Cllnlclan's Quick Reference
`
`Subantimicrobial Dose Doxycycline for Acne
`and Rosacea
`
`on psychosocial development and the quality
`of life of those who suffer from it.1
`
`Rosacea is also a common, chronic dennatosis
`estimated to algfect at least 1 in 20 people-1n the
`United-States. The ma1onty are fair-sklpned,
`Caucasran women, aged 30—50 years old. One
`community 5‘de found 10% Of those 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.9
`
`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. cares-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 normal
`shedding and discharge through the follicular
`openingthecellsformamicroscopichyperker-
`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. oases. Overgrowth of
`this anaerobic organism, which is otherwise a
`normal constituent of the skin flora, occurs in
`
`loseph B. Bikowski, MD
`
`Acne vuigaris and rosacea present therapeutic
`Homflreflqaammof
`draiienges due to theirchronicit); potential for dis-
`W Md
`WWorm ligament, and psychosociai impact. Although
`W in mm distinct, bothoonditions have
`m I"
`_
`maim- inflammatory W“- Consequentiy,
`a H ”E imam
`topicai andsystemic antimicrobiai agents are rou-
`ESP?
`I
`tineiy prescribed for extended W5- Emergence
`.
`I Strut! ’
`Wk” ”1514““;
`of resistant strains of Proplonibacterlum acnes,
`Em
`adverse m, and compliance issues associated
`Wit-Tartan
`with chronic systemic tetracycline use have led to
`new treatment approaches. At suhantimicrobiai
`doses, tetmqmiines reduce inflammation via anti-
`coiiagenoiytic, antimatrix-degrading metaiiopm-
`teinase, and cytokine down-reguiating propertifi.
`Subantimicrobiai dose (SD) doxycydine (Periostat
`20mgjhasciinicaiutiiityinperiodontitisandhas
`hem investigated in a double-blind; piacdm-con-
`tniiied triai'in thetreatmentofmoderatefaciai
`
`acneaswreiiasinanopeniahdstudyinthetreat-
`ment of rosacea. The result: of suhantimicrohiai
`
`dosedoxycyciine treatmentineWtr-iaissupport
`its benefits and further investigation in acne and
`rosacea. (SKiNmed. 2003;2234—245)
`lrl2‘t‘Jt‘JJ Lelacq Camunicutiom, the.
`
`cue vulgaris is the most common
`chronic slcin disorder in the United
`I
`- Staten, affecting approximately 80% of
`persons at some pointbetween 11 and30years
`of age.1 In 1996 in the United States,
`the
`National Health Interview Survey reported the
`prevalence of acne was 26i1000 in persons <45
`years of age} Although the data in adults are
`sparse, one community-based study in England
`formd the prevalence of clinical acne in women
`>25 years was 12% and in men it was 3%.3 In
`addition to the economic costs of physician vis-
`its,‘ medications, and over-the-oormter treat-
`
`the lipid-rich environment of the pilosebaceous
`units containing microoomedones. The host
`ments,5 the disfigurement and permanent scar-
`inflammat
`res me to P. acnes causes
`‘
`from amecanalsohaveanadverseim
`SKINmed: Dermatol
`for the Clinician (ISSN 1540-BI’40) is
`blished bi-month
`(Jan; Mac; Ma ; lu ; Se
`.; Nov.)
`Le lac Communications, Inc., Th
`jacq Communications, inc. NI ri htspigserved. No part 0 his publicationhaylybe mplgroducedbgr transgritted i
`'
`jIle . Amneal 1 060
`1'254' ht© 2002 by
`, without permission in writing from the publisher. The facts, 0 ‘nit
`|
`my recording; or any inionnation storage and retrieval
`Amneal v. Supernus
`reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`rah Howel at showell@i
`arm on not necasari
`|PR2013-00371
`
`
`
`1
`
`

`

`damage to and rupture of the follicular wall
`which extends the inflammatory process into
`the surrounding dermis, resulting in the forma-
`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. 1’10
`
`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-
`tules), the clinical signs of rosacea.ll 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.12
`
`Extravasmlar fluid from the flushing reaction
`accumulate in 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 acfinic
`exposure is probably a common cause of lym-
`phatic failure. The upregulafion of proteolytic
`activity during inflammation, along with neu-
`trophfl infiltration, exacerbates the degrada-
`tion of elasfin. Neutrophfl elastase and gelati-
`nase, from a variety of cellular sources, are
`capable of degrading the type IV collegen in
`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).11
`
`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. ln 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}1
`
`Medtarlsm of Action of Anflnlcrohlds In
`
`Ante. The nrulfifactorial nature of acne ideally
`requires an agent with a variety of
`mechanisms, exerting an effect
`not only on the bacteria but also
`on the inflammatory host
`response induced by the bacteria.1
`Certain antimicrobials 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
`chemotacfic factor); reduce lipase producfion in
`Ramosresultinginareducfionoffattyaddsin
`sebum on the skin surface-13'l4 affect comple-
`ment pathways, down-regulate inflammatory
`cytokine production,- and inhibit host col-
`lagenolytic activity. These pleiotropic properties
`haveledtothewidespreaduseoftetracydinrs
`for the treatment of acne.
`
`Systemic Antimicrobial 111erapy
`Systemic antimicrobial therapy is generally
`more effective than topical therapy presum-
`ably because the drugs penetrate the follicle
`more readily. Oral anfimicrobials are indicated
`for persons with moderate-to-severe acne, per-
`sons with inflammatory acne in whom topical
`anfimicrobials 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 hyperpigrnentation).lo
`
`'Ihemostoommonoralantimiaobialsusedare
`
`tetracycline HCl, doxycycline, and minocycline.
`The selection of an anfimiaobial is typically
`
`2
`
`
`
`SKINmed: Dermatologyfor the_Clinician (ISSN ‘IS40-9?40)Is published bi--monto?( (Jan; Mar; May; luly; Sept; Nov.) by Le lacq Communications, Inc, Three PaHslands Drive, Darien, CT 06!
`Copyrig'July“Kit-(5051' 2005
`‘
`Ml rights reserved. No part mis publicah'on may be reproduced or transmitted'In any form or by any means, electronic
`1255 hanical,
`photocc
`| retneval system, without permission in writing from the publisher The facts, 0 nions and ideas expressedIn this publicatio
`use of ti
`and do not necessanry reflect those or the tortors or Publisher For copies in excess of 25 or for commercial purposes, please contact
`rah Howe] at showeil®lejacqcom or 2036.30. I I I 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 HCI. 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 HCl.
`In addition, their increased half-fife allows once-
`
`or twice-daily dosing, potentially facilitating
`patient adherence to the dosing regimen. 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
`
`Therapyforrosaceausuallyconsistsofacembi—
`nation of topical and oral antimicrobials.ll
`Papules and pustules in rosacea are generally
`eliminated with systemic antimicrobials, such as
`tetracycline HCl, and remission can be main-
`tained to some extent with topical treatment,
`such as metronidaaole.” Approximately 25% of
`patients relapse within 1 month after discontinu-
`ation of active therapy, approximately 50% to
`60% at 6 months, and approximately Whitby 1—4
`years in the absence of maintenance therapylm?
`The literature concerning rosacea is even more
`sparsethanthatofaaie,but'lablel]]smnmarizrs
`some of the few comparative studies that have
`been done with tetracyclines in rosacea.
`
`Drawbacks of Long-Term
`Standard Dose 11Ierapy
`111a thlem ofm The widespread use
`of oral antintiaobials for long-term acne thera-
`py has resulted in the development of resistant
`strains of P. acnes. There is a clear association
`
`between the emergence of resistant P. acnes and
`the therapeutic use of these antimicrobials.13-19
`speculated that the difference is related to the
`Resistance of P. cares to tetracyclines increased
`
`
`for the Clinician (ISSN ‘|_540-9?40)Is published bi-month
`(Jan; Mar; May; luly; Sept; Nov.) by Le lacq Communications, Inc, Three Pardands Drive, Darien, CT 06!
`SKINrned: Dermatol
`
`or mechanical,
`jacq Communications inc. All ri hts reserved. No part
`mis publication may be reproduced or transmittedI
`17256
`ht Q 2002 by
`n are those of ti
`luly- Auqusr 2005-
`rpy recoroin
`or any information storage and retneval
`without permission in writing from the publisher The facts, 0 nit
`
`reflect due of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`'dnu on not necessan
`rah Howel at showell@lejacq.com or 203656 1711 x106
`
`
`
`tion,” demonstrating the effect of an antimi-
`crobial regimen of tetracycline use in acne ther-
`apy on bacterial resistance.21
`
`Overall resistance of P. cores 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,
`dindamydn, tetracycline HCl, doxycycline, and
`trimethoprim are the most common.“I3 The
`Minimum Inhibitory Concentrations (MICs) of
`tetracycline required to kill 50% of a population
`ofP.ormtesflsdICm)aretypicallyl'righerthanMICso
`for doxycydine, which are typically higher than
`those of minocydine. Eady et al” found that
`tetracycline-resistant organisms were cross resist-
`ant to doxycydine but susceptible to minocy-
`cline. Because resistance to mimcydine was
`rarely observed, minocydine has been the pre-
`ferred tetracycline for use in acne.” More recent-
`ly, high-level resistance to minocydine (MICSO,
`4—16ugme)hasbeenformdinpormlationsin
`the United States.26 While P. cores resistance per
`seisnotamaiorpublichealthconcern,theabili—
`ty of microbes to pae resistance from one to
`another is well known, and even more important
`is the observation that resistance determinants
`
`cance-travel,resultinginthepotentialforspread
`of multiantibiotic resistance with potentially dev-
`astating effects in clinical practice?”
`
`One strategy designed to minimize the develop-
`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-inflam-
`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 susceptibility.
`
`Other Adverse Consequences of Long-Term
`Tetracycline Therapy. Based on available infor-
`mation, there are more reports of serious adverse
`events associated with the use of minocydine
`than with tetracycline HCl or doxycydine. It is
`
`3
`
`

`

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`thedinician (I§SN ‘I_S40-9?40) is published bi-rnonth
`(Jan; Mar; May; July; Sept; Nov.) by Le lacq Communications, Inc, Three Paddands Drive, Darien, CT 06!
`Co
`Ml rights reserved. No part
`IFy
`, electronic
`produced or transmitted in any form or by any means
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`257 hank-3|,
`O
`use of ti
`Auqusr 2005
`pyn'g'juiy
`photocc
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`E]
`rah Howel at showelltiflieiacqcnm Dr 203.630. I I I l x106.
`and do not necasaniy reflect those of the tdltOl'S or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`
`mug—H02
`
`4
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`
`
`
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`reserved. No part 0 this publication may be reproduced or transmitted i
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`2005in02rrénemclgsaeni§fli
`July . Auqusr
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`system,
`without permission in writing from the publisher. The fa
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`eflect those of the Editors 0r Publisher. For copies in excess of 25 car for commercial purposes, please contact
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`5
`
`

`

`
`
`Table III. Efficacyof’retracycllnes in Rosacea
`
`STUDY RESULTS DESIGN EFFICACY MEASURES
`
`
`
`
`Snedslon, I966
`Tetracycline vs. placebo;
`78 pts, all degrees of
`severity
`
`Urabe, 1976
`Doxycycline or
`tetracycline;
`9 pts perioral dermatitis
`(red papules);
`16 rosacea-like
`dermatitis (all stages);
`19 rosacea
`
`Tor-maul, I997
`Doxycydine vs. clari;
`40 pts
`
`Tetracycline (n=36)
`250 mg b.i.d
`vs.
`Placebo (n=42) x 4 wk,
`are: all tetracycline 250 mg
`.I.
`.
`
`3-yr period
`All previously txd topical
`fluorinated steroids
`discontinued
`Doxycycline or tetracycline
`(dosage not given) for 2—3 mo;
`concomitant oral prednisolone
`5—15 mqu 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
`
`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
`
`1.06 (mild SE5)
`
`Disappearance of pustules, flattening of
`papules, diminution of eryflrema
`(assessment not described)
`
`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 efficacyo (no efficacy);
`1 (low); 2 (traceable); 3 (mild); 4
`(good); 5 (high);
`Tolerability score 0 (no SE5); 1
`(occasional); 2 (many sxs); 3 (mild SE5);
`4 (sev SB); 5 (very sev, discont)
`
`Afterl month:
`Tetracycline 78% improved;
`Placebo 45% improved
`After 2nd month:
`Tetracycline 50% improved;
`Placebo (now txd wim
`tetracycline) 74% improved
`7,!9 with perioral dermatitis =
`healing and full remission
`14l16 rosacea-like dermatitis =
`healing and full remission
`141'19 rosacea = clinical
`improvement
`5 = complete cure
`
`Pt 1: cleared eruptionsingwk;
`Pt 2: marked ~L erythema +
`lesions after 4 Wlts; '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
`Papules: i mean score 3.8—0.2
`Pustules: J. mean score 3.8-0.2
`Efficacy mean score:
`Clari: 4.8
`Tolerability
`Doxycycline: 4.2
`Clari mean score: 0.32 (occas SE5)
`Doxycycline mean score:
`
`Clari=Clarithromycin; txd=prescribed; SE=side effect; sev=severe; discont=discontinued
`
`an amino acid side chain with potential to form
`a reactive metabolite. Neither tetracycline HCl
`nor doxycydine contains the amino acid side
`chain; therefore, the hypersensitivity reactions
`associated with minocycline may be specific to
`this antimicrobial.28 In vitro studies have
`
`demonstrated the presence of a minocydine-glu-
`tathione conjugate when minocydine is incu-
`bated with hypochlorous acid, as is found in
`neutrophils. When a reactive metabolite is gerr-
`erated, ghrtathione transferase acts to detoxify
`this product. The presence of minocydine-
`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.29
`
`Adverse Events Associated With
`
`Acne Therapy
`Tetracycises as a Class of Antlnicnoblals. 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.30
`
`Prescribing information for all tetracyclines
`warns that they can cross the placenta and
`have shown evidence of embryotoxicity with
`
`
`
`(Jan; Mac; May; July; Sept; Nov.) by Le lacq Communications, Inc, Three Paddands Drive, Darien, CT 06!
`SKINmed: Dermatology for the Clinician (ISSN ‘IS40—9?40) is published bi-month
`t’Zopyrig'J'Ul‘y ‘.‘ Kuqust ' 2005
`'
`"
`'
`Ml rights reserved. No part 0 this publication may be reproduced or transmitted in any form or by any means, electronic
`hanical,
`photocc
`| retrieval system, without permission in writing from the publisher: The facts, 0 ‘nions and ideas expressed in this publicatio
`use of ti
`and do not necasanly reflect those of the tortors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`rah Howel at showell@leiacq.com or 203.630. r I r 1 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.31
`
`Tehacydne HCI. Tetracycline HCl has been
`implicated in an increased incidence of
`esophageal ulceration,” particularly when
`administered in capsule form. The use of
`tetracycline HCl has also been associated with
`the development of pseudotumor cerebri in
`adult and pediatric patients33 and in patients
`receiving concomitant isotretinoin therapy.“
`
`Dmycyclhe. 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. ‘5
`
`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-tenn 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, adjtmctive 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.36
`
`IInocycllne. 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}?!33 These effects arise because the
`
`lipophilicity of minocycline results in some
`
`degree of blood-brain barrier penetration.
`
`Hyperpigmentation or a bluei'black 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-
`dromeshavebeendescribedinpatientstaldng
`minocydine for acne. Drug-induced lupus and
`hepatitis are the most common reactions and
`except for serum sickness (mean time to occur-
`rence: 16 days); these syndromes typically pres-
`ent after prolonged use (mean time to occur-
`rence: 25.3 months)."2-“‘3 Coexistent minocy-
`cline-induced lupus erythematosus and autoim-
`mune hepatitis after long-term use (4—121)
`months) occurred at close ranges of 50—200
`mg/day.“‘1 Hepatitis with minocycline use is
`most often associated with hypersensitivity syn-
`dromes or delayed autoimmune hepatitis.“"5
`
`Case reports of pnelunonitis,451ymphadenopa-
`thy, and an infectious mononucleosis-type
`reaction“ have been reported. Rare cases of
`pseudotumor cerebri (idiopathic intracranial
`hypertension)48 associated with long-term
`minocycline treatment (4 weeks—18 months)
`have occurred.“49 Long-term administration
`in rat studies resulted in evidence of thyroid
`tumor production and thyroid hyperplasia in
`rats and dogs.31 Based on reports of adverse
`drug reactions, Gough et a1.” recommended
`that safer alternatives than minocycline should
`be considered for treating acne.
`
`A New 111erapeutic Option—
`SD Doxycycline
`Within a decade of their discovery in 1947,
`tetracyclines were widely used as anti-infec-
`tives and for the treatment of acne.51 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.52 This finding
`spawned an extensive series of experiments
`to elucidate the nonantimicrobial properties
`of tetracyclines, suggesting a new therapeutic
`
`
`
`$Kleed: Dermatol
`1240 ht Q 2002 by
`|
`up}; recordin
`'dnu on not necessan
`
`(Jan; Man; May; luly; Sept; NOV.) by Le lacq Communications, Inc, Three PaHslends Drive, Darien, CT 06!
`for the Clinician (ISSN 1540-9?40) is published bi-month
`jacq Communications, inc. All ri hts reserved. No part
`dais publication may be reproduced or transmitted i
`'
`luly . AUQUST ' 2003: or mechanical,
`without permission in writing from the publisher. The facts, 0 ‘nit
`n are those of ti
`or any information storage and retneval
`reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact
`rah Howel at showelltelejacqrom or 203.6561 ?11 x106.
`
`7
`
`

`

`potential for the tetracyclines. This promoted
`a renewed interest in this class of drugs.
`
`Nonantbnlcmblal Properties of Tetracyclnes.
`Much of the early research investigating the
`nonantimicrobial potential of tile 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 patients with certain spe-
`cific risk factors and underlying systemic dis-
`ease processes, this ultimately leads to the net
`loss of connective tissue attachment and sup-
`porting alveolar bone, the latter being the sig-
`nature event of periodontitis.“ In vivo and in
`vitro studies in humans and animals found
`
`that tetracyclines can independently inhibit
`MMP activity and stimulate new bone forma-
`tion,
`thereby preventing connective tissue
`breakdown and contributing to the preven-