SECTION 1 - PRODUCT & COMPANY IDENTIFICATION ARYSTA LifeScience South Africa (Pty) Ltd Tel: 031 514 5600 Co. Reg. No.: 2009/019713/07 Fax: 031 514 5611 7 Sunbury Office Park, Off Douglas Saunders Drive, La Lucia Ridge, South Africa, 4019 e-mail: [email protected] Web address: arystalifescience.co.za Substance: Product Name: MASTA 900 SP Produc
Doi:10.1016/j.jaad.2005.10.004Allen N. Sapadin, MD, and Raul Fleischmajer, MD Tetracyclines are broad-spectrum antibiotics that act as such at the ribosomal level where they interferewith protein synthesis. They were first widely prescribed by dermatologists in the early 1950s when it wasdiscovered that they were effective as a treatment for acne. More recently, biologic actions affectinginflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolismhave been researched. The therapeutic effects of tetracycline and its analogues in various diseases havealso been investigated. These include rosacea, bullous dermatoses, neutrophilic diseases, pyodermagangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, and autoimmune disorderssuch as rheumatoid arthritis and scleroderma. We review the nonantibiotic properties of tetracycline and itsanalogues and their potential for clinical application. ( J Am Acad Dermatol 2006;54:258-65.) Tetracyclines were discovered in 1948 as Abbreviationsused: natural fermentation products of a soilbacterium, Streptomyces aureofaciens. The first chemically purified tetracycline was chlortetra- cycline Currently, 3 groups of tetracyclinesare available: tetracycline natural products, tetracy-cline semisynthetic compounds, and chemicallymodified tetracyclines (CMTs).Perusal of the The ring structure of tetracyclines is surrounded literature suggests that tetracyclines, besides acting by upper and lower peripheral zones. These contain as antibiotics, may also affect inflammation, immu- various chemical functional groups and substitu- Synthetic modification of the lower peripheral region reduces both antibiotic and nonantibioticproperties. On the other hand, biological targets may be enhanced by modifying the upper peripheral Tetracyclines and analogues with biological zone, particularly in positions C7 through C9 of the effects on bacteria and mammalian targets show a D ring. This has been accomplished with tetracycline basic chemical structure consisting of a tetracyclic semisynthetic compounds such as minocycline and naphthacene carboxamide ring system ().
Tetracyclines with antibiotic activity have a dimethyl-amine group at carbon 4 (C4) in ring A. Removal ofthe dimethylamino group from C4 reduces its anti- biotic properties, but enhances nonantibiotic ac- Ionophores are organic compounds capable of tions.Utilization of this strategy was the basis for forming lipid-soluble complexes with metal cations.
the development of several chemically modified Transportation of these cations across hydrophobic barriers, such as artificial or biological membranes,is an important function of these compounds.
Tetracyclines bind divalent metal cations, mostly From the Department of Dermatology, Mount Sinai School of along the lower peripheral region, and circulate in blood plasma primarily as Ca11 and Mg11 chelates.
Funding sources: None.
Conflicts of interest: None identified.
Their role as calcium ionophores has important Reprint requests: Allen N. Sapadin, MD, Box 1048, Mount Sinai biologic implications. After its intracellular incorpo- School of Medicine, One Gustave L. Levy Place, New York, NY ration, Ca11 can act as a secondary messenger and affect pathways such as secretory processes, receptor activation or inhibition, cell division, and ª 2006 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2005.10.004 The nonantibiotic properties of tetracyclines are summarized in and discussed in detail below.
Both laboratory and clinical studies have investi- gated the anti-inflammatory properties of tetracy-clines. summarizes inhibitory effects oftetracyclines on inflammation.
Tetracyclines and their analogues inhibit matrix metalloproteinases (MMPs). MMPs are zinc-depen-dent endopeptidases that play an important role inthe remodeling of the connective tissue and areinvolved in embryogenesis, wound healing, rheu-matoid arthritis, and tumor invasion and metasta-sis.There are MMPs that break down fibrillarcollagens known as collagenases (MMP-1, MMP-8,MMP-13) and those that can affect basement mem-brane collagen (collagen IV) known as gelatinases(MMP-2, MMP-9). Tetracycline and its analogues caninhibit both collagenases and gelat Angiogenesis, the formation of new blood ves- sels, occurs in many diseases. These include benignconditions (eg, rosacea) and malignant processes(eg, cancer). Matrix-degrading enzymes, present inthe extracellular matrix of tissues, facilitate angio-genesis by allowing new blood vessels to penetrateinto the matrix. MMPs represent one such class ofenzymes involved in this process.
Fig 1. Chemical structures of tetracycline, doxycycline, Minocycline and doxycycline inhibit angiogenesis induced by implanted tumors in rabbit cornea.Doxycycline and, to a lesser degree, CMTs inhibitsynthesis of MMPs (MMP-8, MMP-9) by endothelial specific proteinases) play an important role in the cells. This inhibition, noted at the protein and mRNA regulation of mammalian apoptotic cell dea levels, may affect migration of endothelial cells Caspase-1, also known as the interleukin 1b (IL- during angiogenesis.The antiangiogenic effect of 1b)-converting enzyme for its ability to convert the tetracyclines may have therapeutic implications in precursor IL-1b into mature IL-1b, is important in inflammatory processes accompanied by new blood mediating neuronal cell death after experimental vessel formation (eg, autoimmune disorders, rosa- traumatic brain injury in mice. Decreased mature cea, cancer invasion). Well-controlled studies must IL-1b production may be correlated with a reduction be performed, at both the laboratory and clinical in tissue injury and an improvement in neurological levels, to investigate this potential.
Recent experimental data indicate that tetracy- Apoptosis, programmed cell death, is of funda- neal administration of minocycline 12 hours before or mental importance for the homeostasis and devel- 30 minutes after traumatic brain injury was shown to opment of any organism. Disease states such as prevent neuronal cell death in mice by inhibiting cancer and neurodegenerative disorders may result This effect had clinical implications since from its deregulation. Crucial components of the it reduced tissue injury and neurological deficits.
apoptotic pathway have been elucidated. A family Improved neurological function correlated with of proteases termed caspases (cysteinyl aspartate- decreased lesion size and decreased capsase-1 Fig 2. Nonantimicrobial properties of tetracycline and its derivatives.
Table I. Inhibitory effects of tetracyclines on osteoarthritic knees of untreated dogs are signifi- cantly higher than the levels in doxycycline-treateddogs. This effect is accompanied by inhibition of proliferation and hypertrophy of chondrocytes and Recent experimental evidence indicates that min- ocycline, by stimulating new bone formation, pre- vents the decrease in mineral density (osteoporosis) observed in ovariectomized old rats.This model mimics the accelerated bone loss commonly experi- enced by postmenopausal women. The effect could be related to a reduction in osteoclast function by tetracycline and CMTAdditional well-controlled studies must be performed to more clearly elucidate the cellular and molecular mechanisms involved.
Diseases, both dermatologic and nondermato- logic, that have been investigated for the therapeutic The mechanisms of action of the tetracyclines and tetracycline derivatives in the treatment of variousskin diseases discussed in this section are summa- CMT, Chemically modified tetracycline; DCN, doxycycline; IL-10, interleukin 10; MCN, minocycline; MMP, matrix metalloproteinase; Acne. Tetracycline, minocycline, and doxycycline are effective in the treatment of acne, particularly activity, as measured by mature IL-1b production.
during the inflammatory stage. It has previously Minocycline may also have beneficial effects in been suggested that the beneficial effect of tetracy- chronic neurodegenerative diseases such as Hun- cline is due to the inhibition of Propionibacterium tington diseaseand amyotrophic lateral sclerosis.
acnes accompanied by a reduction in sebum freefatty acids and extracellular lipases.However, it is currently believed that the inflammatory reaction Prophylactic administration of doxycycline re- plays an important role in the pathophysiology of duces the severity of canine osteoarthritis in the acne.The exact cascade of events that is respon- dog anterior cruciate model.Levels of active and sible for inflammation in acne is not known.
total collagenase activity in extracts of cartilage from However, there is evidence of chemotaxis of Table II. Therapeutic use of tetracyclines in Table III. Mechanisms of action of tetracycline and tetracycline derivatives in the treatment ofskin disease inflammatory reaction involving lymphocytes andneutrophils. The mechanism of action may includeinhibition of neutrophil and eosinophil chemotaxis neutrophils,which are known to store MMP-9.
or inhibition of protease release from granulocytes.
Thus the therapeutic effect of tetracyclines in acne Tetracycline or minocycline, alone or in combination may at least in part be due to reduction in neutro- with nicotinamide, were shown to be effective in philic chemotaxisas well as their inhibitory effect bullous dermatoses affecting the dermoepidermal on proinflammatory cytokines and MMP-9. This junction, such as bullous pemphigoid, cicatricial contention is supported by a recent study that pemphigoid, linear IgA disease, and lichen planus showed that subantimicrobial-dose doxycycline (20 pemphigoides.These reports are generally un- mg taken twice daily) reduced the number of both controlled, and it is possible that a selection bias inflammatory and noninflammatory lesions in pa- toward patients with milder disease or spontaneous tients with moderate facial acne.No detectable remission may be operative. Additional studies are also necessary to evaluate whether tetracycline in combination with nicotinamide is more effective than Rosacea. Tetracyclines and their analogues are either of the two drugs administered as monotherapy.
effective in the treatment of rosacea and related Nevertheless, this therapeutic option represents an disorders, such as perioral dermatitis, ocular rosacea, attractive alternative to systemic corticosteroids in the and steroid-related rosaceaA single daily dose initial treatment of bullous dermatoses affecting the of doxycycline may be effective for ocular rosacea.
dermoepidermal junction. While avoiding the poten- The anti-inflammatory effects of tetracyclines already tial complications of immunosuppressive agents, the mentioned may explain, at least in part, their bene- combination of tetracycline and nicotinamide offers ficial effects in rosacea. Inhibition of angiogenesis obvious advantages for older patients who may have may be a contributory factor in the therapeutic effect concomitant osteoporosis, diabetes mellitus, or of tetracyclines in this group of disorders. Features hypertension. Finally, if the administration of an that favor angiogenesis may contribute to the telan- immunosuppressive agent is deemed necessary, giectasia of rosacea. These include protease-trig- tetracycline may be administered concomitantly as gered release of angiogenetic factors stored in the combination therapy so that the dosage of the extracellular matrix, release of inhibition of endo- immunosuppressant may be tapered more rapidly.
thelial factors, and release of angiogenic factors from Cutaneous sarcoidosis. More recently, the use of minocycline for the treatment of sarcoidosis was Bullous dermatoses. Subepidermal bullae are reported.Minocycline, 200 mg daily for 12 months, frequently accompanied by splitting or dissolution was administered to 12 patients. The median follow- of the basement membrane accompanied by an demonstrated complete clearing of their lesions, collagenase activity in synovial fluid and synovial whereas 2 patients showed a partial response. The fibroblasts.Oral administration of minocycline in duration of response ranged from 10 to 41 months.
adjuvant and collagen-induced arthritis in rats re- No relapse occurred during the 12-month treatment duced the incidence of arthritisFurthermore, period. However, maintenance of remission re- minocycline administration reduced collagenase ac- quired concomitant administration of corticosteroids tivity in the synovial fluid derived from patients with in several of the patients. In addition, a moderately severe hypersensitivity reaction to minocycline was There have been several double-blind, placebo- experienced by one patient in the study.
controlled clinical trials using 200 mg daily of min- It is interesting to note that tetracyclines, minocy- ocycline in patients with rheumatoid arthritis.
cline and doxycycline inhibit in vitro granuloma Kloppenburg et al treated a cohort of 80 patients formation by monocytes exposed to dextrin beads.
and noted significant improvement in joint tender- This effect is thought to be due to inhibition of ness, number of swollen joints, and levels of C- protein kinase C by tetracycline. These in vitro results reactive protein. In another study involving 219 provided the rationale for the successful use of patients with mild to moderate arthritis treated for minocycline in the treatment of other granulomatous 48 weeks with minocycline, there was alleviation of dermatoses, such as silicone-induced subcutaneous joint swelling and tenderness, although the effect was moderate.A more significant result was noted Kaposi’s sarcoma. Kaposi’s sarcoma is charac- in a study involving 60 patients with early (\1 year terized by proliferation of endothelial cells and duration) rheumatoid arthritis treated for 2 years with increase in MMP activity. A preliminary clinical trial 200 mg daily of minocycline versus hydroxychlor- involved 18 patients with AIDS-related Kaposi’s sarcoma who were treated with a chemical modified Scleroderma. In an uncontrolled study, mino- tetracycline, COL-3.After receiving 25, 50, or 70 cycline 200 mg daily was administered for 12 months mg/m2 per day for 25 weeks, one patient showed to 11 patients with early diffuse scleroderma. Four complete resolution and 7 demonstrated partial patients showed complete resolution.Confirma- improvement of skin lesions. The overall response tion from a larger scale, controlled study would add rate was 44%, and median time to response was 4 validity to this spectacular response. It would be of weeks. There was also a reduction in MMP-2 serum interest to determine whether minocycline specifi- levels. On the basis of these preliminary data, addi- cally alters the inflammatory response in sclero- tional studies investigating the use of COL-3 as derma. If so, it would be worthwhile to conduct a monotherapy in patients with early Kaposi’s sarcoma similar study with localized scleroderma.
and in combination with other therapies in patients Cancer. Carcinogenesis is a 3-step process in- with more severe disease seem warranted.
volving tumor cell adhesion, extracellular matrix Miscellaneous dermatoses. There have been proteolysis, and cell migration.Degradation of isolated reports describing the effectiveness of tetra- basement membrane and its surrounding connective cyclines in pyoderma gangrenosum,hidradenitis tissue stroma plays a major role in cancer invasion and metastasis. MMP-2 and MMP-9 (gelatinases A drome,a1-antitrypsin deficiency panniculitis, and B) are frequently expressed in various malignant and pityriasis lichenoides chrEvaluation of tumors.Experimental data using various carci- larger numbers of patients in well-controlled studies noma cell lines and animal carcinogenesis models is necessary before any conclusions can be drawn showed that doxycycline, minocycline, and CMTs regarding the efficacy of tetracycline and its deriva- may inhibit tumor growth by inhibiting MMPs and by tives in the treatment of these conditions.
a direct effect on cell proliferation.Few clinicaltrials investigating the use of tetracyclines in cancer treatment have been conducted. Recently, a phase I The immunomodulatory and anti-inflammatory clinical trial of oral COL-3 (6-demethyl, 6-deoxy, 4- properties of minocycline suggested that this drug dedimethylaminotetracycline) was administered to might be effective in the treatment of autoimmune 35 patients with multiple refractory metastasizing tumors. Although COL-3 appeared to have stabilized Rheumatoid arthritis. Rheumatoid arthritis is nonepithelial-type malignancies, additional follow- a chronic inflammatory disease affecting about 2 mil- up studies are necessary to determine its true efficacy lion Americans. Although the cause of rheumatoid in the prevention of progression of cancer metastasis arthritis is not entirely known, it has been shown that Cardiovascular system. Abdominal aortic an- joint destruction is at least in part due to enhanced associated with a life-threatening risk of rupture.
2. Golub LM, Soummalainen K, Sorsa T. Host modulation with Degradation of aortic wall elastin and collagen tetracyclines and their chemically modified analogues. CurrOpin Dent 1992;2:80-90.
occurs secondary to local production of several 3. Nelson ML. Chemical and biological dynamics of tetracyclines.
MMPs. Doxycycline inhibits MMP-2 and MMP-9 derived from human vascular cell types and from 4. Shapira LL, Soskolne WA, Houri Y, Barak V, Halabi A, Stabholz tissue explants from abdominal aortic aneurysms.
A. Protection against endotoxic shock and lipopolysaccharide- The administration of 200 mg of doxycycline for induced local inflammation by tetracycline: correlation withinhibition of cytokine secretion. Infect Immun 1996;64:825-8.
7 days before aortic aneurysm surgery resulted in a 5. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T.
3-fold reduction of aortic MMP-2 expression and Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998;12:12-26.
double-blind placebo-controlled pilot study involv- 6. Martin RB. Tetracyclines and daunorubicin in metal ions in ing 32 patients, the administration of doxycycline biological systems. In: Sigel H, editor. Antibiotics and theircomplexes. New York: Marcel Dekker; 1985. pp. 19-40.
was associated with a significant reduction in aneu- 7. White JR, Pearce FL. Characterization of chlortetracycline rysm expansion rates as demonstrated by ultrasound (aureomycin) as a calcium ionophore. Biochemistry 1982;21: surveillance.Preliminary data also showed that doxycycline reduces polymorphonuclear leukocyte 8. Thong YH, Ferrante A. Inhibition of mitogen-induced human lymphocyte proliferative responses to tetracycline analogues.
Clin Exp Immunol 1979;35:443-6.
9. Martin RR, Warr GA, Couch RB, Yeager H, Knight V. Effects of Periodontitis. Chronic periodontal inflamma- tetracyclines on leukotaxis. J Infect Dis 1974;129:110-6.
tion is a common cause of irreversible loss of tooth 10. Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial attachment. This process involves increased apical agents on leukocyte chemotaxis. J Invest Dermatol 1978; proliferation and migration of gingival sulcular epi- 11. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW.
thelial cells, an increase in periodontal microbial Targeting leukocyte MMPs and transmigration: minocycline pathogens, and eventual destruction of collagen in as a potential therapy for multiple sclerosis. Brain 2002;125: the gingival, periodontal ligament, and alveolar bone.
The source of the proteolytic enzymes is the gingival 12. Plewig G, Schopf E. Anti-inflammatory effects of antimicrobial epithelial sulcular epithelium (MMP-2, -7, -8, -13, agents. An in vivo study. J Invest Dermatol 1975;65:532-6.
13. Kloppenburg M, Breedveld FC, Terwiel J, Mallee C, Dijkmans -14)and from periodontal pathogens.Early stud- BAC. Minocycline in active rheumatoid arthritis: a double ies showed that tetracycline, doxycycline, and min- blind, placebo-controlled trial. Arthritis Rheum 1994;37: ocycline inhibit collagenase of gingival crevicular fluid derived from adult periodontitis.The oral 14. Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, administration of submicrobial dose of doxycycline Vadas P. Inhibition of enzymatic activity of phospholipaseA (20 mg twice daily) as an adjuvant for conventional by minocycline and doxycycline. Biochem Pharmacol procedures for adult periodontitis resulted in a sig- 15. Ritchlin CT, Haas-Smith SA, Schwarz EM. Minocycline but not nificant improvement in tooth attachment as well as doxycycline upregulates IL-10 production in human synovio- reduction of pocket depth and bleeding after prob- cytes, mononuclear cells and synovial explants. Arthritis More recently, local delivery of doxycycline 16. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, showed similar effects in chronic periodontitis.
et al. A novel mechanism of action of tetracyclines: effects ofnitric oxide synthases. Proc Nat Acad Sci U S A 1996;93:14014-9.
17. Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG, Tetracycline and its analogues have been used in Abramson SB. Post-transcriptional regulation of induciblenitric oxide synthase mRNA in murine macrophages by the treatment of various dermatologic and non- doxycycline and chemically modified tetracyclines. FEBS Lett dermatologic diseases. Although there is some evidence for anti-inflammatory and immunomodu- 18. Stetler-Steveson WG, Liotta LA, Kleiner DE. Extracellular matrix latory effects, additional studies must be performed, 6: role of matrix metalloproteinases in tumor invasion and at both the laboratory and clinical levels, to corrob- 19. Golub LM, Lee HM, Lehrer G, Nemiroff A, McNamara TF, Kaplan R, et al. Minocycline reduces gingival collagenolytic activity We thank David Feman for assistance with the prep- during diabetes: preliminary observations and a proposednew mechanism of action. J Periodont Res 1983;18:516-26.
20. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin BR. Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit 1. Stephens CR, Conover LH, Pasternak R, Hochstein FA, More- land WT, Regna PP, et al. The structure of aureomycin. J Am 21. Tamargo RJ, Bok RA, Brem H. Angiogenesis inhibition by minocycline. Cancer Res 1991;51:672-5.
22. Hanemaaijer R, Visser H, Koolwijk P, Sorsa T, Salo T, Golub LM, 40. Jansen T, Plewig G. Rosacea: classification and treatment.
et al. Inhibition of MMP synthesis by doxycycline and chem- ically modified tetracyclines (CMTs) in human endothelial cells.
41. Frucht-Pery J, Chayet AS, Feldman ST, Lin S, Brown SJ. The effect of doxycycline on ocular rosacea. Am J Ophthalmol 23. Fink KB, Andrews LJ, Butler WE, Ona VO, Li M, Bogdanov M, et al. Reduction of post-traumatic brain injury and free radical 42. Wilkin JK. Rosacea—pathophysiology and treatment. Arch production by inhibition of the caspase-1 cascade. Neurosci- 43. Beck MA, Lorincz AL. The treatment of bullous pemphigoid 24. Friedlander RM, Gagliardini V, Hara H, Fink KB, Li W, successfully controlled by tetracycline and nicotinamide.
MacDonald G, et al. Expression of a dominant negative mutant A preliminary report. Arch Dermatol 1986;122:670-4.
of interleukin-1 beta converting enzyme in transgenic mice 44. Peoples D, Fivenson DP. Linear IgA bullous dermatosis: prevents neuronal cell death induced by trophic factor successful treatment with tetracyclines and nicotinamide.
withdrawal and ischemic brain injury. J Exp Med 1997;185: 45. Chaffins ML, Collison D, Fivenson DP. Treatment of pemphigus 25. Li M, Ona VO, Chen M, Kaul M, Tenneti L, Zhang X, et al.
and linear IgA dermatosis with nicotinamide and tetracycline: Functional role and therapeutic implications of neuronal a review of 13 cases. J Am Acad Dermatol 1993;28:998-1000.
caspase-1 and -3 in a mouse model of traumatic spinal cord 46. Fivenson D, Breneman D, Rosen GB, Hersh CS, Cardone S, injury. Neuroscience 2000;99:333-42.
Mutasim D. Nicotinamide and tetracycline therapy of bullous 26. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J.
pemphigoid. Arch Dermatol 1994;130:753-8.
Tetracyclines inhibit microglial activation and are neuropro- 47. Poskitt L, Wojnarowska F. Minimizing cicatricial pemphigoid tective in global brain ischemia. Proc Natl Acad Sci U S A orodynia with minocycline. Br J Dermatol 1995;132:784-9.
48. Kolbach DN, Remme JJ, Bos WH, Jonkman MF, De Jong MCJM, 27. Yrjanheikki J, Tikka T, Keinanen R, Goldstein G, Chan PH, Pas HH, et al. Bullous pemphigoid successfully controlled by Koistinaho J. A tetracycline derivative, minocycline, reduces tetracycline and nicotinamide. Br J Dermatol 1995;133:88-90.
inflammation and protects against focal cerebral ischemia 49. Fivenson DP, Kimbrough TL. Lichen planus pemphigoides: with a wide therapeutic window. Proc Natl Acad Sci U S A combination therapy with tetracycline and nicotinamide. J Am 28. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline 50. Yomoda M, Komai A, Hashimoto T. Sublamina densa-type reduces traumatic brain injury-mediated caspase-1 activation, linear IgA bullous dermatosis successfully treated with oral tissue damage, and neurological dysfunction. Neurosurgery tetracycline and niacinamide. Br J Dermatol 1999;141:608-9.
51. Wojnarowska F, Kirtschig G, Khumalo N. Treatment of sub- 29. Chen M, On VO, Mingwei L, Ferrante RJ, Fink KB, Zhu S, et al.
epidermal immunobullous diseases. Clin Dermatol 2001;19: Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington 52. Loo WJ, Kirtschig G, Wojnarowska F. Minocycline as a thera- peutic option in bullous pemphigoid. Clin Exp Dermatol 2001; 30. Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, Ona V, Mingwei LI, et al. Minocycline inhibits cytochrome c release and delays 53. Chaidemenos GCh. Tetracycline and niacinamide in the treat- progression of amyotrophic lateral sclerosis in mice. Nature ment of blistering skin diseases. Clin Dermatol 2001;19: 31. Yu LP, Smith GN, Brandt KD, Myers SL, O’Connor BL, Brandt 54. Bachelez H, Senet P, Candranel J, Kaoukhov A, Dubertret L.
DA. Reduction of the severity of canine osteoarthritis by The use of tetracyclines for the treatment of sarcoidosis. Arch prophylactic treatment with oral doxycycline. Arthritis Rheum 55. Webster GF, Toso SM, Hegemann L. Inhibition of a model of in 32. Williams S, Wakisaka A, Zeng QQ, Barnes J, Seyedin S, Martin G, vitro granuloma formation by tetracyclines and ciprofloxacin.
et al. Effect of minocycline on osteoporosis. Adv Dent Res 56. Senet P, Bachelez H, Ollivaud L, Vignon-Pennamen D, Duber- 33. Ryan ME, Greenwald RA, Golub LM. Potential of tetracycline tret L. Minocycline for the treatment of cutaneous silicone to modify cartilage breakdown in osteoarthritis. Curr Opin granulomas. Br J Dermatol 1999;140:985-7.
57. Veller Fornasa C, Catalano P, Peserico A. Minocycline in 34. Vernillo AT, Rifkin BR. Effects of tetracyclines on bone metab- granulomatous cheilitis: experience with 6 cases. Dermatology 35. Plewig G, Kligman AM. Acne and rosacea. 2nd ed. Berlin: 58. Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L, et al. Matrix metalloproteinase inhibitor COL-3 in 36. Del Rosso J. A status report on the use of subantimicrobial- the treatment of AIDS-related Kaposi’s sarcoma: a phase I dose doxycycline. A review of the biologic and antimicrobial AIDS malignancy consortium study. J Clin Oncol 2002;20: effects of the tetracyclines. Cutis 2004;74:118-22.
37. Esterly NB, Koransky JS, Furey NL, Trevisan M. Neutrophil 59. Berth-Jones J, Tan SV, Graham-Brown RAC, Pembroke AC. The chemotaxis in patients with acne receiving oral tetracycline successful use of minocycline in pyoderma gangrenosum-a therapy. Arch Dermatol 1984;120:1308-13.
report of seven cases and review of the literature. J Dermatol 38. Skidmore R, Kovach R, Walker C, Thomas J, Bradshaw M, Leyden J, et al. Effects of subantimicrobial-dose doxycycline 60. Jemec GB, Wendelboe P. Topical clindamycin versus systemic in the treatment of moderate acne. Arch Dermatol 2003;139: tetracycline in hidradenitis suppurativa. J Am Acad Dermatol 39. Macdonald A, Feiwel M. Perioral dermatitis: aetiology and 61. Vignon-Pennamen MD, Wallach D. Cutaneous manifestations treatment with tetracycline. Br J Dermatol 1972;87:315-9.
of neutrophilic disease. Dermatologica 1991;183:255-64.
62. Joshi RK, Atukorala DN, Abanmi A, al Khamis O, Haleem A.
metastasis by an oral non-antimicrobial tetracycline analog Successful treatment of Sweet’s syndrome with doxycycline.
(COL-3) in a metastatic prostate cancel model. Int J Cancer 63. Humbert P, Faivre B, Gibey R, Agache P. Use of anti-collagenase 75. Rubins JB, Charboneau D, Alter MD, Bitterman PB, Kratzke RA.
properties of doxycycline in treatment of alpha 1-antitrypsin Inhibition of mesothelioma cell growth in vitro by doxycycline.
deficiency panniculitis. Acta Derm Venereol 1991;71:189-94.
64. Piamphongsan TT. Tetracycline for the treatment of pityriasis 76. Rudek MA, Figg WD, Dyer V, Dahut W, Turner ML, Seth M, et al.
lichenoides. Br J Dermatol 1974;91:319-22.
Phase I clinical trail of oral COL-3, a matrix metalloproteinase 65. Hanemaaijer R, Sorsa T, Konttinen YT, Ding Y, Sutinen M, Visser inhibitor in patients with refractory metastatic cancer. J Clin H, et al. Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor 77. Thompson RW, Baxter BT. MMP inhibition in abdominal aortic necrosis factor-a and doxycycline. J Biol Chem 1997;272: aneurysms. Ann N Y Acad Sci 1999;878:159-78.
78. Mosorin M, Juvonen J, Biancari F, Satta J, Surcel HM, Leinonen 66. Sewell KL, Breedveld F, Furrie E, O’Brien J, Brinckerhoff C, M, et al. Use of doxycycline to decrease the growth rate of Dynesius-Trentham R, et al. The effect of minocycline in rat abdominal aortic aneurysms: a randomized double-blind, models of inflammatory arthritis: correlation of arthritis sup- placebo-controlled pilot study. J Vasc Surg 2001;34:757-8.
pression with enhanced T-cell calcium flux. Cell Immunol 79. Takeshita S, Ono Y, Kozuma K, Suzuki M, Kawamura Y, Yokoyama T, et al. Modulation of oxidative burst of neutro- 67. Kloppenburg M, Verweij CL, Miltenburg AMM, Verhoeven AJ, phils by doxycycline in patients with acute myocardial infarc- Daha MR, Dijkmans BAC, et al. The influence of tetracyclines tion. J Antimicrob Chemother 2002;49:411-3.
on T cell activation. Clin Exp Immunol 1995;102:635-41.
80. Tervahartiala T, Pirila E, Ceponis A, Maisi P, Salo T, Tuter G, 68. Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, et al. The in vivo expression of the collagenolytic matrix Kaplan DA, et al. Trial Group. Minocycline in rheumatoid metalloproteinase (MMP-2, -8, -13 and -14) and matrilysin arthritis: a 48 week double-blind placebo controlled trial. Ann (MMP-7) in adult and localized juvenile periodontitis. J Dent 69. O’Dell JR, Blakely KW, Mallek JA, Eckhoff PJ, Leff RD, Wees SJ, 81. Grenier D, Plamondon P, Sorsa T, Lee HM, McNamara T, et al. Treatment of early seropositive rheumatoid arthritis: Ramamurthy NS, et al. Inhibition of proteolytic serpinolytic a two-year double-blind comparison of minocycline and and progelatinase-b activation activities of periodontopath- hydroxychloroquine. Arthritis Rheum 2001;44:2235-41.
ogens by doxycycline and the non-antimicrobial chemically 70. Le CH, Morales A, Trentham DE. Minocycline in early diffuse modified tetracycline derivatives. J Periodontol 2002;73:79-85.
scleroderma. Lancet 1998;352:1755-6.
82. Golub LM, Ramamurthy NS, McNamara TF, Gomes BC, Wolff 71. Westermarck J, Kahari V-M. Regulation of matrix metallopro- MS, Casino A. Tetracyclines inhibit tissue collagenase activity: teinase expression in tumor invasion. FASEB J 1999;13:781-92.
a new mechanism in the treatment of periodontal disease.
72. Duivenvoorden WC, Hirte HW, Singh G. Use of tetracycline as an inhibitor of matrix metalloproteinase activity secreted by 83. Ciancio S, Ashley R. Safety and efficacy of sub-antimicrobial human bone-metastasizing cancer cells. Invasion Metastasis dose doxycycline therapy in patients with adult periodontitis.
73. Hidalgo M, Eckhardt SG. Development of matrix metallopro- 84. Wennstrom JL, Newman HN, MacNeill SR, Killoy WJ, Griffiths teinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; GS, Gillam DG, et al. Utilization of locally delivered doxycycline in non-surgical treatment of chronic adult periodontitis: 74. Lokeshwar BL, Selzer MG, Zhu BQ, Block NL, Golub LM.
a comparative multi-center trial of 2 treatment approaches.
Inhibition of cell proliferation, invasion, tumor growth and
8. Modelos experimentais em pesquisa1 Lydia Masako Ferreira2, Bernardo Hochman3, Marcus Vinícius Jardini Barbosa4 1. Trabalho desenvolvido no Programa de Pós-Graduação em Cirurgia Plástica da Universidade Federal de São Paulo – Escola Paulista de2. Professora Titular da Disciplina de Cirurgia Plástica e Coordenadora do Programa de Pós-Graduação em Cirurgia Plástica da UNIFESP �