Succinic acid inhibits the activity of cytochrome P450 (CYP450) enzymes.

CONTEXT: Succinic acid, extracted from amber, is widely used in cardiovascular therapy. OBJECTIVE: The effect of succinic acid on the activity of cytochrome P450 (CYP450) enzymes was investigated in this study. MATERIALS AND METHODS: The effect of succinic acid (100 µM) on the activity of eight isoforms of CYP450 (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) was investigated compared to the specific inhibitor and blank controls in pooled human liver microsomes in vitro. The inhibition of CYPs was fitted with competitive or non-competitive inhibition models and corresponding parameters were also obtained. RESULTS: Succinic acid exerted inhibitory effect on the activity of CYP3A4, 2D6, and 2C9 with the IC50 values of 12.82, 14.53, and 19.60 µM, respectively. Succinic acid inhibited the activity of CYP3A4 in a non-competitive manner with the Ki value of 6.18 µM, and inhibited CYP2D6 and 2C9 competitively with Ki values of 7.40 and 9.48 µM, respectively. Furthermore, the inhibition of CYP3A4 was found to be time-dependent with the KI/Kinact value of 6.52/0.051 min-1·µM-1. DISCUSSION AND CONCLUSIONS: Succinic acid showed in vitro inhibitory effects on the activity of CYP3A4, 2D6, and 2C9, which indicated the potential drug-drug interactions. Succinic acid should be carefully co-administrated with the drugs metabolized by CYP3A4, 2D6, and 2C9.

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS-induced sepsis.

Sepsis commonly progresses to disseminated intravascular coagulation and induces the activation of heparanase (HPA) and the shedding of endothelial glycocalyx constituents, including syndecan-1 (SDC-1) and heparan sulphate (HS). However, the degradation of glycocalyx and its association with coagulation disorders remains undetermined. The present study aimed to evaluate the effect of unfractionated heparin (UFH) and N-acetylheparin (NAH), which is a non-anticoagulant heparin derivative, on endothelial glycocalyx and coagulation function in a lipopolysaccharide (LPS)-induced sepsis rat model, and to compare the differences observed in coagulation function between UFH and NAH. Experimental rats were randomly assigned to four groups: Control; LPS; UFH + LPS; and NAH + LPS. Rats were administered UFH or NAH and subsequently, ~1 min later, administered LPS (10 mg/kg; intravenous). The blood and lung tissues of rats were collected 0.5, 2 and 6 h after LPS injection, and were used for subsequent analysis. The results demonstrated that HPA activity and SDC-1 and HS levels increased, and this increase was associated with inflammatory cytokines and coagulation/fibrinolysis markers in the sepsis rat model. Histopathological examination was performed, and the lung injury score and lung wet/dry ratio indicated that UFH and NAH also significantly improved lung tissue injury. The results of the ELISA analysis demonstrated that UFH and NAH treatment: i) significantly decreased the levels of inflammatory cytokines including tumor necrosis factor-α and interleukin-6; ii) inhibited HPA activity and protected the integrity of the glycocalyx, which was identified by decreased HS and SDC-1 levels; and iii) decreased the levels of prothrombin fragment 1+2, thrombin-antithrombin complex, and plasminogen activator inhibitor-1 and increased the levels of fibrinogen and antithrombin-III. Preconditioning with UFH decreased the plasma activated partial thromboplastin time. These results indicated that UFH and NAH may alleviate sepsis-induced coagulopathy, and this effect may have been due to an inhibition of HPA activity and decrease in the shedding of the endothelial glycocalyx.

Use of an E2SFCA Method to Measure and Analyse Spatial Accessibility to Medical Services for Elderly People in Wuhan, China.

Current studies on measuring the accessibility of medical services for the elderly (AMSE) have ignored the potential competition among supply and demand and the distance decay laws. Hence, an enhanced two-step floating catchment area (E2SFCA) method (i.e., the road network-based Gaussian 2SFCA method) is proposed to calculate AMSE scores after considering different types of roads, including urban rail transit, freeways, major roads, minor roads and rural roads. Based on the first National Geographic Conditions Monitoring (NGCM) data, this study took Wuhan, China, as a case study and assessed the variation of AMSE using two different threshold times (i.e., Platinum Ten and Golden Hour). Next, global (i.e., sensitivity and hot spot analysis) and local analyses (i.e., three regional area internal comparisons) of AMSE scores were conducted to accurately identify details in the variation of spatial accessibility. It was observed that the E2SFCA method could be easily applied to measure AMSE. The results showed that 48.63% of the elderly population in Wuhan had a higher or the highest level of medical accessibility in "Platinum Ten", while 72.97% had a higher or the highest level in the "Golden Hour", and hot spots of AMSE scores were located in central urban areas and presented an enclosure structure using both threshold travel times, which could provide guidance to governments or planners on issues of spatial planning and identifying elderly medical services shortage areas.