C UTANEOUS MEDICINE
`FOR THE PRACTITIONER
`A YORKE
`v
`• M EDICAL JOURNAL
`CAHNERS
`PUBLISHING COMPANY
`V OL48N0. 5
`N OVEMBER 1991
`
`Pseudohorn Associated with Basal Cell Carcinoma
`Philodendron-Induced Dermatitis
`Aquagenic Pruritus
`Complications of Ear Piercing
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1067
`
`Exh. 1067
`
`

`
`- THE-RAPEUTICS FOR THE CLitUCU(N
`
`NEW REPORTS 0 1\J TREATM ENT MODALI TIES OF
`POSSIBLE INTEREST TO PATIENT-CARI NG PHYSICIANS
`
`1 Seeond-Generation Tetraeyelines, A
`1 Dermatologie Oveniew: Clinical Uses
`and Pharmaeology
`
`Howard Maibach, MO, San Francisco, California
`
`Tetracycl ine and its de ri vative s are frc que ntly
`used in the tt·eatment of acne , soft tissue bacterial in-
`f~ctions, Lyme disease (bon-el iosis ), chlamydia l infec-
`hons, and respiratory tract infections . Seventl phat·-
`macologic and micn >bio log ical properties o f these
`antibiotics make the m particul arly s ui table for such
`~ses . First-ge nenttion te tracyc lines have long becn
`muse; howcvet·, the second-ge ne ration te tn tcyclines
`minocyclinc , doxycyclinc hyclate, and doxycycline
`monohydrate have also be come w ide ly prescribed,
`and can offer advantages to the de rmatologist over
`te tracyclinc.
`Thi s papc t· reviews the impot·tant phannaco-
`Iogi c and microbio logical characte ri s tics of these
`three commonly used second-ge ne ration te tracy-
`clines, and the irclinical applications in dc rmato logy.
`
`M inocycline and doxycyclinc . which are lc tracy-
`
`cline structur;tl an;1logs , ha ve bee n use d in human
`me dicine for twe nly- live ye;1rs . Uoxycycline ;md
`.
`rnmocycline <lre diffe re nti<lte d from the o ri gin<~ l
`te tracy-
`chnes by s truclural diffe rc nccs in pos itions !'i and 6 (doxycy-
`cline ) and by thc s ubstitution of a climelhylamino group in
`position 7 ( ntinocycline ). These subs titutions cause fcw
`Variations in lhe b;1ctc riologic propc rtie s, bul s i)..'llific mtly
`e nhance the ph ysicoche mic;tl and ph;1rmacokinetic prope r-
`lie s, in particular, incrcas ing the ir lipophilicity.
`These compouncls are obtaine d sernis ynthc ticall y
`.
`lrom oxytet rac ycline or methacycline and arc s ignificantl y
`more lipophilic th;m tc tracycline , which pc rmi ts c xce llc nt
`tissue pe ne lration. II ighe r lipophilicity results in a !arge vol-
`ume of dis tribution, s ubs tanlial bincling to pl<ls tml prole ins ,
`ancl rcabsorption in t he rc n;ll t:ubulcs ancl gas lrointeslin;JI
`tract. T his gives the drugs Ionge r e lim inalion half-lives. Ex-
`celle nl absorption ;1 ftc r or;tl adminis tration ;tllows the use o f
`low oral dosages and minimize s thc siele e ffc cts of le tracy-
`cline de rivatives on Lhe gas trointestin;1l lr<lCl.
`
`REPRINT REOUESTS to the Un1vc rs1ty ol Calilorn1n HOSfJII<ll, San
`Franc1sco . Calilorn1a 94 ltl 3 .
`
`l
`
`I )oxycycline is ;Jvail;lble in two forms: cloxycycline
`hyclate, <I s;ilt form combining doxycycline (;J we;1k basc ).
`hydrochloric acid (a s trong ;Kid), plus ctllanol ;mcl W<Jicr ;
`and the more recentl y ;1vaila!Jie cloxycycline monoh yclr;Jtc,
`which is doxycycline free base with an associated w;lle r
`molcculc.
`
`Pharmacologic Characteristics
`fl nlimicro/Jial Ac/i{)i/v--T he Lctracyclines an: b<Kieriostatic
`through their ability to inhibil prote ii1 synthesis. T his group of
`;mlibiotics is act ive against a broad n mge of gram-posit ive ;md
`gram -ne,gativc bacteria <J S weil as M ycofJ/IIS/1111, Ur('(fjJIIISIIIII.
`and Ch/amydi11.
`Ml';·hrmism o/lvliCm!Jilll Nesislrnm '-
`lnherent in thc
`usc of all antibiolies ·is thc appear;mce of rcsistant str;Jins of
`micro-organisms. Thc dcgrce of resistance is depenclcnl upon
`seve ral factors, including resislance of the host. conccntr;Jtion
`of the ;mtibiotic, ancl e vcn the location of Lhc IJ;Jcteri;l in thc
`body. As with other ;mtibiotics, resistant str;1ins of micro-or-
`ganisms h;1vc bee n observed wilh ;JII lctracyclines.
`l<esis l;mce to lctr;Jcycline is thought to occur as <I rc-
`sult of either an altered ribosome (;11! hough le tr;lcycline -rcsis-
`tant ribosomes havc yel to !Je isobtccl) or the prescnce of a
`pb smicl that de cre;1ses uptake of the antibiotic by the b;lctcri-
`um. 1 Resis t;mce is usually confc rrecl upon thc lxwte ria in the
`form of R -plasmicl s _:.~ . :;
`Resis lancc is dctined witllin thc parametc rs of thc
`rninirmun inhibitory concc ntr;ltion of ;1 clrug requircd to inllibit
`bacle rial growlh. Mitlimum inhibilory r once nlt"<ltion Ievels un-
`cle r '1 f-Lg/ml are dc lincd <ls "susceptiblc ," frorn 4 to I (:j p.g/ml
`as ''partially resist;mt," and leveJ:.; over l b f.L,g/ml <IS "resis-
`tant. "·1 T wo types of resis t;mce m;1y be idcnt ilied: a bro;Jd
`high-le vcl resisl;mcc Lo ;1ll tctr; Jcyclincs. and a lnodc r;lt e-levcl
`rcsistance in wlür h the minimum inhibitory conccntr;Jtion of
`various micro-org;misms incrc;1ses in rcsistance from lninocy-
`cline,
`through cloxycycline, de mcthylchlorll'lr;JcyclinL'. aml
`tct racycline to ox yte t racyclinc . r,, '' Organisms resist ;mt to Let-
`r;1cycline h;1ve been sho\ovn to be susce pt ible to cloxycyclinc
`;md minocyclinc . 1
`· " In some instances of progressive resis-
`t;mce. thc rninimum inhibitory cotlCL'Illr<Jlion for doxycyclinc is
`lower Lhan for minocycline. 7
`
`\'OI.I IMJ·: .Jx. NOV J·:MJII·:t<
`
`1 ~ 1~11 41 1
`
`Exh. 1067
`
`

`
`AbsorjJtion!Distribution- Doxycycline and minocycline
`are the best absorbed of the tetracyclines because of their
`high lipophilicity. This Iipid solubility facilitates the transport of
`the drug across lipid-rich cell membranes and allows far better
`tissue penetration than all other tetracyclines. Distribution in
`body tissues is widespread and weil documented. ', ~, H
`Absorption of orally administered doxycycline in a
`dose of 100 to 200 mg is greater than 80 percent, the mean
`values being closer to 95 percent. Doxycycline absorption is
`rapid, and is detectable in the blood fifteen to thirty minutes
`after administration. '· 9-- ll
`Minocycline is also 95 percent available following a 200
`mg lo~tding dose and maintenance dosages of 100 mg every
`twelve hours. Serum Ievels are detectable within one hour of
`administration. ~. H, 1 ~, 1 :J
`The major absorption site for both antibiotics is
`thought to be in the duodenum. 1 • ~ Several studies have
`shown that, at the same dosage, minocycline serum Ievels ap-
`pear to peak somewhat earlier (approximately two hours)
`than those of doxycycline (approximately three hours), while
`the peak concentration of doxycycline is higher (approximately
`7 f.Lg/ml) than that of minocycline (approximately 5. 5 f.Lg/
`mf). J.i, IS
`.
`. No difference has been found in the absorption or bio-
`availability of the two derivatives of doxycycline, the monohy-
`drate free base and the hydrochloride salt. 9, 16
`Fasting Not Required- Doxycycline and minocycline
`may. be administered with food or dairy products without
`causmg a ma]or reduction in absorption. Tetracycline absorp-
`twn, however .. is significantly infJuenced by food and dairy
`products. Welhng et al studied the inOuence of various test
`meals and Ouid volwnes on the relative bioavailability of com-
`memal formulations of tetracycline and doxycycline. Senffil
`Ievels of tetracycline were wliformly reduced by 50 percent
`by all test meals, whereas serum Ievels of doxycycline were
`reduced by only 20 percent. The 50 percent reduction in tet-
`racychn_e senffil Ievels was found to have clinical signifi-
`cance. 17 Leyden investigated serum concentrations of tetra-
`cychne and minocycline when administered with water, milk, a
`meal, a nd :300 mg ferrous sulfate, and fmmd absorption of tet-
`racychne. to be significantly decreased by administration with
`rmlk ( - b5 percent) <md food ( - 46 percent). Mi.nocycline ab-
`sorptJon was alfected less (27 percent and l:l percent reduc-
`tJon, respectJvely). IK
`Other studies have shown that the extent to which
`doxycycline and minocycline absoqJtion is reduced when ad-
`mmister~d w1th food or clairy proclucts is not clinically signifi-
`c.lilt l , .• , .l " ' I •\ 17
`'h \ I
`II
`. d
`.
`,.
`d I
`,.
`Je et1ze mmocyc me an
`c oxycyc me
`<
`•
`'
`'
`' --
`arc absorbecl at <I slower rate when taken with foocl than by a
`patlcnt who has fastecl. 2". " 6
`.
`.Bccause these antibiotics may be taken with meals,
`lhc lnctclcncc of gastric upset is reclucecl. 1• 2 Patient compli-
`<mce may bc cnhancecl in two ways: " reduction in gastroin-
`lcstJn;il dtslrcss, ;md the "mcmory jog" of taking their medicii-
`tlon Wllh~ for cx<mlplc, thcir evcning mcal.
`E lmnnalllin- Drug climin;tlion may occur via two
`routcs: mctabolism or cxcrc tion. Elficient clrug elimination is
`csscntl;il lo ;woid loxic <lccumulation in body tissues.
`. Me/(fbo!ism- No doxycyclinc melabolites havc bcen
`.
`lound 111 blood, urinc, or fcces. 1 • '' Minocycline is JXtrtially dc-
`griidcd lo lhrcc inactivc mct.abolilcs in the Ii ver. 2 • ' '
`fc'xrrelion-. J ~xcrction of Lct.racyclinc li1kcs pl;1ce pri-
`
`marily through glomerular filtration. l~enal excretion of doxy-
`cycline and minocycline takes place in the kidney to a lesser
`extent than tetracycline, and both have a higher ~astrointesti­
`nal excretion component than tetracycli.ne. 1 • ~. 9
`2 Both doxy-
`•
`cycline and minocycline concentrate in the bile, although this
`accounts for only a small portion of the administerecl dose,
`with primary gastrointestinal excretion resulting from secre-
`tion into tl1e Iumen.
`Consistent with tl1is elimination pattem, cloxycycline
`serum Ievels are only minimally affected in patients with renal
`insufficiency and require no adjustment in dosage. 1 • ~~ Minocy-
`cline elimination in patients with renal insufficiency also ap-
`pears to be little changed due to the small amount normally
`excretecl via tl1<1t route, although several studies have pre-
`sented conflicting data, some suggesting that a lowerecl dose
`may be warranted
`in patients with
`renal
`insufficien-
`cy. 2, 1:1, J~ ,n..; M
`Doxycycline and minocycline have a Ionger half-life
`than the other tetracyclines, with reported half-lives for doxy-
`cycline varying between fifteen and twenty-five hours, while
`the half-life of minocycline is reported to be twelve to sixteen
`hours. 2
`• 9
`
`Physiological Variables
`Age and Geneier--Sem
`and tissue concentrations of doxycy-
`cline in elderly subjects are h.igher than those observed U1
`young adults, and are thought to be due to decreased fecal
`elinlination. The clinical significance of this accumulation is not
`clear, but adjustment of the dosage is probably unnecessary
`due to the drug's low toxicity. Adolescents appear to require a
`higher dosage than adults, altl1ough t11e specific mechanism
`involved is not known. No data are available conceming tl1e
`use of minocycline in the elderly. 9
`There do not seern to be any gender-relatecl modifica-
`tions in the pham1acokinetic parameters of doxycycline. No
`data are available on nlinocycline. 9
`Pregnancy and Lactation- Doxycycline and minocy-
`
`cline are botl1 excreted in breast milk. 2• 9 Like other tetracy-
`cli.nes, doxycycline and minocycline are known to cause tooth
`cliscoloration (yellow-gray- brownish) during tooth develop-
`ment (last tri.mester of pregnancy, neonatal period, and early
`cllildhood). Use of tetracyclines should be avoided in pregnant
`and nursing women, <md in infants and young chilclren unless
`other therapeutic options are contrainclicatecl.
`DruK lnteractions- Doxycycline and minocycline ab-
`sorption is generally clecreased by antacids, although t11ey
`have less effect th<m on the other tetracyclines. Waiting three
`hours between administration of these drugs and an antaCt9
`II
`I t
`') I I .!.>
`.
`t
`.
`should enable clrug absorptlon to Je v1rtua . y comp e e. ·'
`'
`lron also inhibits the absorption of doxycycline and rninocy-
`cline, and shoulcl also only be administered after a thrce-hour
`interval.
`
`Adverse Reactions
`Somc uf the aclverse reactions associalecl with the use of sec-
`oncl-generation tctracyclincs are lislcd in Table I.
`Gastrointestinal- Nausea, vomiling, ;md cliarrhea arc
`lypical reactions that may occur with the tclracyclines, and
`appear to be close relatecl. 1 A ~'1
`Centntl Nervaus ~yslem-Minocy clinc can procluce
`
`412 l liTIS
`
`Exh. 1067
`
`

`
`TABLEI
`ADVERSE REACTIONS
`
`Potential Adverse Reactions~
`
`Drug
`Minocycline
`Doxycycline Hyclate
`Doxycycline Monohydrate
`
`Esophageal
`Injury
`
`-
`+
`-
`
`Vertigo,
`Vestibular
`Symptoms
`+
`-
`-
`
`Photosensitivity
`+I-
`+
`+
`
`Photo-Onycholysis
`+I-
`+
`+
`
`Tissue
`Pigmentation
`+
`-
`-
`
`clizziness, vertigo, or lightheadedness, which are apparently
`more common than those occurring after the administration of
`antihistamines, tranquilizers, sedatives, rifampin, penicillin,
`and the other tetracyclines. 1, 2' 3, 14, 19, 36-38 Patients who ex-
`perience this side effect should be cautioned not to drive or
`operate hazardous machinery while receiving therapy. 26
`These vestibular effects are rarely seen in patients taking
`doxycycline. 1, 39
`Other-Minocycline use, usually for prolonged peri-
`ods, has been associated with hyperpigmentation of skin, thy-
`roid, teeth, and hone. Pigmentation of the skin and mucous
`membranes occurs as a blue-gray discoloration at either the
`site of previous inflammation or in previously normal skin. A
`darker blue-gray or muddy brown discoloration rnay also oc-
`cur in areas exposed to the sun. This effect is reported to fade
`with time. Thyroid discoloration is not known to cause any
`dysfunction. 14, 40-46
`Of more concem, blood urea nitrogen concentrations
`during therapy with minocycline should be carefully monitared
`in patients with significant renal impairment due to the prod-
`uct's antianabolic activity. 14 Elevation in blood urea nitrogen
`levels in these patients appears to be dose related. 26 This
`problern has not been reported with doxycycline administra-
`tion. 1, 47-57
`Phototaxicity-Most currently prescribed tetracyclines
`are phototoxic to some extent. The mechanism of phototoxic
`reactions is not known, but may be associated with production
`of reactive oxygen radicals. Individual factors rnay also be of
`significance in the relationship of tetracycline derivatives and
`phototoxicity.
`Most phototoxic reactions are manifest as an exagger-
`ated sunbum or, more rarely, photo-onycholysis. The report-
`ed incidence wfth the use of doxycycline and minocycline is
`low (minoctcline, less than 2 percent, doxycyline, less than 5
`percent). 2, 4, 39, 58, 59 Doxycycline is widely used for the pre-
`vention of traveler's diarrhea in the tropics. The rate of re-
`ported photosensitivity is low. 60
`The relationship of tetracycline dosage, serum Ievels,
`and tissue levels with phototoxicity remains to be defined.
`Since this is a phototoxic and not an allergic reaction, there
`may be a dosage-dependent relationship. In the meantime,
`patients should be advised to minimize exposure to the sun
`while taking these antibiotics.
`Esophageal Irritation-The acidic doxycycline hyclate
`salt (pH 2 to 3) is one of the most common causes of drug-
`induced esophageal ulceration. Most patients who experi-
`
`enced esophageal ulcers reported that they had taken doxycy-
`cline with little or no water and then reclined. 61--63 The hy-
`clate formulation is soluble at neutral pHs; hence, should the
`tablet or capsule become lodged in the esophagus due to in-
`sufficient liquid intake, reclining after taking the medication, or
`due to an esophageal stricture, it will dissolve rapidly and can
`cause esophageal irritation or ulceration.
`Results of preclinical sturlies have shown that doxycy-
`cline monohydrate may significantly reduce the risk of esopha-
`geal injury due to its virtually neutral pH pro:file (pH 5 to 6).
`Furthermore, the monohydrate is not as soluble at esophageal
`pH, but is freely soluble in the gastric milieu, thereby dissolv-
`ing more slowly than other salts in the esophagus but rapidly
`in the stomach. The substitution of doxycycline monohydrate
`for doxycycline hyclate rnay therefore reduce the risk of
`esophageal adverse reactions, particularly for patients who
`may have clifficulty taking medication or following instruc-
`tions. 24, 61--64
`
`Clinical Uses
`Given the pharmacokinetics and in vitro spectrum of activity,
`the second-generation tetracyclines doxycycline and minocy-
`cline are ideally suited for treatment of two common derrnato-
`logic conditions: soft tissue infections and acne. In addition,
`doxycycline has been recommended by the Centers for Dis-
`ease Control as the drug of choice for the treatment of genital
`chlamydial infections and for L yme disease.
`The simpler dosage regimen of these two compounds
`compared with tetracycline (twice daily rather than four times
`a day) and lowered dose (200 mg instead of 1000 mg) may
`enhance patient compliance. Furthermore, a once daily sched-
`ule at reduced doses for the treatment of acne has come un-
`der investigation and appears to show promise.
`
`Skin and Soft Tissue lnfections
`Doxycyclines-Doxycycline has been shown to be effective in
`treating a range of soft tissue infections, including infectious
`ulcers, cellulitis, gangrene, and a variety of abscesses, due to
`its broad spectrum of antibacterial activity and high Iipid solu-
`bility. 1
`
`As part of a larger study, sixteen patients with acute
`traumatic infectious ulcers of the lower extremities were
`treated with oral doxycycline; :fifteen of the patients' condi-
`tions (94 percent) responded to treatment. ' 65 In another
`
`VOLUME 48, NOVEMBER 1991 413
`
`Exh. 1067
`
`

`
`study of soft tissue infections, primarily cellulitis and abscess,
`the dinical response was good in 81 percent of the patients,
`satisfactory in 16 percent, and poor in 4 percent. Staphylococ-
`cus aureus, beta-hemolytic StrejJtococcus, and Escherichia coli
`were the most frequently isolated pathogens and showed an
`excellent bacteriologic response. The small number of less fa-
`vorable responses resulted from cases in which Proteus, Kleb-
`siella, or Pseudomonas sp. were isolated. 1
`•66
`A further study evaluated combined intravenous and
`oral doxycycline in the treatment of soft tissue infection, pri-
`marily perirectal abscess, cellulitis, gangrene, and pedal or
`other superficial abscesses. A good clinical response was seen
`in 78 percent of the patients, 22.percent showed satisfactory
`results, and no clinical failures were noted. 1• 67
`Minocycline-Minocycline has demonstrated efficacy
`in soft tissue infections caused by Staphylococcus aureus, al-
`though tetracyclines are not the drug of choice in patients with
`any type of staphylococcal infection. 14
`Minocycline has also been successfully used in treating
`infections due to Mycobacterium marinum, although optimal
`dosages have not been established. 14• 68-72 Pyoderma gan-
`grenosum has been successfully treated with a higher dosage
`minocycline (300 mg/day) over an extended period of
`time. 14• 73, 74 Minocycline has also been used to treat myceto-
`ma and Serratia granuloma. 14
`75• 76
`•
`Acne-The use of antibiotics in the treatment of acne
`vulgaris is based on research on the interaction of hormones,
`sebaceous glands, and bacteria. Free fatty acids are generally
`considered the primary source of irritation, and are produced
`both in the pilosebaceous canals and on the skin surface by the
`hydrolysis of triglycerides in sebum. The hydrolyzing agents
`are lipases of aerobic coagulase-negative Staphylococcus epi-
`dermidis and anaerobic Propionibacterium acnes, both of
`which are flora of normal skin. Successful treatment of acne
`with antibiotics may prevent bacteriallipases from forming the
`irritant free fatty acids or may eliminate the causative bacte-
`ria. 77
`
`Tetracyclines have been used successfully for years in
`the treatment of acne. 77- 79 They are believed to lower the
`production of free fatty acids either indirectly by interfering
`with nucleic acid metabolism and protein synthesis, thus de-
`creasing the bacterial population and attendant lipases, or di-
`rectly by binding lipases so that they cannot hydrolyze triglyc-
`erides. In fact, botl1 processes may be involved. 77
`The doxycyclines and minocycline have an advantage
`over tetracycline because of their higher degree of lipophili-
`city/absorption. A lower dosage regimen than with tetracy-
`cline is tl,1erefore possible, providing for greater patient com-
`pliance. The ability of doxycyclines and minocycline to be ad-
`ministered with food further enhances patient compliance, as
`has been discussed already. The efficacy of doxycycline and
`minocycline in the treatment of acne will be summarized.
`Doxycycline vs. Placebo-In an early double-blind
`crossover study of sixty-two patients with acne vulgaris that
`com~ared doxycycline at 50 mg twice daily to placebo, Plewig
`et al 0 showed a highly significant improvement in the twenty-
`eight patients initially randomized to receive doxycycline (p is
`less than 0.001). During the four-week rest period, the twen-
`ty-eight patients initially treated with doxycycline showed sig-
`nificant worsening of their symptoms (p is less than 0. 05). In
`phase 2, the thirty-four subjects initially treated with placebo
`showed significant improvement (p is less than 0. 05) in reduc-
`
`tion of inflammatory lesions when crossed over to receive
`doxycycline. Patients receiving placebo in either phase 1 or 2
`showed no significant reduction in number of lesions.
`Another double-blind twelve-week study compared
`two dosa~es of doxycycline, 50 mg daily and 100 mg daily, to
`placebo. 8 After four weeks of treatment, 68 percent of pa-
`tients treated with 100 mg doxycycline were judged to be
`"cured" compared with 27 percent of placebo-treated pa-
`tients. In the 50 mg doxycycline-treated group, 72 percent
`were judged "cured" after six weeks of therapy compared to
`27 percent of those receiving placebo. At week twelve, the
`percentage of "cured" patients was 90 percent compared with
`89 percent for the 100 mg and 50 mg doxycycline-treated
`groups, respectively.
`Minocycline vs. Placebo-A double-blind crossover
`study was conducted in fifty patients with acne vulgaris. In the
`first phase, minocycline or placebo was administered to pa-
`tients: 200 mg daily for seven days, followed by 100 mg daily
`for five weeks. The two groups' treatments were switched
`for the last five weeks of therapy. There was a significant
`decrease (p is less than 0. 05) in baseline acne lesion counts in
`the group taking minocycline, while the decrease in placebo-
`treated patients was not significant. 14, 82
`Minocycline vs. Tetracycline-Minocycline has been
`compared in a number of studies to tetracycline in the treat-
`ment of acne and has been equally effective or superior in
`some respects. 14• 83-86 A few are summarized here.
`In one double-blind six-month study, 104 patients re-
`ceived either minoczcline 50 mg/twice daily or tetracycline
`250 mg/twice daily. 1 •84 Although there were no statistical dif-
`ferences between the groups in the number of patients who
`reached and maintained grade I (noninflammatory) status, a
`higher percentage of the minocycline-treated patients (92 per-
`cent) reached that status more quickly (sixty-three days) than
`did tetracycline-treated patients (75 percent at seventy-six
`days). Seventeen patients reported side effects; these oc-
`curred equally in the two treatment groups.
`In another study, fifty patients were treated with ei-
`ther 50 mg minocycline twice daily or 250 mg tetracycline
`twice daily for eighteen weeks. Eighty-six percent of the min-
`ocycline-treated patients and 80 percent of the tetracycline-
`treated patients exhibited a satisfactory clinical response.
`Two patients from each group experienced drug-related side
`effects. 14
`• 83
`Doxycycline vs. Minocycline-In an early study, 87 six-
`teen patients with acne were treated with either minocycline
`or doxycycline at 100 mg/day for twelve days. Both drugs
`appeared to have similar efficacy; no patients dropped out of
`the study due to adverse side effects.
`In 1988, Harrison completed an observer -blinded
`twelve-week study comparing doxycycline 50 mg/once daily
`to minocycline 50 mg/twice daily. 88 Treatment efficacy was
`considered good or excellent in 73 percent of the doxycycline-
`treated group compared with 84 percent in the minocycline-
`treated group; the difference was not statistically significant.
`Side effects were minimal in both groups; only one patient in
`the doxycycline-treated group and two patients in the minocy-
`cline-treated group experienced treatment-related side ef-
`fects.
`
`More recently, doxycycline and minocycline were
`compared in an open study over a twelve-week period, with
`100 patients receiving either doxycycline 50 mg once daily or
`
`414 CUTIS
`
`Exh. 1067
`
`

`
`50 mg minocycline twice claily.x!' Altending physicians evaluat-
`ecl the cloxycycline-treatecl t-,•roup as healecl or improved in 7l:l
`percent of the patients, ancl in l::\2 percent of the minocycline-
`treatecl patients.
`In another recent stucly, sl,xty-four p;1tients with acne
`were treatecl with either cloxycycline or minocycline <Il SO mg
`twice daily for the first four weeks, Lhen SO mg oncc cbily for
`the remaining eight weeks. '" ' A signilicant recluction of all
`types of lesions W<Is observed in a!J areas cluring the Lwelve
`weeks of treatment for both groups, with no statistie<d differ-
`ence occurring at any time between the cloxycycline-lreated
`and minocycline-trealed groups. Both p<Ilients ;md physici<ms
`ratecl the doxycycline therapy as dfective or very elkctive in
`l::\5 percent of the e<Iscs; this was true for minocydine in ll7
`percent and 90 percenl of the e<Ises <Is r;1tecl by physicians and
`patients, respectively. lnveslig;Ilors conclucled th;It cloxycy-
`cline and minocycline were equally dfcctive in the treatment
`of moderate to moder;Jtely severe <Icne vulgaris. Fivc patients
`(two in the doxycyclinc-treated group ancl threc in the mino-
`cycline-treatecl group) wilhclrew from the stucly clue to trcat-
`ment -relatecl side cffects.
`Chlamydia- Chl;ml ydi<I is thc most prcv;Ilent bactcrial
`sexuaJJy transmittecl disease in thc United States, with about
`four million cases occurrin,l( ;nmuaJJy. !' 1 in womcn, Chlmnydia
`trachomalis can Iead to pelvic inllammatory clise<ISe, which can
`further result in infertility ancl ;m increasecl 1isk of eclopic
`pregnancy. in men, C. tmchomrllis is the most comrnon cause
`of nongonococcal uretlu·itis, which can Iead to <Icute epidicly-
`mitis and reclucecl fcrtility. ''~ Chl;unydi<JI inJcctions clo not ;d-
`ways prcsenl symptornaLically or the symptoms lll<IY be mild;
`thus it is oflen rderrecl to as "Lhc silenl sexually lnmsmitted
`disease. "!':; ln fact, stuclies have shown that SO percent of
`male sexual p;1rtners of infcctecl women are asyrnptornal-
`ic. 9L, ~H
`
`Doxycycline is Lhe Centcrs for I lisease Cont:rol's ein ig
`of choice for the lre;Ilmcnt of Chlamydtil. Thc rcconnncncled
`re~-,rirn en is I()() mg twice d<Iily for sevcn cl;1ys. Because lhe
`tetr<tcyclines are contntindicated in pregnancy, crythro-
`mycin is lhe reconunencled drug for pregn;ml Jl<Ilienls. 'I!< Al-
`though minocyclinc is ;ilso ellcdivc ;1gainst C . lmclwmtilis. its
`association with vcstilmlar side dfccts ;md high cost h;Ive rc-
`stricled its use. '' 1
`
`Summary
`The ldracycline group of ;mtibiotics is usdul to lhc denn;Jt ol-
`ogist for thc lrca[!llCil[ of <ICnl', soft
`tissue infcctions, <lllcl
`chlarn ycli;L /\lthough first-.l(cncr;IlioiJ ll·tr;wycline rem;1ins use-
`ful, thc second-,l(encr<Ilioll tl'tr;lcyclinl's in the form ol minocy-
`d ine ;md doxycyclinl' hyclatL' ;mcl. IIIost rccently, doxycyciine
`monohydr;1Le, oller <I numiJl'r of <Idv;mta.l(cs ovcr tclracycline.
`Thc newcr td r;Icyclinl's h<1ve markeclly incrc;Ised bio-
`av;lilability, wc;1tly improvccl <Ibsorption in IIK· presencc of
`foods, and <I l>rm clcr r<lll,l(e of ;mt ib<Idcri;il <lctivity. The in-
`crcased bioav;Iii;Ibility allows for oncc-ci;Iily <Iclminislr;Ition in
`the lre<Illllenl of acne ;mcl a l wicc-d<Iily regimcn for soft Lissuc
`infcctions ;md chbmycli;L
`Doxycydinc i<Icks Lhe Vl'slibular side clfects of nlino-
`cycline, IJut h;1s <I hi,l(hcr incidcncc of exa,l(gerat cd sunburn
`reaclion Lh;m minocycline. With thc cxceplion of esoph;1ge;il
`injury, seen with the hyclate form IJut app;1rently <Iilsent with
`the rnonohyclall' form. the doxycyclines appc<Ir to bc identical
`
`to one <Inother <mcl closely comparable in efficacy to minocy-
`cline.
`REFERENCES
`1. Cunhii HA. Siblcy CJ\il, Ristuccia AM : Review doxyc·yclinc. l111·rlJn (t{
`Moml rt: 11 5· 1:35, 1 9:-l~ .
`2 . .fonas 1\11, Cunh;1 II/\: l(cview minocyclinc. 7/;r·r / Jn(t{ Jl1oml rt: U 7-
`1~ S . 1'1:-JL.
`3. Kruccrs A. lk nnct N: Thc llsc ol f\ ntibiotics. :Jrd cd. l'hib dd phiii . .11\
`Lippincott. 1979.
`4. Lcnncl l t• Eil. B;dows 1\ . llausk·r WJ .Ir. t'l al (l'ds): M ;HJu;d ol Clinic;d
`Mi<Tobiology. Washin).>;lon IJC. AnK-rir;m Society ol M icrobiolo.l,')'. 1'1:-JS.
`5. Scavizzi M 1(: Exist ;mcc dc deti X c;tr;,cti<rl's Lr;Hlsfcrahlt.:s dt• rcsist;mn ·
`;1ux tct rarydinc. / 11!11 !11.1"1 l'r!.,lmr 122: :l- 17. 1!172.
`6. Lcvy SH: l~csis t ; mcc to the tl'iracydincs. In. Antitnicrohial llru.~ l(t··
`sist;mn· (llry;m LI ~ . cd), p 19 1. Url;mdo. Florid;,, Araden tic Press.
`I'J:-Jrl.
`7. Lt'IJcck C. Fort cr "/.: Fnlplindlichkeit tl'lr;,zyklin·rl'sistentn h ;mkhcil·
`scrrcger des 111enshcn .t.>:c.~en tninozyklin und doxyzyklin. Sl11r 'r'1~· !11l'fl
`1/'r;t/;msrl;r HH: 11 2t(. J U'l. 1 ~1 74 .
`8. Macdon;tld II, 1\clly 1((;, Alll'n ES: l'h;um;tcokinct ic stmlics of minocy-
`clinc in m m. C/ii; 1'/;rmllrrm/ 7'/;rT I 1(: K:J2. 1'17:l.
`9. S;tivin S. 1-louin C: Clinic;tl ph;tnnacokinct ics of doxycydinc ;mcl 1nino·
`cydinc. Clri; 1'/;rmllttmk;i;l'l l S: :;s:J.:Hi6, EIKK.
`10. Fabrc J. Milt'l; E. l<;ilfopoulos 1'. el ;tl: Th~.: kinl'lics of ll't r;lcydincs in
`tn;m. l li.t.>;l'slivc ;tiJ:;orption ;md scnm1 conn·ntr;1\ions . • Sd;m/z Jlktll/ rJ·
`r/;r'll.wl;r 10 1: S'J:l<i'IK, I ~1/"1.
`11 . Lowcnt hal W. Vit sky ll L: Computc1· pro.w;un lor ;t double cxpoill'll·
`ti;tl L·qu;ll ion lo dctcmliltL' biolo.t.>;ic; tl n mst;mts. / 1'/;rmll .'>Ii :>ti: I ti!l-17:\.
`1%7.
`12. C 1rtwright AC. ll;,tlidd 111.. YL'ittk'r A. l'i ;tl: i\ cotnpa rison of lht:
`bimvail;tbilill" of minocydinc c·;qJsttll' :111d !ihn cmted t;dJict s. / .·1 1111imim/'
`..- J.,•r•llf.,· ( '/;mmllll"r 1: :; 17, I m:J.
`13. l.;ulg W: l'h&lllil<"okinctics of minocyclillL'. l 'l"l>l"L'L"dings of thl' M il li>·
`cydin<· Sympositttn, Ccnn;uty, I '171.
`14. I .t·dn l~.: l.;ti HII";Itoril's. Minot·in: 1ninon·cline hvdrochlmide. I ' IK7.
`15. (;reel l 1( . 1\ruwn .JI(. C:tl\"l·rt I(T : Th,· disJHisitionof four IL-t r;l<"l"t"iinl's
`in tH>rtml subjects. l:"111 j C '!ri1 / 'llillmm"O! Ii): ~- \ S-~:i\1. 1' 17ti.
`16. M; tl n l hor.~ i\S: 1\ioi!\";lib iJility or doxvcyd ine llll>ttOh\"(lr;liL'. c '11111/11
`/lrr·mj;,.;\0 7ti-C:O, Jl)K I.
`17. Wdliug I'C. 1\och 1'/\, L urt is Cl .. c\ ;d: lli<m';lil:thilily of lt-l r<~nTlinl"
`;md cloX\"l")'l"linl' in f; ISIL·d ;111d 11011 \;IS\l'd subjt'!"h . . ·fii//JJ//rmf,.·f.,•t'J//.,· ( /11 ··
`111olllr'l 11 11i2-·lti' l. I ' 177.
`18. Lcyden Jl: 1\ IJsorption of mi11ocydint· hydmt"illtll"idc· ;md ll'tr;H·vrlilll·
`livdrochlorick· . ./.·1111 .·fmt! / kmllflol U : :lOK<>I~. 1'1:-i:i.
`19. i\ llcn .IC: l'v!inlJt"\'clinl' . . I 1/11 !11/t"m Mn!:-::>: 1 :-l~. I <i7ti.
`20. F;dm· .1 . Mild; L. 1\; dkopoulos 1'. c\ ;d: Tlw ki1ll"lics of ll'l l·acyclin<" in
`tlliltl. Sylnpllsitll lt Oll lhc· llll"Cin nislll ol <ICiillll or illltibiotics. S;tragosa.
`( htobn '1. 1'170.
`21. llkhubo I I. FujinH>I o Y. ( lbmo\o Y. l"\ ;tl : l.'und;u JH'Ili;tl ;u1d ,·Jinic;d
`sl udics " " doX\"l"\"clilll". ( '111'1/lo!lll·mfii" II": 2 1 ti-~ 1'1. I %'1.
`22. Roscllbblt JE. lhrrt:t l .W. 1\rodil' .II.. L"i ;d: L'olltp;trison " f ,;, nlnt
`;tcl ivit y ;mcl d i11ic; d ph; m n<~n>log)· of do:-:\"l·yclinc· with othn ll't l·a,·v,·linl's.
`.·llllmllrm/, _· /p·lll.,· c '/;mmll11·r l%1i: U •t- J.\ 1. 1%7.
`23. Sch;1ch V<Hl Will l'm ll l'vl: SonJt· ph&nl;ll·<>killl'li<· ;,spl'l"i s <>f d<>wn··
`clim· llll'i;lbolisnl in 111;111. ( '/;r·mo//;nYI/11" ( 1/rr.w/) (.'>lr/>/11) \:\: -11 -:ill, I '1\i:-i.
`24. l';dle\1 1\ 1'. Smyt ll I·:C: Clinici:111's guidt· to ;,ntihiotirs. T l'tr;,cyt"iitw.
`1/r./ 1/wjl!lkr/ r\1): : ;:-;:,.;;~1\1, 1'10:-l.
`25. Willi:11ns I lll . O'l(,·illy W.l. il<>dml ( ;, ,., ;tl: 1\bsorption ol d<>:\\"1"1"< linl"
`fron1 ;1 c<>ntrollt-d rl"biS<' pl'llct ftll"t1H tl;,tiotl : thc inlltt<'ncL' <>f lood on bio·
`; l v<~ibbilitv. l!rilfJ/irJJ'lll Ihr('' JJi,j;os 11
`'l:l- lll:i, 1'111\1.
`
`\ 'OI.IIM 1·. -IK, N()l ' l ·:~.ult ·: t ~ I ~~~II 415