The concomitant administration of systemic amoxicillin and metronidazole compared to scaling and root planing alone in treating periodontitis: =a systematic review=

Dina Zandbergen, Dagmar Else Slot, Richard Niederman, Fridus A Van der Weijden, Dina Zandbergen, Dagmar Else Slot, Richard Niederman, Fridus A Van der Weijden

Abstract

Background: The treatment of periodontitis begins with a non-surgical phase that includes scaling and root planing(SRP) and on occasion the use of systemic antibiotics. The goal was to systematically evaluate in systemic healthy adults the effect of the concomitant administration of amoxicillin (amx) and metronidazole (met) adjunctive to SRP compared to SRP alone.

Methods: The PubMed-MEDLINE, Cochrane-CENTRAL and EMBASE databases were searched up to November 2014 to identify appropriate studies. Probing Pocket Depth (PD), Clinical Attachment Level (CAL), Bleeding on Pocket Probing(BOP) and Plaque Indices(PI) were selected as outcome variables. Based on the extracted data a meta-analysis was conducted.

Results: A total of 526 unique articles were found, 20 studies met the eligibility criteria. A meta-analysis showed that SRP + amx + met provided significantly better effects overall and more pronounced PD reduction in periodontal pockets initially measuring ≥6 mm (DiffM:-0.86 mm, p < 0.00001) and gain in CAL(DiffM:+0.75 mm, p = 0.0001). The meta-analysis for the secondary inflammatory parameter BOP showed that SRP + amx + met provided full mouth significantly greater reduction in BOP than SRP alone (DiffM:-6.98 %, p = 0.0001).

Conclusion: Adjunctive systemic amoxicillin and metronidazole medication to SRP significantly improved the clinical outcomes with respect to mean PD, CAL and BOP compared to SRP alone. There is moderate to strong evidence in support of the recommendation that adjunctive amx + met therapy to SRP significantly improves the clinical outcomes, with respect to mean PD and CAL compared to SRP alone especially in initially deep (≥6 mm) pockets. No major side effects associated with the intake of amx + met were reported. This treatment regimen is an efficacious, minimally invasive, practical and inexpensive approach for periodontitis therapy. The key components are mechanical tooth and pocket debridement, supportive treatment of the disease with systemic antibiotics and attention to proper self-care.

References

    1. Niederman R, Feres M, Ogunbodede E. In: Disease Control Priorities, Third Edition: Volume 1. Essential Surgery, pages 173–195, Chapter 10: Dentistry. Available at: [Accessed 1 April 2015].
    1. Herrera D, Sanz M, Jepsen S, Needleman I, Roldán S. A systematic review on the effect of systemic antimicrobials as andjunct to scaling and root planing in periodontitis patients. J Clin Periodontol. 2002;29:136–159. doi: 10.1034/j.1600-051X.29.s3.8.x.
    1. Herrera D, Alonso B, León R, Roldán S, Sanz M. Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm. J Clin Periodontol. 2008;35:45–66. doi: 10.1111/j.1600-051X.2008.01260.x.
    1. Serino G, Rosling B, Ramberg P, Hellström MK, Socransky SS, Lindhe J. The effect of systemic antibiotics in the treatment of patients with recurrent periodontitis. J Clin Periodontol. 2001;28:411–418. doi: 10.1034/j.1600-051x.2001.028005411.x.
    1. López NJ, Gamonal JA. Effects of metronidazole plus amoxicillin in progressive untreated adult periodontitis: results of a single 1-week course after 2 and 4 months. J Periodontol. 1998;69:1291–1298. doi: 10.1902/jop.1998.69.11.1291.
    1. Buchmann R, Nunn ME, Van Dyke TE, Lange DE. Aggressive periodontitis: 5-year follow-up of treatment. J Periodontol. 2002;73:675–683. doi: 10.1902/jop.2002.73.6.675.
    1. Giannopoulou C, Andersen E, Brochut P, Plagnat D, Mombelli A. Enamel matrix derivative and systemic antibiotics as adjuncts to non-surgical periodontal treatment: biologic response. J Periodontol. 2006;77:707–713. doi: 10.1902/jop.2006.050166.
    1. Van der Weijden GA, Timmerman MF. A systematic review on the clinical efficacy of subgingival debridement in the treatment of chronic periodontitis. J Clin Periodontol. 2002;29:55–71. doi: 10.1034/j.1600-051X.29.s3.3.x.
    1. Cugini MA, Haffajee AD, Smith C, Kent RL, Jr, Socransky SS. The effect of scaling and root planing on the clinical and microbiological parameters of periodontal diseases: 12-month results. J Clin Periodontol. 2000;27:30–36. doi: 10.1034/j.1600-051x.2000.027001030.x.
    1. Carvalho LH, D'Avila GB, Leão A, Gonçalves C, Haffajee AD, Socransky SS, Feres M. Scaling and root planing, systemic metronidazole and professional plaque removal in the treatment of chronic periodontitis in a Brazilian population II--microbiological results. J Clin Periodontol. 2005;32:406–411. doi: 10.1111/j.1600-051X.2005.00720.x.
    1. Ehmke B, Moter A, Beikler T, Milian E, Flemmig TF. Adjunctive antimicrobial therapy of periodontitis: long-term effects on disease progression and oral colonization. J Periodontol. 2005;76:749–759. doi: 10.1902/jop.2005.76.5.749.
    1. Feres M. Antibiotics in the treatment of periodontal diseases: microbiological basis and clinical applications. Ann R Australas Coll Dent Surg. 2008;19:37–44.
    1. Mombelli A, Brochut P, Plagnat D, Casagni F, Giannopoulou C. Enamel matrix proteins and systemic antibiotics as adjuncts to non-surgical periodontal treatment: clinical effects. J Clin Periodontol. 2005;32:225–230. doi: 10.1111/j.1600-051X.2005.00664.x.
    1. Van Winkelhoff AJ, Rodenburg JP, Goené RJ, Abbas F, Winkel EG, de Graaff J. Metronidazole plus amoxycillin in the treatment of Actinobacillus actinomycetemcomitans associated periodontitis. J Clin Periodontol. 1989;16:128–131. doi: 10.1111/j.1600-051X.1989.tb01626.x.
    1. Rooney J, Wade WG, Sprague SV, Newcombe RG, Addy M. Adjunctive effects to non surgical periodontal therapy of systemic metronidazole and amoxycillin alone and combined. A placebo controlled study. J Clin Periodontol. 2002;29:342–350. doi: 10.1034/j.1600-051X.2002.290410.x.
    1. Pavicić MJ, van Winkelhoff AJ, de Graaff J. Synergistic effects between amoxicillin, metronidazole, and the hydroxymetabolite of metronidazole against Actinobacillus actinomycetemcomitans. Antimicrob Agents Chemother. 1991;35:961–966. doi: 10.1128/AAC.35.5.961.
    1. Zandbergen D, Slot DE, Cobb CM, Van der Weijden FA. The clinical effect of scaling and root planing and the concomitant administration of systemic amoxicillin and metronidazole: a systematic review. J Periodontol. 2013;84:332–351. doi: 10.1902/jop.2012.120040.
    1. PRISMA statement, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Available at: [Accessed 1 April 2015].
    1. Dutch Cochrane Center: RCT-checklist. [Accessed 1 April 2015].
    1. CONSORT Group. The CONSORT statement 2001 – Checklist: Items to include when reporting a randomized trial. Available at: [Accessed 1 April 2015].
    1. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement. Quality of reporting of meta-analyses. Lancet. 1999;354:1896–1900. doi: 10.1016/S0140-6736(99)04149-5.
    1. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357:1191–1194. doi: 10.1016/S0140-6736(00)04337-3.
    1. Needleman I, Moles DR, Worthington H. Evidence-based periodontology, systematic reviews and research quality. J Periodontol. 2000;37:12–28. doi: 10.1111/j.1600-0757.2004.37100.x.
    1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. doi: 10.1016/0197-2456(95)00134-4.
    1. Verhagen AP, de Vet HC, de Bie RA, Kessels AG, Boers M, Bouter LM, Knipschild PG. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol. 1998;51:1235–1241. doi: 10.1016/S0895-4356(98)00131-0.
    1. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. The Cochrane Collaboration, 2009. Available at . [Accessed 1 April 2015].
    1. Egger M, Smith GD, Sterne JA. Uses and abuses of meta-analysis. Clinical Medicine. 2001;1:478–484. doi: 10.7861/clinmedicine.1-6-478.
    1. GRADE Working Group. Grading of Recommendations Assessment, Development and Evaluation (short GRADE) Working Group. Available at: [Accessed 1 April 2015].
    1. AAP. American Academy of Periodontology Position paper: epidemiology of periodontal diseases. J Periodontol. 1996;67:935–945.
    1. Van Dyke TE. The clinical significance of new therapies for the management of periodontal disease. J Int Acad Periodontol. 2005;7:191–196.
    1. Sgolastra F, Petrucci A, Gatto R, Giannoni M, Monaco A. Long-term efficacy of subantimicrobial-dose doxycycline as an adjunctive treatment to scaling and root planing: a systematic review and meta-analysis. J Periodontol. 2011;82:1570–1581. doi: 10.1902/jop.2011.110026.
    1. Sgolastra F, Gatto R, Petrucci A, Monaco A. Effectiveness of systemic amoxicillin/metronidazole as adjunctive therapy to scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis. J Periodontol. 2012;83:1257–1269. doi: 10.1902/jop.2012.110625.
    1. Sgolastra F, Petrucci A, Gatto R, Monaco A. Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis. J Periodontol. 2012;83:731–743. doi: 10.1902/jop.2011.110432.
    1. Van der Weijden GA, van Bemmel KM, Renvert S. Implant therapy in partially edentulous, periodontally compromised patients: a review. J Clin Periodontol. 2005;32:506–511. doi: 10.1111/j.1600-051X.2005.00708.x.
    1. Van der Velden U. Diagnosis of periodontitis. J Clin Periodontol. 2000;27:960–961. doi: 10.1034/j.1600-051x.2000.027012960.x.
    1. Cobb CM. Non surgical pocket therapy: mechanical. Ann Periodontol. 1996;1:443–490. doi: 10.1902/annals.1996.1.1.443.
    1. Guerrero A, Griffiths GS, Nibali L, Suvan J, Moles DR, Laurell L, Tonetti MS. Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol. 2005;32:1096–1107. doi: 10.1111/j.1600-051X.2005.00814.x.
    1. Barza M, Cuchural G. General principles of antibiotic tissue penetration. J Antimicrob Chemother. 1985;15(Suppl A):59–75. doi: 10.1093/jac/15.suppl_A.59.
    1. Bergeron MG. Tissue penetration of antibiotics. Clin Biochem. 1986;19:90–100. doi: 10.1016/S0009-9120(86)80054-6.
    1. Kaner D, Christan C, Dietrich T, Bernimoulin JP, Kleber BM, Friedmann A. Timing affects the clinical outcome of adjunctive systemic antibiotic therapy for generalized aggressive periodontitis. J Periodontol. 2007;78:1201–1208. doi: 10.1902/jop.2007.060437.
    1. Griffiths GS, Ayob R, Guerrero A, Nibali L, Suvan J, Moles DR, Tonetti MS. Amoxicillin and metronidazole as an adjunctive treatment in generalized aggressive periodontitis at initial therapy or re-treatment: a randomized controlled clinical trial. J Clin Periodontol. 2011;38:43–49. doi: 10.1111/j.1600-051X.2010.01632.x.
    1. Beliveau D, Magnusson I, Bidwell JA, Zapert EF, Aukhil I, Wallet SM, Shaddox LM. Benefits of early systemic antibiotics in localized aggressive periodontitis: a retrospective study. J Clin Periodontol. 2012;39:1075–1081. doi: 10.1111/jcpe.12001.
    1. Cionca N, Giannopoulou C, Ugolotti G, Mombelli A. Amoxicillin and metronidazole as an adjunct to full-mouth scaling and root planing of chronic periodontitis. J Periodontol. 2009;80:364–371. doi: 10.1902/jop.2009.080540.
    1. Flemmig TF, Milián E, Karch H, Klaiber B. Differential clinical treatment outcome after systemic metronidazole and amoxicillin in patients harboring Actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis. J Clin Periodontol. 1998;25:380–387. doi: 10.1111/j.1600-051X.1998.tb02459.x.
    1. Feres M, Figueiredo LC, Soares GM, Faveri M. Systemic Antibiotics in the Treatment of Periodontitis. Periodontology 2000. 2015;67(1):131–86.
    1. Mombelli A. Antimicrobial advances in treating periodontal diseases. Front Oral Biol. 2012;15:133–148. doi: 10.1159/000329676.
    1. Yek EC, Cintan S, Topcuoglu N, Kulekci G, Issever H, Kantarci A. Efficacy of amoxicillin and metronidazole combination for the management of generalized aggressive periodontitis. J Periodontol. 2010;81:964–974. doi: 10.1902/jop.2010.090522.
    1. López NJ, Socransky SS, Da Silva I, Japlit MR, Haffajee AD. Effects of metronidazole plus amoxicillin as the only therapy on the microbiological and clinical parameters of untreated chronic periodontitis. J Clin Periodontol. 2006;33:648–660. doi: 10.1111/j.1600-051X.2006.00957.x.
    1. Guerrero A, Echeverría JJ, Tonetti MS. Incomplete adherence to an adjunctive systemic antibiotic regimen decreases clinical outcomes in generalized aggressive periodontitis patients: a pilot retrospective study. J Clin Periodontol. 2007;34:897–902. doi: 10.1111/j.1600-051X.2007.01130.x.
    1. Herrera D, van Winkelhoff AJ, Dellemijn-Kippuw N, Winkel EG, Sanz M. Beta-lactamase producing bacteria in the subgingival microflora of adult patients with periodontitis. A comparison between Spain and The Netherlands. J Clin Periodontol. 2000;27:520–525. doi: 10.1034/j.1600-051x.2000.027007520.x.
    1. Veloo AC, Seme K, Raangs E, Rurenga P, Singadji Z, Wekema-Mulder G, van Winkelhoff AJ. Antibiotic susceptibility profiles of oral pathogens. Int J Antimicrob Agents. 2012;40:450–454. doi: 10.1016/j.ijantimicag.2012.07.004.
    1. Casarin RC, Peloso Ribeiro ED, Sallum EA, Nociti FH, Jr, Gonçalves RB, Casati MZ. The combination of amoxicillin and metronidazole improves clinical and microbiologic results of one-stage, full-mouth, ultrasonic debridement in aggressive periodontitis treatment. J Periodontol. 2012;83:988–998. doi: 10.1902/jop.2012.110513.
    1. Rabelo CC, Feres M, Gonçalves C, Figueiredo LC, Faveri M, Tu YK, Chambrone L. Systemic antibiotics in the treatment of aggressive periodontitis. A systematic review and a Bayesian Network meta-analysis. J Clin Periodontol. 2015;42:647–657. doi: 10.1111/jcpe.12427.
    1. Keestra JA, Grosjean I, Coucke W, Quirynen M, Teughels W. Non-surgical periodontal therapy with systemic antibiotics in patients with untreated chronic periodontitis: a systematic review and meta-analysis. J Periodontal Res. 2015;50:294–314. doi: 10.1111/jre.12221.
    1. Keestra JA, Grosjean I, Coucke W, Quirynen M, Teughels W. Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and meta-analysis. J Periodontal Res. 2015;50(6):689–706
    1. Soares GM, Mendes JA, Silva MP, Faveri M, Teles R, Socransky SS, Wang X, Figueiredo LC, Feres M. Metronidazole alone or with amoxicillin as adjuncts to non-surgical treatment of chronic periodontitis: a secondary analysis of microbiological results from a randomized clinical trial. J Clin Periodontol. 2014;41:366–376. doi: 10.1111/jcpe.12217.
    1. Feres M, Soares GM, Mendes JA, Silva MP, Faveri M, Teles R, Socransky SS, Figueiredo LC. Metronidazole alone or with amoxicillin as adjuncts to non-surgical treatment of chronic periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. J Clin Periodontol. 2012;39:1149–1158. doi: 10.1111/jcpe.12004.
    1. Silva-Senem MX, Heller D, Varela VM, Torres MC, Feres-Filho EJ, Colombo AP. Clinical and microbiological effects of systemic antimicrobials combined to an anti-infective mechanical debridement for the management of aggressive periodontitis: a 12-month randomized controlled trial. J Clin Periodontol. 2013;40:242–251. doi: 10.1111/jcpe.12052.
    1. Heller D, Varela VM, Silva-Senem MX, Torres MCB, Feres-Filho EJ, Colombo APV. Impact of systemic antimicrobials combined with anti-infective mechanical debridement on the microbiota of generalized aggressive periodontitis: a 6-month RCT. J Clin Periodontol. 2011;38:355–364. doi: 10.1111/j.1600-051X.2011.01707.x.
    1. Varela VM, Heller D, Silva-Senem MX, Torres MCB, Colombo APV, Feres-Filho EJ. Systematic antimicrobials adjunctive to repeated mechanical and antiseptic therapy for aggressive periodontitis: a 6-month randomized controlled trial. J Periodontol. 2011;82:1121–1130. doi: 10.1902/jop.2011.100656.
    1. Lira EA, Ramiro FS, Chiarelli FM, Dias RR, Feres M, Figueiredo LC, Faveri M. Reduction in prevalence of Archaea after periodontal therapy in subjects with generalized aggressive periodontitis. Aust Dent J. 2013;58:442–447. doi: 10.1111/adj.12123.
    1. Mestnik MJ, Feres M, Figueiredo LC, Duarte PM, Lira EA, Faveri M. Short-term benefits of the adjunctive use of metronidazole plus amoxicillin in the microbial profile and in the clinical parameters of subjects with generalized aggressive periodontitis. J Clin Periodontol. 2010;37:353–365. doi: 10.1111/j.1600-051X.2010.01538.x.
    1. de Lima Oliveira AP, de Faveri M, Gursky LC, Mestnik MJ, Feres M, Haffajee AD, Socransky SS, Teles RP. Effects of periodontal therapy on GCF cytokines in generalized aggressive periodontitis subjects. J Clin Periodontol. 2012;39:295–302. doi: 10.1111/j.1600-051X.2011.01817.x.
    1. Mestnik MJ, Feres M, Figueiredo LC, Soares G, Teles RP, Fermiano D, Duarte PM, Faveri M. The effects of adjunctive metronidazole plus amoxicillin in the treatment of generalized aggressive periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. J Clin Periodontol. 2012;39:955–961. doi: 10.1111/j.1600-051X.2012.01932.x.
    1. Mombelli A, Cionca N, Almaghlouth A, Décaillet F, Courvoisier DS, Giannopoulou C. Are there specific benefits of amoxicillin plus metronidazole in Aggregatibacter actinomycetemcomitans-associated periodontitis? Double-masked, randomized clinical trial of efficacy and safety. J Periodontol. 2013;84:715–724. doi: 10.1902/jop.2012.120281.
    1. Goodson JM, Haffajee AD, Socransky SS, Kent R, Teles R, Hasturk H, Bogren A, Van Dyke T, Wennstrom J, Lindhe J. Control of periodontal infections: a randomized controlled trial I. The primary outcome attachment gain and pocket depth reduction at treated sites. J Clin Periodontol. 2012;39:526–536. doi: 10.1111/j.1600-051X.2012.01870.x.
    1. Aimetti M, Romano F, Guzzi N, Carnevale G. Full-mouth disinfection and systemic antimicrobial therapy in generalized aggressive periodontitis: a randomized, placebo-controlled trial. J Clin Periodontol. 2012;39:284–294. doi: 10.1111/j.1600-051X.2011.01795.x.
    1. Baltacioğlu E, Aslan M, Saraç O, Saybak A, Yuva P. Analysis of clinical results of systemic antimicrobials combined with nonsurgical periodontal treatment for generalized aggressive periodontitis: a pilot study. J Can Dent Assoc. 2011;77:1–8.
    1. Silva MP, Feres M, Sirotto TA, Soares GM, Mendes JA, Faveri M, Figueiredo LC. Clinical and microbiological benefits of metronidazole alone or with amoxicillin as adjuncts in the treatment of chronic periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol. 2011;38:828–837. doi: 10.1111/j.1600-051X.2011.01763.x.
    1. Cionca N, Giannopoulou C, Ugolotti GA. Microbiologic testing and outcomes of full-mouth scaling and root planing with or without amoxicillin/metronidazole in chronic periodontitis. J Periodontol. 2010;81:15–23. doi: 10.1902/jop.2009.090390.
    1. Del Pelose Ribeiro EP, Bittencourt S, Zanin IC, Bovi Ambrosano GM, Sallum EA, Nociti FH, Gonçalves RB, Casati MZ. Full-mouth ultrasonic debridement associated with amoxicillin and metronidazole in the treatment of severe chronic periodontitis. J Periodontol. 2009;80:1254–1264. doi: 10.1902/jop.2009.080403.
    1. Matarazzo F, Figueiredo LC, Cruz SE, Faveri M, Feres M. Clinical and microbiological benefits of systemic metronidazole and amoxicillin in the treatment of smokers with chronic periodontitis: a randomized placebo-controlled study. J Clin Periodontol. 2008;35:885–896. doi: 10.1111/j.1600-051X.2008.01304.x.
    1. Moeintaghavi A, Talebi-ardakani MR, Haerian-ardakani A, Zandi H, Taghipour S, Fallahzadeh H, Pakzad A, Fahami N. Adjunctive effects of systemic amoxicillin and metronidazole with scaling and root planing: a randomized, placebo controlled clinical trial. J Contemp Dent Pract. 2007;8:51–59.
    1. Xajigeorgiou C, Sakellari D, Slini T, Baka A, Konstantinidis A. Clinical and microbiological effects of different antimicrobials on generalized aggressive periodontitis. J Clin Periodontol. 2006;33:254–264. doi: 10.1111/j.1600-051X.2006.00905.x.
    1. Guerrero A, Nibali L, Lambertenghi R, Ready D, Suvan J, Griffiths GS, Wilson M, Tonetti MS. Impact of baseline microbiological status on clinical outcomes in generalized aggressive periodontitis patients treated with or without adjunctive amoxicillin and metronidazole: an exploratory analysis from a randomized controlled clinical trial. J Clin Periodontol. 2014;41:1080–1092. doi: 10.1111/jcpe.12299.
    1. Ehmke B, Beikler T, Haubitz I, Karch H, Flemmig TF. Multifactorial assessment of predictors for prevention of periodontal disease progression. Clin Oral Investig. 2003;7:217–221. doi: 10.1007/s00784-003-0227-2.
    1. Winkel EG, Van Winkelhoff AJ, Timmerman MF, Van der Velden U, Van der Weijden GA. Amoxicillin plus metronidazole in the treatment of adult periodontitis patients. A double-blind placebo-controlled study. J Clin Periodontol. 2001;28:296–305. doi: 10.1034/j.1600-051x.2001.028004296.x.
    1. Berglundh T, Krok L, Liljenberg B, Westfelt E, Serino G, Lindhe J. The use of metronidazole and amoxicillin in the treatment of advanced periodontal disease. A prospective, controlled clinical trial. J Clin Periodontol. 1998;25:354–362. doi: 10.1111/j.1600-051X.1998.tb02455.x.

Source: PubMed

3
订阅