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Current HIV Research

Author(s): José Lourenço de Freitas Neto, Ilka do Nascimento Gomes Barbosa*, Camila Gomes de Melo, Matheus Alves Ângelos, Larissa Morgana dos Santos Mendes, Magda Rhayanny Assunção Ferreira, Larissa Araújo Rolim, Luiz Alberto Lira Soares, Rosali Maria Ferreira da Silva and Pedro José Rolim Neto

DOI: 10.2174/1570162X18666200702130449

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Development of Pediatric Orodispersible Tablets Based on Efavirenz as a New Therapeutic Alternative

Page: [342 - 353] Pages: 12

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Abstract

Background: Efavirenz is the most used medication in the treatment of Acquired Immunodeficiency Syndrome (AIDS). The limited number of pediatric antiretroviral formulations approved by regulatory agencies is the most significant obstacle to adequate and efficient pharmacotherapy for this group of patients. The efavirenz has excellent therapeutic potential, but has low aqueous solubility/bioavailability.

Methods: To minimize these limitations, multicomponent systems with β-cyclodextrin and polyvinylpyrrolidone K-30 were obtained. Due to the limited number of pediatric antiretroviral formulations, the development of a pediatric orodispersible tablet is an alternative that is thought easy to administer, since it disintegrates rapidly in the oral cavity. The multicomponent systems were obtained by the method of kneading and characterized by solubility test, X-ray diffraction, differential scanning calorimetry and infrared absorption spectroscopy by Fourier transform. The orodispersible tablets were prepared by direct compression. The quality control of hardness, friability, disintegration, and dissolution was performed. The influence of the components of the formulation on the characteristics of the tablets was evaluated through a 22 factorial design added with three central points, to compare the effect of the dependent variables on the responses.

Results: An increase in drug solubility was observed, with a decrease in crystallinity. Besides that, an excellent dissolution profile presented with more than 83% of the drug's content dissolved in less than 15 minutes. Satisfactory disintegration time and friability were observed.

Conclusion: It was observed that reduced concentrations of mannitol decreased the hardness and disintegration time of the formulations. The orodispersible tablet composed of efavirenz: β- cyclodextrin: polyvinylpyrrolidone, favors greater absorption and bioavailability. It has several advantages for pediatric patients, as the dosage form disintegrates quickly in the mouth and does not require water for administration, thereby improving patient compliance with the treatment.

Keywords: AIDS, efavirenz, multicomponent systems, buccal administration.

Graphical Abstract

[1]
UNAIDS. Joint United Nations Program on HIV/AIDS. Estatísticas globais sobre HIV 2019. Available at https://unaids.org.br/ estatisticas/?gclid=Cj0KCQjwmdzzBRC7ARIsANdqRRlSyJj3WIbFiynQd-qOG1zKnqcubx8H3AJ-K4ygRlbK_EcjfwkeuKIaAsUGEALw_wcB [March 20, 2020]
[2]
WHO World Health Organization Paediatric HIV and Treatment of Children Living with HIV 2010 Available from: http://www.who.int/hiv/topics/paediatric/en/index.html [Accessed Jully 13, 2019.]
[3]
MSF Medécins sans frontiers 2009 Available at: https://www. msf.org.br/noticias/muitas-criancas-com-hivaids-ainda-esperam [Jully 14, 2019.].
[4]
WHO World Health Organization Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection 2016.https://www.who.int/hiv/pub/arv/arv-2016/en/ [April 13, 2019]
[5]
Santos EI. Evidências científicas brasileiras sobre adesão à terapia antirretroviral por pessoas que vivem com HIV/AIDS. Revista Eletrônica Gestão Saúde 2016; 7: 454-70.
[http://dx.doi.org/10.18673/gs.v7i1.22092]
[6]
Bastos MM, Costa CCP, Bezerra TC, da Silva FC, Boechat N. Efavirenz a nonnucleoside reverse transcriptase inhibitor of first-generation: Approaches based on its medicinal chemistry. Eur J Med Chem 2016; 108: 455-65.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.025 ] [PMID: 26708112]
[7]
Cavalcante GIT, Chaves Filho AJ, Linhares MI, et al. HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum. Eur J Pharmacol 2017; 799: 7-15.
[http://dx.doi.org/10.1016/j.ejphar.2017.02.009 ] [PMID: 28188763]
[8]
Sathigari S, Chadha G, Lee YHP, et al. Physicochemical characterization of efavirenz-cyclodextrin inclusion complexes. AAPS PharmSciTech 2009; 10(1): 81-7.
[http://dx.doi.org/10.1208/s12249-008-9180-3 ] [PMID: 19148759]
[9]
Chiappetta DA, Alvarez-Lorenzo C, Rey-Rico A, Taboada P, Concheiro A, Sosnik A. N-alkylation of poloxamines modulates micellar assembly and encapsulation and release of the antiretroviral efavirenz. Eur J Pharm Biopharm 2010; 76(1): 24-37.
[http://dx.doi.org/10.1016/j.ejpb.2010.05.007 ] [PMID: 20493946]
[10]
Jammula S, Patra CN, Swain S, et al. Improvement in the dissolution rate and tableting properties of cefuroxime axetil by melt-granulated dispersion and surfasse adsorption. Acta Pharm Sin B 2013; 3: 113-22.
[http://dx.doi.org/10.1016/j.apsb.2013.01.001]
[11]
Verma U, Naik JB, Mokale VJ. Preparation of freeze-dried solid dispersion poder using mannitol to enhance solubility of lovastatin and development of sustained release tablet dosage form. Am J Pharm Sci Nanotech 2014; 1: 11-26.
[12]
Mabrouk M, Chejara DR, Mulla JAS, et al. Design of a novel crosslinked HEC-PAA porous hydrogel composite for dissolution rate and solubility enhancement of efavirenz. Int J Pharm 2015; 490(1-2): 429-37.
[http://dx.doi.org/10.1016/j.ijpharm.2015.05.082 ] [PMID: 26047962]
[13]
Patel GV, Patel VB, Pathak A, Rajput SJ. Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization, in vitro, in situ and in vivo evaluation. Drug Dev Ind Pharm 2014; 40(1): 80-91.
[http://dx.doi.org/10.3109/03639045.2012.746362 ] [PMID: 23323843]
[14]
Costa BLA, Sauceau M, Del Confetto S, Sescousse R, Ré MI. Determination of drug-polymer solubility from supersaturated spray-dried amorphous solid dispersions: A case study with Efavirenz and Soluplus®. Eur J Pharm Biopharm 2019; 142: 300-6.
[http://dx.doi.org/10.1016/j.ejpb.2019.06.028 ] [PMID: 31247317]
[15]
Alves LDS, de La Roca Soares MF, de Albuquerque CT, et al. Solid dispersion of efavirenz in PVP K-30 by conventional solvent and kneading methods. Carbohydr Polym 2014; 104: 166-74.
[http://dx.doi.org/10.1016/j.carbpol.2014.01.027 ] [PMID: 24607174]
[16]
Yao Y, Xie Y, Hong C, Li G, Shen H, Ji G. Development of a myricetin/hydroxypropyl-β-cyclodextrin inclusion complex: preparation, characterization, and evaluation. Carbohydr Polym 2014; 110: 329-37.
[http://dx.doi.org/10.1016/j.carbpol.2014.04.006 ] [PMID: 24906763]
[17]
Vieira ACC, Ferreira Fontes DA, Chaves LL, et al. Multicomponent systems with cyclodextrins and hydrophilic polymers for the delivery of Efavirenz. Carbohydr Polym 2015; 130: 133-40.
[http://dx.doi.org/10.1016/j.carbpol.2015.04.050 ] [PMID: 26076609]
[18]
Yang LJ, Wang SH, Zhou SY, et al. Supramolecular system of podophyllotoxin and hydroxypropyl-β-cyclodextrin: Characterization, inclusion mode, docking calculation, solubilization, stability and cytotoxic activity. Mater Sci Eng C 2017; 76: 1136-45.
[http://dx.doi.org/10.1016/j.msec.2017.03.197 ] [PMID: 28482478]
[19]
Madhusudhan G, Bhagavanth R, Venkatesham M, Veerabhadram G. Design and Evaluation of Efavirenz loaded Solid Lipid Nanoparticles to Improve the Oral Bioavailability. Int J Pharm Pharm Sci Res 2012; 2: 84-9.
[20]
Gomes TA, Costa SPM, Medeiros GCR, et al. Estratégias utilizadas para o incremento da solubilidade do fármaco antiretroviral classe II: Efavirenz. Rev Cienc Farm Basica Apl 2015; 36: 239-49.
[21]
Zou A, Zhao X, Handge UA, Garamus VM, Willumeit-Römer R, Yin P. Folate receptor targeted bufalin/β-cyclodextrin supramolecular inclusion complex for enhanced solubility and anti-tumor efficiency of bufalin. Mater Sci Eng C 2017; 78: 609-18.
[http://dx.doi.org/10.1016/j.msec.2017.04.094 ] [PMID: 28576029]
[22]
Yan XQ, Shi YL, Qiao CL, Li YY, Wei XM, Qiao XR. Preparation of novel dual-site drug delivery system based on hydroxypropyl methyl cyclodextrin. Mater Sci Eng C 2017; 78: 1016-22.
[http://dx.doi.org/10.1016/j.msec.2017.04.108 ] [PMID: 28575935]
[23]
Martin Del Valle EM. Cyclodextrins and their uses: a review Process Biochem 2004; 39: 1033-46
[http://dx.doi.org/10.1016/S0032-9592(03)00258-9]
[24]
Desai S, Poddar A, Sawant K. Formulation of cyclodextrin inclusion complex-based orally disintegrating tablet of eslicarbazepine acetate for improved oral bioavailability. Mater Sci Eng C 2016; 58: 826-34.
[http://dx.doi.org/10.1016/j.msec.2015.09.019 ] [PMID: 26478377]
[25]
Soares-Sobrinho JL, Santos FLA, Lyra MAM, et al. Benznidazole drug delivery by binary and multicomponent inclusion complexes using cyclodextrins and polymers. Carbohydr Polym 2012; 89(2): 323-30.
[http://dx.doi.org/10.1016/j.carbpol.2012.02.042 ] [PMID: 24750726]
[26]
Verma U, Naik JB, Patil JS, Yadava SK. Screening of process variables to enhance the solubility of famotidine with 2-HydroxyPropyl-β-Cyclodextrin & PVP K-30 by using Plackett-Burman design approach. Mater Sci Eng C 2017; 77: 282-92.
[http://dx.doi.org/10.1016/j.msec.2017.03.238 ] [PMID: 28532031]
[27]
Du J, Guo X, Tu J, et al. Biopolymer-based supramolecular micelles from β-cyclodextrin and methylcellulose. Carbohydr Polym 2012; 90(1): 569-74.
[http://dx.doi.org/10.1016/j.carbpol.2012.05.079 ] [PMID: 24751078]
[28]
Feng C, Lu G, Li Y, Huang X. Self-assembly of amphiphilic homopolymers bearing ferrocene and carboxyl functionalities: effect of polymer concentration, β-cyclodextrin, and length of alkyl linker. Langmuir 2013; 29(34): 10922-31.
[http://dx.doi.org/10.1021/la402335d ] [PMID: 23977901]
[29]
Taupitz T, Dressman JB, Buchanan CM, Klein S. Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: itraconazole. Eur J Pharm Biopharm 2013; 83(3): 378-87.
[http://dx.doi.org/10.1016/j.ejpb.2012.11.003 ] [PMID: 23201048]
[30]
Jug M, Bećirević-Laćan M. Influence of hydroxypropyl-beta-cyclodextrin complexation on piroxicam release from buccoadhesive tablets. Eur J Pharm Sci 2004; 21(2-3): 251-60.
[http://dx.doi.org/10.1016/j.ejps.2003.10.029 ] [PMID: 14757497]
[31]
Ammar HO, Salama HA, Ghorab M, Mahmoud AA. Formulation and biological evaluation of glimepiride-cyclodextrin-polymer systems. Int J Pharm 2006; 309(1-2): 129-38.
[http://dx.doi.org/10.1016/j.ijpharm.2005.11.024 ] [PMID: 16377107]
[32]
Csajka C, Marzolini C, Fattinger K, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther 2003; 73(1): 20-30.
[http://dx.doi.org/10.1067/mcp.2003.22 ] [PMID: 12545140]
[33]
NIH National Library of Medicine An expanded access study of oral liquid efavirenz in the treatment of children with HIV infection NCT ID: NCT00162227 2010 Available at: http://clinicaltrials. gov/show/NCT00162227?order=7 [Accessed January 10, 2019].
[34]
NIH National Library of Medicine An expanded access study of oral liquid efavirenz in the treatment of children with HIV infection: Canada NCT ID: NCT00162188 2010 Available at: http://clinicaltrials.gov/show/NCT00162188?order=8 [Accessed January 10, 2019].
[35]
Ferreira JP. Pediatria: Diagnósticos e Tratamento. Artmed. 2007; p. 709.
[36]
Sellers RS, Antman M, Phillips J, Khan KN, Furst SM. Effects of miglyol 812 on rats after 4 weeks of gavage as compared with methylcellulose/tween 80. Drug Chem Toxicol 2005; 28(4): 423-32.
[http://dx.doi.org/10.1080/01480540500262839 ] [PMID: 16298873]
[37]
Larru B, Eby J, Lowenthal ED. Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz. Pediatric Health Med Ther 2014; 5: 29-42.
[PMID: 25937791]
[38]
Jullian C, Morales-Montecinos J, Zapata-Torres G, et al. Characterization, phase-solubility, and molecular modeling of inclusion complex of 5-nitroindazole derivative with cyclodextrins. Bioorg Med Chem 2008; 16(9): 5078-84.
[http://dx.doi.org/10.1016/j.bmc.2008.03.026 ] [PMID: 18375132]
[39]
Lee BJ. Pharmaceutical preformulation: physicochemical properties of excipients and powders and tablet characterizationPharmaceutical Manufacturing Handbook Production and Process New Jersey. Hoboken: John Wiley & Sons 2010; pp. 926-31.
[http://dx.doi.org/10.1002/9780470571224.pse362]
[40]
Rowe RC, Sheskey PJ, Quin ME. Handbook of Pharmaceutical Excipient 6th edition London, UK: Pharmaceutical Press e Washington, DC: American Pharmacists Association. 2009.
[41]
Ohrem HL, Schornick E, Kalivoda A, Ognibene R. Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms? Pharm Dev Technol 2014; 19(3): 257-62.
[http://dx.doi.org/10.3109/10837450.2013.775154 ] [PMID: 23528124]
[42]
Thoorens G, Krier F, Leclercq B, Carlin B, Evrard B. Microcrystalline cellulose, a direct compression binder in a quality by design environment--a review. Int J Pharm 2014; 473(1-2): 64-72.
[http://dx.doi.org/10.1016/j.ijpharm.2014.06.055 ] [PMID: 24993785]
[43]
Tarlier N, Soulairol I, Bataille B, et al. Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator. Int J Pharm 2015; 495(1): 410-9.
[http://dx.doi.org/10.1016/j.ijpharm.2015.09.007 ] [PMID: 26363108]
[44]
Soares LAL, Ortega GG, Petrovick PR, Schmidt PC. Optimization of tablets containing a high dose of spray-dried plant extract: a technical note. AAPS PharmSciTech 2005; 6(3): E367-71.
[http://dx.doi.org/10.1208/pt060346 ] [PMID: 16353994]
[45]
Brasil.Farmacopeia brasileira, 5 ed. Brasília.: ANVISA, Brasília 2010.
[46]
United States United States Pharmacopeia 37th ed. Convention: Rockville. 2014.
[47]
Szejtli J, Szente L. Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins. Eur J Pharm Biopharm 2005; 61(3): 115-25.
[http://dx.doi.org/10.1016/j.ejpb.2005.05.006 ] [PMID: 16185857]
[48]
Melo PN, Barbosa EG, Caland LB, et al. Host–guest interactions between benznidazoleandbeta-cyclodextrin in multicomponent complex systems involving hydrophilicpolymers and triethanolamine in aqueous solution. J Mol Liq 2013; 186: 147-56.
[http://dx.doi.org/10.1016/j.molliq.2013.07.004]
[49]
Storpirtis S. Biofarmacotécnica - Ciências Farmacêuticas. Guanabara Koogan 2009.
[50]
Radesca LA, Maurin MB, Rabel SR, Moore JR. Crystalline efavirenz. WO1999064405. 1999. Available at: https://patentscope. wipo.int/search/en/detail.jsf;jsessionid=EF85801FF8F061E62AE3AD1550A7B9E4.wapp1nC?docId=WO1999064405&recNum=87&office=&queryString=&prevFilter=%26fq%3DICF_M%3A%22C07D%22%26fq%3DDP%3A1999&sortOption=Pub+Date+Desc&maxRec=1571 [Accessed January 10, 2019].
[51]
Cristofoletti R, Nair A, Abrahamsson B, et al. Biowaiver monographs for immediate release solid oral dosage forms: efavirenz. J Pharm Sci 2013; 102(2): 318-29.
[http://dx.doi.org/10.1002/jps.23380 ] [PMID: 23175470]
[52]
Wang X, Luo Z, Xiao Z. Preparation, characterization, and thermal stability of β-cyclodextrin/soybean lecithin inclusion complex. Carbohydr Polym 2014; 101: 1027-32.
[http://dx.doi.org/10.1016/j.carbpol.2013.10.042 ] [PMID: 24299871]
[53]
Yang Z, et al. Preparation and release behaviour of the inclusion complexes of phenylethanol with β‐cyclodextrin Lavour and Fragrance Journal 2016; 31: 206-16
[http://dx.doi.org/10.1002/ffj.3302]
[54]
Lima ÁAN, Soares-Sobrinho JL, Silva JL, et al. The use of solid dispersion systems in hydrophilic carriers to increase benzonidazole solubility. J Pharm Sci 2011; 100(6): 2443-51.
[http://dx.doi.org/10.1002/jps.22436 ] [PMID: 21491453]
[55]
Mishra S, Tandon P, Ayala AP. Study on the structure and vibrational spectra of efavirenz conformers using DFT: comparison to experimental data. Spectrochim Acta A Mol Biomol Spectrosc 2012; 88: 116-23.
[http://dx.doi.org/10.1016/j.saa.2011.12.010 ] [PMID: 22206896]
[56]
Fontes DAF, Lyra MAM, Andrade JKF, et al. CaAl-layered double hydroxide as a drug delivery system: effects on solubility and toxicity of the antiretroviral efavirenz. J Incl Phenom Macrocycl Chem 2016; 85: 281-8.
[http://dx.doi.org/10.1007/s10847-016-0627-y]
[57]
Abarca RL, Rodríguez FJ, Guarda A, Galotto MJ, Bruna JE. Characterization of beta-cyclodextrin inclusion complexes containing an essential oil component Food Chem 2016; 196: 968-75
[http://dx.doi.org/10.1016/j.foodchem.2015.10.023] [PMID: 26593579]
[58]
Gennaro AR. Remington: A Ciência e a Prática da Farmácia20ª Rio de Janeiro . Guanabara Koogan 2004; p. 2208.
[59]
Reier GE, Shangraw RF. Microcrystalline cellulose in tableting. J Pharm Sci 1966; 55: 510-4.
[http://dx.doi.org/10.1002/jps.2600550513]
[60]
Zhang Y, Law Y, Chakrabarti S. Physical properties and compact analysis of commonly used direct compression binders. AAPS PharmSciTech 2003; 4(4): E62.
[http://dx.doi.org/10.1208/pt040462 ] [PMID: 15198557]
[61]
Doelker E. Comparative compaction properties of various microcrystalline cellulose types and generic products Drug Dev Ind Pharm 1993; 19: 2399-471
[http://dx.doi.org/10.3109/03639049309047196]
[62]
Sinka IC, Burch SF, Tweed JH, Cunningham JC. Measurement of density variations in tablets using X-ray computed tomography. Int J Pharm 2004; 271(1-2): 215-24.
[http://dx.doi.org/10.1016/j.ijpharm.2003.11.022 ] [PMID: 15129988]
[63]
Saroha K, Kumar G, Paul Y. Formulation and evaluation of fast dissolving tablets of amoxicillin trihydrate using synthetic superdisintegrants. Int J Pharma Bio Sci 2013; 4: 254-62.
[64]
Sharma D, Kumar D, Singh M, Singh G, Rathore MS. Fast disintegrating tablets: a new era in novel drug delivery system and new market opportunities. J Drug Deliv Ther 2012; 2: 74-86.
[http://dx.doi.org/10.22270/jddt.v2i3.125]
[65]
Vimal V, Aarathi JSB. Superdisintegrants in fast disintegrating drug delivery systems: a brief review. Int J Pharm 2013; 3: 380-5.
[66]
Sano S, Iwao Y, Noguchi S, Kimura S, Itai S. Design and evaluation of microwave-treated orally disintegrating tablets containing polymeric disintegrant and mannitol. Int J Pharm 2013; 448(1): 132-41.
[http://dx.doi.org/10.1016/j.ijpharm.2013.03.023 ] [PMID: 23524122]
[67]
Kande KV, Kotak DJ, Degani MS, Kirsanov D, Legin A, Devarajan PV. Microwave-Assisted Development of Orally Disintegrating Tablets by Direct Compression. AAPS PharmSciTech 2017; 18(6): 2055-66.
[http://dx.doi.org/10.1208/s12249-016-0683-z ] [PMID: 27995465]
[68]
Augsburger LL. Superdisintegrants: characterization and function. Encyclop Pharmaceut Technol 2007; 20: 269-90.
[69]
Cirri M, Maestrelli F, Mennini N, Mura P. Influence of the preparation method on the physical-chemical properties of ketoprofen-cyclodextrin-phosphatidylcholine ternary systems. J Pharm Biomed Anal 2009; 50(5): 690-4.
[http://dx.doi.org/10.1016/j.jpba.2008.11.002 ] [PMID: 19097721]
[70]
Moyano JM, Ginés M, Arias AMR. Study of the dissolution characteristics of oxazepam via complexation with β-cyclodextrin Int J Pharm 1995; 114: 95-102
[http://dx.doi.org/10.1016/0378-5173(94)00220-Y]
[71]
Badr-Eldin SM, Elkheshen SA, Ghorab MM. Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: preparation and in-vitro evaluation. Eur J Pharm Biopharm 2008; 70(3): 819-27.
[http://dx.doi.org/10.1016/j.ejpb.2008.06.024 ] [PMID: 18655829]
[72]
Patel AR, Vavia PR. Preparation and evaluation of taste masked famotidine formulation using drug/beta-cyclodextrin/polymer ternary complexation approach. AAPS PharmSciTech 2008; 9(2): 544-50.
[http://dx.doi.org/10.1208/s12249-008-9078-0 ] [PMID: 18431648]
[73]
Kou W, Cai C, Xu S, et al. In vitro and in vivo evaluation of novel immediate release carbamazepine tablets: complexation with hydroxypropyl-β-cyclodextrin in the presence of HPMC. Int J Pharm 2011; 409(1-2): 75-80.
[http://dx.doi.org/10.1016/j.ijpharm.2011.02.042 ] [PMID: 21371541]
[74]
Pal A. gaba R, Soni S. Effect of presence of α-cyclodextrin and β- cyclodextrin on solution behavior of sulfathiazole at different temperatures: Thermodynamic and spectroscopic studies. J Chem Thermodyn 2018; 199: 102-13.
[http://dx.doi.org/10.1016/j.jct.2017.12.017]
[75]
Koh PT, Chuah JN, Talekar M, Gorajana A, Garg S. Formulation development and dissolution rate enhancement of efavirenz by solid dispersion systems. Indian J Pharm Sci 2013; 75(3): 291-301.
[http://dx.doi.org/10.4103/0250-474X.117434 ] [PMID: 24082345]