Effect of NFX-179 MEK inhibitor on cutaneous neurofibromas in persons with neurofibromatosis type 1.

This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle (P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume (P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.

Fibronectin fiber creep under constant force loading.

Viscoelasticity is a fundamental property of virtually all biological materials, and proteinaceous, fibrous materials that constitute the extracellular matrix (ECM) are no exception. Viscoelasticity may be particularly important in the ECM since cells can apply mechanical stress resulting from cell contractility over very long periods of time. However, measurements of ECM fiber response to long-term constant force loading are scarce, despite the increasing recognition that mechanical strain regulates the biological function of some ECM fibers. We developed a dual micropipette system that applies constant force to single fibers for up to 8 h. We utilized this system to study the time dependent response of fibronectin (Fn) fibers to constant force, as Fn fibers exhibit tremendous extensibility before mechanical failure as well as strain dependent alterations in biological properties. These data demonstrate the Fn fibers continue to stretch under constant force loading for at least 8 h and that this long-term creep results in plastic deformation of Fn fibers, in contrast to elastic deformation of Fn fibers under short-term, but fast loading rate extension. These data demonstrate that physiologically-relevant loading may impart mechanical features to Fn fibers by switching them into an extended state that may have altered biological functions. STATEMENT OF SIGNIFICANCE: Measurements of extracellular matrix (ECM) fiber response to constant force loading are scarce, so we developed a novel technique for applying constant force to single ECM fibers. We used this technique to measure constant force creep of fibronectin fibers since these fibers have been shown to be mechanotransducers whose functions can be altered by mechanical strain. We found that fibronectin fibers creep under constant force loading for the duration of the experiment and that this creep behavior resembles a power law. Furthermore, we found that constant force creep results in plastic deformation of the fibers, which suggests that the mechanobiological switching of fibronectin can only occur once after long-term loading.

Safety and efficacy of hydrogen peroxide topical solution, 40% (w/w), in patients with seborrheic keratoses: Results from 2 identical, randomized, double-blind, placebo-controlled, phase 3 studies (A-101-SEBK-301/302).

BACKGROUND: Approved topical treatments for seborrheic keratoses (SKs) are an unmet need. OBJECTIVE: To evaluate the safety and efficacy of 40% hydrogen peroxide topical solution (HP40) versus vehicle for the treatment of SKs (A-101-SEBK). METHODS: A total of 937 patients with 4 SKs each (≥1 lesion each on the face and on the trunk and/or an extremity) were randomized 1:1 to HP40 or vehicle. At each visit, SKs were graded using the Physician's Lesion Assessment (PLA) scale (0, clear; 1, nearly clear; 2, ≤1 mm thick; and 3, >1 mm thick). After 1 treatment, SKs with a PLA score higher than 0 were re-treated 3 weeks later. RESULTS: At day 106, significantly more patients treated with HP40 than with vehicle achieved a PLA score of 0 on all 4 SKs (study 1, 4% vs 0%; study 2, 8% vs 0% [both P < .01]) and on 3 of 4 SKs (study 1, 13% vs 0%; study 2, 23% vs 0% [both P < .0001]). A higher mean per-patient percentage of SKs were clear (study 1, 25% vs 2%; study 2, 34% vs 1%) and clear or nearly clear (study 1, 47% vs 10%; study 2, 54% vs 5%) with HP40 than with vehicle. Local skin reactions were largely mild and resolved by day 106. LIMITATIONS: The optimal number of treatment sessions was not evaluated. CONCLUSION: Application of HP40 was well tolerated and effective in the removal of SKs.

A-101, a Proprietary Topical Formulation of High-Concentration Hydrogen Peroxide Solution: A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study of the Dose-Response Profile in Subjects With Seborrheic Keratosis of the Face.

BACKGROUND: Seborrheic keratosis (SK) is a common benign skin tumor, yet no topical treatments are approved in the United States. OBJECTIVE: To evaluate the proprietary, stabilized, high-concentration hydrogen peroxide-based topical solution A-101 (32.5% and 40% concentrations) for treatment of facial SK lesions. MATERIALS AND METHODS: In this multicenter, double-blind, vehicle-controlled study, eligible subjects were randomly assigned to receive up to 2 treatments of A-101 40%, A-101 32.5%, or vehicle solution applied to a single facial SK lesion. The primary efficacy assessment was the Physician's Lesion Assessment (PLA), a validated 4-ordinal scale. RESULTS: The primary end point, the mean reduction in PLA grade from baseline to Day 106 was 1.7 for A-101 40%, 1.4 for A-101 32.5%, and 0.1 for vehicle (p < .001, both concentrations vs vehicle). Lesions for 68%, 62%, and 5% of subjects, respectively, were judged to be clear or near clear (p < .001, both concentrations vs vehicle). Local skin reactions were predominantly mild and transient. No subjects discontinued because of treatment-related adverse events. CONCLUSION: A-101 solution demonstrated efficacy in treating SKs on the face. Greater magnitude of effect was seen with the 40% concentration than the 32.5% concentration. A-101 solution had a favorable safety and tolerability profile at both concentrations.

Surpassing the no-cloning limit with a heralded hybrid linear amplifier for coherent states.

The no-cloning theorem states that an unknown quantum state cannot be cloned exactly and deterministically due to the linearity of quantum mechanics. Associated with this theorem is the quantitative no-cloning limit that sets an upper bound to the quality of the generated clones. However, this limit can be circumvented by abandoning determinism and using probabilistic methods. Here, we report an experimental demonstration of probabilistic cloning of arbitrary coherent states that clearly surpasses the no-cloning limit. Our scheme is based on a hybrid linear amplifier that combines an ideal deterministic linear amplifier with a heralded measurement-based noiseless amplifier. We demonstrate the production of up to five clones with the fidelity of each clone clearly exceeding the corresponding no-cloning limit. Moreover, since successful cloning events are heralded, our scheme has the potential to be adopted in quantum repeater, teleportation and computing applications.

Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial.

Amitifadine (EB-1010, formerly DOV 21,947) is a serotonin-preferring triple reuptake inhibitor with a relative potency to inhibit serotonin, norepinephrine, and dopamine uptake of ∼1:2:8, respectively. This 6-week, multicenter, randomized, double-blind, parallel, placebo-controlled study evaluated the efficacy and tolerability of amitifadine in 63 patients with major depressive disorder. Eligible patients (17-item Hamilton Depression Rating Scale [HAMD-17] ≥ 22 at baseline) were randomized to amitifadine 25 mg twice daily (BID) for 2 weeks, then 50 mg BID for 4 weeks or placebo. Mean baseline scores in the modified intent-to-treat population (n = 56) were 31.4 for the Montgomery-Åsberg Depression Rating Scale (MADRS), 29.6 for the HAMD-17, and 25.4 for the Derogatis Interview for Sexual Functioning - Self Report (DISF-SR). At the end of the 6-week double-blind treatment, estimated least squares mean change from baseline (mixed-model repeated measures [MMRM]) in MADRS total score was statistically significantly superior for amitifadine compared to placebo (18.2 vs. 22.0; p = 0.028), with an overall statistical effect size of -0.601 (Cohen's d). Amitifadine also was statistically significantly superior to placebo (p = 0.03) for the Clinical Global Impression of Change - Improvement. An anhedonia factor score grouping of MADRS Items 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel) demonstrated a statistically significant difference in favor of amitifadine compared to placebo (p = 0.049). No differences were observed between treatments in DISF-SR scores. Amitifadine was well-tolerated. Two patients on each treatment discontinued the study early due to adverse events; however, no serious adverse events were reported. This initial clinical trial in patients with severe major depression demonstrated significant antidepressant activity with amitifadine, including attenuating symptoms of anhedonia, and a tolerability profile that was comparable to placebo. The efficacy and tolerability of amitifadine for major depressive disorder are being investigated in additional clinical trials.

Using molecular mechanics to predict bulk material properties of fibronectin fibers.

The structural proteins of the extracellular matrix (ECM) form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn) and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional network models.

Contribution of unfolding and intermolecular architecture to fibronectin fiber extensibility.

The extracellular matrix contains components with remarkable mechanical properties, including fibronectin (Fn) fibers with extensibilities of >700% strain. We utilized what we consider a novel technique to quantify the extent of molecular unfolding that contributes to Fn fiber extension, and we compared this behavior with stochastic models of Fn fibers with different molecular arrangements. In vitro unfolding as a function of strain was measured by fluorescently labeling cysteines in modules FnIII7 and III15 in artificial Fn fibers. A calibration technique we also consider novel made it possible to demonstrate that 44% of cysteines in these modules were exposed in Fn fibers strained to 421% extension, up from 8% exposure without strain. In silico unfolding was measured by applying a constant strain rate to a fiber represented by a network of wormlike chain springs, each representing an individual Fn molecule. Unfolding rates were calculated with a tension-dependent stochastic model applied to FnIII modules in each molecule. A comparison of these approaches revealed that only a molecular arrangement permitting unequal mechanical loading of Fn molecules recapitulates in vitro unfolding. These data have implications for Fn-dependent mechanotransduction and give insight into how the molecular architecture of natural materials permits such remarkable extensibility.

Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease.

BACKGROUND: Previous studies showed that adjunctive subantimicrobial dose doxycycline (SDD; 20 mg, twice daily) provides significant clinical benefits to scaling and root planing (SRP). A modified-release SDD formulation containing 40 mg doxycycline (SDD-40) to be taken once daily has been developed. The aim of this study was to investigate the efficacy of SDD-40 when used as an adjunct to SRP for the treatment of periodontitis. METHODS: A 9-month, double-masked, randomized, placebo-controlled, multicenter study was conducted to test the efficacy of adjunctive SDD-40 in 266 subjects with periodontitis. Subjects were treated by SRP and randomized to receive SDD-40 or placebo for 9 months with evaluations at 3, 6, and 9 months. RESULTS: Adjunctive SDD-40 provided significantly greater clinical benefits than placebo at all time points. At month 9, at sites with baseline probing depths (PD) > or =6 mm, 72% to 76% of sites in the SDD-40 group demonstrated clinically significant PD reductions and clinical attachment level (CAL) gains > or =2 mm compared to 56% to 58% of sites in the placebo group (P <0.0001); 48% to 52% of sites in the SDD-40 group demonstrated PD reductions and CAL gains > or =3 mm compared to 32% of sites in the placebo group (P <0.0001). In moderate sites (baseline PD 4 to 6 mm), adjunctive SDD-40 provided significant clinical benefits compared to placebo for mean CAL (all time points: P <0.05), PD (3 months: P = 0.002; 6 and 9 months: P = 0.001), and bleeding on probing (BOP) (3 months: P <0.01; 6 months: P <0.02; 9 months: P <0.05). In deep sites (baseline PD > or =7 mm), SDD-40 provided significant benefits over control for mean CAL (3 months: P <0.05; 6 and 9 months: P <0.01), PD (all time points: P <0.001), and BOP (3 months: P <0.05; 6 months: not statistically significant; 9 months: P <0.05). Compliance with study medication was high (>92%) with no significant differences in adverse events between groups and no evidence of microbiologically significant changes or development of antibiotic resistance in the subgingival flora in either group. CONCLUSION: SDD-40 used as an adjunct to SRP resulted in significantly greater clinical benefits than SRP alone in the treatment of periodontitis.

Combining host modulation and topical antimicrobial therapy in the management of moderate to severe periodontitis: a randomized multicenter trial.

BACKGROUND: Previous studies showed that host modulation therapy (HMT) or topical antimicrobial therapy (TAT) provided significant adjunctive benefits to scaling and root planing (SRP) in the treatment of chronic periodontitis (CP). The purpose of this study was to evaluate a combination therapy involving SRP, HMT, and TAT in the treatment of moderate to severe CP. METHODS: A 6-month, randomized, multicenter, placebo-controlled, examiner-masked study was undertaken to evaluate the clinical usefulness of a combination treatment of systemically delivered doxycycline hyclate (HMT; 20 mg, twice a day) plus locally delivered doxycycline hyclate gel (TAT; 10%, in pockets > or =5 mm) in combination with SRP versus SRP plus placebo. Clinical outcomes included mean changes in probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and gingival index (GI) at baseline and at 3 and 6 months. RESULTS: In 171 subjects, combination therapy provided significantly greater clinical benefits than control therapy for all clinical measures at 3 and 6 months. In moderate CP (PD of 4 to 6 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.03), BOP (3 months: P <0.02; 6 months: P <0.05), and GI (3 months: P <0.01; 6 months: P <0.03). In severe CP (PD > or =7 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.02), BOP (3 months: P <0.01; 6 months: P >0.05), and GI (3 months: P <0.01; 6 months: P <0.01). CONCLUSION: Combination therapy, including SRP, HMT, and TAT, provided significantly greater clinical benefits than SRP alone in the treatment of moderate to severe CP.

Anti-inflammatory dose doxycycline (40 mg controlled-release) confers maximum anti-inflammatory efficacy in rosacea.

BACKGROUND: Two large clinical trials have recently demonstrated the efficacy of a 40-mg controlled-release formulation of doxycycline in the treatment of rosacea, a dose well below the conventional level of 100 to 200 mg/d. Since no formal dose-response studies have been conducted, the authors analyzed phase 3 data to determine whether a dose-efficacy relationship exists. METHODS: Standard parametric regression analyses were used to estimate the correlations between dose (mg/kg body weight) and overall drug exposure (area under the curve [AUC]) in a phase 1 pharmacokinetic study and between dose and efficacy (mean change from baseline in total inflammatory lesion count at week 16) in 2 pooled phase 3 clinical efficacy studies. Additional regressions were run at each visit for the clinical efficacy studies to determine whether results differed across visits. A regression analysis was also performed in a subset of patients who showed a greater efficacy response. RESULTS: We found overall drug exposure (AUC) to have a highly significant correlation with dose (mg/kg) (r=0.49; P=.006). In contrast, clinical efficacy did not correlate with dose at any of the visits at week 3 (r=0.01; P=.85), week 6 (r=0.04; P=.53), week 12 (r<0.01; P=.98), and week 16 (r=0.03; P=.64) or among the subset of patients who showed greater clinical benefit. CONCLUSIONS: Higher mg/kg doses led to higher plasma concentrations but did not lead to increased clinical efficacy. Anti-inflammatory dose doxycycline (40-mg controlled-release formulation) conferred peak anti-inflammatory efficacy in the treatment of rosacea.

Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea.

BACKGROUND: Doxycycline monotherapy at antimicrobial doses has been shown to be effective for the treatment of rosacea. OBJECTIVE: To evaluate the efficacy and safety of once-daily anti-inflammatory dose doxycycline for the treatment of rosacea. METHODS: In two phase III, parallel-group, multicenter, randomized, double-blind, placebo-controlled studies (studies 301 and 302), patients received 40-mg of controlled-release doxycycline (n = 269) or placebo (n = 268) for 16 weeks. The primary efficacy end point was the mean change from baseline in facial inflammatory lesion count. RESULTS: The mean lesion count at baseline was approximately 20 in each study arm. At week 16, the mean change from baseline in lesion count in the active-treatment groups was -11.8 in study 301 and -9.5 in study 302 compared with -5.9 and -4.3, respectively, in the placebo groups (P < .001 for both comparisons). Anti-inflammatory dose doxycycline was well tolerated; the most common adverse events were nasopharyngitis (4.8%), diarrhea (4.4%), and headache (4.4%). LIMITATIONS: In both studies, the reduction of inflammatory lesion counts did not plateau within the 16-week time frame in either treatment group. Rosacea is often treated for a period of months or years. The duration of the studies did not allow for assessment of safety beyond 16 weeks or whether the progressive improvement seen with active treatment would continue beyond 16 weeks. Neither study assessed the effect of treatment in patients with only erythematotelangiectatic (subtype 1) rosacea. CONCLUSION: Once-daily anti-inflammatory dose doxycycline appears to be effective and safe for the treatment of rosacea.

Subantimicrobial dose doxycycline in the treatment of recurrent oral aphthous ulceration: a pilot study.

BACKGROUND: Recurrent oral aphthous ulceration (ROAU) is a common problem that can result in considerable pain and distress for patients. The aim of this pilot study was to evaluate the role of subantimicrobial dose doxycycline (SDD - 20 mg doxycycline twice daily) in the management of patients with ROAU. METHODS: 50 patients with ROAU were randomly allocated to treatment with SDD or placebo for 90 days. Daily ulcer diaries were completed by the participants to record the number of new ulcers and the pain associated with the ulcers. RESULTS: There were significantly more days with no new ulcers in the SDD group (80.4 +/- 5.9) than the placebo group (69.8 +/- 18.7; P=0.04). Strong trends were observed towards fewer new ulcers per day, fewer new ulcers over the 90-day period, and more days with no pain in the SDD group compared with the placebo group (P=0.06-0.08). CONCLUSION: SDD shows promise as potential therapy in the management of ROAU, though this needs to be confirmed in further studies.

The pop out of scene-relative object movement against retinal motion due to self-movement.

An object that moves is spotted almost effortlessly; it "pops out". When the observer is stationary, a moving object is uniquely identified by retinal motion. This is not so when the observer is also moving; as the eye travels through space all scene objects change position relative to the eye producing a complicated field of retinal motion. Without the unique identifier of retinal motion an object moving relative to the scene should be difficult to locate. Using a search task, we investigated this proposition. Computer-rendered objects were moved and transformed in a manner consistent with movement of the observer. Despite the complex pattern of retinal motion, objects moving relative to the scene were found to pop out. We suggest the brain uses its sensitivity to optic flow to "stabilise" the scene, allowing the scene-relative movement of an object to be identified.

Surface orientation, modulation frequency and the detection and perception of depth defined by binocular disparity and motion parallax.

Binocular disparity and motion parallax provide information about the spatial structure and layout of the world. Descriptive similarities between the two cues have often been noted which have been taken as evidence of a close relationship between them. Here, we report two experiments which investigate the effect of surface orientation and modulation frequency on (i) a threshold detection task and (ii) a supra-threshold depth-matching task using sinusoidally corrugated surfaces defined by binocular disparity or motion parallax. For low frequency corrugations, an orientation anisotropy was observed in both domains, with sensitivity decreasing as surface orientation was varied from horizontal to vertical. In the depth-matching task, for surfaces defined by binocular disparity the greatest depth was seen for oblique orientations. For surfaces defined by motion parallax, perceived depth was found to increase as surface orientation was varied from horizontal to vertical. In neither case was perceived depth for supra-threshold surfaces related to threshold performance in any simple manner. These results reveal clear differences between the perception of depth from binocular disparity or motion parallax, and between perception at threshold and supra-threshold levels of performance.

Stereoscopic acuity and observation distance.

The amount of depth perceived from a fixed pattern of horizontal disparities varies with viewing distance. We investigated whether thresholds for discriminating stereoscopic corrugations at a range of spatial frequencies were also affected by viewing distance or whether they were determined solely by the angular disparity in the stimulus prior to scaling. Although thresholds were found to be determined primarily by disparity over a broad range of viewing distances, they were on average a factor of two higher at the shortest viewing distance (28.5 cm) than at larger viewing distances (57 to 450 cm). We found the same pattern of results when subjects' accommodation was arranged to be the same at all viewing distances. The change in thresholds at close distances is in the direction expected if subjects' performance is limited by a minimum perceived depth.

2-D tilt and 3-D slant illusions in perception and action tasks.

There is now a well established dissociation between perception and action based primarily on neuropsychological evidence [Milner and Goodale, 1995 The Visual Brain in Action (Oxford: Oxford University Press)]. Although equivocal, an important source of evidence from normal observers is that 'perceptual illusions' may affect the systems differently. We investigated the relative effects of 2-D tilt and 3-D slant illusions in the two domains, using similar tasks to those employed originally by Milner and Goodale. Subjects were required to either post a card through, or set a paddle to match the orientation of, a plane that was presented in two conditions: surrounded by a striped surface tilted between +90 degrees and -90 degrees (2-D tilt contrast), or surrounded by a disparity defined surface slanted in depth between +60 degrees and -60 degrees (3-D depth contrast). For 2-D tilt, action and perception were equally affected by the illusion, whereas in the 3-D condition they were not. Here, the illusion appeared greater in the posting than in the perceptual task. We conclude that, although no qualitative differences exist, there were quantitative differences between perception and action tasks in the binocular condition.

The perception of emotion from body movement in point-light displays of interpersonal dialogue.

We examined whether it is possible to identify the emotional content of behaviour from point-light displays where pairs of actors are engaged in interpersonal communication. These actors displayed a series of emotions, which included sadness, anger, joy, disgust, fear, and romantic love. In experiment 1, subjects viewed brief clips of these point-light displays presented the right way up and upside down. In experiment 2, the importance of the interaction between the two figures in the recognition of emotion was examined. Subjects were shown upright versions of (i) the original pairs (dyads), (ii) a single actor (monad), and (iii) a dyad comprising a single actor and his/her mirror image (reflected dyad). In each experiment, the subjects rated the emotional content of the displays by moving a slider along a horizontal scale. All of the emotions received a rating for every clip. In experiment 1, when the displays were upright, the correct emotions were identified in each case except disgust; but, when the displays were inverted, performance was significantly diminished for some emotions. In experiment 2, the recognition of love and joy was impaired by the absence of the acting partner, and the recognition of sadness, joy, and fear was impaired in the non-veridical (mirror image) displays. These findings both support and extend previous research by showing that biological motion is sufficient for the perception of emotion, although inversion affects performance. Moreover, emotion perception from biological motion can be affected by the veridical or non-veridical social context within the displays.

A randomized, double-blind, placebo-controlled trial of the combined effect of doxycycline hyclate 20-mg tablets and metronidazole 0.75% topical lotion in the treatment of rosacea.

BACKGROUND: Subantimicrobial doses of doxycycline may improve outcomes in rosacea when combined with topical metronidazole and used as maintenance monotherapy. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of doxycycline hyclate 20 mg (subantimicrobial dose doxycycline) administered twice daily as an adjunct to metronidazole 0.75% topical lotion in the treatment of rosacea. METHODS: Patients received subantimicrobial doses of doxycycline twice daily plus metronidazole (n = 20) or placebo plus metronidazole (n = 20) for 12 weeks. Subantimicrobial-dose doxycycline or placebo monotherapy continued for 4 weeks. The primary efficacy measure was change from baseline in total inflammatory lesions at weeks 2 and 16. RESULTS: Total inflammatory lesions were reduced significantly (P =.048) by week 4 and by all subsequent visits in the subantimicrobial-dose doxycycline/metronidazole group compared with placebo/metronidazole. Changes from baseline increased over time and were maintained during subantimicrobial-dose doxycycline monotherapy. CONCLUSION: Adjunctive use of subantimicrobial dose doxycycline significantly reduced the clinical signs of rosacea compared with metronidazole alone and may be useful maintenance monotherapy.

Long-term treatment with sub-antimicrobial dose doxycycline has no antibacterial effect on intestinal flora.

AIM: The purpose of this study was to determine if a 9-month regimen of sub-antimicrobial doxycycline (20 mg, bid) had an effect on either the intestinal or the vaginal microflora. MATERIAL AND METHODS: A total of 69 periodontally diseased subjects were randomized to receive drug or placebo control for a 9-month period. Stool specimens and vaginal swabs were collected at baseline and after 3 and 9 months of therapy. Samples were examined for total anaerobic counts, opportunistic pathogens, and doxycycline-resistant (>or=4 microg/ml) bacteria. All isolates that survived sub-culture were identified and their susceptibilities determined to six antibiotics. Analyses were performed to determine if treatment differences were present. RESULTS: The only statistically significant differences (p<0.05) between the two treatment groups occurred in the doxycycline-resistant counts at the baseline sample period for the faecal samples. This imbalance was before treatment initiation and the administration of the study drug. No between-treatment differences were detected at either the 3- or 9-month sample period either in the predominant bacterial taxa present or in their antibiotic susceptibilities. CONCLUSIONS: There was no evidence that sub-antimicrobial doxycycline treatment exerted an effect on the composition or doxycycline resistance level of either the faecal or the vaginal microflora.