BritishJournal of Dermatology (1980) 102, 443·
`Pharmacology and Treatment
`
`A double-blind trial of metronidazole versus
`oxytetracycline therapy for rosacea
`
`E.M.SAIHAN* AND J.L.BURTON
`Department of Dermatology, Bristol Roylll Infirmary, Bristol
`
`Accepted for publication 17 July 1979
`
`SUMMARY
`Forty patients with papulo-pustular rosacea were treated for 12 weeks on a random double-blind basis
`either with oxytetracycline 250 mg twice daily or with metronidazole 200 mg twice daily. Both drugs
`produced an improvement which was greater after 12 weeks than after 6 weeks, but there was no
`significant difference between them. Metronidazole appears to be a safe and etfective drug for the
`treatment of rosacea.
`
`The antibiotic metronidazole (Flagyl) has been shown to be significantly better than a placebo in the
`treatment of rosacea (Pye & Burton, 1976) but it has not been tested against conventional therapy;
`we have now performed a double-blind trial of metronidazole versus oxytetracycline.
`
`MATERIALS AND MBTHODS
`Forty patients with papulo-pustular rosacea were treated either with oxytetracycline 250 mg twice
`daily (30 min before meals) or with metronidazole 200 mg twice daily on a random double-blind basis,
`coded tablets being issued by the pharmacist. None of the patients had received antibiodes for 4
`weeks prior to the trial. Bachpatient was assessed before treatment by one author (E.S.), the severity
`of the papulo-pustules being graded as mild, moderate or severe. The patients were assessed again
`after 6 weeks' and 12 weeks' treatment and the patients' condition relative to the initial visit was
`independently recorded as 'worse', 'unchanged', 'slightly improved', 'moderately improved' or 'much
`improved', by the same doctor and by the patient. The patients were photographed in colour under
`standard conditions at each visit and after their final visit the three photographs were evaluated by the
`second author (J.L.B.). The two photographstaken during therapy were compared with the initial
`photographs and the changes noted were recorded in the same way. The independent opinions of the
`patient and two doctors were thus obtained at 6 and 12 weeks for each subject and a numerical value
`was assigned to each of the three opinions, as follows: worse (- I); unchanged ( o); slightly improved
`(1); moderately improved (2); much improved (3). The mean ofthe three opinions was then recorded
`and only then was the treatment code broken for the further analysis of the results.
`• Present address: The London Hospital, Whitechapel, London.
`0007-o963/8o/o4oo-o443 So2.oo
`<Ql198o British Associatlon of Dermatologists
`443
`
`Dr. Reddy's Laboratories, Ltd., et al.
`V.
`Galderma Laboratories, lnc.
`IPR2015-__
`Exhibit 1008
`
`I
`Exh. 1008
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`

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`444
`
`E.M.Sat'han and J.L.Burton
`T ABLE r. Degree of improvement in rosacea, ex-
`pressed on an arbitrary numerical scale (mean ±
`s.d.) described in the text
`
`Oxytetracycline Metronidazole
`
`6 weeks
`r2 weeks
`
`I·8 ±0'9
`2·6±0'7
`
`r·6±o·9
`2·3 ± r·o
`
`RBSULTS
`Twenty patients receiving oxytetracycline and eighteen patients receiving metronidazole completed
`the trial. The results (Table 1) show that both drugs produced an improvement, and there was no
`significant difference between them. Both drugs produced significantly more improvement after 12
`weeks than after 6 weeks (P<o·os). No side-effects were reported in either group, but two patients
`taking metronidazole failed to attend for follow-up after the initial visit.
`
`DISCUSSION
`Several groups have shown that metronidazole is an effective treatment for rosacea (Pye & Burton,
`1976; von Braun, Koester ·& Taube, 1978; Guilhou et al., 1978) and the present double-blind study
`has shown that the response to metronidazole does not differ significantly from that produced by
`oxytetracycline.
`The beneficial effect of metronidazole in rosacea cannot be explained since the cause of the disease is
`unknown. Metronidazole acts against a wide variety of protozoa and anaerobic bacteria, but it also has
`anti-infiammatm;y and immunosuppressive effects (Tanga, Antami & Kabade, 1975; Grove, Mahmoud
`& Warren, 1977).
`Metronidazole is a relatively safe drug, although it can occasionally cause alcohol-induced headaches
`by a disulfiram-like effect (Penick, Carrier & Sheddon, 1969) and neuropathy has also been reported
`(Coxon & Pellis, 1976). It has mutagenic effects in some bacteria (Voogd, van der Stell & Jacobs, 1974)
`but the significance of this in man is uncertain.
`Oxytetracycline is probably a safer drug than metronidazole for long-term use but the latter has the
`advantage that it is tolerated weil during pregnancy and has no adverse effects on the offspring (May
`& Baker, 1979) whereas tetracycline administered in the last trimester causes discoloration of the
`fetal teeth.
`We conclude that metronidazole is a worthwhile drug for the treatment of papulo-pustular rosacea,
`especially in patients who have not responded to tetracyclines, or for pregnant women in whom
`systemic treatment is essential.
`
`RBFBRBNCES
`
`VON BRAUN, W., KoESTER, H. & TAUBE, K.M. (1978) Metronidazole bei Rosazea. Dermatologische Monatsschrift
`Bildung, 164, I97·
`CoxoN, A. & PALLIS, L.A. (1976) Metronidazole neuropathy. Journal of Neurology_, Neurosurgery and Psychiatry,
`39, 403.
`GROVE, D., MAHMOuo, A.A.F. & W ARREN, K.S. (1977) Suppression of cell-mediated immunity by metronidazole,
`International Archives of Allergy and Applied Immunology, 54, 422.
`
`Exh. 1008
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`

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`Treatment of rosacea
`445
`GUILHOU, J,J,, MEYNADIER, J,, GUILHOU, E. & MALBos, S. (1978) Traitement de la rosacee par le metronidazole
`Nouvelle Press Medicale, 7, 1960,
`MAY & BAKER LTD (1979) Flagyl, Data Sheet Compendium 1979-80, p. 558. Pharmind Publications, London.
`PENICK, S.B., CARRIER, R.N. & SHEDDON, J,S, (1969) Metronidazole in the treatment of alcoholism. American
`Journal of Psychiatry, 125, 1063.
`PYB, R.J. & BURTON, J.L. (1976) Treatment of rosacea by metronidazole. Lancet, i, 12n.
`TANGA, M.R., ANTAMI, J.A. & KABADB, S.S. (1975) Clinical evaluation ofmetronidazole as an anti-inflammatory
`agent. International Surgery, 6o, 75·
`Vooao, C.E., VAN DBR STELL, J,J, & jAcons,J.J, (1974) Themutagenic action ofnitroimidazoles. I. Metromidazole,
`nimorazole, dimetridazole and ronidazole. Mutation Research, 26, 483.
`
`Exh. 1008