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Vernonia amygdalina

Synonyms

Vernonia senegalensis, Gymnanthemum amygdalinum (Delile) Walp. [1] [3]

Vernacular Names:

Malaysia

Daun Bismillah

English

Bitterleaf, common bitterleaf

French

Vernonie, Vernonie commune, ndole

German

Vernonia

Portuguese

Sucumdiera, pau fede

Afrikaans

Riverbloutee [1] [3]

General Information

Description

Vernonia amygdalina is a member of the Asteraceae family. It is a shrub or small tree that can reach up to 10 m high with trunk diameter reaching up to 40cm. The bark is grey to brown, smooth, becoming fissured and when young is densely pubescent. The leaves are alternate, simple, with petiole measuring 0.2 – 4 cm long. The leaf blade is ovate-elliptical to lanceolate and measures 4 – 15 cm x 1 – 4 cm, cuneate or rounded at base, shortly acuminated at the apex, margin minutely toothed to coarsely serrate, finely pubescent but often glabrescent. The inflorescence is in the form of a head, arranged in terminal, compound, umbel-like cymes. Head stalk is measure about 1 cm long, pubescent. The flowers are bisexyal, regular, 5-merous, strongly exserted from the involucres which are cylindrical to broadly ellipsoid. The fruit is a 10-ribbed achene measuring 1.5 – 3.5 mm long, pubescent and glandular, brawn to black, crowned by a much longer pappus bristles. [1]

Plant Part Used

Leaves, barks and seeds. [3]

Chemical Constituents

Vernodaline; vernomygdin; vernodalol; vernolide; hydroxyvernolide; tannins; vitamin C; luteolin; luteolin 7-O-b-glucoronide; leteolin 7-O-b-glucoside; vernonioside D and E; vernolepin; vernonioside A1 – A4; vernonioside B1 – B3; vernodalinol; alpha-muurolol; 1,5-dicaffeoyl-quinic acid, dicaffeoyl-quinic acid, chlorogenic acid and luteolin-7-O-glucoside. [3] [4] [5] [6] [7] [8] [9] [10]

Traditional Used:

Vernonia amygdalina had been recently introduced into the Malaysian herbal armamet and there has been quite a good followings on the use of the plant to treat diabetes, hypertension and hypercholesterolaemia. The plant is a vegetable in its native land and is put through a detoxification process before being cooked as food. The process involved boiling the leaves several times with change of water after each cycle until the bitterness disappears. [1] [3]

Gastrointestinal Diseases
In West Africa the decoction of the leaves or bark is used in the treatment of diarrhea, dysentery and other gastrointestinal disorders. It is commonly used as a vermifuge not only by humans bit also chimpanzee. The young branches are chewed on to clean and strengthen teeth and clears gum infection. It also acts as an appetite stimulant and a tonic. The cold water extract of the roots together with leaves of Vigna sinensis is a traditional remedy for schistosomiasis.[1] [3]

Inflammatory Diseases
The leaves are used on wounds as a substitute for iodine in Nigeria. The leaves are also used to treat fevers especially malaria, hepatitis, and skin parasitic infestations like scabies. The root infusion are used to treat sexually transmitted diseases while that of the bark clears fever. [1] [3]

Other uses
The decoction of the leaves is prescribed for cough, as a laxative and as a fertility inducer. It is also used to treat headache. The infusion of the roots is used as a douche for uterine pain. [1] [2]

Pre-Clinical Data

Pharmacology

Antiplatelet activity
Vernolepin is a sesquiterpene lactone isolated from the dried fruit of V. amygdalina. It was found to have antiaggregating and diaggregating activity against rabbit platelet aggregation induced by arachindonic acid or ADP without inhibition of cyclo-oxygenase or lipoxygenase. Electronmicroscopy showed that the drug protects platelets against adhesion and desegregation effects. [6] [7]

Antisickling activity
V. amygdalina leaf methanolic extract exhibited significant antisickling activity but not as good as those of Solenostemon monostachyus, Carica papaya seed oil and Ipomoea involucratan in males with sickle-cell anaemia. The effects observed include a) lowering of levels of sickle blood cells; b) reduction in Fe2+/Fe3+ ratio; c) increased in haemoglobin concentration; d) inhibition of sickle cell polymerization. [11]

Antihaemolytic activity
The methanol extract was seen to be able to reduce tert-butyl hydropreoxide (t-BHP)-induced eryhtocyte lysis significantly. The effective dose range is between 25 – 150 microg/l. This protective effects seem to be related to the antioxidant activity of the extract. On the contrary, it has been found that infusion of the leaves induces haemolysis of mammalian erythrocyte in vitro, with Human genotype-SS (1024) having the highest susceptibility. Human genotype-AS were moderately affected while Human genotype-AA (256) were highly resistant. [12] [13]

Anti-allergic activity
The aqueous and methanol extracts of the leaves of V. amygdalina showed anti-allergic activity as a prophylactic and as curative. In the prophylactic protocol both extracts exerted significant inhibitory effects on the development of Atopic Dermatitis symptoms, the production of IgE, TNF-alpha, IL-5 and IFN-gamma and on the increase thickness of ear. In the curative protocol, it was found that topical application of both extracts markedly improved the skin lesions i.e. erythema/haemorrhage, scaling/dryness, erosion/excoriation and decrease ear thickness in mice. There were also decreases in serum total IgE, MCP-1 and eotaxin. The methanol extract was found to improved chronic eczema dermatitis skin symptoms in a patient. [16]

Myometrial contractility
Nine plants were screened for the myometrial contractile activity and included in this study was the leaves of V. amygdalina. It was found that the aqueous extract of V. amygdalina induced significant sustained increases in human myometrial smooth muscle contractility. [17]

Anticancer activity
Many studies had been conducted to determine the effects of v. amygdalina on the activity of cancer cells in particular the human breast cancer and prostatic cancer. It was found that V. amygdalina was able to inhibit the growth of MCF-7 cells in a dose dependent manner upon exposure for 48 hours. There was a slight increase in DNA damage seen in the form of slight increase in comet tail-length, tail arm and tail moment and percentage in DNA cleavage at all tested doses. This indicate that the plant induced minimal genotoxic damage in MCF-7 cells. Similar effects were seen in BT-549 i.e. cell growth inhibition and DNA synthesis inhibition. The plant also exhibited chemopreventive activity attributed to its ability to scavenge free radicals, induce detoxification, inhibit stress response proteins and interfere with DNA binding activity of some transcription factors. Vernodalinol, a sesquiterpene lactone, isolated from the leaves of V. amygdalina effectively inhibited breast cancerous cell growth at a dose of 25 – 50 microg/ml. The LC50 being 70 – 75 mucrig/ml in MCR-7 cells. [9] [18] [19] [20] [21] [22]

Androgen-independent PC-3 cells are sensitive to V. amygdalina treatment in vitro. This qualifies the plants as a candidate agent for the treatment of Paclitaxel-resistant prostatic cancer. The sensitivity of TAX-resistant to V. amygdalina is probably due to the differential regulatory patterns of MAPK, c-Myc, AKT, and p-gp activities/expressions. [23]

Irradiation protection activity
Methanol extract of V. amygdalina leaves exhibited antioxidant activity. Antioxidant is known to mitigate radiation damage in tissues. Rat pretreated with methanol extract of V. amygdalina were subjected to irradiation to their heads. At autopsy it was found that the tested group of rats did not show the effects of gamma irradiation i.e. reduction of relative weight of whole brain, relative weight of the cerebellum, the maximum width, rosrocaudal dimension and dorsoventral extent of the cerebellum. [24]

Induction of hyperacidity and increase intestinal motility
Aqueous extract of V. amygdalina when infused intragastrically caused a significant increase in acid production in rats. This was reduced by ranitidine or atropine. The extract also evoked contraction of isolated guinea pig ileum which was inhibited by atropine. [25]

Hypolipidaemic activity
The aqueous extract of V. amygdalina leaves showed hypolipidaemic and antioxidant activity in streptozotosin induced diabetic rats. This is evidenced by the fact that the extract was able to reduce malondialdehyde levels, significantly reduce triglyceride levels and normalized cholesterol concentration. The methanolic extract of V. amygdalina leaves also exhibited lipid-lowering effects in hypercholesterolaemic and also diabetic rats. The plasma and post mitochondrial fraction cholesterol and LDL-cholestrol levels were observed to have reduced following administration of 100mg/kg and 200mg/kg dose of the extract. There was a corresponding increase in HDL-cholesterol and an augmentation of cholesterol-induced decrease in PMF glutathiones levels. The extracts also decrease significantly lipid peroxidation. These were observed in hypercholestrolaemic rats but not in normal rats. [26] [27]

Anti-hypertensive activity
In a survey on the use of complementary and alternative medicine amongst 225 hypertensive patients in Nigeria, it was found that 9.1% used V. amygdalina together with their antihypertensive therapy. The polyphenolic fraction (cholorophyllic fraction) of the leaf extract of V. amygdalina displayed high potency against angiotensin converting enzyme (ACE) and rennin. This provide some rationale in the use of the plant in the treatment of hypertension. [28] [29]

Antidiabetic activity
V. amygdalina leaves had been used in the treatment of diabetes in African countries with reasonable success. Most used the leaves in combination with conventional antidiabetic therapy. In a study to evaluate the antidiabetic activity of the leaves of V. amygdalilna it was found that the ethanol extract could improve the glucose tolerance test in STZ-induced diabetic rats. The following were also observed: a) decrease in fasting blood glucose level; b) protection of pancreatic beta-cells against STZ-induced damage and c) decrease triglyceride and total cholesterol level. There is evidence that it may stimulate skeletal muscle’s glucose uptake since there were increase in expression of GLUT 4 in diabetic rat skeletal muscles and also increase in GLUT 4 tanslocation to plasma membrane thus its ability to restore skeletal muscle glycogenesis. At the same time the extract inhibited hepatic gluconeogenesis by inhibiting glucose-6-phosphatase. A study of the antidiabetic effects of combining V. amygdalina with Azadirachta indica was done and it was found that in combination the hypoglycaemic effects were rapid and a reversal of hepatic and pancreatic histology was observed. This synergy was believed to be exerted by oxidative stress attenuation, insulin mimetic action and beta-cell regeneration. [30] [31] [32] [33]

Hepatoprotective activity
The leaves of V. amygdalina possess hepatoprotective activity against a number of liver toxins i.e. carbon tetrachloride, acetaminophen and even irradiation. The presence of sesquiterpene lactones in the leaves had been suggested as being responsible for the activity. Administration of various extracts (aqueous/ethanol) prior to induction of liver injury by the mentioned poisons had succeeded in prevention of the occurrence of the damage. This was evidenced by a significant reduction in activities of ALT, AST and OCT and also histologically in animals pretreated with the extracts. There was evidence to suggest this protective activity is mediated through the antioxidant activity in the leaf extracts. [34] [35] [36] [37] [38]

Antimicrobial activities

Antiparasitic
The chloroform and methanol extracts of V. amygdalina showed anti-leishmanial activity. The amstigotes appears to be more sensitive to the extracts than the promastigotes. Between the two extracts, the chloroform extracts had stronger parasitical activity against Leishmania aethiopica with ED50 of 74.4 microg/ml. In the case of Leishmania major the methanol extract was found to be the most potent compared to aqueous and hexane extracts of the leaves. There were high suppression of infectivity and viability of intracellular amastigotes at levels lower than that which elicited cytotoxicity in macrophages. Infected mice treated with the methanol extract showed delayed onset of the disease with a significant reduction in lesion size and attenuation of the histopathological outcome characterized by intact epidermis and less tissue destruction in skin, spleen and liver. [39] [40]

In a survey on the use of plants in the treatment of malaria in Uganda, V. amygdalina seem to be frequently mentioned. In a screening of seven medicinal plant ethanol extracts and twenty fractions from the partition of initial ethanol extracts, the ethanol extract of V. amygdalina leaves showed antimalarial activity (5< IC50 < 10microg/ml) while the petroleum ether fraction showed more pronounced antiplasmodial activity (IC50 < 3microg/ml). The extracts of the leaves and root bark showed significant antiplasmodial activity. Prophylactic use of V. amygdalina extract in combination with chloroquin proved to be more effective against P. berghei in infected mice as compared to chloroquin alone. In this case it was observed that there were a) shortened parasite clearance time; b) prolonged recrudescent time; and c) improved day 14 cure rate. In a clinical trial to assess the efficacy and safety of the infusion of fresh V. amygdalina leaves for the treatment of uncomplicated malaria in patients 12 years and above, the investigators found no evidence of significant side-effects or toxicity from the use of the medication. The adequate clinical response (ACR) at day 14 was 67% and complete parasite clearance was 32% of the ACR and of these recrudescence occurred in 71%. [41] [42] [43] [44] [45] [46] [47] [48]

Antifungal
Two sesquiterpene lactones (vernolide and vernodalol) isolated from the leaves of v. amygdalina exhibited differing antifungal activities. In the case of vernolide the activity was high against Penicillium notatu (LD50 = 0.2 mg/ml), Aspergillus flavus and Aspergillus niger (LD50 = 0.3 mg/ml) and Mucor hiemalis (LD50 = 0.4 mg/ml), while vernodalol showed moderate inhibition against Aspergillus flavus (LD50 = 0.3 mg/ml), Penicillium notatum (LD50 = 0.4 mg/ml) and Aspergillus niger (LD50 = 0.5 mg/ml). [49]

Antibacterial
The methanol leaf extract of V. amygdalina did not show significant antibacterial activity being only effective against S. aureus but not against P. aeruginosa. The two sesquiterpene lactone (vernolide and vernodalol) isolated from the leaves were found to be effective against gram positive bacteria but not the gram negative ones. [49] [50] [51]

Toxicities

No documentation.

Teratogenic effects

No documentation.

Clinical Data

Clinical Trials

No documentation.

Adverse Effects in Human:

Some of the constituents must be regarded as being toxic, and little in known of their effects in humans, In West Africa, V. amygdalina is widely used as a vegetable. It is preprocessed before being consumed to remove the bitterness (toxic elements). The preprocess varies form country to country from repeated boiling and decanting the water to remove the bitter principle to soaking in water to be left to stand before being cooked, a process that removes the bitter taste and presumably reduces the toxic effects of the sesquiterpenes. [1] [3]

Used in Certain Conditions

Pregnancy / Breastfeeding

The aqueous extract of the leaves of V. amgydalina can induced significant myometrial contraction. While this may be useful during the conduct of labours to assist delivery, its use for whatever reason during pregnancy should be contraindicated for fear of leading to abortion. [17]

Age Limitations

Neonates / Adolescents

No documentation.

Geriatrics

No documentation.

Chronic Disease Conditions

No documentation.

Interactions

Interactions with drugs

It has been found that co-administration of V. amygdalina and digoxin increases the absorption of the latter. This is due to the fact that V. amygdalina inhibit p-gp (permeability glycoprotein) and modulating the pharmacokinetic disposition of other p-gp substrate drug. Patients on digoxin should exercise extra caution when taking V. amygdalina leaves either as vegetable or as an alternative/complimentary medication. [14] [15]

There is a risk of potentiation of anticoagulant activity in patients on anticoagulant therapy. There is a possible additive effect on lipid-lowering drug and antihypertensive drugs when used together in therapy. Patients on medications should consult or inform their physicians of their use of the plant as adjuvant to therapy. [6] [7] [26] [27] It would be wise for diabetics on antidiabetic therapy to inform their physician when they are taking the leaves of V. amygdalina. There would eventually arise the need to modify the antidiabetic therapy to suite the probable changes in glycaemic control. [30] [31] [32] [33]

Interactions with Other Herbs / Herbal Constituents

No documentation.

Contraindications

Contraindications

No documentation.

Case Reports

No documentation.

References

1. Grubben GJH. PROTA Volume 2 - Vegetables, PROTA Foundation. Wageningen.2004; 543 – 544 [http://books.google.com.my/books?id=6jrlyOPfr24C&pg=PA543&dq=Vernonia+amygdalina&hl=en&sa=X&ei=EoNTUbXLC8XIrQeW5YEw&redir_esc=y#v=onepage&q=Vernonia%20amygdalina&f=false]
2. Schmidt E, Lotter M, McCleland W. Trees and Shrubs of Mpumalanga and Kruger National Park, Jacana Media. Johannesburg. 2002 pg. 672 [http://books.google.com.my/books?id=RpVJJH3kV0oC&pg=PA672&dq=Vernonia+amygdalina&hl=en&sa=X&ei=EoNTUbXLC8XIrQeW5YEw&redir_esc=y#v=onepage&q=Vernonia%20amygdalina&f=false]
3. Mueller MS, Mechler E. Medicinal Plants in Tropical Countries: Traditional Use, Experience, Facts Geroge Thieme Verlag. Stuttgart. 2005; 147 – 148 [http://books.google.com.my/books?id=AWWkmxKfckcC&pg=PA148&dq=Vernonia+amygdalina&hl=en&sa=X&ei=EoNTUbXLC8XIrQeW5YEw&redir_esc=y#v=onepage&q=Vernonia%20amygdalina&f=false]
4. Kupchan SM, Hemingway RJ, Karim A, Werner D. Tumor inhibitors. XLVII. Vernodalin and vernomygdin, two new cytotoxic sesquiterpene lactones from Vernonia amygdalina Del. J Org Chem. 1969 Dec;34(12):3908-11.
5. Laekeman GM, Mertens J, Totté J, Bult H, Vlietinck AJ, Herman AG. Isolation and pharmacological characterization of vernolepin. J Nat Prod. 1983 Mar-Apr;46(2):161-9.
6. Laekeman GM, De Clerck F, Vlietinck AJ, Herman AG. Vernolepin: an antiplatelet compound of natural origin. Naunyn Schmiedebergs Arch Pharmacol. 1985 Oct;331(1):108-13.
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8. Koshimizu K, Ohigashi H, Huffman MA. Use of Vernonia amygdalina by wild chimpanzee: possible roles of its bitter and related constituents. Physiol Behav. 1994 Dec;56(6):1209-16.
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11. Afolabi IS, Osikoya IO, Fajimi OD, Usoro PI, Ogunleye DO, Bisi-Adeniyi T, Adeyemi AO, Adekeye BT. Solenostemon monostachyus, Ipomoea involucrata and Carica papaya seed oil versus Glutathione, or Vernonia amygdalina: Methanolic extracts of novel plants for the management of sickle cell anemia disease. BMC Complement Altern Med. 2012 Dec 22;12:262. doi: 10.1186/1472-6882-12-262.
12. Adesanoye OA, Molehin OR, Delima AA, Adefegha AS, Farombi EO. Modulatory effect of methanolic extract of Vernonia amygdalina (MEVA) on tert-butyl hydroperoxide-induced erythrocyte haemolysis. Cell Biochem Funct. 2012 Nov 29. doi: 10.1002/cbf.2933. [Epub ahead of print]
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14. Oga EF, Sekine S, Shitara Y, Horie T. P-glycoprotein mediated efflux in Caco-2 cell monolayers: the influence of herbals on digoxin transport. J Ethnopharmacol. 2012 Dec 18;144(3):612-7. doi: 10.1016/j.jep.2012.10.001. Epub 2012 Oct 11.
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18. Yedjou C, Izevbigie E, Tchounwou P. Preclinical assessment of vernonia amygdalina leaf extracts as DNA damaging anti-cancer agent in the management of breast cancer. Int J Environ Res Public Health. 2008 Dec;5(5):337-41.
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33. Atangwho IJ, Ebong PE, Eyong EU, Asmawi MZ, Ahmad M. Synergistic antidiabetic activity of Vernonia amygdalina and Azadirachta indica: biochemical effects and possible mechanism. J Ethnopharmacol. 2012 Jun 14;141(3):878-87. doi: 10.1016/j.jep.2012.03.041. Epub 2012 Apr 10.
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35. Iwalokun BA, Efedede BU, Alabi-Sofunde JA, Oduala T, Magbagbeola OA, Akinwande AI. Hepatoprotective and antioxidant activities of Vernonia amygdalina on acetaminophen-induced hepatic damage in mice. J Med Food. 2006 Winter;9(4):524-30.
36. Adaramoye O, Ogungbenro B, Anyaegbu O, Fafunso M. Protective effects of extracts of Vernonia amygdalina, Hibiscus sabdariffa and vitamin C against radiation-induced liver damage in rats. J Radiat Res. 2008 Mar;49(2):123-31. Epub 2008 Feb 5.
37. Adesanoye OA, Farombi EO. Hepatoprotective effects of Vernonia amygdalina (astereaceae) in rats treated with carbon tetrachloride. Exp Toxicol Pathol. 2010 Mar;62(2):197-206. doi: 10.1016/j.etp.2009.05.008. Epub 2009 Jul 5.
38. Akinola OB, Omotoso GO, Akinola OS, Dosumu OO, Adewoye ET. Effects of combined leaf extract of Vernonia amygdalina and Azadirachta indica on hepatic morphology and hepatotoxicity markers in streptozotocin-induced diabetic rats. Zhong Xi Yi Jie He Xue Bao. 2011 Dec;9(12):1373-9.
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40. Alawa JN, Carter KC, Nok AJ, Kwanashie HO, Adebisi SS, Alawa CB, Clements CJ. Infectivity of macrophages and the histopathology of cutaneous lesions, liver and spleen is attenuated by leaf extract of Vernonia amygdalina in Leishmania major infected BALB/c mice. J Complement Integr Med. 2012 Jun 18;9:Article 10. doi: 10.1515/1553-3840.1617.
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