Chylomicrons-Simulating Sustained Drug Release in Mesenteric Lymphatics for the Treatment of Crohn's-Like Colitis.

BACKGROUND AND AIMS: Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn's disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn's colitis. METHODS: We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10-/- spontaneous experimental colitis. RESULTS: ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN. CONCLUSION: Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment.

Network pharmacology strategy for revealing the pharmacological mechanism of pharmacokinetic target components of San-Ye-Tang-Zhi-Qing formula for the treatment of type 2 diabetes mellitus.

ETHNOPHARMACOLOGICAL RELEVANCE: San-Ye-Tang-Zhi-Qing formula (SYTZQ) is an effective prescription for the treatment of pre-diabetes disorders of glycolipid metabolism in type 2 diabetes mellitus (T2DM). It consists of five Chinese herbs including Mori Folium, Nelumbinis Folium, Crataegi Folium, Salviae Miltiorrhizae Radix et Rhizoma and Paeoniae Radix Rubra. AIM OF THE STUDY: This study was aimed to reveal the pharmacological mechanism of pharmacokinetic target components of SYTZQ for the treatment of T2DM. MATERIALS AND METHODS: A rapid, precise and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to quantify simultaneously nuciferin, vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, paeoniflorin and rosmarinic acid in rat plasma after oral administration of SYTZQ. The network pharmacology was used to analyze the effect of the compounds absorbed into the blood of SYTZQ on T2DM. The effects of paeoniflorin, nuciferine and rosmarinic acid on adipogenic differentiation were validated in vitro experiments. RESULTS: The separation was performed on an ACQUITY UHPLC HSS T3 column (2.1 mm × 100 mm, 1.7 µm) using acetonitrile and 0.1% (v/v) formic acid in water as the mobile phase in gradient elution. The calibration curves of five analytes showed good linearity (r ≥ 0.9991) with the lower limits of quantification (LLOQ) between 0.3 and 5.0 ng/mL. The recoveries and matrix effects of five analytes ranged from 81.1% to 113%. The RSDs of inter-day and intra-day precision were all within 13.7%. The validated method was successfully applied to the pharmacokinetic study of five ingredients after oral administration of SYTZQ to rat. 39 major targets and 22 candidate pathways of five compounds absorbed into the blood of rats after administration of SYTZQ were identified and successfully constructed a compound-target-disease-pathway network. It was confirmed that paeniforin, nuciferine and rosmarinic acid could decrease the adipogenicity differentiation in vitro experiments. CONCLUSIONS: The pharmacokinetic parameters indicated that the five components (nuciferin, vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, paeoniflorin and rosmarinic acid) were absorbed and eliminated quickly in vivo. These five absorbed components were associated with 22 pathways, including insulin resistance, regulation of lipolysis in adipocytes, PI3k/AKT-, TNF-, cAMP- and cGMP-PKG-signaling pathway. Paeoniflorin, nuciferine and rosmarinic acid have the effect of inhibiting adipocyte differentiation. This study could provide more reference for quality control, and provide a firm basis for evaluating the clinical efficiency of SYTZQ.

The Tissue Distribution of Four Major Coumarins after Oral Administration of Angelicae Pubescentis Radix Extract to Rats Using Ultra-High-Performance Liquid Chromatography.

Angelicae pubescentis radix (APR) is widely applied in treating rheumatoid arthritis in China. Coumarins are the major active compounds of APR extract including columbianetin, columbianetin acetate, osthole, and columbianadin. The in vivo behavior of the four major coumarins of APR has not been systematically reported. A feasible and reliable ultra-performance liquid chromatography (UPLC) method was established and validated for the quantification of the above four coumarins in rat various tissues (including heart, liver, spleen, lung, kidney, uterus, ovary, and muscle) after oral administration of APR extract. The separation was implemented on a Waters ACQUITY BEH C18 column (4.6 mm × 100 mm, 1.7 µm) with gradient mobile phase comprising acetonitrile-water (with 1mM formic acid) at a flow rate of 0.3 mL/min. The tissue homogenate samples were prepared by liquid-liquid extraction with ethyl acetate. The calibration curves were linear in the range of 1.6-20000 ng/mL for four coumarins with the lower limit of quantitation of 1.6 ng/mL in rat tissues. The intraday and interday precisions and recoveries were all within 80-100% with the relative standard deviations (RSDs) which were all less than 10.9%. The method was successfully applied to the tissue distribution research after oral administration of 6.0 g/kg APR extract to rat. The results revealed that the tissues distributions of four coumarins were in the liver, followed by the ovary, uterus, kidney, lung, heart, spleen, and muscle.

Pharmacokinetics and tissue distribution study of bisabolangelone from Angelicae Pubescentis Radix in rat using LC-MS/MS.

A sensitive and accurate LC-MS/MS method was established for quantifying bisabolangelone in rat plasma and tissues. Bisabolangelone was isolated and purified from Angelicae Pubescentis Radix. The pharmacokinetic and tissue distribution of bisabolangelone after administration to rat was performed by LC-MS/MS. Separation was carried out on a C8 (4.6 × 100 mm, 1.8 µm) column. The MS/MS transitions of bisabolangelone and tussilagone (internal standard) were set at m/z 249.1 → 109.1 and m/z 391.4 → 217.4, respectively. The lower limit of quantification in plasma and other tissues ranged from 1 to 4 ng/mL. The biosamples were prepared using protein precipitation method with acetonitrile. The recovery was >92%. The results showed that values of maximum concentrations and area under the curve depended linearly on the studied doses (2.5, 5 and 7.5 mg/kg body weight). The other ingredients in Angelicae Pubescentis Radix extract possibly reduce the absorption of bisabolangelone in rat. Tissue distribution revealed that bisabolangelone was widely distributed in vivo. The highest and lowest concentrations of bisabolangelone were found in the stomach and in the brain, respectively. It was concluded that the newly established HPLC-MS/MS method was suitable to describe the pharmacokinetic characteristics of bisabolangelone in rat after administration.

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers.

Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler (LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 µm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.

Simultaneous determination of columbianetin-ß-d-glucopyranoside and columbianetin in a biological sample by high-performance liquid chromatography with fluorescence detection and identification of other columbianetin-ß-d-glucopyranoside metabolites by ultra high-performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry.

Columbianetin-ß-d-glucopyranoside (CBG) and its metabolite columbianetin (CBN) are the bioactive constituents of Angelicae pubescentis radix (APR). They exhibit the anti-platelet aggregation, anti-inflammatory and analgesic properties. The absorption, distribution, metabolism and excretion (ADME) of CBG has not been reported to date. Both high-performance liquid chromatography with fluorescence detection and ultra high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry methods were developed and validated for the study of ADME of CBG. It was found that CBG could be catabolized into its active metabolite CBN in vivo. The absolute bioavailability of columbianetin-ß-d-glucopyranoside was 5.63 ±â€¯4.42%. The other co-existing constituents from the APR ethanol extract could enhance the absorption of CBG. CBG and CBN were rapidly and broadly distributed in the stomach, ovary, kidney, liver, spleen, lung, muscles, heart and brain. Higher levels of accumulation of CBG and CBN were detected in the ovary and kidney tissues. Eight metabolites of CBG were tentatively identified in blood, urine, bile and faeces of rats after oral administration of pure CBG. It was also found that CBG and CBN were mainly excreted through the faecal route. It can be concluded that the validated methods were successfully applied for absorption, distribution, metabolism and excretion study of CBG.

Hyperbaric oxygen treatment for Parkinson's disease with severe depression and anxiety: A case report.

RATIONALE: Patients with Parkinson's disease (PD) frequently suffer from psychiatric disorders, and treating these symptom whereas managing the motor symptoms associated with PD can be a therapeutic challenge. PATIENT CONCERNS: We report a case of PD patient with severe depression and anxiety that refused to be treated with dopaminagonists or SSRIs, the most common treatments for PD patients suffering from psychiatric symptoms. DIAGNOSES: Parkinson's disease with severe depression and anxiety. INTERVENTIONS: This man was treated with hyperbaric oxygen treatment for 30 days. OUTCOMES: Clinical assessment scores for depression and anxiety, including Unified Parkinson's Disease Rating ScaleI (UPDRS I), UPDRS II, Hanmilton Depression Rating Scale, and Hamiliton Anxiety Rating Scale, were improved following the hyperbaric oxygen treatment. LESSONS: Hyperbaric oxygen treatment may be a potential therapeutic method for PD patient suffering from depression and anxiety. Further research is needed to validate this finding and explore a potential mechanism.