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At least 1,441 records · Page 80Linked to original sources
PubMed2000

Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: manufacture and characterization.

PURPOSE: Particles with aerodynamic diameters of 1-5 microm deposit in the periphery of the lungs and are phagocytized by alveolar macrophages, the primary site of Mycobacterium tuberculosis infection. Aerosols of biodegradable polymeric microspheres containing antitubercular agents may be delivered to the lungs to improve the treatment of tuberculosis. METHODS: Poly(lactide-co-glycolide) (PLGA) microspheres containing rifampicin were prepared using solvent evaporation and spray drying methods. The solvent evaporation process was optimized using factorial experimental design and surface response methodology. The morphology, particle size, drug loading, and dissolution of microspheres was evaluated. RESULTS: The spray dried rifampicin loaded PLGA microparticles were shriveled, unlike the spherical particles produced by solvent evaporation. Drug loadings of 20% and 30% were achieved for solvent evaporation and spray dried products, respectively. The particles prepared by solvent evaporation and spray drying had 3.45 microm and 2.76 microm median diameters by volume, respectively. CONCLUSIONS: Respirable rifampicin loaded PLGA microspheres were produced by both solvent evaporation and spray drying methods. These particles are being evaluated in an animal model of tuberculosis.

Antibiotics, Antitubercular↗
PubMed1997

The anaesthetist as determinant factor of quality of surgical antimicrobial prophylaxis. A survey in a university hospital.

In actual surgical antimicrobial prophylaxis, the anaesthetist administers the drugs at induction of anaesthesia. In the first phase of our quality-of-use intervention study on antimicrobial drugs in a large university hospital, information on the practice of antimicrobial prophylaxis was needed. The staff of 44 anaesthetists was interviewed by means of a questionnaire. Response rate was 36/44 (82%). The anaesthetists' method of administering surgical prophylaxis was rather uniform and inexpensive: cephalosporins were almost exclusively administered by bolus method. The main reason was that infusion was more cumbersome (range 77-85%). Communication between surgeon and anaesthetist was reported to be poor, and in two out of three operating departments, orders of prophylaxis transmitted at or after induction accounted for more than 80%. Seventy-seven percent of the responders asked the surgeon if prophylaxis was necessary if they were in doubt; 20% responded that they checked it systematically. The data collected by the inquiry proved useful in the process of optimizing surgical prophylaxis in our hospital.

Adult↗
PubMed2002

Evaluating 3D bone tissue engineered constructs with different seeding densities using the alamarBlue assay and the effect on in vivo bone formation.

Bone tissue engineering using patient derived cells seeded onto porous scaffolds has gained much attention in recent years. Evaluating the viability of these 3D constructs is an essential step in optimizing the process. The alamarBlue (aB) assay was evaluated for its potential to follow in vitro cell proliferation on architecturally standardized hydroxyapatite scaffolds. The impact of the aB assayed and seeding density on subsequent in vivo bone formation was investigated. Twelve scaffolds were seeded with various densities from 250 to 2.5x10(6) cells/scaffold and assay by aB at 5 time points during the 7-day culture period. Twelve additional scaffolds were seeded with 2.5x10(5) cells/scaffold. Two control and 2 aB treated scaffolds were subcutaneously implanted into each of 6 nude mice for 6 weeks. Four observers ranked bone formation using a pair wise comparison of histological sections form each mouse. The aB assay successfully followed cell proliferation, however, the diffusion kinetics of the 3D constructs must be considered. The influence of in vitro aB treatment on subsequent in vivo bone formation cannot be ruled out but was not shown to be significant in the current study. The aB assay appears to be quite promising for evaluating a maximum or end-point viability of 3D tissue engineered constructs. Finally, higher seeding densities resulted in more observed bone formation.

Journal Article↗
PubMed2003

Preparation and in vitro/in vivo evaluation of insulin-loaded poly(acryloyl-hydroxyethyl starch)-PLGA composite microspheres.

PURPOSE: The purpose of this study was to develop and evaluate a novel composite microsphere delivery system composed of poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acryloyl derivatized HES; AcHES) hydrogel using bovine insulin as a model therapeutic protein. METHODS: Insulin was incorporated into the AcHES hydrogel microparticles by a swelling technique, and then the insulin-containing AcHES microparticles were encapsulated in a PLGA matrix using a solvent extraction/evaporation method. The composite microspheres were characterized for loading efficiency, particle size, and in vitro protein release. Protein stability was examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, high-performance liquid chromatography, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The hydrogel dispersion process was optimized to reduce the burst effect of microspheres and avoid hypoglycemic shock in the animal studies in which the serum glucose and insulin levels as well as animal body weight were monitored using a diabetic animal model. RESULTS: Both the drug incorporation efficiency and the in vitro release profiles were found to depend upon the preparation conditions. Sonication effectively dispersed the hydrogel particles in the PLGA polymer solution, and the higher energy resulted in microspheres with a lower burst and sustained in vitro release. Average size of the microspheres was around 22 microm and the size distribution was not influenced by sonication level. High-performance liquid chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, along with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry showed the retention of insulin stability in the microspheres. Subcutaneous administration of microspheres provided glucose suppression <200 mg/dL for 8-10 days with hyperglycemia recurring by day 16. During the treatment, the time points with higher serum insulin level were consistent with a more significant glucose suppression. The microsphere-treated rats also grew virtually at the same rate as normal control until the insulin level declined and hyperglycemia returned. Multiple dosing given every 10 days demonstrated that the pharmacological effect and serum insulin levels from second or third doses were similar and comparable to that of the first dose. CONCLUSION: The AcHES-PLGA composite microsphere system provides satisfactory in vitro and in vivo sustained release performance for a model protein, insulin, to achieve 10-day glucose suppression.

Acrylic Resins↗
PubMed2003

Kinetics of beta-mannanase fermentation by Bacillus licheniformis.

Bacterial growth, konjac powder utilization and beta-mannanase production by Bacillus licheniformis NK-27 in batch fermentation were used to develop a model of the process. The optimal set of parameters was estimated by fitting the model to experimental data. The results predicted by the model were in good agreement with the experimental data. NOMENCLATURE: fs, fraction parameter; Kp, constant in Equation (6) (g l(-1)); Ks, Monod constant for bacteria growth (g l(-1)); m, maintenance coefficient (g g(-1) h(-1)); P, beta-mannanase concentration (g 1(-1)); qm, constant in Equation (6) (h(-1)); S, substrate concentration (g l(-1)); S0, initial substrate concentration (g l(-1)); Si, insoluble substrate concentration (g l(-1)); Ss, soluble substrate concentration (g l(-1)); t, fermentation time (h); tL, lag time (h); mu, specific growth rate (h(-1)); mu(max), maximum specific growth rate (h(-1)); X, biomass concentration (g l(-1)); YP/S, beta-mannanase yield on carbon substrate (g g(-1)); YX/S, biomass yield on carbon substrate (g g(-1)).

Bacillus↗
PubMed2003

Scale-up of erythritol production by an osmophilic mutant of Candida magnoliae.

Erythritol production by an osmophilic mutant of Candida magnoliae was performed in fermentations of up 50 l to develop an optimized commercial process. By simultaneous feeding glucose and yeast extract, erythritol productivity of 1.2 g l(-1) h(-1) was reached giving 200 g erythritol l(-1) with a yield of 0.43 g g(-1).

Bioreactors↗
PubMed2003

Improved alpha-chymotrypsin stability upon encapsulation in PLGA microspheres by solvent replacement.

PURPOSE: To investigate the potential of different solvents with better biocompatibility to replace CH2Cl2 in the encapsulation of alpha-chymotrypsin in poly (lactic-co-glycolic) acid (PLGA) microspheres without causing protein instability. METHODS: The oil-to-water (O:W) ratio in the emulsification step of the solid-in-oil-in-water (s/o/w) encapsulation process was optimized with respect to maximizing protein stability and encapsulation efficiency for various solvents. Formation of insoluble aggregates and residual enzyme activity were primarily used as stability parameters. Several solvents possessing low toxicity with different water solubility were used to prepare alpha-chymotrypsin loaded PLGA microspheres. RESULTS: The O:W ratio in the emulsification step is critical with respect to maintaining protein stability. This was related to the solvents' water solubility. In general, hydrophilic solvents were detrimental to protein stability and encapsulation efficiency. However, after optimization of the O:W ratio for solvents with different water solubility, protein stability was preserved during encapsulation using butyl acetate when poly (ethylene glycol) (PEG) was used as the emulsifying agent (ca. 1% of non-covalent aggregates and 93 +/- 10% of residual specific activity). CONCLUSIONS: The s/o/w technique was successfully improved by replacing the ICH class 2 solvent CH2Cl2 with the class 3 solvent butyl acetate without compromising alpha-chymotrypsin stability.

Chymotrypsin↗
PubMed2006

Working memory involvement in emotion-based processes underlying choosing advantageously.

The Iowa Gambling Task (IGT) is widely used to assess decision making under conditions of uncertainty in clinical as well as in nonclinical populations. However, there is still debate as to whether normal performance at this task relies on implicit, emotion-based processes that are independent of working memory. To clarify the role of working memory on normal performance on the IGT, participants performed the task under low or high working memory load. We used a modified version of the original task, in which the position of the four decks was randomized between trials. Results showed that only participants performing under low memory load significantly chose more advantageously halfway through the task. In addition, when comparing the number of cards chosen from the two decks with frequent losses, one advantageous and one disadvantageous, only participants performing under low memory load chose more cards from the advantageous deck. The present findings indicate that the processes underlying optimal advantageous performance on the IGT rely on working memory functions.

Adult↗
PubMed2000

Expression and localisation of IGF-binding protein mRNAs in regenerating rat skeletal muscle.

The expression of the insulin-like growth factor-binding proteins (IGFBP) -3, -4, -5 and -6 was investigated in neonatal, in normal adult and in regenerating rat skeletal muscle. Semi-quantification was done by densitometric scannings of Northern blots. The expression of all investigated IGFBPs, with the exception of IGFBP-5, was higher in neonatal than in adult muscle. During postischaemic regeneration the expression of all IGFBPs increased, but with different time schedules. IGFBP-3 increased transiently during the early phase of regeneration, while IGFBP-4, -5 and -6 increased during the later phase of regeneration. In situ hybridisation on regenerating muscle showed that the expression of the various IGFBPs was cell specific; thus, IGFBP 3 was mainly expressed in macrophages, IGFBP-4 in connective tissue, IGFBP-5 in regenerating muscle cells, and IGFBP-6 in muscle cells, connective tissue and endothelium. Ligand blotting, using 125I-IGF-I as the ligand, showed a number of bands ranging between 24 and 44 kDa. Samples from neonatal and regenerating muscle contained much higher levels of all IGFBPs than those from normal adult muscle. An ordered and cell-specific expression of IGFBPs, allowing a strict regulation of IGF actions, is probably necessary to ensure an optimal regeneration process.

Animals↗
PubMed1997

In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin.

The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Rapid feasibility studies of tracers for positron emission tomography: high-resolution PET in small animals with kinetic analysis.

The development of methods for production of a radiotracer for use in human studies with positron emission tomography (PET) is often a time-consuming process of optimizing radiolabelling yields and handling procedures. Sometimes the radiotracer is not the original drug, but rather a derivative with unknown in vivo pharmacological properties. We have developed a fast and simple method of testing putative new PET tracers in vivo in small animals. The procedure has been validated in rats with different PET tracers with known kinetic and pharmacological properties ([2-18F]2-fluoro-2-deoxy-D-glucose, [N-methyl-11C]Ro 15-1788, and [15O]butanol). The tracer concentration in arterial blood was continuously measured to obtain the brain input function. Following image reconstruction of the scans, time-activity curves of selected regions of interest were generated. Estimations of CMRglc (1.0 +/- 0.2 mumol g-1 min-1), CBF (1.4 +/- 0.4 ml g-1 min-1) and transport rate constants for [N-methyl-11C]Ro 15-1788 (K1 = 0.44 +/- 0.01 ml g-1 min-1 and k2 = 0.099 +/- 0.005 min-1) as well as calculated first pass extraction (0.32 +/- 0.1) are in reasonable agreement with literature values. Small animal studies require minimal amounts of radioactivity and can be performed without sterility and toxicology tests. They may serve as a preliminary basis for radiation safety calculations because whole body scans can be performed even with a head scanner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Bayesian integration in sensorimotor learning.

When we learn a new motor skill, such as playing an approaching tennis ball, both our sensors and the task possess variability. Our sensors provide imperfect information about the ball's velocity, so we can only estimate it. Combining information from multiple modalities can reduce the error in this estimate. On a longer time scale, not all velocities are a priori equally probable, and over the course of a match there will be a probability distribution of velocities. According to bayesian theory, an optimal estimate results from combining information about the distribution of velocities-the prior-with evidence from sensory feedback. As uncertainty increases, when playing in fog or at dusk, the system should increasingly rely on prior knowledge. To use a bayesian strategy, the brain would need to represent the prior distribution and the level of uncertainty in the sensory feedback. Here we control the statistical variations of a new sensorimotor task and manipulate the uncertainty of the sensory feedback. We show that subjects internally represent both the statistical distribution of the task and their sensory uncertainty, combining them in a manner consistent with a performance-optimizing bayesian process. The central nervous system therefore employs probabilistic models during sensorimotor learning.

Bayes Theorem↗
PubMed1999

Utilization of protein-hydrolyzed cheese whey for production of beta-galactosidase by Kluyveromyces marxianus.

We studied the utilization of protein-hydrolyzed sweet cheese whey as a medium for the production of beta-galactosidase by the yeasts Kluyveromyces marxianus CBS 712 and CBS 6556. The conditions for growth were determined in shake cultures. The best growth occurred at pH 5.5 and 37 degrees C. Strain CBS 6556 grew in cheese whey in natura, while strain CBS 712 needed cheese whey supplemented with yeast extract. Each yeast was grown in a bioreactor under these conditions. The strains produced equivalent amounts of beta-galactosidase. To optimize the process, strain CBS 6556 was grown in concentrated cheese whey, resulting in a higher beta-galactosidase production. The beta-galactosidase produced by strain CBS 6556 produced maximum activity at 37 degrees C, and had low stability at room temperature (30 degrees C) as well as at a storage temperature of 4 degrees C. At -4 degrees C and -18 degrees C, the enzyme maintained its activity for over 9 weeks.

Journal Article↗
PubMed2001

Direct determination of naftopidil by non-protected fluid room temperature phosphorescence.

A selective and sensitive room temperature phosphorimetric method for the direct determination of naftopidil in biological fluids is described. The method is based on obtaining a phosphorescence signal from this antihypertensive drug using TlNO3 as a heavy atom perturber and Na2SO3 as a deoxygenator agent without a protective medium. This technique is named non-protected room temperature phosphorescence (NP-RTP), and enables us to determine analytes in complex matrices without the need for a tedious prior separation process. The optimization of Na2SO3 (8.5 x 10(-3) M) and the accurate value of pH (9.0) were determined using a simplex as a method of optimization. Sodium carbonate-hydrogencarbonate buffer solution (5.0 x 10(-2) M) was used to adjust the suitable pH. The optimum concentration of Tl+ (8.5 x 10(-2) M) was also determined. The delay time, gate time and time between flashes selected were 200 microseconds, 200 microseconds and 5 ms, respectively. Under the above conditions we propose a method to determine naftopidil by direct measurement of phosphorescence intensity with an emission wavelength of 526 nm and an excitation wavelength of 296 nm in the concentration range 0.05-1.00 mg L-1. Under these conditions the phosphorescence signal appears in 3 min once the sample has been prepared. Optimization of the various conditions permitted the establishment of an NP-RTP method for the determination with a detection limit, according to the error propagation theory, of 21.0 ng mL-1. The repeatability was studied using 10 solutions of 0.20 mg L-1 of naftopidil; if error propagation is assumed, the relative error is 1.39%. The standard deviation for replicate samples was 1.1 x 10(-2) mg L-1. This method was successfully applied to the determination of naftopidil, in human urine with recoveries between 106 and 112%.

Adrenergic alpha-Antagonists↗
PubMed2001

Determination of manganese in water samples by flame atomic absorption spectrometry after cloud point extraction.

Cloud point extraction has been used for the preconcentration of manganese, after the formation of a complex with 1-(2-thiazolylazo)-2-naphthol (TAN), and later analysis by flame atomic absorption spectrometry using octylphenoxypolyethoxyethanol (Triton X-114) as surfactant. The chemical variables affecting the separation phase and the viscosity affecting the detection process were optimized. Under the optimum conditions (i.e., pH = 9.2, [TAN] = 2.0 x 10(-5) mol l-1, [Triton X-114] = 0.05%, added methanol volume = 0.2 ml), preconcentration of 50 ml of sample solution permitted the detection of 0.28 ppb for manganese. The enhancement factor was 57.6. The proposed method has been applied to the determination of manganese in water samples.

Azo Compounds↗
PubMed2025

Retinal hypoxia reversal with PLGA-oxygen nanobubbles.

Pathologies associated with retinal hypoxia, including diabetic retinopathy, central/branch retinal artery occlusion (CRAO/BRAO), central/branch retinal vein occlusion (CRVO/BRVO), retinopathy of prematurity, sickle cell retinopathy, etc., have limited effective therapeutic intervention strategies. To address this shortcoming, herein we propose a biocompatible and biodegradable poly (lactic-co-glycolic acid) shell-based oxygen nanobubbles (PLGA-ONBs) platform, formulated with PLGA, polyvinyl alcohol (PVA), and NaHCO3. The formulation of a novel PLGA-ONBs was proposed, and the synthesis process was optimized with respect to dependent (sonication power, PVA, and NaHCO3 concentrations) and response (hydrodynamic diameter and oxygen capacity) variables. The optimized formulation has a concentration of (13.8 &#xb1; 0.01) &#xd7; 1010 particles per ml with a hydrodynamic diameter of 142.83 &#xb1; 11.46 nm, and oxygen loading capacity of 47.2 &#xb1; 2.4 mg L-1. After 4 weeks of storage, the ONBs were found to have an oxygen concentration of 38.9 &#xb1; 2.9 mg L-1, indicating excellent oxygen retention capability. The PLGA-ONBs tested in vitro in Muller and R28 retinal cell lines demonstrated excellent biocompatibility and potential to mitigate hypoxia. In addition, the PLGA-ONBs treatment on hypoxic cells demonstrated restoration of mRNA expression of three key hypoxic genes (HIF-1&#x3b1;, PAI-1, and VEGF-A) to normoxic states, indicating hypoxia reversal potential. Biosafety of the PLGA-ONBs was demonstrated in a rabbit model, demonstrating promise in clinical translation. The PLGA-ONBs developed exhibited excellent oxygen loading and retention, potential in hypoxia mitigation, and a safety profile that could be a promising route to treating ischemic diseases of the eye.

Polylactic Acid-Polyglycolic Acid Copolymer↗
PubMed2003

A-kinase-anchoring proteins and cytoskeletal signalling events.

Targeting of protein kinases and phosphatases to the cytoskeleton enhances the regulation of many signalling events. Cytoskeletal signalling complexes facilitate this process by optimizing the relay of messages from membrane receptors to specific sites on the actin cytoskeleton. These signals influence fundamental cell properties such as shape, movement and division. Targeting of the cAMP-dependent kinase (protein kinase A) and other enzymes to this compartment is achieved through interaction with A-kinase-anchoring proteins (AKAPs). The present paper discusses recent progress on dissecting the biological role of WAVE1 (Wiskott-Alrich syndrome protein family verprolin homology protein 1), an AKAP that assembles a cytoskeletal transduction complex in response to signals that emanate from the low-molecular-mass GTPase, Rac.

Animals↗