Clinician’: Quick Reference
`
`Subantimicrobial Dose Doxycycline for Acne
`and Rosacea
`
`loseph B. Bikowski, MD
`
`'
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`Ame vulgaris and rosacea present therapeutic
`dtallenges due to theircnronlcit); potential for dis-
`flgurement, and psychosocial Impact. Although
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`doses, tetracycline: reduce inflammation via anti-
` , antlmatrix-degmding meta£lopm-
`teinase, and cytoklne down-regulating propertia.
`Subantimicrobial dose (SD) doxycydlne (Periostat
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`
`acneaswieliasinanopenlaba‘studyinthetr'eat-
`merit of rosacea. The result: of su l
`
`dosedaxytycline trieatrnentinearlytrialssapport
`its benefits and further investigation in acne and
`rosacea. (SKlNmed. 2003,-2.-234-245)
`02003 Lejacq Carrmmlcatlom; inc.
`
`cne vulgaris is the most common
`chro11ic slcin disorder in the United
`‘
`— States, affecting approximately 80% of
`persons at some pointbetween 11 and30years
`of age.‘ In 1996 in the United States,
`the
`National Health Interview Survey reported the
`prevalence of acne was 26,i'1000 in persons <45
`years of age? Although the data in adults are
`sparse, one cormnunity-based study in England
`foimd the prevalence of clinical acne in women
`>25 years was 12% and in men it was 3%} In
`addition to the economic costs of physician vis-
`its,‘ medications, and over-the-counter treat-
`
`on psychosocial development and the quality
`of life of those who suffer from it.‘
`
`Rosacea is also a common, chronic dermatosis
`estimated to affect at least 1 in 20 people in the
`United States-6 The maleflty are fail-Skjllned.
`Caucasian women, aged 30-50 years old.’ One
`Community Study found 10% of the-°*e exam‘
`ined had rosacea (14% were women, 5% were
`men).3 Similar to acne, rosacea has a significant
`economic cost“ and psychosocial
`impact.
`Because the features of rosacea are so visible,
`
`people with rosacea are often distressed and
`embarrassed about their appearance and may
`exhibit low self-esteem.”
`
`The Pathogenesis of Acne
`Acne, the major disorder of the pilosebaceous
`unit, presents as noninflammatory (closed and
`open comedones) and inflammatory (papules,
`pustules, nodules) lesions. Several factors con-
`tribute to the pathogenesis of acne including
`androgens (testosterone and DHEA-S),
`in-
`creased sebum production, P. acnes-driven
`inflammation, and abnormal follicular epithe-
`lial differentiation. Desquamated comified cells
`of the upper canal of the follicle become abnor-
`mally adherent. Instead of undergoing nomral
`shedding and discharge through the follicular
`opening,thecellsfom1amicroscopichyperker-
`atotic plug (the microcomedo) in the follicular
`canal, which enlarges and becomes a visible
`comedo.
`Inflammation (and subsequently,
`inflammatory acne) is a direct or indirect result
`of the proliferation of P. acnes. Overgrowth of
`this anaerobic organism, which is otherwise a
`normal constituent of the skin flora, occurs in
`
`the lipid-rich environment of the pilosebaceous
`units containing microoomedones. The host
`ments,5 the disfigurement and permanent scar-
`
`
`inflammat ‘gfromacnecanalsohaveanadverseim res me to R acnes causes
`
`(Jan; Mar.; May; July; Sept; Nov.) by Le lacq Communications, Inc, Th Am nea| 1
`for the Clinician (ISSN ‘I540-9?40) is published bi-month
`jacqlcommulnications, inc. All rights reserved. No part 0 dais publication may be reproduced or transmittedli
`]U[y .
`or any information storage and retrieval
`, without permission In writing from the publisher. The facts, 0 mt
`reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`
`S_K|Nmed: Derrnatol
`Q54 ht © 2002' by
`i
`spy, recordin
`anu uo not necasaii
`
`rah Howel at showelI@I
`
`Am nea| V_ S uper-nus
`|PR2013-00368
`
`1
`
`

`
`damage to and rupture of the follicular wall
`which extends the inflammatory process into
`the surrotmding dermis, resulting in the fonna-
`tion of the inflammatory lesions (papules, pus-
`tules, and nodules} and ultimately, destruction
`of the collagen matrix in the skin and cyst for-
`mation. Each of these pathogenic processes is a
`potential target for treatment. L1“
`
`The Pathogenesis of Rosacea
`Rosacea is a chronic, cutaneous vascular disor-
`der. The earliest manifestations are increased
`
`and prolonged flushing, erythema, and sensi-
`tive skin. Although the etiology of rosacea
`remains unclear, local irritants (e.g., certain
`topical medications, astringents), wind, tem-
`perature extremes, hot andfor spicy foods and
`beverages, and alcohol can precipitate vasodila-
`tion (flushing) and inflammation (papules, pus-
`tulm), the clinical signs of rosacea.“ In addi-
`tion, the erythema of rosacea is apparently
`aggravated by chronic sun exposure and
`photo damage. Exposing facial skin to sources
`of radiant heat, such as from a fireplace, repro-
`duces the erythema.”
`
`Extravascular fluid from the flushing reaction
`accumulates hr the superficial dermis faster
`than the lymphatic vessels can remove it, lead-
`ing to edema and damage to the lymphatic
`vessels. Elastin degeneration due to actinic
`exposure is probably a common cause of lym-
`phatic failure. The upregulation of proteolytic
`activity during inflammation, along with neu-
`trophil infiltration, exacerbates the degrada-
`tion of elastin. Neutrophil elastase and gelati-
`nase, from a variety of cellular sources, are
`capable of degrading the type IV collegen hr
`the extracellular matrix on which the integrity
`of the capillary cell wall depends.
`
`Lymphatic failure results in a sustained
`inflammatory response. In a later vascular
`stage, telangiectasias commonly develop on
`the nose, nasolabial folds, and cheeks. The
`
`condition progresses to an inflammatory
`stage characterized by erythematous papules
`and pustules on the cheeks, forehead, nose,
`and chin- The final stage is the development
`of large inflammatory nodules and connec-
`tive tissue hypertrophy and fibroplasia (a
`result of the accumulation of plasma pro-
`teins). Finally, the fibroplasia may lead to the
`development of rhinophyma (predominantly
`in men).“
`
`Commonly Used Therapy for
`Acne and Rosacea
`Treatment for acne focuses on the resolution
`
`of inflammation, downregulation of sebum
`production, and elimination of the nonin-
`flammatory lesions manifested as micro-
`comedo and comedones. In rosacea, therapy
`is typically anti-inflammatory in nature. For
`acne, the choice of therapy usually depends
`on the grade and severity. Rosacea therapy is
`determined by the stage.“
`
`Medsarlsm of Action of Anlinicroblds In
`
`
`
`Acne. The nrultiiactorial nature of acne ideally
`requires an agent with a variety of
`mechanisms, exerting an effect
`11ot only on the bacteria but also
`on the inflammatory host
`response induced by the bacteria.‘
`Certain
`exhibit
`
`these pleiotropic effects both
`reducing the numbers of bacteria
`and suppressing the host's inflam-
`matory response. For example,
`tetracyclines have been shown to:
`diminish
`polymorphonuclear
`neutrophil
`(PMN) chemotaxis
`(possibly by inhibiting PMN
`chemotactic factor); reduce lipase production in
`l’.acm:s,resulti11gir1aret111ctionoffattya(:idsi11
`sebum on the skin surface,-13'“ affect comple-
`ment pathways; dowri-regulate inflammatory
`cytokine production; and inhibit host col-
`lagenolytic activity. These pleiotropic properties
`haveledtothewidespreaduseoftetracydinrs
`for the treatment of acne.
`
`Systemic Antimicrobial Therapy
`Systemic antimicrobial therapy is generally
`more effective than topical therapy presum-
`ably because the drugs penetrate the follicle
`more readily. Oral antimicrobials are indicated
`for persons with moderate-to-severe acne, per-
`sons with inflammatory acne i11 whom topical
`antimicrobials have failed or are not tolerated,
`
`persons with involvement of the skin of the
`shoulders, back, or chest {where it is difficult
`to apply topical therapy), and persons with
`mild-to-moderate acne who have a potential
`for substantial scarring or pigmentary changes
`(post inflammatory hyperpigmentation).‘°
`
`Themostoornrnonoralantimicrobialsusedare
`
`tetracycline HCI, doxycycline, and minocycline.
`The selection of an
`is typically
`
`
`
`(Jan.; Malt; May; July; Sept; Nov.) by Le lacq Communications, Inc, Three Parklands Drive, Darien, CT 06!
`for the_Clinician (l§SN ‘|§40-W40) is published bi-month
`SK|Nmed: Dermatology
`dais publicadon may be reproduced or transmitted in any form or by any means, electronic
`hanical,
`'
`Ml ri hts reserved. No part
`Copyrig'
`' ‘
`'
`photocc July . Auqusi 2005
`I retngeval system, without permission in writing from the publisher. The facts, 0 ‘nions and ideas expressed in this publicatio Qisose of ti
`and do not necessanty renect those at the tdrtors or Publisher. For copies in excess of 25 or for commercial purposa, please contact
`rah Howel at showel|@lejacq.com or 203.6.au. r .« r I X106.
`
`2
`
`

`
`guided by the drug’s efficacy, safety, convenience
`of use, and cost. The pharmacologic properties of
`doxycycline and minocydine are improved over
`tetracycline l-ICI. They both have improved
`absorption from the gastrointestinal (GI) tract
`along with increased lipophilicity resulting in
`better uptake by the pilosebaceous unit, and thus
`better tissue penetration than tetracycline HCI.
`In addition, their increased half-life allows once-
`
`or twice-daily dosing, potentially facilitating
`patient adherence to the dosing regimeu.15
`
`Efficacy of the Tetracyclines
`in Acne Vulgaris
`There are few well done, placebo-controlled
`clinical trials evaluating the systemic use of
`tetracyclines (especially doxycycline) for the
`treatment of acne- Many studies lack objective
`descriptions of baseline disease severity and
`consistent measures of efficacy and outcome
`between studies, thus making the assessment
`of the relative efficacy of the study drugs even
`more difficult. Despite limitations, overall
`study results and numerous case reports sup-
`port the use of the tetracycline family of drugs
`in the treatment of acne- These studies are
`summarized in Tables I and II.
`
`Efficacy of Tetracyclines
`in Rosacea
`
`'Iherapyforrosaceausuallyconsistsofacornbi-
`nation of topical and oral antimicrobials.11
`Papules and pustules in rosacea are generally
`eliminated with systemic
`such as
`tetracycline HCl, and remission can be main-
`tained to some extent with
`treatment,
`such as metronidazole.” Approximately 25% of
`patients relapse within 1 month after discontinu-
`ation of active therapy, approximately 50% to
`60% at 6 months, and approximately 70%by 1-4
`years in the absence of maintenance therapy.15»17
`The literature concerning rosacea is even more
`spai:sethanthatofac:ne,b11t'I‘ablel]]surnmarizr5
`some of the few comparative studies that have
`been done with tetracyclines in rosacea.
`
`Drawbacks of Long-Term
`Standard Dose 11Ierapy
`11-re Problem of Resistance. The widespread use
`of oral antimicrobials for long-term acne thera-
`py has resulted in the development of resistant
`strains of R acnes. There is a clear association
`
`between the emergence of resistant P. mics and
`the therapeutic use of these 13-19
`Resistance of R tactics to tetracyclines increased
`
`Sl<|Nmed: Dennatol
` for the Clinician (ISSN ‘I540-9?40) is published bi-montw (Jan.; Malt; May; July; Sept; Nov.) by Le lacq Communications, ln_c., Three Parklands Drive, Darien, CT 06!
`
`dais publication may be reproduced or transmitted i
`jacq Communications, inc. All ri hts reserved. No part
`I
`F236" ht©2002_by
`y
`or any Information storage and retneval
`i
`spy, recorclin
`without permission in writing from the publisher. The facts, o ‘nit
`
`
`‘emu uo not necessan
`reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purpose, please contact
`rah Howel at showelI@lejacq.com or 2U3.6.S6.1?11 x106.
`
`
`
`tion,2" demonstrating the effect of an antimi-
`crobial regimen of tetracycline use in acne ther-
`apy on bacterial resistance.”
`
`Overall resistance of P. acres to antibiotics had
`
`increased from 20% in 1973 to 62% in 1996.323
`
`levels of resistance to specific antibiotics vary
`widely, but strains resistant
`to erythromycin,
`dindamycin, tetracycline HCI, doxycycline, and
`trimethoprim are the most con1rnon.13 The
`Minimum Inhibitory Concentrations (MICs) of
`tetracycline required to kill 50% of a population
`ofRaa1es(MIC5u)aietypic:allyhighertl1ai1LiflC5C,
`for doxycycline, which are typically higher than
`those of minocydine. Eady et al_2“ found that
`tetracycline-resistant organinns were cross resist-
`ant to doxycydine but susceptible to minocy-
`cline. Because resistance to minocydine was
`rarely observed, minocydine has been the pre-
`ferred tetracycline for use in acne.’-5 More recent-
`ly, high-level resistance to minocycline (M]C5,,,
`4—16i.rgfmL)hasbeenfoundinpopulationsin
`the United States.” While I’. oases resistance per
`seisnotamaiorpublichealthconcern,theabili-
`ty of microbes to pae resistance from one to
`another is well lcnovwn, and even more important
`is the observation that resistance determinants
`
`canco-travelgrsultinginthepotentialforspread
`of
`resistance with potentially dev-
`astating effects in clinical pracIice.12'27
`
`the develop-
`One strategy designed to
`ment of resistance is to use a combination of
`
`topical and systemic therapies with regimens
`that incorporate agents with complementary
`mechanisms of action. Another innovative
`
`approach is to use a subantimicrobial dose (SD)
`of the antibiotic. As the predominant mecha-
`nism for the development of microbial resist-
`ance is selection of resistant strains over suscep-
`tible strains, a dose could be administered low
`
`enough that even susceptible strains remained
`unaffected. The exploitation of the anti-inf|am-
`matory properties of certain antibiotics might be
`sufficient
`to elicit a meaningful clinical
`response, and the administration of SDs may
`provide effective therapy without the risk of
`soliciting alterations in microbial
`
`Other Adverse Consequences of I.ong-Term
`Tetracyclhe 11-ierapy. Based on available infor-
`mation, there are more reports of serious adverse
`events associated with the use of minocydine
`than with tetracycline HCI or doxycycline. It is
`
`3
`
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`(Jan; Mar.; May; July; Sept; Nov.) by Le lacq Communications, lnc., Three Parklands Drive, Darien, CT 061
`m
`the Clinician (ISSN ‘I540-9?4(J) is published bi-monthly
`MUN
`hanical,
`, electronic
`produced or transmitted in any form or by any means
`this publication may
`'
`"
`'
`Ml rightfi reserved. No part 0
`I retneva system, without permission in writing from th
`nions and ideas expressed in this publicatio
`=1:
`rah Hcrwel at showe||@ieiacq.cam or 203.6».
`and do not necasanry renect those at the tclntors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`
`4
`
`
`
`

`
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`- jacq Communications, inc. All rights reserved. No part 0 this publication may be reproduced or transmitted i
`information storage and retrieval system, without permission in writing from the publisher. The facts, 0
`rah Hcuwel at:
`E
`reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`
`
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`rive, Darien, CT06t
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`h‘|,
`July - Auqusr 2005|n°;r':§1°O:e"§f’t,
`
`5
`
`

`
`.T=!i|ii|fl»=Etfl=a¢r-9fTstra9rsl|'n¢sin-.R°sasea
`RESULTS
`EFFICACY MEASURES
`STUDY
`DE SlGN
`
`Afterl month:
`Sneddon, I966
`Tetracycline (n=36)
`Disappearance of pustules, flattering of
`Tetracycline 78% improved;
`Tetracycline vs. placebo;
`250 mg b.i.d
`papules, diminution of ervthema
`vs.
`78 pts, all degrees of
`Placebo 45% improved
`(assessment not described)
`After 2nd month:
`severity
`Placebo .-(n=42) x 4 wk,
`then all tetracycline 250 mg
`Tetracycline 50% improved;
`b.i.d.
`Placebo (now txd with
`tetracycline) 74%.i.~;1proved
`7;'9 with perioral denrratitis =
`healing and full remission
`14/1 6 rosacea-like dermatitis =
`healing and full remission
`'I4,'19 rosacea = clinical
`improvement
`5 = complete cure
`
`Assessment measures not described
`
`Assessment measures not provided
`
`Erythema assessed colorimetrics
`Telangectasias (TAE) color prints and
`score 0; 1 (<5 TAE nasolabial sulcus); 2
`(5-10); 3 (10-20); 4 (20-30 + on chin
`and forehead); 5 (>30);
`Pt score efficacy0 (no efficacy);
`1 (low); 2 (traceable); 3 (mild); 4
`(90000; 5 (high);
`Tolerability score 0 (no SE5); 1
`(occasional); 2 (many 53:5); 3 (mild SE5),-
`4 (sev SB); 5 (very sev, discont)
`
`Pt 1: cleared eI'uptionsin9wlr;
`Pt 2: marked ~L erythema +
`lesions after 4 wlrs; ‘n follow-up
`cleared (time not given);
`Continued clearing of
`inflammatory lesions at 6- mo
`follow-up in both pts
`After 8 wk:
`Erythema: mean value
`Clar: 4.8-5.8
`Doxycycline 3.8-5.2
`TAEs: i mean score 3.8-2.2
`Papulesz i mean score 3.8-0.2
`Pustules: J. mean score 3.8-0.2
`Efficacy mean score:
`Clan: 4.8
`Tolerability
`Doxycyclinez 4.2
`Clari mean score: 0.32 (OCGIS 5Es)
`Doxycycline mean score:
`1.06 (mild SE5)
`
`Urabe, 1976
`Doxycycline or
`tetracycline;
`9 pts perioral demtatitis
`(red Papllles);
`16 rosacea-like
`demtatitis (all stages);
`19rosacea
`
`3-yr period
`All previously txd topical
`fluorinated steroids
`discontinued
`Doxycycline or tetracydine
`(dosage not given) for 2-3 mo;
`concomitant oral prednisolone
`5-15 mgqd for2-3wkfor
`severe disease;
`19 rosacea pts
`doxycycline 100mg q.d. +
`topical hydrocortisone x 2 mo
`2 case reports
`Pt 1: 100 mg q.d. continued as
`maintenance;
`Pt 2: 50 mg q.d.; reduced to 50
`mg q.d. for maintenance
`
`Torlesanl, I997
`Doxycydine vs. clari;
`40 pts
`
`Clari (n=23)
`250 mg b.i.d. x 4 wk
`then 250 mg q.d. x 4 wk
`vs.
`
`Doxycycline (n=17)
`100 mg b.i.d. x 4 wk
`then 100 mg q.d. x 4wk
`
`Clari=C|arithromycin; txd=prescribed; 5E=side effect; sev=severe; discont=discontinued
`
`an amino acid side chain with potential to form
`a reactive metabolite. Neither tetracycline HCI
`rror doxycydine contains the amino acid side
`chain; therefore, the hypersensitivity reactions
`associated with minocycline may be specific to
`this antimicrobial.” In vitro studies have
`
`demonstrated the presence of a minocydine-gfu-
`tathione conjugate when minocydine is incu-
`bated with hypochlorous acid, as is found in
`neutrophils. When a reactive metabolite is gen-
`erated, ghrtathione transferase acts to detoxify
`this product. The presence of minocycline-
`glutathione conjugates implies the formation of
`potentially toxic metabolites. These potentially
`reactive metabolites generated by minocycline
`may bind to tissue macromolecules causing cell
`damage directly, or they may act as haptens,
`eliciting a secondary immune response.”
`
`Adverse Events Associated With
`
`Acne Therapy
`Telracycises as a Class of Antlnicrioblals. GI
`disturbances (nausea, vomiting, and diarrhea)
`are the most common side effects associated
`
`tetracycline
`the tetracyclines. All
`with all
`antimicrobials carry warnings of phototoxici-
`ty reactions, manifested as an exaggerated
`sunburn reaction. To date, there have been no
`
`double-blind, controlled studies showing that
`tetracycline HCl is a photosensitizer. Mino-
`cycline is generally regarded as the least pho-
`tosensitizing of the tetracycline derivatives at
`the commonly administered dose?”
`
`Prescribing information for all tetracyclines
`warns that they can cross the placenta and
`have shown evidence of embryotoxicity with
`
`
`
`(Jan; Mar.; May; July; Sept; Nov.) by Le lacq Cornniunications, Inc, Three Parklands Drive, Darien, CT 061
`for the Clinician (ISSN 1540-9240) is published bi-month
`SK|Nmed: Dermatology
`.
`C
`. .. - _
`hanical,
`‘
`'
`"
`'
`Ml rights reserved. No part 0 this publication may be reproduced or transmitted in any form or by any means, electronic
`ose of ti
`pfigggluly Auqusr 2003
`I retrieval system, without permission in writing from the publisher. The facts, 0 ‘nions and ideas expressed in this publicatio
`and do not necasanry rerlect those or the horrors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`rah Howel at showe||@leiacq.com or 203.6». I .« r I X106.
`
`6
`
`

`
`toxic effects on the developing fetus.
`Minocycline has been shown to have a car-
`cinogenic metabolite, although the clinical
`relevance of this finding is unknown.“
`
`Tehacyclne I-ICI. Tetracycline HCI has been
`implicated in an increased incidence of
`esophageal ulceration,” particularly when
`administered in capsule fonn. The use of
`tetracycline HCI has also been associated with
`the development of pseudotumor cerebri in
`adult and pediatric patients?“ and in patients
`receiving concomitant
`therapy.“
`
`Daxycyclhe. Esophageal irritation has been
`seen with doxycycline hyclate, which dis-
`solves at a pH of 2-3. In contrast, the pH on
`dissolution of the newer salt, doxycycline
`monohydrate, is 5-6, resulting in no esopha-
`geal irritation and less GI upset. 15
`
`Photosensitivity can be seen with doxycycline
`therapy. The relationship is dose dependent,
`and phototoxicity occurs in 3% of patients tak-
`ing 100 mg/day. This can be a problem clinical-
`ly because patients who do not respond to stan-
`dard doses may be taking maintenance therapy
`doses in excess of 100 mg/day, which greatly
`increases the potential for phototoxic eruptions
`(20% at 150 mg and 42% at 200 mg/day).35
`
`Because these drugs are given long-term for
`acne and rosacea, the possibility for carcino-
`genic potential is also of concern. Recently, dur-
`ing the development of a SD of doxycycline as
`a chronic, adjunctive therapy for the treatment
`of adult periodontitis, this issue was systemati-
`cally addressed for the first time. The labeling
`for this drug (Periostat) states that the carcino-
`genic potential of doxycycline has been investi-
`gated with no findings of changes indicating a
`direct carcinogenic effect. Increases in benign
`fibroadenomas of the breast, polyps of the
`uterus, and adenoma of the thyroid, which are
`consistent with a hormonal effect, were
`
`observed in treated women. Doxycycline has
`shown no mutagenic activity and no convinc-
`ing evidence of clastogenic activity.35
`
`llinocycllne. The vestibular side effects of
`lightheadedness, loss of balance, dizziness, or
`true vertigo in patients taking minocycline
`are well known and occur more often in
`women.3733 These effects arise because the
`
`lipophilicity of minocycline results in some
`
`degree of blood-brain barrier penetration.
`
`Hyperpigmentation or a bluefblack skin or
`mucous membrane discoloration has been
`
`found with long-term use of minocy-
`cline.39r“" In rare cases, such hyperpigmenta-
`tion may occur within 1 month of minocy-
`cline therapy. There are two types: localized
`pigmentation occurring at the site of previ-
`ous inflammation, and a more generalized
`diffuse pigmentation.“
`
`Although rare, a variety of drug-induced syn-
`dromeshavebeendescribedinpatientstaking
`minocydine for acne. Drug-induced lupus and
`hepatitis are the most common reactions and
`except for serum sickness (mean time to occur-
`rence: 16 (lays); these syndromes typically pres-
`ent after prolonged use (mean time to occur-
`rence: 25.3 montl'1s).42-“*3 Coexistent minocy-
`cline-induced lupus erythematosus and autoim-
`mune hepatitis after long-term use (4—12()
`months) occurred at dose ranges of 50-200
`mg/day.“ Hepatitis with minocycline use is
`most often associated with hypersensitivity syn-
`dromes or delayed autoimmune hepatitis.“-‘*5
`
`Case reports of pneumonitis,“ lymphadenopa-
`thy, and an infectious mononucleosis-type
`reaction“ have been reported. Rare cases of
`pseudotumor cerebri (idiopathic intracranial
`hypertension)“ associated with long-term
`minocycline treatment (4 weeks—18 months)
`have occurred.“-49 Long-terrn administration
`in rat studies resulted in evidence of thyroid
`tumor production and thyroid hyperplasia in
`rats and dogs.“ Based on reports of adverse
`drug reactions, Gough et al.-‘*7’ recommended
`that safer alternatives than minocycline should
`be considered for treating acne.
`
`A New Therapeutic Option—
`SD Doxycycline
`Within a decade of their discovery in 1947,
`tetracyclines were widely used as anti-infec-
`fives and for the treatment of acne.“ Steadily
`increasing rates of bacterial resistance limited
`their use for many infections. In 1983, Golub
`reported on a seminal study in rats in which
`minocycline inhibited tissue collagenolytic
`enzyme activity by mechanisms independent
`of its antibacterial activity.” This finding
`spawned an extensive series of experiments
`to elucidate the nonantimicrobial properties
`of tetracyclines, suggesting a new therapeutic
`
`
`
`§l<|Nmed: Derrnatol
`P40 ht © 2002 by
`spy, recordin
`‘emu uu not necessan
`
`(Jan; Malt; May; July; Sept; Nov.) by Le lacq Communications, Inc, Three Parldands Drive, Darien, CT 06!
`for the Clinician (ISSN ‘I540-9?40) is published bi-month
`jacq Communications, inc. All ri hts reserved. No part
`dais publication may be reproduced or transmitted l
`'
`jU[y . Auqus-r ' 2003: or mechanical,
`without permission in writing from the publisher. The facts, o ‘nit
`n are those of ti
`or any information storage and retneval
`reflect those of the Editors or Publrsher. For copies in excess of 25 or for commercial purpose, please contact
`rah Howel at showelI@lejacq.com or 2U3.6.S6.1?11 x106.
`
`7
`
`

`
`potential for the tetracyclines. This promoted
`a renewed interest in this class of drugs.
`
`Nonanthnlrroblal Properties ofT
`Much of the early research investigating the
`nonantirnicrobial potential of tire tetracy-
`clines was done in the treatment of adult peri-
`odontitis.53 The tissue and bone degrading
`characteristics of periodontitis involve a pro-
`longed and excessive host
`inflammatory
`response to the presence of bacteria, which
`promotes the activity of matrix-degrading
`metalloproteinases (MMPS), as well as alter-
`ations in the metabolism of bone. MMPS are
`
`proteolytic enzymes produced by infiltrating
`inflammatory cells and resident connective
`tissue cells. These enzymes induce the exces-
`sive degradation of collagen,
`the primary
`structural component of the periodontal
`matrix. In combination with alterations in the
`
`relative capability of the tissues to form new
`bone, particularly in