Can sebum reduction predict acne outcome?

Sebum excretion has generally been accepted as an important factor in the development of acne vulgaris. However, the relationship of sebum excretion and acne outcome has not yet been clearly demonstrated quantitatively. The objective of this analysis was to explore the correlation of sebum and acne by combining data from studies of various acne treatments that have demonstrated effects on both sebum excretion and acne outcome. Acne measures included total lesion count, inflammatory lesion count and acne severity grade. For each acne measure, data were pooled and analysed at the 3- and 4-month endpoints, when sebum reduction has generally equilibrated and efficacy in acne is approaching the maximum effect for most treatments. A linear model was used to describe the percentage reduction in each acne measure as a function of percentage reduction in sebum excretion. Slope values were similar for the three acne parameters and all were significantly different from zero (P < 0·025), suggesting a significant correlation of sebum and acne. The projected sebum reduction required to achieve 50% reduction in acne measures ranged from 30% to 50%. The results shown here suggest that the collective data across multiple studies may provide a useful generalization of the association of sebum reduction and acne outcome. As the relationship apparently remains consistent regardless of the treatment, it can be inferred that extrapolation to novel exploratory treatments may be valid.

Comparison of the cumulative irritation potential of adapalene gel and cream with that of erythromycin/tretinoin solution and gel and erythromycin/isotretinoin gel.

BACKGROUND: Adapalene is a naphthoic acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris. OBJECTIVE: This study assessed the cumulative irritation potential of adapalene gel (0.1%) and adapalene cream (0.1%) compared with that of erythromycin (4%)/tretinoin (0.025%) solution, erythromycin (4%)/tretinoin (0.025%) gel, erythromycin (2%)/isotretinoin (0.05%) gel, and white petrolatum (negative control). METHODS: This was a single-center, randomized, controlled, investigator-blinded, intraindividual comparison study in healthy subjects with normal skin. The cumulative irritation assay (patch test) was used to assess the potential for irritation (including erythema) of the treatments. Each subject received all study treatments, randomly applied under occlusion (patch), to sites on either side of the midline on the mid-thoracic area of the back. All patches were applied to the same sites throughout the study, unless the degree of reaction to the treatment or adhesive necessitated removal. For 3 weeks, each test material was applied daily, Monday through Friday, for approximately 24 hours; the Friday patches were left in place over the weekend for approximately 72 hours. RESULTS: All 36 subjects (26 men, 10 women; age, 18-49 years [mean, 30 years]) completed the study. In the course of the study, all subjects had > or =1 application discontinued prematurely on > or =1 site due to intolerance. There were no discontinuations with white petrolatum. All erythromycin/tretinoin gel patches were discontinued at day 10; 35 of 36 erythromycin/isotretinoin gel patches were discontinued at day 9; and 35 of 36 erythromycin/tretinoin solution patches were discontinued at day 11 or day 17. The adapalene products, although slightly more irritating (mean cumulative irritation index, 0.25-1) than white petrolatum, were significantly less irritating than the erythromycin/tretinoin and erythromycin/isotretinoin products (P < 0.01). CONCLUSIONS: Adapalene gel and cream were well tolerated, with possible benefits for compliance. Their low irritation potential should be considered when prescribing a topical retinoid for the treatment of acne vulgaris.

CD 2394, a novel synthetic retinoid, initiates an embryonic type of differentiation in hyperproliferative skin.

In human skin, there are 2 types of epidermal differentiation: normal differentiation, characterized by keratin 10 expression, and alternative differentiation. Alternative differentiation may be regeneration-associated differentiation (keratin 6 and 16) or re-induction of embryonic differentiation (expression of keratin 13, 15 and 19). The purpose of this study was to investigate the effect of the novel synthetic retinoid CD 2394 on hyperproliferative human skin, with respect to embryonic differentiation in particular. The effects of CD 2394 were compared with untreated and vehicle-treated skin 48 h after tape-stripping. In a multiparameter flow cytometric assay, parameters of proliferation, normal differentiation, embryonic differentiation and inflammation were assessed. With respect to proliferation, treatment with CD 2394 resulted in a decreased number of cells in the G2M-phase. Normal differentiation was decreased in CD 2394 treated skin. Furthermore, most of the CD 2394 treated samples showed expression of keratin 13, which was not seen in the otherwise treated skin. A correlation between keratin 10 and keratin 13 expression could not be demonstrated. This study showed that CD 2394 is capable of inducing an embryonic pathway of differentiation, which is distinct from normal differentiation or regeneration-associated differentiation.

Adapalene 0.1% gel and adapalene 0.1% cream stimulate retinoic acid receptor mediated gene transcription without significant irritative effects in the skin of healthy human volunteers.

A randomized, investigator masked, intra individual comparative study was conducted in 30 healthy volunteers to compare the cutaneous effects of adapalene 0.1% gel and adapalene 0.1% cream with their respective vehicles, using tretinoin 0.05% cream (n = 21) or tretinoin 0.1% cream (n = 9) and a tretinoin cream vehicle (n = 30) as controls. The products were applied to hip/buttock skin for 4 days under occlusive conditions. Cytosolic retinoic acid binding protein-II (CRABP-II) mRNA levels were measured using the RT-PCR technique in punch biopsies taken from 10 subjects. Epidermal thickness was assessed using image analysis of haematoxylin and eosin stained sections from another 11 subjects. Erythema was assessed in all subjects both by a visual scoring system and by chromameter. Adapalene 0.1% gel and adapalene 0.1% cream produced similar significant increases in CRABP-II mRNA levels compared to their vehicles (P < 0.01). The two tretinoin formulations also resulted in similar significant increases in CRABP-II compared to the cream vehicle (P < 0.001). However, only the two tretinoin formulations resulted in an increase in epidermal thickness and only the tretinoin 0.1% cream resulted in significant erythema. Adapalene 0.1% gel and adapalene 0.1% cream induce RAR-mediated gene expression to a similar degree in this model, without the irritant effects of tretinoin.

Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life.

A randomized, multicentre, investigator-masked study was conducted in 105 patients with mild to moderate acne vulgaris to compare the efficacy and safety of adapalene 0.1% gel with tretinoin 0.025% gel after three months of treatment, with particular emphasis on reduction in inflammatory lesion counts after one week of treatment and impact on quality of life. In terms of efficacy, adapalene gel was found to be superior to tretinoin gel after one week of treatment, with respect to reduction in inflammatory lesion counts (32% vs. 17%, respectively; P = 0.001), total lesion counts (28% vs. 22%, respectively; P = 0.042) and global severity grade (28% vs. 16%, respectively; P = 0.001). No significant difference between the two treatments was found after 12 weeks of treatment for any of these variables. Evaluation of facial skin tolerance parameters showed significant differences between the two treatments in favour of adapalene for dryness, erythema, immediate and persistent burning and pruritus for at least one time point. One patient in the adapalene group and three patients in the tretinoin group experienced medical events which lead to discontinuation of treatment (skin irritation; NS). Quality of life scores improved more rapidly in the adapalene group than in the tretinoin group, with significant differences (P < 0.05) appearing at week 1 for questions related to problems with partners, close friends or relatives and to skin symptoms. There was also a significantly greater improvement in social and leisure activity in the adapalene group at week 12. Adapalene 0.1% gel reduced inflammatory and total lesion counts more rapidly than tretinoin 0.025% gel, and was also better tolerated. These differences appear to result in an earlier and greater quality of life improvement for the patients receiving adapalene.

Adapalene 0.1% gel has low skin-irritation potential.

BACKGROUND: Adapalene is a new naphthoic acid derivative with potent retinoid and antiinflammatory properties, developed for the topical treatment of acne vulgaris. OBJECTIVE: We compare the cutaneous safety of adapalene in different gel vehicles with tretinoin 0.025% gel. METHODS: A total of 42 healthy human subjects were enrolled in two randomized, double-blind, controlled, intraindividual studies. In the first study (study A), adapalene aqueous 0.03% and 0.1% gels were evaluated for their 21-day cumulative irritation potential compared with vehicle alone, patch alone, and tretinoin 0.025% gel under occlusion. In the second study (study B), adapalene aqueous (0.03% and 0.1%) gels and adapalene alcoholic (0.03% and 0.1%) gels were evaluated for their 5-day cumulative irritation potential compared with their respective vehicles and tretinoin 0.025% gel. Transepidermal water loss (TEWL) was measured daily at each visit. RESULTS: In study A, adapalene had a slight irritation potential that was in the same range as the gel vehicle and the patch alone, whereas tretinoin 0.025% gel was a severe irritant. In study B, no irritation was seen with either adapalene aqueous gels or adapalene gel vehicles or patch alone. The adapalene alcoholic gels were slightly irritating, and tretinoin gel produced intense irritation reactions in the majority of subjects. TEWL increased fourfold at the tretinoin site but remained unchanged at all adapalene sites. CONCLUSION: Adapalene 0.1% gel was significantly less irritating than tretinoin 0.025% gel.

Split-face comparison of adapalene 0.1% gel and tretinoin 0.025% gel in acne patients.

BACKGROUND: Adapalene is a new naphthoic acid derivative developed for the topical treatment of acne vulgaris. OBJECTIVE: We compared the skin tolerance of adapalene 0.1% gel with tretinoin 0.025% gel in subjects with acne. METHODS: Fifteen acne patient volunteers were enrolled in this investigator-masked, left-right comparison, randomized, controlled, intraindividual study. Adapalene 0.1% gel and tretinoin 0.025% gel were applied once a day to one half-face by the volunteers for 14 consecutive days. Clinical signs (erythema, desquamation, papules, vesicles, edema) and subjective symptoms (tightness, pruritus, burning) were evaluated and scored daily except on weekends. RESULTS: Adapalene 0.1% gel was better tolerated than tretinoin 0.025% gel. The overall mean score calculated from all features combined was significantly higher with tretinoin gel than with adapalene gel (p = 0.002). CONCLUSION: Adapalene 0.1% gel was significantly less irritating than tretinoin 0.025% gel when tested in acne patients.

Skin tolerance of adapalene 0.1% gel in combination with other topical antiacne treatments.

BACKGROUND: Adapalene (Differin gel) is a new naphthoic acid derivative developed for the topical treatment of acne vulgaris. OBJECTIVE: We assessed, in healthy volunteers, the skin irritancy potential of three combinations, each including adapalene 0.1% gel and one topical marketed antiacne product. METHODS: Twenty-five healthy volunteers were enrolled in a 21-day cumulative irritancy study performed in a double-blind, randomized, controlled, intraindividual design. Five days a week, the three materials (benzoyl peroxide, clindamycin phosphate, and erythromycin) were applied in a nonocclusive manner either alone or in combination with adapalene gel on seven cutaneous sites on the upper back. Adapalene was applied in the evening whereas the three other materials were applied in the morning. Irritation was evaluated and scored daily except on weekends. RESULTS: All materials were well-tolerated when tested alone. The combinations of adapalene 0.1% gel and either benzoyl peroxide, clindamycin phosphate, or erythromycin were also well-tolerated. The mean cumulative irritancy indices indicated that all three combinations were nonirritating. CONCLUSION: Under the conditions of the study, all tested treatments alone or in combination appeared nonirritating.

Adapalene 0.1% gel is better tolerated than tretinoin 0.025% gel in acne patients.

BACKGROUND: Adapalene is a new naphthoic acid derivative developed for the topical treatment of acne vulgaris. OBJECTIVE: We describe the results of a combined safety analysis of two multicenter trials conducted in the U.S. and Europe in which adapalene 0.1% gel was compared with tretinoin 0.025% gel in the treatment of mild to moderate acne vulgaris. METHODS: A total of 591 acne patients were enrolled in these investigator-masked, randomized, controlled, parallel group studies. In the two studies, each patient was randomly assigned to receive topical adapalene 0.1% gel or tretinoin 0.025% gel once daily at bedtime, for 12 weeks. In addition to assessments of efficacy and facial skin tolerance, data on adverse events were recorded at each visit or at any other time the patient reported problems. We extracted data concerning adverse reactions (i.e., adverse events judged to be related to the study treatment) from both studies and combined the results to obtain a global comparison of safety of the two products. RESULTS: A total of 15 of 296 patients (5.1%) reported 19 adverse reactions in the adapalene-treated groups, compared with 27 of 295 patients (9.1%) reporting 39 adverse reactions in the tretinoin-treated groups (p < 0.05). The number of patients discontinuing the study because of adverse events was approximately twice as low with adapalene (1.3% compared with 2.4%). Most adverse reactions for both products were related to skin irritation. No systemic adverse reactions were reported. CONCLUSION: The results of these two multicenter clinical studies indicate that adapalene gel is better tolerated than tretinoin gel.

Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers.

RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and ex-vivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg.l-1. There were no clinical or biological adverse reactions to RP 48740 during the study.

Effects of acebutolol on the serum lipid profile.

Epidemiological and recent interventional studies have emphasised the relationship between plasma lipid parameters and the incidence of coronary heart disease. beta-Blockers, particularly those without intrinsic sympathomimetic activity (ISA), are generally reported to increase triglyceride levels and decrease high density lipoprotein (HDL)-cholesterol levels, both changes theoretically increasing the risk of coronary heart disease. A review of all published trials concerning the effects of acebutolol (a cardioselective beta-blocker with mild ISA) on the plasma lipid profile was carried out, with a particular emphasis on studies reporting a comparison with other beta-blockers. The results indicate that, on average, acebutolol does not have any adverse effects on plasma lipids and may even reduce total and low density lipoprotein (LDL)-cholesterol by 7 and 5%, respectively. In contrast, the other beta-blockers compared under the same conditions (propranolol, pindolol and penbutolol) tended to increase triglyceride levels (+19% when compared with acebutolol) and decrease HDL-cholesterol (-7% when compared with acebutolol) to an extent that was consistent with previous reports in the literature. In interpreting these differences in lipid parameters in the light of epidemiological and interventional study data, the use of acebutolol as opposed to the other beta-blockers could theoretically lead to a relative reduction in coronary risk of 20% or more.

The antisecretory effects of zaltidine, a novel long-acting H2-receptor antagonist, in healthy volunteers and in subjects with a past history of duodenal ulcer.

The potency and duration of the antisecretory action of zaltidine, a novel H2-receptor antagonist, have been examined in healthy volunteers and in patients with previous duodenal ulceration. In eight healthy male volunteers single oral doses of 5 mg, 25 mg and 100 mg produced dose-related inhibition of basal and pentagastrin-stimulated acid output (M.A.O.) with an estimated ID50 of 40 mg for the latter. In eight subjects with duodenal ulceration single 100 mg and 200 mg doses produced 85% and 97% inhibition of M.A.O. at peak (3 h post-dose) and 20% and 23% inhibition at 24 h, respectively; inhibition of basal acid output was 97% at 3 h and 50% at 24 h with both doses. The long duration of action of zaltidine is ascribed to its relatively slow elimination from the plasma.