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Abstract GLH8NDE, a derivative of eupatilin, is currently under development to treat dry eye disease. We conducted a randomized, double‐masked, placebo‐controlled, single‐ and multiple‐day study to evaluate safety, tolerability, pharmacodynamics, and pharmacokinetics of ocular GLH8NDE in healthy male adults. Subjects randomly received topical ocular dosing of GLH8NDE or its matching placebo for a day, then for 7 consecutive days with a 62‐h washout at one of the following daily doses: 9, 18, 36 (Koreans), and 36 mg (Whites). The study drug was administered in divided doses over 10 h with 2‐ or 5‐h intervals. Thirty‐nine (97.5%) out of 40 subjects completed the study. A total of 17 subjects experienced 31 treatment‐emergent adverse events, all of which were mild in severity and recovered without sequelae. Neither pathological changes in eye compartments nor clinically significant systemic effects were observed. GLH8NDE was rapidly absorbed reaching the peak concentration within 0.25–0.75 h postdose. The systemic exposure as measured by area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration (AUClast) after single‐day administration of the same dose was 109% higher in Koreans than in Whites. In conclusion, GLH8NDE was safe and well‐tolerated in healthy Korean and White male adults at 9–36 mg/day after single‐ and multiple‐day administrations.

The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus (HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS. Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper self-microemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS. Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.

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. Keywords: Bioavailability, Ginsenosides, Pharmacokinetic, Protopanaxadiol, Protopanaxatriol

Polyglycerol dendrimers (PGD) exhibit unique properties such as drug delivery, drug solubilization, bioimaging, and diagnostics. In this study, PGD hydrogels were prepared and evaluated as devices for controlled drug release with good solubilization properties. The PGD hydrogels were prepared by crosslinking using ethylene glycol diglycidylether (EGDGE). The concentrations of EGDGE and PGDs were varied. The hydrogels were swellable in ethanol for loading paclitaxel (PTX). The amount of PTX in the hydrogels increased with the swelling ratio, which is proportional to EGDGE/OH ratio, meaning that heterogeneous crosslinking of PGD made high dense region of PGD molecules in the matrix. The hydrogels remained transparent after loading PTX and standing in water for one day, indicating that PTX was dispersed in the hydrogels without any crystallization in water. The results of FTIR imaging of the PTX-loaded PGD hydrogels revealed good dispersion of PTX in the hydrogel matrix. Sixty percent of the loaded PTX was released in a sink condition within 90 min, suggesting that the solubilized PTX would be useful for controlled release without any precipitation. Polyglycerol dendrimer hydrogels are expected to be applicable for rapid release of poorly water-soluble drugs, e.g., for oral administration.

Panax ginseng has been used as an herbal medicine for thousands of years. Most of its pharmacological effects are attributed to its constituent ginsenosides, including 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (20(S)-25-OCH3-PPD), which is one of the protopanaxadiol type ginsenosides. It has been found to exhibit anticancer effects by interacting with multiple pharmacological pathways, such as the Wnt/β-catenin, MDM2, ERK/MAPK, and STAT3 signaling pathways. However, its therapeutic potential could be limited by its low bioavailability mainly due to its low aqueous solubility. Thus, several studies have been conducted on its pharmacokinetics and its delivery systems, so as to increase its oral bioavailability. In this review, comprehensive information on its varying pharmacological pathways in cancer, as well as its pharmacokinetic behavior and pharmaceutical strategies, is provided. This information would be useful in the understanding of its diverse mechanisms and pharmacokinetics as an anticancer drug, leading to the design of superior 20(S)-25-OCH3-PPD-containing formulations that maximize its therapeutic potential.

Ginsenosides, dammarane-type triterpene saponins obtained from ginseng, have been used as a natural medicine for many years in the Orient due to their various pharmacological activities. However, the therapeutic potential of ginsenosides has been largely limited by the low bioavailability of the natural products caused mainly by low aqueous solubility, poor biomembrane permeability, instability in the gastrointestinal tract, and extensive metabolism in the body. To enhance the bioavailability of ginsenosides, diverse micro-/nano-sized delivery systems such as emulsions, polymeric particles, and vesicular systems have been investigated. The delivery systems improved the bioavailability of ginsenosides by enhancing solubility, permeability, and stability of the natural products. This mini-review aims to provide comprehensive information on the micro-/nano-sized delivery systems for increasing the bioavailability of ginsenosides, which may be helpful for designing better delivery systems to maximize the versatile therapeutic potential of ginsenosides. Keywords: bioavailability, delivery system, ginsenosides, permeability, solubility

Amorphization technology has been the subject of continuous attention in the pharmaceutical industry, as a means to enhance the solubility of poorly water-soluble drugs. Being in a high energy state, amorphous formulations generally display significantly increased apparent solubility as compared to their crystalline counterparts, which may allow them to generate a supersaturated state in the gastrointestinal tract and in turn, improve the bioavailability. Conventionally, hydrophilic polymers have been used as carriers, in which the amorphous drugs were dispersed and stabilized to form polymeric amorphous solid dispersions. However, the technique had its limitations, some of which include the need for a large number of carriers, the tendency to recrystallize during storage, and the possibility of thermal decomposition of the drug during preparation. Therefore, emerging amorphization technologies have focused on the investigation of novel amorphous-stabilizing carriers and preparation methods that can improve the drug loading and the degree of amorphization. This review highlights the recent pharmaceutical approaches utilizing drug amorphization, such as co-amorphous systems, mesoporous particle-based techniques, and in situ amorphization. Recent updates on these technologies in the last five years are discussed with a focus on their characteristics and commercial potential.

Pharmaceutical scientists throughout the world are trying to explore thin films as a novel drug delivery tool. Thin films have been identified as an alternative approach to conventional dosage forms. The thin films are considered to be convenient to swallow, self-administrable, and fast dissolving dosage form, all of which make it as a versatile platform for drug delivery. This delivery system has been used for both systemic and local action via several routes such as oral, buccal, sublingual, ocular, and transdermal routes. The design of efficient thin films requires a comprehensive knowledge of the pharmacological and pharmaceutical properties of drugs and polymers along with an appropriate selection of manufacturing processes. Therefore, the aim of this review is to provide an overview of the critical factors affecting the formulation of thin films, including the physico-chemical properties of polymers and drugs, anatomical and physiological constraints, as well as the characterization methods and quality specifications to circumvent the difficulties associated with formulation design. It also highlights the recent trends and perspectives to develop thin film products by various companies.

Adenosine (AD), which is used for treating wrinkles, exhibits poor skin permeation. The aim of the present study was to develop a cross-linked silicone-based cellulose elastomer as an elastic artificial skin for the treatment of skin wrinkles, a biocompatible lipid-based nano-carrier for enhancing the skin permeation of AD, and a formulation consisting of the lipid-based carrier incorporated in the elastic artificial skin. AD-loaded solid lipid nanoparticles (SLNs) were prepared using a double-emulsion method. Particle characteristics and mechanical properties of SLNs and elastic artificial skin, respectively, were assessed. Skin permeation was evaluated using SkinEthic RHE tissue, a reconstructed human epidermis model. The mean particle size and zeta potential for SLNs ranged from 123.57 to 248.90 nm and −13.23 to −41.23 mV, respectively. The components of neither SLNs nor the elastic artificial skin were cytotoxic, according to cell- and tissue-viability assays and EU classification. SLNs and the elastic artificial skin exhibited sustained drug release for 48 h. The amount of AD released from SLNs and elastic artificial skin was approximately 10 times and 5 times higher, respectively, than that from AD solution. Therefore, elastic artificial skin incorporated with AD-loaded SLNs may serve as a promising topical delivery system for cosmeceutical treatment of skin wrinkles.

This study aimed to improve the solubility and dissolution of aprepitant, a drug with poor aqueous solubility, using a phosphatidylcholine (PC)-based solid dispersion system. When fabricating the PC-based solid dispersion, we employed mesoporous microparticles, as an adsorbent, and disintegrants to improve the sticky nature of PC and dissolution of aprepitant, respectively. The solid dispersions were prepared by a solvent evaporation technique and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry, and X-ray powder diffraction. The FTIR results showed that aprepitant interacted with the PC carrier by both hydrogen bonds and van der Waals forces that can also be observed in the interaction between aprepitant and polymer carriers. The solid dispersions fabricated with only PC were not sufficient to convert the crystallinity of aprepitant to an amorphous state, whereas the formulations that included adsorbent and disintegrant successfully changed that of aprepitant to an amorphous state. Both the solubility and dissolution of aprepitant were considerably enhanced in the PC-based solid dispersions containing adsorbent and disintegrant compared with those of pure aprepitant and polymer-based solid dispersions. Therefore, these results suggest that our PC-based solid dispersion system is a promising alternative to conventional formulations for poorly water-soluble drugs, such as aprepitant.

As the main symptom of Alzheimer’s disease-related dementia is memory loss, patient compliance for donepezil hydrochloride (donepezil), administered as once-daily oral formulations, is poor. Thus, we aimed to design poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) with alginate-coated large pores as an injectable depot of donepezil exhibiting sustained release over 2–3 weeks. The PLGA MS with large pores could provide large space for loading drugs with high loading capacity, and thereby sufficient amounts of drugs were considered to be delivered with minimal use of PLGA MS being injected. However, initial burst release of donepezil from the porous PLGA MS was observed. To reduce this initial burst release, the surface pores were closed with calcium alginate coating using a spray-ionotropic gelation method. The final pore-closed PLGA MS showed in vitro sustained release for approximately 3 weeks, and the initial burst release was remarkably decreased by the calcium alginate coating. In the prediction of plasma drug concentration profiles using convolution method, the mean residence time of the pore-closed PLGA MS was 2.7-fold longer than that of the porous PLGA MS. Therefore, our results reveal that our pore-closed PLGA MS formulation is a promising candidate for the treatment of dementia with high patient compliance.

PURPOSEWe aimed to compare polyvinyl alcohol (PVA) particles with calibrated superparamagnetic iron oxide (SPIO) nanoparticle-loaded chitosan microspheres in a rabbit model, specifically regarding the relative distribution of embolic agents within the uterus based on magnetic resonance imaging (MRI) and pathological evaluation.METHODSTwelve New Zealand white rabbits underwent uterine artery embolization using either standard PVA particles (45–150 µm or 350–500 µm) or calibrated SPIO-embedded chitosan microspheres (45–150 µm or 300–500 µm). MRI and histopathological findings were compared one week after embolization.RESULTSCalibrated SPIO-loaded chitosan microspheres 45–150 µm in size were detected on T2-weighted images. On histological analysis, calibrated SPIO-embedded chitosan microspheres were found in both myometrium and endometrium, whereas PVA particles were found only in the perimyometrium or extrauterine fat pads. A proportional relationship was noted between the calibrated SPIO-embedded chitosan microsphere size and the size of the occluded artery.CONCLUSIONCalibrated SPIO-embedded chitosan microspheres induced greater segmental arterial occlusion than PVA particles and showed great potential as a new embolic material. SPIO-embedded chitosan microspheres can be used to follow distribution of embolic particles through MRI studies.

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.

In this study, we aimed to design a highly swellable and mechanically robust matrix tablet (SMT) as a gastroretentive drug-delivery system (GRDDS) capable of improving the dissolution behavior of β-lapachone with low aqueous solubility. For the preparation of SMTs, the cogrinding technique and freeze−thaw method were used to disperse β-lapachone in SMTs in an amorphous state and to enhance the swelling and mechanical properties of SMTs, respectively. As a result, the crystallinity of coground β-lapachone incorporated in the SMTs was found to be considerably decreased; thereby, the dissolution rates of the drug in a simulated gastric fluid could be substantially increased. The SMTs of β-lapachone also demonstrated significantly enhanced swelling and mechanical properties compared to those of a marketed product. The reason for this might be because the physically crosslinked polymeric networks with a porous structure that were formed in SMTs through the freeze−thaw method. In addition, β-lapachone was gradually released from the SMTs in 6 h. Therefore, SMTs of β-lapachone developed in this study could be used as GRDDS with appropriate swelling and mechanical properties for improving the dissolution behavior of hydrophobic drugs such as β-lapachone.

Itraconazole (ITZ) is an anti-fungal agent generally used to treat cutaneous mycoses. For efficient delivery of ITZ to the skin tissues, an oil-in-water (O/W) cream formulation was developed. The O/W cream base was designed based on the solubility measurement of ITZ in various excipients. A physical mixture of the O/W cream base and ITZ was also prepared as a control formulation to evaluate the effects of the solubilized state of ITZ in cream base on the in vitro skin deposition behavior of ITZ. Polarized light microscopy and differential scanning calorimetry demonstrated that ITZ was fully solubilized in the O/W cream formulation. The O/W cream formulation exhibited considerably enhanced deposition of ITZ in the stratum corneum, epidermis, and dermis compared with that of the physical mixture, largely owing to its high solubilization capacity for ITZ. Therefore, the O/W cream formulation of ITZ developed in this study is promising for the treatment of cutaneous mycoses caused by fungi such as dermatophytes and yeasts.

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 selectively associated with apoptosis signal-regulating kinase 1 (ASK1), MAPK kinase 7 (MKK7), and JNK1/2. Both JNK phosphorylation and JNK-mediated apoptosis increased in a concentration-dependent manner regardless of DUSP22 phosphatase activity at low DUSP22 concentrations, but then decreased at higher DUSP22 concentrations, which is the prominent feature of a scaffold protein. Thus, our data suggest that DUSP22 regulates cell death by acting as a scaffold protein for the ASK1-MKK7-JNK signal transduction pathway independently of its phosphatase activity.

This study aimed to design phosphatidylcholine (PC)-based solid dispersion (SD) systems for enhancing the apparent aqueous solubility and dissolution of celecoxib (CLC), a selective cyclooxygenase-2 inhibitor with a highly hydrophobic property. Although PC-based dispersion formulations considerably increased solubilities of CLC, the lipidic texture of PC was not appropriate as a solid dosage form for oral administration of CLC. To mask the lipidic texture of PC-based matrices, Neusilin® US2, an adsorbent material with a porous structure and large surface area widely used in the pharmaceutical industry, was employed and thereby fully powderized PC-based dispersion formulations could be fabricated. However, PC matrices containing CLC strongly adsorbed to the pores of Neusilin® US2 was not able to be rapidly released. To address this problem, different hydrophilic materials were examined to promote the release of the CLC-dispersed PC matrices from Neusilin® US2. Among tested hydrophilic materials, croscarmellose sodium was the most suitable to facilitate fast drug dissolution from Neusilin® US2 particles, showing significantly enhanced apparent aqueous solubility and dissolution behavior of CLC. Through differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy (FT-IR) analysis, a considerably reduced crystallinity of CLC dispersed in the PC-based dispersion formulations was demonstrated. The PC-based SD formulations developed in this study would be useful for improving the oral bioavailability of poorly soluble drugs such as CLC.

Chitosan has been widely used as a key biomaterial for the development of drug delivery systems intended to be administered via oral and parenteral routes. In particular, chitosan-based microparticles are the most frequently employed delivery system, along with specialized systems such as hydrogels, nanoparticles and thin films. Based on the progress made in chitosan-based drug delivery systems, the usefulness of chitosan has further expanded to anti-cancer chemoembolization, tissue engineering, and stem cell research. For instance, chitosan has been used to develop embolic materials designed to efficiently occlude the blood vessels by which the oxygen and nutrients are supplied. Indeed, it has been reported to be a promising embolic material. For better anti-cancer effect, embolic materials that can locally release anti-cancer drugs were proposed. In addition, a complex of radioactive materials and chitosan to be locally injected into the liver has been investigated as an efficient therapeutic tool for hepatocellular carcinoma. In line with this, a number of attempts have been explored to use chitosan-based carriers for the delivery of various agents, especially to the site of interest. Thus, in this work, studies where chitosan-based drug delivery systems have successfully been used for local delivery will be presented along with future perspectives.

Intrinsic drug resistance of pancreatic ductal adenocarcinoma (PDAC) warrants studies using models that are more clinically relevant for identifying novel resistance mechanisms as well as for drug development. Tumor spheroids (TS) mimic in vivo tumor conditions associated with multicellular resistance and represent a promising model for efficient drug screening, however, pancreatic cancer cells often fail to form spheroids using conventional methods such as liquid overlay. This study describes the induction of TS of human pancreatic cancer cells (Panc-1, Aspc-1, Capan-2) in concave polydimethylsiloxane (PDMS) microwell plates and evaluation of their usefulness as an anticancer efficacy test model. All three cell lines showed TS formation with varying degree of necrosis inside TS. Among these, Panc-1 spheroid with spherical morphology, a rather rough surface, and unique adhesion structures were successfully produced with no notable necrosis in concave microwell plates. Panc-1 TS contained growth factors or enzymes such as TGF-β1, CTGF, and MT1-MMP, and extracellular matrix proteins such as collagen type I, fibronectin, and laminin. Panc-1 cells grown as TS showed changes in stem cell populations and in expression levels of miRNAs that may play roles in chemoresistance. Visualization of drug penetration and detection of viability indicators, such as Ki-67 and MitoSOX, were optimized for TS for quantitative analysis. Water-soluble tetrazolium (MTS) and acid phosphatase (APH) assays were also successfully optimized. Overall, we demonstrated that concave PDMS microwell plates are a novel platform for preparation of TS of weakly aggregating cells and that Panc-1 spheroids may represent a novel three-dimensional model for anti-pancreatic cancer drug screening.

Electrical stimulation with a weak current has been demonstrated to modulate various cellular and physiological responses, including the differentiation of mesenchymal stem cells and acute or chronic physical pain. Thus, a variety of investigations regarding the physiological role of nano- or microlevel currents at the cellular level are actively proceeding in the field of alternative medicine. In this study, we focused on the anti-inflammatory activity of aluminum-copper patches (ACPs) under macrophage-mediated inflammatory conditions. ACPs generated nanolevel currents ranging from 30 to 55 nA in solution conditions. Interestingly, the nanocurrent-generating aluminum-copper patches (NGACPs) were able to suppress both lipopolysaccharide-(LPS-) and pam3CSK-induced inflammatory responses such as NO and PGE2 production in both RAW264.7 cells and peritoneal macrophages at the transcriptional level. Through immunoblotting and immunoprecipitation analyses, we found that p38/AP-1 could be the major inhibitory pathway in the NGACP-mediated anti-inflammatory response. Indeed, inhibition of p38 by SB203580 showed similar inhibitory activity of the production of TNF-α and PGE2 and the expression of TNF-α and COX-2 mRNA. These results suggest that ACP-induced nanocurrents alter signal transduction pathways that are involved in the inflammatory response and could therefore be utilized in the treatment of various inflammatory diseases such as arthritis and colitis.

Marine biopolymers have been explored as a promising cell therapy system for efficient cell delivery and tissue engineering. However, the marine biomaterial-based systems themselves have exhibited limited performance in terms of maintenance of cell viability and functions, promotion of cell proliferation and differentiation as well as cell delivery efficiency. Thus, numerous novel strategies have been devised to improve cell therapy outcomes. The strategies include optimization of physical and biochemical properties, provision of stimuli-responsive functions, and design of platforms for efficient cell delivery and tissue engineering. These approaches have demonstrated substantial improvement of therapeutic outcomes in a variety of research settings. In this review, therefore, research progress made with marine biomaterials as a platform for cell therapy is reported along with current research directions to further advance cell therapies as a tool to cure incurable diseases.

Nanostructured, self-assembling peptides hold promise for a variety of regenerative medical applications such as 3D cell culture systems, accelerated wound healing, and nerve repair. The aim of this study was to determine whether the self-assembling peptide K5 can be applied as a carrier of anti-inflammatory drugs. First, we examined whether the K5 self-assembling peptide itself can modulate various cellular inflammatory responses. We found that peptide K5 significantly suppressed the release of tumor-necrosis-factor- (TNF-) α and prostaglandin E2 (PGE2) from RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Similarly, there was inhibition of cyclooxygenase- (COX-) 2 mRNA expression assessed by real-time PCR, indicating that the inhibition is at the transcriptional level. In agreement with this finding, peptide K5 suppressed the translocation of the transcription factors activator protein (AP-1) and c-Jun and inhibited upstream inflammatory effectors including mitogen activated protein kinase (MAPK), p38, and mitogen-activated protein kinase kinase 3/6 (MKK 3/6). Whether this peptide exerts its effects via a transmembrane or cytoplasmic receptor is not clear. However, our data strongly suggest that the nanostructured, self-assembling peptide K5 may possess significant anti-inflammatory activity via suppression of the p38/AP-1 pathway.

BAY 11-7082 (BAY) is an inhibitor of κB kinase (IKK) that has pharmacological activities that include anticancer, neuroprotective, and anti-inflammatory effects. In this study, BAY-pharmacological target pathways were further characterized to determine how this compound simultaneously suppresses various responses. Primary and cancerous (RAW264.7 cells) macrophages were activated by lipopolysaccharide, a ligand of toll-like receptor 4. As reported previously, BAY strongly suppressed the production of nitric oxide, prostaglandin E2, and tumor necrosis factor-α and reduced the translocation of p65, major subunit of nuclear factor-κB, and its upstream signaling events such as phosphorylation of IκBα, IKK, and Akt. In addition, BAY also suppressed the translocation and activation of activator protein-1, interferon regulatory factor-3, and signal transducer and activator of transcription-1 by inhibiting the phosphorylation or activation of extracellular signal-related kinase, p38, TANK-binding protein, and Janus kinase-2. These data strongly suggest that BAY is an inhibitor with multiple targets and could serve as a lead compound in developing strong anti-inflammatory drugs with multiple targets in inflammatory responses.

Red ginseng acidic polysaccharide (RGAP), isolated from Korean red ginseng, displays immunostimulatory and antitumor activities. Even though numerous studies have been reported, the mechanism as to how RGAP is able to stimulate the immune response is not clear. In this study, we aimed to explore the mechanism of molecular activation of RGAP in macrophages. RGAP treatment strongly induced NO production in RAW264.7 cells without altering morphological changes, although the activity was not strong compared to LPS-induced dendritic-like morphology in RAW264.7 cells. RGAP-induced NO production was accompanied with enhanced mRNA levels of iNOS and increases in nuclear transcription factors such as NF-κB, AP-1, STAT-1, ATF-2, and CREB. According to pharmacological evaluation with specific enzyme inhibitors, Western blot analysis of intracellular signaling proteins and inhibitory pattern using blocking antibodies, ERK, and JNK were found to be the most important signaling enzymes compared to LPS signaling cascade. Further, TLR2 seems to be a target surface receptor of RGAP. Lastly, macrophages isolated from RGS2 knockout mice or wortmannin exposure strongly upregulated RGAP-treated NO production. Therefore, our results suggest that RGAP can activate macrophage function through activation of transcription factors such as NF-κB and AP-1 and their upstream signaling enzymes such as ERK and JNK.

Cinnamaldehyde (CA) has been known to exhibit anti-inflammatory and anticancer effects. Although numerous pharmacological effects have been demonstrated, regulatory effect of CA on the functional activation of monocytes and macrophages has not been fully elucidated yet. To evaluate its monocyte/macrophage-mediated immune responses, macrophages activated by lipopolysaccharide (LPS), and monocytes treated with proaggregative antibodies, and extracellular matrix protein fibronectin were employed. CA was able to suppress both the production of nitric oxide (NO) and upregulation of surface levels of costimulatory molecules (CD80 and CD69) and pattern recognition receptors (toll-like receptor 2 (TLR2) and complement receptor (CR3)). In addition, CA also blocked cell-cell adhesion induced by the activation of CD29 and CD43 but not cell-fibronectin adhesion. Immunoblotting analysis suggested that CA inhibition was due to the inhibition of phosphoinositide-3-kinase (PI3K) and phosphoinositide-dependent kinase (PDK)1 as well as nuclear factor-(NF-) κB activation. In particular, thiol compounds with sulphydryl group, L-cysteine and dithiothreitol (DTT), strongly abrogated CA-mediated NO production and NF-κB activation. Therefore, our results suggest that CA can act as a strong regulator of monocyte/macrophage-mediated immune responses by thiolation of target cysteine residues in PI3K or PDK1.

Nimodipine is a highly lipophilic calcium channel blocker presenting extremely low aqueous solubility. This study aimed to develop solid self-microemulsifying tablets (SSMETs) that can considerably increase the apparent aqueous solubility and dissolution of nimodipine. For the selection of proper components of liquid state self-microemulsifying formulations (LSMEFs), nimodipine solubility and emulsification capability were evaluated. Based on these two factors, Capryol™ 90, Cremophor® EL, and polyethylene glycol 400 (PEG 400) were chosen as oil, surfactant, and co-surfactant, respectively. The optimized LSMEF was then established through the construction of pseudo-ternary phase diagrams. Next, to solidify the optimized LSMEF, several adsorbents were screened, and the LSMEF solidified with Neusilin® UFL2 showed the highest dissolution profile with an appropriate solvent binding capacity. To further facilitate the drug release from the SSMETs, several disintegrants were investigated, and the SSMET containing Primellose® as a disintegrant substantially increased the dissolution of nimodipine. In addition, when the SSMET re-dispersed in simulated intestinal fluid, the SSMET successfully formed microdroplets presenting similar small size (~90 nm) to droplets dispersed from the LSMEF. These results demonstrated that this SSMET we designed is a promising drug delivery system for poorly soluble drugs, such as nimodipine. [ABSTRACT FROM AUTHOR]

Eupatilin is known to possess anti-apoptotic, anti-oxidative, and antiinflammatory properties. We report here that eupatilin has a protective effect on the ethanol-induced injury in rats. Sprague-Dawley rats were divided into 6 groups: control, vehicle, silymarin, eupatilin 10 mg/kg, eupatilin 30 mg/kg, and eupatilin 100 mg/kg. Plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed to determine the extent of liver damage. Total cholesterol (TC) and triglycerides (TG) were analyzed to determine the level of liver steatosis. Malondialdehyde level, superoxide dismutase (SOD) activity, and glutathione (GSH) level were analyzed to determine the extent of oxidative stress. Tumor necrosis factor (TNF)-α and interleukin (IL)-1β were quantified to verify the degree of inflammation. Based on our findings, chronic alcohol treatment significantly changed the serum indexes and liver indicators of the model rats, which were significantly improved by eupatilin treatment. Rats in the eupatilin-treatment group showed reduced levels of AST, ALT, TG, TC, TNF-α, and IL-1β, increased SOD activity and GSH levels, and improved overall physiology compared to the alcoholic liver disease model rats. H&E staining also verified the eupatilin-mediated improvement in liver injury. In conclusion, eupatilin inhibits alcohol-induced liver injury via its antioxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Bladder dysfunction is a common complication of diabetes mellitus (DM). However, there have been a few studies evaluating bladder smooth muscle contraction in DM in the presence of pharmacological inhibitors. In the present study, we compared the contractility of bladder smooth muscle from normal rats and DM rats. Furthermore, we utilized pharmacological inhibitors to delineate the mechanisms underlying bladder muscle differences between normal and DM rats. DM was established in 14 days after using a single injection of streptozotocin (65 mg/kg, intraperitoneal) in Sprague-Dawley rats. Bladder smooth muscle contraction was induced electrically using electrical field stimulation consisting of pulse trains at an amplitude of 40 V and pulse duration of 1 ms at frequencies of 2-10 Hz. In this study, the pharmacological inhibitors atropine (muscarinic receptor antagonist), U73122 (phospholipase C inhibitor), DPCPX (adenosine A1 receptor antagonist), udenafil (PDE5 inhibitor), prazosin (α1-receptor antagonist), verapamil (calcium channel blocker), and chelerythrine (protein kinase C inhibitor) were used to pretreat bladder smooth muscles. It was found that the contractility of bladder smooth muscles from DM rats was lower than that of normal rats. In addition, there were significant differences in percent change of contractility between normal and DM rats following pretreatment with prazosin, udenafil, verapamil, and U73122. In conclusion, we suggest that the decreased bladder muscle contractility in DM rats was a result of perturbations in PLC/IP3-mediated intracellular Ca2+ release and PDE5 activity. [ABSTRACT FROM AUTHOR]

We investigated the combined moisturizing effect of liposomal serine and a cosmeceutical base selected in this study. Serine is a major amino acid consisting of natural moisturizing factors and keratin, and the hydroxyl group of serine can actively interact with water molecules. Therefore, we hypothesized that serine efficiently delivered to the stratum corneum (SC) of the skin would enhance the moisturizing capability of the skin. We prepared four different cosmeceutical bases (hydrogel, oil-in-water (O/W) essence, O/W cream, and water-in-oil (W/O) cream); their moisturizing abilities were then assessed using a Corneometer®. The hydrogel was selected as the optimum base for skin moisturization based on the area under the moisture content change-time curves (AUMCC) values used as a parameter for the water hold capacity of the skin. Liposomal serine prepared by a reverse-phase evaporation method was then incorporated in the hydrogel. The liposomal serine-incorporated hydrogel (serine level=1%) showed an approximately 1.62~1.77 times greater moisturizing effect on the skin than those of hydrogel, hydrogel with serine (1%), and hydrogel with blank liposome. However, the AUMCC values were not dependent on the level of serine in liposomal serine-loaded hydrogels. Together, the delivery of serine to the SC of the skin is a promising strategy for moisturizing the skin. This study is expected to be an important step in developing highly effective moisturizing cosmeceutical products. [ABSTRACT FROM AUTHOR]

Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor (NF)-κB, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages. [ABSTRACT FROM AUTHOR]

Retinyl palmitate (RP)-loaded pectinate micro- and nano-particles (PMP and PNP) were designed for stabilization of RP that is widely used as an anti-wrinkle agent in anti-aging cosmeceuticals. PMP/PNP were prepared with an ionotropic gelation method, and anti-oxidative activity of the particles was measured with a DPPH assay. The stability of RP in the particles along with pectin gel and ethanolic solution was then evaluated. In vitro release and skin permeation studies were performed using Franz diffusion cells. Distribution of RP in each skin tissue (stratum corneum, epidermis, and dermis) was also determined. PMP and PNP could be prepared with mean particle size diameters of 593∼843 μm (PMP) and 530 nm (i.e., 0.53 μm, PNP). Anti-oxidative activity of PNP was greater than PMP due largely to larger surface area available for PNP. The stability of RP in PMP and PNP was similar but much greater than RP in pectin bulk gels and ethanolic solution. PMP and PNP showed the abilities to constantly release RP and it could be permeated across the model artificial membrane and rat whole skin. RP was serially deposited throughout the skin layers. This study implies RP loaded PMP and PNP are expected to be advantageous for improved anti-wrinkle effects. [ABSTRACT FROM AUTHOR]

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility. [ABSTRACT FROM AUTHOR]

This article presents a study on the use of pharmaceutical excipients for the in vitro metabolic modulation of aryl sulfotransferases (SULT). It offers information on pharmaceutical excipients and discusses the use of solid and liquid oral dosage forms of excipients, and the enzyme kinetics of aryl SULT in the presence of pharmaceutical excipients.

The purpose of this study was to examine the anti-oxidative activity of pectin and other polysaccharides in order to develop a cosmeceutical base having anti-oxidative effects towards retinyl palmitate (RP). The anti-oxidative stabilizing effects of pectin and other polysaccharides on RP were evaluated by DPPH assay and then the stabilizing effect of pectin on RP was examined as a function of time. Among the polysaccharides we examined, pectin exhibited a considerably higher anti-oxidative activity, with an approximately 5-fold greater DPPH radical scavenging effect compared to other polysaccharides. The DPPH radical scavenging effect of pectin increased gradually with increasing concentrations of pectin. At two different RP concentrations, 0.01 and 0.1% in ethanol, addition of pectin improved the stability of RP in a concentration dependent manner. The stabilizing effect of pectin on RP was more effective for the lower concentration of RP (0.01%, v/v). Further, degradation of RP was reduced following the addition of pectin as measured over 8 hours. From the results obtained, it can be suggested that pectin may be a promising ingredient for cosmeceutical bases designed to stabilize RP or other pharmacological agents subject to degradation by oxidation. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the effect of micellar systems on the absorption of beta-lapachone (b-lap) through different intestinal segments using a single-pass rat intestinal perfusion technique. B-lap was solubilized in mixed micelles composed of phosphatidylcholine and sodium deoxycholate, and in sodium lauryl sulfate (SLS)-based conventional micelles. Both mixed micelles and SLS micelles improved the in situ permeability of b-lap in all intestinal segments tested although the mixed micellar formulation was more effective in increasing the intestinal absorption of b-lap. The permeability of b-lap was greatest in the large intestinal segments. Compared with SLS micelles, the effective permeability coefficient values measured with mixed micelles were 5- to 23-fold higher depending on the intestinal segment. Our data suggest that b-lap should be delivered to the large intestine using a mixed micellar system for improved absorption. [ABSTRACT FROM AUTHOR]

The objective of the present study was to establish the method of measurement of hydrogen peroxide and to estimate the anti-oxidative effect of genistein in the skin. UVB induced skin oxidation and anti-oxidative effect of genistein formulations were evaluated by determining levels of hydrogen peroxide. The mechanism involved in the determination of hydrogen peroxide is based on a color reaction between ferric ion (Fe3+) and xylenol orange, often called FOX assay and subsequent monitoring of absorbance values of the reactant at 540 nm. The reaction was to some extent pH-dependent and detection sensitivity was greatest at pH 1.75. Genistein liposomal gel demonstrated better anti-oxidative effect with regard to lowering hydrogen peroxide levels elevated by UVB irradiation compared to genistein-suspended gel. A linear relationship has been observed between anti-oxidative effect of genistein and drug deposition in the skin tissue. Genistein liposomal gel resulting in the localization of the drug in the deeper skin led to improved anti-oxidative effect compared to genistein gel. The suggested method for evaluation of oxidation of the skin can be used as a tool to screen effective anti-oxidative agents and their delivery systems acting on the skin. [ABSTRACT FROM AUTHOR]

Nanostructured, self-assembling peptides hold promise for a variety of regenerative medical applications such as 3D cell culture systems, accelerated wound healing, and nerve repair. The aim of this study was to determine whether the self-assembling peptide K5 can be applied as a carrier of anti-inflammatory drugs. First, we examined whether the K5 self-assembling peptide itself can modulate various cellular inflammatory responses. We found that peptide K5 significantly suppressed the release of tumor-necrosis-factor- (TNF-) α and prostaglandin E2 (PGE2) from RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Similarly, there was inhibition of cyclooxygenase- (COX-) 2 mRNA expression assessed by realtime PCR, indicating that the inhibition is at the transcriptional level. In agreement with this finding, peptide K5 suppressed the translocation of the transcription factors activator protein (AP-1) and c-Jun and inhibited upstream inflammatory effectors including mitogen activated protein kinase (MAPK), p38, and mitogen-activated protein kinase kinase 3/6 (MKK 3/6). Whether this peptide exerts its effects via a transmembrane or cytoplasmic receptor is not clear. However, our data strongly suggest that the nanostructured, self-assembling peptide K5 may possess significant anti-inflammatory activity via suppression of the p38/AP-1 pathway. [ABSTRACT FROM AUTHOR]

The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous reports have addressed the tumorigenesis-inducing effects of HQ, few papers have explored its molecular regulatory mechanism in immunological responses. In this study we characterized Akt (protein kinase B)-targeted regulation by HQ and its derivatives, in suppressing inflammatory responses using cellular, molecular, biochemical, and immunopharmacological approaches. HQ down-regulated inflammatory responses such as NO production, surface levels of pattern recognition receptors, and cytokine gene expression with IC50 values that ranged from 5 to 10 μM. HQ inhibition was mediated by blocking NF-κB activation via suppression of its translocation pathway, which is composed of Akt, IκBα kinase β, and IκBα. Of the targets in this pathway, HQ directly targeted and bound to the suithydryl group of Cys-310 of Akt and sequentially interrupted the phosphorylation of both Thr-308 and Ser-473 by mediation of β-mercaptoethanol, according to the liquid chromatography! mass spectroscopy analysis of the interaction of HQ with an Aktderived peptide. Therefore, our data suggest that Akt and its target site Cys-310 can be considered as a prime molecular target of HQ-mediated immunosuppression and for novel antiAkt-targeted immunosuppressive drugs. [ABSTRACT FROM AUTHOR]