New formulations for the controlled release of local anesthetics in dentistry: from development to clinical tests

• Grant number: 06/00121-9
• Support type: Research Projects - Thematic Grants
• Duration: May 01, 2007 - June 30, 2012
• Field of knowledge: Health Sciences - Dentistry - Dental Clinics
• Principal researcher: Eneida de Paula
• Grantee: Eneida de Paula
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Francisco Carlos Groppo
• Assoc. researchers: José Ranali ; Leonardo Fernandes Fraceto ; Maria Cristina Volpato
• Associated grant(s): 09/05848-2 - 36th Annual Meeting and Exposition of the Controlled Release Society, AR.EXT; 09/00466-4 - Meeting on Nanotechnology, Liposomes and Health, AR.BR
• Associated scholarship(s): 11/15768-6 - Modulatory effects of 2%, 3% and 4% plain articaine and articaine encapsulated into liposomes on citocine production by human gingival fibroblasts., BP.MS; 11/21735-3 - Liposome-based drug delivery systems for ropivacaine encapsulated by remote (pH and ion gradient) loading., BP.DR; 11/09849-3 - Long lasting treatment for gingivitis, BE.PQ; + associated scholarships 11/12666-8 - Effects of local anesthetic associated with carriers in the modulation of inflammatory mediators, cell viability and apoptosis induction, BP.DD; 11/08070-2 - DEVELOPMENT OF AN INCLUSION COMPLEX FOR THE LOCAL ANESTHETIC DIBCAINE IN HYDROPROPYL-BETA-CYCLODEXTRIN: IN VITRO AND IN VIVO TESTS, BP.IC; 11/05581-6 - Thermoreversible polymeric hydrogels and liposomal systems for transdermal delivery of lidocaine, BP.MS; 11/02486-2 - Modulatory effects of articaine 4%, with or without liposomes on cytokine production in human oral epithelial cells., BP.IC; 11/00844-9 - Preparation and characterization of polymeric nanoparticles for modified release of local anesthetic articaine, BP.IC; 10/18529-0 - Modified release systems for local anesthetic articaine aim to odontological applications, BP.DR; 10/13088-5 - Drug delivery systems for tramadol in thermoreversible polymeric gels: cytotoxicity and pharmacological evaluation studies, BP.MS; 10/18755-0 - Preparation and characterization of nanostructured lipid carriers containing dibucaine, BP.IC; 10/20382-7 - Efficacy of lipossomal lidocaine in topical anesthesia of palatal mucosa., BP.IC; 09/11797-1 - Anesthetic eficacy of uni and multi-lamellar prilocaine formulations in infra-orbital and inferior alveolar nerves block and in wound healing, in rats., BP.MS; 09/11820-3 - The anesthetic eficacy of hydroxypropyl-beta-cyclodextrin bupivacaine formulations in alveolar inferior nerve block and wound healing in rats., BP.MS; 09/11842-7 - Anesthetic efficacy of uni and multilamelar liposomal articaine formulations in infraorbital and inferior alveolar nerve blocks and in surgical wound, in rats., BP.MS; 09/11848-5 - Anesthetic efficacy of uni and multilamelar liposomal mepivacaine formulations in infraorbital and inferior alveolar nerve blocks and in surgical wound, in rats., BP.MS; 09/11854-5 - Modulatory effects of local anesthetics associated with drug-carriers over cytokines production in human epithelial oral cells and gingival fibroblasts., BP.MS; 09/12009-7 - Anesthetic efficacy of ropivacaine with hydroxypropyl-beta-cyclodextrin formulation in infraorbital and inferior alveolar nerve blocks and in surgical wound, in rats., BP.MS; 09/16225-6 - The modulatory effects of lidocaine associated with drug-carriers over cytokines production of human oral epithelial cells., BP.IC; 09/09815-1 - Preparation and characterization of polylactate-glycolate nanoparticles for the local anesthetic dibucaine, BP.IC; 09/08860-3 - Transdermal permeation and biocompatibility studies on gel formulations of benzocaine encapsulated in elastic and conventional liposomes, BP.PD; 08/09822-5 - Anesthetic efficacy of liposomal lidocaine in inferior alveolar nerve block in rats., BP.IC; 08/09079-0 - Anesthetic efficacy of liposomal ropivacaine in inferior alveolar nerve block in rats., BP.IC; 08/01222-9 - Preparation and characterization of alginate nanoparticle with bupivacaine, BP.IC; 07/05734-1 - Efficacy of a liposomal articaine hydrocloride formulation in rats., BP.MS; 07/05850-1 - LOCAL ANESTHETIC ACTIVITY OF LIPOSSOMAL FORMULATIONS IN DENTISTRY, BP.MS - associated scholarships

Abstract

The structure and physicochemical features of local anesthetics (LA) are determinant fort heir potency and toxicity (Araújo et al, 2003). Water solubility is, for instance, an essential parameter for the transport of the anesthetic molecule to the nerve fibers as well as to the ionization equilibrium that guarantees the existence of both ionized and non-ionized LA forms. On the other hand lipid solubility is also crucial for drug partitioning into the axon, so that enough amounts of LA molecules will sit inside that membrane in order to keep the sodium channel in its non-conducting state (Butterworth & Strichartz, 1990). In general, the potency of an LA molecule is proportional to its toxicity, an impediment to the development of more potent drugs. The development of new LA formulations is nowadays a challenge in dentistry. For topical anesthesia, for instance, new therapeutic forms that allow mucous absorption leading to deeper and longer anesthetic effects are highly desirable since infiltrative anesthesia could be replaced for topical products, reducing the aversive responses associated with infiltrative procedures. Liposomes have been shown to be interesting drug-delivery systems for LA since they enhance the availability of compounds, reduce their systemic toxicity and increase their half-life in vivo (Boogaerts et al, 1994; Grant, 2002). Similar advantages have been claimed for cyclodextrin formulations of poorly water-soluble anesthetics (Dollo et al, 1996, Pinto et al, 2004), for hydrogel formulations (Hillingso et al, 2002) and, more recently, for LA in polymers. The team of researchers joined together in this thematic proposal has a large experience in the development of liposomal and cyclodextrin LA preparations (Biomembranas group, Instituto de Biologia-Unicamp) and also in the odontology, specifically in the terapeuthics of local anesthetics (Anesthesia Lab., Faculdade de Odontologia de Piracicaba-Unicamp). We intend with this project to develop new pharmaceutical forms for the controlled release of classic LA molecules, in vehicles such as liposomes, cyclodextrins, gels and polymers. Our aim is to enhance de pharmacological actions and to reduce the local and systemic toxicity of LA, looking forward to a future application in dentistry. The potentiality of projects designed to the development of new LA formulations for human application can be understood by the dimensions of the LA market in Brazil: ca. US$ 12.5 billion per year, according to the Brazilian's Pharmaceutical Industry Association. A fraction of that, ca. US$ 2 billion/year, represents the sales only in LA for topical use... (AU)

Scientific publications

(32)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SAIA CEREDA, CINTIA MARIA; GUILHERME, VIVIANE APARECIDA; ALKSCHBIRS, MELISSA INGER; DE BRITO JUNIOR, RUI BARBOSA; TOFOLI, GIOVANA RADOMILLE; FRANZ-MONTAN, MICHELLE; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA. Liposomal butamben gel formulations: toxicity assays and topical anesthesia in an animal model. Journal of Liposome Research, v. 27, n. 1, p. 74-82, MAR 2017. Web of Science Citations: 1.

DA SILVA, CAMILA BATISTA; GROPPO, FRANCISCO CARLOS; DOS SANTOS, CLEITON PITA; SERPE, LUCIANO; FRANZ-MONTAN, MICHELLE; DE PAULA, ENEIDA; RANALI, JOSE; VOLPATO, MARIA CRISTINA. Anaesthetic efficacy of unilamellar and multilamellar liposomal formulations of articaine in inflamed and uninflamed tissue. BRITISH JOURNAL OF ORAL & MAXILLOFACIAL SURGERY, v. 54, n. 3, p. 295-300, APR 2016. Web of Science Citations: 6.

BRAGA, M. A.; MARTINI, M. F.; PICKHOLZ, M.; YOKAICHIYA, F.; FRANCO, M. K. D.; CABECA, L. F.; GUILHERME, V. A.; SILVA, C. M. G.; LIMIA, C. E. G.; DE PAULA, E. Clonidine complexation with hydroxypropyl-beta-cyclodextrin: From physico-chemical characterization to in vivo adjuvant effect in local anesthesia. Journal of Pharmaceutical and Biomedical Analysis, v. 119, p. 27-36, FEB 5 2016. Web of Science Citations: 7.

FRANZ-MONTAN, MICHELLE; BARONI, DANIELA; BRUNETTO, GIOVANA; VIEIRA SOBRAL, VIVIANE ROBERTA; GONCALVES DA SILVA, CAMILA MORAIS; VENANCIO, PAULO; ZAGO, PATRICIA WIZIACK; SAIA CEREDA, CINTIA MARIA; VOLPATO, MARIA CRISTINA; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA; GROPPO, FRANCISCO CARLOS. Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans. Journal of Liposome Research, v. 25, n. 1, p. 11-19, MAR 2015. Web of Science Citations: 21.

MENDONCA DOS SANTOS, ANA CLAUDIA; SANTOS AKKARI, ALESSANDRA CRISTINA; SILVA FERREIRA, IASMIN ROSANNE; MARUYAMA, CINTIA RODRIGUES; PASCOLI, MONICA; GUILHERME, VIVIANE APARECIDA; DE PAULA, ENEIDA; FRACETO, LEONARDO FERNANDES; DE LIMA, RENATA; MELO, PATRICIA DA SILVA; DE ARAUJO, DANIELE RIBEIRO. Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation. INTERNATIONAL JOURNAL OF NANOMEDICINE, v. 10, p. 2391-2401, 2015. Web of Science Citations: 18.

DE ARAUJO, DANIELE R.; DA SILVA, DEYSE C.; BARBOSA, RAQUEL M.; FRANZ-MONTAN, MICHELLE; CEREDA, CINTIA M. S.; PADULA, CRISTINA; SANTI, PATRIZIA; DE PAULA, ENEIDA. Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches. Expert Opinion on Drug Delivery, v. 10, n. 11, p. 1551-1563, NOV 2013. Web of Science Citations: 31.

SAIA CEREDA, CINTIA MARIA; FRANZ-MONTAN, MICHELLE; GONCALVES DA SILVA, CAMILA MORAIS; CASADEI, BRUNA RENATA; DOMINGUES, CLEYTON CREPALDI; TOFOLI, GIOVANA RADOMILLE; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA. Transdermal delivery of butamben using elastic and conventional liposomes. Journal of Liposome Research, v. 23, n. 3, p. 228-234, SEP 2013. Web of Science Citations: 17.

CARUSO, BENJAMIN; SANCHEZ, JULIETA M.; GARCIA, DANIEL A.; DE PAULA, ENEIDA; PERILLO, MARIA A. Probing the Combined Effect of Flunitrazepam and Lidocaine on the Stability and Organization of Bilayer Lipid Membranes. A Differential Scanning Calorimetry and Dynamic Light Scattering Study. Cell Biochemistry and Biophysics, v. 66, n. 3, p. 461-475, JUL 2013. Web of Science Citations: 2.

FRANZ-MONTAN, MICHELLE; SAIA CEREDA, CINTIA MARIA; GASPARI, ADELE; GONCALVES DA SILVA, CAMILA MORAIS; DE ARAUJO, DANIELE RIBEIRO; PADULA, CRISTINA; SANTI, PATRIZIA; NARVAES, ELIENE; NOVAES, PEDRO DUARTE; GROPPO, FRANCISCO CARLOS; DE PAULA, ENEIDA. Liposomal-benzocaine gel formulation: correlation between in vitro assays and in vivo topical anesthesia in volunteers. Journal of Liposome Research, v. 23, n. 1, p. 54-60, MAR 2013. Web of Science Citations: 15.

RAMOS CAMPOS, ESTEFANIA VANGELIE; SILVA DE MELO, NATHALIE FERREIRA; GUILHERME, VIVIANE APARECIDA; DE PAULA, ENEIDA; ROSA, ANDRE HENRIQUE; DE ARAUJO, DANIELE RIBEIRO; FRACETO, LEONARDO FERNANDES. Preparation and characterization of poly(e-caprolactone) nanospheres containing the local anesthetic lidocaine. Journal of Pharmaceutical Sciences, v. 102, n. 1, p. 215-226, JAN 2013. Web of Science Citations: 24.

BARBOSA, RAQUEL DE M.; KLASSEN, ALINE; MARCATO, PRISCYLA D.; FRANZ-MONTAN, MICHELLE; GRILLO, RENATO; FRACETO, LEONARDO F.; DE PAULA, ENEIDA. Validation of an HPLC Method for the Determination of Dibucaine Encapsulated in Solid Lipid Nanoparticles and Nanostructured Lipid Carriers. Latin American Journal of Pharmacy, v. 32, n. 9, p. 1362-1369, 2013. Web of Science Citations: 6.

DE PAULA, ENEIDA; CEREDA, CINTIA M. S.; FRACETO, LEONARDO F.; DE ARAUJO, DANIELE R.; FRANZ-MONTAN, MICHELLE; TOFOLI, GIOVANA R.; RANALI, JOSE; VOLPATO, MARIA C.; GROPPO, FRANCISCO C. Micro and nanosystems for delivering local anesthetics. Expert Opinion on Drug Delivery, v. 9, n. 12, p. 1505-1524, DEC 2012. Web of Science Citations: 48.

SAIA CEREDA, CINTIA MARIA; TOFOLI, GIOVANA RADOMILLE; MATURANA, LUIZ GABRIEL; PIERUCCI, AMAURI; SOARES NUNES, LAZARO ALESSANDRO; FRANZ-MONTAN, MICHELLE; RODRIGUES DE OLIVEIRA, ALEXANDRE LEITE; ARANA, SARAH; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA. Local Neurotoxicity and Myotoxicity Evaluation of Cyclodextrin Complexes of Bupivacaine and Ropivacaine. ANESTHESIA AND ANALGESIA, v. 115, n. 5, p. 1234-1241, NOV 2012. Web of Science Citations: 23.

VOLOBUEF, CRISTIANE; MORAES, CAROLINA M.; NUNES, LAZARO A. S.; CEREDA, CINTIA M. S.; YOKAICHIYA, FABIANO; FRANCO, MARGARETH K. K. D.; BRAGA, ANGELICA F. A.; DE PAULA, ENEIDA; TOFOLI, GIOVANA RADOMILLE; FRACETO, LEONARDO F.; DE ARAUJO, DANIELE R. Sufentanil-2-hydroxypropyl-beta-cyclodextrin inclusion complex for pain treatment: Physicochemical, cytotoxicity, and pharmacological evaluation. Journal of Pharmaceutical Sciences, v. 101, n. 10, p. 3698-3707, OCT 2012. Web of Science Citations: 6.

FRANZ-MONTAN, M.; DE PAULA, E.; GROPPO, F. C.; RANALI, J.; VOLPATO, M. C. Efficacy of liposome-encapsulated 0.5% ropivacaine in maxillary dental anaesthesia. BRITISH JOURNAL OF ORAL & MAXILLOFACIAL SURGERY, v. 50, n. 5, p. 454-458, JUL 2012. Web of Science Citations: 7.

TOFOLI, GIOVANA RADOMILLE; CEREDA, CINTIA M. S.; ARAUJO, DANIELE RIBEIRO; FRANZ-MONTAN, MICHELLE; GROPPO, FRANCISCO CARLOS; QUAGLIO, DAIANE; PEDRAZZOLI JUNIOR, JOSE; CALAFATTI, SILVANA APARECIDA; PROENCA BARROS, FABIO ALESSANDRO; DE PAULA, ENEIDA. Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers. Journal of Pharmacy and Pharmacology, v. 64, n. 3, p. 397-403, MAR 2012. Web of Science Citations: 7.

FRANZ-MONTAN, M.; DE PAULA, E.; GROPPO, F. C.; SILVA, A. L. R.; RANALI, J.; VOLPATO, M. C. Liposomal delivery system for topical anaesthesia of the palatal mucosa. BRITISH JOURNAL OF ORAL & MAXILLOFACIAL SURGERY, v. 50, n. 1, p. 60-64, JAN 2012. Web of Science Citations: 19.

SILVA DE MELO, NATHALIE FERREIRA; GRILLO, RENATO; GUILHERME, VIVIANE APARECIDA; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA; ROSA, ANDRE HENRIQUE; FRACETO, LEONARDO FERNANDES. Poly(Lactide-co-Glycolide) Nanocapsules Containing Benzocaine: Influence of the Composition of the Oily Nucleus on Physico-Chemical Properties and Anesthetic Activity. PHARMACEUTICAL RESEARCH, v. 28, n. 8, p. 1984-1994, AUG 2011. Web of Science Citations: 29.

TOFOLI, GIOVANA R.; CEREDA, CINTIA M. S.; GROPPO, FRANCISCO C.; VOLPATO, MARIA C.; FRANZ-MONTAN, MICHELLE; RANALI, JOSE; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA. Efficacy of liposome-encapsulated mepivacaine for infiltrative anesthesia in volunteers. Journal of Liposome Research, v. 21, n. 1, p. 88-94, MAR 2011. Web of Science Citations: 16.

WIZIACK ZAGO, PATRICIA MARIA; BARONI, DANIELA BELISARIO; GROPPO, FRANCISCO CARLOS; DE PAULA, ENEIDA; RANALI, JOSE; VOLPATO, MARIA CRISTINA. Anesthetic efficacy of liposomal prilocaine in maxillary infiltration anesthesia. Journal of Liposome Research, v. 21, n. 1, p. 81-87, MAR 2011. Web of Science Citations: 4.

DE MELO‚ N.F.S.; GRILLO‚ R.; GUILHERME‚ V.A.; DE ARAUJO‚ D.R.; DE PAULA‚ E.; ROSA‚ A.H.; FRACETO‚ L.F. Poly (lactide-co-glycolide) nanocapsules containing benzocaine: Influence of the composition of the oily nucleus on physico-chemical properties and anesthetic activity. PHARMACEUTICAL RESEARCH, p. 1-11, 2011.

GRILLO, RENATO; DE MELO, NATHALIE F. S.; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA; ROSA, ANDRE HENRIQUE; FRACETO, LEONARDO FERNANDES. Polymeric alginate nanoparticles containing the local anesthetic bupivacaine. Journal of Drug Targeting, v. 18, n. 9, p. 688-699, NOV 2010. Web of Science Citations: 44.

DE ARAUJO, DANIELE RIBEIRO; PADULA, CRISTINA; SAIA CEREDA, CINTIA MARIA; TOFOLI, GIOVANA RADOMILLE; BRITO, JR., RUI BARBOSA; DE PAULA, ENEIDA; NICOLI, SARA; SANTI, PATRIZIA. Bioadhesive Films Containing Benzocaine: Correlation Between In Vitro Permeation and In Vivo Local Anesthetic Effect. PHARMACEUTICAL RESEARCH, v. 27, n. 8, p. 1677-1686, AUG 2010. Web of Science Citations: 22.

GRILLO, RENATO; DE MELO, NATHALIE F. S.; DE ARAUJO, DANIELE R.; TROSSINI, GUSTAVO H. G.; DA CUNHA, ELAINE F. F.; RAMALHO, TEODORICO DE CASTRO; FRACETO, LEONARDO FERNANDES. Host-guest complexation of a nitroheterocyclic compound with cyclodextrins: a spectrofluorimetric and molecular modeling study. JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY, v. 66, n. 3-4, p. 417-421, APR 2010. Web of Science Citations: 4.

TOFOLI, GIOVANA RADOMILLE; SAIA CEREDA, CINTIA MARIA; DE ARAUJO, DANIELE RIBEIRO; DE PAULA, ENEIDA; BRITO JUNIOR, RUI BARBOSA; PEDRAZZOLI JUNIOR, JOSE; MEURER, EDUARDO; PROENCA BARROS, FABIO ALESSANDRO; GROPPO, FRANCISCO CARLOS; VOLPATO, MARIA CRISTINA; RANALI, JOSE. Pharmacokinetic and local toxicity studies of liposome-encapsulated and plain mepivacaine solutions in rats. DRUG DELIVERY, v. 17, n. 2, p. 68-76, FEB 2010. Web of Science Citations: 6.

FRANZ-MONTAN, MICHELLE; DE PAULA, ENEIDA; GROPPO, FRANCISCO C.; SILVA, ANDRE L. R.; RANALI, JOSE; VOLPATO, MARIA C. Liposome-encapsulated ropivacaine for intraoral topical anesthesia. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, v. 110, n. 6, p. 800-804, 2010. Web of Science Citations: 16.

PICKHOLZ, MONICA; FRACETO, LEONARDO FERNANDES; DE PAULA, ENEIDA. Preferential location of prilocaine and etidocaine in phospholipid bilayers: A molecular dynamics study. Synthetic Metals, v. 159, n. 21-22, SI, p. 2157-2158, NOV 2009. Web of Science Citations: 4.

GRILLO, RENATO; DE MELO, NATHALIE F. S.; DE ARAUJO, DANIELE R.; DE PAULA, ENEIDA; DIAS FILHO, NEWTON L.; ROSA, ANDRE H.; FRACETO, LEONARDO F. Validation of an HPLC Method for quantitative Determination of Benzocaine in PHBV-Microparticles and PLA-Nanoparticles. Latin American Journal of Pharmacy, v. 28, n. 3, p. 393-399, MAY-JUN 2009. Web of Science Citations: 16.

CABECA, LUIS F.; PICKHOLZ, MONICA; DE PAULA, ENEIDA; MARSAIOLI, ANITA J. Liposome-Prilocaine Interaction Mapping Evaluated through STD NMR and Molecular Dynamics Simulations. Journal of Physical Chemistry B, v. 113, n. 8, p. 2365-2370, FEB 26 2009. Web of Science Citations: 16.

DE ARAUJO, DANIELE RIBEIRO; SAIA CEREDA, CINTIA MARIA; BRUNETTO, GLOVANNA BRUSCHINI; VOMERO, VIVIANE URBINI; PIERUCCI, AMAURI; SANTO NETO, HUMBERTO; RODRIGUES DE OLIVEIRA, ALEXANDRE LEITE; FRACETO, LEONARDO FERNANDES; DE ASSUNCAO BRAGA, ANGELICA DE FATIMA; DE PAULA, ENEIDA. Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine. Journal of Pharmacy and Pharmacology, v. 60, n. 11, p. 1449-1457, NOV 2008. Web of Science Citations: 30.

DANIELE RIBEIRO DE ARAUJO; ENEIDA DE PAULA; LEONARDO FERNANDES FRACETO. Anestésicos locais: interação com membranas biológicas e com o canal de sódio voltagem-dependente. Química Nova, v. 31, n. 7, p. 1775-1783, 2008.

SAIA CEREDA, CINTIA M.; TOFOLI, GIOVANA R.; DE BRITO JUNIOR, RUI B.; DE JESUS, MARCELO B.; FRACETO, LEONARDO F.; GROPPO, FRANCISCO C.; DE ARAUJO, DANIELE R.; DE PAULA, ENEIDA. Stability and Local Toxicity Evaluation of a Liposomal Prilocaine Formulation. Journal of Liposome Research, v. 18, n. 4, p. 329-339, 2008. Web of Science Citations: 18.