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      Evaluation of Marine Diindolinonepyrane in Vitro and in Vivo: Permeability Characterization in Caco-2 Cells Monolayer and Pharmacokinetic Properties in Beagle Dogs

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          Abstract

          A marine fibrinolytic compound was studied for use in thrombolytic therapy. Firstly, the absorption and transportation characteristics of 2,5-B HPA (2,5-B HPA:2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-tertahydro-6 H-pyran[a]isoindol-2-yl]-pentanoic acid, a novel pyran-isoindolone derivative with bioactivity isolated from a rare marine microorganism in our laboratory) in the human Caco-2 cells monolayer model were investigated. We collected 2,5-B HPA in the cells to calculate the total recovery, and its concentration was analyzed by LC/MS/MS (Liquid Chromatography/Mass Spectrum/Mass Spectrum). The results showed that 2,5-B HPA has low permeability and low total recoveries in the Caco-2 cells membrane. Pharmacokinetics and tissue distribution of 2,5-B HPA were investigated in beagle dogs using HPLC (High Performance Liquid Chromatography) after intravenous administration of three different doses (7.5, 5.0, 2.5 mg·kg −1). Pharmacokinetic data indicated that 2,5-B HPA fitted well to a two-compartment model. Elimination half-lives (T 1/2) were 49 ± 2, 48 ± 2, and 49 ± 2 min, respectively; the peak concentrations (C max) were 56.48 ± 6.23, 48.63 ± 5.53, and 13.64 ± 2.76 μg·mL −1, respectively; clearance rates (CL) were 0.0062 ± 0.0004, 0.0071 ± 0.0008, and 0.0092 ±0.0006 L·min −1·kg −1, respectively; mean retention times (MRT) were 28.17 ± 1.16, 26.23 ± 0.35, and 28.66 ± 0.84 min, respectively. The low penetrability of 2,5-B HPA indicated that the intravenous route of administration is more appropriate than the oral route. Meanwhile, 2,5-B HPA showed a good pharmacokinetic profile in beagle dogs. The tissue distribution showed that 2,5-B HPA could quickly distribute into the heart, intestines, liver, stomach, spleen, lungs, testicles, urine, intestine, kidneys, brain, and feces. The concentration of 2,5-B HPA was higher in the liver and bile. Interestingly, 2,5-B HPA was detected in the brain. Taken together, the above results suggested that our work might be beneficial in the development of agents for thrombolytic treatment.

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          Most cited references 20

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          This study presents PKSolver, a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications (VBA), for solving basic problems in pharmacokinetic (PK) and pharmacodynamic (PD) data analysis. The program provides a range of modules for PK and PD analysis including noncompartmental analysis (NCA), compartmental analysis (CA), and pharmacodynamic modeling. Two special built-in modules, multiple absorption sites (MAS) and enterohepatic circulation (EHC), were developed for fitting the double-peak concentration-time profile based on the classical one-compartment model. In addition, twenty frequently used pharmacokinetic functions were encoded as a macro and can be directly accessed in an Excel spreadsheet. To evaluate the program, a detailed comparison of modeling PK data using PKSolver and professional PK/PD software package WinNonlin and Scientist was performed. The results showed that the parameters estimated with PKSolver were satisfactory. In conclusion, the PKSolver simplified the PK and PD data analysis process and its output could be generated in Microsoft Word in the form of an integrated report. The program provides pharmacokinetic researchers with a fast and easy-to-use tool for routine and basic PK and PD data analysis with a more user-friendly interface. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
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            Incidence and mortality of venous thrombosis: a population-based study.

            Estimates of the incidence of venous thrombosis (VT) vary, and data on mortality are limited. We estimated the incidence and mortality of a first VT event in a general population. From the residents of Nord-Trøndelag county in Norway aged 20 years and older (n = 94 194), we identified all cases with an objectively verified diagnosis of VT that occurred between 1995 and 2001. Patients and diagnosis characteristics were retrieved from medical records. Seven hundred and forty patients were identified with a first diagnosis of VT during 516,405 person-years of follow-up. The incidence rate for all first VT events was 1.43 per 1000 person-years [95% confidence interval (CI): 1.33-1.54], that for deep-vein thrombosis (DVT) was 0.93 per 1000 person-years (95% CI: 0.85-1.02), and that for pulmonary embolism (PE) was 0.50 per 1000 person-years (95% CI: 0.44-0.56). The incidence rates increased exponentially with age, and were slightly higher in women than in men. The 30-day case-fatality rate was higher in patients with PE than in those with DVT [9.7% vs. 4.6%, risk ratio 2.1 (95% CI: 1.2-3.7)]; it was also higher in patients with cancer than in patients without cancer [19.1% vs. 3.6%, risk ratio 3.8 (95% CI 1.6-9.2)]. The risk of dying was highest in the first months subsequent to the VT, after which it gradually approached the mortality rate in the general population. This study provides estimates of incidence and mortality of a first VT event in the general population.
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              Venous thromboembolism: disease burden, outcomes and risk factors.

              The epidemiology of venous thromboembolism (VTE) in the community has important implications for VTE prevention and management. This review describes the disease burden (incidence), outcomes (survival, recurrence and complications) and risk factors for deep vein thrombosis and pulmonary embolism occurring in the community. Recent comprehensive studies of the epidemiology of VTE that reported the racial demography and included the full spectrum of disease occurring within a well-defined geographic area over time, separated by event type, incident vs. recurrent event and level of diagnostic certainty, were reviewed. Studies of VTE outcomes had to include a relevant duration of follow-up. VTE incidence among whites of European origin exceeded 1 per 1000; the incidence among persons of African and Asian origin may be higher and lower, respectively. VTE incidence over recent time remains unchanged. Survival after VTE is worse than expected, especially for pulmonary embolism. Thirty percent of patients develop VTE recurrence and venous stasis syndrome. Exposures can identify populations at risk but have a low predictive value for the individual. An acquired or familial thrombophilia may predict the subset of exposed persons who actually develop symptomatic VTE. In conclusion, VTE is a common, lethal disease that recurs frequently and causes serious long-term complications. To improve survival and prevent complications, VTE occurrence must be reduced. Better individual risk stratification is needed in order to modify exposures and target primary and secondary prophylaxis to the person who would benefit most.
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                Author and article information

                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                20 November 2019
                December 2019
                : 17
                : 12
                Affiliations
                [1 ]College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; zibinma@ 123456163.com (Z.M.); rhguo@ 123456shou.edu.cn (R.G.); srijeevithan@ 123456gmail.com (J.E.)
                [2 ]Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai 201306, China
                Author notes
                [* ]Correspondence: bbao@ 123456shou.edu.cn (B.B.); whwu@ 123456shou.edu.cn (W.W.); Tel./Fax: +86-21-61900364 (B.B.); +86-21-61900388 (W.W.)
                Article
                marinedrugs-17-00651
                10.3390/md17120651
                6950567
                31757085
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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