Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study.

BACKGROUND: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD). METHODS: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. RESULTS: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. CONCLUSIONS: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.

Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: A phase 3 study.

BACKGROUND: FMX101 4% topical minocycline foam has been shown to be an effective and safe treatment for acne vulgaris (AV). OBJECTIVE: To further evaluate the efficacy and safety of FMX101 4% in treating moderate to severe acne vulgaris. METHODS: A 12-week, multicenter, randomized (1:1), double-blind, vehicle-controlled study was conducted. Coprimary end points were the absolute change in inflammatory lesion count from baseline and the rate of treatment success (Investigator's Global Assessment score of 0 or 1 with a ≥2-grade improvement). RESULTS: There were 1488 participants in the intent-to-treat population. The FMX101 4% group had significantly greater reductions in the number of inflammatory lesions from baseline (P < .0001) and a greater rate of treatment success based on Investigator's Global Assessment (P < .0001) versus the foam vehicle group at week 12. FMX101 4% was generally safe and well tolerated. LIMITATIONS: The efficacy and safety of FMX101 4% were not characterized in participants with mild AV. CONCLUSION: FMX101 4% topical minocycline foam was effective and safe for the treatment of moderate to severe AV.

Ethnicity, Race and Skin Color: Challenges and Opportunities for Atopic Dermatitis Clinical Trials.

The number of clinical trials conducted in patients with atopic dermatitis is increasing steadily. These trials are conducted in several countries across all continents and include patients of different ethnicity, race and skin color. This diversity is desired, but it also brings challenges, including the diagnosis and evaluation of disease severity in patients with different skin colors; the influence of ethnicity on the perception of quality of life and patient reported outcomes; the inclusion of ethnicities that are only present in one country or that live far from clinical research sites; and the reporting of drug safety information. There is a need to better train physicians on the evaluation of atopic dermatitis in patients with different skin colors and a need to improve the systematic reporting of ethnicity, race and skin color in clinical trial publications.

Contact sensitivity in patients with venous leg ulcers in Serbia: comparison with contact dermatitis patients and relationship to ulcer duration.

BACKGROUND: Contact hypersensitivity is a common occurrence in patients with chronic venous leg ulcers (CVLU) with allergen profiles depending upon the local treatment policies. OBJECTIVE: This study was to determine the frequency of contact sensitivity, prevalence of individual allergens, polyvalent sensitization, and/or their relationship to ulcers duration in the population of CVLU and contact dermatitis patients in Serbia. PATIENTS: 75 patients with CVLU and 82 patients with clinically suspected contact dermatitis were prospectively included in the study. The patients were patch tested with a series of 21 standard and 22 supplemental allergens. RESULTS: 73% (n = 55) of CVLU and 52% (n = 43) of control subjects had 1 or more positive patch test results (P < 0.01). Polysensitization was found in 53% of patients and 21% of controls (P < 0.01). CVLU patients run 2.5 and 4.3 higher risk for contact sensitization and polysensitization, respectively. The most common allergens were Balsam of Peru (21.3%), carba mix (18.7%), fusidic acid (17.3%), colophony (13.3%), paraben mix (12%), chloramphenicol (12%), silver nitrate (12%), and neomycin (10.7%). Polivalent sensitization and higher mean number of allergens were associated with ulcer duration >5 years. CONCLUSIONS: The results confirm a high rate of contact (poly)sensitization in patients with CVLU and local variability in allergen prevalence.

[Therapeutic aspects of trichomoniasis]. / Terapijski aspekt trihomonijaze.

INTRODUCTION: Trichomoniasis is frequent, parasitic and sexually transmitted infection of genitourinary tract. It is treated by metronidazole (5-nitroimidazole), according to protocol recommended by Center for Disease Control (CDC, formerly called: Communicable Disease Center) [19]. The resistance of Trichomonas vaginalis (TV) strains to metronidazole (MND) was described in USA in 1960, and later on in many European countries [8, 9, 10, 11, 12, 13]. In these cases, due to persistent trichomonas infection, it is necessary to repeat MND treatment with moderate modification of dose and/or length of its application. Nevertheless, oncogenic and toxic effects of MND have to be taken into consideration. AIM: The aim of this study was to investigate and analyse the incidence of TV in STD and lower susceptibility of certain TV strains to MND were analyzed. METHODS: In three-year period (1999-2001) 612 patients (244 females and 368 males) suspected of STD were examined clinically and microbiologically at the Institute of Dermatovenereology in Belgrade. The patients detected for TV were treated according to CDC protocol. The affected were considered cured if there was no manifest clinical infection, and no TV verified by microbiological test. RESULTS: TV was isolated in 216 patients (35.29% of all subjects). Trichomonas infection was found in 90 (36.88%) out of 244 tested females and in 126 (32.34%) of 368 males. Clinically manifested infection, with extensive urethral and vaginal secretion, was recorded in 161 patients, while the asymptomatic form was found in 55 subjects. This result indicates the predominance of manifested trichomonas infections (75.54% of cases). The difference of distribution of clinical forms of trichomoniasis, in relation to sex, was not statistically significant (chi 2 = 0.854; p > 0.05). The patients with verified trichomonas infection were treated by metronidazole according to CDC protocol. The recommended therapeutical scheme consisted of three phases proceeding in succession, in so far TV had not been eliminated by previous one. The number of cured patients, according to therapeutical phases, was shown in Table 4. Three patients (1.39%, 2 males and 1 female) were not cured in spite of all three completed phases of therapeutical protocol. In all three cases, TV was eliminated by MND application in dose of 3 g/daily, during two days. The failure of minute MND treatment was analyzed in relation to clinical forms of the infection (manifested or asymptomatic), as well as in relation to types of infection (single- or associated infection). The incidence of refractory trichomoniasis treated by a single metronidazole dose of 2 g was significantly higher in the group of patients with polyinfection (c2 = 18.270; p < 0.01). There was no significant difference of resistance to a single MND dose between the groups with manifested and asymptomatic trichomoniasis (chi 2 = 0.321; p < 0.01). DISCUSSION: The prevalence of TV in vaginal and urethral smears indicates the significant incidence of trichomoniasis in STD. TV was more frequently isolated in patients with clinically manifested infection. TV susceptibility to MND was tested in vitro in aerobic and anaerobic conditions. The resistance of strains under in vitro conditions did not correlate with refractory feature of trichomoniasis to MND application [7, 17, 18]. The success of trichomoniasis treatment depends upon multiple factors, including: a) TV susceptibility to drug, b) intravaginal redox potential, c) drug concentration in situ, d) associated microorganisms that may modify the amount of the drug available in situ [7, 18, 21]. The results of our investigation argue for the latter item, verifying that TV resistance to MND is higher in patients with polyinfection in relation to those with monoinfection (significant difference, chi 2 = 18.270; p < 0.01). Repeated administration of low metronidazole doses may prolong the therapy of trichomonas infections, while application of high doses (over 3 g/day) may result in undesired complications. Given the well-known fact that repeated sublethal doses induce the resistance, would it be more beneficial to begin with slightly higher metronidazole dose (3 g/day) during short period of time (3-5 days)? This will be the subject of our further investigation.