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D O I 1 0 . 1 1 1 1 / j . 1 3 6 5 - 2 1 3 3 . 2 0 0 7 . 0 8 2 8 6 . x Efficacy of tetracyclines in the treatment of acne vulgaris:a reviewT. Simonart, M. Dramaix* and V. De Maertelaer  Department of Dermatology, Erasme University Hospital, 808 Route de Lennik, B-1070 Brussels, Belgium*Department of Biostatistics, School of Public Health, Universite´ Libre de Bruxelles, Brussels, Belgium Department of Biostatistics and Medical Informatics, IRIBHM, Universite´ Libre de Bruxelles, Brussels, Belgium Background Oral tetracyclines are routinely used for the management of inflamma- tory acne. However, there is a lack of evidence-based data on their relative effec- tiveness and appropriate dosages.
Objectives To assess the relative effectiveness and the optimal dosage of tetracyclines for the treatment of inflammatory acne.
Methods We designed a systematic review of the clinical trials (1962–2006) inves- tigating oral tetracyclines for the treatment of inflammatory acne. We obtained data from MEDLINE, PubMed, Current Contents, reference lists and specialisttextbooks.
Results There was substantial heterogeneity in the design of the trials. We identi- fied only seven randomized trials which were set up to compare the efficacy oftetracyclines in reducing acne lesion counts. These showed no evidence of superi-ority of one tetracycline over another. Overall, there was also no significantdifference between the available tetracyclines in terms of improvement in inflam-matory (32 trials, P = 0Æ898) and noninflammatory (23 trials, P = 0Æ429)lesions. In the range of investigated dosages, the antibiotic dosage had no impacton efficacy in inflammatory (P = 0Æ609) and noninflammatory (P = 0Æ654)lesions. There was no decrease in efficacy during the study period.
Conclusions There is insufficient evidence to support one tetracycline rather thananother in terms of efficacy. In the range of investigated dosages, the antibioticdosage seems to have no impact on efficacy. Despite increased resistance to anti-biotics, oral tetracycline formulations displayed no change in efficacy duringthe study period. Further studies are, however, required to determine if the anti-inflammatory properties of tetracyclines are sufficient in managing acne.
Oral tetracyclines are indicated for the management of moder- by climate (for example doxycycline, known to have the ate and severe acne, acne that is resistant to topical treatment, potential to cause dose-dependent photosensitivity, is less and acne that covers large parts of the body surface.1–3 commonly prescribed in southern Europe), by various phar- Despite major concerns over antibiotic-resistant acne in Eur- macoeconomic considerations, and by the lack of evidence- ope and in the U.S.A.,4,5 tetracyclines continue to play an based data on efficacy.1 It has previously been suggested that integral role in the management of acne1–4 and are considered the beneficial effect of tetracycline is due to the inhibition of as the first-line oral antibiotic therapy in acne.4,6 The most Propionibacterium acnes accompanied by a reduction in sebum free commonly prescribed tetracyclines are first-generation cyclines fatty acids and extracellular lipases. However, the effect of tetra- (tetracycline HCl and oxytetracycline) and second-generation cyclines on acne may be due not only to an antimicrobial cyclines (doxycycline, minocycline and lymecycline).1 Sec- effect but also to their ability to reduce neutrophil chemo- ond-generation cyclines have a better pharmacokinetic profile, taxis as well as on their inhibitory effect on cytokines and which has been thought to be associated with increased anti- matrix metalloproteinase (MMP)-9.7 Based on this contention, acne efficacy, but are more expensive.1 The preferred choice recent studies have shown that subantimicrobial-dose doxy- of cyclines varies greatly from physician to physician and cycline (40 mg daily) reduced the number of both inflamma- from country to country, which may be partly accounted for tory and noninflammatory lesions in patients with moderate Journal Compilation Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2008 158, pp208–216 Acne and tetracyclines, T. Simonart et al. 209 acne.8,9 No detectable antimicrobial effect on the skin flora quality indicators: year of publication or completion; and percentage of subjects not evaluated after treatment. Wher- Thus, although oral tetracyclines are one of the cornerstones ever possible, ‘intention-to-treat’ data were used in the analy- of acne management, several questions remain unanswered sis. Possible relationships between the duration of treatment (e.g. regarding the most efficient tetracycline, the optimal and the year of publication, and between the dosage and the dose of antibiotic, the optimal duration of treatment). Given year of publication, were investigated with Spearman’s cor- the high number of patients with acne treated with antibiotics, relation coefficients (rs) based on all (inflammatory and non- it is surprising that so little effort has been expended by clini- inflammatory) lesions. The efficacy of the treatment as cians, researchers, regulatory authorities and drug companies expressed by the proportion of reduction in inflammatory in determining guidelines for the use of tetracyclines in acne.
and noninflammatory lesion counts was compared between The aim of this study was to conduct a systematic review on the four groups of cyclines with Kruskal–Wallis tests. Possible the efficacy of first-generation cyclines, doxycycline, mino- relationships between the efficacy of the treatment and the cycline and lymecycline in the treatment of moderate to severe mean dose, treatment duration and year of publication were investigated with the use of a multiple regression (enter pro-cedure) for inflammatory lesions and for noninflammatory A systematic electronic search strategy was used to retrieve all clinical trials investigating therapy with oral tetracyclines forinflammatory acne published between 1962 and March 2006.
The following bibliographic databases were searched: MED- tetracycline treatment efficacy in inflammatory acne,11–58 LINE (National Library of Medecine), PubMed (National Library of Medicine) and Current Contents. Selected key words efficacy,28,37,39,45,46,54,58–80 10 trials investigating doxycycline were: acne (vulgaris), antibiotic, treatment, tetracycline, oxy- systemic treatment efficacy8,9,20,62,68,69,81–84 and seven trials tetracycline, minocycline, lymecycline, doxycycline and clini- investigating lymecycline systemic treatment efficacy,77,80,85–89 cal trial. Other sources were textbooks and the reference list 57 of which were included.8,9,12,14,16,17,19–21,23,25–38,41,42,44– 52,54,56–58,62,66,69,71,72,75–81,83–88 Trials were excluded for thefollowing reasons: combination with other topical or systemicdrug with antiacne efficacy,18,53,55,64,68,73,74,82,89 use of obso- Study selection: inclusion and exclusion criteria lete drugs,11,15,22 antibiotic treatment < 1 month prior to We considered all clinical trials investigating the clinical effi- the study or selection of cases unresponsive to other anti- cacy of oral tetracyclines (oxytetracycline, lymecycline, doxy- biotics,24,53,59,61,63,67,74 duplicate reports,70 specific forms cycline and minocycline) in patients with mild to moderate of acne (nodulocystic acne,43,65 oil acne40), cross-over inflammatory acne. Excluded were duplicate trials, trials on severe nodulocystic acne or on other specific forms of acne,studies that reported on fewer than six patients, studies on obsolete drugs (demeclocycline), studies investigating theeffect of antibiotics in combination with other therapies (topi- A huge profusion of outcome measures has been reported, cal retinoids, topical antibiotics, benzoyl peroxide, azelaic including various acne grade ⁄ severity scores, as well as doc- acid, salicylic acid, isotretinoin, hormones) or after failure of tor’s and patient’s global assessments (Table 1), reflecting the another antibiotic therapy, split-face design studies and studies difficulties in defining which objective features best reflect with insufficient data on effectiveness or with no quantitative treatment efficacy. The most commonly reported objective methods of measurement. Studies published in non-English outcome measures were decrease in inflammatory lesions and languages for which a published English translation was not decrease in noninflammatory lesions (Table 1). Lesion count available were excluded. In case of double publications, the was also the only objective outcome measure reported in most elaborate publication was selected.
older81 and more recent studies,83,84 making comparisonacross clinical trials possible. Of the 57 eligible controlled tri-als identified in this study, 35 (61%) incorporated a lesion count. Thirty-two trials incorporated an inflammatory lesion We extracted information on factors that we hypothesized a (papules + pustules) count and 23 trials incorporated a priori to be potential sources of treatment effect variation.
noninflammatory lesion count. There were 22 double-blind Those included the dosage and the duration of treatment.
studies,28–30,34–36,41,42,44,47,48,50,52,56,58,69,72, Instead of using quality scoring, which has well-described three placebo-controlled trials,8,9,81 six single- methodological shortcomings,10 we examined the following blind trials38,66,75,83,84,86 and three open trials.45,76,78 Studies Journal Compilation Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2008 158, pp208–216 210 Acne and tetracyclines, T. Simonart et al.
Table 1 Outcome measures used in clinical trials investigating systemic tetracyclines for acne Journal Compilation Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2008 158, pp208–216 Acne and tetracyclines, T. Simonart et al. 211 evaluating the effect of tetracycline, minocycline, doxycycline for doxycycline (between 40 and 200 mg), for which some and lymecycline are summarized in Tables 2–5, respectively.
trials investigated the effect of subantimicrobial doses of anti- Several studies were not considered because they included no biotics.8,9 The most commonly used dosages were 500 mg for reproducible assessment of efficacy or no quantitative data on first-generation tetracyclines (eight of 18 trials), 100 mg for lesion count.12,14,16,17,19–21,23,25–27,32,33,37,46,49,51,54,57,62,71,76,85 minocycline (10 of 13 trials) and 300 mg for lymecycline(three of five trials). An increase in antibiotic dosage overtime was observed for the first-generation tetracyclines (n = 17, rs = 0Æ733, P = 0Æ001), but not for doxycycline The duration of treatment varied between 829,34,36,38,42 and (n = 6, rs = )0Æ334, P = 0Æ518), minocycline (n = 14, rs = 2444 weeks for first-generation tetracylines, between 481 and )0Æ246, P = 0Æ397) or lymecycline (n = 7, rs = )0Æ100, 248 weeks for doxycycline, between 678 and 2466 weeks for minocycline and was 12 weeks in all trials on lyme- Relatively few studies investigated the effect of antibiotic cycline77,80,86–88 (Tables 2–5). The most common trial dura- dosage on efficacy. One double-blind, placebo-controlled tion was 12 weeks (39% of the studies for tetracycline, 50% study showed that subantimicrobial-dose doxycycline (20 mg of the studies for doxycycline, 69% of the studies for mino- taken twice daily) significantly reduced the number of inflam- cycline and 100% of the studies for lymecycline). The median matory and noninflammatory lesions in patients with inflam- study duration was the same (12 weeks) for all investigated matory acne.8 One double-blind study found that minocycline antibiotics. There was no significant change in study duration 100 ⁄ 50 mg was superior for the treatment of inflammatory over time (n = 45, rs = 0Æ273, P = 0Æ070).
acne than minocycline 50 mg.80 A dose–response analysis ofpooled data showed no significant effect of drug dosage onefficacy either for inflammatory lesions (n = 32, r P = 0Æ609) or for noninflammatory lesions (n = 23, rs = Because the drug dosage varied over the study period in some trials (i.e. higher doses during the first weeks and then lowerdoses), we considered the mean drug dosage over the study period. The mean drug dosage varied from 375 to 1000 mgdaily for first-generation tetracyclines, between 50 and There are very few randomized trials that were set up to com- 100 mg daily for minocycline, and between 150 and 300 mg pare one tetracycline against another. We identified three ran- daily for lymecycline. Higher dosage variations were observed domized trials that compared tetracycline with minocycline Table 2 Summary of trials evaluating the effect of tetracycline aData extrapolated from graphs. NR, not reported.
Journal Compilation Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2008 158, pp208–216 212 Acne and tetracyclines, T. Simonart et al.
Table 3 Summary of trials evaluating the effect of minocycline aData extrapolated from graphs. NR, not reported.
Table 4 Summary of trials evaluating the effect of doxycycline aData extrapolated from graphs. NR, not reported.
Table 5 Summary of trials evaluating the effect of lymecycline and that included lesion counts.28,45,58 The minocycline dos- twice daily,28 with tetracycline at a dose of 500 mg twice age was the same in those three trials (50 mg twice daily) daily58 or with tetracycline at an unspecified dose.45 Two tri- and was compared with tetracycline at a dose of 250 mg als found no statistically significant differences between the Journal Compilation Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2008 158, pp208–216 Acne and tetracyclines, T. Simonart et al. 213 two therapies,28,58 while the other found minocycline to be superior.45 This study was, however, conducted under openconditions and several methodological flaws can be identified The aim of this study was systematically to review the results (tetracycline dosage not specified, absence of information on of clinical trials investigating oral tetracyclines for the treat- dropouts, absence of measure of statistical dispersion, variable ment of inflammatory acne and to determine the relative assessment intervals). Three other trials, including no lesion effectiveness and the optimal dosage of these antibiotics. To counts but grade ⁄ severity scores,37,46,57 also failed to demon- evaluate the efficacy of a therapy is difficult because the inter- strate the superiority of minocycline over tetracyline. Mino- pretation of the results is dependent on comparison of data cycline was compared with lymecycline in three trials.
from many different sources, and is hindered by wide varia- Minocycline at a mean dosage of 50 mg,80 58 mg,77 66 mg80 tions in trial methodology. Several methods of efficacy assess- or 100 mg86 over 12 weeks was compared with lymecycline ment, including various grades ⁄ scoring systems, have been at a dose of 175 (mean)77 or 300 mg80,86 over 12 weeks.
reported for the past 30 years. Of the reproducible outcome One large multicentre, randomized, double-blind trial77 and measures identified in this review, lesion count has been most one randomized, single-blind86 trial found that the efficacy widely employed and tested over the past 30 years. Of the 57 of minocycline (mean dosage over 12 weeks: 58 mg77 or eligible studies investigating oral tetracyclines in acne patients, 100 mg86) and lymecycline (mean dosage over 12 weeks: 61% included a lesion count. The advantage of this outcome measure is that it has been used almost consistently across old Another randomized, double-blind study80 found that mino- and recent studies, making comparison across trials possible.
cycline 100 mg for 4 weeks followed by 50 mg for 8 weeks Variation in duration of the trials and assessment of the effi- was superior to minocycline 50 mg for 12 weeks or lyme- cacy by physicians at different time points may be another cycline 300 mg for 12 weeks in reducing the number of pap- factor hindering evidence-based practice. Most studies used ules, while no other clinically relevant between-treatment end points ranging from 8 to 12 weeks, which appears con- differences in lesion counts were present. Minocycline was sequent with the observation that the clinical effect of oral compared with comparable doses of doxycycline in one antibiotics typically requires 4–8 weeks.91 Although longer double-blind, double-dummy, randomized study [66 mg administration periods do not seem to be associated with (mean) for 12 weeks].69 Both drugs were found to be equally higher clinical efficacy, our results were adjusted for this effective in the treatment of acne vulgaris.69 The effect of cyclines on lesion count decrease has been Analogously, variation in antibiotic dosage across trials is analysed in a number of clinical trials that were not set up to another source of bias and inaccuracy. There is no consensus compare one tetracycline against another, making further on the optimal dosing of oral antibiotics in acne.91 The mean comparisons across trials possible (Tables 2–5). Overall, there drug dosage varied from 375 to 1000 mg daily for first-gen- was no significant difference between the available tetra- eration tetracyclines, between 50 and 100 mg daily for mino- cyclines in terms of efficacy in inflammatory (P = 0Æ898) and cycline, and between 150 and 300 mg daily for lymecycline.
noninflammatory lesion count (P = 0Æ429).
This study demonstrates that, within the range of the studied Neither the duration of the assessment, nor the drug dos- antibiotic dosages, low doses of cyclines were as efficient as age nor the year of publication had an impact on inflam- higher doses. This is in line with previous studies sugges- matory lesions (n = 32, multiple R = 0Æ139, P = 0Æ907) or ting that the beneficial effect of tetracyclines in patients with acne may be partly due to nonantimicrobial properties of P = 0Æ279). For inflammatory lesions, the partial correlation coefficients were: r = )0Æ006 (P = 0Æ976) for the duration showed that subantimicrobial-dose doxycycline resulted in a > 50% reduction in the number of acne lesions. Treat- r = 0Æ106 (P = 0Æ575) for the year of publication. For non- ment with subantimicrobial-dose doxycycline had no effect on inflammatory lesions, the partial correlation coefficients were: P. acnes or other microflora of the skin. It has been suggested r = )0Æ398 (P = 0Æ074) for the duration of treatment, that this antiacne effect of subantimicrobial-dose doxycycline r = 0Æ209 (P = 0Æ363) for the dosage, r = )0Æ042 (P = may be due its ability to reduce neutrophil chemotaxis as well 0Æ843) for the year of publication.
as on its inhibitory effect on cytokines and MMP-9.7 We also found that, despite dissemination of cross-resistant strains of propionibacteria,4 oral tetracycline formulations dis- played no change in efficacy during the study period. These A possible bias in the interpretation of the results could have results are in opposition with those found for topical ery- been a change in efficacy over time, as described for topical thromycin formulations,90 and may be explained by lower erythromycin.90 By contrast to topical erythromycin,90 oral resistance rates to orally administered tetracyclines or by non- tetracycline formulations displayed no change in efficacy dur- antimicrobial properties of cyclines.
There is a lack of evidence in the literature over the relative rs = )0Æ076, P = 0Æ674; noninflammatory lesions (n = 24), effectiveness of tetracyclines. Second-generation tetracyclines are known to have a better pharmacokinetic profile than Journal Compilation Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2008 158, pp208–216 214 Acne and tetracyclines, T. Simonart et al.
first-generation tetracyclines.93,94 Minocycline has also greater For this reason, it is difficult to extrapolate data from one antimicrobial effects on P. acnes than first-generation tetracy- country to another. From this perspective, only first-genera- clines and doxycycline, and higher lipid solubility,94 favouring tion tetracyclines appear to be unequivocally cheaper than the its bioavailability in pilosebaceous units. However, very few randomized trials have been set up to compare the efficacy of Overall, there is insufficient evidence to support one tetra- tetracyclines in lesion count reduction. Those trials focused on cycline rather than another in terms of efficacy. Thus, the the comparison of minocycline with tetracycline or with other choice of tetracycline for acne should be based on criteria second-generation tetracyclines. Of the seven comparative ran- other than efficacy, such as cost and safety profile. In the domized trials included, six found no difference in lesion range of investigated dosages, the antibiotic dosage seems to count reduction. We then analysed the effect of tetracyclines have no impact on efficacy. Despite dissemination of cross- on lesion count reduction in trials that were not set up to resistant strains of propionibacteria, oral tetracycline formula- compare one tetracycline against another. Overall, this con- tions also displayed no change in efficacy during the study firms that, on the basis of reduction in lesion counts, all tetra- period. Further studies are, however, required to determine if cyclines appear to be similarly effective. In particular, second- the anti-inflammatory properties of tetracyclines are sufficient generation cyclines, which are the most expensive regimens and have replaced tetracycline as first-line antiacne antibioticsin many countries,2 were not found to be superior to first- generation tetracyclines. When comparing trials both withinand across tetracycline class, the summary estimates often 1 Dreno B, Bettoli V, Ochsendorf F et al. European recommendations demonstrate substantial heterogeneity. It would be tempting on the use of oral antibiotics for acne. Eur J Dermatol 2004; 14:391–9.
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Increased male mating rate in Drosophila is associated withWolbachia infectionF. E. CHAMPION DE CRESPIGNY,*  T. D. PITT* & N. WEDELL* *School of Biology, The University of Leeds, Leeds, UK Centre for Ecology and Conservation, University of Exeter, Cornwall Campus, Penryn, Cornwall, UKThe maternally inherited bacterium Wolbachia pipientis infects 25–75% ofarthropods and manipulates hos


Servitude of Russia The historical information: The servitude - is literally from the Arabian language means the receipt, the obligation. It is known in Russia since 14 centuries and has figurative sense - oppression, dependence. Russian Judaism - Russian Judaism the heresy or the Novgorod-Moscow heresy connected to penetration Judaism in Orthodoxy,is known in Russia from 14-15 cent

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