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Piper longum

Synonyms

Chavica roxburghii

Vernacular Names:

Malaysia Chabai Jawa, Akar Chabai, Akar Putih
English Long Pepper
Indonesia

Chabai Jawa

China
Bi-bo (China); But-boot (Hong Kong)
Japan
Hibatsu
Korea Pil-bal
India

Pipel (Hindi); Tabee (Malabar); Pippali (Sanskrit); Krishna (Kannada); Pipul (Bengali)

French Poivre longue
Italian Pepe lungo
Spanish Pimieta larga [3] [39]

General Information

Description

Piper longum is a member of the Piperaceae family. The stem is shrubby and climbing. The lower leaves are ovate-cordate with three to five-nerved; the upper ones are on short petioles, oblong, acuminated, oblique, and somewhat cordate at the base, obsoletely found five-nerved and veined, coriaceous, smooth, greyish-green beneath. Penducles longer than the petiole. Spandix almost cylindrical.[5]

Plant Part Used

Dried fruits, roots [3] [4]

Chemical Constituents

(+) -aphanamol I; (R)-(-) –turmerone; 1-[1-oxo-5 (3,4-methylenedioxyphenyl) -2E,4E-pentadienyl] –pirrolidine; 1-[1-oxo-5 (3,4-methylenedioxyphenyl) -2E-pentenyl] –pirrolidine; 1-[1-oxo-9 (3,4-methylene dioxyphenyl)-2E, 8E-nonadienyl] –pyrrolidine; 1-(3',4'-methylenedioxyphenyl)-1E-tetradecene; (2E,4E)-N-isobutyl-eicosa-2,4-dienamide; (2E,4E,14Z)-N-isobutyl-eicosa-2,4,14-trienamide; (2E,4E,12Z)-N-isobutyl-ocatadeca-2,4,12-trienamide; 2E, 4E-dienamide;(2E, 4E, 8E) -N-isobutylhenicosa-2,4,8-trienamide; (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine; 3-(3', 4'-methylenedioxophenyl)-propenal; 3',4'-di-hydroxy-biabola-1,10-diene; 7-epi- eudesm-4( 15)-ene-1beta, 6beta-diol; bisdemethoxycurcumin; coumaperine; dehydropipernonaline; demethoxycurcumin; eudesm-4(15)-ene-1beta, 6alpha-diol; guineensine; isodihydropiperlonguminine; methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine; methyl piperate; N-5-(4-hydroxy-3-methoxyphenyl)-2E-pentenoyl piperidine; octahydro-4-hydroy-3alpha-methyl-7-methylene-alpha-(1-methylethyl)-1H-indene-1-methanol; pellitorine; piperchabamide; piperanine; pipericide;  piperine; piperlonguminine; pipernonaline; piperoic acid; piperolactam A; piperrolein B; retrofractamide; retrofracamide C;[1] [2] [12]

Traditional Used:

The roots and the dried fruits of P. longum are considered heating, stimulant, aphrodisiac, carminative, alterative, and laxative. The old P. longum is said to be more efficacious than the fresh ones.  Together with black pepper and ginger they form what the Indian called trikatu (three acids) and they are an aromatic adjunct in compound prescription.

Gastrointestinal Diseases

In the alimentary tract, P. longum aids in improving appetite, relieves abdominal distension and colic. It helps relieve diarrhoea and dysentery while at the same time relieves constipation. In East Asia the fruit is used to treat nausea and vomiting, epigastic pain and acute gastroenteritis.[4] [32] [38] [39]

Respiratory Diseases

In India the dried fruit is used in remedies for cough, hoarseness of voice and asthma. For this purpose, they prescribed the powdered fruit in honey. Another remedy which addresses catarrh and hoarseness of voice is a combination of P. longum fruit, black pepper and ginger in equal portions. When the fruit is mixed with black pepper, ginger, cinnamon and caraway they act as an expectorant. On the other hand for dry cough, equal parts of P. longum, round zedoary, ginger, root of Clerodendron siphonanthus and raisins is a very useful remedy given in doses of 30 grains with honey or treacle.[4] [32]

Central Nervous System

The Hindus highly prized the roots of long pepper, it possesses similar qualities as the fruit, and is prescribed in cases of palsy, tetanus and apoplexy. P. longum and black pepper form part of several irritating snuff used in coma and drowsiness. It is also used in insomnia. The oil prepared with P. longum in it is used to treat sciatica and paraplegia.[3] [4]

Other Uses

Other uses of P. longum include the treatment of fever, inflammation, urinary discharges, leprosy and tuberculous glands. The root and fruit in combination is good for gout and lumbago. Infusion of the roots is prescribed after delivery to induce the expulsion of placenta.[38]

Pre-Clinical Data

Pharmacology

Hepatoprotective activity

Piperine is an active alkaloidal constituent of extract of P. longum. Koul IB et al evaluated its hepatoprotective ability and found that the significant protective effects against liver damage was due to its ability to redcue the lipid peroxidation and enzymatic leakage of GPT and AP and by preventing the depletion of GSH and total thiols in the intoxicated mice. Piperine showed a lower hepatoprotective potency than silymarin. Christina AJ et al found that in their rat model, the ethanolic extract of P. longum could reduce the hydroxyl proline and other serum enzyme parameters for liver damage. They noticed that the deposition of collagen was also reduced. This shows that the extract could inhibit liver fibrosis induced by CCl4.

Antifertility activity

An ayurvedic contraceptive containing equal parts of powdered seeds or fruit berries of Embelia ribes, fruit of P. longum and borax was the subject of scrutiny by Chaudhury et al. In 2001[8] they reported the effects on foetal birth weight and length after administration of the drug. The birth weight and length were lower than those of control group. In 2007[9] they reported their evaluation of the drug on postnatal development toxicity and reproductive performance of the progeny exposed to the drug in utero. They found that the drug did not possess any significant effects on the postnatal development and reproductive performance of the progeny. Lakshmi et al[10] found that crude extract of P. longum and its hexane fraction had antifertility effects in female rats.

Antiulcer activity

The water extract of P. longum was found to have significant gastric ulcer protective properties when rats were given 50mg/kg orally 60 mintues prior to subjecting them to ulreogenic activities including cold restrained stress, aspirin (200mg/kg, 4hrs) and 4 hr pylorus ligation did not develop gastric ulcer. It seems that this effects is due to the augmentation of mucin secreting and decreased cell shedding rather than offensive acid and pepsin secretion.[11]

Antihyperlipidaemic activity

Jin Z. et al[12] found that  piperlonguminine, piperine and pipernonaline isolated from ethanol axtract of the fruit of Piper longum were the main antihyperlipidaemic constituents. Their activity is comparable to those of simvastatin.

Bioavailability of drugs activity

P. longum had been used to enhance digestion in Ayurvedic medicine. Atal CK et al[13] studied the effects of giving P. longum in combination with vaccine and sparteine in an attempt to determine whether it would affect the bioavailability of the drug. They found that the extract could increase blood levels of vasicine by nearly 233% while piperine in particular increased the blood levels of sparteine by more than 100%. The probable mechanism is by promoting rapid absorption from gastrointestinal tract, or by protecting the drug from being metabolized/oxidised in its first passage through the liver or by a combination of both. Khajuria et al[14] suggested that piperine may induce alterations in membrane dynamics and permeation characteristics, along with inducing the synthesis of protein associated with cytoskeletal functions, resulating in an increase in the small intestinal absorptive surface, thus assisting efficient permeation through the epithelial barrier. In a clinical trial conducted by Pattanaik S et al[15], they found that by adding piperine 20mg along with phenytoin there was an increase in the mean plasma concentration of phenytoin at different time points (o, 0.5, 1, 2, 4, 6, 9, 12 hr.) This shows that piperine acts in similar manner in humans as in animal studies cited above, i.e. it enhances the bioavailability of drugs when given in combination.[34]

Anti-inflammatory activity

The dried fruit oil of P. longum exhibited significant anti-inflammatory activity.[16] Singh N et al[17] showed that the P. longum chloroform extract expressed the anti-inflammatory activity by inhibiting adhesions of neutrophils to endothelial monolayer by blocking the TNF-alpha-induced expression of CAMs i.e. ICAM-1, VCAM-1 and E-selectin through inhibition of NF-kappaB in endothelial cells. At the same time the extract exhibited antioxidant activity which further contributes to the anti-inflammatory activity. A component of the oil of P. longum is piperine which expressed its anti-inflammatory activity through inhibition of LPS-induced endotoxin shock via inhibition of 1 IFN production.[18]

Anti-platelet aggregation activity

In a preliminary study on the anti-platelet aggregation activity of P. longum Iwashita M et al[19] found that the ethanol extract contain factore the inhibit platelet aggregation as a non-competitive thromboxane A(2) receptor antagonist. They subsequently isolated a compound piperlongumine which proved to be a thromboxane A(2) receptor antagonist.[20] Park BS et al[21] found that three other acidamides (piperine, pipernonaline and piperoctadecalidine) also has similar effects but not as strong as piperlongumine. Park BS et al[22] further used piperlongumine as the lead compound to synthesize seven other derivatives with anti-platelet aggregation activities (1-piperidin-1-yl-3-(3,4,5-trimethoxy-phenyl)prop-2-en-1-one (1'), 1-morpholin-4-yl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (2'), 1-(3,5-dimethylpiperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (3'), 1-(2-methylpiperidin-1-yl)-3-(3,4,5-tri-methoxyphenyl)prop-2-en-1-one (4'), 1-(3-hydroxypiperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)- prop-2-en-1-one (5'), 1-[3-(3,4,5-tri-methoxyphenyl) acryloyl]-piperidin-2-one (6') and ethyl 1-[3-(3,4,5-trimethoxyphenyl)-acryloyl]piperidine-4-carboxylate (7').

Analgesic activity

Vedhanayaki[23] reported some analgesic activity in the root extracts of P. longum . Their studies indicated that the root has weak opoid but potent NSAID type of analgesic activity.

MAO Inhibitior and Antidepressant activity

Lee SA et al[24] [25] studied the MAO and Anti-depressant activity of P. longum extracts. They isolared three compound which showed activity against MAO and also anti-depressant activity. These compounds are piperine, methylpiperine and guineensine.

Anti-melanogenesis activity

Min KR et al identified Piperlonguminine to possess an inhibitory effect on alpha-melanocyte stimulating hormone-induced melanogenesis. This effect is by an inhibitory effect on alpha_MSH-induced tyrosinase synthesis. This effect  was through inhibiting the alpha-MSH-induced signalling through cAMP to the cAMP responsive element binding protein that in turn regulates the expression of the microphthalmia-associated transcription factor which is a key activator of the tyrosinase promoter. However, it was further found that it did not suppressed tyrosinase activity nor has a direct depigmenting effect on melanin.[26] [27] [28]

Antioxidant activity

Piperine, an alkaloid is a major component of the fruit of P. longum . Its antioxidant activity was studied and it was found that it could lower the TNF-alpha levels in lipopolysaccharide and concanavalin-A stimulated animals. It also redued the nitrite level in Concanavalin-A and Lipopolysaccharide treated animals. Wakade AS found that the anti-oxidative activity could reduce the cardiotoxicity effects of adriamycin. Thomas M et al found that their ethanol extract of Piper longum could reduce the oxidative stress induced by monosodium glutamate.[29] [30] [31] [32]

Cytotoxic activity

Piperine seems to be the most actively known alkaloid in P. longum . It also expressed cytotoxic activity in many different cell lines. It was found to be toxic to Dalton’s lymphoma ascites and Ehrlich ascites carcinoma cells.[33] Apart from affecting the cell viability, piperine showed chemopreventive activity. Selvendiran[35] showed that piperine enhanced the detoxification enzyme system and reduced DNA damage. Thus it played a role in the prevention of carcinogenesis. Again Selvendiran et al[36] showed that the chemopreventive effect can also be attributed to its ability to increase the activities of mitochondrial enzymes suggesting its role in motichondiral energy production. In another study, Selvendrian[40] found that the chemopreventive activity could also be through modulation of protein bound carbohydrate levels as they are one of the markers of tumorigenesis. Pradeep et al[37] reported its ability to inhibit lung metastasis induced by B16F-10 melanoma cells in mice. Another anticancer activity of piperine is its ability to inhibit angiogenesis as observed by Sunila et al[41]. This is attributed to its regulation of pro-inflammatory cytokines and growth factors.

Radioprotective activity

The ethanol extract of P. longum showed radioprotective activity as evidenced by the following changes seen in animal treated with the extract prior to irradiation. 1. The white blood cell count was 2783.3 cells/mm3 after 3 days as compared to 1900 cells//mm3 in untreated animals. 2. The extract enhanced the number of bone marrow cells and alpha-estrase positive cells. 3. The extract reduced the elevated levels of glutathione pyruvate transferase, alkaline phoshatase and lipid peroxidation and increased the reduced glutathione production.[42]

Antiamoebic & Antiprotozoal activity

Antigiardiasis

Agarwal AK et al[43] [44] initially studied the antigiardiasis activity of a herbal preparation called Pipali rasayana which contained Piper longum as a component of the prepation. Their findings showed that the preparation per se did not have giardiacidal activity but rather an immunostimulatory activity which induced activation of macrophage. When studying the individual effects of various extracts of P. longum they found that the aqueous and ethanol extracts have 100% giardiacidal activity. The extracts also showed demonstrable immune-stimulatory activity both specific and non-specific. Their clinical study showed that treating patients with giardiasis using Pippali rasayana could provide marked improvement in the clinical and haematological profiles of the patients with a complete disappearance of Giardia lamblia from 23 out of 25 patients treated.[45]

Antiprotozoal

Ghoshal S et al[46] [47] found that extracts of the fruits and roots of P. longum is effective against Entamoeba histolytica infection in rats. Piperine was found to be the compound responsible for this activity. Sawangjaroen et al[48] found similar effects in their study. Other protozoa affected by P. longum include Blastocytis hominis[49], Fasciola gigantic[50] and Leishmania donovani[51].

Toxicities

No documentation

Clinical Data

Clinical Trials

 

Yamada[52] [53] studied that effects on taking P. longum capsules on women complaining of chills. A skin surface temperature recording every minute for 11 minutes showed that Piper longum significantly facilitated the recovery of skin surface temperature at both low and high doses.

Adverse Effects in Human:

No documentation

Used 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

Caution should be exercised when taking preparation containing P. longum or piperine when taking medications. It may cause overdosage or enhance the toxicity of the medicine. P. longum or piperine has the ability to enhance absorption of drugs, thus increasing the bioavailability of drugs.

 

The drug should not be used together in anti-coagulant therapy as it may lead to uncontrolled bleeding and over dosing of the anti-coagulant.

Interactions with Other Herbs / Herbal Constituents

No documentation

Contraindications

Contraindications

No documentation

Case Reports

No documentation

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  2) Ayuverda

References

  1. Chatterjee A, Dutta CP. Alkaloids of Piper longum Linn. I. Structure and synthesis of piperlongumine and piperlonguminine. Tetrahedron. 1967 Apr;23(4):1769-81.
  2. Shoji N, Umeyama A, Saito N, Takemoto T, Kajiwara A, Ohizumi Y.Dehydropipernonaline, an amide possessing coronary vasodilating activity, isolated from Piper longum L. J Pharm Sci. 1986 Dec;75(12):1188-9.
  3. John Stephenson, James Morss Churchill Medical Botany, or Illustrations and Descriptions of the Medicinal Plants Volume IV John Churchill London, 1831
  4. U.C. Dutt The Materia Medica of the Hindus K.M Rai Mittal Publication New Delhi 1995 pg. 243 – 244
  5. Jonathan Pereira The Elements of Materia Medica and Therapeutics Longman, Brown , Green and Longmans London 1842 pg. 1104
  6. Koul IB, Kapil A. Evaluation of the liver protective potential of piperine, an active principle of black and long peppers. Planta Med. 1993 Oct;59(5):413-7.
  7. Christina AJ, Saraswathy GR, Robert SJ, Kothai R, Chidambaranathan N, Nalini G, Therasal RL. Inhibition of CCl4-induced liver fibrosis by Piper longum Linn.? Phytomedicine. 2006 Feb;13(3):196-8. Epub 2005 Jun 24.
  8. Chaudhury MR, Chandrasekaran R, Mishra S Embryotoxicity and teratogenicity studies of an ayurvedic contraceptive--pippaliyadi vati. J Ethnopharmacol. 2001 Feb;74(2):189-93.
  9. Balasinor N, Bhan A, Paradkar NS, Shaikh A, Nandedkar TD, Bhutani KK, Roy-Chaudhury M. Postnatal development and reproductive performance of F1 progeny exposed in utero to an ayurvedic contraceptive: Pippaliyadi yoga. J Ethnopharmacol. 2007 Feb 12;109(3):406-11. Epub 2006 Aug 15.
  10. Lakshmi V, Kumar R, Agarwal SK, Dhar JD. Antifertility activity of Piper longum Linn. in female rats. Nat Prod Res. 2006 Mar;20(3):235-9.
  11. Agrawal AK, Rao CV, Sairam K, Joshi VK, Goel RK. Effect of Piper longum Linn, Zingiber officianalis Linn and Ferula species on gastric ulceration and secretion in rats. Indian J Exp Biol. 2000 Oct;38(10):994-8.
  12. Jin Z, Borjihan G, Zhao R, Sun Z, Hammond GB, Uryu T. Antihyperlipidemic compounds from the fruit of Piper longum L. Phytother Res. 2009 Aug;23(8):1194-6.
  13. Atal CK, Zutshi U, Rao PG. Scientific evidence on the role of Ayurvedic herbals on bioavailability of drugs. J Ethnopharmacol. 1981 Sep;4(2):229-32.
  14. Khajuria A, Thusu N, Zutshi U. Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine. 2002 Apr;9(3):224-31.
  15. Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P. Effect of piperine on the steady-state pharmacokinetics of phenytoin in patients with epilepsy. Phytother Res. 2006 Aug;20(8):683-6.
  16. Kumar A, Panghal S, Mallapur SS, Kumar M, Ram V, Singh BK. Antiinflammatory Activity of Piper longum Fruit Oil. Indian J Pharm Sci. 2009 Jul;71(4):454-6.
  17. Singh N, Kumar S, Singh P, Raj HG, Prasad AK, Parmar VS, Ghosh B. Piper longum Linn. Extract inhibits TNF-alpha-induced expression of cell adhesion molecules by inhibiting NF-kappaB activation and microsomal lipid peroxidation. Phytomedicine. 2008 Apr;15(4):284-91. Epub 2007 Aug 8.
  18. Bae GS, Kim MS, Jung WS, Seo SW, Yun SW, Kim SG, Park RK, Kim EC, Song HJ, Park SJ. Inhibition of lipopolysaccharide-induced inflammatory responses by piperine. Eur J Pharmacol. 2010 Sep 10;642(1-3):154-62. Epub 2010 Jun 8.
  19. Iwashita M, Saito M, Yamaguchi Y, Takagaki R, Nakahata N Inhibitory effect of ethanol extract of Piper longum L. on rabbit platelet aggregation through antagonizing thromboxane A2 receptor. Biol Pharm Bull. 2007 Jul;30(7):1221-5.
  20. Iwashita M, Oka N, Ohkubo S, Saito M, Nakahata N. Piperlongumine, a constituent of Piper longum L., inhibits rabbit platelet aggregation as a thromboxane A(2) receptor antagonist. Eur J Pharmacol. 2007 Sep 10;570(1-3):38-42. Epub 2007 Jun 15.
  21. Park BS, Son DJ, Park YH, Kim TW, Lee SE. Antiplatelet effects of acidamides isolated from the fruits of Piper longum L. Phytomedicine. 2007 Dec;14(12):853-5. Epub 2007 Aug 6.
  22. Park BS, Son DJ, Choi WS, Takeoka GR, Han SO, Kim TW, Lee SE. Antiplatelet activities of newly synthesized derivatives of piperlongumine. Phytother Res. 2008 Sep;22(9):1195-9.
  23. Vedhanayaki G, Shastri GV, Kuruvilla A. Analgesic activity of Piper longum Linn. root. Indian J Exp Biol. 2003 Jun;41(6):649-51.
  24. Lee SA, Hong SS, Han XH, Hwang JS, Oh GJ, Lee KS, Lee MK, Hwang BY, Ro JS. Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity. Chem Pharm Bull (Tokyo). 2005 Jul;53(7):832-5.
  25. Lee SA, Hwang JS, Han XH, Lee C, Lee MH, Choe SG, Hong SS, Lee D, Lee MK, Hwang BY. Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase. Arch Pharm Res. 2008 Jun;31(6):679-83. Epub 2008 Jun 19.
  26. Min KR, Kim KS, Ro JS, Lee SH, Kim JA, Son JK, Kim Y. Piperlonguminine from Piper longum with inhibitory effects on alpha-melanocyte-stimulating hormone-induced melanogenesis in melanoma B16 cells. Planta Med. 2004 Dec;70(12):1115-8.
  27. Kim KS, Kim JA, Eom SY, Lee SH, Min KR, Kim Y. Inhibitory effect of piperlonguminine on melanin production in melanoma B16 cell line by downregulation of tyrosinase expression. Pigment Cell Res. 2006 Feb;19(1):90-8.
  28. Ohno O, Watabe T, Nakamura K, Kawagoshi M, Uotsu N, Chiba T, Yamada M, Yamaguchi K, Yamada K, Miyamoto K, Uemura D. Inhibitory effects of bakuchiol, bavachin, and isobavachalcone isolated from Piper longum on melanin production in B16 mouse melanoma cells. Biosci Biotechnol Biochem. 2010 Jul 23;74(7):1504-6. Epub 2010 Jul 7
  29. Pradeep CR, Kuttan G. Effect of piperine on the inhibition of nitric oxide (NO) and TNF-alpha production. Immunopharmacol Immunotoxicol. 2003 Aug;25(3):337-46.
  30. Pathak N, Khandelwal S. Modulation of cadmium induced alterations in murine thymocytes by piperine: oxidative stress, apoptosis, phenotyping and blastogenesis. Biochem Pharmacol. 2006 Aug 14;72(4):486-97. Epub 2006 Jun 14.
  31. Wakade AS, Shah AS, Kulkarni MP, Juvekar AR. Protective effect of Piper longum L. on oxidative stress induced injury and cellular abnormality in adriamycin induced cardiotoxicity in rats. Indian J Exp Biol. 2008 Jul;46(7):528-33.
  32. Thomas M, Sujatha KS, George S. Protective effect of Piper longum Linn. on monosodium glutamate induced oxidative stress in rats. Indian J Exp Biol. 2009 Mar;47(3):186-92
  33. Sunila ES, Kuttan G. Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J Ethnopharmacol. 2004 Feb;90(2-3):339-46.
  34. H. Panda Herbs Cultivation and Medicinal Uses National Institute of Inducrial Research New Delhi 2000 pg. 451 - 453
  35. Selvendiran K, Banu SM, Sakthisekaran D. Oral supplementation of piperine leads to altered phase II enzymes and reduced DNA damage and DNA-protein cross links in Benzo(a)pyrene induced experimental lung carcinogenesis. Mol Cell Biochem. 2005 Jan;268(1-2):141-7.
  36. Selvendiran K, Thirunavukkarasu C, Singh JP, Padmavathi R, Sakthisekaran D. Chemopreventive effect of piperine on mitochondrial TCA cycle and phase-I and glutathione-metabolizing enzymes in benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice. Mol Cell Biochem. 2005 Mar;271(1-2):101-6.
  37. Pradeep CR, Kuttan G. Effect of piperine on the inhibition of lung metastasis induced B16F-10 melanoma cells in mice. Clin Exp Metastasis. 2002;19(8):703-8.
  38. Alice Kurian and M. Asha Sankar Medicinal Plants Jai Bharat Printing Press Delhi 2007 pg. 166
  39. Chung Ki Sung, Takeatsu Kimuram, Paul P.H. But, Ji-Xian Guo International Collation of Traditional and Folk Medicine: Northeast Asia Volume 3 Part III World Scientific Publishing Co. Pte. Ltd. Singapore 1998
  40. Selvendiran K, Prince Vijeya Singh J, Sakthisekaran D. In vivo effect of piperine on serum and tissue glycoprotein levels in benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice. Pulm Pharmacol Ther. 2006;19(2):107-11. Epub 2005 Jun 21.
  41. Sunila ES, Kuttan G. Piper longum inhibits VEGF and proinflammatory cytokines and tumor-induced angiogenesis in C57BL/6 mice. Int Immunopharmacol. 2006 May;6(5):733-41. Epub 2005 Dec 19.
  42. Sunila ES, Kuttan G. Protective effect of Piper longum fruit ethanolic extract on radiation induced damages in mice: a preliminary study. Fitoterapia. 2005 Dec;76(7-8):649-55. Epub 2005 Oct 21.
  43. Agarwal AK, Singh M, Gupta N, Saxena R, Puri A, Verma AK, Saxena RP, Dubey CB, Saxena KC. Management of giardiasis by an immuno-modulatory herbal drug Pippali rasayana. J Ethnopharmacol. 1994 Dec;44(3):143-6.
  44. Tripathi DM, Gupta N, Lakshmi V, Saxena KC, Agrawal AK. Antigiardial and immunostimulatory effect of Piper longum on giardiasis due to Giardia lamblia. Phytother Res. 1999 Nov;13(7):561-5.
  45. Agarwal AK, Tripathi DM, Sahai R, Gupta N, Saxena RP, Puri A, Singh M, Misra RN, Dubey CB, Saxena KC. Management of giardiasis by a herbal drug 'Pippali Rasayana': a clinical study. J Ethnopharmacol. 1997 May;56(3):233-6.
  46. Ghoshal S, Prasad BN, Lakshmi V. Antiamoebic activity of Piper longum fruits against Entamoeba histolytica in vitro and in vivo. J Ethnopharmacol. 1996 Mar;50(3):167-70
  47. Ghoshal S, Lakshmi V. Potential antiamoebic property of the roots of Piper longum Linn. Phytother Res. 2002 Nov;16(7):689-91.
  48. Sawangjaroen N, Sawangjaroen K, Poonpanang P. Effects of Piper longum fruit, Piper sarmentosum root and Quercus infectoria nut gall on caecal amoebiasis in mice. J Ethnopharmacol. 2004 Apr;91(2-3):357-60.
  49. Sawangjaroen N, Sawangjaroen K. The effects of extracts from anti-diarrheic Thai medicinal plants on the in vitro growth of the intestinal protozoa parasite: Blastocystis hominis. J Ethnopharmacol. 2005 Apr 8;98(1-2):67-72.
  50. Singh TU, Kumar D, Tandan SK, Mishra SK. Inhibitory effect of essential oils of Allium sativum and Piper longum on spontaneous muscular activity of liver fluke, Fasciola gigantica. Exp Parasitol. 2009 Dec;123(4):302-8. Epub 2009 Aug 11.
  51. Singh SK, Bimal S, Narayan S, Jee C, Bimal D, Das P, Bimal R. Leishmania donovani: Assessment of leishmanicidal effects of herbal extracts obtained from plants in the visceral leishmaniasis endemic area of Bihar, India. Exp Parasitol. 2010 Nov 9. [Epub ahead of print]
  52. Yamada N, Nishihara C, Yoshimura H, Yamaguchi Y, Takagaki R, Miyakoshi M, Mizutani K. [Effects of Piper longum L. on chills in Japanese young women: time-dependent changes in skin surface temperature and its recovery rate following the exposure to mild cold stress] Nihon Shinkei Seishin Yakurigaku Zasshi. 2009 Feb;29(1):7-15.
  53. Yamada N, Yoshimura H. [Determinants of chilliness among young women and their application to psychopharmacological trials] Nihon Shinkei Seishin Yakurigaku Zasshi. 2009 Nov;29(5-6):171-9.

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