TherapyTetracyclines: Nonantibiotic properties and their clinical implications
Section snippets
Chemistry
Tetracyclines and analogues with biological effects on bacteria and mammalian targets show a basic chemical structure consisting of a tetracyclic naphthacene carboxamide ring system (Fig 1). Tetracyclines with antibiotic activity have a dimethylamine group at carbon 4 (C4) in ring A. Removal of the dimethylamino group from C4 reduces its antibiotic properties, but enhances nonantibiotic actions.3 Utilization of this strategy was the basis for the development of several chemically modified
Tetracyclines as ionophores
Ionophores are organic compounds capable of forming lipid-soluble complexes with metal cations.7 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 along the lower peripheral region, and circulate in blood plasma primarily as Ca++ and Mg++ chelates.3 Their role as calcium ionophores has important biologic implications. After its intracellular
Nonantibiotic properties of tetracyclines
The nonantibiotic properties of tetracyclines are summarized in Fig 2 and discussed in detail below.
Clinical studies
Diseases, both dermatologic and nondermatologic, that have been investigated for the therapeutic use of tetracyclines are listed in Table II.
Conclusions
Tetracycline and its analogues have been used in the treatment of various dermatologic and nondermatologic diseases. Although there is some evidence for anti-inflammatory and immunomodulatory effects, additional studies must be performed, at both the laboratory and clinical levels, to corroborate these properties.
References (84)
- et al.
The effect of antimicrobial agents on leukocyte chemotaxis
J Invest Dermatol
(1978) - et al.
Anti-inflammatory effects of antimicrobial agents. An in vivo study
J Invest Dermatol
(1975) - et al.
Inhibition of enzymatic activity of phospholipase A2 by minocycline and doxycycline
Biochem Pharmacol
(1992) - et al.
Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines
FEBS Lett
(1997) - et al.
Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade
Neuroscience
(1999) - et al.
Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury
Neuroscience
(2000) - et al.
The effect of doxycycline on ocular rosacea
Am J Ophthalmol
(1989) - et al.
Linear IgA bullous dermatosis: successful treatment with tetracyclines and nicotinamide
J Am Acad Dermatol
(1992) - et al.
Treatment of pemphigus and linear IgA dermatosis with nicotinamide and tetracycline: a review of 13 cases
J Am Acad Dermatol
(1993) - et al.
Lichen planus pemphigoides: combination therapy with tetracycline and nicotinamide
J Am Acad Dermatol
(1997)
Treatment of subepidermal immunobullous diseases
Clin Dermatol
Topical clindamycin versus systemic tetracycline in hidradenitis suppurativa
J Am Acad Dermatol
Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor necrosis factor-α and doxycycline
J Biol Chem
The effect of minocycline in rat models of inflammatory arthritis: correlation of arthritis suppression with enhanced T-cell calcium flux
Cell Immunol
Inhibition of mesothelioma cell growth in vitro by doxycycline
J Lab Clin Med
The structure of aureomycin
J Am Chem Soc
Host modulation with tetracyclines and their chemically modified analogues
Curr Opin Dent
Chemical and biological dynamics of tetracyclines
Adv Dent Res
Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion
Infect Immun
Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms
Adv Dent Res
Tetracyclines and daunorubicin in metal ions in biological systems
Characterization of chlortetracycline (aureomycin) as a calcium ionophore
Biochemistry
Inhibition of mitogen-induced human lymphocyte proliferative responses to tetracycline analogues
Clin Exp Immunol
Effects of tetracyclines on leukotaxis
J Infect Dis
Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis
Brain
Minocycline in active rheumatoid arthritis: a double blind, placebo-controlled trial
Arthritis Rheum
Minocycline but not doxycycline upregulates IL-10 production in human synoviocytes, mononuclear cells and synovial explants
Arthritis Rheum
A novel mechanism of action of tetracyclines: effects of nitric oxide synthases
Proc Nat Acad Sci U S A
Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis
FASEB J
Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observations and a proposed new mechanism of action
J Periodont Res
Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs
Crit Rev Oral Biol Med
Angiogenesis inhibition by minocycline
Cancer Res
Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells
Adv Dent Res
Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury
J Exp Med
Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia
Proc Natl Acad Sci U S A
A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window
Proc Natl Acad Sci U S A
Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction
Neurosurgery
Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease
Nat Med
Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice
Nature
Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline
Arthritis Rheum
Effect of minocycline on osteoporosis
Adv Dent Res
Potential of tetracycline to modify cartilage breakdown in osteoarthritis
Curr Opin Rheumatol
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