Systemic exposure to benzoic acid and hippuric acid following topical application of clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel in Japanese patients with acne vulgaris.

Clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel (CLDM/BPO3%) is a topical product for the treatment of acne vulgaris. In this study, plasma and urine concentrations of benzoic acid (BA) and hippuric acid (HA) were analyzed to estimate the pharmacokinetics (PK) of BPO after application of CLDM/BPO3% twice-daily for 7 days in Japanese patients with acne vulgaris. Seven-day repeated application of CLDM/BPO3% appears to be safe in this patient population. Concentrations of plasma and urine BA were below the limit of quantification before and after repeated application in most of the 12 adult male patients. Mean difference in Cmax and AUC0-last for plasma HA indicated increased exposures after repeated application, but with wide 90% confidence intervals. Mean Ae0-12 for urine HA was similar before and after repeated application. Repeated application of CLDM/BPO3% is thus unlikely to result in accumulation of BA and HA. The study suggests negligible systemic exposure to BPO metabolites from CLDM/BPO3% after 7-day repeated application in male patients with acne vulgaris.

The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects.

OBJECTIVE: To evaluate the safety, pharmacokinetics and pharmacodynamics of fluticasone furoate (FF) and vilanterol (VI) administered alone or in combination in three Phase I studies in healthy Japanese male subjects. MATERIALS: FF, VI and FF/VI inhalation powder in a novel dry powder inhaler (nDPI). METHODS: Study A: 48 subjects received the first dose on Day 1, followed by a 4-day washout and once-daily (OD) repeat doses of FF 200, 400 or 800 µg or placebo from Day 5 to Day 11 (7 days). Study B: 32 subjects received repeat doses of VI (12.5, 25 µg) OD for 7 days. Study C: 16 subjects received single doses of FF (800 µg), VI (50 µg), FF/VI (800/50 µg) and placebo. RESULTS: Overall, there were no safety concerns and no major differences were found in treatment-related adverse events when FF and VI were administered alone or in combination. Peak plasma concentration of FF and VI following repeat dosing was up to two times higher compared with the single dose. Individual pharmacokinetic parameters of FF and VI differed when co-administered but the differences from monotherapy were not clinically significant. Repeat dosing of FF affected weighted mean (0 - 24 hours) serum cortisol with FF 200, 400 and 800 µg resulting in respective reductions from placebo of 32%, 38% and 97%, respectively. Mean maximum heart rate (0 - 4 hours) was comparable between placebo, VI 12.5 and 25 µg over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 µg, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 µg (66 bpm) or placebo (64 bpm), but the difference was not clinically significant. CONCLUSIONS: In healthy Japanese subjects, no safety concerns were found following repeat dosing of FF and VI or single dosing of FF, VI and FF/VI. Systemic exposure to FF and VI increased in a dose-dependent manner. Serum cortisol level was suppressed by 97% after 7 days repeat administration of FF at a dose of 800 µg. Heart rate with a single dose of VI 50 µg was higher than that of placebo, though not to a clinically significant extent.

Efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension.

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label, uncontrolled, dose-escalation study, 25 Japanese patients with PAH were scheduled to receive 5 mg of ambrisentan once daily for the first 12 weeks, and 10 mg once daily for an additional 12 weeks. The primary endpoint was improvement in exercise capacity from baseline which was indicated by 6-minute walk distance; the secondary endpoints included World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, and cardiopulmonary hemodynamics. CLINICAL TRIAL REGISTRATION: NCT00540436. RESULTS: At week 24, improvements were noted in all endpoints, with no clinically significant elevation of serum aminotransferase level. Pharmacokinetics in these Japanese patients was similar to that of non-Japanese populations, suggesting that once-daily dosing is appropriate in Japanese patients. Ambrisentan was generally well tolerated. No new safety signals were identified. LIMITATION: This study lacked a control group and was insufficiently powered to reach definitive conclusions on the efficacy of ambrisentan. CONCLUSION: Ambrisentan is considered as safe and effective for Japanese adults with PAH.

HTLV-1 basic leucine-zipper factor, HBZ, interacts with MafB and suppresses transcription through a Maf recognition element.

HTLV-1 infection causes adult T-cell leukemia (ATL). The development of ATL is thought to be associated with disruption of transcriptional control of cellular genes. HTLV-1 basic leucine-zipper (bZIP) factor, HBZ, is encoded by the complementary strand of the provirus. We previously reported that HBZ interacts with c-Jun and suppresses its transcriptional activity. To identify the cellular factor(s) that interact with HBZ, we conducted a yeast two-hybrid screen using full-length HBZ as bait and identified MafB. HBZ heterodimerizes with MafB via each bZIP domain. Luciferase analysis revealed a significant decrease in transcription through Maf recognition element (MARE) in a manner dependent on the bZIP domain of HBZ. Indeed, production of full-length HBZ in cells decreased the MARE-bound MafB protein, indicating that HBZ abrogates the DNA-binding activity of MafB. In addition, HBZ reduced the steady-state levels of MafB, and the levels were restored by treatment with a proteasome inhibitor. These results suggest a suppressive effect of HBZ on Maf function, which may have a significant role in HTLV-1 related pathogenesis.

Sumoylation of CoREST modulates its function as a transcriptional repressor.

It is emerging that covalent modifications of many transcription factors and co-factors by the small ubiquitin-like modifier (SUMO) can have a key role in modulating their transcriptional regulation. As SUMO modification is often associated with transcriptional repression, we studied whether it was involved in modulating the repressive activity of CoREST. We showed that CoREST can be modified by SUMO-1 at lysine 294. PIASxbeta interacted with CoREST in vitro and in vivo, and functions as an E3-ligase to mediate its sumoylation. Furthermore, SENP1 mediated the desumoylation of CoREST. Interestingly, mutation of the CoREST sumoylation site compromised its ability as a corepressor. These results demonstrate that SUMO-1 modification modulates the transcriptional repression by CoREST and is needed for its full repressive activity.