdominal pain and as a detoxification agent. [4][6][11][15] In eastern Thailand, it is used as a folk remedy for cancer and HIV infection. [15][16] The leaves and stem are used in the treatment of cough, headache, rhinitis, sore, wounds, yaws and for detoxification. [16] An infusion of the stem is used for colic. [15][17] It is claimed as a useful folk remedy for the treatment of paralysis, colic, fever and headache.  It is also used as a tonic, diuretic, as an astringent and a vermifuge, and also as an insecticide. [15][17] The leaves are used in the treatment for cold, malaria and dysentery. [11] The sap is used as a rub for all kinds of muscular pain while malarial fever is treated with the root decoction. [17]

Pre-Clinical Data

Pharmacology

Antiplatelet and vascular activity

The clausine-D that was isolated from C. excavata exhibited an antiplatelet effect which was mediated by inhibition of thromboxane A2 formation. The aggregation and release reaction of washed rabbit platelets induced by arachidonic acid (100µM) and collagen were inhibited by clausine-D in a concentration-dependent manner with IC50 values of 9.0 ± 1.1 and 58.9 ± 0.9µM, respectively.  Complete inhibition of arachidonate-induced platelet aggregation and ATP release reaction was elicited by 15µM clausine-D.  A higher concentration of clausine-D (150µM) was required to produce almost complete inhibition of collagen-induced platelet aggregation.  Even at this high concentration (150µM), clausine-D only minimally inhibited aggregation induced by U46619 (1µM), PAF (2 ng/ml)and thrombin (0.1U/mL) in rabbit platelets.  The clausine-D (3-30µM) also produced a concentration-dependent suppression of arachidonic acid-induced formation of thromboxane B2, a stable metabolite of thromboxane A2.  The thromboxane B2 formation induced by collagen (10µg/mL), PAF (2ng/ml), and thrombin (0.1U/ml) were markedly inhibited by clausine-D (30µM).  Arachidonate-induced formation of prostaglandin D2 was inhibited by clausine-D (30µM). [18]

The effect was similar to that produced by indomethacin (1µM), a cycloxygenase inhibitor, while a thromboxane synthase inhibitor, imidazole (1mM), decreased arachidonate-induced formation of thromboxane B2 but produced marked potentiation of  arachidonate-induced formation of prostaglandin D2.  Many inducers of platelet aggregation cause breakdown of phosphoinositides.  Clausine-D (30µM) abolished arachidonate(100µM)-induced generation of inositol monophosphate.  However, the generation of inositol monophosphate by collagen (10µg/mL), U46619 (1µM), PAF (2ng/mL) and thrombin (0.1U/mL), agonists which were known to activate platelets, was unaffected by clausine-D.  The increase in intracellular calcium concentration in platelets that was inducible by both arachidonic acid (100µM) and collagen (10µg/mL) was inhibited by clausine-D (30µM).  Epinephrine (5µM) and ADP (3µM) caused biphasic aggregation in human citrated platelet-rich plasma.  The secondary phase, although not the primary phase, of epinephrine- and ADP-induced aggregation in human platelet-rich plasma was inhibited by clausine-D in a concentration-dependent manner. Thesecondary aggregation was known to depend on the generation of thromboxane A2 and on the release of ADP, and to be inhibited by cyclooxygenase inhibitors.  The antiplatelet effect of clausine-D closely resemble that of indomethacin but was different from that of the thromboxane synthase inhibitor, imidazole. [18]

The compounds isolated from C. excavata produced significant inhibition of rabbit platelet aggregation induced by arachidonic acid (100µM), collagen (10µg/mL) and platelet activation factor (2ng/mL) and inhibited vasocontraction. Clausine E produced 58.3% and 89.3% inhibition of rat aorta phasic and tonic contraction induced by NE (3µM), together with 87.0% inhibition of tonic contraction induced by K+ (80 mM) plus Ca2+ (1.9 mM).  Only one promotive constituent, O-methylclausenolide, was isolated, however the crude MeOH extract, partitioned layers and chromatographic fractions displayed both inhibitive and promotive effects on platelet aggregation. The simultaneous presence of both promotive and inhibitive constituents provided an explanation for the philosophy of use of C. excavata in Chinese medicine whereby promotive or inhibitive effects can be produced during therapy depending on the dose used and the variation in content. [6]

The clausenaquinone-A (10µg/mL) which was isolated from the stem bark of C. excavata completely inhibited (100 ±0.8%) rabbit platelet aggregation induced by arachidonic acid (100µM) and was cytotoxic to HCT-8, RPMI-7951 and TE671 tumor cells with IC50 values of 0.92, 0.22 and 3.82 I. µg/mL, respectively. [7]

The safrole (20µg/mL) which was isolated from the leaves of C. excavata produced 70% inhibition of rabbit platelet aggregation which was induced by arachidonic acid (100µM).  At a higher concentration, safrole (50 µg/mL) produced 48% inhibition of collagen (10µg/mL)-induced platelet aggregation. [19]

Inhibition of cyclin-dependent kinase 5 activity

The clausine Z which was isolated from the stems and leaves of C. excavata showed inhibitory activity against cyclin-dependent kinase 5 and protected cerebellar granule neurons in vitro. [20] 

Immunomodulating activity

The aqueous extract of the wood of C. excavata and a Thai folklore preparation of the plant showed potential in vivo immunomodulating activities in Balb/C mice. Prior to treatment with the extracts, mice were injected with sheep erythrocyte suspension (1×108 cells/0.2mL buffered saline, i.p.).  The mice were then fed (2.5g/mL dose for each extract) or intraperitoneally (i.p.) injected (0.4 g/mL dose for each extract) with the extracts daily for 5 days after which all mice were again immunized with sheep erythrocyte suspension.  The serum haemagglutinating antibody titers were determined at days 0, 7, 14, 21, 28 and 35 for evaluation of humoral mediated immunity.  The cimetidine (10mg/mL) was used as the positive control.  Cell mediated immunity to determine delayed type hypersensitivity was assessed by the footpad swelling test.  Mice were first immunized with an i.p. injection of sheep erythrocyte suspension (1×108 cells/0.2mL buffered saline) and then treated with the extracts (0.4g/mL dose for each extract) by i.p. or oral administrations or with dexamethasone (0.5mg/mL, i.p.) or indomethacin (10mg/mL, i.p.) which were the positive controls. [16]

Seven days later, the left hind paw was challenged with sheep erythrocyte suspension (1×108 cells), while the right hind paw served as the control.  Both the aqueous extract and the folklore preparation when administered i.p., produced the same maximum antibody production of 1/800 on day 21, which was twice that of the control.  The cimetidine as the positive control, produced a maximum titer of 1/1600 on day 21.  With oral administration, both extracts and cimetidine produced the maximum antibody titer of 1/800 on day 7 which was twice that of the control.  The oral response occurred earlier than the response elicited by intraperitoneal injections of the extracts.  The antibody titers elicited by the aqueous extract, i.p., was not retained while that produced by the folklore preparation was retained for 1 week.  The aqueous extract was more effective than the folklore extract for reduction of cell mediated immunity. The footpad swelling was reduced by the aqueous extract to a similar extent as the reduction caused by indomethacin, and about 95% of that due to dexamethasone. [16]

The effects of fractions from the hot aqueous extract, acetone extract and the folklore preparation of C. excavata were studied on mouse splenocyte proliferation to demonstrate the plant’s immunomodulatory activity. The fractions eluted from the hot aqueous extract and acetone extract significantly increased mouse splenocyte proliferation although not in a dose-dependent manner, while fractions obtained from the folklore preparation were less active.  In vitro, the crude extracts obtained by aqueous and acetone hot extraction produced significant phagocytosis and proliferative activity in the mouse immune system. [15]

The aqueous extract, acetone extract and the Thai folklore extract of C. excavata showed immunomodulatory activities on the mouse immune system. The extracts showed effective phagocytic activation with the aqueous extract eliciting the maximum response on both the respiratory burst and lysosomal enzyme activity while the responses elicited by the acetone and Thai folklore extracts were smaller.  The splenocyte proliferation assay was carried out in the absence and presence of mitogens (lipopolysaccharide, LPS or pokeweed mitogen).  In this assay, the Thai folklore extract with LPS elicited the maximum response, higher than that obtained with pokeweed mitogen.  This suggests that the Thai folklore extract was specific for B cell proliferation through the T cell independent pathway, similar to LPS. [21]

Anticancer activity

The clausemine-A which was isolated from the stem and root bark of C. excavata showed moderate activity in a disease-oriented antitumor screen in vitro which determined a compound’s effectiveness on the growth parameters of approximately 60 human tumor cell lines. The clausemine-A exhibited fairly good activity against leukemia, nonsmall cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer. [22]

Antinociceptive activity

The ethanolic extract of C. excavata leaves (125.25 and 500mg/kg body weight, p.o.) produced significant antinociceptive activity in the acetic acid-induced writhing test in mice. [17]

Antibacterial activity

The nordentatin isolated from the root bark exhibited strong antibacterial activity. [5] The coumarins, dentatin, nordentatin, clausenidin and the carbazole derivatives, 3-formylcarbazole, mukonal, 3-methoxycarbonylcarbazole, 2-hydroxy-3-formyl-7-methoxycarbazole and clauszoline J exhibited antimycobacterial activity with minimum inhibitory concentrations (MIC) of 50, 100, 200, 100, 200, 50, 100 and 100µg/mL, respectively. 3-Formylcarbazole, mukonal, 3-methoxycarbonylcarbazole and 2-hydroxy-3-formyl-7-methoxycarbazole also showed antifungal activity with IC50 values of 13.6, 29.3, 9.5 and 2.8µg/mL, respectively.  None of the compounds was cytotoxic to KB and BC-1 cell lines. [12]

Anti-HIV activity

The O-Methylmukonal, 3-formyl-2,7-dimethoxycarbazole and clauszoline J and clausenidin isolated from the rhizomes and roots of C. excavata exhibited anti-HIV-1 activity in a syncytial assay with EC50 values of 12, 29.1, 34.2 and 5.3µM, respectively. [8] All four compounds were non cytotoxic to KB and BC-1 cancer cell lines.

Clausenolide-1-ethyl ether, which was obtained from the crude ethanol extract of the rhizomes and the roots exhibited HIV-1 inhibitory activity. [23] The dentatin and nordentatin which were obtained from the crude chloroform extract of the rhizomes induced toxicity to cells used in a syncytium assay for anti-HIV-1 activity.

Toxicities

The thai folklore extract of the wood of C. excavata had an i.p. LD50 value in rats of 1.6g/kg body weight while the oral LD50 value in rats was more than 10g/kg body weight. [16]

The clausenolide-1-ethyl ether, dentatin and nordentatin were not cytotoxic against KB and BC-1 cell lines (IC50 value > 20µgram/mL). [23]

Genotoxicities and Mutagenicity Studies

No documentation

Clinical Data

Clinical Trials

The folklore preparation of C. excavata wood produced an increase of CD4/CD8 ratio in advanced cancer patients who took the crude extract orally. [15]

Adverse Effects in Human:

No documentation

Use in Certain Conditions

Pregnancy / Breastfeeding

No documentation

Age Limitations

Neonates / Adolescents

No documentation

Geriatrics

No documentation

Chronic Disease Conditions

No documentation

Interactions

Interactions with drugs

No documentation

Interactions with Other Herbs / Herbal Constituents

No documentation

Contraindications

Contraindications

No documentation

Case Reports

No documentation

References

    1. Australian new crops.  http://www.newcrops.uq.edu.au/listing/commonnameslistingindexw.htm
    2. Clausenia names. http://www.plantnames.unimelb.edu.au/Sorting/Clausena.html
    3. Swingle WT.  Chapter 3. The Botany of Citrus and Its Wild Relatives.  http://lib.ucr.edu/agnic/webber/Vol1/Chapter3.html
    4. Wu TS, Huang SC, Wu PL, Kuoh CS.  Alkaloidal and other constituents from the root bark of Clausena excavata .  Phytochemistry, 52(3): 523-527, 1999.
    5. Huang SC, Wu PL, Wu TS.  Two coumarins from the root bark of Clausena excavata. Phytochemistry, 44(1): 179-181, 1997.
    6. Wu TS, Huang SC, Wu PL, Teng CM.  Carbazole alkaloids from Clausena excavata and their biological activity.  Phytochemistry, 43(1): 133 140, 1996.
    7. Wu TS, Huang SC, Wu PL, Lee KH.  Structure and synthesis of clausenaquinone-A. A novel carbazolequinone alkaloid and bioactive principle from Clausena excavata. Bioorganic & Medicinal Chemistry Letters, 4(20): 2395-2398, 1994.
    8. Kongkathip B, Kongkathip N, Sunthitikawinsakul A, Napaswat C, Yoosook C.  Anti-HIV-1 constituents from Clausena excavata: Part II. Carbazoles and a pyranocoumarin.  Phytother Res., 19(8):728-31, 2005.
    9. Wu TS, Huang SC, Wu PL.  Carbazole alkaloids from stem bark of Clausena excavata. Phytochemistry, 43(6): 1427-1429, 1996.
    10. Wu TS, Huang SC, Wu PL.  Carbazole-pyranocoumarin dimer and binary carbazole alkaloid from Clausena excavata.  Tetrahedron Letters, 37(43): 7819-7822, 1996.
    11. Wu TS, Huang SC, Lai JS, Teng CM, Ko FN, Kuoh CS.  Chemical and antiplatelet aggregative investigation of the leaves of clausena excavata.  Phytochemistry, 32(2): 449-451, 1993.
    12. Sunthitikawinsakul A, Kongkathip N, Kongkathip B, Phonnakhu S, Daly JW, Spande TF, Nimit Y, Rochanaruangrai S.  Coumarins and carbazoles from Clausena excavata exhibited antimycobacterial and antifungal activities.  Planta Med., 69(2):155-7, 2003.
    13. Trinh TT, Ripperger H, Porzel A, Tran VS, Adam G.  Coumarins, limonoids and an alkaloid from Clausena excavata. Phytochemistry, 52(3): 511-516, 1999.
    14. Takemura Y, Nakamura K, Hirusawa T, Ju-ichi M, Ito C, Furukawa H.  Four new furanone-coumarins from Clausena excavata.  Chem Pharm Bull (Tokyo)., 48(4):582-4, 2000.
    15. Manosroi A, Saraphanchotiwitthaya A, Manosroi J.  Immunomodulatory activities of fractions from hot aqueous extract of wood from Clausena excavata. Fitoterapia, 75(3-4): 302-308, 2004.
    16. Manosroi A, Saraphanchotiwitthaya A, Manosroi J.  In vivo immunomodulating activity of wood extracts from Clausena excavata Burm. f.  J Ethnopharmacol., 102(1): 5-9, 2005.
    17. Rahman MT,  Alimuzzaman M, Shilpi JA, Hossain MF.  Antinociceptive activity of Clausena excavata  leaves.  Fitoterapia, 73(7-8): 701-703, 2002.
    18. Wu CC, Ko FN, Wu TS, Teng CM.  Antiplatelet effects of Clausine-D isolated from Clausena excavata. Biochimica et Biophysica Acta, 1201: 1-6, 1994.
    19. Wu RS, Huang SC, Lai JS, Teng CM, Ko FN, Kuoh CS.  Chemical and antiplatelet aggregative investigation of the leaves of Clausen A excavata.  Phytochemistry, 32(2): 449-451, 1993.
    20. Potterat O, Puder C, Bolek W, Wagner K, Ke C, Ye Y, Gillardon F. Clausine Z, a new carbazole alkaloid from Clausena excavata with inhibitory activity on CDK5.  Pharmazie., 60(8): 637-9, 2005.
    21. Manosroi A, Saraphanchotiwitthaya A, Manosroi J Immunomodulatory activities of Clausena excavata Burm. f. wood extracts.  J Ethnopharmacol., 89(1):155-60, 2003.
    22. Zhang A and Lin G.  The first synthesis of clausenamine-A and cytotoxic activities of three biscarbazole analogues against cancer cells.  Bioorganic & Medicinal Chemistry Letters, 10(10): 1021-1023, 2000.
    23. Sunthitikawinsakul A, Kongkathip N, Kongkathip B, Phonnakhu S, Daly JW, Spande TF, Nimit Y, Napaswat C, Kasisit J, Yoosook C.  Anti-HIV-1 limonoid: first isolation from Clausena excavata.  Phytother Res., 17(9):1101-3, 2003.

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