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Exploring the role of modified-release doxycycline in rosacea.

Rosacea, a common dermatologic disorder that affects the central part of the face, is most prevalent in pale-skinned individuals of Celtic, Northern, or Eastern European background. The disorder is estimated to affect more than 16 million Americans. Among the factors contributing to the disease are a genetic predisposition, increasing age, emotional stress, alcohol, menopause, weather, UV radiation, and vasodilating medication. The disorder can present as persistent redness of the facial skin, dome-shaped red papules with or without pustules, and telangiectasia. In addition, because of its red-faced, acne-like effects on personal appearance, it can cause significant psychological, social, and occupational problems if left untreated. (1)

Although the etiology of rosacea remains unknown, inflammation is known to play a prominent role in its pathophysiology. According to Del Rosso et al, (2) collagen-degrading matrix metalloproteinases (MMPs) and proteases may be responsible for the inflammation occurring in rosacea, and drugs in the tetracycline family have been shown to inhibit MMPs, as well as reduce cytokine expression and inhibit serine proteases--two additional mechanisms that have been implicated in the disease.

Doxycycline, a member of the tetracycline family, has been proven effective in the treatment of rosacea because of its anti-inflammatory effects. (2) Unfortunately, doses of doxycycline 50 mg or above have also been shown to increase antibiotic resistance and alter the normal intestinal flora. A randomized double-blind trial in which 100 mg of oral doxycycline was given to healthy adults, for instance, found that at this dose, the drug increases the concentration of doxycycline-resistant nasopharyngeal flora in as little as 7 days. (3) Long-term administration of 40 mg of modified-release doxycycline, on the other hand, did not affect bacterial susceptibility over a 9-month period. (4,5)

In his review on antibiotic resistance as it applies to dermatologic practice, Rosen (6) further emphasizes the need for caution in prescribing long-term antimicrobial agents. He points out that "widespread antibiotic use for acne and rosacea has been implicated in the conversion of normal cutaneous saprophytes into drug-resistant pathogens." As an example, the author cites the fact that tetracycline-resistant Micrococcus luteus has been implicated as a cause of bacterial endocarditis.

By way of contrast, a subantimicrobial-dose (40 mg) modified-release formulation that combined 30 mg of immediate-release and 10 mg of modified-release doxycycline (Oracea[R]) has been proven effective in reduction of the total inflammatory lesions of rosacea.

Del Rosso et al, (2) for instance, found that 40 mg of modified-release doxycycline is just as efficacious as 100 mg of doxycycline during a 16-week trial and was less likely to produce adverse effects. Similarly, a community-based open label trial by Webster (7) has found that at 12 weeks on 40 mg of modified-release doxycycline, nearly 75% of the patients were clear or near clear, based on the 5-point Investigator's Global Assessment scale. This same open-label trial also demonstrated that a subantimicrobial dose of doxycycline improves patients' quality of life, as measured by a rosacea-specific quality-of-life questionnaire. (8)

To test the effects of modified-release oral doxycycline in combination with a topical agent, Fowler (9) administered 40 mg of modified-release doxycycline capsules (Oracea[R]) once daily with topical metronidazole 1% (MetroGel[R]). The combination was compared to placebo plus MetroGel in a double-blind fashion. Combining Oracea and MetroGel was found to be more effective than was placebo plus MetroGel, and combination therapy resulted in faster and greater reduction of inflammatory lesions than did MetroGel monotherapy.

This Journal Scan supplement to FAMILY PRACTICE NEWS summarizes some of the recent studies that have investigated the use of subantimicrobial-dose modified-release oral doxycycline. Our goal is to provide clinicians with a therapeutic tool for rosacea that is both effective and potentially more tolerable than other treatment options.

References

(1.) National Rosacea Society. What is rosacea? http://www.rosacea.org/index.php. Accessed January 24, 2012.

(2.) Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-576.

(3.) Walker C, Bradshaw M. The effect of oral doxycycline 100 mg once-daily for 14 days on the nasopharyngeal flora of healthy volunteers: A preliminary analysis. Poster presented at: 26th Anniversary Fall Clinical Dermatology Conference; October 18-27, 2007; Las Vegas, NV.

(4.) Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56:791-802.

(5.) Walker C, Webster G. The effect of anti-inflammatory dose doxycycline 40 mg once-daily for 9 months on bacterial flora: Subset analysis from a multicenter, double-blind, randomized trial. Poster presented at: 26th Anniversary Fall Clinical Dermatology Conference; October 18-27, 2007; Las Vegas, NV.

(6.) Rosen T. Antibiotic resistance: An editorial review with recommendations. J Drug Dermatol. 2011;10:724-733.

(7.) Webster GF. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads). Cutis. 2010;86(5 suppl):7-15.

(8.) Baldwin HE. A community-based study of the effectiveness of doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads) on quality of life and satisfaction with treatment in participants with rosacea. Cutis. 2010;86(5 suppl): 26-36.

(9.) Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, USP monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645.

Brian Berman, MD, PhD Voluntary Professor of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, and Co-Director, Center for Clinical and Cosmetic Research, Skin & Cancer Associates, LLP, Aventura, FL
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Author:Bernman, Brian
Publication:Family Practice News
Geographic Code:1USA
Date:Apr 15, 2012
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