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Find video protocols related to scientific articles indexed in Pubmed.
Proposed strategy for the use of high-dose chemotherapy with stem cell rescue and intrathecal topotecan without whole-brain irradiation for infantile classic medulloblastoma.
Pediatr Blood Cancer
PUBLISHED: 08-30-2014
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We describe a 6-month-old infant with classic medulloblastoma. Gross total resection of the left cerebellar tumor was performed; however, relapse occurred during the administration of intrathecal and intravenous methotrexate-based chemotherapy. After undergoing resection, high-dose chemotherapy was administered consisting of topotecan, melphalan, and cyclophosphamide with autologous peripheral stem cell rescue followed by local irradiation and intrathecal topotecan, which resulted in a complete response for more than two years. The administration of high-dose chemotherapy followed by intrathecal topotecan as maintenance therapy is an effective strategy, without losses in the cognitive function, for avoiding the use of whole-brain irradiation for infantile classic medulloblastoma. Pediatr Blood Cancer 2014;61:2316-2318. © 2014 Wiley Periodicals, Inc.
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Quantitative Assessment of Intestinal First-pass Metabolism of Oral Drugs Using Portal-vein Cannulated Rats.
Pharm. Res.
PUBLISHED: 08-28-2014
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To evaluate the impact of intestinal first-pass metabolism (Fg) by cytochrome P4503A (CYP3A) and uridine 5'-diphosphate-glucuronosyltransferases (UGT) on in vivo oral absorption of their substrate drugs.
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Separation and Detection of Plasmalogen in Marine Invertebrates by High-Performance Liquid Chromatography with Evaporative Light-Scattering Detection.
Lipids
PUBLISHED: 05-22-2014
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We have developed a new method for determining ethanolamine plasmalogen contents in marine invertebrates. This quantification method involves derivatization of ethanolamine glycerophospholipid (EtnGpl) subclasses, alkenylacyl (plasmalogen), diacyl, and alkylacyl subclasses, by enzyme treatment and acetylation, followed by separation and detection by high-performance liquid chromatography (HPLC) with evaporative light-scattering detection (ELSD). This method enabled complete separation of the subclasses, and the limit of detection for plasmalogen was 200 ng (260 pmol). The peak area of plasmalogen by ELSD was unaffected by the degree of unsaturated fatty acids in EtnGpl, in contrast to ultraviolet (UV) detection. Thus, this method enables accurate determination of plasmalogen contents in various species containing marine products possessing abundant polyunsaturated fatty acids (PUFA). The method developed here was applied to marine invertebrates available in Japan. The examined marine invertebrates showed a wide range of plasmalogen contents ranging from 19 to 504 ?mol/100 g wet wt. The plasmalogen levels in samples except those of class Cephalopoda and Crustacea were more than 60 mol% of EtnGpl.
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Formulation design for orally disintegrating tablets containing enteric-coated particles.
Chem. Pharm. Bull.
PUBLISHED: 05-03-2014
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The purpose of this study was to investigate the applicability of our newly developed technology (RACTAB® technology) for preparing orally disintegrating tablets (ODTs) containing enteric-coated particles. Tamsulosin hydrochloride (TAM) was used as a model drug contained in the enteric-coated particles. Enteric-coated particles containing TAM (ECP-T) were prepared by spray coating a mixture of TAM with controlled-release materials. ECP-T was then mixed with rapidly disintegrating granules (RDGs), which were prepared using the suspension spray-coating method, and was tableted to form ODTs (ODTRAC). ODTRAC was evaluated for its hardness, thickness, internal structure (X-ray-CT scanning), functional properties (controlled-release profile), and in vivo disintegration time. Since RDGs with micronized ethylcellulose (MEC) increased tablet hardness by increasing the contact frequency between granules, ODTRAC containing ECP-T exhibited high hardness (>50?N) and low friability (<0.5%) with a relatively low compression force. After tableting, the structure of ECP-T in ODTRAC remained intact and no damage was observed on the surface. ECP-T recovered from ODTRAC showed the same dissolution profile of TAM in Japanese Pharmacopoeia (JP) 1st and JP 2nd media as that of intact ECP-T, which indicated that the tableting process did not affect the acid-resistibility of the particle. In addition, ODTRAC rapidly disintegrated in vivo (< 30?s), even at a high compression force (at 9 kN). These findings clearly suggest that RACTAB® technology is a useful approach to prepare ODTs containing enteric-coated particles.
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Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution.
Eur J Pharm Sci
PUBLISHED: 04-29-2014
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The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (1H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid.
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A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.
Neurol. Med. Chir. (Tokyo)
PUBLISHED: 04-18-2014
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Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.
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Effect of excipients on the particle size of precipitated pioglitazone in the gastrointestinal tract: impact on bioequivalence.
AAPS J
PUBLISHED: 04-14-2014
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This study sought to understand the reasons for the bioinequivalence of a newly developed generic product of pioglitazone hydrochloride and to improve its formulation so that it is equivalent to that of the reference listed drug (RLD). In this clinical study, despite a similar in vitro dissolution profile, the new oral product exhibited a lower plasma concentration of pioglitazone compared to the RLD. The strong pH-dependency of pioglitazone solubility as a weak base indicates that pioglitazone would precipitate in the small intestine after being dissolved in the stomach. Thus, in vitro experiments were performed to investigate the effect of excipients on the particle size distribution of precipitated pioglitazone. Then, the impact of particle size on in vivo absorption was discussed. The precipitated pioglitazone from the RLD showed a peak for small particles (less than 1 ?m), which was not observed in the precipitate from the new product. As an excipient, hydroxypropyl cellulose (HPC) influenced the particle size of precipitated pioglitazone, and the amount of HPC in the formulation was increased to the same level as that in the RLD. The precipitate from this improved product showed approximately the same particle size distribution as that of the RLD and successfully demonstrated bioequivalence in the clinical study. In conclusion, for drugs with low solubility, this type of analysis of the particle size distribution of precipitated drugs, in addition to the dissolution test, may help to obtain a better in vitro-in vivo correlation for oral absorption and to develop a bioequivalent product.
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Preparation of marine plasmalogen and selective identification of molecular species by LC-MS/MS.
J Oleo Sci
PUBLISHED: 04-09-2014
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In this study, we investigated the laboratory-scale preparation and characteristics of ethanolamine plasmalogen from marine invertebrates. The preparation method consists of fractionation by acetone and ether treatment, and separation using column chromatography with silica gel and different eluents. Plasmalogen fractions (Pls fraction) were obtained from the viscera of the ascidian Halocynthia roretzi, and the prominent fatty acids were present as 20:5 (33.0%) and 22:6 (29.6%) n-3 polyunsaturated fatty acids (PUFA). The plasmalogen purity was 40%, and the alkenyl chains consisted of 18:0 (86.1%), 16:0 (5.9%) and 18:1 (4.9%). Precursor ion scanning in negative and positive ion modes using liquid chromatography tandem mass spectrometry (LC-MS/MS) enabled the profiling of phosphatidylethanolamine (PE) molecular species in ascidian viscera. Following LC-MS/MS with multiple reaction monitoring (MRM), the prominent plasmalogen species were found to be 18:0p/20:5 (30.4%) and 18:0p/22:6 (24.6%) (p at sn-1 position indicates alkenyl linkage). In conclusion, this preparative procedure using ascidian viscera as a source achieved 40% pure plasmalogen that was rich in n-3 PUFA. In addition, an LC-MS/MS assay enabled rapid analysis of plasmalogen species with selectivity and sensitivity. The present results will contribute to the understanding of dietary plasmalogen absorption and metabolism.
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Specificity of lectin-immobilized fluorescent nanospheres for colorectal tumors in a mouse model which better resembles the clinical disease.
Contrast Media Mol Imaging
PUBLISHED: 03-17-2014
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We have been investigating an imaging agent that enables real-time and accurate diagnosis of early colorectal cancer at the intestinal mucosa by colonoscopy. The imaging agent is peanut agglutinin-immobilized polystyrene nanospheres with surface poly(N-vinylacetamide) chains encapsulating coumarin 6. Intracolonically-administered lectin-immobilized fluorescent nanospheres detect tumor-derived changes through molecular recognition of lectin for the terminal sugar of cancer-specific antigens on the mucosal surface. The focus of the present study was to evaluate imaging abilities of the nanospheres in animal models that reflect clinical environments. We previously developed an orthotopic mouse model with human colorectal tumors growing on the mucosa of the descending colon to better resemble the clinical disease. The entire colon of the mice in the exposed abdomen was monitored in real time with an in vivo imaging apparatus. Fluorescence from the nanospheres was observed along the entire descending colon after intracolonical administration from the anus. When the luminal side of the colon was washed with phosphate-buffered saline, most of the nanospheres were flushed. However, fluorescence persisted in areas where cancer cells were implanted. Histological evaluation demonstrated that tumors were present in the mucosal epithelia where the nanospheres fluoresced. In contrast, no fluorescence was observed when control mice, without tumors were tested. The lectin-immobilized fluorescent nanospheres were tumor-specific and remained bound to tumors even after vigorous washing. The nanospheres nonspecifically bound to normal mucosa were easily removed through mild washing. These results indicate that the nanospheres combined with colonoscopy, will be a clinically-valuable diagnostic tool for early-stage primary colon carcinoma. Copyright © 2014 John Wiley & Sons, Ltd.
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In vitro-in vivo correlation of the effect of supersaturation on the intestinal absorption of BCS Class 2 drugs.
Mol. Pharm.
PUBLISHED: 02-06-2014
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The aim of this study was to establish an in vitro method for evaluating the effect of supersaturation on oral absorption of poorly water-soluble drugs in vivo. Albendazole, dipyridamole, gefitinib, and ketoconazole were used as model drugs. Supersaturation of each drug was induced by diluting its stock solution by fasted state simulated intestinal fluid (FaSSIF) (solvent-shift method), then dissolution and precipitation profile of the drug was observed in vitro. The crystalline form of the precipitate was checked by differential scanning calorimetry (DSC). For comparison, control suspension was prepared by suspending a drug powder directly into FaSSIF (powder-suspending method). In vivo intestinal absorption of the drug was observed in rats by determined the plasma concentration after intraduodenal administration of drug suspensions. For all drugs, suspensions prepared by solvent-shift method showed significantly higher dissolved concentration in vitro than that prepared by powder-suspending method, clearly indicated the induction of supersaturation. DSC analysis revealed that crystalline form of the precipitate profoundly affects the extent and the duration of supersaturation. A rat in vivo study confirmed that the supersaturation of these drugs increased the fraction absorbed from the intestine, which corresponded well to the in vitro dissolution and precipitation profile of drugs except for ketoconazole. For ketoconazole, an in vivo absorption study was performed in rats pretreated with 1-aminobenzotriazole, a potent inhibitor of CYP mediated metabolism. CYP inhibition study suggested that the high luminal concentration of ketoconazole caused by supersaturation saturated the metabolic enzymes and further increased the systemic exposure of the absorbed drug. The additional effects of supersaturation on the absorption of ketoconazole are consistent with previous studies in humans under differing gastric pH conditions. In conclusion, effects of supersaturation on the intestinal absorption of poorly water-soluble drugs could be predicted from in vitro dissolution and a precipitation study. However if supersaturation affects the pharmacokinetic profiles of drugs, such as a first-pass metabolism, a combination with in vivo study should be required to evaluate its impact on oral bioavailability.
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A new in vitro system for evaluation of passive intestinal drug absorption: Establishment of a double artificial membrane permeation assay.
Eur J Pharm Biopharm
PUBLISHED: 01-16-2014
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The aim of this present study was to establish a new in vitro assay, double artificial membrane permeation assay (DAMPA), to evaluate the human intestinal permeability of drugs. A double artificial membrane with an intracellular compartment was constructed in side-by-side chambers by sandwiching a filter containing buffer solution with impregnated lipophilic filters with dodecane containing 2w/v% phosphatidylcholine. Permeation data of ionic compounds clearly indicated that not only the pH value of the apical solution but also that of the intracellular compartment affected the permeability across the double artificial membrane. DAMPA was performed with 20 compounds at physiological pH (apical; 6.5, intracellular and basal; 7.4). Paracellular and transcellular permeabilities of compounds in human epithelium were estimated based on the characteristics of the paracellular pathway using physicochemical properties of compounds with the Renkin function and the area factor i.e. the difference in the effective surface area between human epithelium and the double artificial membrane, respectively. The human intestinal permeability of each compound was predicted by the sum of estimated transcellular and paracellular permeabilities. Predicted human intestinal permeability was significantly correlated with the fraction of absorbed dose in humans, indicating that DAMPA has the potential to predict oral absorption of drugs in humans.
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The DASH score: a simple score to assess risk for development of malignant middle cerebral artery infarction.
J. Neurol. Sci.
PUBLISHED: 01-16-2014
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The aim of the present study was to devise a simple grading scale for assessing the risk of development of malignant MCA infarction (MMI).
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A case of primary diffuse leptomeningeal gliomatosis.
Brain Tumor Pathol
PUBLISHED: 01-09-2014
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Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal disease characterized by diffuse infiltration of the leptomeninges by neoplastic glial cells without evidence of tumor in the brain parenchyma or spinal cord. We report a 60-year-old man with PDLG. He suffered transient right hemiparesis and generalized seizures. MRI showed diffuse leptomeningeal thickening and enhancement throughout the brain and spinal cord without any intraaxial involvement. Biopsy resulted in a diagnosis of glioblastoma with methylated MGMT promoter and wild-type IDH1. He underwent craniospinal radiotherapy and temozolomide treatment but despite concomitant adjuvant therapy he died 8 months after initial presentation.
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A Multicenter Phase I/II Study of the BCNU Implant (Gliadel(®) Wafer) for Japanese Patients with Malignant Gliomas.
Neurol. Med. Chir. (Tokyo)
PUBLISHED: 12-03-2013
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Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.
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Cardioembolic stroke associated with atrial fibrillation.
Rinsho Shinkeigaku
PUBLISHED: 12-03-2013
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Cardioembolic stroke is approximately 30% of brain infarction, and most of the embolus sources are atrial fibrillation (AF). Brain infarction with AF was associated with an elderly woman, main brain arterial occlusion, and large infarcts. Therefore, patient outcome is so sever, and mortality is very high compared with other stroke types. Use of the anticoagulant before stroke onset is only 32%, and less than 1.6 of PT-INR was 58.4%. The hospitalized recurrence was 7.5%, which was not higher than stroke patients without AF. For detection of the intracardiac tthrombus, transesophageal cardiac-echogram detected thrombus in 16.4%. Within five years after discharge, mortality rate was higher in stroke patients with AF than those without AF. Brain infarction with AF should be knock-out stroke.
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Optimization of output power in a fiber optical parametric oscillator.
Opt Express
PUBLISHED: 10-10-2013
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Fiber optical parametric oscillators (FOPOs) are coherent sources that can provide ultra-broadband tunability and high output power levels and are been considered for applications such as medical imaging and sensing. While most recent literature has focused on advancing the performance of these devices experimentally, theoretical studies are still scarce. In contrast, ordinary laser theory is very mature, has been thoroughly studied and is now well understood from the point of view of fundamental physics. In this work, we present a theoretical study of OPOs and in particular we theoretically discuss the process of gain saturation in optical parametric amplifiers. In order to emphasize the significant difference between the two coherent sources, we compare the optimized coupling ratios for maximum output powers of the ordinary laser and the optical parametric oscillator and demonstrate that in contrast to ordinary lasers, highest output powers in optical parametric oscillators are achieved with output coupling ratios close to 1. We confirm experimentally our theoretical studies by building a narrowband fiber optical parametric oscillator at 1450nm with multi-watt output power. We show that the device is robust to intracavity losses and achieve peak power as high as 2.4W.
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Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.
Eur J Pharm Biopharm
PUBLISHED: 06-10-2013
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This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.
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In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.
Drug Metab. Dispos.
PUBLISHED: 05-16-2013
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The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.
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Dynamic analysis of fluid distribution in the gastrointestinal tract in rats: positron emission tomography imaging after oral administration of nonabsorbable marker, [(18)F]Deoxyfluoropoly(ethylene glycol).
Mol. Pharm.
PUBLISHED: 05-07-2013
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To develop potent drugs for oral use, information on their pharmacokinetic (PK) properties after oral administration is of great importance. We have recently reported the utility of positron emission tomography (PET) for the analysis of gastrointestinal (GI) absorption of radiolabeled compounds. In this study, PET image analysis was performed in rats using a novel PET probe, [(18)F]deoxyfluoropoly(ethylene glycol)s, with an average molecular weight of 2 kDa ([(18)F]FPEG), as a nonabsorbable marker to elaborate the GI physiology in more detail, such as segmental transition of the administered water, and fluid volume and distribution in the intestine. After oral administration of [(18)F]FPEG solution to rats, a 90 min PET scan with continuous blood sampling was performed, and then the disposition of radioactivity in each part of GI tract was investigated. From blood PK analysis, it was confirmed that the bioavailability of [(18)F]FPEG was quite low in rats. PET image analysis showed that the radioactivity after oral administration of [(18)F]FPEG solution rapidly passed through the stomach, spread into the proximal small intestine, and then transited toward the distal region of the small intestine without decreasing the radioactivity during GI transition. Radiometabolite analysis revealed that the radioactivity in intestinal mucosal tissues, blood, and urine was mainly derived from unchanged [(18)F]FPEG. It was also found that the volume of interest (VOI) after oral administration of the radiotracer enables an understanding of the time-dependent manner of effective fluid volume changes in the stomach and the small intestine. In addition, the rate constant of the intestinal transition of radioactivity in each intestinal segment was calculated by kinetic model analysis, which revealed that PET analysis enables us to determine the GI transit from the same individuals and that it is applicable to determine site-specific intestinal absorption. In conclusion, we demonstrated the high potency of PET imaging technique to elucidate the distribution of orally administered solution in the GI tract in vivo.
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Maintenance hemodialysis independently increases the risk of early death after acute intracerebral hemorrhage.
Cerebrovasc. Dis.
PUBLISHED: 04-10-2013
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It is unknown whether the clinical features and outcomes of intracerebral hemorrhage (ICH) patients who undergo maintenance hemodialysis (HD) at the time of ICH are similar to those of general ICH patients.
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High-speed dispersion-tuned wavelength-swept fiber laser using a reflective SOA and a chirped FBG.
Opt Express
PUBLISHED: 03-14-2013
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We present a high-speed wavelength-swept fiber laser based on a dispersion tuning method using a reflective semiconductor optical amplifier (RSOA) and a chirped fiber Bragg grating (CFBG). By using these devices, the cavity length can be shortened drastically. The short cavity improves the laser performance at high sweep rates over 200 kHz. We achieve a sweep range of 60 nm and an output power of 8.4 mW at 100 kHz sweep. We applied the dispersion-tuned fiber laser to the swept-source OCT system and successfully obtained OCT images of an adhesive tape at up to 250 kHz sweep rate.
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Enhanced stability of nitrogen-sealed carbon nanotube saturable absorbers under high-intensity irradiation.
Opt Express
PUBLISHED: 03-14-2013
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Due to their broadband saturable absorption and fast response, carbon nanotubes have proven to be an excellent material for the modelocking of fiber lasers and have become a promising device for the implementation of novel laser configurations. However, it is imperative to address the issue of their long-term reliability under intense optical pulses before they can be exploited in widespread commercial applications. In this work, we study how carbon nanotubes degrade due to oxidation when exposed to high-intensity continuous-wave light and we demonstrate that by sealing the carbon nanotubes in a nitrogen gas, the damage threshold can be increased by over one order of magnitude. We then monitor over 24 hours the performance of the carbon nanotube saturable absorbers as the passive modelocking device of an erbium-doped fiber laser with intracavity powers ranging from 5 mW to 316 mW. We observe that when the carbon nanotubes are sealed in nitrogen environment, oxidation can be efficiently prevented and the laser can operate without any deterioration at intracavity powers higher than 300 mW. However, in the case where carbon nanotubes are unprotected (i.e. those directly exposed to the air in the environment), the nanotubes start to deteriorate at intracavity powers lower than 50 mW.
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Carbon nanotube/polymer composite coated tapered fiber for four wave mixing based wavelength conversion.
Opt Express
PUBLISHED: 03-14-2013
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In this paper, we demonstrate a nonlinear optical device based on a fiber taper coated with a carbon nanotube (CNT)/polymer composite. Using this device, four wave mixing (FWM) based wavelength conversion of 10 Gb/s Non-return-to-zero signal is achieved. In addition, we investigate wavelength tuning, two photon absorption and estimate the effective nonlinear coefficient of the CNTs embedded in the tapered fiber to be 1816.8 W(-1)km(-1).
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Evaluation of the internal structure of normal and pathological Guinea pig cochleae using optical coherence tomography.
Audiol. Neurootol.
PUBLISHED: 03-11-2013
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Optical coherence tomography (OCT) makes it possible to visualize the internal structures of several organs, such as the eye, in vivo. Although visualization of the internal structures of the inner ear has been used to try and identify certain pathological conditions, attempts have failed mainly due to the thick bony capsule surrounding this end organ. After decalcifying the bony wall of the cochlea with ethylenediamine tetraacetic acid, we could clearly visualize its internal structures by using OCT. We identified endolymphatic hydrops, strial atrophy and damage to the organ of Corti, evident as a distention of Reissners membrane, thinning of the lateral wall and flattening of the organ of Corti, respectively. When specimens embedded in paraffin, sliced and stained with hematoxylin and eosin (HE) were examined under a light microscope, the OCT images of normal and pathological cochleae were virtually identical with those of the HE specimens, except that the HE specimens exhibited several artifacts unrecognized in OCT images, which were considered to be induced during the preparation process. Since OCT enables one to obtain arbitrary plane images by manipulating the slice axis of the specimens and avoids any misinterpretation due to artifacts induced during histological preparation, our technique would be useful for examining cochlear pathologies without or prior to histological evaluations.
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Preparation of fenofibrate solid dispersion using electrospray deposition and improvement in oral absorption by instantaneous post-heating of the formulation.
Int J Pharm
PUBLISHED: 02-19-2013
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A coaxial electrospray technique was applied to a poorly soluble drug, fenofibrate (FEN), to increase its bioavailability. A particulate core-shell solid dispersion was designed using poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100) as a shell material and poly(vinyl pyrrolidone) K12-17 as a dispersant for FEN in the core phase. Although 58% of FEN remained in the crystalline state in the electrosprayed formulation, the dissolution behavior was significantly improved due to decrease in particle size, decrease in crystallinity, and increase in dispersion efficiency. The formulation was subjected to post-heating at 100 °C for 30 s to transform the remaining crystals into the amorphous state to further improve the dissolution behavior. Oral bioavailability was also on the order of: heated formulation>intact formulation>crystalline FEN. Instantaneous heating significantly improved the performance of the formulation despite its simple procedure, and thus can be a powerful step to be incorporated in the formulation manufacturing process.
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A huge intraventricular congenital anaplastic astrocytoma: case report with histopathological and genetic consideration.
Brain Tumor Pathol
PUBLISHED: 10-19-2011
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Congenital malignant gliomas are rare brain tumors about which few reports have been published. We present the clinical course and genetic alterations in an infant with a congenital malignant glioma detected incidentally by ultrasonography at 36 weeks. The tumor occupied the right temporoparietal region, extended to the posterior fossa, and significantly compressed surrounding structures. The female infant was entirely normal without macrocrania, tense fontanel, or sucking difficulties. The tumor was subtotally resected by two-stage surgery; pathological diagnosis was anaplastic astrocytoma. Immunohistochemical staining was positive for p53 and negative for epidermal growth factor receptor. There was no O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, no 1p/19q loss of heterozygosity, and no isocitrate dehydrogenase 1 (IDH1) mutation. She underwent postoperative chemotherapy and is alive and well 12 months after surgery.
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A Myxococcus xanthus bacterial tyrosine kinase, BtkA, is required for the formation of mature spores.
J. Bacteriol.
PUBLISHED: 08-12-2011
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A Myxococcus xanthus cytoplasmic bacterial tyrosine kinase, BtkA, showed phosphorylation activity in the presence of Exo. Phosphorylated BtkA was expressed late after starvation induction and early after glycerol induction. The btkA mutant was unable to complete maturation to heat- and sonication-resistant spores under both starvation- and glycerol-induced developmental conditions.
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Improvement of low bioavailability of a novel factor Xa inhibitor through formulation of cationic additives in its oral dosage form.
Int J Pharm
PUBLISHED: 08-11-2011
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A clinical trial of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphtyl) propanoic acid (DX-9065) revealed that its oral bioavailability was only 3% when it was administered as a conventional capsule formulation. The low bioavailability of DX-9065 was likely caused by both its poor membrane permeability and its electrostatic interaction with anionic bile acids. We hypothesized that DX-9065 absorption would be enhanced when the cationic drug was free from the complex through its replacement with other cationic substances. Polystyrene nanospheres coated with cationic poly(vinylamine) and cholestyramine, which is clinically used as a cholesterol-lowering agent, dramatically prevented DX-9065 from interacting with chenodeoxycholic acid in vitro. Successive animal experiments showed that bioavailability of DX-9065 administered with these cationic substances was 2-3 times that of DX-9065 administered solely. A dry syrup formulation with one-half of a minimal cholesterol-lowering equivalent dose of cholestyramine was designed, and the clinical trial was resumed. A 1.3-fold increase in bioavailability of DX-9065 was observed when the dry syrup was administered. We successfully demonstrated that DX-9065 absorption was enhanced when the drug was administered with cationic additives; however, it appeared that the absorption-enhancing function of cholestyramine largely depended on its dose. The dose escalation is probably prerequisite for the significant improvement of DX-9065 absorption in humans.
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Further improvement of orally disintegrating tablets using micronized ethylcellulose.
Int J Pharm
PUBLISHED: 08-01-2011
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The aim of this study is to design a new orally disintegrating tablet (ODT) containing micronized ethylcellulose (MEC). The new ODT was prepared by physical mixing of rapidly disintegrating granules (RDGs) with MEC. To obtain RDGs, mannitol was spray-coated with a suspension of corn starch and crospovidone (9:1, w/w ratio) using a fluidized-bed granulator (suspension spray-coating method). The new ODTs were evaluated for their hardness, friability, thickness, internal structure (X-ray-CT scanning), in vivo disintegration time, and water absorption rate. Since MEC increases tablet hardness by increasing the contact frequency between the granules, the new ODTs could obtain high hardness (>50 N) and low friability (<0.5 %) with relatively low compression force. In addition, fine capillary channels formed in ODTs facilitated the wicking action and enabled rapid disintegration in vivo (<30 s). On the other hand, since MEC has low hygroscopicity, the tablet hardness of ODTs containing MEC remained high for 1 month in high-humidity conditions. In conclusion, the new ODTs containing MEC developed in this study possessed superior properties for clinical use and are expected to be applied for a wide range of functionally released drugs for bitter taste masking, sustained release, and controlled release (pH-dependent film coating, matrix, and microcapsule).
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Application of dissolution/permeation system for evaluation of formulation effect on oral absorption of poorly water-soluble drugs in drug development.
Pharm. Res.
PUBLISHED: 07-20-2011
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The aim of the present study is to evaluate the formulation effect on the oral absorption of poorly water-soluble drugs using a dissolution/permeation system (D/P system).
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Phytoceramide and sphingoid bases derived from brewers yeast Saccharomyces pastorianus activate peroxisome proliferator-activated receptors.
Lipids Health Dis
PUBLISHED: 06-28-2011
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate lipid and glucose metabolism. PPAR? is highly expressed in the liver and controls genes involved in lipid catabolism. We previously reported that synthetic sphingolipid analogs, part of which contains shorter-length fatty acid chains than natural sphingolipids, stimulated the transcriptional activities of PPARs. Sphingosine and dihydrosphingosine (DHS) are abundant sphingoid bases, and ceramide and dihydroceramide are major ceramide species in mammals. In contrast, phytosphingosine (PHS) and DHS are the main sphingoid bases in fungi. PHS and phytoceramide exist in particular tissues such as the epidermis in mammals, and involvement of ceramide species in PPAR? activation in cultured keratinocytes has been reported. The purpose of the present study is to investigate whether natural sphingolipids with C18 fatty acid and yeast-derived sphingoid bases activate PPARs as PPAR agonists.
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A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system.
Mol. Pharm.
PUBLISHED: 06-17-2011
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The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category. A small variation in the number of subjects was constantly observed in bioequivalence studies using dosage forms containing an identical BCS class 1 or class 3 drug, even though formulations of the generic product differ between companies. The variation was extremely enlarged when the drugs were substituted with BCS class 2 drugs. Rate-determining steps in oral absorption of highly water-soluble BCS class 1 and class 3 drugs are independent of formulations when there is no significant difference in the in vitro dissolution profiles between formulations. The small variation observed for both BCS categories indicates that the number of subjects converges into one value for each drug. Our analysis indicates the appropriateness of biowaiver of bioequivalence studies for immediate-release solid oral dosage forms containing not only BCS class 1 drugs but also class 3 drugs.
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Oligodendroglial ganglioglioma.
Brain Tumor Pathol
PUBLISHED: 06-02-2011
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Gangliogliomas are rare tumors of the central nervous system, usually containing neoplastic ganglion cells and astrocytic components. Few cases of ganglioglioma containing only oligodendrocytic tissue have been reported to date. We present a case of a 40-year-old woman with ganglioglioma consisting mostly of oligodendroglial components. Magnetic resonance imaging showed a well-demarcated cystic lesion with slight perifocal edema in the right parietal lobe. The wall of the cyst was not enhanced after administration of Gd-DTPA contrast media. The mass was totally resected. Histological examination showed a mixture of two distinct components: oligodendroglioma and dysplastic ganglions. The first component was diffusely proliferated cells with round nuclei and perinuclear halo; the second showed marked nucleoli and basophilic cytoplasm containing Nissl bodies. Immunohistochemical study of the oligodendroglial component was positive for OLIG 2 and NKX2.2 but negative for synaptophysin. In addition, LOH of 1p/19q was detected by FISH. Although no adjuvant therapy was carried out, follow-up MRI showed no recurrence of the tumor 41 months after the operation.
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Essence of affinity and specificity of peanut agglutinin-immobilized fluorescent nanospheres with surface poly(N-vinylacetamide) chains for colorectal cancer.
Eur J Pharm Biopharm
PUBLISHED: 04-12-2011
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We have designed a novel colonoscopic imaging agent that is composed of submicron-sized fluorescent polystyrene nanospheres with two functional groups - peanut agglutinin (PNA) and poly(N-vinylaceamide) (PNVA) - on their surfaces. PNA is a targeting moiety that binds to ?-d-galactosyl-(1-3)-N-acetyl-d-galactosamine (Gal-?(1-3)GalNAc), which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells; it is anchored on the nanosphere surface via a poly(methacrylic) acid (PMAA) linker. PNVA is immobilized to enhance the specificity of PNA by reducing nonspecific interactions between the imaging agent and normal tissues. The essential nature of both functional groups was evaluated through in vivo experiments using PNA-free and PNVA-free nanospheres. The imaging agent recognized specifically tumors on the cecal mucosa of immune-deficient mice in which human colorectal cancer cells had been implanted; however, the recognition capability disappeared when PNA was replaced with wheat germ agglutinin, which has no affinity for Gal-?(1-3)GalNAc. PNA-free nanospheres with exclusively surface PNVA chains rarely adhered to the cecal mucosa of normal mice that did not undergo the cancer cell implantation. In contrast, there were strong nonspecific interactions between normal tissues and PNA-free nanospheres with exclusively surface PMAA chains. In vivo data proved that PNA and PNVA were essential for biorecognition for tumor tissues and a reduction of nonspecific interactions with normal tissues, respectively.
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Multi-gigahertz repetition rate passively modelocked fiber lasers using carbon nanotubes.
Opt Express
PUBLISHED: 04-01-2011
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There is an increasing demand for all-fiber passively mode-locked lasers with pulse repetition rates in the order of gigahertz for their potential applications in fields such as telecommunications and metrology. However, conventional mode-locked fiber lasers typically operate at fundamental repetition rates of only a few megahertz. In this paper, we report all-fiber laser operation with fundamental repetition rates of 4.24 GHz, 9.63 GHz and 19.45 GHz. This is, to date and to the best of our knowledge, the highest fundamental repetition rate reported for an all-fiber laser. The laser operation is based on the passive modelocking of a miniature all-fiber Fabry-Pérot laser (FFPL) by a carbon nanotube (CNT) saturable absorber. The key components for such device are a very high-gain Er:Yb phosphosilicate fiber and a fiber compatible saturable absorber with very small foot print and very low losses. The laser output of the three lasers was close to transform-limited with a pulsewidth of approximately 1 ps and low noise. As a demonstration of potential future applications for this laser, we also demonstrated supercontinuum generation with a longitudinal mode-spacing of 0.08 nm by launching the laser operating at 9.63 GHz into 30 m of a highly nonlinear dispersion shifted fiber.
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Kurashiki Prehospital Stroke Subtyping Score (KP3S) as a means of distinguishing ischemic from hemorrhagic stroke in emergency medical services.
Eur. Neurol.
PUBLISHED: 03-31-2011
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The aim of this study was to devise a new ischemic stroke (IS)/hemorrhagic stroke (HS) stroke score to distinguish IS from HS for emergency medical services (EMS).
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Coaxial electrospray formulations for improving oral absorption of a poorly water-soluble drug.
Mol. Pharm.
PUBLISHED: 03-25-2011
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Development of oral dosage forms containing poorly water-soluble drugs is a major challenge in the pharmaceutical industry. This paper describes the use of coaxial electrospray deposition as a promising formulation technology for oral delivery of poorly water-soluble drugs. The technology produced core-shell particles composed of griseofulvin and poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100), with a diameter of around 1 ?m. The drug phase was in an amorphous state when the griseofulvin core was coated with the Eudragit L-100 shell. The in vitro dissolution and in vivo oral absorption studies revealed that the core-shell formulation significantly improved dissolution and absorption behaviors, presumably because of a reduction in particle size, improvement in dispersity, and amorphization. Results demonstrated that coaxial electrospray deposition possesses great potential as novel formulation technology for enhancing oral absorption of poorly water-soluble drugs.
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Estimation of Michaelis-Menten constant of efflux transporter considering asymmetric permeability.
Int J Pharm
PUBLISHED: 03-15-2011
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It was previously reported that the apparent K(m) values of P-gp in apical to basal (A to B) and basal to apical (B to A) directions were different. The purpose of the present study was to derive a theoretical framework by which this asymmetric concentration-permeability profile can be explained using a single intrinsic K(m) value. A three compartment model was used to represent the apical, cytosol and basal compartments. The difference of passive permeability and the surface areas between the apical and basolateral membrane were explicitly taken into account. Applying the steady state approximation and considering the mass balance in the cytosol compartment, an open analytical solution was obtained. By using this equation, the asymmetric concentration-permeability profile was appropriately reproduced. In addition, the expression level dependency of apparent K(m) was also reproduced.
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In vitro dissolution/permeation system to predict the oral absorption of poorly water-soluble drugs: effect of food and dose strength on it.
Biol. Pharm. Bull.
PUBLISHED: 03-05-2011
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The aim of the present work was to confirm the usefulness of the dissolution/permeation system (D/P system) in the estimation of human oral absorption of poorly water-soluble drugs. The D/P system, which can simultaneously evaluate drug absorption processes, dissolution and permeation, can predict the oral absorption of poorly water-soluble drugs in fasted and fed humans, with a correlation between in vivo oral absorption (% of absorbed) and in vitro permeated amount (% of dose/2 h) in the D/P system. The oral absorption (fraction of absorbed dose, %) of poorly water-soluble drugs in the fasted and fed states was predicted using the D/P system. The effect of food on the oral absorption of various drugs estimated by the D/P system significantly correlated with clinical data (correlation coefficient: r(2)=0.924). Moreover, the proportion of oral absorption of cilostazol was predicted to decrease with an increase in its dose strength, which significantly correlated with in vivo human absorption. Consequently, the D/P system was demonstrated to be a useful in vitro system for prediction of the oral absorption of poorly water-soluble drugs.
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Prior oral antithrombotic therapy is associated with early death in patients with supratentorial intracerebral hemorrhage.
Intern. Med.
PUBLISHED: 03-01-2011
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Although oral antithrombotic therapy (OAT) is a risk factor of intracerebral hemorrhage (ICH), the clinical course of supratentorial ICH with prior OAT is unclear. We therefore assessed the characteristics of supratentorial ICH with OAT to determine whether OAT is independently associated with early death in supratentorial ICH.
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Estimation of P-glycoprotein-mediated efflux in the oral absorption of P-gp substrate drugs from simultaneous analysis of drug dissolution and permeation.
Eur J Pharm Sci
PUBLISHED: 02-26-2011
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The purpose of this study was to establish an in vitro system that evaluates the effects of P-glycoprotein (P-gp)-mediated efflux on the oral absorption of P-gp substrates. An in vitro system (dissolution/permeation system, D/P system) was developed that consisted of apical and basal chambers and a Caco-2 cell monolayer mounted between the chambers. Both sides of the monolayer were filled with physiological solution and were stirred at 200rpm. The dissolution in the apical medium and permeation to the basal medium were monitored for 2h after P-gp substrates were applied to the apical side of the system. When erythromycin existed in the apical medium, the permeations of fexofenadine and talinolol were significantly enhanced without change in their dissolution. The prediction of oral absorptions of fexofenadine and talinolol from in vitro data indicated that co-administration of erythromycin results in 2.1- and 1.9-fold higher oral absorptions, respectively. Moreover, the D/P system could estimate the effect of cremophor EL on the oral absorption of saquinavir. These estimations corresponded well to in vivo human observations. Our in vitro system is useful in assessment of the effect of P-gp-mediated efflux on in vivo oral absorption of P-gp substrates.
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Lectin-immobilized fluorescent nanospheres for targeting to colorectal cancer from a physicochemical perspective.
Curr Drug Discov Technol
PUBLISHED: 02-26-2011
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The goal of this research is to develop an imaging agent that enables real-time and accurate diagnosis of small-sized colorectal cancer. Since colorectal cancer initially develops in the mucous membrane of the large intestine, a nonabsorbable colonoscopic imaging agent capable of being administered intracolonically was designed. The imaging agent is peanut agglutinin (PNA)-immobilized polystyrene nanospheres with surface poly(N-vinylacetamide) (PNVA) chains encapsulating coumarin 6. PNA is a targeting moiety that binds to ?-D-galactosyl-(1-3)-N-acetyl-D-galactosamine, which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells. PNVA is immobilized with the aim of reducing nonspecific interactions between the imaging agent and normal tissues, because the initial tumor-derived change is very small throughout the entire large intestine. Coumarin 6 is encapsulated into nanosphere cores to provide endoscopically-detectable fluorescence intensity. It is anticipated that the intracolonically-administered imaging agent recognizes tumor-derived changes in the large intestinal mucosa with high affinity and specificity. Real-time and accurate diagnosis of small-sized early colorectal cancer can be achieved through an imaging agent providing clear fluorescence contrast between normal and cancer tissues observed with a florescence endoscope. This review describes the design concept of this nanoprobe from a physicochemical perspective.
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Scale-up of in vitro permeation assay data to human intestinal permeability using pore theory.
Int J Pharm
PUBLISHED: 02-09-2011
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The aim of this study is to establish a theoretical method for the prediction of human intestinal permeability from in vitro permeation assay. Pore radius and porosity/length and ion selectivity of the paracellular pathway were calculated using the Renkin function using permeabilities of mannitol and urea and potential difference study to evaluate paracellular permeability in Caco-2 cell monolayer; they were calculated to be 5.91 ?, 7.51 cm(-1) and 2.75, respectively. These values in the human epithelium were calculated from the reported intestinal permeability. The area factor, which can correct the difference in the transcellular permeability between Caco-2 cell monolayer and human epithelium, was obtained using the ratio of permeability of high lipophilicity compounds (human/Caco-2) and was calculated to be 13.3. Paracellular and transcellular permeabilities of 9 compounds in human epithelium were estimated on the basis of the characteristics of the paracellular pathway using physicochemical properties of compounds and the area factor, respectively. Human intestinal permeabilities were predicted by the sum of estimated transcellular and paracellular permeabilities. A linear correlation whose slope and intercept were nearly 1 and 0, respectively, was observed between predicted and reported human intestinal permeabilities. We successfully predicted human intestinal permeability from in vitro data.
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Nasal delivery of P-gp substrates to the brain through the nose-brain pathway.
Drug Metab. Pharmacokinet.
PUBLISHED: 02-08-2011
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The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose-CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors.
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Enteric-coated tablets improve oral bioavailability of DX-9065, a novel anticoagulant.
Eur J Pharm Sci
PUBLISHED: 01-10-2011
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Oral bioavailability of DX-9065, a factor Xa inhibitor, was only 3% when it was administered as a conventional capsule formulation in fasted humans, and was further reduced to about one-tenth when it was administered to fed humans. The poor absorption of DX-9065 probably resulted from its low membrane permeability and its electrostatic interaction with bile acid. We designed enteric-coated tablets with the expectation that this pharmaceutical technology will prevent DX-9065 from interacting with bile acid. More than 85% of DX-9065 was released from the tablet coated with hypromellose acetate succinate within 10min in simulated intestinal fluid (pH 6.8). Monkey experiments demonstrated that AUC of DX-9065 after oral administration of its enteric-coated tablet was about 5 times that of its aqueous solution in the fasted state. The food effect on drug absorption was also reduced when DX-9065 was administered as an enteric-coated tablet. The average ratio of AUC in a fed state to that in a fasted state was approximately 0.5, even though the ratio was 0.1 when the enteric-coated tablet was substituted with the drug solution. Enteric coating could be a useful method for improving oral absorption of DX-9065 with reduced food effects on drug absorption.
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A potential of peanut agglutinin-immobilized fluorescent nanospheres as a safe candidate of diagnostic drugs for colonoscopy.
Eur J Pharm Sci
PUBLISHED: 01-07-2011
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We designed peanut agglutinin (PNA)-immobilized fluorescent nanospheres as a non-absorbable endoscopic imaging agent capable of being administered intracolonically. Following our previous researches with evidence that the imaging agent recognized small-sized colorectal tumors on the mucosal surface with high affinity and specificity in animal experiments, a potential of this nanoprobe as a drug candidate was evaluated from a safety perspective. The imaging agent detects colorectal tumors through recognition of the tumor-specific antigen by PNA immobilized on the nanosphere surface, and the detection is made via the fluorescent signal derived from coumarin 6 encapsulated into the nanosphere core. The stability studies revealed that the high activity of PNA was maintained and there was no significant leakage of coumarin 6 after intracolonic administration of the imaging agent. Cytotoxicity studies indicated that no local damage to the large intestinal membrane was induced by the imaging agent. Further, in vitro and in vivo permeation studies demonstrated that there was no significant permeation of the imaging agent through the monolayer of cultured cells and that the imaging agent administered locally to the luminal side of the large intestine was almost completely recovered from the administration site. Therefore, we concluded that the imaging agent is a safe and stable probe which remains in the large intestine without systemic exposure.
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Optical deposition of graphene and carbon nanotubes in a fiber ferrule for passive mode-locked lasing.
Opt Express
PUBLISHED: 12-18-2010
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Mode-locked fiber lasers are currently undergoing a significant evolution towards higher pulse energies and shorter pulse durations. A key enabler in this progress has been the discovery of novel saturable absorbers (SA) such as carbon nanotubes (CNT) and graphene. The exceptional properties of CNTs as SA have been extensively studied in recent years. Graphene, a one atom thick planar sheet of carbon atoms arranged into a hexagonal lattice, has been recently proposed as an alternative to CNTs in several photonics applications. Here, we propose a method for the integration of graphene into a fiber ferrule using an optical deposition technique, which has been also employed for the deposition of CNT directly on the core of a fiber edge and in tapered fibers. We investigate and compare the optical properties of CNT-SA and graphene-SA fabricated by this optical deposition technique. Soliton-like, mode-locked lasing is confirmed using an erbium doped optical fiber in an all-fiber ring cavity laser configuration.
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High-permeability criterion for BCS classification: segmental/pH dependent permeability considerations.
Mol. Pharm.
PUBLISHED: 09-03-2010
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The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the ?-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F(abs). The effective permeabilities (P(eff)) of sotalol and metoprolol, a FDA standard for the low/high P(eff) class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P(eff) at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolols at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolols P(eff) value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalols permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F(abs). In conclusion, we have shown that, in fact, there is no discrepancy between P(eff) and F(abs) in sotalols absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.
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Impact of microdosing clinical study -- why necessary and how useful?
Adv. Drug Deliv. Rev.
PUBLISHED: 08-29-2010
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The microdose (MD) clinical study enables to select a "better" compound for new drug candidate that shows desirable PK profiles in human. This new methodology is highly expected to streamline the drug development and to increase the success probability in the clinical trial. Since only a small amount of the test compound (less than 100 ?g) is administered, the risk of harmful events to a human subject is regarded as minimal in the MD clinical study. However, the low dose also incurs the arguments about the usefulness of this method, since it may result in different PK profiles of drugs from that at the therapeutic dose. In addition, information on the efficacy/safety of the test compound cannot be obtained from the MD clinical study. On the other hand, PBPK model analysis based on the data of both the MD clinical study and in vitro study on metabolism, transport and binding enables the accurate prediction of PK profiles in humans at the therapeutic dose. PET molecular imaging technology further enhances the usability and applicability of the MD clinical study by offering the information on efficacy/safety. These methodologies, if coordinated effectively, are expected to innovate the new drug discovery and development.
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Quantitative analysis of the effect of supersaturation on in vivo drug absorption.
Mol. Pharm.
PUBLISHED: 08-12-2010
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The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.
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Transnasal delivery of methotrexate to brain tumors in rats: a new strategy for brain tumor chemotherapy.
Mol. Pharm.
PUBLISHED: 08-09-2010
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Brain tumors are one of the most lethal and difficult to treat. Their treatment is limited by the inadequate delivery of antitumor drugs to the tumor. In order to overcome this limitation, the possibility of the nose-brain direct transport pathway was evaluated using methotrexate (MTX) as a model antitumor agent. The direct transport of nasal MTX to the cerebrospinal fluid (CSF) was examined by comparing the concentration of MTX in the plasma and the CSF after intraperitoneal (IP) and intranasal (IN) administrations. The brain uptake of MTX was evaluated based on a multiple-time/graphical analysis by measuring the concentration of MTX in the plasma and in the brain. The feasibility of nasal chemotherapy was examined by three nasal dosings of MTX to tumor-bearing rats in vivo at two day intervals with peritoneal application as a positive control. MTX showed a significant inhibitory effect on the in vitro growth of 9L glioma cells with 50% growth inhibitory concentration at 7.99 ng/mL. The pharmacokinetic studies clarified the significant direct transport of MTX from nasal cavity both to the CSF and to the brain. Nasal chemotherapy with MTX significantly reduced the tumor weight as compared to nontreatment control and IP group. The strategy to utilize the nose-brain direct transport can be applicable to a new therapeutic system not only for brain tumors but also for other central nervous system disorders such as neurodegenerative diseases.
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Passive mode-locked lasing by injecting a carbon nanotube-solution in the core of an optical fiber.
Opt Express
PUBLISHED: 07-01-2010
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In this paper, we propose a saturable absorber (SA) device consisting on an in-fiber micro-slot inscribed by femtosecond laser micro fabrication, filled by a dispersion of Carbon Nanotubes (CNT). Due to the flexibility of the fabrication method, efficient and simple integration of the mode-locking device directly into the optical fiber is achieved. Furthermore, the fabrication process offers a high level of control over the dimensions and location of the micro-slots. We apply this fabrication flexibility to extend the interaction length between the CNT and the propagating optical field along the optical fiber, hence enhancing the nonlinearity of the device. Furthermore, the method allows the fabrication of devices that operate by either a direct field interaction (when the central peak of the propagating optical mode passes through the nonlinear media) or an evanescent field interaction (only a fraction of the optical mode interacts with the CNT). In this paper, several devices with different interaction lengths and interaction regimes are investigated. Self-starting passively modelocked laser operation with an enhanced nonlinear interaction is observed using CNT-based SAs in both interaction regimes. This method constitutes a simple and suitable approach to integrate the CNT into the optical system as well as enhancing the optical nonlinearity of CNT-based photonic devices.
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HbA1c and atrial fibrillation: a cross-sectional study in Japan.
Int. J. Cardiol.
PUBLISHED: 05-07-2010
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The aim of the present study was to investigate whether the prevalence of atrial fibrillation (AF) is associated with the level of glycated hemoglobin (HbA1c) in Japanese adults in Kurashiki-city.
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Carboxyl group-terminated polyamidoamine dendrimers bearing glucosides inhibit intestinal hexose transporter-mediated D-glucose uptake.
Eur J Pharm Biopharm
PUBLISHED: 04-07-2010
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We are investigating non-absorbable polymeric conjugates bearing glucosides via a omega-amino triethylene glycol linker as oral anti-diabetic drugs that suppress an increase in the blood glucose level after meals through inhibition of Na(+)/glucose cotransporter (SGLT1). When the linker was bound to phloridzin, which is a SGLT1 inhibitor, to yield a precursor of the conjugate, the in vitro inhibitory effect on SGLT1-mediated d-glucose uptake was reduced to about one-tenth that of phloridzin. The inhibitory effect was recovered completely when the precursor was immobilized on the surface of poly(amidoamine) (PAMAM) dendrimers (generation: 3.0) by coupling with one-eighth or less of the terminal carboxyl groups. We considered that the phloridzin-derived glucose moiety on the dendrimer surface was prerequisite for SGLT1 inhibition but that the aglycon part was not always required for the inhibition. Commercially used arbutin, a SGLT1 substrate, was substituted for phloridzin whose aglycon is composed of toxic phloretin. The in vitro inhibitory effect of arbutin was about one-thirtieth that of intact phloridzin; however, the inhibitory effect of the PAMAM dendrimer-arbutin conjugates was as strong as that of the PAMAM dendrimer-phloridzin conjugates. Rat experiments further showed that the PAMAM dendrimer-arbutin conjugates significantly suppressed d-glucose-induced hyperglycemic effects. The dendritic conjugate bearing arbutin appears to be a good candidate as an oral anti-diabetic drug.
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Oligoarginine-linked polymers as a new class of penetration enhancers.
J Control Release
PUBLISHED: 04-03-2010
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Oligoarginines, which are known as cell-penetrating peptides, enhance the cellular uptake of poorly membrane-permeable bioactive molecules that are chemically conjugated to them. We designed a novel polymer: oligoarginine-linked poly(N-vinylacetamide-co-acrylic acid), with the expectation that the polymers will enhance the cellular uptake of the bioactive molecules that are physically mixed with them. Oligoarginines were grafted onto the polymer backbone through the chemical reaction with acrylic acid functional groups. The changes in the blood glucose concentration after nasal administration of insulin with and without the polymer were monitored in mice. The blood glucose concentration was slightly reduced when insulin was given solely at a dose of 10IU/kg. A D-octaarginine-linked poly(N-vinylacetamide-co-acrylic acid) with a grafting degree of 2% significantly enhanced the insulin-induced hypoglycemic effect. A similar enhancement was not observed when the polymer was substituted with intact D-octaarginine. The penetration-enhancing function of D-octaarginine-linked poly(N-vinylacetamide-co-acrylic acid) increased dramatically with an increase in the grafting degree of D-octaarginine. Substitution of D-octaarginine with the corresponding optical isomer and an increase in the number of arginine residues rather reduced the penetration-enhancing function. In vitro cell studies also indicated that a D-octaarginine-linked poly(N-vinylacetamide-co-acrylic acid) with a grafting degree of 17% enabled fluorescein isothiocyanate-dextran to effectively penetrate the cell membrane. Results demonstrated that our oligoarginine-linked polymer has a potential to provide a new class of penetration enhancers.
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Hyper-acute stroke patients associated with aortic dissection.
Intern. Med.
PUBLISHED: 03-15-2010
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Intravenous thrombolysis using tissue plasminogen activator (tPA) can improve patient outcomes in acute stroke if administered within 3 hours of onset. However, patients with aortic dissection should avoid tPA therapy due to the possibility of tPA administration inducing rupture of the aortic dissection. We studied the frequency and clinical characteristics of stroke patients presenting with aortic dissection within 3 hours of onset.
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Prediction of food effect by bile micelles on oral drug absorption considering free fraction in intestinal fluid.
Eur J Pharm Sci
PUBLISHED: 02-18-2010
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The purpose of the present study was to derive a theoretical framework for prediction of the food effects by interactions with bile micelles on oral drug absorption. The effect of bile micelles was discussed based on the categories of permeability limited (PL), dissolution rate limited (DRL) and solubility limited (SL) absorption. SL was further categorized as the solubility-epithelial membrane limited (SL-E) and the solubility-unstirred water layer (UWL) limited (SL-U). In PL, an increase of bile micelles in the fed state was suggested to result in a negative food effect if the drug molecules bind to bile micelles because of a decrease of free monomer concentration. In DRL, a positive food effect was anticipated. In SL-E (e.g., pranlukast), little or no food effect was anticipated since the increase of apparent solubility (bile micelle bound molecule+free molecule) would be cancelled out by the decrease of effective permeability (the free monomer concentration at the epithelial membrane surface would remain the same. Total flux=solubilityxpermeability). In SL-U (e.g., danazol), a positive food effect was anticipated since the bile micelle bound molecules can permeate the UWL (however, slower than free monomer molecules). Based on this discussion, it was suggested that a formulation which could increase the free fraction at the epithelial membrane surface would be required to enhance oral absorption for SL-E (e.g., supersaturable formulations), whereas any formulation which can increase the UWL flux would be effective for SL-U (e.g., micro- to nano-emulsion systems, nano-milling and cyclodextrins). It was also suggested that a simple dissolution test would be misleading for SL-E and a simultaneous assessment of dissolution and permeation would be required.
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Acute stroke patients have occult malignancy more often than expected.
Eur. Neurol.
PUBLISHED: 02-08-2010
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The aim of the present study was to investigate the frequency of having occult malignancy in patients with acute ischemic stroke and their clinical characteristics. We retrospectively enrolled 1,714 consecutive ischemic stroke patients within 7 days of onset. The patients were divided into two groups: the Non-M group had no malignancy, and the M group had malignancy. We compared the clinical characteristics of the two groups. Of 1,714 ischemic stroke patients, 51 patients (3.0%; M group) were newly diagnosed as having malignancy. The M group was significantly older than the Non-M group (p = 0.009). Hemoglobin (Hb) was less and D-dimer was higher in the M group than in the Non-M group (p < 0.001). The patients with both D-dimer >or=1.3 ng/dl and Hb <12.8 g/dl more frequently had occult malignancy than patients without (p = 0.0088).
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Early stroke treatment with IV t-PA associated with early recanalization.
J. Neurol. Sci.
PUBLISHED: 02-05-2010
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Time from stroke onset to treatment (OTT) is potentially an important factor affecting subsequent outcome in patients treated with t-PA. The aim of the study was to assess the correlation between OTT and early recanalization rate after IV-t-PA therapy.
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Model analysis of the concentration-dependent permeability of P-gp substrates.
Pharm. Res.
PUBLISHED: 02-05-2010
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Recently, it was reported that the apparent Michaelis-Menten constant (Km(app)) of a P-glycoprotein (P-gp) substrate, defined for the extracellular substrate concentration, increases as the P-gp expression level in the cell increases. By its nature, the Km value should not depend on the level of P-gp expression. The purpose of this study is to establish a model which can estimate the Km value independent of the P-gp expression level in cells.
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Detection of early colorectal cancer imaged with peanut agglutinin-immobilized fluorescent nanospheres having surface poly(N-vinylacetamide) chains.
Eur J Pharm Biopharm
PUBLISHED: 01-05-2010
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Peanut agglutinin (PNA)-immobilized fluorescent nanospheres were designed as a novel imaging agent for colonoscopy. PNA is a targeting moiety that binds to beta-D-galactosyl-(1-3)-N-acetyl-D-galactosamine, which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells. The in vivo performance of the imaging agent was evaluated using a human colorectal cancer orthotopic animal model. Human colorectal adenocarcinoma cell lines, HT-29, HCT-116, and LS174T, were implanted on the cecal serosa of immune-deficient mice. A loop of the tumor-bearing cecum was made, and the luminal side was treated with the imaging agent. Strong fluorescence was observed at several sites of the cecal mucosa, irrespective of cancer cell type. Microscopic histological evaluation of the cecal mucosa revealed that bright areas with fluorescence derived from the imaging agent and dark areas without the fluorescence well denoted the presence and absence, respectively, of the invasion of implanted cancer cells on the mucosal side. This good correlation showed that PNA-immobilized fluorescent nanospheres recognized millimeter-sized tumors on the cecal mucosa with high affinity and specificity.
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Investigation of the intestinal permeability and first-pass metabolism of drugs in cynomolgus monkeys using single-pass intestinal perfusion.
Biol. Pharm. Bull.
PUBLISHED: 01-05-2010
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To clarify the causes of low oral bioavailability (BA) of drugs in cynomolgus monkeys, the experimental method to evaluate the drug permeability and the metabolism in the intestine of cynomolgus monkeys was established. An in situ intestinal perfusion method was performed with blood sampling from both portal and peripheral veins to calculate the intestinal permeability and the metabolism of drugs simultaneously. In all experiments, antipyrine was co-perfused with test drugs as a non-metabolized reference to calculate the individual portal vein blood flow. The effective permeability coefficient (P(eff)) of acetaminophen and piroxicam were high, and the fraction of dose absorbed from the gastrointestinal tract (Fa) thought to be 1. The intestinal availability (Fg) of acetaminophen and piroxicam were calculated to be 0.39 and 1.09, respectively. The Fa*Fg values of these drugs calculated from the perfusion study almost coincided with those obtained from the in vivo PK analysis in the previous report. In addition, the Fg values of verapamil and midazolam were calculated as 0.16 and 0.26, respectively, suggesting these drugs were metabolized extensively in the intestine after oral administration to cynomolgus monkey. Furthermore, the Fg values of these drugs were increased to 0.8-0.85 in the presence of 1-aminobenzotriazole, a typical cytochrome P450 (CYP) inhibitor. In conclusion, it was clarified that acetaminophen, verapamil and midazolam were metabolized extensively in the intestine of cynomolgus monkeys. This intestinal perfusion method is considered to be useful to identify the factors of species difference in the oral absorption of drugs.
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Deposition of carbon nanotubes around microfiber via evanascent light.
Opt Express
PUBLISHED: 11-13-2009
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Optical devices based on carbon nanotubes (CNTs) have been realized with several fabrication methods in different structures, such as free-space, fiber-end, waveguide, and fiber structures. Most of waveguide- and fiber-type devices utilize evanescent coupling between the guided light and CNT layers, and offer very high optical damage threshold and high third-order nonlinearity. However, the conventional fabrication methods require complicated processes and waste much of CNTs. In this work, we propose and demonstrate CNT deposition around microfibers induced by injecting light through the fibers. This method can area-selectively deposit desired number of CNTs around microfibers, and can be realized by a simple process and setup. We also demonstrate a passively mode-locked fiber laser using a CNT-deposited microfiber as a passive mode-locker.
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A theoretical-empirical analysis on the initial dissolution rate of drugs from polydispersed particles.
Biol. Pharm. Bull.
PUBLISHED: 11-03-2009
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The purpose of this work is to clarify the relationship of mean particle size to the dissolution rate of polydispersed particles for Biopharmaceutical Classification System (BCS) Class II drugs. An equation for the initial dissolution rate of polydispersed particles relative to mean particle diameter was theoretically derived from the Noyes-Whitney equation assuming spherical particles and sink conditions. To verify the relationship of dissolution to the mean particle diameters, the dissolution rates of 6 types of hypothetically-generated log-normal polydispersed particles and 3 different sized particles of aprepitant, a designated BCS class II drug, were compared with known mean diameters calculated according to surface area-weighted mean diameter (D(3,2), commonly referred to as the Sauter mean diameter), length-weighted mean diameter (D(3,1)) and number-weighted mean diameter (D(3,0)). The results confirmed that the initial dissolution rates of polydispersed particles reflect the mean diameter and correlated best with the reciprocal of D(3,2) at the start of dissolution, in accord with our theoretical conclusions. The particle size required for sufficient dissolution of aprepitant was also investigated by examining the relationship between D(3,2) and oral absorption predicted using a physiological-based model.
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Carbon nanotube-doped polymer optical fiber.
Opt Lett
PUBLISHED: 10-20-2009
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We present a method to fabricate graded-index multimode polymer optical fibers doped with carbon nanotubes (CNTs). Such fiber structures provide the means to fully utilize the exceptional optical properties of the CNTs. The core region of the fiber is composed of CNTs and polymethyl methacrylate (PMMA) with the addition of diphenyl sulfide (DPS), which acts as the dispersion stabilizer of CNTs in PMMA as well as the dopant to increase the refractive index of the core. Utilizing 2.5 cm of the fiber as a saturable absorber, passively mode-locked lasing with duration of 3.0 ps and repetition rate of 30.3 MHz was demonstrated.
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IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system.
J Pharm Sci
PUBLISHED: 07-28-2009
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The usefulness of a dissolution/permeation (D/P) system to predict the in vivo performance of solid dosage forms containing the poorly soluble drug, fenofibrate, was studied. Biorelevant dissolution media simulating the fasted and fed state conditions of the human gastrointestinal tract were used in order to simulate the effect of food on the absorption of fenofibrate. Moreover, the results obtained from the D/P system were correlated with pharmacokinetic parameters obtained following in vivo studies in rats. The in vitro parameter (amount permeated in the D/P system) reflected well the in vivo performance in rats in terms of AUC and C(max) of fenofibric acid. This study thus demonstrates the potential of the D/P system as valuable tool for absorption screening of dosage forms for poorly soluble drugs.
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A pulmonary embolism caused by delayed-onset heparin-induced thrombocytopenia in a patient with ischemic stroke.
Intern. Med.
PUBLISHED: 06-01-2009
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We report a case of an acute stroke patient with pulmonary embolism (PE) caused by delayed-onset heparin-induced thrombocytopenia (HIT). She was treated with heparin to prevent neurological deterioration. However, 5 days after heparin had been given for 7 days, she developed PE. Heparin was re-started, but the platelet count decreased significantly, and a right ventricular thrombus appeared. She was finally diagnosed as having PE due to delayed-onset HIT because the HIT antibody was positive. When a patient develops thrombotic events during or after heparin therapy, the possibility of HIT should be considered.
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Fast and wide tuning range wavelength-swept fiber laser based on dispersion tuning and its application to dynamic FBG sensing.
Opt Express
PUBLISHED: 05-13-2009
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We report a wavelength-swept fiber laser with high speed and wide tuning range, and its application to fiber sensors. The laser is based on the dispersion tuning technique, which does not require any optical tunable filter in the laser cavity. By directly modulating the semiconductor amplifier and adjusting the dispersion in the cavity, a wide wavelength tuning range of 178.7 nm and a fast tuning rate of over 200 kHz are obtained. The wavelength-swept laser source is applied to a dynamic fiber Bragg grating sensing system. Dynamic measurement of a 150 Hz sinusoidal strain is demonstrated with a measuring speed as fast as 40 kHz.
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