Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial.

OBJECTIVE: We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. METHODS: Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. RESULTS: In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was -86.2 mL/year (nintedanib) and -90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, -103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. CONCLUSION: In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

Alstiphyllanines I-O, ajmaline type alkaloids from Alstonia macrophylla showing vasorelaxant activity.

Seven new ajmaline type alkaloids, alstiphyllanines I-O (1-7) were isolated from the leaves of Alstonia macrophylla together with six related alkaloids (8-13). Structures and stereochemistry of 1-7 were fully elucidated and characterized by 2D NMR analysis. A series of alstiphyllanines I-O (1-7) as well as the known ajmaline type alkaloids (8-13) showed that they relaxed phenylephrine (PE)-induced contractions against rat aortic ring. Among them, vincamedine (10) showed potent vasorelaxant activity, which may be mediated through inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs) as well as partially mediated the NO release from endothelial cells. The presence of substituents at both N-1 and C-17 may be important to show vasorelaxation activity.

Incidence Rate and Prevalence of Systemic Sclerosis and Systemic Sclerosis-Associated Interstitial Lung Disease in Japan: Analysis Using Japanese Claims Databases.

INTRODUCTION: Systemic sclerosis (SSc) is a complex autoimmune disease with increased mortality, and interstitial lung disease (ILD) is a major cause of death. There are no recent epidemiological data on SSc and SSc-associated ILD (SSc-ILD) in Japan and little is known about how patients with these diseases are treated. METHODS: The incidence rate and prevalence of SSc and SSc-ILD in Japan were estimated using the Japanese Medical Data Centre (JMDC) database. The demographic and clinical characteristics of patients and the immunomodulatory medications they received were also assessed using JMDC and the Medical Data Vision (MDV) databases. All analyses were descriptive. RESULTS: The overall incidence rates of SSc and SSc-ILD per 100,000 person-years were 6.6 (95% confidence interval [CI] 6.2-7.1) and 1.9 (95% CI 1.6-2.1), respectively, and the overall prevalence per 100,000 persons was 37.0 (95% CI 35.6-38.5) and 13.9 (95% CI 13.0-14.8), respectively. ILD was the most common comorbidity in patients with SSc present in approximately 30% of patients (JMDC, 29.3%; MDV, 30.1%). The immunomodulatory medications prescribed were similar in patients with SSc and SSc-ILD, and each of the medications in this analysis was prescribed in less than 15% of patients. CONCLUSION: We have demonstrated that estimates of prevalence and incidence rates of SSc and SSc-ILD in Japan are comparable to similar database studies conducted in the USA, using a medical claims database. Only a small proportion of patients were receiving immunomodulatory treatments, suggesting undertreatment in Japan. Incidence Rate and Prevalence of Systemic Sclerosis and Systemic Sclerosis-associated Interstitial Lung Disease in Japan: Analysis Using Japanese Claims Databases-A Video Abstract. (MP4 68892 KB).

Vasorelaxant effects of macrocyclic bis(bibenzyls) from liverworts.

Vasorelaxant effects of a series of bis(bibenzyls) from liverworts such as Marchantia polymorpha and Marchantia paleacea on rat aorta demonstrated that they relaxed phenylephrine (PE)-induced contractions, which may be mediated through the increased release of NO from endothelial cells as well as opening of K(+) channels, and inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs). Structure-activity relationship based on their structures was discussed. The presence of two aromatic rings which can be connected through two atoms bridge spacer may play an important role for vasorelaxant effect.

Vasorelaxant effect of isoquinoline derivatives from two species of Popowia perakensis and Phaeanthus crassipetalus on rat aortic artery.

Five bisbenzyl isoquinolines (1-5), three benzyl isoquinolines (6-8), four isoquinoline alkaloids (9-12), and two unclassified compounds (13 and 14) from Popowia perakensis and Phaeanthus crassipetalus were evaluated for their vasorelaxant effect on rat aortic arteries. In aortic rings pre-contracted with phenylephrine (PE, 0.3 µM), some of the bisbenzyl isoquinoline alkaloids, benzyl isoquinoline alkaloids, and isoquinoline alkaloids showed clearly vasorelaxant effects at 30 µM. The action of (-)-limacine (4) was deduced to be mediated through the increased release of NO from endothelial cells, and that of pecrassipine A (7) and backebergine (12) partly mediated by NO release. Further, the action of pecrassipine A (7) and backebergine (12) may be attributed to their inhibition of the voltage-dependent Ca(2+) channel and receptor-operated Ca(2+) channel.