Four new diarylheptanoids from Rhizoma Zingiberis

Four new diarylheptanoids, (1S, 3R, 5R, 6R)-1, 5-epoxy-3, 6 dihydroxy-1-(4-hydroxy-3, 5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl) heptane (1), (1R, 3R, 5S)-1, 5-epoxy-3-acetoxy-1-(4, 5-dihydroxy-3-methoxyphenyl)-7-(3, 4- hydroxyphenyl) heptane (2), (3R, 5S, 6R, 7S)-3, 6-epoxy-7-hydroxyl-1-(4-hydroxyphenyl)-7-(3-methoxy-4-hydroxyphenyl) heptane (3), (E)-3-keto-1-(3-methoxy-4-hydroxyphenyl)-7-(4, 5-dihydroxy-3-methoxyphenyl)-4- heptene (4), were isolated from Rhizoma Zingiberis, and their structures were determined based on HR-ESI-MS and extensive spectroscopic techniques (UV, IR, 1D-NMR and 2D-NMR). Compounds 1–4 exhibited no cytotoxicity against HepG2 cell lines.

     

Chemical constituents from the whole herb of Hemiphragma heterophyllum

Phytochemical investigation on Hemiphragma heterophyllum led to the isolation of two new compounds, heterophyllumin A (1) and heterophylliol (3), along with nine known compounds, (?)-sibiricumin A (2), iridolactone (4), jatamanin A (5), dihydrocatalpolgenin (6), 25-hydroperoxycycloart-23-en-3β-ol (7), 24-methylenecycloartanol (8), (+)-pinoresinol (9), hexadec-(4Z)-enoic acid (10), and 9,12, 15-octadecatrienoic acid (11). Their structures were elucidated on the basis of detailed spectroscopic analyses and by comparison with literature data. Further, the structure of compound 3 was unambiguously confirmed by single-crystal X-ray analysis. Some of those compounds showed moderate activity in the α-glucosidase inhibition assay.

     

Diterpenoid glycosides and monoterpenoid glycosides from the fruits of Xanthium chinense

Two new diterpenoid glycosides, fructusnoids D (1) and E (2), and two new monoterpenoid glycosides (3, 4), together with three known diterpenoid glycosides (5-7) and three known monoterpenoid glycosides (8-10), were isolated from the fruits of Xanthium chinense. Their structures were elucidated by spectrometric analyses.

     

Mimengosides J and K: two new neuroprotective triterpenoids from the fruits of Buddleja lindleyana

Two new 11-methoxyl substituted triterpenoids, named as mimengosides J (1) and K (2), along with seven known compounds, were isolated from the fruits of Buddleja lindleyana. Their structures were elucidated on the basis of spectroscopic analysis. In addition, the new ones were evaluated for protective effects against damage of SH-SY5Y cells induced by 1-methyl-4-phenylpyridinium ion (MPP⁺) and the results indicated that those may be one of the candidate compositions of Buddleja lindleyana for the treatment of neurodegenerative disease.

     

Five new iridoids from the whole plants of Rehmannia henryi

Five new iridoids (1-5), jiohenrins A-E, together with sixteen known compounds (6-21), were isolated from the whole plants of Rehmannia henryi. The structures of these compounds were elucidated on the basis of their spectroscopic data.

     

A new brominated polyacetylene from Chinese marine sponge Xestospongia testudinaria

A new brominated polyacetylene xestonariene J (1), bearing a rare 2,4-dibromo-1-ene-3-yne terminal in the molecule, along with two known related analogues (2 and 3), was obtained from Chinese marine sponge Xestospongia testudinaria. Its structure was determined on the basis of detailed spectroscopic analysis and comparison with literature data.

     

Human PXR-mediated transcriptional activation of CYP3A4 by ‘Fuzi’ extracts

Objective: This study focused on determining whether the ‘Fuzi’ (FZ) extracts from different extraction methods are related to pregnane X receptor (PXR) and cytochrome P450 3A4 (CYP3A4), and explore the mechanism.

Methods: FZ was extracted under various conditions, and the components were identified by Ultra Performance Liquid Chromatography/Quad Time of Flight Mass Spectrometry (UPLC/Q-TOF-MS). Annexin V-FITC and propidium iodide staining assays were used to measure the cell cytotoxicity of these extracts. Real-time PCR, western blot analysis and reporter gene assay were used to detect the expression changes of PXR and CYP3A4.

Results: FZ extracts were found to contain high levels of monoester-diterpene alkaloids (MDAs) and diester-diterpene alkaloids (DDAs). FZ extracts were cytotoxic. Interestingly, we found that FZ extracts and DDAs can induce the expressions of PXR and CYP3A4. And the MDAs can inhibit the expressions of PXR and CYP3A4.

Conclusion: Different extracts of FZ can induce the expressions of PXR and CYP3A4 in different degrees. This may be related to the drug-drug interactions.     

Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

Background: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC).

Research design and methods: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared.

Results: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects.

Conclusion: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048.

Trial registration: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.     

Pirfenidone improves the survival of patients with idiopathic pulmonary fibrosis hospitalized for acute exacerbation

Objective: To examine the effect of pirfenidone on the survival of patients hospitalized due to acute exacerbation of idiopathic pulmonary fibrosis (AE–IPF).

Methods: The outcomes of 11 consecutive AE–IPF patients who were receiving pirfenidone treatment when they were admitted to a respiratory intensive care unit (RICU) for acute respiratory failure (ARF) (treatment group) were retrospectively compared with those of 9 patients who were not on pirfenidone treatment at admission (control group). The study’s primary outcome measure was survival following RICU admission; the patients’ mortality rate and the length of time spent in the RICU were also assessed.

Results: The treatment group had significantly longer survival than the control group (median survival time: 137.0 [95% CI, 39.0–373.0] versus 16.0 [95% CI, 14.0–22.0] days; p?=?.0009); the hazard ratio for death was 0.2896 (95% CI, 0.09541–0.8791). The treatment group also tended to have a lower RICU mortality rate (3/11 vs. 7/9; p?=?.0698).

Conclusions: Pirfenidone significantly improved survival in IPF patients hospitalized for severe acute exacerbation compared to controls.     

Urinary mutagenicity and other biomarkers of occupational smoke exposure of wildland firefighters and oxidative stress

Background: Wildland firefighters conducting prescribed burns are exposed to a complex mixture of pollutants, requiring an integrated measure of exposure.

Objective: We used urinary mutagenicity to assess if systemic exposure to mutagens is higher in firefighters after working at prescribed burns versus after non-burn work days. Other biomarkers of exposure and oxidative stress markers were also measured.

Methods: Using a repeated measures study design, we collected urine before, immediately after, and the morning after a work shift on prescribed burn and non-burn work days from 12 healthy subjects, and analyzed for malondialdehyde (MDA), 8-isoprostane, 1-hydroxypyrene (OH-pyrene), and mutagenicity in Salmonella YG1041 +S9. Particulate matter (PM_2.5) and carbon monoxide (CO) were measured by personal monitoring. Light-absorbing carbon (LAC) of PM_2.5 was measured as a surrogate for black carbon exposure. Linear mixed-effect models were used to assess cross-work shift changes in urinary biomarkers.

Results: No significant differences occurred in creatinine-adjusted urinary mutagenicity across the work shift between burn days and non-burn days. Firefighters lighting fires had a non-significant, 1.6-fold increase in urinary mutagenicity for burn versus non-burn day exposures. Positive associations were found between cross-work shift changes in creatinine-adjusted urinary mutagenicity and MDA (p?=?0.0010), OH-pyrene (p?=?0.0001), and mass absorption efficiency which is the LAC/PM_2.5 ratio (p?=?0.2245), respectively. No significant effect of day type or work task on cross-work shift changes in MDA or 8-isoprostane was observed.

Conclusion: Urinary mutagenicity may serve as a suitable measure of occupational smoke exposures among wildland firefighters, especially among those lighting fires for prescribed burns.     

Andrographolide is neither a human organic anion transporter 1 (hOAT1) substrate nor inhibitor

Andrographolide, a major bioactive compound isolated from Andrographis paniculata (Burm. F.) Nees, was evaluated for its effects on the hOAT1 membrane transporter. Substrate determination and inhibition of hOAT1-mediated uptake transport assay was carried out using recombinant CHO-hOAT1 cells. The results showed that the uptake ratio of andrographolide was less than 2.0 at all concentrations tested, indicating that andrographolide is not a hOAT1 substrate. Andrographolide has no significant effects on the p-aminohippuric acid uptake and on the mRNA and protein expression of hOAT1. In conclusion, andrographolide may not pose a drug–herb interaction risk related to hOAT1.

     

Real-world treatment patterns of PCSK9 inhibitors among patients with dyslipidemia in Germany,Spain, and the United Kingdom

Objective: Proprotein convertase subtilisin/kexin type 9 antibody inhibitors (PCSK9i) are approved as adjuncts to maximal tolerated statin therapy to lower low-density lipoprotein cholesterol (LDL-C). This study describes real-world use, characteristics of PCSK9i users and non-users, and factors influencing treatment choice.

Methods: A physician and patient survey was conducted in Germany, Spain, and the UK from December 2016 to April 2017 through the Adelphi Dyslipidemia Disease Specific Program. Physicians reported patients’ lipid-lowering therapy (LLT) history and characteristics. PCSK9i users were systematically over-sampled. Results were summarized using frequencies and proportions.

Results: The study included 110, 123, and 117 physicians from Germany, Spain, and the UK, respectively, providing data on 3,073 patients (mean age?=?62 years; 60% male). Most patients (63–73%) had prior statin and/or ezetimibe use. Compared to patients receiving other LLT (n?=?2686), PCSK9i users (222 in Germany, 97 in Spain, 68 in the UK) were, on average, 5–7.5 years younger and had LDL-C at diagnosis averaging 23–53?mg/dl higher. Familial hypercholesterolemia (FH), coronary heart/artery disease, myocardial infarction, and acute coronary syndrome were more common among PCSK9i users than non-users. PCSK9i users were also more likely to use high-intensity statins in their current LLT regimen (64–89% vs 28–50%). Physicians commonly reported PCSK9i benefits on LDL-C and total cholesterol as reasons for initiating these agents, and PCSK9i users reported good knowledge of cardiovascular disease and treatment options.

Conclusions: Results indicate that physicians are prescribing PCSK9i to patients with high cardiovascular risk in accordance with European guidelines and reimbursement requirements.     

Ginsenoside Rg1 prevents acetaminophen-induced oxidative stress and apoptosis via Nrf2/ARE signaling pathway

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. Ginsenoside Rg1 is a major active ingredient in processed Panax ginseng, which is proved to elicit biological effects. We hypothesized the beneficial effect of Rg1 on APAP-mediated hepatotoxicity was through Nrf2/ARE pathway. The study was conducted in cells and mice, comparing the actions of Rg1. Rg1 significantly improved cell survival rates and promoted the expression of antioxidant proteins. Meanwhile, Rg1 reduced the excessive ROS and the occurrence of cell apoptosis, which were related to Nrf2/ARE pathway. Expression of Nrf2 has a certain cell specificity.

     

Secondary cannabis use among London drug treatment service clients

Background: Cannabis is the second most commonly used substance after alcohol among people seeking treatment for other drug use, but no statistics are available regarding secondary cannabis use among drug treatment clients.

Objectives: To investigate levels of secondary cannabis use among drug treatment clients and perceived need for support addressing this use among clients and staff.

Methods: Cross-sectional surveys of clients (N?=?295) and staff (N?=?33) were conducted in 2015 at four London drug and alcohol treatment services. Client measures included recent drug use, type of cannabis used, Severity of Dependence Scale for cannabis, and views on secondary cannabis use treatment. Staff measures included definition of problem cannabis use, importance and timing for addressing secondary cannabis use.

Results: Among clients, 39.7% reported recent secondary cannabis use, with 30.8% of these clients meeting criteria for problem use. Problem users were more likely to be interested in receiving treatment for cannabis use than non-problem users (51.4% versus 10.8%, p?<?.001). Nearly half of staff (48.5%) thought secondary cannabis use should be addressed early in treatment.

Conclusions: Two out of five drug treatment clients used cannabis and a third experienced cannabis-related problems. Many are willing to address cannabis use, but defined treatment pathways are needed.     

Serum osteocalcin level as an indicator of low-grade albuminuria in Chinese men free of kidney disease

Objective: The presence of low-grade albuminuria (LGA) suggested that the pathophysiology of vascular dysfunction has been initiated. Clear evidence supports a role for osteocalcin in energy metabolism and a great incidence of pathological cardiovascular changes. The observational community-based study aims to examine the association of osteocalcin with LGA, which may provide new insight into potential involvement of osteocalcin in cardiovascular diseases.

Methods: A total of 1951 adults [58.37 (53.34–63.13) years, 41.3% men] from Shanghai were enrolled. LGA was defined as a urinary albumin-to-creatinine ratio (UACR)?<?30?mg/g. Serum osteocalcin was measured using an electrochemiluminescence immunoassay.

Results: Serum osteocalcin level in men decreased with increasing UACR after adjusting for potential covariates (p?=?0.045); however, the adjusted association disappeared in women (p?=?0.258). Linear regression analysis showed that osteocalcin was a negative variable of UACR in men (standardized β =??0.074, p?=?0.030), particularly prominent in non-hyperglycemic, non-hypertensive men, even regardless of estimated glomerular filtration rate (eGFR) (60?≤?eGFR <90?mL/min/1.73 m², standardized β =?0.422, p?=?0.004; ≥ 90?mL/min/1.73 m², standardized β =??0.167, p?=?0.037).

Conclusion: After controlling for confounders, serum osteocalcin level was independently associated with LGA in men, which suggested that osteocalcin was closely related with atherosclerosis and vascular dysfunction.     

Time course of arsenic species in red blood cells of acute promyelocytic leukemia (APL) patients treated with single agent arsenic trioxide

Background:Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). To elucidate metabolism and toxicity of arsenic, we analyzed time course of arsenic species in red blood cells (RBCs) of APL patients.

Methods:Nine APL patients received ATO (0.16 mg/kg/day) through 18-h infusion. Blood was collected before daily administration (days 2 to 9), and at different time points on day 8. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were detected by HPLC-ICP-MS.

Results:Arsenic species reached C_max at 18 h on day 8. Arsenicals gradually accumulated during days 2 to 9, whereas their percentages remained almost constant. The general trend in red blood cells (RBCs) was iAs > MMA > DMA. MMA was consistently the predominant methylated arsenic metabolite in RBCs. iAs, MMA, and tAs (tAs = iAs + DMA + MMA) concentrations (P < 0.0001), MMA/DMA ratios (P = 0.0016) and iAs% (P = 0.0013) were higher in RBCs than in plasma.

Conclusions:Time course of arsenic species reveal kinetic characteristic of ATO metabolites in RBCs. Arsenic species accumulated with administration frequency. Arsenic species in RBCs were remarkably different from those in plasma. Time course of arsenic species in RBCs is important in ATO clinical application.     

Waterpipe tobacco smoke distresses cardiovascular biomarkers in mice: alterations in protein expression of metalloproteinases,endothelin and myeloperoxidase

Introduction: Tobacco use is a major risk factor of cardiovascular diseases (CVD) and atherosclerosis in particular. The use of waterpipe smoking (WPS) is increasing due to the misperception that it is less harmful than cigarette smoking due to its flavor and the use of water as a filter. Thus, research that investigates toxic effects of WPS is essential. The aim of this study was to investigate the effect of WPS on major cardiovascular biomarkers that may develop atherosclerosis in mice.

Methods: BALB/c mice were exposed to WPS for either two weeks (acute exposure) or eight weeks (chronic exposure). Then, the heart tissue homogenates were analyzed to elucidate the effects of WPS on matrix metalloproteinase (MMPs: isoforms 1, 3, and 9), metallopeptidase inhibitor (TIMP1), endothelin-1 (ET-1) and myeloperoxidase (MPO) using ELISA technique.

Results: Current data showed that acute exposure to WPS significantly enhanced the levels of MMP-3, MMP-9, and MPO (p?<?0.05) compared to their corresponding control. However, the body was capable to restore the increased levels of these parameters following chronic exposure to WPS for 8?weeks (p?>?0.05). Additionally, the levels of ET-1 were significantly higher upon chronic exposure to WPS compared to both control and acute exposure groups (p?<?0.05).

Conclusions: Waterpipe exposure has a significant negative effect on the cardiovascular system. The enhancement of the atherosclerotic biomarkers (MMP-3, MMP-9, MPO, and ET-1) might represent an early scavenger of compensatory efforts to maintain cardiovascular function after WPS exposure.     

Clarithromycin laurate salt: physicochemical properties and pharmacokinetics after oral administration in humans

Objective: To prepare and characterize the physicochemical and pharmacokinetic properties of clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM).

Methods: CLM-L was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, ¹H NMR, and ¹³C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets.

Results: CLM-L showed lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. C_max, T_max and AUC_0→∞ of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC_0→∞ for the CLM-L tablets tended to be higher than that of CLM tablets at all-time points.

Conclusion: CLM-L was successfully prepared and its formation was confirmed. CLM-L was more hydrophobic than CLM. It exhibited a slight in vivo absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM.     

Comparative efficacy of first-line ceritinib and crizotinib in advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer: an adjusted indirect comparison with external controls

Objective: In the absence of head-to-head trials, this study indirectly compared progression free survival (PFS) and overall survival (OS) between ceritinib and crizotinib among patients with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).

Methods: A matching-adjusted indirect comparison method was implemented to adjust for cross-trial differences in patient characteristics between ASCEND-4 and PROFILE 1014 trials. Patient-level data from ASCEND-4 and published summary data from PROFILE 1014 were used. Patients in ASCEND-4 were reweighted to match average baseline characteristics (i.e. age, sex, race, tumor histology, ECOG score, smoking status, extent of disease, and presence of brain metastases) reported for PROFILE 1014 patients using propensity score weighting. PFS and OS were then compared between balanced populations.

Results: ASCEND-4 included more current smokers (8.0% vs 4.4%) and fewer patients under the age of 65 years (78.5% vs 84.0%) compared to PROFILE 1014. After matching, these and all other patient characteristics were balanced between the two trial populations. Compared to crizotinib, ceritinib was associated with a significantly longer PFS (hazard ratio [95% confidence interval] (HR [CI])?=?0.64 [0.47–0.87]; median PFS: 25.2 vs 10.8 months, log-rank p-value?=?0.003). OS did not differ significantly, with a HR of 0.82 [0.54–1.27] for ceritinib compared to crizotinib.

Conclusions: In the adjusted indirect comparison with external controls, the second generation ALK inhibitor, ceritinib, was associated with a significantly prolonged PFS compared to crizotinib as first-line treatment for ALK-positive NSCLC.     

Specific hypertension smartphone application to improve medication adherence in hypertension: a cluster-randomized trial

Introduction: Digital interventions, such as smartphone applications (apps), are becoming an increasingly common way to support medication adherence and self-management in chronic illness.

Aim: To evaluate the effectiveness of the intervention in pharmacological therapeutic adherence in mild to moderate arterial hypertension (AHT), through an app installed on a mobile phone, as well as the degree of control reached by the patient with this tool.

Methods: Prospective, randomized controlled trial, full study and multicenter study. Four primary care centers participated. One hundred and fifty-four hypertensive patients under antihypertensive treatment were included. Two groups were established: a control group (CG) with usual intervention (n?=?77) and an intervention group (n?=?77) (IG), targeting hypertensive people who owned and regularly used a mobile smartphone, specifically using the app called AlerHTA to promote health education and reminder of appointments. There were three visits: initial, 6 and 12 months. Drug adherence was measured by electronic monitors (MEMSs). The primary outcomes were average daily percentage adherence between 80 and 100%, and AHT control.

Results: A total of 148 patients finished the study. Mean age was 57.5?±?9.9. Global adherence was 77.02% (CI?=?70.25–83.79) and daily adherence was 74.32% (CI?=?67.29–81.35%). Daily adherence was 93.15% and 86.3% in IG, and 70.66% and 62.66% in CG after 6 and 12 months respectively (p < .05). The percentage of uncontrolled patients was 28.3% (CI?=?21.05–35.55%). The control of high blood pressure at 12 months was 17.8% and 38.6% for IG and CG respectively (p < .05). The number of patients needed to treat to avoid non-adherence (NNT) was 4.23 patients.

Conclusions: The intervention with an app installed on the mobile phones of hypertensive patients favors pharmacological therapeutic adherence and improves the percentage of hypertensive patient control.

Trial registration: Spanish Agency of Medicine: EPA-SP UN-HTA-2015-01.