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Slow Release (slow + release)
Selected AbstractsSynthesis of rhombohedral strontium carbonate aggregates at the water/hexamethylene interface with cetyltrimethylammonium bromideCRYSTAL RESEARCH AND TECHNOLOGY, Issue 8 2008Long Chen Abstract Unusual rhombohedral strontium carbonate (SrCO3) aggregates have been synthesized in situ from strontium nitrate by the slow release of carbon dioxide by alkaline hydrolysis of diethyl carbonate at the water/hexamethylene interface in the presence of cetyltrimethylammonium bromide (CTAB). Transmission electron microscopy, Fourier transform infrared spectroscopy and X-ray powder diffractometry were used to characterize the products. The results indicate that rhombohedral SrCO3 aggregates are obtained with weaker crystallinity and sizes of several micrometers. The possible formation mechanism of the SrCO3 aggregates at the interface is discussed, which can be interpreted by particle-aggregation based non-classical crystallization laws. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Methylmercury uptake and distribution kinetics in sheepshead minnows, Cyprinodon variegatus, after exposure to CH3Hg-spiked foodENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2004Joy J. Leaner Abstract The distribution kinetics of methylmercury (CH3Hg[II]) was determined in sheepshead minnows (Cyprinodon variegatus) after a single dose of different CH3Hg(II)-spiked food to determine what factors influence the bioavailability, uptake, and redistribution of CH3Hg(II) to various organs of C. variegatus. The kinetics of CH3Hg(II) distribution was measured in the different organs during a period of 0.1 to 35 d after dosage. The CH3Hg(II) distribution kinetics in the different tissues was modeled using a simple multicompartmental pharmacokinetic model, which assumed that blood was the conduit linking the CH3Hg(II) exchange between the different organs. The CH3Hg(II) was taken up into the intestinal tissue within hours after feeding, followed by a slow release to the blood and the other organs of the body. Exchange between the blood and the visceral organs was relatively slow, with maximum CH3Hg(II) uptake in the liver and gill occurring at 1.5 d following dietary exposure. Subsequently, the majority of the CH3Hg(II) was channeled from the viscera to the rest of the body with a substantial lag time after feeding. However, the rate of transfer between tissues in the studies reported here were faster than those measured by others for larger fish. [source] Influence of silica gel in production of diacylglycerol via enzymatic glycerolysis of palm oleinEUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY, Issue 6 2009Chiou Moi Yeoh Abstract Enzymatic glycerolysis was explored in this paper for the production of diacylglycerol (DAG) oils from palm olein. Three commercial enzymes, Lipozyme TL,IM, Lipozyme RM,IM and Novozym 435 were used for their ability to synthesize DAG in a solvent-free system. Novozym 435 was found to be the more effective enzyme, resulting in a high DAG production even in the absence of an adsorbent such as silica gel. The yields of DAG were between 43 and 50,wt-%. Lipozyme TL,IM and RM,IM, being supported on hydrophilic materials, require an adsorbent to allow slow release of glycerol for reaction with the enzyme and oil. In the absence of silica, no reaction was observed. The success of the reaction is therefore very dependent on the amount of silica used. The yields of DAG using Lipozyme TL,IM and RM,IM were 52 and 45,wt-%, respectively. In addition, the degree of reduction in tocopherols and tocotrienols appeared correlated with the efficacy of the glycerolysis reaction. Changes in the slip melting points and solid fat contents of the products are indicative of the reaction occurring. [source] Intracellular trafficking and release of intact edible mushroom lectin from HT29 human colon cancer cellsFEBS JOURNAL, Issue 7 2000Lu-Gang Yu Our previous studies have shown that the Gal,1,3GalNAc,- (Thomsen,Friedenreich antigen)-binding lectin from the common edible mushroom Agaricus bisporus (ABL) reversibly inhibits cell proliferation, and this effect is a consequence of inhibition of nuclear localization sequence-dependent nuclear protein import after ABL internalization [Yu, L.G., Fernig, D.G., White, M.R.H., Spiller, D.G., Appleton, P., Evans, R.C., Grierson, I., Smith, J.A., Davies, H., Gerasimenko, O.V., Petersen, O.H., Milton, J.D. & Rhodes, J.M. (1999) J. Biol. Chem.274, 4890,4899]. Here, we have investigated further the intracellular trafficking and fate of ABL after internalization in HT29 human colon cancer cells. Internalization of 125I-ABL occurred within 30 min of the lectin being bound to the cell surface. Subcellular fractionation after pulse labelling of the cells with 125I-ABL for 2 h at 4 °C followed by culture of the cells at 37 °C demonstrated a steady increase in radioactivity in a crude nuclear extract. The radioactivity in this extract reached a maximum after 10 h and declined after 20 h. Release of ABL from the cell, after pulse labelling, was assessed using both fluorescein isothiocyanate-labelled ABL and 125I-ABL and was slow, with a t1/2 of 48 h. Most of the 125I-ABL both inside cells and in the medium remained intact, as determined by trichloroacetic acid precipitation and SDS/PAGE, and after 48 h only 22 ± 2% of ABL in the medium and 14 ± 2% inside the cells was degraded. This study suggests that the reversibility of the antiproliferative effect of ABL is associated with its release from cells after internalization. The internalization and subsequent slow release, with little degradation of ABL, reflects the tendency of lectins to resist biodegradation and implies that other endogenous or exogenous lectins may be processed in this way by intestinal epithelial cells. [source] A Multifunctional Nanodevice Capable of Imaging, Magnetically Controlling, and In Situ Monitoring Drug ReleaseADVANCED FUNCTIONAL MATERIALS, Issue 21 2009Shang-Hsiu Hu Abstract The multifunctional nanodevice described here integrates nanoscaled imaging, targeting, and controlled drug delivery, as well as the capability to monitor, in situ, the amount of drug released from the nanodevice with single-cell resolution. The nanodevice is composed of a polymer core/single-crystal iron oxide shell nanostructure bonded to a quantum dot. It shows outstanding release and retention characteristics via an external on/off manipulation of a high-frequency magnetic field. Upon magnetic stimulation, the single-crystal iron oxide shell demonstrates formation of nanometer-sized polycrystal domains of varying orientation. This allows a variation between retention and slow release of the drug. Further stimulation causes permanent rupturing of the shell, causing release of the drug in a burst-like manner. The quantum dot bonded to the nanodevice provides optical information for in situ monitoring of the drug release through use of a magnetic field. Remote control drug release from the nanodevice in a cancerous cell line (HeLa) was successfully accomplished using the same induction scenario. When nanodevices equipped with quantum dots are taken into cancerous cells, they are able to provide real-time drug dose information through a corresponding variation in emission spectrum. The nanodevice designed in this study has achieved its potential as a cell-based drug-delivery system for therapeutic applications. [source] Biomedical Materials: Nanoporous Biodegradable Elastomers (Adv. Mater.ADVANCED MATERIALS, Issue 2 20092/2009) The mechanical properties and degradation rate of elastomers can be tailored with nanoporosity. The elastomers described in this study by Guillermo Ameer and co-workers (p. 188) are based on citric acid and are biocompatible. The nanopores also facilitate the entrapment and slow release of macromolecular therapeutics. The inside cover depicts the nano- and microarchitecture of the elastomer prior to pore collapse. [source] In vitro release of complexed pDNA from biodegradable polymer filmsJOURNAL OF APPLIED POLYMER SCIENCE, Issue 1 2008Y. Ramgopal Abstract The controlled delivery of low-molecular weight drugs and proteins from biodegradable polymers has received considerable attention. However, controlled release studies of pDNA from such polymers have not been reported to date. In this study, a plasmid DNA was complexed with the cationic polymer called polyethylenimine (PEI). This gene vector has been shown to be very effective in transfecting cells. The complexed DNA were then incorporated into different types of poly-lactic- co -glycolic acid (PLGA) film; PLGA 53/47 (Mw 90 kDa), 50/50 (Mw 11 kDa, end group is lauryl ester) and 75/25 (Mw 120 kDa). Their release profiles from a buffer solution were studied. An initial (small) burst release of PEI-DNA from film was observed in PLGA 53/47 and 50/50, followed by a plateau phase and finally a rapid erosion-controlled release. For PLGA 50/50, the rapid release started after 14 days; erosion-controlled release for PLGA 53/47 started after 9 days; for PLGA 75/25, the release rate was governed by an initial burst release (10%) followed by a slow release controlled by diffusion. No obvious erosion-controlled release rate was observed for this polymer up to 27 days. Thus, the controlled release of complexed DNA follows the general features exhibited by lower- Mw drugs. This is of significance in designing gene vector matrices that offer the promise of more lasting gene therapy compared with particulate formulations. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source] Intermittent watt-level ultrasonication facilitates vancomycin release from therapeutic acrylic bone cementJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 1 2009Xun-Zi Cai Abstract Ultrasound holds promise for enhancing the vancomycin release from cement though the length of time when local drug level exceeded the minimum inhibitory concentration (T>MIC) was not prolonged by the previous protocol of milliwatt-level ultrasonication. Here vancomycin-loaded cements were subjected to continuous watt-level ultrasonication (CUG), intermittent watt-level ultrasonication (IUG) or no ultrasonication (NUG) for 14 d during immersion in 40-ml phosphate buffered saline (PBS) for 28 d. The T>MIC for IUG was more than three times that for NUG. In contrast, T>MIC for CUG was slightly shortened. The subtherapeutic release of vancomycin between 15 d and 28 d for IUG was one-ninth that for NUG. The fitting equations indicated a significant enhancement on the burst release and the slow release for IUG; however, the continuous ultrasonication hampered the slow release. SEM images exhibited denser craters and pores with larger diameters and less residual drug in specimens from IUG relative to those from both CUG and NUG. Intermittent watt-level ultrasonication improved the ultrasound-enhanced vancomycin release from cement in view of the prolonged T>MIC and the inhibited subtherapeutic release compared with continuous ultrasonication. The mechanisms may be associated with the distinctive effects of detaching forces and pushing forces by acoustic microstreams. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009 [source] A biodegradable copolymer for the slow release of growth hormone expedites scarring in diabetic ratsJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 2 2007Francisco García-Esteo Abstract In many diseases wound healing is impaired. This study was designed to establish whether the healing process in diabetes could be improved using a site-specific polymer delivery system containing hGH. The system was first optimized in in vitro experiments performed on cultured fibroblasts taken from healthy and diabetic rats and then tested in an incisional wound model created in the diabetic Wistar rat. In the in vitro experiments using cultured fibroblasts, cell viability, growth, and proliferation were determined, along with polymer degradation, hormone release rates and the expression of TGF,1 in the culture medium. For the in vivo experiments, polymer discs with/without GH were inserted through 3 cm incisions made on the backs of the animals. Wound specimens were obtained 7 and 30 days after surgery to evaluate inflammatory/apoptotic cells, metalloprotease expression and neoangiogenesis using microscopy and immunohistochemical techniques. The local administration of GH using a polymer delivery system did not affect the normal wound healing process. Conversely, when used in diabetic animals, epidermal and dermal repair was expedited. Our findings indicate that GH induces cell proliferation, enhances CD4+ infiltration; increases extracellular matrix protein deposition; stimulates angiogenesis; and diminishes apoptosis at the diabetic wound site. These effects give rise to a comparable wound healing process to that observed in healthy animals. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006 [source] Development of a 1-Methylcyclopropene (1-MCP) Sachet Release SystemJOURNAL OF FOOD SCIENCE, Issue 1 2006Younsuk S. Lee ABSTRACT The partitioning of 1-methylcyclopropene (1-MCP) between the gas/polymer matrix was determined for 2 adsorbing agents and 4 sachet materials to estimate the adsorption potential of 1-MCP at 23°C. The release study was performed using a closed system under 2 different environmental conditions, dry air (0% RH) and 90% RH. Sachets made from Tyvek®, paper, low-density polyethylene (LDPE), and polyvinyl acetate (PVA) materials were fabricated to contain silica gel and activated carbon. Activated carbon sachets did not release 1-MCP at either testing condition. Activated carbon had a very strong affinity for 1-MCP. The permeability coefficients of 1-MCP and water in polyethylene and polyvinyl acetate films were determined using a quasi-isostatic method. LDPE sachets containing silica gel had similar 1-MCP release rates at both 0% and 90% RH. PVA sachets containing silica gel had slow release of 1-MCP. The amount of 1-MCP released from PVA sachets containing silica gel at 90% RH was larger than the amount of 1-MCP released at 0% RH. Release of 1-MCP from paper and Tyvek sachets was largely dependent on the sorbate-absorbing ability of the adsorbing agents. [source] Fluoride release and uptake by four new fluoride releasing restorative materialsJOURNAL OF ORAL REHABILITATION, Issue 9 2003P. Dionysopoulos Summary, The present study compared the initial fluoride release and release following refluoridation of a conventional glass,ionomer Ketac-Molar (ESPE), a resin-modified glass,ionomer, Vitremer (3M), and two compomers F-2000 (3M) and Hytac (ESPE). Fifteen test specimens were prepared for each brand and immersed in deionized water. The fluoride released was measured every 2 days for 22 days. Refluoridation of the test specimens was done with solutions of 0·02, 0·04 and 0·2% NaF for 5 min on days 22, 30, 38 and 46. The fluoride released from recharged specimens was measured every 2 days until day 54. The fluoride release was highest during the first days after preparation, after which it decreased sharply and then more slowly. The four materials became ,recharged' with fluoride following repeated fluoride exposure in solution, the 0·2% solution being the most effective. From a clinical point of view, the results from this study imply that all the restorative materials tested may act as intra-oral devices for the controlled slow release of fluoride at sites at risk of recurrent caries. Fluoride release and uptake by four new fluoride releasing restorative materials. [source] In Heavy Drinkers Fatty Acid Ethyl Esters in the Serum Are Increased for 44 hr After Ethanol ConsumptionALCOHOLISM, Issue 7 2004Katrin Borucki Background: Fatty acid ethyl esters (FAEEs) have been proposed as a marker of ethanol consumption because they can be detected for up to 24 hr after a moderate intake of ethanol, even though blood ethanol remains increased for only 8 hr. Therefore, this study investigated whether FAEEs can be found during a time period exceeding 24 hr in a group of patients who were hospitalized for ethanol detoxification. A second aim was to study the distribution of FAEEs between lipoproteins during that time. Methods: Serum samples of 12 patients with acute ethanol intoxication were assayed for FAEEs. Blood samples were drawn 8.2, 20.2, 32.2, and 44.2 hr after hospitalization. FAEEs were quantified by gas chromatography-mass spectrometry. Results: Ethanol was no longer detectable after 20.2 hr from hospitalization, whereas FAEEs were still found after 32.2 and 44.2 hr. These late FAEEs were significantly higher than the FAEEs in 15 different healthy men who had abstained from ethanol for 4.5 days (p < 0.001 and p= 0.001). FAEEs were associated mainly with lipid-free serum but tended to accumulate in very-low-density lipoprotein in patients with moderate hypertriglyceridemia. Conclusions: In heavy drinkers, the FAEEs were increased after ethanol consumption for at least 44 hr. It remains to be studied whether they originate from a single ethanol intake or, in addition, from a slow release out of body storage compartments. [source] Return of the cycad hypothesis , does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2005P. G. Ince Recently published work provides evidence in support of the cycad hypothesis for Lytico,Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of ,-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a ,tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of ,AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for ,ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for ,-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of ,incidental',-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico,Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies. [source] Slow-release nanoparticle-encapsulated delivery system for laryngeal injection,THE LARYNGOSCOPE, Issue 5 2010Vasantha L. Kolachala PhD Abstract Objectives/Hypothesis: There is a need for a slow-release system for local delivery of therapeutics to the larynx. Most therapeutic substances, such as steroids or chemotherapeutic agents that are injected into the larynx are cleared rapidly. Repeated laryngeal injection of these substances at short intervals is impractical. Injectable encapsulated poly(lactide-co-glycolide) (PLGA) nanoparticles offer a potential slow-release delivery system for biologically active substances in the larynx. Study Design: Controlled animal study. Methods: PLGA nanoparticles were fabricated using a double emulsion method and were loaded with Texas Red-dextran (NPTR), hepatocyte growth factor (NPHGF), and bovine serum albumin (NPBSA). In vitro release of NPTR, NPBSA, and NPHGF was determined over approximately 2 weeks to assess potential duration of PLGA nanoparticle delivery. In vivo release of NPTR was assessed in a murine vocal fold injection model. The transcriptional effect of NPHGF on procollagen was measured in vitro to assess whether released growth factor retained functionality. Results: In vitro release kinetics demonstrated slow release of NPTR, NPBSA, and NPHGF over 12 to 14 days. In vitro NPTR release correlated with in vivo results. In vivo presence of NPTR occurred up to 7 days compared to 1 day for Texas Red control. In addition, NPHGF ameliorated transforming growth factor-, induced procollagen in vitro in 3T3 fibroblast cells. Conclusions: The results demonstrate the potential utility of nanoparticle encapsulation as an effective method for long-term delivery of specific drugs and biologically active substances to the larynx. Laryngoscope, 2010 [source] Phase transition of triclinic hen egg-white lysozyme crystal associated with sodium bindingACTA CRYSTALLOGRAPHICA SECTION D, Issue 4 2004Kazuaki Harata A triclinic crystal of hen egg-white lysozyme obtained from a D2O solution at 313,K was transformed into a new triclinic crystal by slow release of solvent under a temperature-regulated nitrogen-gas stream. The progress of the transition was monitored by X-ray diffraction. The transition started with the appearance of strong diffuse streaks. The diffraction spots gradually fused and faded with the emergence of diffraction from the new lattice; the scattering power of the crystal fell to a resolution of 1.5,Å from the initial 0.9,Å resolution. At the end of the transition, the diffuse streaks disappeared and the scattering power recovered to 1.1,Å resolution. The transformed crystal contained two independent molecules and the solvent content had decreased to 18% from the 32% solvent content of the native crystal. The structure was determined at 1.1,Å resolution and compared with the native structure refined at the same resolution. The backbone structures of the two molecules in the transformed crystal were superimposed on the native structure with root-mean-square deviations of 0.71 and 0.96,Å. A prominent structural difference was observed in the loop region of residues Ser60,Leu75. In the native crystal, a water molecule located at the centre of this helical loop forms hydrogen bonds to main-chain peptide groups. In the transformed crystal, this water molecule is replaced by a sodium ion with octahedral coordination that involves water molecules and a nitrate ion. The peptide group connecting Arg73 and Asn74 is rotated by 180° so that the CO group of Arg73 can coordinate to the sodium ion. The change in the X-ray diffraction pattern during the phase transition suggests that the transition proceeds at the microcrystal level. A mechanism is proposed for the crystal transformation. [source] Enzymatic stability of 2,-ethylcarbonate-linked paclitaxel in serum and conversion to paclitaxel by rabbit liver carboxylesterase for use in prodrug/enzyme therapyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2008Tadatoshi Tanino Abstract In prodrug/enzyme therapy for cancer, information on the sensitivity of hydrolytic enzymes to prodrug is required to reduce adverse effects of the parental drug and to find the activating enzyme. The aim of this study was to characterize the enzymatic stability of 2,-ethylcarbonate-linked paclitaxel (TAX-2,-Et) in the sera of several different species including humans. TAX-2,-Et disposition in serum was kinetically analysed using models with hydrolytic and/or degradation processes. To further evaluate the capability of liver carboxylesterases (CESs) in TAX-2,-Et hydrolysis, a CES isolated from rabbit liver (Ra-CES) was utilized as a model enzyme. Rat serum provided rapid enzymatic hydrolysis of TAX-2,-Et with a half-life of 4 min. The degradation of paclitaxel (TAX) (degradation rate constant, 0.16,h,1) was accompanied by the formation of an unknown compound. The conversion to TAX was almost completely inhibited by phenylmethyl sulfonylfluoride (PMSF) and bis(p-nitrophenyl) phosphate (BNPP). In human and rabbit sera, the degradation rate constant of TAX-2,-Et was 5.1,×,10,2 and 0.15,h,1, respectively, when excepting hydrolysis. The degradation products had the same molecular weight as TAX-2,-Et. The amount of TAX produced accounted for only 8,11% of the decrease in TAX-2,-Et after a 9 h exposure to rabbit or human serum. PMSF, but not BNPP, inhibited more than 90% of the TAX production in a 1.5,h incubation with human or rabbit serum. Ra-CES enzyme converted TAX-2,-Et to TAX with Vmax and Km of 74.7±13.8 nmol/min/mg protein and 8.8±2.8 µM, respectively. These results indicate that TAX-2,-Et is sensitive to serum CESs, but not cholinesterases. However, serum CESs show species-dependent hydrolysis of TAX-2,-Et. Although human serum allows the slow release of TAX, TAX-2,-Et is expected to reduce the side-effects of TAX. The Ra-CES enzyme is capable of hydrolysing TAX-2,-Et, which may be beneficial for the development of a TAX-2,-Et/enzyme therapy strategy for ovarian cancer. Copyright © 2008 John Wiley & Sons, Ltd. [source] Immobilized Metal Affinity Chromatography without Chelating Ligands: Purification of Soybean Trypsin Inhibitor on Zinc Alginate BeadsBIOTECHNOLOGY PROGRESS, Issue 1 2002Munishwar N. Gupta Immobilized metal affinity chromatography (IMAC) is a widely used technique for bioseparation of proteins in general and recombinant proteins with polyhistidine fusion tags in particular. An expensive and critical step in this process is coupling of a chelating ligand to the chromatographic matrix. This chelating ligand coordinates metal ions such as Cu2+, Zn2+, and Ni2+, which in turn bind proteins. The toxicity of chemicals required for coupling and their slow release during the separation process are of considerable concern. This is an important issue in the context of purification of proteins/enzymes which are used in food processing or pharmaceutical purposes. In this work, a simpler IMAC design is described which should lead to a paradigm shift in the application of IMAC in separation. It is shown that zinc alginate beads (formed by chelating alginate with Zn2+ directly) can be used for IMAC. As "proof of concept", soybean trypsin inhibitor was purified 18-fold from its crude extract with 90% recovery of biological activity. The dynamic binding capacity of the packed bed was 3919 U mL -1, as determined by frontal analysis. The media could be regenerated with 8 M urea and reused five times without any appreciable loss in its binding capacity. [source] Strategies to improve efficacy and safety of a novel class of antiviral hyper-activation-limiting therapeutic agents: the VS411 model HIV/AIDSBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2010D De Forni BACKGROUND AND PURPOSE Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HALT, is a single-dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (Cmax) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity. EXPERIMENTAL APPROACH This was a pilot phase I, open-label, randomized, single-dose, four-way crossover trial to investigate the fasted and non-fasted residual variance of AUC, Cmax and the oral bioavailability of ddI and HU, co-formulated as VS411, and administered as two different fixed-dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously. KEY RESULTS Formulation VS411-2 had a favourable safety profile, displayed a clear trend for lower ddI Cmax (P= 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio of Cmax did not include 100%. ddI AUC, was not significantly decreased compared to Videx EC. HU pharmacokinetic parameters were essentially identical to Hydrea, although there was a decrease in HU exposure under fed versus fasted conditions. CONCLUSIONS AND IMPLICATIONS A phase IIa trial utilizing VS411-2 formulation has been fielded to identify the optimal doses of HU plus ddI as an AV-HALT for the treatment of HIV disease. [source] Modulation of platelet activation and initial cytokine release by alloplastic bone substitute materialsCLINICAL ORAL IMPLANTS RESEARCH, Issue 3 2010M. O. Klein Abstract Objectives: Platelet-derived cytokines play a crucial role in tissue regeneration. In regenerative dental medicine, bone substitute materials (BSM) are widely used. However, initial interactions of BSM and platelets are still unknown. The aim of this study was to evaluate the potential of platelet activation and subsequent initial cytokine release by different commercial alloplastic BSM. Material and methods: Eight commercial BSM of different origins and chemical compositions (tricalcium phosphate, hydroxyapatite, bioactive glass: SiO2 and mixtures) were incubated with a platelet concentrate (platelet-rich plasma, PRP) of three healthy volunteers at room temperature for 15 min. Platelet count, aggregation, degranulation (activated surface receptor CD62p) and cytokine release (Platelet-derived growth factor, Vascular endothelial growth factor) into the supernatant were quantified. Highly thrombogenic collagen served as a reference. Results: The investigated PRP samples revealed different activation patterns when incubated with different BSM. In general, SiO2 -containing BSM resulted in high platelet activation and cytokine release. In detail, pure bioactive glass promoted platelet activation most significantly, followed by hybrid BSM containing lower ratios of SiO2. Additionally, we found indications of cytokine retention by BSM of large specific surfaces. Conclusions: Platelet activation as well as consecutive storage and slow release of platelet-derived cytokines are desirable attributes of modern BSM. Within the limits of the study, SiO2 -containing BSM were identified as promising biomaterials. Further investigations on cytokine adsorption and cytokine release kinetics by the respective BSM have to be conducted. To cite this article: Klein MO, Kämmerer PW, Scholz T, Moergel M, Kirchmaier CM, Al-Nawas B. Modulation of platelet activation and initial cytokine release by alloplastic bone substitute materials. Clin. Oral Impl. Res. 21, 2010; 336,345 doi: 10.1111/j.1600-0501.2009.01830.x [source] | |||||||||||||||||||