International Journal of Pharmaceutics, Jun 1, 2007
Genistein (GT) is an isoflavone from Leguminosae and has received much attention as a phytoestrog... more Genistein (GT) is an isoflavone from Leguminosae and has received much attention as a phytoestrogen. Genistin is a glycoside form of GT (genistein-7-O-beta-D-glucopyranoside, GT-glu) is mainly found in soy-derived foods. In this study, we examined the pharmacokinetic properties and bioavailability of GT in rats and compared with those of GT-glu. In order to characterize and compare the pharmacokinetics of GT and GT-glu, these compounds were administered intravenously and orally. The plasma concentration of GT was determined by HPLC after enzymatic hydrolysis. After oral administration of GT with various doses (4, 20, 40 mg/kg), the bioavailability of GT was 38.58, 24.34 and 30.75%, respectively. The T(max), C(max) and AUC(0-infinity) of GT after oral administration of GT (40 mg/kg), were 2h, 4876.19 ng/ml, 31,269.66 ng h/ml, respectively. When smaller amount of GT was administered, the faster T(max) was observed. Oral administration of GT-glu resulted in longer T(max), lower C(max), and greater bioavailability than that of GT. The pharmacokinetic parameters of GT following oral administration of GT-glu (64 mg/kg as GT-glu, 40 mg/kg as GT) were obtained as follows: 8h (T(max)), 3763.96 ng/ml (C(max)), 51,221.08 ng h/ml (AUC(0-infinity)) and 48.66% (absolute bioavailability), respectively. These results indicate that the oral bioavailability of GT-glu is greater than that of GT.
Pellets, which are multiple-unit dosage systems, have the several therapeutic advantages over sin... more Pellets, which are multiple-unit dosage systems, have the several therapeutic advantages over single-unit dosage systems in oral drug delivery. This review focuses on the current status and explores extrusion-spheronization technique with special attention to controlled-release application of pellets including coated pellets for delayed release formulations, coated pellets for colon delivery, coated pellets for sustained drug delivery, sustained-release matrix pellets, pellets compressed into tablets, bioadhesive pellets, floating pellets, and pelletization with solubilization techniques.
The present study was aimed to investigate the effect of food components and dosing time on the o... more The present study was aimed to investigate the effect of food components and dosing time on the oral exposure of nifedipine in rats. Nifedipine was given orally to rats with and without food components at 8:00 a.m. (morning time) or 4:00 p.m. (evening time) during winter periods. Food components included milk, sodium chloride, oleic acid, and sodium taurocholate. Plasma concentration profiles of nifedipine showed double peak phenomena which were generally retained regardless of food components, vehicle types and the dosing time. Sodium chloride, milk and sodium taurocholate significantly increased the AUC while oleic acid did not, when drug was dosed in the morning time. After the dosing in the evening time, milk and sodium chloride significantly increased the plasma concentrations of nifedipine but oleic acid and sodium taurocholate decreased them. Overall, the systemic in vivo exposure of nifedipine was invariably lower with the evening dosing compared to the dosing in the morning, but this circadian rhythm dependency was not reversed by the multiple dosing of food components in rats. Food components and dosing time significantly altered the oral pharmacokinetics of nifedipine in rats, implying that the altered bioavailability and higher plasma concentrations in the morning time may influence dosing regimens of nifedipine for hypertension patients.
We have demonstrated that mitochondrial oxidative damage and PKCd overexpression contribute to me... more We have demonstrated that mitochondrial oxidative damage and PKCd overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild-type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCd during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase to examine whether melatonin modulates PKCd-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCd, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild-type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild-type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCd (À/À) mice or PKCd antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCd. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition and that PKCd is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.
Ethnopharmacological relevance: Cinnamomum cassia Blume (Aceraceae) has been traditionally used t... more Ethnopharmacological relevance: Cinnamomum cassia Blume (Aceraceae) has been traditionally used to treat various inflammatory diseases such as gastritis. However, the anti-inflammatory mechanism of Cinnamomum cassia has not been fully elucidated. This study examined the anti-inflammatory mechanism of 95% ethanol extract (Cc-EE) of Cinnamomum cassia. Materials and methods: The effect of Cc-EE on the production of inflammatory mediators in RAW264.7 cells and peritoneal macrophages was investigated. Molecular mechanisms underlying the effects, especially inhibitory effects, was elucidated by analyzing the activation of transcription factors and their upstream signaling, and by evaluating the kinase activity of target enzymes. Results: Cc-EE of Cinnamomum cassia diminished the production of nitric oxide (NO), tumor necrosis factor (TNF)-␣, and prostaglandin (PG)E 2 , in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages in a dose-dependent manner. Cc-EE also blocked mRNA expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and TNF-␣ by suppressing the activation of nuclear factor (NF)-B, and simultaneously inhibited its upstream inflammatory signaling cascades, including spleen tyrosine kinase (Syk) and Src. Consistent with these findings, the extract directly blocked the kinase activities of Src and Syk. Conclusion: Cc-EE exerts strong anti-inflammatory activity by suppressing Src/Syk-mediated NF-B activation, which contributes to its major ethno-pharmacological role as an anti-gastritis remedy. Future work will be focused on determining whether the extract can be further developed as an antiinflammatory drug.
Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulat... more Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C max and AUC last parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.
Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stabilit... more Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.
Ginsenosides, the major active ingredients of ginseng and other plants of the genus Panax, have b... more Ginsenosides, the major active ingredients of ginseng and other plants of the genus Panax, have been used as natural medicines in the East for a long time; in addition, their popularity in the West has increased owing to their various beneficial pharmacological effects. There is therefore a wealth of literature regarding the pharmacological effects of ginsenosides. In contrast, there are few comprehensive studies that investigate their pharmacokinetic behaviors. This is because ginseng contains the complicated mixture of herbal materials as well as thousands of constituents with complex chemical properties, and ginsenosides undergo multiple biotransformation processes after administration. This is a significant issue as pharmacokinetic studies provide crucial data regarding the efficacy and safety of compounds. Moreover, there have been many difficulties in the development of the optimal dosage regimens of ginsenosides and the evaluation of their interactions with other drugs. Therefore, this review details the pharmacokinetic properties and profiles of ginsenosides determined in various animal models administered through different routes of administration. Such information is valuable for designing specialized delivery systems and determining optimal dosing strategies for ginsenosides.
This review provides an overview of critical factors, characterization methods, and quality speci... more This review provides an overview of critical factors, characterization methods, and quality specifications for development of thin film formulations for drug delivery along with the recent trends and future perspectives.
Cell-based therapies have been increasingly explored as a potential alternative treatment method ... more Cell-based therapies have been increasingly explored as a potential alternative treatment method of corneal endothelial dysfunction. Up to date, researchers have mainly dedicated enormous efforts to establishing fundamental techniques for culture and characterization of human corneal endothelial cells (HCECs) and human corneal endothelial progenitor cells (HCEPCs). However, in terms of cell delivery methods, existing approaches have shown many limitations such as low cell delivery efficiency, intricate processes, and inevitable damages on the cornea occurring during surgical procedure. The problems related to cell delivery to the eye have significantly hindered translation of the novel cell-based therapeutic systems into clinical practice. Thus, importance of developing novel strategies for cell delivery to the corneal endothelium has been increasingly growing. In this context, this review will discuss key approaches investigated until recently for efficient cell delivery to the cor...
To classify Glycyrrhiza species, samples of different species were analyzed by 1 H NMR-based meta... more To classify Glycyrrhiza species, samples of different species were analyzed by 1 H NMR-based metabolomics technique. Partial least squares discriminant analysis (PLS-DA) was used as the multivariate statistical analysis of the 1 H NMR data sets. There was a clear separation between various Glycyrrhiza species in the PLS-DA derived score plots. The PLS-DA model was validated, and the key metabolites contributing to the separation in the score plots of various Glycyrrhiza species were lactic acid, alanine, arginine, proline, malic acid, asparagine, choline, glycine, glucose, sucrose, 4-hydroxyphenylacetic acid, and formic acid. The compounds present at relatively high levels were glucose, and 4-hydroxyphenylacetic acid in G. glabra; lactic acid, alanine, and proline in G. inflata; and arginine, malic acid, and sucrose in G. uralensis. This is the first study to perform the global metabolomic profiling and differentiation of Glycyrrhiza species using 1 H NMR and multivariate statistical analysis.
The buccal mucosa has been investigated for the local drug therapy and the systemic delivery of p... more The buccal mucosa has been investigated for the local drug therapy and the systemic delivery of potent peptides, proteins, and other small drug molecules that are subjected to hepatic metabolism and enzymatic degradation in the gastrointestinal tract. Being non-invasive, this route is more feasible for the delivery of therapeutic entities than that of invasive or parenteral drug administration. However, the mucosa of oral cavity represents a major barrier to drug penetration. In addition, the presence of several enzymes in saliva, salivary flow, discomfort feelings after administration of dosage forms, and bitter taste of the drugs have limited the drug delivery via the buccal cavity. Thus, extensive studies have been conducted to develop novel pharmaceutical formulations for effective buccal drug delivery. Various buccal dosage forms such as tablets, gels, and patches/films are now commercially available and have demonstrated high patient compliance. Recently, several manufacturing companies have launched new buccal drug delivery systems such as aerosol, sprays, and particulate systems and they have actively been investigated by numerous pharmaceutical scientists. If the successful development of such systems could be achieved, buccal drug delivery systems would be one of the most promising technology in the near future. In this review, we described the recent development of buccal dosage forms, anatomy of buccal mucosa, drug transport mechanisms, and formulation strategies to enhance the drug permeation through the buccal mucosa.
Korean mistletoe lectin (KML) is the major component found in Viscum album var. (coloratum), disp... more Korean mistletoe lectin (KML) is the major component found in Viscum album var. (coloratum), displaying anti-cancer and immunostimulating activities. Even though it has been shown to boost host immune defense mechanisms, the regulatory roles of KML on the functional activation of macrophages have not been fully elucidated. In this study, regulatory mechanism of KML on macrophage-mediated immune responses was examined in terms of KML-mediated signaling event. KML clearly induced mRNA expression of tumor necrosis factor (TNF)-α, the generation of reactive oxygen species (ROS) and phagocytic uptake in RAW264.7 cells. All of these events were strongly suppressed by U0126, whereas TNF-α mRNA was not diminished by SB203580 and SP600125, indicating ERK as a central enzyme managing KML-induced up-regulation of macrophage functions. Indeed, KML strongly induced the phosphorylation of ERK in a time-dependent manner without altering its total level. Therefore, these data suggest that ERK may be a major signaling enzyme with regulatory property toward various KML-mediated macrophage responses.
Ginsenoside (G)-F1 is an enzymatic metabolite generated from G-Rg1. Although this metabolite has ... more Ginsenoside (G)-F1 is an enzymatic metabolite generated from G-Rg1. Although this metabolite has been reported to suppress platelet aggregation and to reduce gap junction-mediated intercellular communication, the modulatory activity of G-F1 on the functional role of skin-derived cells has not yet been elucidated. In this study, we evaluated the regulatory role of G-F1 on the cellular responses of B16 melanoma cells. G-F1 strongly suppressed the proliferation of B16 cells up to 60% at 200 µg/mL, while only diminishing the viability of HEK293 cells up to 30%. Furthermore, G-F1 remarkably induced morphological change and clustering of B16 melanoma cells. The melanin production of B16 cells was also significantly blocked by G-F1 up to 70%. Interestingly, intracellular signaling events involved in cell proliferation, migration, and morphological change were up-regulated at 1 h incubation but down-regulated at 12 h. Therefore, our results suggest that G-F1 can be applied as a novel anti-skin cancer drug with anti-proliferative and anti-migration features.
Mitogen-activated protein kinases (MAPKs) are involved in a variety of intracellular events such ... more Mitogen-activated protein kinases (MAPKs) are involved in a variety of intracellular events such as gene expression, cell proliferation, and programmed cell death. MAPKs are activated by dual phosphorylation on threonine and tyrosine residues through sequential activation of protein kinases. Recent studies have shown that the protein kinases involved in MAPK signal transductions might be organized into signaling complexes by scaffold proteins. These scaffold proteins are essential regulators that function by assembling the relevant molecular components in mammalian cells. In this study, we report that dual-specificity phosphatase 22 (DUSP22), a member of the protein tyrosine phosphatase family, acts as a distinct scaffold protein in c-Jun N-terminal kinase (JNK) signaling. DUSP22 increased the phosphorylation in the activation loop of JNK regardless of its phosphatase activity but had no effect on phosphorylation levels of ERK and p38 in mammalian cells. Furthermore, DUSP22 selectiv...
Berberis koreana has been known as enthopharmacologically valuable plant in Korea, China and Japa... more Berberis koreana has been known as enthopharmacologically valuable plant in Korea, China and Japan. This plant has been reported to display numerous pharmacological activities such as anti-oxidative, neuroprotective, and anti-cancer effects. Although the pharmacological potentials have been demonstrated, anti-inflammatory effect of this plant has not been fully elucidated yet. To evaluate its anti-inflammatory activity, macrophages activated by lipopolysaccharide (LPS) were employed and the production of inflammatory mediators was explored in terms of understanding its molecular inhibitory mechanism. Hot water extract from B. koreana (Bk-HWE) was able to suppress the production of NO and TNF-production and up-regulation of surface levels of costimulatory molecules such as CD80 and CD86. The anti-inflammatory effect of Bk-HWE seemed to be due to the inhibition of MAPK activation and c-fos translocation, according to immunoblotting analysis. In addition, Bk-HWE strongly suppressed the cell-cell adhesion events induced by functional activation of adhesion molecules such as CD29 and CD43. Therefore, our results suggest that Bk-HWE can be applied as an anti-inflammatory herbal medicine. To prove this assumption, further in vivo efficacy test will be continued in the following project.
The Korean Journal of Critical Care Medicine, 2010
Background: To evaluate the post-resuscitation intensive care unit outcome of patients who initia... more Background: To evaluate the post-resuscitation intensive care unit outcome of patients who initially survived out-of-hospital cardiac arrest (OHCA). Methods: We retrospectively analyzed patients who were admitted to the ICU after OHCA in a tertiary hospital between January, 2005 and December, 2009. We compared the patients' clinical data, the factors associated with admission and the prognosis of patients in cardiac and non-cardiac groups. Results: Sixty-four patients were included in this study. Thirty-four patients were in the cardiac group and thirty patients were in the non-cardiac group. The mean age was 57.3 ± 15.1 years of age in the cardiac group and 61.9 ± 15.7 years of age in the non-cardiac group (p = 0.235). The collapse-to-start of the CPR interval was 5.9 ± 3.8 min in the cardiac group and 6.0 ± 3.2 min in the non-cardiac group (p = 0.851). The complaint of chest pain occurred in 12 patients (35.3%) in the cardiac group and 1 patient (3.3%) in the non-cardiac group (p = 0.011). The time duration for making a decision for admission was 285.2 ± 202.2 min in the cardiac group and 327.7 ± 264.1 min in the non-cardiac group (p = 0.471). The regional wall motion abnormality and ejection fraction decrease were significant in the cardiac group (p = 0.002, 0.030). Grade 5 CPC was present in 8 patients (23.5%) in the cardiac group and 14 patients (46.7%) in the non-cardiac group. Conclusions: The key symptom that could initially differentiate the two groups was chest pain. The time duration for making an admission decision was long in both groups. The CPC score of the cardiac group was lower than that for the non-cardiac group.
International Journal of Pharmaceutics, Jun 1, 2007
Genistein (GT) is an isoflavone from Leguminosae and has received much attention as a phytoestrog... more Genistein (GT) is an isoflavone from Leguminosae and has received much attention as a phytoestrogen. Genistin is a glycoside form of GT (genistein-7-O-beta-D-glucopyranoside, GT-glu) is mainly found in soy-derived foods. In this study, we examined the pharmacokinetic properties and bioavailability of GT in rats and compared with those of GT-glu. In order to characterize and compare the pharmacokinetics of GT and GT-glu, these compounds were administered intravenously and orally. The plasma concentration of GT was determined by HPLC after enzymatic hydrolysis. After oral administration of GT with various doses (4, 20, 40 mg/kg), the bioavailability of GT was 38.58, 24.34 and 30.75%, respectively. The T(max), C(max) and AUC(0-infinity) of GT after oral administration of GT (40 mg/kg), were 2h, 4876.19 ng/ml, 31,269.66 ng h/ml, respectively. When smaller amount of GT was administered, the faster T(max) was observed. Oral administration of GT-glu resulted in longer T(max), lower C(max), and greater bioavailability than that of GT. The pharmacokinetic parameters of GT following oral administration of GT-glu (64 mg/kg as GT-glu, 40 mg/kg as GT) were obtained as follows: 8h (T(max)), 3763.96 ng/ml (C(max)), 51,221.08 ng h/ml (AUC(0-infinity)) and 48.66% (absolute bioavailability), respectively. These results indicate that the oral bioavailability of GT-glu is greater than that of GT.
Pellets, which are multiple-unit dosage systems, have the several therapeutic advantages over sin... more Pellets, which are multiple-unit dosage systems, have the several therapeutic advantages over single-unit dosage systems in oral drug delivery. This review focuses on the current status and explores extrusion-spheronization technique with special attention to controlled-release application of pellets including coated pellets for delayed release formulations, coated pellets for colon delivery, coated pellets for sustained drug delivery, sustained-release matrix pellets, pellets compressed into tablets, bioadhesive pellets, floating pellets, and pelletization with solubilization techniques.
The present study was aimed to investigate the effect of food components and dosing time on the o... more The present study was aimed to investigate the effect of food components and dosing time on the oral exposure of nifedipine in rats. Nifedipine was given orally to rats with and without food components at 8:00 a.m. (morning time) or 4:00 p.m. (evening time) during winter periods. Food components included milk, sodium chloride, oleic acid, and sodium taurocholate. Plasma concentration profiles of nifedipine showed double peak phenomena which were generally retained regardless of food components, vehicle types and the dosing time. Sodium chloride, milk and sodium taurocholate significantly increased the AUC while oleic acid did not, when drug was dosed in the morning time. After the dosing in the evening time, milk and sodium chloride significantly increased the plasma concentrations of nifedipine but oleic acid and sodium taurocholate decreased them. Overall, the systemic in vivo exposure of nifedipine was invariably lower with the evening dosing compared to the dosing in the morning, but this circadian rhythm dependency was not reversed by the multiple dosing of food components in rats. Food components and dosing time significantly altered the oral pharmacokinetics of nifedipine in rats, implying that the altered bioavailability and higher plasma concentrations in the morning time may influence dosing regimens of nifedipine for hypertension patients.
We have demonstrated that mitochondrial oxidative damage and PKCd overexpression contribute to me... more We have demonstrated that mitochondrial oxidative damage and PKCd overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild-type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCd during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase to examine whether melatonin modulates PKCd-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCd, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild-type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild-type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCd (À/À) mice or PKCd antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCd. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition and that PKCd is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.
Ethnopharmacological relevance: Cinnamomum cassia Blume (Aceraceae) has been traditionally used t... more Ethnopharmacological relevance: Cinnamomum cassia Blume (Aceraceae) has been traditionally used to treat various inflammatory diseases such as gastritis. However, the anti-inflammatory mechanism of Cinnamomum cassia has not been fully elucidated. This study examined the anti-inflammatory mechanism of 95% ethanol extract (Cc-EE) of Cinnamomum cassia. Materials and methods: The effect of Cc-EE on the production of inflammatory mediators in RAW264.7 cells and peritoneal macrophages was investigated. Molecular mechanisms underlying the effects, especially inhibitory effects, was elucidated by analyzing the activation of transcription factors and their upstream signaling, and by evaluating the kinase activity of target enzymes. Results: Cc-EE of Cinnamomum cassia diminished the production of nitric oxide (NO), tumor necrosis factor (TNF)-␣, and prostaglandin (PG)E 2 , in lipopolysaccharide (LPS)-activated RAW264.7 cells and peritoneal macrophages in a dose-dependent manner. Cc-EE also blocked mRNA expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and TNF-␣ by suppressing the activation of nuclear factor (NF)-B, and simultaneously inhibited its upstream inflammatory signaling cascades, including spleen tyrosine kinase (Syk) and Src. Consistent with these findings, the extract directly blocked the kinase activities of Src and Syk. Conclusion: Cc-EE exerts strong anti-inflammatory activity by suppressing Src/Syk-mediated NF-B activation, which contributes to its major ethno-pharmacological role as an anti-gastritis remedy. Future work will be focused on determining whether the extract can be further developed as an antiinflammatory drug.
Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulat... more Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C max and AUC last parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.
Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stabilit... more Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.
Ginsenosides, the major active ingredients of ginseng and other plants of the genus Panax, have b... more Ginsenosides, the major active ingredients of ginseng and other plants of the genus Panax, have been used as natural medicines in the East for a long time; in addition, their popularity in the West has increased owing to their various beneficial pharmacological effects. There is therefore a wealth of literature regarding the pharmacological effects of ginsenosides. In contrast, there are few comprehensive studies that investigate their pharmacokinetic behaviors. This is because ginseng contains the complicated mixture of herbal materials as well as thousands of constituents with complex chemical properties, and ginsenosides undergo multiple biotransformation processes after administration. This is a significant issue as pharmacokinetic studies provide crucial data regarding the efficacy and safety of compounds. Moreover, there have been many difficulties in the development of the optimal dosage regimens of ginsenosides and the evaluation of their interactions with other drugs. Therefore, this review details the pharmacokinetic properties and profiles of ginsenosides determined in various animal models administered through different routes of administration. Such information is valuable for designing specialized delivery systems and determining optimal dosing strategies for ginsenosides.
This review provides an overview of critical factors, characterization methods, and quality speci... more This review provides an overview of critical factors, characterization methods, and quality specifications for development of thin film formulations for drug delivery along with the recent trends and future perspectives.
Cell-based therapies have been increasingly explored as a potential alternative treatment method ... more Cell-based therapies have been increasingly explored as a potential alternative treatment method of corneal endothelial dysfunction. Up to date, researchers have mainly dedicated enormous efforts to establishing fundamental techniques for culture and characterization of human corneal endothelial cells (HCECs) and human corneal endothelial progenitor cells (HCEPCs). However, in terms of cell delivery methods, existing approaches have shown many limitations such as low cell delivery efficiency, intricate processes, and inevitable damages on the cornea occurring during surgical procedure. The problems related to cell delivery to the eye have significantly hindered translation of the novel cell-based therapeutic systems into clinical practice. Thus, importance of developing novel strategies for cell delivery to the corneal endothelium has been increasingly growing. In this context, this review will discuss key approaches investigated until recently for efficient cell delivery to the cor...
To classify Glycyrrhiza species, samples of different species were analyzed by 1 H NMR-based meta... more To classify Glycyrrhiza species, samples of different species were analyzed by 1 H NMR-based metabolomics technique. Partial least squares discriminant analysis (PLS-DA) was used as the multivariate statistical analysis of the 1 H NMR data sets. There was a clear separation between various Glycyrrhiza species in the PLS-DA derived score plots. The PLS-DA model was validated, and the key metabolites contributing to the separation in the score plots of various Glycyrrhiza species were lactic acid, alanine, arginine, proline, malic acid, asparagine, choline, glycine, glucose, sucrose, 4-hydroxyphenylacetic acid, and formic acid. The compounds present at relatively high levels were glucose, and 4-hydroxyphenylacetic acid in G. glabra; lactic acid, alanine, and proline in G. inflata; and arginine, malic acid, and sucrose in G. uralensis. This is the first study to perform the global metabolomic profiling and differentiation of Glycyrrhiza species using 1 H NMR and multivariate statistical analysis.
The buccal mucosa has been investigated for the local drug therapy and the systemic delivery of p... more The buccal mucosa has been investigated for the local drug therapy and the systemic delivery of potent peptides, proteins, and other small drug molecules that are subjected to hepatic metabolism and enzymatic degradation in the gastrointestinal tract. Being non-invasive, this route is more feasible for the delivery of therapeutic entities than that of invasive or parenteral drug administration. However, the mucosa of oral cavity represents a major barrier to drug penetration. In addition, the presence of several enzymes in saliva, salivary flow, discomfort feelings after administration of dosage forms, and bitter taste of the drugs have limited the drug delivery via the buccal cavity. Thus, extensive studies have been conducted to develop novel pharmaceutical formulations for effective buccal drug delivery. Various buccal dosage forms such as tablets, gels, and patches/films are now commercially available and have demonstrated high patient compliance. Recently, several manufacturing companies have launched new buccal drug delivery systems such as aerosol, sprays, and particulate systems and they have actively been investigated by numerous pharmaceutical scientists. If the successful development of such systems could be achieved, buccal drug delivery systems would be one of the most promising technology in the near future. In this review, we described the recent development of buccal dosage forms, anatomy of buccal mucosa, drug transport mechanisms, and formulation strategies to enhance the drug permeation through the buccal mucosa.
Korean mistletoe lectin (KML) is the major component found in Viscum album var. (coloratum), disp... more Korean mistletoe lectin (KML) is the major component found in Viscum album var. (coloratum), displaying anti-cancer and immunostimulating activities. Even though it has been shown to boost host immune defense mechanisms, the regulatory roles of KML on the functional activation of macrophages have not been fully elucidated. In this study, regulatory mechanism of KML on macrophage-mediated immune responses was examined in terms of KML-mediated signaling event. KML clearly induced mRNA expression of tumor necrosis factor (TNF)-α, the generation of reactive oxygen species (ROS) and phagocytic uptake in RAW264.7 cells. All of these events were strongly suppressed by U0126, whereas TNF-α mRNA was not diminished by SB203580 and SP600125, indicating ERK as a central enzyme managing KML-induced up-regulation of macrophage functions. Indeed, KML strongly induced the phosphorylation of ERK in a time-dependent manner without altering its total level. Therefore, these data suggest that ERK may be a major signaling enzyme with regulatory property toward various KML-mediated macrophage responses.
Ginsenoside (G)-F1 is an enzymatic metabolite generated from G-Rg1. Although this metabolite has ... more Ginsenoside (G)-F1 is an enzymatic metabolite generated from G-Rg1. Although this metabolite has been reported to suppress platelet aggregation and to reduce gap junction-mediated intercellular communication, the modulatory activity of G-F1 on the functional role of skin-derived cells has not yet been elucidated. In this study, we evaluated the regulatory role of G-F1 on the cellular responses of B16 melanoma cells. G-F1 strongly suppressed the proliferation of B16 cells up to 60% at 200 µg/mL, while only diminishing the viability of HEK293 cells up to 30%. Furthermore, G-F1 remarkably induced morphological change and clustering of B16 melanoma cells. The melanin production of B16 cells was also significantly blocked by G-F1 up to 70%. Interestingly, intracellular signaling events involved in cell proliferation, migration, and morphological change were up-regulated at 1 h incubation but down-regulated at 12 h. Therefore, our results suggest that G-F1 can be applied as a novel anti-skin cancer drug with anti-proliferative and anti-migration features.
Mitogen-activated protein kinases (MAPKs) are involved in a variety of intracellular events such ... more Mitogen-activated protein kinases (MAPKs) are involved in a variety of intracellular events such as gene expression, cell proliferation, and programmed cell death. MAPKs are activated by dual phosphorylation on threonine and tyrosine residues through sequential activation of protein kinases. Recent studies have shown that the protein kinases involved in MAPK signal transductions might be organized into signaling complexes by scaffold proteins. These scaffold proteins are essential regulators that function by assembling the relevant molecular components in mammalian cells. In this study, we report that dual-specificity phosphatase 22 (DUSP22), a member of the protein tyrosine phosphatase family, acts as a distinct scaffold protein in c-Jun N-terminal kinase (JNK) signaling. DUSP22 increased the phosphorylation in the activation loop of JNK regardless of its phosphatase activity but had no effect on phosphorylation levels of ERK and p38 in mammalian cells. Furthermore, DUSP22 selectiv...
Berberis koreana has been known as enthopharmacologically valuable plant in Korea, China and Japa... more Berberis koreana has been known as enthopharmacologically valuable plant in Korea, China and Japan. This plant has been reported to display numerous pharmacological activities such as anti-oxidative, neuroprotective, and anti-cancer effects. Although the pharmacological potentials have been demonstrated, anti-inflammatory effect of this plant has not been fully elucidated yet. To evaluate its anti-inflammatory activity, macrophages activated by lipopolysaccharide (LPS) were employed and the production of inflammatory mediators was explored in terms of understanding its molecular inhibitory mechanism. Hot water extract from B. koreana (Bk-HWE) was able to suppress the production of NO and TNF-production and up-regulation of surface levels of costimulatory molecules such as CD80 and CD86. The anti-inflammatory effect of Bk-HWE seemed to be due to the inhibition of MAPK activation and c-fos translocation, according to immunoblotting analysis. In addition, Bk-HWE strongly suppressed the cell-cell adhesion events induced by functional activation of adhesion molecules such as CD29 and CD43. Therefore, our results suggest that Bk-HWE can be applied as an anti-inflammatory herbal medicine. To prove this assumption, further in vivo efficacy test will be continued in the following project.
The Korean Journal of Critical Care Medicine, 2010
Background: To evaluate the post-resuscitation intensive care unit outcome of patients who initia... more Background: To evaluate the post-resuscitation intensive care unit outcome of patients who initially survived out-of-hospital cardiac arrest (OHCA). Methods: We retrospectively analyzed patients who were admitted to the ICU after OHCA in a tertiary hospital between January, 2005 and December, 2009. We compared the patients' clinical data, the factors associated with admission and the prognosis of patients in cardiac and non-cardiac groups. Results: Sixty-four patients were included in this study. Thirty-four patients were in the cardiac group and thirty patients were in the non-cardiac group. The mean age was 57.3 ± 15.1 years of age in the cardiac group and 61.9 ± 15.7 years of age in the non-cardiac group (p = 0.235). The collapse-to-start of the CPR interval was 5.9 ± 3.8 min in the cardiac group and 6.0 ± 3.2 min in the non-cardiac group (p = 0.851). The complaint of chest pain occurred in 12 patients (35.3%) in the cardiac group and 1 patient (3.3%) in the non-cardiac group (p = 0.011). The time duration for making a decision for admission was 285.2 ± 202.2 min in the cardiac group and 327.7 ± 264.1 min in the non-cardiac group (p = 0.471). The regional wall motion abnormality and ejection fraction decrease were significant in the cardiac group (p = 0.002, 0.030). Grade 5 CPC was present in 8 patients (23.5%) in the cardiac group and 14 patients (46.7%) in the non-cardiac group. Conclusions: The key symptom that could initially differentiate the two groups was chest pain. The time duration for making an admission decision was long in both groups. The CPC score of the cardiac group was lower than that for the non-cardiac group.
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Papers by Jaehwi Lee