• Archives of Pharmacal Research
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• v.26 no.12
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• pp.1096-1101
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• 2003

To enhance the liver targeting and reduce the side effects of 5-fluorouracil (5-Fu), it was acylated by stearyl chloride to obtain .$\b{N}_{\b{1}}$stearyl-5-Fu (5-FuS). The chemical structure of the prodrug was confirmed by Nuclear Magnetic Resonance and Infrared Spectrometry. 5-FuS was incorporated into solid lipid nanoparticles (SLN), which were prepared by the physical agglomeration method. The mean diameter of 5-FuS-SLN was 240.19 nm and the drug loading was 20.53%. The release characteristics in vitro of 5-FuS-SLN were fitted to the first-order pharmacokinetic model. Compared with 5-Fu injection, a study on the distribution of 5-FuS-SLN in mice showed that 5-FuS-SLN could double 5-Fu concentration in mice livers. The main pharmacokinetic parameters of 5-FuS-SLN in rabbits is shown as follows: $V_d$=0.04336L/kg, $T_{1/2} \beta$=1.2834h, CL=0.1632 L/h. In conclusion, 5-FuS-SLN has significant liver targeting properties. The employment of a prodrug to enhance drug liposoluble properties and the preparation method presented in this paper, seem to be an alternative strategy to the traditional colloidal delivery system.

• Macromolecular Research
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• v.11 no.4
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• pp.283-290
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• 2003

Organic drugs including aspirin, omeprazole, and naproxen with three different levels of octanol/water partition coefficient were examined for their release behavior from the amphiphilic PCL-b-PEO-b-PCL (PCEC) matrix. Scanning electron micrograph (SEM) of PCEC illustrated a well defined two-phase morphology consisted of dispersed poly(ethylene oxide) (PEO) domain and continuous polycaprolactone (PCL) phase. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) experiments veri tied that three model drugs are dissolved as a molecular dispersion in PCEC matrix. The release of hydrophilic aspirin closely followed the water absorption profile of the matrix indicating that its major fraction is present in PEO domain. However, substantial amount of aspirin present in less hydrophilic region displayed discontinuous biphasic release pattern. In the case of omeprazole with intermediate hydrophobicity consistent release behavior was observed for a period of 24 hrs after the rapid liberation of ca. 10% of the drug presumably partitioned in PEO phase. It was ascribed to the fact that the progressive hydration of PCEC matrix gradually increased the chance of drug/water exposure to compensate the exhaustion of device. Naproxen with the highest octanol/water distribution coefficient among three model drugs exhibited a limited release of 35% for 24 hrs. Finally, hydroxypropyl methylcellulose phthalate (HPMCP)/PCEC blend matrix demonstrated an accelerated and quantitative release of hydrophobic naproxen by generating high porosity and thereby expanding polymer/water interface.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.86-95
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• 2020

Background: Ginsenoside Rb1 (Rb1), one of the most abundant protopanaxadiol-type ginsenosides, exerts excellent neuroprotective effects even though it has low intracephalic exposure. Purpose: The present study aimed to elucidate the apparent contradiction between the pharmacokinetics and pharmacodynamics of Rb1 by studying the mechanisms underlying neuroprotective effects of Rb1 based on regulation of microflora. Methods: A pseudo germ-free (PGF) rat model was established, and neuroprotective effects of Rb1 were compared between conventional and PGF rats. The relative abundances of common probiotics were quantified to reveal the authentic probiotics that dominate in the neuroprotection of Rb1. The expressions of the gamma-aminobutyric acid (GABA) receptors, including GABAA receptors (α2, β2, and γ2) and GABAB receptors (1b and 2), in the normal, ischemia/reperfusion (I/R), and I/R+Rb1 rat hippocampus and striatum were assessed to reveal the neuroprotective mechanism of Rb1. Results: The results showed that microbiota plays a key role in neuroprotection of Rb1. The relative abundance of Lactobacillus helveticus (Lac.H) increased 15.26 fold after pretreatment with Rb1. I/R surgery induced effects on infarct size, neurological deficit score, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were prevented by colonizing the rat gastrointestinal tract with Lac.H (1 × 10⁹ CFU) by gavage 15 d before I/R surgery. Both Rb1 and Lac.H upregulated expression of GABA receptors in I/R rats. Coadministration of a GABA_A receptor antagonist significantly attenuated neuroprotective effects of Rb1 and Lac.H. Conclusion: In sum, Rb1 exerts neuroprotective effects by regulating Lac.H and GABA receptors rather than through direct distribution to the target sites.

• Membrane Journal
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• v.27 no.6
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• pp.511-518
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• 2017

The membrane emulsification (ME) is a technology for producing emulsions with narrow size distribution by using the well-defined porous membranes such as the SPG membrane. In this study, the preparation of polycaprolactone (PCL) microcapsules by using the multiple emulsions obtained from membrane emulsification method is studied. After the making of $W_1/O$ single emulsions by sonication method, then $W_1/O/W_2$ multiple emulsions are formed by premix-ME method. The PCL microcapsules impregnated with BSA model drug are prepared by solvent evaporating from $W_1/O/W_2$ multiple emulsions. The effects of various parameters such as the ratio of disperse/continuous phase (D/C ratio), the concentration of PCL, emulsifier and model drug and the transmembrane pressure on the size and distribution of PCL microcapsules are investigated. The uniform PCL microcapsules with about $5{\sim}6{\mu}m$ of mean size and 26% of BSA loading are obtained by the premix membrane emulsification.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.2
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• pp.99-104
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• 2015

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra- abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, $C_{max}$ was $11.151{\mu}g/mL$ at 5 min after the intravenous injection and $t_{1/2}$ was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.

• Journal of Pharmaceutical Investigation
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• v.24 no.2
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• pp.73-83
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• 1994

Applications of liposomes as a drug carrier for the oral delivery of poorly-absorbable macromolecular drugs have been limited, because of their instability in gastrointestinal environments including pH, bile salts, and digestive enzymes. Two polysaccharides, dextran(DX) and pullulan(PL), were introduced to the preformed liposomes in order to enhance the stability. Palmitoyl derivatives of polysaccharides, palmitoyldextran(PalDX) and palmitoylpullulan(PalPL), were synthesizd and introduced to the liposomes during preparation for the same purpose of stability. The effects of these polysaccharides coating were evaluated basically by physical properties of particle size distribution and optical microscopy, then compared with uncoated liposomes by the observations of both in vitro stability and in vovo absorption characteristics. The geometric mean diameters of polysaccharide-coated liposomes were greater than that of uncoated liposome, showing the outermost polysaccharide-coated layer under the optical microscopy. In vitro stabilities of uncoated or polysaccharides-coated liposomes were measured by turbidity changes in various pH buffer solutions containing sodium choleate as bile salts. While uncoated liposome was very sensitive to bile salts, polysaccharides-coated liposomes were stable in relatively higher concentrations of sodium choleate, giving the results of better stability of PalDX- and PalPL-coated liposomes than that of DX- and PL-coated liposomes. After liposomal encapsulation of acyclovir(ACV), an antiviral agent as a model drug, it has been administered orally to rats as dose of ACV 40 mg/kg. Plasma concentrations of ACV were assayed by HPLC and analyzed by model-independent pharmacokinetics. Pharmacokinetic parameters of Cmax, tmax, and [AUC] have been compared.

• Korea Journal of Hospital Management
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• v.8 no.1
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• pp.64-80
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• 2003

The separation policy of prescription and drug dispensing which has been implemented since the 1st of July, 2000, has brought about great changes in patients flow within the healthcare delivery system. The changes in the patients flow, in turn, resulted in the change in the distribution of financial resources among the participating entities in the healthcare delivery system: pharmacies, clinics, small hospitals, general hospitals, and teaching hospitals. The purpose of this study is to shed some light in the change in the financial performance of teaching hospitals under the separation policy that has created environmental changes such as the decrease in the number of out patients visits, the increase in the capital expenditures, the rapid increase in labor costs and so on. For the purpose, this study has compared and analyzed the balance sheets, the income statements and other operational data of three teaching hospitals located in D area. The data include two periods: before(year 1999) and after(year 2001) the implementation of the separation policy. The analysis was conducted with an emphasis on the changes in the financial ratios such as liquidity, turnover ratio, performance ratio. and capitalization ratio. The results show that the financial performances of the hospitals under study were weaker than before the implementation of the separation policy, and that, while the operating expenses have increased remarkably, there was no tendency to corresponding increase in revenue. And the result of analysis of other operational indicators also show that the performance of the hospitals is getting worse. Based on the results, this study has suggested the directions of the healthcare policies. This study suggests to improve the current model of separation of prescription and drug dispensing, to grant subsidies for the training of residents in teaching hospitals, and to lower the rate of patients' out of porket payment in teaching hospitals.

• Journal of Pharmaceutical Investigation
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• v.16 no.3
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• pp.110-117
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• 1986

Plasma disappearance of amaranth (AM), a model compound of organic anionic drugs, was retarded by intravenous infusion of taurodeoxycholate (TDC), a representative bile acid, in the rat. Biliary excretion accounted for 30-60% of the systemic excretion of AM. AM seemed to be metabolised in the hepatocyte to form a compound that is excreted more rapidly into the bile than AM itself, considering apparent biliary clearance, $CL_{bil}$, is much larger than systemic clearance, $CL_s$. Decrease in $CL_{bil}$ by TDC infusion might be due to elevated plasma level rather than decreased biliary excretion of AM. Decreased distribution or urinary excretion of AM by TDC was supposed to be one of the probable reasons of elevated plasma level. Competitive inhibition between AM and TDC on tissue distribution and urinary excretion might explain the mechanism. The effect of TDC on the $CL_{bil}$ of methylene blue, a cationic dye, was quite different from that of AM, as reported previously by us. More intensive study would be necessary to elucidate the difference of biliary excretion between organic anions and cations.

• Food Science of Animal Resources
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• v.37 no.4
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• pp.579-592
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• 2017

This study assessed the quantitative microbial risk of non-enterohemorrhagic Escherichia coli (EHEC). For hazard identification, hazards of non-EHEC E. coli in natural and processed cheeses were identified by research papers. Regarding exposure assessment, non-EHEC E. coli cell counts in cheese were enumerated, and the developed predictive models were used to describe the fates of non-EHEC E. coli strains in cheese during distribution and storage. In addition, data on the amounts and frequency of cheese consumption were collected from the research report of the Ministry of Food and Drug Safety. For hazard characterization, a doseresponse model for non-EHEC E. coli was used. Using the collected data, simulation models were constructed, using software @RISK to calculate the risk of illness per person per day. Non-EHEC E. coli cells in natural- (n=90) and processed-cheese samples (n=308) from factories and markets were not detected. Thus, we estimated the initial levels of contamination by Uniform distribution ${\times}$ Beta distribution, and the levels were -2.35 and -2.73 Log CFU/g for natural and processed cheese, respectively. The proposed predictive models described properly the fates of non-EHEC E. coli during distribution and storage of cheese. For hazard characterization, we used the Beta-Poisson model (${\alpha}=2.21{\times}10^{-1}$, $N_{50}=6.85{\times}10^7$). The results of risk characterization for non-EHEC E. coli in natural and processed cheese were $1.36{\times}10^{-7}$ and $2.12{\times}10^{-10}$ (the mean probability of illness per person per day), respectively. These results indicate that the risk of non-EHEC E. coli foodborne illness can be considered low in present conditions.

• The Korean Journal of Applied Statistics
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• v.34 no.1
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• pp.9-23
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• 2021

In the following paper we introduce a variational Bayes method that approximates posterior distributions with mean-field method. In particular, we introduce automatic differentiation variation inference (ADVI), which approximates joint posterior distributions using the product of Gaussian distributions after transforming parameters into real coordinate space, and then apply it to pharmacokinetic models that are models for the study of the time course of drug absorption, distribution, metabolism and excretion. We analyze real data sets using ADVI and compare the results with those based on Markov chain Monte Carlo. We implement the algorithms using Stan.