Current Issue : July - September Volume : 2019 Issue Number : 3 Articles : 5 Articles
Concomitant use of rivaroxaban with non-dihydropyridine calcium channel blockers\n(non-DHPs) might lead to an increase of systemic rivaroxaban exposure and anticoagulant effects\nin relation to the inhibition of metabolic enzymes and/or transporters by non-DHPs. This study\nwas designed to evaluate the effects of verapamil and diltiazem on the pharmacokinetics and\nthe prolongation of prothrombin time of rivaroxaban in rats. The data were analyzed using\na pharmacokinetic/pharmacodynamics (PK/PD) modeling approach to quantify the influence of\nverapamil. Verapamil increased the systemic exposure of rivaroxaban by 2.8-fold (p <0.001) which\nwas probably due to the inhibition of efflux transportation rather than metabolism. Prothrombin\ntime was also prolonged in a proportional manner; diltiazem did not show any significant effects,\nhowever. A transit PK model in the absorption process comprehensively describes the double-peaks\nof rivaroxaban plasma concentrations and the corresponding change of prothrombin time with\na simple linear relationship. The slope of prothrombin time vs. rivaroxaban plasma concentration\nin rats was retrospectively found to be insensitive by about 5.4-fold compared to than in humans.\nMore than a 67% dose reduction in rivaroxaban is suggested in terms of both a pharmacokinetic\npoint of view, and the sensitivity differences on the prolongation of prothrombin time when used\nconcomitantly with verapamil....
Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic\nstroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve\nthe obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective\nand it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we\npropose an efficient mathematical modelling approach that can be used to evaluate the therapeutic\nefficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines\nthe pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying\nthe drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing\nprotocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation\nresults are compared for temporal concentrations of fibrinolytic proteins in plasma and the time\nthat is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid\ndegradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily\nlead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in\nplasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal\nadministration regimen should be sought by keeping the tPA level sufficiently high throughout the\ntreatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic\nplasma. This can be achieved through model-based optimisation in the future....
Genistein is a naturally occurring phytoestrogen isoflavone and is the active drug ingredient\nin BIO 300, a radiation countermeasure under advanced development for acute radiation syndrome\n(H-ARS) and for the delayed effects of acute radiation exposure (DEARE). Here we have assessed\nthe pharmacokinetics (PK) and safety of BIO 300 in the nonhuman primate (NHP). In addition, we\nanalyzed serum samples from animals receiving a single dose of BIO 300 for global metabolomic\nchanges using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass\nspectrometry (QTOF-MS). We present a comparison of how either intramuscularly (im) or orally\n(po) administered BIO 300 changed the metabolomic profile. We observed transient alterations in\nphenylalanine, tyrosine, glycerophosphocholine, and glycerophosphoserine which reverted back to\nnear-normal levels 7 days after drug administration. We found a significant overlap in the metabolite\nprofile changes induced by each route of administration; with the po route showing fewer metabolic\nalterations. Taken together, our results suggest that the administration of BIO 300 results in metabolic\nshifts that could provide an overall advantage to combat radiation injury. This initial assessment\nalso highlights the utility of metabolomics and lipidomics to determine the underlying physiological\nmechanisms involved in the radioprotective efficacy of BIO 300....
Acetyl triethyl citrate (ATEC) is a water-soluble plasticizer used in pharmaceutical\nplasticized polymers. In this study, the pharmacokinetics and metabolism of ATEC were\ninvestigated using liquid chromatographyâ??tandem mass spectrometry (LCâ??MS/MS) in rats. Plasma\nprotein precipitation with methanol was used for sample preparation. For chromatographic\nseparation, a C18 column was used. The mobile phases consisted of 0.1% formic acid and 90%\nacetonitrile, and gradient elution was used. The following precursor-product ion pairs were selected\nfor reaction monitoring analysis: ....................
Galangin has been reported to have many pharmacological effects including being anti-inflammatory, antibacterial, and antifungal\nand a suppressor of vitiligo, Alzheimerâ??s disease, and cancer. The purpose of this research was to characterize and determine the\nefficacy of the antitumor activity and pharmacokinetics of galangin-loaded PEGylated liposomes compared with free galangin.\nGalangin-loaded liposomes and galangin-loaded PEGylated liposomes were prepared using thin-film dispersion prior to\nultrasonication. The mean particle size of the galangin-loaded PEGylated liposomes was approximately 120 nm, the\npolydispersity index was 0.212, the zeta potential was -2.24 mV, and the entrapment efficiency was 76.31%. The release of\ngalangin from galangin-loaded PEG-modified liposomes was slowest as gauged by dynamic dialysis in vitro. In the apoptosis\nexperiment, galangin-loaded PEG-modified liposomes demonstrated cytotoxicity to hepatoma cells by apoptosis that was greater\nthan the two other forms of drug carrier. In vivo experiments demonstrated that the half-life of galangin in PEG-modified\nliposomes was 4 hours in the plasma of rats, significantly longer than that of free galangin. The experimental results suggest that\nthe PEG modification of liposomes effectively increases the solubility of galangin and alters its pharmacokinetic parameters,\nsuch that it may be effective in the treatment of liver cancer....
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