An experience on the model-based evaluation of pharmacokinetic drug-drug interaction for a long half-life drug.

Fixed-dose combinations development requires pharmacokinetic drugdrug interaction (DDI) studies between active ingredients. For some drugs, pharmacokinetic properties such as long half-life or delayed distribution, make it difficult to conduct such clinical trials and to estimate the exact magnitude of DDI. In this study, the conventional (non-compartmental analysis and bioequivalence [BE]) and modelbased analyses were compared for their performance to evaluate DDI using amlodipine as an example. Raw data without DDI or simulated data using pharmacokinetic models were compared to the data obtained after concomitant administration. Regardless of the methodology, all the results fell within the classical BE limit. It was shown that the model-based approach may be valid as the conventional approach and reduce the possibility of DDI overestimation. Several advantages (i.e., quantitative changes in parameters and precision of confidence interval) of the model-based approach were demonstrated, and possible application methods were proposed. Therefore, it is expected that the model-based analysis is appropriately utilized according to the situation and purpose.

Anti-inflammatory activities of crocetin derivatives from processed Gardenia jasminoides.

This study was designed to investigate changes of anti-oxidant and anti-nitric oxide (NO) production activities of Gardenia jasminoides (Gj) by roast processing, and anti-inflammatory activities of crocetin derivatives isolated from Gj. In order to evaluate anti-oxidant and anti-inflammatory activities, DPPH radical scavenging activities and inhibitory activities against lipopolysaccharide (LPS)-induced NO production were determined. Then we isolated crocin (1), gentiobiosyl glucosyl crocetin (3), and mono-gentiobiosyl crocetin (4) from the fruit of Gj, and crocetin (2) from the processed fruit of Gj (PGj) by column chromatography. Their structures were based on spectroscopic methods including IR, MS, and NMR (1D and 2D). Then we assayed contents of crocetin derivatives by HPLC analysis. These crocetin derivatives were evaluated the inhibitory activities on NO production in LPS-stimulated macrophage RAW 264.7 cells and expressions of protein and m-RNA of iNOS and COX-2 by western blot analysis and RT-PCR experiment. The DPPH radical scavenging activities were increased and NO productions in LPS-stimulated RAW 264.7 cells were decreased dose-dependently by processing. Crocin contents were decreased and crocetin contents were increased by processing in HPLC analysis. Compounds 1, 2, 3 and 4 reduced NO production in a dose-dependent manner with IC50 values of 58.9 µM (1), 29.9 µM (2), 31.1 µM (3), and 37.6 µM (4) respectively. Crocetin (2) showed the most potent anti-inflammatory activity (IC50 = 29.9 µM), and compound 3 and 4 were firstly measured for inhibitory activities on NO production. Their correlation between structure and activity was not clear but the activity of aglycone type showed the most potent activity. They also suppressed the protein and m-RNA expressions of iNOS and COX-2 in LPS-activated macrophage. These results suggest that anti-oxidant and anti-NO production activities of Gj were increased by processing, and increased anti-inflammatory activities of Gj by processing were due to the increase of crocetin, the aglycone that has greater activity than crocin.

Cognitive dysfunction in drug induced parkinsonism (DIP).

Several studies have suggested that the presence of dementia increases the risk of developing DIP. However, these prior studies exclusively focused on the underlying conditions before the development of DIP and there are no studies about the characteristics and prognosis of the cognitive status associated with DIP. We investigate the cognitive impairments associated with DIP by comparing neuro-psychological test results in patients with Parkinson's disease (PD) and normal controls and the longitudinal outcome of cognition in DIP. The cohort in this study included 13 consecutive patients with DIP and 91 patients with PD; all subjects completed a clinical assessment, neuropsychological investigation, and magnetic resonance imaging of brain. All patients with DIP were followed closely for more than six months after withdrawal of the offending drug. The cognitive function in DIP was significantly worse than in controls for most domains; however, there were no significant differences found in the comparisons with the PD patients. In addition, the severity of motor impairment was in part associated with cognitive function. Some patients had transient and reversible cognitive impairment, similar to other Parkinsonian motor features, and others experienced persistence and eventual worsening of their cognitive dysfunction after discontinuation of the offending drug. The results of this study suggest that cognitive impairment in patients with DIP reflects the toxic/metabolic symptoms associated with the offending drug in addition to being a risk factor for DIP.

A new method for the preparation of bioactive calcium phosphate films hybridized with 1alpha,25-dihydroxyvitamin D3.

The primary goal of this investigation was to develop a calcium phosphate film hybridized with 1alpha,25-dihydroxyvitamin D(3) for the improvement of osteoconductivity of bone substitutes. The hybrid films (hCaP) were prepared at the different concentrations of 1 x 10(-10), 1 x 10(-8), and 1 x 10(-6) M designated as hCaPL, hCaPM, and hCaPH, respectively. The change of the hormone concentration during the preparation of the hybrid films did not cause significant variations on the physical properties of hCaPs, i.e. surface morphology and roughness. On the other hand, X-ray photon spectroscope (XPS) measurements revealed that the concentration change affected the chemical composition of the hybrid films. Recruitment of osteoblast-like MG-63 cells was considerably improved on hCaPs compared to tissue culture plate (TCP). However, cell proliferation on hCaPs was substantially suppressed and inversely proportional to the hormone concentration used. It was observed that bone-like nodules which consisted of bead-like components and well-developed matrix were rapidly formed on hCaPs. Masson's trichrome and safranin-O stainings elucidated that the bead-like components were MG-63 cells. Safranin-O staining showed that proteoglycan was produced actively. These results indicate that the cells cultured on hCaPs were strongly stimulated by the hormone to produce proteoglycan which can be considered as an induction of premature bone formation. The number of the nodules was increased with hormone concentration and most pronounced at the hCaPH. Gene expression patterns of alkaline phosphatase (ALP), transforming growth factor-beta (TGF-beta), and osteopontin (OPN) were strongly modulated by hybridized the hormone. For ALP and OPN, gene expressions were activated earlier on hCaPs than untreated calcium phosphate (CaP) confirming the effect of the hybridization was substantial. The TGF-beta gene expression was immediately activated after seeding but difference between samples was not significant suggesting that the gene expression was modulated not by the hormone hybridization but by CaP itself. As a result, hybridization of 1,25(OH)(2)D(3) with CaP can be a potentially strong candidate to promote osteoconductivity of implant materials.