Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs.

Rivaroxaban (RIV) is a direct Factor Xa inhibitor anticoagulant, but the oral bioavailability of RIV is estimated to be only 60% due to its poor solubility. The aim of the present study was to improve the solubility and bioavailability of RIV. Five cocrystals-p-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DBA), nicotinamide (NA), isonicotinamide (IA), and succinic acid (SA)-were used as cofomers and were successfully obtained and characterized by powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectra. RIV-DBA and RIV-HBA cocrystals showed obvious improvements in solubility, dissolution (under sink conditions), and intrinsic dissolution rates versus RIV. Moreover, the dissolution of RIV-HBA, RIV-DBA, and RIV-SA cocrystals under non-sink conditions showed obvious "spring and parachute" patterns. The in vitro permeability levels in a Caco-2 cell model of RIV-DBA and RIV-IA cocrystals were significantly improved versus RIV. Pharmacokinetic studies in beagle dogs showed that RIV-DBA and RIV-HBA cocrystals had higher bioavailability than RIV. The enhancements in solubility and bioavailability indicate the potential of RIV cocrystals as a better candidate for the treatment of thrombosis versus RIV.

Cepharanthine loaded nanoparticles coated with macrophage membranes for lung inflammation therapy.

Acute lung injury (ALI) is a disease associated with suffering and high lethality, but to date without any effective pharmacological management in the clinic. In the pathological mechanisms of ALI, a strong inflammatory response plays an important role. Herein, based on macrophage 'homing' into inflammation sites and cell membrane coating nanotechnology, we developed a biomimetic anti-inflammation nanosystem (MM-CEP/NLCs) for the treatment of ALI. MM-CEP/NLCs were made with nanostructured lipid carriers (NLCs) coated with natural macrophage membranes (MMs) to achieve effective accumulation of cepharanthine (CEP) in lung inflammation to achieve the effect of treating ALI. With the advantage of suitable physicochemical properties of NLCs and unique biological functions of the macrophage membrane, MM-CEP/NLCs were stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. In vivo, the macrophage membranes enabled NLCs to be targeted and accumulated in the inflammation sites. Further, MM-CEP/NLCs significantly attenuated the severity of ALI, including lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammation cytokines. Our results provide a bionic strategy via the biological properties of macrophages, which may have greater value and application prospects in the treatment of inflammation.

Reconstruction of conductivity distribution with electrical impedance tomography based on hybrid regularization method.

Purpose: Physiological or pathological variation would cause a change of conductivity. Electrical impedance tomography (EIT) is favorable in reconstructing conductivity distribution inside the detected area. However, the reconstruction is an ill-posed inverse problem and the spatial resolution of the reconstructed image is relatively poor. Approach: To deal with the problem, a regularization method is commonly applied. Traditional regularization methods have their own disadvantages. In this work, we develop an innovative hybrid regularization method to determine the conductivity distribution from the boundary measurement. To address the unwanted artifact observed in the total variation (TV) method, the proposed approach incorporates the TV method with the non-convex sparse penalty term-based wavelet transform. In the reconstruction, the sensitivity matrix is also normalized to increase the sensitivity of the measurement to the variation of the conductivity. The objective function is minimized with the split augmented Lagrangian shrinkage algorithm. Results: The feasibility of the proposed method is evaluated by numerical simulation and phantom experiment. The results verify that the reconstruction with the proposed method is more advantageous, as obvious improvement is observed in the reconstructed image. Conclusions: With the proposed method, the artifact can be effectively suppressed and the reconstructed image of conductivity distribution is improved. It has great potential in medical imaging, which would be helpful for the accurate diagnosis of disease.

Sparse image reconstruction of intracerebral hemorrhage with electrical impedance tomography.

Purpose: Intracerebral hemorrhage (ICH) is a common disease that is known for its high morbidity, high mortality, and high disability. The fast and accurate detection of ICH is essential for the acute care of patients. Electrical impedance tomography (EIT) offers an alternative with which pathological tissues can be detected by reconstructing conductivity variation. Nevertheless, the sensitive field of EIT is greatly affected by medium distribution, which is referred to as soft-field effect. In addition, the image reconstruction is a severely ill-posed inverse problem. Furthermore, due to the low conductivity of skull, the sensitivity in the sensing area is extremely low. Therefore, the reconstruction of ICH with EIT is great challenge. Approach: A sparse image reconstruction method is proposed for EIT to visualize the conductivity variation caused by ICH. To reduce the impact of soft-field effect, the normalization of sensitivity distribution is conducted for monolayer and three-layer head model. In addition, a constrained sparse L 1 -norm minimization model is developed for the image reconstruction. Augmented Lagrangian multiplier method and alternating minimization scheme are adopted to solve the proposed model. Results: The results show that the sensitivity in the sensing area is largely enhanced. Numerical simulation based on monolayer head model and three-layer head model is respectively carried out. Both the reconstructed images and the quantitative evaluations show that image reconstructed by the proposed method is much better than that reconstructed by traditional Tikhonov method. The reconstructions evaluated under the impact of noise also show that the proposed method has superior anti-noise performance. Conclusions: With the proposed method, the quality of the reconstructed image would be greatly improved. It is an effective approach for imaging ICH with EIT technique.

Pharmacological targets and molecular mechanisms of plumbagin to treat colorectal cancer: A systematic pharmacology study.

Plumbagin (PL) pharmacologically plays the anti-proliferative effects in cancer cells, including effective suppression of colorectal cancer (CRC). However, the exact molecular mechanism of PL to treat CRC remains unclear. Using available SwissTargetPrediction and SuperPred databases, the anti-cancer biotargets of PL were identified, and the CRC-diseased targets were obtained through a DisGeNET database. The biological processes, and signaling pathways of PL to treat CRC were identified and visualized. Further, clinical and cell culture data were used to validate some bioinformatic findings. As shown in bioinformatics findings, 64 predictive biotargets of PL to treat CRC were collected, and 7 most important biotargets of tumor protein p53 (TP53), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), mitogen-activated protein kinase 1 (MAPK1), E1A-associated protein p300 (EP300), poly (ADP-ribose) polymerase 1 (PARP1), nuclear factor kappa p65 protein (RELA), Bcl-2 like protein 1 (BCL2L1) were identified respectively. In addition, top 20 functional biological processes, signaling pathways of PL to treat CRC were screened and prioritized. In human study, CRC samples showed elevated expressions of neoplastic MAPK1, PARP1 mRNAs and reduced EP300 mRNA level. In cell culture study, PL-treated CRC cells resulted in down-regulated MAPK1, PARP1 mRNA expressions and up-regulation of EP300 mRNA level, characterized with suppressed cell proliferation. Taken together, the therapeutic biotargets and molecular mechanisms of PL to treat CRC were screened and identified by using a systematic pharmacology analysis, and some bioinformatic findings were validated in clinical and cell line experiments. Potentially, these hub biotargets may be the biomarkers for CRC detection and treatment.

Clinical Therapeutic Effects of Aspirin in Combination with Fufang Danshen Diwan, a Traditional Chinese Medicine Formula, on Coronary Heart Disease: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Coronary heart disease is characterized by vascular stenosis or occlusion resulting in myocardial ischemia, hypoxia and necrosis. In China, the combination of aspirin and Fufang Danshen Diwan (FDD), a traditional Chinese medicine formula, has been suggested in the treatment of coronary heart disease. There have been several studies comparing the effectiveness of aspirin alone and in combination with FDD to treat coronary artery disease; however, it remains unclear whether combined aspirin therapy is superior. This study was thus designed to clarify this issue through a systematic review and meta-analysis. METHODS: Databases including PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) database, Wanfang Data and VIP Information were searched. Papers were reviewed systematically by two researchers and analyzed using Cochrane software Revman 5.1. RESULTS: Fourteen randomized controlled trials enrolling 1367 subjects were included. Meta-analyses revealed that aspirin in combination with FDD was significantly more effective at alleviating angina pectoris and improving electrocardiogram (ECG) results relative to aspirin therapy alone, reflected by the summary effects for the clinical markedly effective (OR = 2.45; 95% CI 1.95-3.08) and the total effective (OR = 3.92; 95% CI 2.87-5.36) rates. In addition, combined aspirin and FDD was significantly more efficacious than aspirin monotherapy at improving blood lipid levels, as indicated by the following outcomes: 1) reduction of TC level (SMD -1.12; 95% CI -1.49 to -0.76); 2) reduction of TG level (SMD -0.94; 95% CI -1.15 to -0.74); 3) reduction of LDL level (SMD -0.68; 95% CI -0.88 to -0.48); and 4) improvement of HDL level (SMD 0.52; 95% CI 0.04 to 0.99 ). No serious adverse events were reported in any of the included trials. CONCLUSION: The present meta-analysis demonstrated that aspirin in combination with FDD was more effective than aspirin alone for treating coronary heart disease. More full-scale randomized clinical trials with reliable designs are recommended to further evaluate the clinical benefits and long-term effectiveness of FDD for the treatment of coronary heart disease.