minocycline pigmentation 2

Minocycline-Induced PigmentationIncidence, Prevention and Management

Drore Eisen1 and Miriam D. Hakim2

1 Dermatology Research Associates of Cincinnati, Cincinnati, Ohio, USA2 University of Cincinnati Medical Center, Cincinnati, Ohio, USA

ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4311. Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

1.1 Minocycline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4321.2 Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

2. Minocycline-Induced Pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4332.1 Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4332.2 Nails . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4342.3 Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4352.4 Thyroid and Other Viscera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4362.5 Breastmilk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4372.6 Skeleton and Cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4372.7 Ocular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

Summary Pigmentation is a well recognised adverse effect of minocycline therapy. Var-ious body sites, most notably the skin, nails, bones, thyroid, mouth and eyes areaffected and the pigmentation may appear at multiple sites. In general, pigmen-tation results from long term administration of minocycline at cumulative dosesgreater than 100g, although cutaneous or oral mucosal pigmentation may appear,regardless of dose or duration of therapy. When the skin is involved, the blue-black pigmentation develops most frequently on the shins, ankles and arms. Otherpatterns of skin involvement include pigmentation that is either generalised andsymmetrical, or that develops at sites of inflammation. The bones of the oralcavity are probably the most frequently affected sites of pigmentation affectinggreater than 20% of patients taking minocycline for more than 4 years. In contrast,the oral mucous membranes and teeth are infrquently pigmented from minocyc-line. Ocular, thyroid and visceral pigmentation is also relatively uncommon andusually develops only with high doses and long term minocycline use. Whereaspigmentation of the skin and oral mucosa is generally reversible when the drugis discontinued, the pigmentation is often permanent when other sites are in-volved. Although minocycline-induced pigmentation is not harmful, the drugshould be discontinued when the adverse effect is recognised. All patients receiv-ing minocycline, especially those treated for longer than 1 year, require screeningfor the development of pigmentation.

PHARMACOEPIDEMIOLOGY Drug Safety 1998 Jun; 18 (6): 431-4400114-5916/98/0006-0431/$05.00/0

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1. Tetracyclines

The tetracyclines, antibacterials with antimicro-bial, anti-inflammatory and immunosuppressiveproperties, are widely employed for the treatmentof acne, rosacea and a variety of other dermatolog-ical conditions.[1] Although once considered theantibacterials of choice for selected Gram-positiveand Gram-negative infections, their broad antimi-crobial spectrum make them valuable for the treat-ment of many infections such as atypical pneumo-nias, sexually transmitted diseases, traveller’sdiarrhoea, rickettsial infections, periodontal dis-ease and methicillin-resistant Staphylococcus au-reus (MRSA) colonisation.[2] In addition, a double-blind study has confirmed efficacy in rheumatoidarthritis.[3]

1.1 Minocycline

Minocycline is a semi-synthetic broad-spectrumtetracycline antimicrobial agent that was intro-duced in 1967. It is a popular member of the tetra-cycline class because of several advantages thedrug has compared with other tetracyclines. Inaddition to achieving peak serum concentrationswithin several hours after administration, it is wellabsorbed and possesses greater antimicrobial ac-tivity than other tetracyclines.[4] Also, orally ad-ministered minocycline hydrochloride is highlybound to plasma proteins and is lipid soluble, thusfacilitating penetration into body fluids (such assaliva, bile and breastmilk) and tissues (includingthe skin, brain, thyroid, fat and liver).[4,5] Bacterialresistance to minocycline is minimised by the highliphophilicity of the drug. Minocycline resistanceis mediated through chromosomally located Tetgenes, and occurs less frequently than resistance totetracycline which is mediated through Tet geneswithin a plasmid locus.[6]

1.2 Pigmentation

Pigmentation is a well recognised adverse reac-tion associated with all tetracyclines, with the ex-ception of doxycycline. For example, methacycline,a tetracycline used infrequently in the treatment of

acne, may, with prolonged administration, result ingrey-black pigmentation of nails, conjunctiva andsun-exposed skin.[7,8] Tetracycline hydrochloridehas also been reported to cause pigmentation ofteeth and nails[9,10] and osteoma cutis.[11]

However, of all of the tetracyclines, minocycl-ine is most often associated with the adverse effectof pigmentation, potentially affecting various or-gans and body fluids (table I). Although minocyc-line is a yellow crystalline material, its black deg-radation product may be deposited in varioustissues.[12] The accumulation of high concentra-tions of minocycline at various sites may, in part,explain the pigmentation that results with its use.

Although the safety of long term high-dosage(200 mg/day) minocycline for the treatment ofacne has recently been demonstrated, cutaneouspigmentation was the most frequently observed ad-verse reaction.[13] Failure to recognise this rela-tively common cause of pigmentation of the skinand other body sites may lead to unnecessary test-

Table I. Minocycline-induced pigmentation: sites of involvement(after Dummett and Barens,[44] with permission)

CutaneousSkin

Nails

Oral cavityTeeth

Mucous membranes

Alveolar bone and hard palate

OcularSclerae

Conjunctiva

Skeleton and cartilageVertebrae

Costal cartilage

Parietal bone

Alae nasi

Viscera and body fluidsThyroid

Substantia nigra

Aortic and mitral valves

Atherosclerotic plaques

Breastmilk

432 Eisen & Hakim

Adis International Limited. All rights reserved. Drug Safety 1998 Jun; 18 (6)

ing and confusion with other causes of pigmenta-tion.

2. Minocycline-Induced Pigmentation

As mentioned in section 1.2, minocycline canbe associated with the development of pigmenta-tion in a number of body areas.

2.1 Skin

2.1.1 Types of PigmentationMinocycline-induced pigmentation of the skin

is readily identifiable and 3 patterns of involve-ment have been well described (type I, type II andtype III).

Type IType I cutaneous pigmentation is characterised

by blue-black macules that are localised to sites ofscarring or inflammation.[14] Although the pigmen-tation appears predominantly on the face withinacne scars (fig. 1), it has also been reported at othersites of inflammation on the chest and legs. Thisdistribution was emphasised by Fleming et al.[15]

who described a patient with lepromatous leprosywho developed multiple blue-black lesions at var-ious sites of inflammation.

Pigmentation from minocycline followingsclerotherapy has also been reported, highlightingthe localisation of type I pigment to sites of inflam-mation.[16] Additionally, minocycline, like tetracy-cline, may cause pigmentation of post-acne oste-oma cutis.[17] These osteomas, which representmetaplastic bone formation, are rare complicationsof chronic acne and typically develop on the face.

Microscopically, pigment granules in type I pig-mentation, free within macrophages, have beenidentified in the dermis and consist of minocyclineor a minocycline degradation product chelatedwith haemosiderin, ferritin or iron.[14]

Type IIType II cutaneous pigmentation appears as

blue-black, brown or slate-grey pigmentation anddevelops on healthy skin, primarily the skin of theshins, ankles and arms (fig. 2). The staining mayappear to be either well circumscribed or diffuse.

The pigment is found in the dermis and subcu-tis, often in macrophages, where it may be mem-brane bound or freely scattered among dermal col-lagen fibres.[18] Although microanalysis hasrevealed the presence of sulphur, chlorine and cal-cium, the cutaneous pigment is thought to consistof insoluble complexes of minocycline or a mino-cycline oxidation product chelated to iron.[19-21]

Type IIIType III cutaneous pigmentation appears as

muddy-brown in hue and develops on healthy skinin a generalised and symmetrical pattern, accentu-ated in sun exposed areas.[22] The pigmentresembles a persistent, deep brown tan and mayresult from increased melanisation of the basal celllayer. Melanin or a minocycline-melanin complexwithout iron may be demonstrated microscopicallyin the epidermis and papillary dermis.[22]

Additional TypesA fourth type of cutaneous pigmentation has

been proposed by Chu and Van,[23] who describeda patient taking minocycline who developed darkbrown macular pigmentation of the lips. Micro-scopically, post-inflammatory changes were con-sistent with a resolving fixed drug eruption. Ridg-way and Reizner[24] observed similar clinical andmicroscopic features in a patient taking minocycl-ine.

Pigmentation can also be classified according toits distribution as either: (i) local, corresponding to

Fig. 1. Minocycline–induced type I cutaneous pigmentation de-velops most commonly on the face within acne scars.

Minocycline-Induced Pigmentation 433


Pigmentation can also be classified according toits distribution as either: (i) local, corresponding totype I; or (ii) diffuse, which typifies types II andIII. Patients may display features of several typesat a given time, and cutaneous pigmentation mayalso be accompanied by pigmentation involvingother organs.

2.1.2 IncidenceThe incidence of pigmentation resulting from

minocycline appears to be related to several fac-tors. Whereas the duration of therapy and total cu-mulative dose do not influence the onset of type Ipigmentation, types II and III pigmentation de-velop predominantly in patients who are treated forprolonged periods with high dosages of thedrug.[25] This is evidenced by reports of type I pig-mentation developing after only a few weeks ofminocycline therapy.[15,16] In contrast, types II andIII pigmentation generally do not develop until pa-tients have received a cumulative dose of minocyc-line exceeding 70 to 100g.[26,27] The intensity of thepigmentation does not appear to correlate with thetotal dose of minocycline or the duration of treat-ment.

Patients treated for rosacea develop pigmenta-tion from minocycline more often than thosetreated for acne.[25] This may be related to the olderage of patients with rosacea, who demonstrategreater age-related solar elastosis and receivehigher cumulative doses of minocycline than pa-

tients with acne. In the study by Dwyer andCuddihy[25] of 54 patients treated with minocyclinefor a mean duration of 17 months for acne or rosa-cea, approximately 15% (8 patients) developedpigmentation. Six of the 8 identified patients weretreated for rosacea and the remaining 2 for acne.These figures are in agreement with others whohave reported an incidence of pigmentation of 3%in patients with acne who were treated with mino-cycline for prolonged periods.[28]

2.1.3 ManagementPatients undergoing therapy with minocycline

should be informed of the possible adverse effectof cutaneous pigmentation and should be appropri-ately screened for its development. This is espe-cially true for patients treated for extended periodsof time with cumulative doses greater than 100g.

Fortunately, both type I and II pigmentation isharmless, but it may be unsightly and darken sig-nificantly if the drug is not withdrawn. In almostall cases, the pigmentation resolves after the drugis stopped; however, several months may elapsebefore complete resolution is achieved. In contrast,the diffuse muddy brown pigmentation observedwith type III pigmentation may persist indefi-nitely,[25,29] although, based on paucity of reportsin the literature and our own observations, this typeis the most rare.

Successful treatment of minocycline-inducedpigmentation without scarring or hypopigmenta-tion has been reported with a Q-switched laser.[30]

Management of pigmented osteoma cutis involvessurgical removal of the epidermal nodules or theuse of tretinoin cream for dermal osteomas.

2.2 Nails

Nail pigmentation caused by minocycline is un-usual and far less common than skin involvement.Although a number of colour changes have beenreported, a slate-grey discoloration of the proximalnail bed appears to be the most frequent type (fig.3).[31] Even more rare are longitudinal melan-onychia, diffuse nail pigmentation and photo-onycholysis.[32,33]

Fig. 2. The ankle is a common location for the development oftype II cutaneous minocycline-associated staining.

434 Eisen & Hakim


Generally, nail pigmentation develops concom-itantly with other sites of involvement and it israrely an isolated finding. Stimulation of nail ma-trix melanocytes with increased melanin deposi-tion in the nail plate has been described as the causeof pigmentation in longitudinal melanonychia.[34]

This is similar to the mechanism in type III cuta-neous pigmentation.

Pigmentation of the nail may persist for pro-longed periods despite withdrawal of the drug. Therecognition of these changes may avoid unneces-sary biopsy.

2.3 Oral Cavity

Minocycline may cause pigmentation of theteeth, the oral mucosal surfaces and the underlyingbones of the oral cavity.

2.3.1 TeethAlthough the incidence of tooth discoloration in

the erupted permanent dentition has been reportedto be as high as 6% in 1 retrospective study,[35] ourown experience and that of others reveal a muchlower rate.[36] In fact, we have only observed thistype of pigmentation in a few cases after treatingseveral hundred patients with minocycline, andonly when therapy was administered for an ex-tended period of years. When present, the discol-oration is greyish-blue. Unlike staining caused bytetracycline, which primarily affects the proximalthird of the tooth, minocycline staining is most ev-

ident in the middle portion of the tooth and occa-sionally involves the lower incisal third. The bluepigmentation is generally permanent, unless it ap-pears shortly after the initiation of minocyclinetherapy and the drug is promptly withdrawn.[37]

Some have suggested that the pigmentation ofthe teeth may be caused by either demineralisationand etching of the enamel by minocycline resultingin a persistent extrinsic stain[38] or deposition ofminocycline in dentin which becomes visiblethrough the enamel.[39] Since the concentration ofsystemically administered minocycline in the gin-gival fluid is 5 times that of serum,[40] pigmenta-tion near the gingival margin would be expected.Additionally, after the teeth erupt, dentin forma-tion is greatly reduced. Thus, both theories are in-sufficient to explain why minocycline but not tet-racycline cause erupted teeth to discolour.

Staining of the roots of teeth has been well doc-umented.[41,42] Indeed, our oral surgeons have fre-quently observed this during extraction of thirdmolars (wisdom teeth) from patients with acnewho were treated with minocycline during root de-velopment.

2.3.2 Oral Mucosal SurfacesReports of minocycline-induced pigmentation

affecting the oral mucous membranes are equallyrare and have included the buccal mucosa, gingiva,lips and tongue.[36,43,44] Although minocycline is theonly tetracycline associated with oral mucosal pig-mentation, its cause remains unknown. It has beensuggested that either a minocycline-metabolitecomplex or melanin, iron and calcium-containinggranules are the source of the pigment.[41] We haveobserved that the oral pigmentation develops atsites predisposed to oral trauma such as the tongueand buccal mucosa. The pigmentation appears tobe unrelated to the duration of minocycline therapyor the cumulative dose, and resolves completelywhen the drug is discontinued. These features areidentical to those described for type I cutaneouspigmentation (see section 2.1.1).

2.3.3 Bones of the Oral CavityWithout question, almost all cases of intraoral

pigmentation represent minocycline staining of theFig. 3. Minocycline–induced slate-grey pigmentation of the prox-imal nail bed.



underlying bones without involvement of the over-lying oral mucosal surfaces. As we recently re-ported, the incidence of intraoral bone pigmenta-tion from minocycline, at dosages of 100 to 200mg/day, is 10% after 1 year of therapy.[45] The in-cidence increases to 20% in patients taking mino-cycline for 4 years.

Based on these results, it is apparent that intra-oral bone represents the body site most often af-fected by minocycline-induced pigmentation, butthat it is also perhaps the most overlooked. Distinctblue or blue-black bone pigmentation, also knownas black bone disease,[46] is most evident beneaththe semi-translucent maxillary and mandibular an-terior alveolar mucosa (fig. 4). To visualise theseareas properly, the lips should be fully retracted andthe alveolar mucosa inspected. Involvement of thehard palate and lingual alveolar bone, however, isalso frequently observed. The pigmentation of thebone is probably irreversible in most patients be-cause of the formation of insoluble salts fromminocycline degradation.[47] When the drug is dis-continued, the intensity of pigmentation does,however, reduce significantly over a number ofyears.

2.3.4 ManagementThe recognition of minocycline-induced pig-

mentation in the oral cavity may avoid unnecessarytesting and confusion with systemic diseases thatmay also result in pigmentation. Like cutaneouspigmentation, oral pigmentation of the mucousmembranes or bones is innocuous. Although someauthors have advocated testing of renal and hepaticfunction to exclude the possibility of impaired ex-cretion of minocycline in patients with black bonedisease,[46] we do not feel this is necessary basedon our personal experiences with such patients whohave undergone laboratory testing without detec-tion of abnormalities.

2.4 Thyroid and Other Viscera

The development of a black discoloration of thethyroid gland associated with long term minocycl-ine therapy has been reported by many investiga-tors.[48-50] According to Landas et al.,[49] a black

pigment, which can best be described as neuro-melanin, accumulates normally in the thyroid withadvancing age. Minocycline may accelerate the on-set of black pigmentation of the thyroid. It has beenpostulated that minocycline may cause melanosiseither by acting as a premelanin substrate concen-trated in thyroid tissue, or by altering the amountof oxidative activity or oxidative products in thy-roid epithelium.[51]

In 1993, Enochs et al.[52] further characterisedthe black thyroid pigment as a polymeric productof the in vivo oxidation of minocycline by thyroidperoxidase. Taurog et al.[53] recently confirmed therole of thyroid peroxidase in the production ofminocycline–induced black pigment and, of fargreater significance, demonstrated the potent anti-thyroid effects of minocycline in vitro. These data,coupled with those of Alexander et al.,[54] who re-ported a patient with minocycline–induced blackthyroid and clinical and laboratory evidence of thy-roid hypofunction, prompted several investigatorsto suggest a need to monitor patients receiving longterm minocycline therapy for thyroid function. Al-though these have been the only studies that haveimplicated minocycline-induced pigmentation aspotentially harmful, it may be prudent to investi-gate thyroid studies in patients treated long termwith this drug.

Fig. 4. Minocycline–induced oral pigmentation of the underlyingalveolar bones visible through the semi-transparent alveolar mu-cosa. The mucous membranes are uninvolved.

436 Eisen & Hakim


In addition to the thyroid gland, minocycline-associated pigmentation has been reported in thesubstantia nigra and atherosclerotic plaques,[49] aswell as in aortic and mitral valves.[55] In all of thesecases, pigmentation was found incidentally, andadditional information regarding any harmful ef-fects of the pigmentation was not reported.

2.5 Breastmilk

Because of its lipophilic nature, minocycline ishighly soluble in body fluids and may be excretedin breastmilk. We know of only 2 cases that reportblack galactorrhoea in patients taking minocycl-ine.[56,57] The first patient developed galactorrhoeafrom phenothiazine, and after 4 years of takingminocycline 200 mg/day developed black breast-milk. The second patient, who had completedbreast feeding 18 months prior to her presentation,had been treated for only 4 weeks with minocycl-ine at a dosage of 150 mg/day before she notedsmall amounts of black milk. The milk of bothpatients demonstrated macrophages containingparticles that stained positive for iron. It was pos-tulated that the pigmentation consisted of an ironchelate of minocycline or one of its derivatives.[56]

2.6 Skeleton and Cartilage

Rumback et al.[58] reported a case of blackenedthoracic vertebrae discovered incidentally duringan elective neurosurgical procedure, without evi-dence of pigmentation elsewhere. The pigmenta-tion occurred in a woman who had a cumulativeingestion of minocycline of greater than 220g.Other patients who had been administered smallercumulative doses were noted to have pigmentedbones, usually in association with pigmentation ofthe skin and nails.[59]

Minocycline-staining involving other portionsof the skeleton, including costal cartilage, parietalbones and alae-nasi, were reported in a single pa-tient.[48] These findings occurred simultaneouslyafter treatment with minocycline 200 mg/day forover a year and were found concurrently with auniformly black thyroid.

The dark pigment in bone may represent a deg-radation product or a drug complex, and has beenshown to consist of a deposit containing iron andcalcium and resemble haemosiderin.[58,60]

The effect of minocycline on bone metabolismis unknown, although no adverse effects of mino-cycline on the structure or function of bone havebeen reported. Tetracycline is known to chelate cal-cium phosphate and bind loosely to polypeptidesin bone, but despite considerable accumulation ofthe drug in adult bone, no adverse consequenceshave been noted.[61] The metabolic effects of mino-cycline on bone require further investigation.

2.7 Ocular

Minocycline staining of the ocular structures in-cluding the conjunctiva and the sclera has been re-ported by several investigators.[18,62-64] Distinctpigmented changes involving the sclera include ablue-grey, 3 to 5mm band starting at the limbus,which is usually enhanced in the palpebral aper-ture.[65] Diffuse blue discoloration of the sclera hasalso been observed.[18] It has been noted that al-most all patients who report scleral pigmentationalso display pigmentation of the nails. Further-more, in addition to taking high dosages of mino-cycline for prolonged periods (exceeding 2 years),all patients exhibited type III, diffuse muddy-brown cutaneous pigmentation.

Subconjunctival, densely pigmented spots lo-cated on the inferior tarsal plate, hypothesised tobe conjunctival cysts, have also been noted in pa-tients taking minocycline.[18,66] These pigmentedabnormalities have been reported in both the pres-ence and absence of skin changes.

Pigmentation involving the ocular structuresmay resolve within years or it may persist indefi-nitely. Fortunately, no harmful effects of the pig-mentation have been reported.

3. Conclusion

Minocycline has been demonstrated to causedark pigmentation of various body sites, mostprominently the skin, nails, bones, thyroid and



eyes. Table II provides an overview of this adverseeffect.

In general, with the exceptions of type I cutane-ous pigmentation and intraoral mucous membranepigmentation which develop independent of doseor duration of therapy, all other minocycline-induced pigmentations develop after long term ad-ministration of the drug and high cumulative doses.Multiple sites of pigmentation are frequently de-tected. Since almost all cases of pigmentation de-velop in patients with acne and rosacea who havebeen treated long term, minimising the cumulativedose of minocycline by discontinuing the drug af-ter 6 months will avoid this common adverse ef-fect.

The pigmentation may lead to confusion if notproperly recognised and may result in unnecessarytesting to exclude other causes of pigmentation. Allpatients receiving minocycline therapy should becarefully screened for the development of pigmen-tation. In addition to a twice yearly examination ofthe skin, nails, eyes and oral cavity, some authorsadvocate thyroid function testing for those patientstreated with minocycline for longer than 1 year, orfor those receiving cumulative doses of greaterthan 100g. Additional research on the effects ofminocycline on thyroid function is required beforeroutine testing can be recommended.

Once pigmentation has been identified, the drugshould be promptly discontinued and substitutedwith an alternative antibacterial. Pigmentation ofthe skin usually resolves within months or years,although pigmentation of other body sites is morelikely to be permanent.

With proper monitoring, minocycline remainsan invaluable drug for the treatment of acne and avariety of other conditions.

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Table II. An overview of minocycline-induced pigmentation

Organ involvement Clinical features of pigmentation Effects of dose and duration of drug therapy

Skin

type I At sites of inflammation on face, chest and legs Does not influence onset

type II On healthy skin of shins, ankles and arms Cumulative dose >70-100g

type III Generalised, symmetrical on sun-exposed areas Cumulative dose >70-100g

Nails Slate-grey discoloration of the proximal nail bed Usually with prolonged therapy

Oral cavity

teeth Middle of tooth, occasionally the incisal third After years of therapy

mucous membranes Sites predisposed to trauma, e.g. tongue and buccal mucosa Does not influence onset

alveolar bone Beneath the semitranslucent maxillary and mandibularalveolar mucosa, and hard palate

Evident after 1 year of therapy; incidenceincreases with prolonged therapy

Thyroid Black discoloration of the thyroid gland Usually after long term therapy

Skeleton/cartilage Thoracic vertebrae, costal cartilage, parietal bones andalae-nasi

Usually after long term therapy

Ocular Blue-grey scleral pigmentation and subconjunctivalpigmented spots

After high doses for extended periods

438 Eisen & Hakim


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Correspondence and reprints: Dr Drore Eisen, DermatologyResearch Associates of Cincinnati, 7691 Five Mile Road,Cincinnati, OH 45230, USA.

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