title: Synergistic enhancement of parasiticidal activity of amphotericin B using copaiba oil in nanoemulsified carrier for oral delivery: an approach for non-toxic chemotherapy.
abstract: OBJECTIVE
  The aim of this study was to devise a nanoemulsified carrier system (CopNEC) to improve the oral delivery of amphotericin B (AmB) by increasing its oral bioavailability and synergistically enhance its antileishmanial activity with copaiba oil (Cop).
  
  
  METHODS
  The AmB encapsulated NEC (CopNEC-AmB) comprised of Cop, d-α-tocopheryl polyethylene glycol 1000 succinate and phosphatidylcholine was prepared by high-pressure homogenization method. Stability study of CopNEC-AmB was carried out in simulated gastric fluid and simulated intestinal fluid. The CopNEC-AmB and plain AmB were compared as regards their in vitro antileishmanial activity, pharmacokinetics, organ distribution and toxicity.
  
  
  RESULTS
  The optimal CopNEC-AmB had a small globule size, low polydispersity index, high ζ potential and encapsulation efficiency. The high resolution transmission electron microscopy illustrated spherical particle geometry with homogeny in their sizes. The optimal CopNEC-AmB was found to be stable in gastrointestinal fluids showing insignificant changes in globule size and encapsulation efficiency. The AUC0-48 value of CopNEC-AmB in rats was significantly improved showing 7.2-fold higher oral bioavailability than free drug. The in vitro antileishmanial activity of CopNEC-AmB was significantly higher than that of the free drug as Cop synergistically enhanced the antileishmanial effect of AmB by causing drastic changes in the morphology of Leishmania parasite and rupturing its plasma membrane. The CopNEC-AmB showed significantly less haemolytic toxicity and cytotoxicity and did not change the histopathology of kidney tissues as compared with AmB alone.
  
  
  CONCLUSIONS
  This prototype CopNEC formulation showed improved bioavailability and had a non-toxic synergistic effect on the antileishmanial activity of AmB.
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Gupta
authors.affiliation: Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Teja B
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Shukla
authors.affiliation: Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Neeti
authors.initials: N
authors.lastname: Sagar
authors.affiliation: Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dube
authors.affiliation: Toxicology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Srikanta K
authors.initials: SK
authors.lastname: Rath
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India.
authors.forename: Prabhat R
authors.initials: PR
authors.lastname: Mishra
mesh_terms: D000284:Administration, Oral; D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D002460:Cell Line; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry*; D004655:Emulsions; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D008297:Male; D051379:Mice; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D021261:Parasitic Sensitivity Tests; D010938:Plant Oils / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000981:Antiprotozoal Agents; D004337:Drug Carriers; D004655:Emulsions; D010938:Plant Oils; D000666:Amphotericin B
references.citation: Antimicrob Agents Chemother. 1992 Nov;36(11):2518-22
references.pmid: 1489196
references.citation: Lancet. 2005 Oct 29-Nov 4;366(9496):1561-77
references.pmid: 16257344
references.citation: Exp Parasitol. 2011 Oct;129(2):145-51
references.pmid: 21771592
references.citation: Int J Pharm. 2007 Dec 10;345(1-2):9-25
references.pmid: 17945446
references.citation: Bioconjug Chem. 2014 Jun 18;25(6):1091-102
references.pmid: 24842628
references.citation: Mol Pharm. 2007 May-Jun;4(3):465-74
references.pmid: 17367162
references.citation: J Ethnopharmacol. 2008 Nov 20;120(2):141-8
references.pmid: 18762237
references.citation: Int J Pharm. 2013 Sep 15;454(1):539-52
references.pmid: 23871737
references.citation: AAPS PharmSciTech. 2009;10(4):1343-7
references.pmid: 19904614
references.citation: J Invest Dermatol. 1957 Mar;28(3):217-31; discussion, 231-2
references.pmid: 13429161
references.citation: J Biol Chem. 2003 Jul 4;278(27):25120-32
references.pmid: 12707265
references.citation: Int J Pharm. 2009 May 8;372(1-2):76-84
references.pmid: 19236839
references.citation: Trans R Soc Trop Med Hyg. 2000 Sep-Oct;94(5):465-71
references.pmid: 11132368
references.citation: Antimicrob Agents Chemother. 2008 Mar;52(3):1080-93
references.pmid: 18056276
references.citation: Phytother Res. 2003 Nov;17(9):1048-53
references.pmid: 14595585
references.citation: Pharm Res. 1995 Mar;12(3):413-20
references.pmid: 7617530
references.citation: Br J Pharmacol. 2010 Aug;160(7):1573-6
references.pmid: 20649560
references.citation: Evid Based Complement Alternat Med. 2012;2012:898419
references.pmid: 21716677
references.citation: Eur J Clin Pharmacol. 2007 Feb;63(2):165-72
references.pmid: 17180621
references.citation: Int J Pharm. 2014 Jan 2;460(1-2):131-43
references.pmid: 24239580
references.citation: J Oral Rehabil. 1993 Jul;20(4):379-84
references.pmid: 8350172
references.citation: Pharm Res. 1999 Mar;16(3):455-8
references.pmid: 10213379
references.citation: Int J Pharm. 2013 Mar 10;445(1-2):141-7
references.pmid: 23396256
references.citation: Exp Mol Pathol. 2002 Apr;72(2):132-41
references.pmid: 11890722
references.citation: Eur J Pharm Biopharm. 2006 Jul;63(3):288-94
references.pmid: 16527467
references.citation: Antimicrob Agents Chemother. 2013 Apr;57(4):1714-22
references.pmid: 23357762
references.citation: Int J Pharm. 2003 Mar 18;254(1):73-5
references.pmid: 12615413
references.citation: J Control Release. 2002 Jan 17;78(1-3):15-24
references.pmid: 11772445
references.citation: Mol Pharm. 2013 May 6;10(5):2062-70
references.pmid: 23557122
references.citation: Mem Inst Oswaldo Cruz. 2013 Feb;108(1):59-64
references.pmid: 23440116
references.citation: Int J Pharm. 2008 Dec 8;364(2):213-26
references.pmid: 18602774
references.citation: PLoS Negl Trop Dis. 2010;4(12):e913
references.pmid: 21151883
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Mol Pharm. 2008 Jul-Aug;5(4):505-15
references.pmid: 18672949
references.citation: Genet Mol Biol. 2012 Jul;35(3):664-72
references.pmid: 23055807
references.citation: J Antimicrob Chemother. 2009 Jul;64(1):101-8
references.pmid: 19398459
references.citation: J Ethnopharmacol. 2006 Jul 19;106(3):390-402
references.pmid: 16517108
references.citation: J Antimicrob Chemother. 2010 Mar;65(3):535-7
references.pmid: 20026611
references.citation: Cancer Lett. 2011 Dec 22;312(2):178-88
references.pmid: 21924548
references.citation: Annu Rev Immunol. 1999;17:593-623
references.pmid: 10358769
references.citation: Int J Parasitol. 2007 Aug;37(10):1087-96
references.pmid: 17543969
references.citation: PLoS One. 2013;8(12):e81492
references.pmid: 24339938
references.citation: Eur J Pharm Biopharm. 2007 Nov;67(3):759-65
references.pmid: 17499981
references.citation: J Biol Chem. 2000 Mar 10;275(10):7087-94
references.pmid: 10702275
references.citation: Biomacromolecules. 2010 Apr 12;11(4):1027-35
references.pmid: 20178378
references.citation: Antimicrob Agents Chemother. 2000 Apr;44(4):898-904
references.pmid: 10722488
references.citation: Curr Mol Med. 2004 Sep;4(6):649-65
references.pmid: 15357214
references.citation: Lancet. 2002 Jun 22;359(9324):2188-94
references.pmid: 12090998
references.citation: Micron. 1995;26(5):405-30
references.pmid: 8640360
references.citation: J Control Release. 2006 Mar 10;111(1-2):35-40
references.pmid: 16410030
references.citation: Cell Death Differ. 2004 Aug;11(8):924-36
references.pmid: 15118764
references.citation: Mol Pharm. 2014 Mar 3;11(3):951-63
references.pmid: 24495144
references.citation: Antimicrob Agents Chemother. 2002 Aug;46(8):2704-7
references.pmid: 12121962
references.citation: Infection. 1982;10(4):223-7
references.pmid: 7129644
references.citation: Expert Opin Drug Deliv. 2013 Dec;10(12):1633-51
references.pmid: 24147603
references.citation: Colloids Surf B Biointerfaces. 2000 Oct 1;18(3-4):315-323
references.pmid: 10915953
references.citation: J Antimicrob Chemother. 2007 May;59(5):941-51
references.pmid: 17400589
references.citation: Evid Based Complement Alternat Med. 2013;2013:761323
references.pmid: 23864897
references.citation: J Med Chem. 2012 Apr 12;55(7):2994-3001
references.pmid: 22440015
references.citation: Biomaterials. 2012 Jun;33(19):4889-906
references.pmid: 22498300
references.citation: Phytomedicine. 2012 Nov 15;19(14):1307-14
references.pmid: 23062361
references.citation: J Ethnopharmacol. 2008 Nov 20;120(2):204-8
references.pmid: 18775772
references.citation: Mol Pharmacol. 2008 Nov;74(5):1292-307
references.pmid: 18703668
references.citation: J Agric Food Chem. 2003 Dec 31;51(27):8073-9
references.pmid: 14690399
references.citation: Br J Pharmacol. 2010 Aug;160(7):1577-9
references.pmid: 20649561
references.citation: Clin Infect Dis. 2006 Oct 1;43(7):917-24
references.pmid: 16941377