Synergistic Effect of Piperine and its Derivatives: A Comprehensive
Review

Neha      Saini; Bhawna      Chopra; Ashwani   K.   Dhingra
Abstract

Piperine is a fascinating substance since it can be used as a biomarker in combination with other bioactive compounds or their analogues, as well as therapeutic molecules used for the healing of a variety of diseases. It displays a plentiful therapeutic potential and various health benefits when administered alone or in combination with several other drugs and/or phytochemicals. It has also been used to enhance the pharmacokinetic profile of many nutraceutical compounds like curcumin, resveratrol, quercetin, beta-carotene, barbiturates, propranolol, metformin, theophylline etc. The present review discloses the synergistic effect of piperine and its derivatives, clinical studies, and patent studies of piperine.
Keywords: Piperine, synergistic effect, anti-cancer, neuroprotective, clinical studies, biomarker.
Graphical Abstract

[1]
Singh YN. Kava: An overview. J Ethnopharmacol  1992; 37(1): 13-45.
 [http://dx.doi.org/10.1016/0378-8741(92)90003-A] [PMID: 1453702]

[2]
Chopra B, Dhingra AK, Prasad DN. Modification in natural bioactive molecule: Piperine; a continuing source for drug development. Curr Bioact Compd  2020; 16(6): 714-25.
 [http://dx.doi.org/10.2174/1573407215666190318125023]

[3]
Kanaki N, Dave M, Padh H, Rajani M. A rapid method for isolation of piperine from the fruits of Piper nigrum Linn. J Nat Med  2008; 62(3): 281-3.
 [http://dx.doi.org/10.1007/s11418-008-0234-3] [PMID: 18404304]

[4]
Mohapatra M, Basak U. Evaluation of piperine content from roots of Piper longum Linn., originated from different sources with comparison of zonal variation in Odisha, India. Int J Pharm Sci Rev Res  2015; 4(9): 1-8.

[5]
Rameshkumar KB, Aravind APA, Mathew PJ. Comparative phytochemical evaluation and antioxidant assay of Piper longum L. and Piper chaba hunter used in Indian traditional systems of medicine. J Herbs Spices Med Plants  2011; 17(4): 351-60.
 [http://dx.doi.org/10.1080/10496475.2011.632116]

[6]
Juliani HR, Koroch A, Giordano L, Amekuse L, Koffa S. Piper guineense (Piperaceae): Chemistry, traditional uses, and functional properties of west African black pepper. In: African Natural Plant Products, Volume II: Discoveries and Challenges in Chemistry, Health, and Nutrition. Washington, USA: ACS Publications 2013; pp. 33-48.

[7]
Hussain K, Ismail Z, Sadikun A, Ibrahim P. Antioxidant, anti-TB activities, phenolic and amide contents of standardised extracts of Piper sarmentosum Roxb. Nat Prod Res  2009; 23(3): 238-49.
 [http://dx.doi.org/10.1080/14786410801987597] [PMID: 19235024]

[8]
Warrier PK. The importance of black pepper in Ayurveda. Indian Spices  1981; 18(2-4): 3-5.

[9]
Haq IU, Imran M, Nadeem M, Tufail T, Gondal TA, Mubarak MS. Piperine: A review of its biological effects. Phytother Res  2021; 35(2): 680-700.
 [http://dx.doi.org/10.1002/ptr.6855] [PMID: 32929825]

[10]
Jangra A, Kwatra M, Singh T, et al. Piperine augments the protective effect of curcumin against lipopolysaccharide-induced neurobehav-ioral and neurochemical deficits in mice. Inflammation  2016; 39(3): 1025-38.
 [http://dx.doi.org/10.1007/s10753-016-0332-4] [PMID: 26970969]

[11]
Singh S, Kumar P. Neuroprotective activity of curcumin in combination with piperine against quinolinic acid induced neurodegeneration in rats. Pharmacology  2016; 97(3-4): 151-60.
 [http://dx.doi.org/10.1159/000443896] [PMID: 26828892]

[12]
Abdul Manap AS, Wei Tan AC, Leong WH, et al. Synergistic effects of curcumin and piperine as potent acetylcholine and amyloidogenic inhibitors with significant neuroprotective activity in SH-SY5Y cells via computational molecular modeling and in vitro assay. Front Aging Neurosci  2019; 11: 206.
 [http://dx.doi.org/10.3389/fnagi.2019.00206] [PMID: 31507403]

[13]
Delecroix B, Abaïdia AE, Leduc C, Dawson B, Dupont G. Curcumin and Piperine supplementation and recovery following exercise induced muscle damage: A randomized controlled trial. J Sports Sci Med  2017; 16(1): 147-53.
 [PMID: 28344463]

[14]
Fadus MC, Lau C, Bikhchandani J, Lynch HT. Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. J Tradit Complement Med  2017; 7(3): 339-46.
 [http://dx.doi.org/10.1016/j.jtcme.2016.08.002] [PMID: 28725630]

[15]
Hewlings S, Kalman D. Curcumin: A review of its effects on human health. Foods  2017; 6(10): 92.
 [http://dx.doi.org/10.3390/foods6100092] [PMID: 29065496]

[16]
Yu D, Kan Z, Shan F, Zang J, Zhou J. Triple strategies to improve oral bioavailability by fabricating coamorphous forms of Ursolic Acid with Piperine: Enhancing water-solubility, permeability, and inhibiting Cytochrome P450 Isozymes. Mol Pharm  2020; 17(12): 4443-62.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.0c00443] [PMID: 32926628]

[17]
Junsaeng D, Anukunwithaya T, Songvut P, Sritularak B, Likhitwitayawuid K, Khemawoot P. Comparative pharmacokinetics of oxyresveratrol alone and in combination with piperine as a bioenhancer in rats. BMC Complement Altern Med  2019; 19(1): 235.
 [http://dx.doi.org/10.1186/s12906-019-2653-y] [PMID: 31477089]

[18]
Ray L, Karthik R, Srivastava V, et al. Efficient antileishmanial activity of amphotericin B and piperine entrapped in enteric coated guar gum nanoparticles. Drug Deliv Transl Res  2021; 11(1): 118-30.
 [http://dx.doi.org/10.1007/s13346-020-00712-9] [PMID: 32016707]

[19]
Feng X, Liu Y, Wang X, Di X. Effects of piperine on the intestinal permeability and pharmacokinetics of linarin in rats. Molecules  2014; 19(5): 5624-33.
 [http://dx.doi.org/10.3390/molecules19055624] [PMID: 24786847]

[20]
Di X, Wang X, Di X, Liu Y. Effect of piperine on the bioavailability and pharmacokinetics of emodin in rats. J Pharm Biomed Anal  2015; 115: 144-9.
 [http://dx.doi.org/10.1016/j.jpba.2015.06.027] [PMID: 26201645]

[21]
Bi X, Yuan Z, Qu B, Zhou H, Liu Z, Xie Y. Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2. Phytomedicine  2019; 54: 98-108.
 [http://dx.doi.org/10.1016/j.phymed.2018.09.217] [PMID: 30668388]

[22]
Li C, Wang Z, Wang Q, et al. Enhanced anti-tumor efficacy and mechanisms associated with docetaxel-piperine combination- in vitro and in vivo investigation using a taxane-resistant prostate cancer model. Oncotarget  2018; 9(3): 3338-52.
 [http://dx.doi.org/10.18632/oncotarget.23235] [PMID: 29423050]

[23]
Moorthi C, Kathiresan K. Curcumin-Piperine/Curcumin–Quercetin/Curcumin-Silibinin dual drug-loaded nanoparticulate combination therapy: A novel approach to target and treat multidrugresistant cancers. J Med Hypothes Ideas  2013; 7(1): 15-20.
 [http://dx.doi.org/10.1016/j.jmhi.2012.10.005]

[24]
Abolhassani H, Safavi MS, Handali S, Nosrati M, Shojaosadati SA. Synergistic effect of self-assembled curcumin and piperine co-loaded human serum albumin nanoparticles on suppressing cancer cells. Drug Dev Ind Pharm  2020; 46(10): 1647-55.
 [http://dx.doi.org/10.1080/03639045.2020.1820032] [PMID: 32892656]

[25]
Ding Y, Ding Y, Wang Y, et al. Soluplus®/TPGS mixed micelles for co-delivery of docetaxel and piperine for combination cancer therapy. Pharm Dev Technol  2020; 25(1): 107-15.
 [http://dx.doi.org/10.1080/10837450.2019.1679834] [PMID: 31603017]

[26]
Dahiya S, Rani R, Dhingra D, Kumar S, Dilbaghi N. Conjugation of epigallocatechin gallate and piperine into a zein nanocarrier: implication on antioxidant and anticancer potential. Adv Nat Sci  2018; 9(3): 035011.
 [http://dx.doi.org/10.1088/2043-6254/aad5c1]

[27]
Patial V SM, Sharma S, Pratap K, Singh D, Padwad YS. Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol  2015; 40(2): 445-52.
 [http://dx.doi.org/10.1016/j.etap.2015.07.012] [PMID: 26278679]

[28]
Motiwala MN, Rangari VD. Combined effect of paclitaxel and piperine on a MCF-7 breast cancer cell line in vitro: Evidence of a synergistic interaction. Synergy  2015; 2(1): 1-6.
 [http://dx.doi.org/10.1016/j.synres.2015.04.001]

[29]
Pushpa RS, Naga DAV, Anusha CH, Kanthaiah YV. Enhancement of paclitaxel and doxorubicin cytotoxicity in breast cancer cell lines in combination with piperine treatment and analysis of expression of autophagy and apoptosis genes. J Med Sci Res  2014; 2: 62-7.

[30]
Woo CC, Hsu A, Kumar AP, Sethi G, Tan KHB. Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: The role of p38 MAPK and ROS. PLoS One  2013; 8(10): e75356.
 [http://dx.doi.org/10.1371/journal.pone.0075356] [PMID: 24098377]

[31]
Kakarala M, Brenner DE, Korkaya H, et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat  2010; 122(3): 777-85.
 [http://dx.doi.org/10.1007/s10549-009-0612-x] [PMID: 19898931]

[32]
Khamis AAA, Ali EMM, El-Moneim MAA, Abd-Alhaseeb MM, El-Magd MA, Salim EI. Hesperidin, piperine and bee venom synergistically potentiate the anticancer effect of tamoxifen against breast cancer cells. Biomed Pharmacother  2018; 105: 1335-43.
 [http://dx.doi.org/10.1016/j.biopha.2018.06.105] [PMID: 30021371]

[33]
Talib W. Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci Pharm  2017; 85(3): 27.
 [http://dx.doi.org/10.3390/scipharm85030027] [PMID: 28671634]

[34]
Greenshields AL, Doucette CD, Sutton KM, et al. Piperine inhibits the growth and motility of triple-negative breast cancer cells. Cancer Lett  2015; 357(1): 129-40.
 [http://dx.doi.org/10.1016/j.canlet.2014.11.017] [PMID: 25444919]

[35]
Abdelhamed S, Yokoyama S, Refaat A, et al. Piperine enhances the efficacy of TRAIL-based therapy for triple-negative breast cancer cells. Anticancer Res  2014; 34(4): 1893-9.
 [PMID: 24692724]

[36]
Aumeeruddy MZ, Mahomoodally MF. Combating breast cancer using combination therapy with 3 phytochemicals: Piperine, sulforaphane, and thymoquinone. Cancer  2019; 125(10): 1600-11.
 [http://dx.doi.org/10.1002/cncr.32022] [PMID: 30811596]

[37]
Quijia CR, Chorilli M. Piperine for treating breast cancer: A review of molecular mechanisms, combination with anticancer drugs, and nanosystems. Phytother Res  2022; 36(1): 147-63.
 [http://dx.doi.org/10.1002/ptr.7291] [PMID: 34559416]

[38]
Jadhav P, Bothiraja C, Pawar A. Resveratrol-piperine loaded mixed micelles: formulation, characterization, bioavailability, safety and in vitro anticancer activity. RSC Advances  2016; 6(114): 112795-805.
 [http://dx.doi.org/10.1039/C6RA24595A]

[39]
Betina S, Carlos Luan AP, Christian F,. Jerson L da S, Eliane F. Synergistic effect of curcumin, piperine and resveratrol in MCF-7 and MDAMB-231 breast cancer cells. Biomed Res  2020; 31(5): 113-8.

[40]
Do MT, Kim HG, Choi JH, et al. Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells. Food Chem  2013; 141(3): 2591-9.
 [http://dx.doi.org/10.1016/j.foodchem.2013.04.125] [PMID: 23870999]

[41]
Lai L, Fu Q, Liu Y, et al. Piperine suppresses tumor growth and metastasis in vitro and in vivo in a 4T1 murine breast cancer model. Acta Pharmacol Sin  2012; 33(4): 523-30.
 [http://dx.doi.org/10.1038/aps.2011.209] [PMID: 22388073]

[42]
Pal MK, Jaiswar SP, Srivastav AK, et al. Synergistic effect of piperine and paclitaxel on cell fate via cyt-c, Bax/Bcl-2-caspase-3 pathway in ovarian adenocarcinomas SKOV-3 cells. Eur J Pharmacol  2016; 791: 751-62.
 [http://dx.doi.org/10.1016/j.ejphar.2016.10.019] [PMID: 27756602]

[43]
Bolat ZB, Islek Z, Demir BN, Yilmaz EN, Sahin F, Ucisik MH. Curcumin- and Piperine-loaded emulsomes as combinational treatment approach enhance the anticancer activity of curcumin on HCT116 colorectal cancer model. Front Bioeng Biotechnol  2020; 8: 50.
 [http://dx.doi.org/10.3389/fbioe.2020.00050] [PMID: 32117930]

[44]
mgbeahuruike EE, Stålnacke M, Vuorela H, Holm Y. Antimicrobial and synergistic effects of commercial piperine and piperlongumine in combination with conventional antimicrobials. Antibiotics (Basel)  2019; 8(2): 55.
 [http://dx.doi.org/10.3390/antibiotics8020055] [PMID: 31060239]

[45]
Chopra B, Dhingra AK, Dhar KL. Synthesis and Characterization of Piperine analogs as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors. Chem Methodol  2019; 3(1): 104-14.

[46]
Khan IA, Mirza ZM, Kumar A, Verma V, Qazi GN. Piperine, a phytochemical potentiator of ciprofloxacin against Staphylococcus aureus. Antimicrob Agents Chemother  2006; 50(2): 810-2.
 [http://dx.doi.org/10.1128/AAC.50.2.810-812.2006] [PMID: 16436753]

[47]
Hegeto LA, Caleffi-Ferracioli KR, Nakamura-Vasconcelos SS, et al. In vitro combinatory activity of piperine and anti-tuberculosis drugs in Mycobacterium tuberculosis. Tuberculosis (Edinb)  2018; 111: 35-40.
 [http://dx.doi.org/10.1016/j.tube.2018.05.006] [PMID: 30029912]

[48]
Murase LS, Perez de Souza JV, Meneguello JE, et al. Possible binding of piperine in Mycobacterium tuberculosis RNA polymerase and rifampin synergism. Antimicrob Agents Chemother  2019; 63(11): e02520-18.
 [http://dx.doi.org/10.1128/AAC.02520-18] [PMID: 31481438]

[49]
Nazifi M, Oryan S, Esfahani DE, Ashrafpoor M. The functional effects of piperine and piperine plus donepezil on hippocampal synaptic plasticity impairment in rat model of Alzheimer’s disease. Life Sci  2020; 265: 118802.
 [PMID: 33242524]

[50]
Antony B, Merina B, Iyer VS, Judy N, Lennertz K, Joyal S. A pilot cross-over study to evaluate human oral bioavailability of BCM-95®CG (BiocurcumaxTM), a novel bioenhanced preparation of curcumin. Indian J Pharm Sci  2008; 70(4): 445-9.
 [http://dx.doi.org/10.4103/0250-474X.44591] [PMID: 20046768]

[51]
Sehgal A, Kumar M, Jain M, Dhawan DK. Synergistic effects of piperine and curcumin in modulating benzo(a)pyrene induced redox imbalance in mice lungs. Toxicol Mech Methods  2012; 22(1): 74-80.
 [http://dx.doi.org/10.3109/15376516.2011.603392] [PMID: 21859361]

[52]
Pandey A, Gupta RK, Lawrence R, Lawrence K, Srivastava R. Synergistic study of antioxidant potential of different spices and their bioactive constituents. Int J Pharm Sci Res  2014; 5(8): 3267-72.

[53]
Veeresham C, Sujatha S, Rani TS. Effect of piperine on the pharmacokinetics and pharmacodynamics of glimepiride in normal and streptozotocin-induced diabetic rats Nat Prod Commun  2012; 7(10): 1934578X1200701.
 [http://dx.doi.org/10.1177/1934578X1200701009] [PMID: 23156991]

[54]
Li Q, Zhai W, Jiang Q, et al. Curcumin–piperine mixtures in selfmicroemulsifying drug delivery system for ulcerative colitis therapy. Int J Pharm  2015; 490(1-2): 22-31.
 [http://dx.doi.org/10.1016/j.ijpharm.2015.05.008] [PMID: 25957703]

[55]
Ghelishli N, Ghasemi A, Hosseinimehr SJ. The influence of piperine on the radioprotective effect of curcumin in irradiated human lymphocytes. Turkish J Pharm Sci  2019; 16(3): 366-70.
 [http://dx.doi.org/10.4274/tjps.galenos.2018.50103] [PMID: 32454737]

[56]
Li G, Ruan L, Chen R, et al. Synergistic antidepressant-like effect of ferulic acid in combination with piperine: Involvement of monoaminergic system. Metab Brain Dis  2015; 30(6): 1505-14.
 [http://dx.doi.org/10.1007/s11011-015-9704-y] [PMID: 26220010]

[57]
Setiawan PYB, Kertia N, Arief N, Wahyuono S. Curcumin in combination: Review of synergistic effects and mechanisms in the treatment of inflammation. J Appl Pharm Sci  2021; 11(2): 1-11.

[58]
Biswas J, Sinha D, Mukherjee S, Roy S, Siddiqi M, Roy M. Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal. Hum Exp Toxicol  2010; 29(6): 513-24.
 [http://dx.doi.org/10.1177/0960327109359020] [PMID: 20056736]

[59]
Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther  2002; 302(2): 645-50.
 [http://dx.doi.org/10.1124/jpet.102.034728] [PMID: 12130727]

[60]
Chopra B, Dhingra AK, Kapoor RP, Prasad DN. Piperine and its various physicochemical and biological aspects: A review. Open Chem J  2016; 3(1): 75-96.
 [http://dx.doi.org/10.2174/1874842201603010075]

[61]
Hiwale AR, Dhuley JN, Naik SR. Effect of co-administration of piperine on pharmacokinetics of beta-lactam antibiotics in rats. Indian J Exp Biol  2002; 40(3): 277-81.
 [PMID: 12635696]

[62]
Shah SV, Ballaga R. Composition and methods using agents that reduce availability of a catalytic iron source in glomeruli for treating glomerular disorders. US Pat Appl Publ US 2002183333 AI, 2002.

[63]
Singh A, Jain R. Novel pharmaceutical composition of antitubercular drugs and process for their preparation China Patent CN 1339298A 2002.

[64]
Balakrishan V, Varma S, Chatterji D. Piperine auguments transcription inhibitory activity of rifampicin by several fold in Mycobacterium smegmatis. Curr Sci  2001; 80(10): 1302-5.

[65]
Mujumdar AM, Dhuley JN, Deshmukh VK, Naik SR. Effect of piperine on bioavailability of oxyphenylbutazone in rats. IDrugs  1999; 36(2): 123-6.

[66]
Gupta SK, Bansal P, Bhardwaj RK, Velpandian T. Comparative antinociceptive, anti-inflammatory and toxicity profile of nimesulide vs. nimesulide and piperine combination. Pharmacol Res  2000; 41(6): 657-62.
 [http://dx.doi.org/10.1006/phrs.1999.0640] [PMID: 10816335]

[67]
Tang X. Compound traditional medicine with piperine for increasing bioavailability of paeoniflorin and its preparing methods. US2002091146A1, 2002.

[68]
Velpandian T, Jasuja R, Bhardwaj RK, Jaiswal J, Gupta SK. Piperine in food: Interference in the pharmacokinetics of phenytoin. Eur J Drug Metab Pharmacokinet  2001; 26(4): 241-7.
 [http://dx.doi.org/10.1007/BF03226378] [PMID: 11808866]

[69]
Singh A, Jain R. Pharmaceuticals composition NSAID’S and piperine Eur Pat Appl  1999; 935-64.

[70]
Shah SV, Baliga R. Compositions and method for chemotherapy having reduced nephrotoxicity. US Pat Appl Publ US 2002183333 AI, 2002.

[71]
Rosenberg Zand RS, Jenkins DJA, Brown TJ, Diamandis EP. Flavonoids can block PSA production by breast and prostate cancer cell lines. Clin Chim Acta  2002; 317(1-2): 17-26.
 [http://dx.doi.org/10.1016/S0009-8981(01)00698-2] [PMID: 11814454]

[72]
Majeed M, Badmaev V, Bammi RK, Prakash S, Natarajan S. Methods for increased bioavailability of nutrients and pharmaceuticals by tetrahydropiperine and its analogue and derivatives United States patent US 6849645B2 2005.

[73]
Reen RK, Singh J. In vitro and in vivo inhibition of pulmonary cytochrome P450 activities by piperine, a major ingredient of piper species. Indian J Exp Biol  1991; 29(6): 568-73.
 [PMID: 1889831]

[74]
Badmaev V, Majeed M, Rajendran R. Use of piperine to increase the bioavailability of nutritional compounds United States patent US 5536506A 1996.

[75]
Atal CK, Zutshi U, Rao PG. Scientific evidence on the role of Ayurvedic herbals on bioavailability of drugs. J Ethnopharmacol  1981; 4(2): 229-32.
 [http://dx.doi.org/10.1016/0378-8741(81)90037-4] [PMID: 7311598]

[76]
Shin KH, Woo WS. Studies on crude drugs acting on drug metabolizing enzymes: Effect of piperine on hepatic microsomal mixed function oxidase system. Korean Biochem J  1985; 18: 9-15.

[77]
Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Thorat SL, Naik SR. Effect of piperine on pentobarbitone induced hypnosis in rats. Indian J Exp Biol  1990; 28(5): 486-7.
 [PMID: 2401524]

[78]
Reen RK, Jamwal DS, Taneja SC, et al. Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small intestine of rat and guinea pig in vitro by piperine. Biochem Pharmacol  1993; 46(2): 229-38.
 [http://dx.doi.org/10.1016/0006-2952(93)90408-O] [PMID: 8347144]

[79]
Badmaev V, Majeed M, Prakash L. Piperine derived from black pepper increases the plasma levels of coenzyme q10 following oral supplementation. J Nutr Biochem  2000; 11(2): 109-13.
 [http://dx.doi.org/10.1016/S0955-2863(99)00074-1] [PMID: 10715596]

[80]
Badmaev V, Majeed M, Norkus EP. Piperine, an alkaloid derived from black pepper increases serum response of beta-carotene during 14-days of oral beta-carotene supplementation. Nutr Res  1999; 19(3): 381-8.
 [http://dx.doi.org/10.1016/S0271-5317(99)00007-X]

[81]
Karan RS, Bhargava VK, Garg SK. Effect of Trikatu (Piperine) on the pharmacokinetic profile of isoniazid in rabbits. Indian J Pharmacol  1998; 30: 254-6.

[82]
Dama MS, Varshneya C, Dardi MS, Katoch VC. Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats. J Vet Sci  2008; 9(1): 25-9.
 [http://dx.doi.org/10.4142/jvs.2008.9.1.25] [PMID: 18296885]

[83]
Atal CK, Manavalan R, Nighojkar R, Sareen AN, Gupta OP. Studies on Piper chabaas a bioavailable agents. IDrugs  1980; 17: 266-8.

[84]
Singh M, Varshneya C, Telang RS, Srivastava AK. Alteration of pharmacokinetics of oxytetracycline following oral administration of Piper longum in hens. J Vet Sci  2005; 6(3): 197-200.
 [http://dx.doi.org/10.4142/jvs.2005.6.3.197] [PMID: 16131821]

[85]
Patel S, Devada S, Patel H, Patel N, Bhavsar S, Thaker A. Influence of co-administration of piperine on pharmacokinetic profile of gatifloxacin in layer birds. Glob Vet  2011; 7: 427-32.

[86]
Janakiraman K, Manavalan R. Studies on effect of piperine on oral bioavailability of ampicillin and norfloxacin. Afr J Tradit Complement Altern Med  2008; 5(3): 257-62.
 [http://dx.doi.org/10.4314/ajtcam.v5i3.31281] [PMID: 20161946]

[87]
Kasibhatta R, Naidu MUR. Influence of piperine on the pharmacokinetics of nevirapine under fasting conditions: A randomised, crossover, placebo-controlled study. Drugs R D  2007; 8(6): 383-91.
 [http://dx.doi.org/10.2165/00126839-200708060-00006] [PMID: 17963429]

[88]
Singh A, Pawar VK, Jakhmola V, Parabia MH, Awasthi R, Sharma G. In vivo assessment of enhanced bioavailability of metronidazole with piperine in rabbits. Res J Pharm Biol Chem Sci  2010; 1: 273-8.

[89]
Pooja S, Agrawal RP, Nyati P, Savita V, Phadnis P. Analgesic activity of Piper nigrum extract per se and its interaction with diclofenacsodium and pentazocine in albino mice. Int J Pharmacol  2007; 5(1): 30.

[90]
Gupta SK, Velpandian T, Sengupta S, Mathur P, Sapra P. Influence of piperine on nimesulide induced antinociception. Phytother Res  1998; 12(4): 266-9.
 [http://dx.doi.org/10.1002/(SICI)1099-1573(199806)12:4<266:AID-PTR291>3.0.CO;2-S]

[91]
Bano G, Amla V, Raina R, Zutshi U, Chopra C, Chopra CL. The effect of piperine on pharmacokinetics of phenytoin in healthy volunteers. Planta Med  1987; 53(6): 568-9.
 [http://dx.doi.org/10.1055/s-2006-962814] [PMID: 3444866]

[92]
Ren T, Zuo Z. Role of piperine in CNS diseases: Pharmacodynamics, pharmacokinetics and drug interactions. Exp Opinion Drug Metabol Toxicol  2019; 2019: 1672658.
 [http://dx.doi.org/10.1080/17425255.2019.1672658]

[93]
Auti P, Choudhary A, Gabhe S, Mahadik K. Bioanalytical method development, validationand its application in Pharmacokinetic studies of Verapamil in the presence of Piperine in rats. Int J Pharm Res  2018; 10: 119.

[94]
Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol  1991; 41(6): 615-7.
 [http://dx.doi.org/10.1007/BF00314996] [PMID: 1815977]

[95]
Bedada SK, Appani R, Boga PK. Effect of piperine on the metabolism and pharmacokinetics of carbamazepine in healthy volunteers. Drug Res (Stuttg)  2017; 67(1): 46-51.
 [PMID: 27776366]

[96]
Singh A, Verma S, Al Zarari NMH, Singh AP, Fuloria NKK, Fuloria S. Effect of Piperineon Pharmacokinetics of Rifampicin and Isoniazid: Development and Validation of HighPerformance Liquid Chromatography Method. J Appl Pharm Sci  2018; 8: 72-81.

[97]
Bedada SK, Boga PK. The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers. Eur J Clin Pharmacol  2017; 73(3): 343-9.
 [http://dx.doi.org/10.1007/s00228-016-2173-3] [PMID: 27981349]

[98]
Auti P, Gabhe S, Mahadik K. Bioanalytical method development and its application to pharmacokinetics studies on Simvastatin in the presence of piperine and two of its synthetic derivatives. Drug Dev Ind Pharm  2019; 45(4): 664-8.
 [http://dx.doi.org/10.1080/03639045.2019.1569034] [PMID: 30649976]

[99]
Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas P. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med  1998; 64(4): 353-6.
 [http://dx.doi.org/10.1055/s-2006-957450] [PMID: 9619120]

[100]
Reddy KR, Faruqui AA. Efficacy and tolerability of fixed dose combination of curcumin and piperine in Indian osteoarthritic patients. Int J Orthopaed Sci  2016; 2(4g): 445-9.
 [http://dx.doi.org/10.22271/ortho.2016.v2.i4g.67]

[101]
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; 20(8): 683-6.
 [http://dx.doi.org/10.1002/ptr.1937] [PMID: 16767797]

[102]
Di Pierro F, Settembre R. Safety and efficacy of an add-on therapy with curcumin phytosome and piperine and/or lipoic acid in subjects with a diagnosis of peripheral neuropathy treated with dexibuprofen. J Pain Res  2013; 6: 497-503.
 [http://dx.doi.org/10.2147/JPR.S48432] [PMID: 23861596]

[103]
Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P. Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients. Phytother Res  2009; 23(9): 1281-6.
 [http://dx.doi.org/10.1002/ptr.2676] [PMID: 19283724]

[104]
Rezaee MM, Kazemi S, Kazemi MT, et al. The effect of piperine on midazolam plasma concentration in healthy volunteers, a research on the CYP3A-involving metabolism. Daru  2014; 22(1): 8.
 [http://dx.doi.org/10.1186/2008-2231-22-8] [PMID: 24398010]

[105]
Wightman EL, Reay JL, Haskell CF, Williamson G, Dew TP, Kennedy DO. Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: A randomised, double-blind, placebo-controlled, crossover investigation. Br J Nutr  2014; 112(2): 203-13.
 [http://dx.doi.org/10.1017/S0007114514000737] [PMID: 24804871]

[106]
Vora A, Patel S, Patel K. Role of Risorine in the treatment of drug susceptible pulmonary tuberculosis: A pilot study. J Assoc Physicians India  2016; 64(11): 20-4.
 [PMID: 27805329]

[107]
Bedada SK, Boga PK, Kotakonda HK. Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers. Xenobiotica  2017; 47(2): 127-32.
 [http://dx.doi.org/10.3109/00498254.2016.1163752] [PMID: 27052193]

[108]
Shafiee A, Hoormand M, Shahidi-Dadras M, Abadi A. The effect of topical piperine combined with narrowband UVB on vitiligo treatment: A clinical trial study. Phytother Res  2018; 32(9): 1812-7.
 [http://dx.doi.org/10.1002/ptr.6116] [PMID: 29781089]

[109]
Mihăilă B, Dinică RM, Tatu AL, Buzia OD. New insights in vitiligo treatments using bioactive compounds from Piper nigrum. Exp Ther Med  2019; 17(2): 1039-44.
 [PMID: 30679971]

[110]
Rofes L, Arreola V, Martin A, Clavé P. Effect of oral piperine on the swallow response of patients with oropharyngeal dysphagia. J Gastroenterol  2014; 49(12): 1517-23.
 [http://dx.doi.org/10.1007/s00535-013-0920-0] [PMID: 24326980]

[111]
O’Connor A, Corbin KD, Nieman DC, Swick AG. A randomized, controlled trial to assess short-term black pepper consumption on 24-hour energy expenditure and substrate utilization. Funct Food Health Dis  2013; 3(10): 377-88.
 [http://dx.doi.org/10.31989/ffhd.v3i10.38]

[112]
Kaur S, Sharma R, Sarangal V, Kaur N, Prashar P. Evaluation of antiinflammatory effects of systemically administered curcumin lycopene and piperine as an adjunct to scaling and root planing: A clinical study. Ayu  2017; 38(2): 117-21.
 [http://dx.doi.org/10.4103/ayu.AYU_63_17] [PMID: 30254390]

[113]
Panahi Y, Ghanei M, Hajhashemi A, Sahebkar A. Effects of curcuminoids-piperine combination on systemic oxidative stress, clinical symptoms and quality of life in subjects with chronic pulmonary complications due to sulfur mustard: A randomized controlled trial. J Diet Suppl  2016; 13(1): 93-105.
 [http://dx.doi.org/10.3109/19390211.2014.952865] [PMID: 25171552]

[114]
Panahi Y, Hosseini MS, Khalili N, Naimi E, Majeed M, Sahebkar A. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis. Clin Nutr  2015; 34(6): 1101-8.
 [http://dx.doi.org/10.1016/j.clnu.2014.12.019] [PMID: 25618800]

[115]
Lakshmipati A. One hundred Useful Drugs.  (3rd ed.), Madras, India: Arogya Ashram Samithi 1946.

[116]
Lele RD. Ayurveda through modern eyes Bharatiya Vidya Bhavan. Bombay: Ayurveda Mod Med 1986.

[117]
Johri RK, Zutshi U. An Ayurvedic formulation ‘Trikatu’ and its constituents. J Ethnopharmacol  1992; 37(2): 85-91.
 [http://dx.doi.org/10.1016/0378-8741(92)90067-2] [PMID: 1434692]

[118]
Anonymous . The Ayurvedic Formulary of India Part-II.  (1st ed.), New Delhi: Government of India, Ministry of Health and Family Welfare, Department of Indian Systems of Medicine & Homeopathy 2000.

[119]
Nadkarni KM. Piper nigrum L Indian Materia Medica.  Bombay: Popular Prakashan Press 1986; pp. 969-72.

[120]
Usmanghani K, Saeed A, Alam MT. Indusyunic Medicine. Karachi: University of Karachi Press 1997.

[121]
Upadhyay S, Mitra A, Hazra J, Singh RK, Banerjee R. Toxicological evaluation of Panchakola Avaleha, an Ayurvedic classical formulation, in albino rats. Ayu  2012; 33(2): 303-6.
 [http://dx.doi.org/10.4103/0974-8520.105257] [PMID: 23559809]

[122]
Patel K, Soni A, Gupta SN. Clinical evaluation of Vardhamana Pippali Rasayana in the management of Amavata (rhematoid arthritis). Ayu  2011; 32(2): 177-80.
 [http://dx.doi.org/10.4103/0974-8520.92555] [PMID: 22408298]

[123]
Gyawali S, Khan GM, Lamichane S, et al. Evaluation of anti-secretory and antiulcerogenic activities of avipattikar churna on the peptic ulcers in experimental rats. J Clin Diagn Res  2013; 7(6): 1135-9.
 [http://dx.doi.org/10.7860/JCDR/2013/5309.3058] [PMID: 23905120]

[124]
Zaveri M, Khandhar A, Patel S, Patel A. Chemistry and pharmacology of Piper longum L. Int J Pharm Sci Rev Res  2010; 5: 67-76.

[125]
Ngono Ngane A, Biyiti L, Bouchet P, Nkengfack A, Amvam Zollo PH. Antifungal activity of Piper guineense of Cameroon. Fitoterapia  2003; 74(5): 464-8.
 [http://dx.doi.org/10.1016/S0367-326X(03)00112-6] [PMID: 12837362]

[126]
Dzoyem JP, Kuete V. Review of the antifungal potential of African medicinal plants.In: Antifungal Metabolites from Plants.  Springer 2013; pp. 79-153.
 [http://dx.doi.org/10.1007/978-3-642-38076-1_4]

[127]
Dzoyem JP, Tchuenguem RT, Kuiate JR, Teke GN, Kechia FA, Kuete V. In vitro and in vivo antifungal activities of selected Cameroonian dietary spices. BMC Complement Altern Med  2014; 14(1): 58.
 [http://dx.doi.org/10.1186/1472-6882-14-58] [PMID: 24533718]

[128]
Ebana RUB, Edet UO, Ekanemesang UM, Ikon GM, Etok CA, Edet AP. Antimicrobial activity, phytochemical screening and nutrient analysis of Tetrapleura tetraptera and Piper guineense. Asian J Med Heal  2016; 1(3): 1-8.

[129]
mgbeahuruike EE, Holm Y, Vuorela H, Amandikwa C, Fyhrquist P. An ethnobotanical survey and antifungal activity of Piper guineense used for the treatment of fungal infections in West-African traditional medicine. J Ethnopharmacol  2019; 229: 157-66.
 [http://dx.doi.org/10.1016/j.jep.2018.10.005] [PMID: 30336302]

[130]
Tiwari A, Mahadik KR, Gabhe SY. Piperine: A comprehensive review of methods of isolation, purification, and biological properties. Med Drug Discov  2020; 7: 100027.
 [http://dx.doi.org/10.1016/j.medidd.2020.100027]

[131]
Syed S. Unanni Advia Murakkaba.  New Delhi: Aijaz Publishing House 2010; pp. 17-274.

[132]
Ansari KA, Akram M. FilfilSiyah (Piper nigrum Linn) an important Drug of Unani System of Medicine: A Review. J Pharmacogn Phytochem  2014; 2: 219-21.

[133]
Bashir F, Afrin Z. Zanjabeel (Zingiber offcinale) Transformation of Culinary Spice to a multi-functional Medicine. J Drug Deliv Ther  2019; 9(4-s): 721-5.
 [http://dx.doi.org/10.22270/jddt.v9i4-s.3299]

[134]
Ahmad B, Akhtar J. Unani system of medicine. Pharmacogn Rev  2007; 1: 210.

[135]
Afzal M, Khan NA, Ghufran A, Iqbal A, Inamuddin M. Diuretic and nephroprotective effect of Jawarish Zarooni Sada—a polyherbal unani formulation. J Ethnopharmacol  2004; 91(2-3): 219-23.
 [http://dx.doi.org/10.1016/j.jep.2003.12.029] [PMID: 15120442]

[136]
Ganga B, Wadud A, Jahan N, Makbul SAA. Anti-inflammatory and analgesic activity of HabbeGuleAakh, A polyherbal Unani formulation in animal models. J Ayurveda Integr Med  2021; 12(1): 9-12.
 [PMID: 30414716]

[137]
Jeganathan NS, Anbazhagan S, Aruna P, Deepa D, Kalaivani A. Preparation and quality control of a Siddha formulation – Kesari Lehyam. Int J Adv Res Biol Sci (IJARBS)  2016; 3(11): 180-5.
 [http://dx.doi.org/10.22192/ijarbs.2016.03.11.022]

[138]
Riyasdeen A, Periasamy VS, Paul P, Alshatwi AA, Akbarsha MA. Chloroform Extract of Rasagenthi Mezhugu, a Siddha formulation, as an evidence-based complementary and alternative medicine for HPV-Positive Cervical Cancers. Evid Based Complement Alternat Med  2012; 2012: 136527.
 [http://dx.doi.org/10.1155/2012/136527] [PMID: 22114617]

[139]
Gorgani L, Mohammadi M, Najafpour GD, Nikzad M. Piperine-The bioactive compound of black pepper: From isolation to medicinal formulations. Compr Rev Food Sci Food Saf  2017; 16(1): 124-40.
 [http://dx.doi.org/10.1111/1541-4337.12246] [PMID: 33371546]

[140]
Majeed M, Badmaev V, Rajendran RJE. Use of piperine as a gastrointestinal absorption enhancer European Patent EP 0810868B1 2001.

[141]
Patel RB, Modi IA. Compositions containing piperine United States patent US 5616593A 1997.

[142]
Singh A, Jain R. Pharmaceutical compositions containing NSAIDs and piperine European Patent EP 0935964A1 1999.

[143]
Gaikar VG, Raman G. Process for extraction of piperine from piper species United States patent US 6365601B1 2002.

[144]
Hering S, Erker T, Schwarz T, Igor B, Schellmann D. Novel piperine derivatives as gaba-a receptors modulators European Patent EP 2519511B1 2015.

[145]
Raman A, Lin Z. Use of piperine and analogues thereof in the prevention of skin cancer. Canada patent. CA (Edinb)  2013; 2735844C.

[146]
Kapil RS, Zutshi U, Bedi KL, et al. Pharmaceutical compositions containing piperine and an antituberculosis or antileprosydrug European Patent EP 0650728A1 2002.

[147]
Alexander M. Light-sensitive piperine compositions United States patent US 2475980A 1949.
Cite As
Current Drug Research Reviews

Synergistic Effect of Piperine and its Derivatives: A Comprehensive Review

Abstract

Graphical Abstract
