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Drug Delivery Letters

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ISSN (Print): 2210-3031
ISSN (Online): 2210-304X

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Review Article

Nasal In-situ Gel: An Approach to Enhance Therapeutic Benefits of the Drug

Author(s): Kapil Khatri*, Shikha Jain and Satish Shilpi

Volume 10, Issue 2, 2020

Page: [85 - 95] Pages: 11

DOI: 10.2174/2210303109666190926110927

Price: $65

Abstract

Objective: Drug delivery through the nasal route is emerging as a promising approach due to its capability to transport the drug to the systemic circulation and the central nervous system for therapeutic benefits.

Methods: In-situ gelling formulations comprising polymeric substances are emerging as preferential nasal drug delivery systems. When exposed to biological stimuli, they have the ability to undergo a solgel conversion.

Result: Such mucoadhesive in-situ gel formulations designed and developed for the nasal administration have the ability to prolong the residence time of formulation in the nasal cavity, thereby serving better for complete uptake of the drug across the nasal mucosa.

Conclusion: Thus, this review focuses on temperature-responsive, pH-responsive and ion responsive polymers utilized in the nasal in-situ gels together with their physicochemical characterization, evaluation and pharmaceutical applications.

Keywords: Nasal drug delivery, mucoadhesion, in-situ gels, in-situ gelling polymers, first passes effect, enhanced bioavailability, absorption

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[1]
Mahdi, M.H.; Conway, B.R.; Smith, A.M. Development of mucoadhesive sprayable gellan gum fluid gels. Int. J. Pharm., 2015, 488(1-2), 12-19.
[http://dx.doi.org/10.1016/j.ijpharm.2015.04.011] [PMID: 25863119]
[2]
Ugwoke, M.I.; Agu, R.U.; Verbeke, N.; Kinget, R. Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. Adv. Drug Deliv. Rev., 2005, 57(11), 1640-1665.
[http://dx.doi.org/10.1016/j.addr.2005.07.009] [PMID: 16182408]
[3]
Salunke, S.R.; Patil, S.B. Ion activated in situ gel of gellan gum containing salbutamol sulphate for nasal administration. Int. J. Biol. Macromol., 2016, 87, 41-47.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.02.044] [PMID: 26899173]
[4]
Saudagar, R.B.; Deore, S.B.; Gondkar, S.B. Formulation development and evaluation of in-situ the nasal gel of lisinoprildihydrate. Sch. Acad. J. Pharm., 2016, 5(7), 277-283.
[5]
Chonkar, A.; Nayak, U.; Udupa, N. Smart Polymers in Nasal Drug Delivery. Indian J. Pharm. Sci., 2015, 77(4), 367-375.
[http://dx.doi.org/10.4103/0250-474X.164770] [PMID: 26664051]
[6]
Thorat, S. Formulation and Product Development of The nasal Spray: An Overview. Sch. J. App. Med. Sci., 2016, 4(8D), 2976-2985.
[7]
Buvaneswari, G.; Rajalakshmi, A.N. Emerging trends in novel drug delivery system: intra the nasal drug delivery. Int. J. Pharm. Chem. Sci., 2016, 5(1), 66-111.
[8]
Aderibigbe, B.A. In situ-based gels for nose to brain delivery for the treatment of neurological diseases. Pharmaceutics, 2018, 10(2), 1-17.
[http://dx.doi.org/10.3390/pharmaceutics10020040] [PMID: 29601486]
[9]
Watelet, J.B.; Van Cauwenberge, P. Applied anatomy and physiology of the nose and paranasal sinuses. Allergy, 1999, 54(57)(Suppl. 57), 14-25.
[http://dx.doi.org/10.1111/j.1398-9995.1999.tb04402.x] [PMID: 10565476]
[10]
Menaka, M.; Pandey, V.P.; Smith, A.A. Formulation development and evaluation of ondansetron hydrochloride the nasal spray. Int. J. Pharm. Pharm. Sci., 2013, 5(4), 150-154.
[11]
Kakad, J.K.; More, P.K.; Gondkar, S.B.; Saudagar, S.B. A recent review on the nasal drug delivery system. World J. of Pharm. Res., 2015, 4(2), 269-281.
[12]
Chhajed, S.; Sangale, S.; Barhate, S.D. Advantageous the nasal drug delivery system: a review. Int. J. Pharm. Sci. Res., 2011, 2(6), 1322-1336.
[13]
Ghori, M.U.; Mahdi, M.H.; Smith, A.M.; Conway, B.R. The nasal drug delivery systems: an overview. Am. J. Pharmacol. Sci., 2015, 3(5), 110-119.
[14]
Appasaheb, P.S.; Manohar, S.D.; Saudagar, R.B. A review on the nasal drug delivery system. J. Adv. Pharm. Educ. Res., 2013, 3(4), 333-346.
[15]
Dey, S.; Mahanti, B.; Mazumder, B.; Malgope, A.; Dasgupta, S. The nasal drug delivery: an approach of drug delivery through the nasal route. Pharm. Sin., 2011, 2(3), 94-106.
[16]
Bitter, C.; Suter-Zimmermann, K.; Surber, C. Nasal drug delivery in humans. Curr. Probl. Dermatol., 2011, 40, 20-35.
[http://dx.doi.org/10.1159/000321044] [PMID: 21325837]
[17]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 1997, 23, 23-25.
[http://dx.doi.org/10.1016/S0169-409X(96)00423-1]
[18]
Sherafudeen, S.P.; Vasantha, P.V. Development and evaluation of in situ nasal gel formulations of loratadine. Res. Pharm. Sci., 2015, 10(6), 466-476.
[PMID: 26779266]
[19]
Rajput, A.; Bariya, A.; Allam, A.; Othman, S.; Butan, S.B. In situ nanostructured hydrogel of resveratrol for brain targeting: in vitro-in vivo characterization; Drug Deliv. Translat. Res, 2018.
[20]
Perez, A.P.; Mundiña-Weilenmann, C.; Romero, E.L.; Morilla, M.J. Increased brain radioactivity by intranasal P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int. J. Nanomedicine, 2012, 7, 1373-1385.
[PMID: 22457595]
[21]
Grasdalen, H.; Smidsroed, O. Gelation of gellan gum. Carbohydr. Polym., 1987, (7), 371-393.
[http://dx.doi.org/10.1016/0144-8617(87)90004-X]
[22]
Karavasili, C.; Fatouros, D.G. Smart materials: in situ gel-forming systems for nasal delivery. Drug Discov. Today, 2016, 21(1), 157-166.
[http://dx.doi.org/10.1016/j.drudis.2015.10.016] [PMID: 26563428]
[23]
More, A.B.; Mene, H.R.; Pawar, R.K.; Misal, N.S.; Pathak, S.S.; Shivsharan, K.J. A Review on In-situ The nasal Gel Drug Delivery System. Int. J. Pharm. Sci. Rev. Res., 2015, 33(1), 199-207.
[24]
Ban, M.M.; Chakote, V.R.; Dhembre, G.N.; Rajguru, J.R.; Joshi, D.A. In-situ gel for nasal drug delivery. Int. J. Develop. Res., 2018, 08(2), 18763-18769.
[25]
Patil, P.R.; Shaikh, S.S.; Shivsharan, K.J.; Shahi, S.R. In situ gel: a novel drug delivery system. Indo. Am. J. Pharm. Res., 2014, 4(11), 5406-5414.
[26]
Bhatt, V.; Karakoti, R.; Bhatt, B.; Singh, A.K.; Sharma, D.K. Formulation and evaluation of antiemetic the nasal spray of limonene. World J. Pharm. Pharm. Sci., 2015, 4(1), 1381-1391.
[27]
Kumar, G.P.; Kiran, S. Strategies and Prospectus of The nasal Drug Delivery System. Int. J. Pharm. Sci. Res., 2012, 2(1), 33-41.
[28]
Saudagar, R.B.; Kulkarni, M.M. Review on in-situ The nasal Gel Drug Delivery System. Res. J. Pharm. Tech., 2017, 10(6), 1-6.
[http://dx.doi.org/10.5958/0974-360X.2017.00328.6]
[29]
Grassin-Delyle, S.; Buenestado, A.; Naline, E.; Faisy, C.; Blouquit-Laye, S.; Couderc, L.J.; Le Guen, M.; Fischler, M.; Devillier, P. Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids. Pharmacol. Ther., 2012, 134(3), 366-379.
[http://dx.doi.org/10.1016/j.pharmthera.2012.03.003] [PMID: 22465159]
[30]
Fisher, A.; Watling, M.; Smith, A.; Knight, A. Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188. Int. J. Clin. Pharmacol. Ther., 2010, 48(2), 138-145.
[http://dx.doi.org/10.5414/CPP48138] [PMID: 20137766]
[31]
Hussain, A.A.; Dakkuri, A.; Itoh, S. Nasal absorption of ondansetron in rats: an alternative route of drug delivery. Cancer Chemother. Pharmacol., 2000, 45(5), 432-434.
[http://dx.doi.org/10.1007/s002800051014] [PMID: 10803929]
[32]
Kumar, M.; Upadhayay, P.; Shankar, R.; Joshi, M.; Bhatt, S.; Malik, A. Chlorpheniramine maleate containing chitosan-based nanoparticle-loaded thermosensitive in situ gel for management in allergic rhinitis. Drug Deliv. Trans. Res., 2019.
[http://dx.doi.org/10.1007/s13346-019-00639-w]
[33]
Mahajan, H.S.; Tyagi, V.K.; Patil, R.R.; Dusunge, S.B. Thiolated xyloglucan: Synthesis, characterization and evaluation as mucoadhesive in situ gelling agent. Carbohydr. Polym., 2013, 91(2), 618-625.
[http://dx.doi.org/10.1016/j.carbpol.2012.08.077] [PMID: 23121955]
[34]
Tas, C.; Kose, O.C.; Saravar, A.; Ozkan, Y.; Tasdemir, V.; Altmay, H. The nasal absorption of metoclopramide from different carbopol 981 based formulations: in-vivo, ex-vivo and in-vivo evaluation. Drug Deliv., 2009, 16, 167-175.
[http://dx.doi.org/10.1080/10717540902764172] [PMID: 19514977]
[35]
Zaki, N.M.; Awad, G.A.; Mortada, N.D. Enhanced the metoclopramide hydrochloride by the nasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties. Eur. J. Pharm. Sci., 2007, 32(4-5), 296-307.
[http://dx.doi.org/10.1016/j.ejps.2007.08.006] [PMID: 17920822]
[36]
Bernkop-Schnürch, A.; Dünnhaupt, S. Chitosan-based drug delivery systems. Eur. J. Pharm. Biopharm., 2012, 81(3), 463-469.
[http://dx.doi.org/10.1016/j.ejpb.2012.04.007] [PMID: 22561955]
[37]
Gavini, E.; Rassu, G.; Muzzarelli, C.; Cossu, M.; Giunchedi, P. Spray-dried microspheres based on methylpyrrolidinone chitosan as new carrier for nasal administration of metoclopramide. Eur. J. Pharm. Biopharm., 2008, 68(2), 245-252.
[http://dx.doi.org/10.1016/j.ejpb.2007.05.002] [PMID: 17574825]
[38]
Majithiya, R.J.; Ghosh, P.K.; Umrethia, M.L.; Murthy, R.S. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech, 2006, 7(3), 67.
[http://dx.doi.org/10.1208/pt070367] [PMID: 17025248]
[39]
Youssef, N.A.H.A.; Kassem, A.A.; Farid, R.M.; Ismail, F.A.; El-Massik, M.A.E.; Boraie, N.A. A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation. Int. J. Pharm., 2018, 548(1), 609-624.
[http://dx.doi.org/10.1016/j.ijpharm.2018.07.014] [PMID: 30033394]
[40]
Gholizadeh, H.; Cheng, S.; Pozzoli, M.; Messerotti, E.; Traini, D.; Young, P.; Kourmatzis, A.; Ong, H.X. Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders. Expert Opin. Drug Deliv., 2019, 16(4), 453-466.
[http://dx.doi.org/10.1080/17425247.2019.1597051] [PMID: 30884987]
[41]
Galgatte, U.C.; Kumbhar, A.B.; Chaudhari, P.D. Development of in situ gel for nasal delivery: design, optimization, in vitro and in vivo evaluation. Drug Deliv., 2014, 21(1), 62-73.
[http://dx.doi.org/10.3109/10717544.2013.849778] [PMID: 24191774]
[42]
Abdelnabi, D.M.; Abdallah, M.H.; Elghamry, H.A. Buspirone Hydrochloride Loaded In Situ Nanovesicular Gel as an Anxiolytic Nasal Drug Delivery System: In Vitro and Animal Studies. 2019, 20, pp. (134)1-14.
[43]
More, P.K.; Saudagar, R.B.; Gondkar, S.B. The nasal in-situ gel: a novel approach for the nasal drug delivery system. World J. Pharm. Res., 2015, 4(2), 686-708.
[44]
Khan, S.; Gajbhiye, C.; Singhavi, D.J.; Yeole, P. In situ gel of metoprolol tartrate: physicochemical characterization, in-vitro diffusion and histological studies. Indian J. Pharm. Sci., 2012, 74(6), 564-570.
[http://dx.doi.org/10.4103/0250-474X.110608] [PMID: 23798784]
[45]
Patil, S.K.; Dhage, A.N.; Patil, S.V.; Patil, S.S. Formulation and evaluation of the nasal in situ gel for alzheimer Disease. Int. Res. J. Pharm. Bio. Sci., 2015, 2(2), 41-58.
[46]
Saudagar, R.B.; Deore, S.B.; Gondka, S.B. Formulation development and evaluation of in-situ the nasal gel of lisinopril dehydrate. Sch. Acad. J. Pharm., 2016, 5(7), 277-283.
[47]
Saudagar, R.B.; Kulkarni, M.M. Formulation development and evaluation of in-situ the nasal gel of ziprasidone hydrochloride. Int. J. Chemtech Res., 2017, 10(9), 195-211.
[48]
Agarwal, P.; Kumar, A.; Tanwar, Y.S.; Sharma, S. Formulation and evaluation of in-situ nasal gel of rizatriptan benzoate by using mucoadhesive polymers. J. Drug Deliv. Ther., 2017, 7(2), 132-140.
[http://dx.doi.org/10.22270/jddt.v7i2.1333]
[49]
Dukovskia, B.J.; Plantica, I.; Cuncica, I.; Krtalicb, I.; Juretica, M.; Pepica, I.; Lovrica, J.; Hafnera, A. Lipid/alginate nanoparticle-loaded in situ gelling system tailored for dexamethasone nasal delivery; Int. J. Pharma, 2017, pp. 1-30.
[50]
Gaikwad, V. Formulation and evaluation of in-situ gel of metoprolol tartrate for the nasal delivery. J. Pharm. Res., 2010, 3, 788-793.
[51]
Gowda, D.V.; Tanuja, D.; Khan, M.S. Formulation and evaluation of in-situ gel of diltiazem hydrochloride for the nasal delivery. Der. Pharmacia. Letter., 2011, 3, 371-381.
[52]
Agrawal, A.K.; Gupta, P.N.; Khanna, A.; Sharma, R.K.; Chandrawanshi, H.K.; Gupta, N.; Patil, U.K.; Yadav, S.K. Development and characterization of in situ gel system for nasal insulin delivery. Pharmazie, 2010, 65(3), 188-193.
[PMID: 20383938]
[53]
Xie, H.; Li, L.; Sun, Y.; Wang, Y.; Gao, S.; Tian, Y.; Ma, X.; Guo, C.; Bo, F.; Zhang, L. An available strategy for nasal brain transport of nanocomposite based on PAMAM dendrimers via in situ gel. Nanomaterials (Basel), 2019, 9(2), 1-25.
[http://dx.doi.org/10.3390/nano9020147] [PMID: 30682799]
[54]
Rajpoot, A.K.; Kumar, H.; Jain, H.; Verma, H.C. Formulation and evaluation of mucoadhesive the nasal in-situ gel of diclofenac sodium. MIT Int. J. Pharma. Sci., 2015, 1(2), 21-55.
[55]
Mahathi, K. devi, A.S. Formulation and evaluation of the nasal in-situ gel of levofloxacin hemihydrate. Indo. Am. J. Pharm. Res., 2014, 4(12), 5817-5827.
[56]
Yadav, D.J.; Kunjwani, H.K.; Suryawanshi, S.S. Formulation and evaluation of thermosensitive in situ gel of salbutamol sulphate for the nasal drug delivery system. Int. J. Pharm. Pharm. Sci., 2012, 4(4), 188-194.
[57]
Harmonised Tripartite Guideline, ICH Stability testing of newdrug substances and products, Q1A(R2). 2003.
[58]
Gaikwad, M.; Sahasrabuddhe, S.; Puranik, P. Development and evaluation of carbamazepine loaded transfersomal in-situ gel for nose to brain delivery. Indo. Am. J. Pharm. Res., 2015, 5(5), 2047-2053.
[59]
Shahi, S.R.; Gugulkar, R.R.; Kulkarni, M.S. Formulation development and evaluation of in situ the nasal gel of zolpidem tartrate. Int. J. Innov. Sci. Res., 2015, 4(8), 431-436.
[60]
Makwana, S.B.; Patel, V.A.; Parmar, S.J. Development and characterization of in-situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride. Results Pharma Sci., 2015, 6, 1-6.
[http://dx.doi.org/10.1016/j.rinphs.2015.06.001] [PMID: 26949596]
[61]
Pandey, P.; Cabot, P.J.; Wallwork, B.; Panizza, B.J.; Parekh, H.S. Formulation, functional evaluation and ex vivo performance of thermoresponsive soluble gels - A platform for therapeutic delivery to mucosal sinus tissue. Eur. J. Pharm. Sci., 2017, 96, 499-507.
[http://dx.doi.org/10.1016/j.ejps.2016.10.017] [PMID: 27771516]
[62]
Paul, A.; Fathima, K.M.; Nair, S.C. Intra nasal in situ gelling system of lamotrigine using ion activated mucoadhesive polymer. Open Med. Chem. J., 2017, 11, 222-244.
[http://dx.doi.org/10.2174/1874104501711010222] [PMID: 29399211]
[63]
Saraswathi, B.; Balaji, A.; Umashankar, M.S. Polymers in mucoadhesive drug delivery system-latest updates. Int. J. Pharm. Pharm. Sci., 2013, 5(3), 423-430.
[64]
Madan, M.; Bajaj, A.; Lewis, S.; Udupa, N.; Baig, J.A. In situ forming polymeric drug delivery systems. Indian J. Pharm. Sci., 2009, 71(3), 242-251.
[http://dx.doi.org/10.4103/0250-474X.56015] [PMID: 20490289]
[65]
Andrews, G.P.; Laverty, T.P.; Jones, D.S. Mucoadhesive polymeric platforms for controlled drug delivery. Eur. J. Pharm. Biopharm., 2009, 71(3), 505-518.
[http://dx.doi.org/10.1016/j.ejpb.2008.09.028] [PMID: 18984051]
[66]
Wang, Y.; Jiang, S.; Wang, H.; Bie, H. A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. PLoS One, 2017, 12(12)e0189478
[http://dx.doi.org/10.1371/journal.pone.0189478] [PMID: 29240797]
[67]
Soliman, M.E.; Elmowafy, E.; Casettari, L.; Alexander, C. Star-shaped poly(oligoethylene glycol) copolymer-based gels: thermo-responsive behaviour and bioapplicability for risedronate intranasal delivery; Int. J. Pharma, 2018, pp. 1-34.
[68]
Yuguchi, Y.; Urakawa, H.; Kitamura, S.; Wataoka, I.; Kajiwara, K. The sol-gel transition of gellan gum aqueous solutions in the presence of various metal salts. Prog. Colloid Polym. Sci., 1999, 114, 41-47.
[69]
Watts, P.; Smith, A. PecSys: in situ gelling system for optimised nasal drug delivery. Expert Opin. Drug Deliv., 2009, 6(5), 543-552.
[http://dx.doi.org/10.1517/17425240902939135] [PMID: 19413461]
[70]
Sriamornsak, P. Chemistry of pectin and its pharmaceutical uses: A review. Silpakorn Univ. Jour. Soc. Sci. Humanit. Arts., 2003, 3, 206-223.
[71]
Patil, R.P.; Pawara, D.D.; Gudewar, C.S.; Tekade, A.R. Nanostructured cubosomes in an in situ nasal gel system: an alternative approach for the controlled delivery of donepezil HCl to brain; J. Lipo. Res, 2018, pp. 1-27.
[72]
Kun, N.; Bae, Y.H. pH sensitive polymers for drug delivery. In: Kwon GS, editors. Polymeric Drug Del. Systems. 1st ed. Florida, USA: Talor and Francis Group; 2005, pp. 94-129.
[73]
Nandgude, T.; Thube, R.; Jaiswal, N.; Deshmukh, P.; Chatap, V.; Hire, N. Formulation and evaluation pH induced in-situ the nasal gel of salbutamol sulphate. Int. J. Pharm. Sci. Nanotechnol., 2008, 1, 177-183.
[74]
Nakamura, K.; Maitani, Y.; Lowman, A.M.; Takayama, K.; Peppas, N.A.; Nagai, T. Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery. J. Control. Release, 1999, 61(3), 329-335.
[http://dx.doi.org/10.1016/S0168-3659(99)00150-9] [PMID: 10477805]
[75]
Sherje, A.P.; Londhe, V. Development and evaluation of pH-responsive cyclodextrin-based in situ gel of paliperidone for intranasal delivery; Amer. Assoc. Pharma. Sci, 2017.
[76]
Pund, S.; Rasve, G.; Borade, G. Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur. J. Pharm. Sci., 2013, 48(1-2), 195-201.
[http://dx.doi.org/10.1016/j.ejps.2012.10.029] [PMID: 23159662]
[77]
Zaki, N.M.; Awad, G.A.; Mortada, N.D. AbdElhady, S.S. Enhanced bioavailability of metoclopramide HCl by the nasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties. Eur. J. Pharm. Sci., 2007, 32, 296-307.
[http://dx.doi.org/10.1016/j.ejps.2007.08.006] [PMID: 17920822]
[78]
Castile, J.; Cheng, Y.H.; Simmons, B.; Perelman, M.; Smith, A.; Watts, P. Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip. Drug Dev. Ind. Pharm., 2013, 39(5), 816-824.
[http://dx.doi.org/10.3109/03639045.2012.707210] [PMID: 22803832]
[79]
Belgamwar, V.S.; Chauk, D.S.; Mahajan, H.S.; Jain, S.A.; Gattani, S.G.; Surana, S.J. Formulation and evaluation of in situ gelling system of dimenhydrinate for nasal administration. Pharm. Dev. Technol., 2009, 14(3), 240-248.
[http://dx.doi.org/10.1080/10837450802498910] [PMID: 19235555]
[80]
Cao, S.L.; Zhang, Q.Z.; Jiang, X.G. Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy. Acta Pharmacol. Sin., 2007, 28(4), 584-590.
[http://dx.doi.org/10.1111/j.1745-7254.2007.00540.x] [PMID: 17376300]

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