Oral R115866 in the treatment of moderate to severe facial acne vulgaris: an exploratory study

BACKGROUND: R115866 (Rambazole; Barrier Therapeutics NV, Geel, Belgium), a new-generation retinoic acid metabolism-blocking agent, is a nonretinoid compound enhancing intracellularly the endogenous levels of all-trans-retinoic acid by blocking its catabolism. By virtue of this property, and the proven positive effects of retinoids in the treatment of acne, R115866 could potentially be a useful drug for acne. OBJECTIVES: To explore the efficacy, safety and tolerability of systemic R115866 in male patients with moderate to severe facial acne vulgaris (at least 15 papules and/or pustules and at least two nodulocystic lesions). METHODS: In this exploratory trial, 17 patients were treated with oral R115866 1 mg once daily for 12 weeks, followed by a 4-week treatment-free period. RESULTS: At the end of treatment (week 12, n = 16) a mean reduction in inflammatory lesion count of 77.4% (P < 0.001), in noninflammatory lesion count of 58.3% (P < 0.001) and in total lesion count of 76.0% (P < 0.001) was observed as compared with baseline. All lesion counts were significantly reduced from week 4 onwards. Mild side-effects were reported occasionally. CONCLUSIONS: The current data indicate that treatment with oral R115866 1 mg once daily for 12 weeks in patients with moderate to severe facial acne vulgaris is efficacious and well tolerated and merits further investigation.     

The CYP26 inhibitor R115866 potentiates the effects of all-trans retinoic acid on cultured human epidermal keratinocytes

Background  All- trans retinoic acid (RA) is known to regulate keratinocyte proliferation and differentiation, and retinoids are used as therapeutic agents in certain dermatological disorders, such as psoriasis and acne. Epidermal expression of the heparin-binding epidermal growth factor-like growth factor (HB-EGF) is induced by RA treatment and HB-EGF is responsible for RA-mediated epidermal hyperplasia in vivo . RA also induces HB-EGF expression in cultured keratinocytes and alters their differentiating phenotype. R115866 is a specific inhibitor of the cytochrome P450 isoform CYP26, which is involved in the metabolic inactivation pathway of RA. Thereby, R115866 is thought to be able to increase the intracellular levels of endogenous RA.
Objectives  To determine whether or not R115866 potentiates the effect of low concentrations of RA on keratinocytes.
Methods  We analysed HB-EGF, involucrin and keratin 10 mRNA and protein levels in autocrine human keratinocyte cultures incubated for 18 h with RA or R115866 alone and with RA and R115866 combinations.
Results  RA induced HB-EGF and involucrin expression in a concentration-dependent manner, whereas it inhibited keratin 10 expression. R115866 alone had no effect on the expression of these genes. However, when R115866 was combined with low concentrations of RA, HB-EGF and involucrin expression was induced.
Conclusion  These results strongly suggest that R115866 potentiates the effects of RA on epidermal keratinocytes when RA is present at low concentrations.     

Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial

BACKGROUND: There is a need for safe and effective alternative treatments for patients with moderate to severe psoriasis. OBJECTIVES: Pimecrolimus is a calcineurin inhibitor that is being investigated in oral form for the treatment of psoriasis. PATIENTS AND METHODS: A double-blind, randomized, parallel-group, dose-finding study was performed. Healthy adult outpatients with moderate to severe chronic plaque-type psoriasis (n = 143) were randomized to receive oral placebo or pimecrolimus 10 mg, 20 mg or 30 mg twice daily (b.d.) for 12 weeks. Main outcome measures: The Psoriasis Area and Severity Index (PASI) was used to assess clinical severity of psoriasis. Results were analysed at weeks 7 (primary endpoint) and 13. Safety was assessed by monitoring all adverse events, laboratory investigations (blood chemistry, urinalysis, haematology) and physical examinations. RESULTS: The change from baseline in PASI at week 7 showed a dose-dependent effect. The differences between each of the two higher doses of pimecrolimus and placebo were statistically significant (P < 0.001; ANOVA). The mean percentage decreases from baseline in PASI in the placebo group and pimecrolimus 10 mg, 20 mg and 30 mg b.d. groups at week 7 were 3.1%, 22.2%, 51.3% and 54.0%, respectively. Most adverse events were of mild or moderate severity. The only adverse event to show a dose-response relationship was a transient feeling of warmth. No clinically relevant effects on laboratory parameters were observed, and no increase in skin infection with pimecrolimus was seen. CONCLUSIONS: Oral pimecrolimus produces a dose-dependent reduction in psoriasis severity, with doses of 20 mg and 30 mg b.d. being the most effective and well tolerated.     

Oral retinoic acid metabolism blocking agent Rambazole for plaque psoriasis: an immunohistochemical study

BACKGROUND: The novel systemic all-trans retinoic acid metabolism blocking agent (RAMBA) R115866 (Rambazole(TM); Barrier Therapeutics, Geel, Belgium; further referred to as rambazole) increases intracellular levels of endogenous all-trans retinoic acid (RA). Well-known effects of RA are normalization of aberrant epithelial growth and differentiation. Hence, rambazole might be beneficial in the treatment of plaque psoriasis. OBJECTIVES: The dynamics of epidermal proliferation, keratinization, lesional T-cell subsets and cells expressing natural killer (NK)-receptors in plaque psoriasis were assessed during treatment with rambazole, as part of a phase IIa open-label clinical trial. METHODS: Six patients were treated with rambazole, 1 mg, once daily, for 8 weeks. At weeks 0, 2 and 8, psoriatic plaque severity scores (SUM) and biopsies from a target lesion were assessed. Epidermal proliferation (Ki67), keratinization markers (K10, K13, K19), T-cell subsets (CD3, CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+, GITR+) and cells expressing NK-receptors (CD94, CD161) were immunohistochemically stained and quantified with image analysis. RESULTS: At week 2 the mean SUM-score was virtually equal to baseline, which was accompanied immunohistochemically by equal epidermal hyperproliferation, a nonsignificant decrease in K10 positive epidermis and, overall, a nonsignificant increase in immunocyte subsets. At week 8, in contrast, plaque severity was reduced by 34% from baseline (P < 0.05). Improvements were also detected for epidermal proliferation (-63%; P < 0.01) and K10 expression (+29%; P < 0.01), compared with baseline. No induction of retinoid-specific keratinization (K13, K19) was observed. A nonsignificant reduction of all pathogenic T-cell subsets and cells expressing NK-receptors was observed at week 8 of treatment (P > 0.05). CONCLUSIONS: Clinical efficacy of rambazole is primarily the result of restoring proliferation (Ki67) and differentiation (K10) of epidermal keratinocytes. Secondly, relevant T-cell subsets and cells expressing NK-receptors showed nonsignificant reductions after 8 weeks of treatment with rambazole.     

甲氨蝶呤治疗中、重度银屑病的疗效观察

目的:观察甲氨蝶呤(methotrexate,MTX)治疗中、重度银屑病的临床疗效和安全性。方法:41例银屑病患者每周接受MTX5～15mg静脉滴注治疗1次,共20次。结果:41例患者经过10～20周治疗后,痊愈16例(39.0%),显效17例(41.5%),好转7例(17.1%),无效1例(2.4%),有效率为80.5%,不良反应为纳差、恶心、呕吐、头痛、荨麻疹、月经过多、丙氨酸转氨酶轻度升高。结论:MTX5～15mg每周1次静脉滴注治疗中、重度银屑病安全有效。     

Clobetasol propionate lotion in the treatment of moderate to severe plaque-type psoriasis

Owing to its anti-inflammatory, antipruritic, vasoconstrictive, and immune-modulating properties, clobetasol propionate is used to treat psoriasis. This study was conducted to evaluate the efficacy, safety, and cosmetic acceptability of clobetasol propionate lotion compared with its vehicle and with clobetasol propionate cream in the treatment of moderate to severe plaque-type psoriasis. A total of 222 patients were treated. After 4 weeks of treatment, clobetasol propionate lotion was more efficient than vehicle lotion and of equivalent efficacy as clobetasol propionate cream. Cosmetic acceptability was significantly better with clobetasol propionate lotion than with clobetasol propionate cream. Clobetasol propionate lotion was efficient, safe, and well tolerated and offers a significantly higher cosmetic advantage in the treatment of moderate to severe plaque-type psoriasis compared with clobetasol propionate cream.     

Ustekinumab治疗中重度斑块状银屑病的系统评价

银屑病是一种慢性复发性炎症性皮肤病,在我国患病率约0.123％［１］,因其慢性、顽固难愈、复发率高,成为皮肤科领域重点研究防治的疾病之一。Ustekinumab在2009年获准治疗中重度斑块状银屑病,它可与人体白介素12/白介素23的p40亚单位结合,抑制其生物活性,达到治疗银屑病的作用［2］,但其疗效结论尚不统一,且缺乏长期有效性及安全性评价［3］。我们检索文献,对Ustekinumab治疗中重度斑块状银屑病的疗效和安全性进行系统评价……     

Adalimumab for treatment of moderate to severe psoriasis and psoriatic arthritis

Psoriasis and psoriatic arthritis are common diseases associated with considerable morbidity and disability. Their pathophysiology comprises similar processes leading to inflammation of skin, entheses, and joints. Although traditional systemic agents can be effective, their use may be limited by lack of efficacy and concerns regarding adverse effects. The objective of this study was to assess the efficacy and safety of adalimumab, a fully human antitumor necrosis factor (anti-TNF) monoclonal antibody, over 16 weeks. The present authors report their personal experience in 15 patients with severe plaque psoriasis and psoriatic arthritis, refractory to other treatments, in which a decisive regression of joint/skin involvement was obtained. Psoriasis and psoriatic arthritis are chronic inflammatory disorders resulting from a combination of genetic and environmental factors.     

Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis

Background  An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all- trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866).
Objectives  To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial.
Methods  Gels containing talarozole (0·35% or 0·07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1α and tumour necrosis factor-α].
Results  Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1α compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected.
Conclusions  Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.     

阿维A治疗斑块状银屑病临床疗效观察

目的:观察阿维A治疗中、重度斑块状银屑病的疗效.方法:将中、重度斑块状银屑病患者随机分成两组,分别给予阿维A和海棠合剂治疗,疗程均为8周,以银屑病面积和严重度指数(PASI)和皮肤病生活质量指数(DLQI)作为观察指标,比较两种药物的疗效.结果:治疗后,两组患者的PASI评分和DLQI评分与治疗前比较均显著下降(P＜0.01),但PASI改善率和DLQI改善率两组间比较差异无统计学意义,PASI50和PASI75有效率亦无统计学意义(P＞0.05).结论:阿维A治疗中、重度斑块状银屑病有效.     

Oral liarozole vs. acitretin in the treatment of ichthyosis: a phase II/III multicentre, double-blind, randomized, active-controlled study

BACKGROUND: Liarozole, a retinoic acid metabolism blocking agent, has been granted orphan drug status for congenital ichthyosis by the European Commission and the U.S. Food and Drug Administration. OBJECTIVES: The purpose of this trial was to investigate the efficacy, tolerability and safety of oral liarozole vs. acitretin in patients with ichthyosis. METHODS: In this double-blind comparative trial of liarozole vs. acitretin, 32 patients with ichthyosis were randomized to be treated with either oral liarozole 75 mg in the morning and 75 mg in the evening or with acitretin 10 mg in the morning and 25 mg in the evening for 12 weeks. Clinical efficacy, tolerability and safety were monitored. RESULTS: Between-group comparisons for efficacy and tolerability revealed no statistically significant differences except for scaling on the trunk at baseline which was significantly worse in the liarozole group (P = 0.024) and showed a more pronounced improvement in this group than in the acitretin-treated patients (P = 0.047). Based on the overall evaluation of the response to treatment at endpoint, 10 of 15 patients in the liarozole group and 13 of 16 patients in the acitretin group were considered by the investigator to be at least markedly improved. The expected retinoic acid-related adverse events were mostly mild to moderate and tended to occur less frequently in the liarozole group. No serious adverse events related to the drugs occurred. CONCLUSIONS: The present study indicates that liarozole at a daily dose of 150 mg is equally effective as a treatment for ichthyosis as acitretin but shows a trend towards a more favourable tolerability profile. The results of this trial warrant further clinical trials to confirm efficacy and safety of liarozole as an orphan drug in ichthyosis.     

Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study

BACKGROUND: Palmoplantar pustular psoriasis (PPP) is a chronic, relapsing condition often recalcitrant to therapy. Synthetic retinoids have been found to be efficacious in the treatment of PPP, but their use is limited by side-effects. Liarozole is an imidazole-like compound that inhibits the retinoic acid (RA) 4-hydroxylase-mediated breakdown of all-trans RA, causing elevation of plasma and cutaneous levels of RA. Thus liarozole acts as a retinoid-mimetic drug. Liarozole has already been found to be effective in the treatment of retinoid-responsive conditions such as chronic plaque psoriasis and ichthyoses. OBJECTIVES: To assess the efficacy and side-effect profile of liarozole in the treatment of PPP. METHODS: We performed a double-blind, randomized, placebo-controlled trial of oral liarozole 75 mg twice daily for 12 weeks in the treatment of PPP. The trial was conducted at two centres and involved 15 patients. RESULTS: Using the PPP Area and Severity Index we found a statistically significant (P = 0.02) improvement in PPP in subjects on liarozole (median 3, range 1.8-14.1) as compared with placebo (median 12.1, range 5-18) by the end of the treatment phase. There was also a statistically significant difference (P = 0.006) in the number of fresh pustules after treatment for the two study groups (liarozole median 2, range 0-18; placebo median 38, range 2-75). The severity of disease (on a scale of 0-8) between the two groups was significantly different at the end of treatment (liarozole median 1, range 1-5; placebo median 3, range 2-6; P = 0.04). No patients withdrew from the trial because of adverse events. The most commonly reported side-effects were pruritus, cheilitis and xerosis but these were rarely severe and resolved rapidly on discontinuation of treatment. Laboratory results, including haematology, liver function tests and serum cholesterol and triglycerides were not significantly different between the liarozole and placebo groups. CONCLUSIONS: The results of this pilot study suggest that liarozole 75 mg twice daily is an effective and well-tolerated therapy for PPP. In addition, the pharmacokinetics of liarozole may help to circumvent side-effects associated with synthetic retinoids and allow its use in premenopausal women.     

司库奇尤单抗治疗中重度斑块状银屑病20例临床观察

目的:观察司库奇尤单抗注射液治疗中重度斑块状银屑病的临床疗效及安全性.方法:纳入20例中重度斑块状银屑病患者,给予司库奇尤单抗注射液皮下注射治疗,300 mg/次,分别于第0、1、2、3、4周注射1次,随后每4周1次,于第4、8、12周时记录患者银屑病皮损面积和严重度指数(PASI)、中性粒细胞和淋巴细胞比值(NLR)...     

Apremilast,an oral phosphodiesterase 4 inhibitor,in the treatment of Japanese patients with moderate to severe plaque psoriasis: Efficacy,safety and tolerability results from a phase 2b randomized controlled trial

Apremilast, an oral, small‐molecule phosphodiesterase 4 inhibitor, works intracellularly within immune cells to regulate inflammatory mediators. This phase 2b randomized, placebo‐controlled study evaluated efficacy and safety of apremilast among Japanese patients with moderate to severe plaque psoriasis. In total, 254 patients were randomized to placebo, apremilast 20 mg b.i.d. (apremilast 20) or apremilast 30 mg b.i.d. (apremilast 30) through week 16; thereafter, all placebo patients were re‐randomized to apremilast 20 or 30 through week 68. Efficacy assessments included achievement of 75% or more reduction from baseline in Psoriasis Area and Severity Index score (PASI‐75; primary) and achievement of static Physician Global Assessment (sPGA; secondary) score of 0 (clear) or 1 (minimal) at week 16. Safety was assessed through week 68. At week 16, PASI‐75 response rates were 7.1% (placebo), 23.5% (apremilast 20; P = 0.0032 vs placebo) and 28.2% (apremilast 30; P = 0.0003 vs placebo); sPGA response rates (score of 0 or 1) were 8.8% (placebo), 23.9% (apremilast 20; P = 0.0165 vs placebo) and 29.6% (apremilast 30; P = 0.0020 vs placebo). Responses were maintained with apremilast through week 68. Most common adverse events (AEs) with placebo, apremilast 20 and apremilast 30 (0–16 weeks) were nasopharyngitis (8.3%, 11.8%, 11.8%), diarrhea (1.2%, 8.2%, 9.4%), and abdominal discomfort (1.2%, 1.2%, 7.1%), respectively. Exposure‐adjusted incidence of these AEs did not increase with continued apremilast treatment (up to 68 weeks). Apremilast demonstrated efficacy and safety in Japanese patients with moderate to severe plaque psoriasis through 68 weeks that was generally consistent with prior studies.     

Low-dose etanercept therapy in moderate to severe psoriasis in Korean

Etanercept is a fully humanized soluble tumor necrosis factor (TNF)-alpha receptor that competitively inhibits the interaction of TNF-alpha with cell-surface receptors. It was approved as monotherapy for psoriasis in the USA in 2004, but in Korea, no clinical reports on its use for psoriasis are available. We performed a retrospective analysis of 26 moderate-to-severe psoriasis patients who had been treated with etanercept. Patients received twice-weekly injections of 25 mg etanercept s.c. for at least 4 weeks. When the patients achieved a 50% reduction of the psoriasis area severity index (PASI 50) they received once-weekly injections, then biweekly injections were provided for maintenance. Patients were evaluated biweekly by clinical photographs and PASI scoring. Treatment efficacy was as follows. A PASI 75 was achieved in 14 patients (54%) and the mean number of injections before achieving a PASI 75 was 10 +/- 7.5. Patients whose initial PASI was less than 10 (iPASI < 10) showed an earlier response (2.6 +/- 1.3 weeks) and a higher PASI 75 rate (63%), than with iPASI > or = 10 (6.9 +/- 4.5 weeks, 50%). Eight patients (31%) received additional phototherapy or systemic therapy because of insufficient responses or for faster improvements and they were excluded in the efficacy evaluation. Adverse events were observed in eight patients (31%), but were not serious. This is the first report on the effectiveness of low-dose etanercept regimen on Asian psoriasis patients. Results in this study showed that low-dose etanercept therapy is effective for moderate-to-severe Asian psoriasis patients, and it may be a valuable treatment option even for relatively moderate psoriasis patients not responsive to conventional treatment. In addition, the medical cost was relatively low compared to that of the standard regimen for white patients.     

生物制剂治疗中重度斑块状银屑病及关节病型银屑病的进展

银屑病是一种免疫介导的慢性复发性炎症性疾病,针对其发病机制中细胞因子及受体的生物制剂近年成为银屑病重要的治疗手段。随着司库奇尤单抗（secukinumab）和乌司奴单抗（ustekinumab）等生物制剂在我国陆续上市,生物制剂在银屑病治疗中的应用将越来越普遍。本文综述不同生物制剂治疗中重度斑块状银屑病及关节病型银屑病...     

复方丙酸氯倍他索软膏治疗寻常性银屑病临床疗效观察

目的:观察复方丙酸氯倍他索软膏治疗寻常性银屑病的疗效和安全性。方法:将入组的360例寻常性银屑病患者分为治疗组(复方丙酸氯倍他索软膏组120例)、对照1组(0.02%丙酸氯倍他索霜组120例)和对照2组(0.05%全反式维A酸霜组120例),采用多中心、随机双盲、平行对照的方法对寻常性银屑病患者连续用药4周。结果:3组患者的痊愈率分别为48.33%、18.33%和3.48%,有效率分别为92.50%、50.83%和31.30%。组间比较(试验组与对照1组比较,试验组与对照2组比较)显示,痊愈率和有效率差异均有显著性(P<0.01)。试验组和对照1组的不良反应发生率较轻微,对照2组不良反应发生率为11.67%,有3例因不良反应较重中途停止治疗。结论:复方丙酸氯倍他索软膏是一种安全有效的治疗寻常性银屑病的外用药,其疗效优于单用丙酸氯倍他索霜或全反式维A酸霜。     

Tofacitinib for the treatment of moderate to severe chronic plaque psoriasis in Japanese patients: Subgroup analyses from a randomized,placebo‐controlled phase 3 trial

Tofacitinib is an oral Janus kinase inhibitor. These post‐hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52‐week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo‐treated patients advanced to tofacitinib at week 16. Primary efficacy end‐points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI‐75) and Physician's Global Assessment (PGA) of “clear” or “almost clear” (PGA response) at week 16. Other end‐points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI‐75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis.