Doi:10.1080/08910600410026355Periodontal Disease, Matrix Metalloproteinases andChemically Modified Tetracyclines From the Department of Periodontology, Faculty of Dentistry, University of Oslo, Oslo, Norway Correspondence to: Svein Steinsvoll, Sagvollveien 1, 2830 Raufoss, Norway. Tel.: / 47 61191481; Fax: /4761191481; E-mail: [email protected] Microbial Ecology in Health and Disease 2004; 16: 1 /7 Matrix metalloproteinases (MMPs) are crucial in the degradation of the main components in the extracellular matrix and thereby playimportant roles in cell migration, wound healing and tissue remodelling. MMPs have pathogenic roles in arthritis, periodontitis, hepatitis,glomerulonephritis, atherosclerosis and cancer cell invasion. MMPs are activators of pro-inflammatory mediators that occur in latent forms,such as interleukin (IL)-1b, membrane-bound tumour necrosis factor (TNF) and different MMPs. To regulate their action, MMPs aresecreted in latent, inactive pro-enzyme forms, with plasmin and other MMPs as likely activators. MMP activity is further modulated by thetissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4), which partly control and stabilize MMPs. In normal steady-state tissues, onlylow levels of MMPs are detected intra- and extra-cellularly because MMPs are tightly regulated at the level of transcription and secretion. Ininflamed periodontal tissue, numbers of cells expressing MMPs are increased as compared with healthy gingival tissue. Recently, novel non-antimicrobial MMP-inhibitory effects of tetracyclines were discovered, and subsequently a panel of chemically modified non-antimicrobialtetracyclines (CMTs) was developed. This paper discusses these new drugs and their possible biological effects in periodontal disease.
PERIODONTAL INFLAMMATION participate in the tissue breakdown occurring in period- Accumulation of bacteria at the dentogingival margin induces gingival inflammation and may trigger periodontaldisease. The host generates inflammation adjacent to the PERIODONTAL DEGRADATION periodontal pocket as a defence against the microbial Matrix metalloproteinases (MMPs) are crucial in the threat. Leukocytes including plasma cells, lymphocytes, degradation of main components in extracellular matrix macrophages and neutrophils are known to infiltrate and thereby play important roles in cell migration, wound the gingival tissue (1) and have been studied in great healing and tissue remodelling (16 /18). MMPs have detail, but only modest attention has been given to mast pathogenic roles in arthritis, periodontitis, hepatitis, glo- cells (2). Yet, mast cells are important multifunctional cells merulonephritis, atherosclerosis and cancer cell invasion in the first line of defence against bacterial and parasitic (16 /23). MMPs are activators of pro-inflammatory media- infections (3 /7), and occur in numbers comparable to tors that occur in latent forms, such as interleukin (IL)-1b, macrophages in the inflamed periodontal lesion (8). Mast transforming growth factor-b1 (TGF-b1), membrane- cells can secrete a range of substances that regulate bound tumour necrosis factor (TNF)-a and different angiogenesis, tissue remodelling and wound healing, which MMPs (16 /18, 24, 25). To regulate their action, MMPs include both degradation and synthesis of tissue compo- are secreted in latent, inactive pro-enzyme forms, with nents (9). A recent study showed that the numbers of plasmin and other MMPs as likely activators (16 /18).
gingival mast cells are markedly increased in the gingival MMP activity is further modulated by the tissue inhibitors tissue of HIV-infected persons with periodontitis as com- of metalloproteinases (TIMP-1, -2, -3 and -4), which partly pared with HIV counterparts (8). The increase in mast cell control and stabilize MMPs (16 /18, 26). In normal steady- numbers was pronounced (10-fold) even in the early state tissues, only low levels of MMPs are detected intra- stages of HIV infection, indicating that this could be an and extra-cellularly because MMPs are tightly regulated at HIV-induced effect (8). As patients with HIV infection the level of transcription and secretion (16 /18). In inflamed display increased susceptibility to periodontitis (10 /15), periodontal tissue, numbers of cells expressing MMPs are there may be a link between mast cells and periodontal increased as compared with healthy gingival tissue (16, breakdown. We therefore wanted to explore whether mast 27 /30). It was recently shown that gingival mast cells cells have properties that indicate that they can directly strongly expressed MMP-1, MMP-2 and MMP-8, and to a # Taylor & Francis 2004. ISSN 0891-060X Microbial Ecology in Health and Disease Periodontitis, MMPs and CMTs lesser degree TIMP-1/-2 (31) (Figs. 1 and 2). Higher PERIODONTAL DISEASE AND CHEMICALLY numbers of MMP- and TIMP-positive mast cells were MODIFIED TETRACYCLINES (CMTS) detected in inflamed as compared with healthy gingiva. This Periodontal disease is the major cause of tooth loss in the indicates that mast cells are likely to play an important role adult population, characterized by destruction of the in inflammation and tissue degradation in periodontal collagen fibres and other matrix constituents of the gingiva, diseases (31).
periodontal ligament and alveolar bone. Although the Fig. 2. Microphotographs of double immunostaining of mast cell tryptase (in red) with (in green) TIMP-1 (a) and TIMP-2 (b) in a gingivalbiopsy from an HIV patient with CMP. Overlapping colours (double-stained) appear in yellow. Blue colour is nuclear staining with DAPI.
Single staining from the indicated field is displayed to the right for TIMP-1/TIMP-2 (in green) and mast cells (in red). (a) Left: TIMP-1-expressing mast cells below the oral gingival epithelium (yellow). Some intra-epithelial mast cells can also be seen (red cells). Right: Singleexposures show staining for TIMP-1 (TIMP-1) and mast cell tryptase (MC) separately. (b) Left: TIMP-2-expressing mast cells below thepocket epithelium (yellow). Right: Single exposures show staining for TIMP-2 (TIMP-2) and mast cell tryptase (MC) separately. Originalmagnification /4.
Fig. 1. Microphotographs of double immunostaining for mast cell tryptase (in red) with (in green) MMP-1 (a /d), MMP-2 (e, f), or MMP-8(g, h) in a biopsy from an HIV patient with chronic marginal periodontitis (CMP). Blue colour is nuclear staining with DAPI. Overlappingcolors (double-stained) appear in yellow. (a) MMP-1-producing mast cells (in yellow) subjacent to oral gingival epithelium. (b) Singleexposure of mast cell tryptase and (c) MMP-1. (d) Double exposure of (b) and (c), showing partial co-localization of MMP-1 and mast celltryptase (yellow). (e) MMP-2-producing mast cells below pocket epithelium (red cells with yellow spots). (f) Higher magnification of fieldindicated in (e). White broken lines indicate the lumen of two MMP-2-venules, and an arrow points to a probably emigrating MMP-2-cell. (g) Inflammatory cell infiltrate below the pocket epithelium, showing MMP-8 mast cells (yellow and orange cells). MMP-8 mast cellswere often found within the dense parts of inflammatory cell infiltrates. (h) MMP-8 mast cells were often seen close to blood vessels (whitebroken line /blood vessel lumen). Original magnifications: /40 (a, h), /60 (b /d), /25 (e), /100 (f), /20 (g).
Fig. 3. Potential outcomes of gingival and periodontal infection. As a first line of defence against infection, the host tries to preventmicroorganisms from colonizing the tissue (epithelial barriers, antibacterial substances in saliva). If immune exclusion is unsuccessful,microbes or their products may penetrate or invade gingival and periodontal tissues. This will induce immune elimination systems(phagocytosis, complement activation, generation of specific immune processes mediated by B and T cells). If the invading agents are clearedaway, the tissue will become healthy again. If clearance fails, chronic infection of the gingival or periodontal tissue ensues. This is a balanced(but dynamic) condition where the infection is restrained physically (encapsulation) and functionally (phagocytosis and bacterial cell lysis).
Pro- and anti-inflammatory agents are kept in balance and the disease remains non-progressive (gingivitis or quiescent periodontitis).
Periodically, however, the balance may be disturbed, either by increasing strength of the attack or diminished defence by the host, andprogressive loss of gingival and periodontal tissue may occur (active or necrotizing periodontitis). CMTs reduce the MMP activity, thegeneration of inflammatory cytokines such as IL-1, IL-6 and TNF, and the subsequent release of prostaglandins.
microflora, primarily the anaerobic gram-negative micro- pocket by mechanical debridement and can also involve the organisms that accumulate in the gingival crevice, initiate use of topical or systemic antibiotics as an adjunct. A novel this inflammatory disease in the gingival tissues, the approach currently gaining interest is the use of ‘host- connective tissue breakdown that occurs in this disease, modulating therapy', which attempts to supplement the and subsequently in the deeper periodontal tissues, is traditional antimicrobial treatment strategies with drugs mediated by excessive levels of activated MMPs (and other that (1) inhibit the production of inflammatory mediators, proteases such as serine proteases and neutrophilic elas- such as prostaglandins and pro-inflammatory cytokines, or tase), produced by host cells (e.g. neutrophils, macrophages, (2) block the production and activity of host-generated, mast cells, epithelial cells, endothelial cells, fibroblasts, tissue-destructive proteinases such as the MMPs (33).
osteoblasts, osteoclasts), overcoming the endogenous pro- teinase inhibitor (e.g. TIMPs, a2-macroglobulin) shield (32).
mediated bone resorption, are a third category of host- Treatment of periodontal disease has traditionally fo- modulating drugs that are currently being explored as cused on the reduction of bacterial ‘load' in the periodontal adjuncts in the treatment of periodontal disease; these Periodontitis, MMPs and CMTs Fig. 4. Biological roles of CMTs in inflammation and wound healing. In early phases of inflammation and at low concentrations, CMTs maymodulate integrin expression on endothelial cells (1). CMTs will counteract the effects of TGF-b1 being chemotactic for mast cells,monocytes, neutrophils and fibroblasts, and enhance expression of enzymes (e.g. matrix metalloproteinases) that are important forextravasation and migration in the extracellular matrix (2). In the inflamed area, increasing levels of TGF-b1 activate and stimulate theleukocytes to secrete pro-inflammatory cytokines and growth factors (3), and to further increase expression of surface molecules such asFcgRIII for more effective phagocytosis (4). As the leukocytes are activated they alter their TGF-b1 receptor expression and becomesusceptible to deactivation and growth arrest (5). Fibroblasts that early in inflammation produce collagenases are later induced by TGF-b1 todecrease their protease production. The fibroblasts are further stimulated to increase the production of protease inhibitors such as tissueinhibitor of metalloproteinase-1 (TIMP-1), plasminogen activator inhibitor-1 (PAI-1), and to synthesize matrix molecules (6). Finally, TGF-b1 is an IgA switch factor (7). Solid lines indicate pro-inflammatory effects while dashed lines indicate anti-inflammatory and wound healingeffects. CMTs will favour a shift of the local microenvironment towards an anti-inflammatory anabolic situation with matrix and collagendeposition, partly due to lower MMP activity and increased activity of MMP inhibitors and reduced activity of inflammatory cytokines (e.g.
IL-1, IL-6, TNF) and prostaglandins.
compounds were also recently reported to exhibit MMP- regulation of MMP expression, and the protection of inhibitory properties (34). With regard to the second endogenous MMP and serine proteinase inhibitors from therapeutic strategy, Golub et al. (35) discovered that proteolytic or oxidative inactivation (37). Numerous dis- tetracyclines (TCs) can inhibit collagenase and other eases may be beneficially affected by TCs and CMTs MMPs by non-antimicrobial mechanisms, and subse- including periodontitis, various types of arthritis, sterile quently developed a series of chemically modified TC corneal ulcers, aortic aneurysms and cancer invasion and analogues (called CMT-1 /10) that lost their antimicrobial metastasis. CMT-3 and CMT-8 were found to be the most activity but retained (and even showed enhanced) MMP- potent inhibitors of MMPs and bone resorption in tissue inhibitory properties (36 /39). These TCs and CMTs are culture (39 /41). CMT-3 has been extensively tested and now recognized to have multiple mechanisms of action, found to be effective as an inhibitor of cancer cell gelatinase including the inhibition of already active MMPs, the activity in vitro, cancer cell invasiveness in culture, and inhibition of activation of latent pro-MMPs, the down- cancer metastasis in rats in vivo (42, 43). CMT-8 has been tested as a potential therapeutic agent in animal models of ME, Strober W, Bienenstock J, McGhee JR, eds. Mucosal bone loss because of its potent efficacy as an inhibitor of Immunology. San Diego: Academic Press, 1999: 469 /82.
8. Myint M, Steinsvoll S, Yuan ZN, Johne B, Helgeland K, both bone resorption and cartilage destruction in culture, Schenck K. Highly increased numbers of leukocytes in inflamed and bone/cartilage-type collagenase (MMP-13) activity in gingiva from patients with HIV infection. AIDS 2002; 16: 235 / vitro (39, 40), as well as in other diseases such as diabetes (38). Consistent with the animal studies, Scarpellini et al.
9. Galli SJ. Mast cells and basophils. Curr Opin Hematol 2000; 7: (44) found that the administration of a 3-month regimen of a regular antimicrobial dose of doxycycline to postmeno- 10. Winkler JR, Robertson PB. Periodontal disease associated with HIV infection. Oral Surg Oral Med Oral Pathol Oral Radiol pausal women produced shifts in serum and urine markers Endod 1992; 73: 145 /50.
of bone resorption (e.g. hydroxyprolinuria) and bone 11. Yeung SC, Stewart GJ, Cooper DA, Sindhusake D. Progression formation (e.g. serum alkaline phosphatase and osteocalcin) of periodontal disease in HIV seropositive patients. J Period- consistent with a partial normalization of the high-turnover ontol 1993; 64: 651 /7.
bone loss seen in these osteoporotic women. As described 12. Holmstrup P, Westergaard J. Periodontal diseases in HIV- infected patients. J Clin Periodontol 1994; 21: 270 by Cianco and Ashley (45), sub-antimicrobial (low-dose) 13. Lamster IB, Grbic JT, Bucklan RS, Mitchell-Lewis D, Rey- regimens of doxycycline (shown to suppress MMP activity nolds HS, Zambon JJ. Epidemiology and diagnosis of HIV- in gingival crevicular fluid and in gingival tissues of associated periodontal diseases. Oral Dis 1997; 3: 141 /8.
periodontitis patients), administered to humans in long- 14. Lamster IB, Grbic JT, Mitchell-Lewis D, Begg MD, Mitchell term double-blind studies, significantly reduced the severity A. New concepts regarding the pathogenesis of periodontaldisease in HIV infection. Ann Periodontol 1998; 3: 62 of periodontal disease, including alveolar bone loss.
15. Robinson PG. Which periodontal changes are associated with Referring again to periodontal disease, although micro- HIV infection? J Clin Periodontol 1998; 25: 278 /85.
bially induced and mediated by excessive activity of host- 16. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, generated MMPs and other tissue-destructive proteinases, it Birkedal-Hansen B, DeCarlo A, et al. Matrix metalloprotei- is now recognized that this local oral disease can be nases: a review. Crit Rev Oral Biol Med 1993; 4: 197 /250.
exacerbated by certain systemic and environmental factors 17. Nagase H. Activation mechanisms of matrix metalloprotei- nases. Biol Chem 1997; 378: 151 /60.
(e.g. several IL-1 gene polymorphisms, HIV infection, 18. Parsons SL, Watson SA, Brown PD, Collins HM, Steele RJ.
diabetes and smoking). Figures 3 and 4 indicate possible Matrix metalloproteinases. Br J Surg 1997; 84: 160 /6.
biological effects of CMTs in periodontal pathogenesis.
19. Parsons SL, Watson SA, Collins HM, Griffin NR, Clarke PA, CMTs have so far been shown to have beneficial effects in Steele RJ. Gelatinase (MMP-2 and -9) expression in gastro- the treatment of chronic periodontal disease. However, the intestinal malignancy. Br J Cancer 1998; 78: 1495 /502.
20. McCawley LJ, Matrisian LM. Matrix metalloproteinases: mainstay and gold standard in the treatment of periodontal multifunctional contributors to tumor progression. Mol Med disease is still mechanical debridement of the infected root Today 2000; 6: 149 /56.
surfaces. CMTs are an important adjunct to this standard 21. Martignetti JA, Aqeel AA, Sewairi WA, Boumah CA, Kam- treatment. Studies are needed to further uncover the bouris M, Mayouf SA, et al. Mutation of the matrix pathogenesis of periodontal disease and to develop new metalloproteinase 2 gene (MMP2) causes a multicentric drugs that help to facilitate resolution of such inflammatory osteolysis and arthritis syndrome. Nat Genet 2001; 28: 261 /5.
22. Vu TH. Don't mess with the matrix. Nat Gen 2001; 28: 202 /3.
23. Wielockx B, Lannoy K, Shapiro SD, Itoh T, Itohara S, Vandekerckhove J, et al. Inhibition of matrix metalloprotei-nases blocks lethal hepatitis and apoptosis induced by tumornecrosis factor and allows safe antitumor therapy. Nat Med 2002; 7: 1202 /8.
1. Page RC, Schroeder HE. Pathogenesis of inflammatory period- 24. Hazuda DJ, Strickler J, Kueppers F, Simon PL, Young PR.
ontal disease. A summary of current work. Lab Invest 1976; 33: Processing of precursor interleukin 1 beta and inflammatory disease. J Biol Chem 1990; 265: 6318 /22.
2. Zachrisson BU, Schultz-Haudt SD. A comparative histological 25. Gearing AJ, Beckett P, Christodoulou M, Churchill M, study of clinically normal and chronically inflamed gingivae Clements J, Davidson AH, et al. Processing of tumour necrosis from the same individuals. Odontol Tidskr 1968; 6: 179 factor-alpha precursor by metalloproteinases. Nature 1994; 3. Echtenacher B, Mannel DN, Hultner L. Critical protective role 370: 555 /7.
of mast cells in a model of acute septic peritonitis. Nature 1996; 26. Matrisian LM, Ganser GL, Kerr LD, Pelton RW, Wood LD.
Negative regulation of gene expression by TGF-beta. Mol 4. Nilsson G, Metcalfe DD. Contemporary issues in mast cell Reprod Dev 1992; 32: 111 /20.
biology. Allergy Asthma Proc 1996; 17: 59 27. Tonetti MS, Freiburghaus K, Lang NP, Bickel M. Detection of 5. Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell interleukin-8 and matrix metalloproteinases transcripts in modulation of neutrophil influx and bacterial clearance at sites healthy and diseased gingival biopsies by RNA/PCR. J Period- of infection through TNF-alpha. Nature 1996; 381: 77 /80.
ont Res 1993; 28: 511 /3.
6. Abraham SN, Arock M. Mast cells and basophils in innate 28. Ingman T, Sorsa T, Michaelis J, Konttinen YT. Immunohisto- immunity. Semin Immunol 1998; 10: 373 /81.
chemical study of neutrophils- and fibroblast-type collagenases 7. Lin T-J, Befus AD. Mast cells and eosinophils in mucosal and stromelysin-1 in adult periodontitis. Scand J Dent Res defenses and pathogenesis. In: Ogra PL, Mestecky J, Lamm 1994; 102: 342 /9.
Periodontitis, MMPs and CMTs 29. Westerlund U, Ingman T, Lukinmaa PL, Salo T, Kjeldsen L, multiple non-antibacterial mechanisms. Adv Dent Res 1998; Borregaard N, Tjaderhane L, Konttinen YT, Sorsa T. Human 12: 12 /26.
neutrophils, gelatinase and associated lipocalin in adult and 38. Ryan ME, Ramamurthy NS, Golub LM. Matrix metallopro- localized juvenile periodontitis. J Dent Res 1996; 75: 1553 /63.
teinases and their inhibition in periodontal treatment. Curr 30. Tervahartiala T, Pirila E, Ceponis A, Maisi P, Salo T, Tuter G, Opin Periodontol 1996; 3: 85 /96.
Kallio P, Tornwall J, Srinivas R, Konttinen YT, Sorsa T. The in 39. Greenwald RA, Golub LM, Ramamurthy NS, Chowdhury M, vivo expression of collagenolytic matrix metalloproteinases Moak SA, Sorsa T. In vitro sensitivity of the three mammalian (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in adult collagenases to tetracycline inhibition: relationship to bone and and localized juvenile periodontitis. J Dent Res 2000; 79: 1969 / cartilage degradation. Bone 1998; 22: 33 /8.
40. Rifkin BR, Vernillo AT, Golub LM, Ramamurthy NS.
31. Næsse EP, Schreurs O, Helgeland K, Schenck K, Steinsvoll S.
Modulation of bone resorption by tetracyclines. Ann N Y Matrix metalloproteinases and their inhibitors in gingival mast Acad Sci 1994; 732: 165 /80.
cells in persons with and without HIV-infection. J Periodont 41. Ramamurthy NS, Golub LM, Gwinnett AJ, Salo T, Ding Y, Res 2003; 38: 575 /82.
Sorsa T. In vivo and in vitro inhibition of matrix metallopro- 32. Birkedal-Hansen H. Role of cytokines and inflammatory teinases including MMP-13 by several chemically modified mediators in tissue destruction. J Periodont Res 1993; 28: tetracyclines (CMTs). In: Davidovitch Z, Mah J, eds. Biological Mechanisms of Tooth Eruption, Reabsorption and Replace- 33. Golub LM, Wollf M, Roberts S, Lee H, Leung M, Payonk GS.
ment by Implants. Boston: Harvard Soc Adv Orthodont, 1998: Treating periodontal diseases by blocking tissue-destructive enzymes. J Am Dental Assoc 1994; 125: 163 /9.
42. Lokeshwar BL, Seltzer MG, Dudak SM, Bloch LN, Golub 34. Teronen O, Konttinen YT, Lindquist C, Salo T, Ingman T, LM. Inhibition of tumor growth and metastasis by oral Lauhio A, Ding Y, Santivirta S, Valleala H, Sorsa T. Inhibition administration of a non-antimicrobial tetracycline analog of matrix metalloproteinase-1 by dichloromethylene bispho- (CMT-3), and doxycycline in a metastatic prostate cancer sphonate (clodronate). Calcif Tissue Int 1997; 61: 59 /61.
model. Int J Cancer 2002; 98: 297 /309.
35. Golub LM, Lee HM, Nemiroff A, McNamara TF, Kaplan R, 43. Seftor REB, Seftor EA, De Larco JE, Kleiner DE, Leferson J, Ramamurthy NS. Minocycline reduces gingival collagenolytic Stetler-Stevenson WG, McNamara TF, Golub LM, Hendrix activity during diabetes: preliminary observations and a MJC. Chemically-modified tetracyclines inhibit human mela- proposed new mechanism of action. J Periodont Res 1983; noma cell invasion and metastasis. Clin Exp Metastasis 1998; 18: 516 /26.
16: 217 /25.
36. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, 44. Scarpellini F, Scarpellini L, Andreassi S, Cosmi EV. Doxycy- Rifkin BR. Tetracyclines inhibit connective tissue breakdown: cline may inhibit postmenopausal bone damage: preliminary new therapeutic implications for an old family of drugs. Crit observations. Ann N Y Acad Sci 1994; 732: 493 /4.
Rev Oral Biol Med 1991; 2: 297 /322.
45. Cianco S, Ashley R. Safety and efficacy of sub-antimicrobial 37. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, dose doxycycline therapy in patients with adult periodontitis.
Sorsa T. Tetracylines inhibit connective tissue breakdown by Adv Dent Res 1998; 12: 27 /31.
International journal of advance research and innovation
Volume 2, Issue 2 (2014) 373-378 ISSN 2347 - 3258 International Journal of Advance Research and Innovation Fluoroquinolones-A New Definition of Antibiotics Nishant Verma *, a, K. K. Jha a, Rajesh Sharma a, Niraj K. Singh a, Ajai Kumar Singh b, Sachin Tyagi c, Umesh kumar d a Department of Pharmacy, T. M. College of Pharmacy, TMU, Moradabad, Uttar Pradesh, India b Department of Pharmaceutics, Gandhi College of Pharmacy, Karnal, Haryana, India c School of Pharmacy, Bharat Institute of Technology, Meerut, Uttar Pradesh, India d Translam Institute of Pharmaceutical Education & Research, Meerut, Uttar Pradesh, India
Alendronat stada veckotablett 70mg tabl eng
SUMMARY OF PRODUCT CHARACTERISTICS NAME OF THE MEDICINAL PRODUCT Osteomel Once Weekly 70 mg Tablets QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 70 mg alendronic acid (as sodium alendronate trihydrate). Excipients: each tablet contains 142.64 mg lactose monohydrate. For a full list of excipients, see section 6.1.