Comparing the permeability of human and porcine small intestinal mucus for particle transport studies.

The gastrointestinal mucus layer represents the last barrier between ingested food or orally administered pharmaceuticals and the mucosal epithelium. This complex gel structure plays an important role in the process of small intestinal absorption. It provides protection against hazardous particles such as bacteria but allows the passage of nutrients and drug molecules towards the intestinal epithelium. In scientific research, mucus from animal sources is usually used to simulate difficult-to-obtain human small intestinal mucus for investigating the intramucus transport of drug delivery systems or food nanoparticles. However, there is a lack of evidence the human mucus can be reliably substituted by animal counterparts for human-relevant transport models. In this report, a procedure for collecting human mucus has been described. More importantly, the permeability characteristics of human and porcine small intestinal mucus secretions to sub-micron sized particles have been compared under simulated intestinal conditions. Negatively charged, 500 nm latex beads were used in multiple-particle tracking experiments to examine the heterogeneity and penetrability of mucus from different sources. Diffusion of the probe particles in adult human ileal mucus and adult pig jejunal and ileal mucus revealed no significant differences in microstructural organisation or microviscosity between the three mucus types (P > 0.05). In contrast to this interspecies similarity, the intraspecies comparison of particle diffusivity in the mucus obtained from adult pigs vs. 2-week old piglets showed better penetrability of the piglet mucus. The mean Stokes-Einstein viscosity of the piglet jejunal mucus was approx. two times lower than the viscosity of the pig jejunal mucus (P < 0.05). All mucus structures were also visualised by scanning electron microscopy. This work validates the use of porcine small intestinal mucus collected from fully-grown pigs for studying colloidal transport of sub-micron sized particles in mucus under conditions mimicking the adult human small intestinal environment.

Anthocyanins decrease the internalization of TiO2 nanoparticles into 3D Caco-2 spheroids.

The influence of food components on nanoparticle (NP) internalization indicates a need to investigate the behaviors of NPs in a complex system. This study measured the changes of TiO2 NP colloidal stability and quenching of anthocyanin fluorescence to indicate NP-anthocyanin interactions, and cytotoxicity, oxidative stress, expression of ABC transporters and intracellular Ti concentrations in 3D Caco-2 spheroids co-exposed to NPs and anthocyanins to indicate the influence of anthocyanins on NP bio-effects. The anthocyanins were observed to have minimal impacts on colloidal properties of TiO2 NPs. Meanwhile, NP-anthocyanin co-exposure did not induce cytotoxicity or oxidative stress. The fluorescence quenching study indicated the binding of anthocyanins onto TiO2 NPs, and the binding affinity was inversely correlated with NP internalization into 3D Caco-2 spheroids. This may be partially related with the up-regulation of ABC transporters. Our results may provide novel insights into understanding the interactions of NPs and anthocyanins with human intestinal cells.

Poloxamer-407 thickened lipid colloidal system of agomelatine for brain targeting: Characterization, brain pharmacokinetic study and behavioral study on Wistar rats.

The current study was designed to enhance the brain bioavailability and to extract maximum therapeutic benefit from a novel antidepressant drug, agomelatine. For this purpose, a thermoresponsive in situ gel was prepared by dissolving 20% w/v of Poloxamer-407 in agomelatine containing nanoemulsion. To impart mucoadhesive property, 0.5% w/v concentration of chitosan was ensured in the final formulation, named as Ago-NE-gel+0.5%chitosan. The gelling point and mucoadhesive strength of Ago-NE-gel+0.5%chitosan were found to be 28 ± 1 °C, and 6246.27 dynes/cm2 respectively. The size of free micelles of Poloxamer-407 was recorded graphically at 18.43 ± 0.95 nm whereas the size of sterically stabilized Ago-NE was observed at 142.58 ± 4.21 nm. The viscosity and pH of Ago-NE-gel+0.5%chitosan were found to be 2439 ± 23 cP (at 35 ± 1 °C temperature) and 5.8 ± 0.2 respectively. The developed formulation was found safe on nasal mucosa during the toxicity study. CLSM based brain distribution study suggested that Ago-NE-gel+0.5%chitosan is more competent to deliver the drug into the brain as compared to agomelatine-suspension. After intranasal administration of Ago-NE-gel+0.5%chitosan in Wistar rats, the AUC0-8h in brain and plasma were found to be 1418.591 ± 71.87 and 473.901 ± 32.42 ng.h/ml respectively. The hypothesis conceived at the beginning of this research work was delivered as 2.82 folds enhanced bioavailability of agomelatine in the brain. The behavioral studies confirmed that the antidepressant activity of agomelatine can be improved by loading the drug into a mucoadhesive-nanoemulsion-gel system followed by its intranasal administration.

Recombinant Protein Polymers for Colloidal Stabilization and Improvement of Cellular Uptake of Diamond Nanosensors.

Fluorescent nanodiamonds are gaining increasing attention as fluorescent labels in biology in view of the fact that they are essentially nontoxic, do not bleach, and can be used as nanoscale sensors for various physical and chemical properties. To fully realize the nanosensing potential of nanodiamonds in biological applications, two problems need to be addressed: their limited colloidal stability, especially in the presence of salts, and their limited ability to be taken up by cells. We show that the physical adsorption of a suitably designed recombinant polypeptide can address both the colloidal stability problem and the problem of the limited uptake of nanodiamonds by cells in a very straightforward way, while preserving both their spectroscopic properties and their excellent biocompatibility.

Adverse effects of crystalloid and colloid fluids.

Guidelines for infusion fluid therapy rarely take into account that adverse effects occur in a dose-dependent fashion. Adverse effects of crystalloid fluids are related to their preferential distribution to the interstitium of the subcutis, the gut, and the lungs. The gastrointestinal recovery time is prolonged by 2 days when more than 2 litres is administered. Infusion of 6-7 litres during open abdominal surgery results in poor wound healing, pulmonary oedema, and pneumonia. There is also a risk of fatal postoperative pulmonary oedema that might develop several days after the surgery. Even larger amounts cause organ dysfunction by breaking up the interstitial matrix and allowing the formation of lacunae of fluid in the skin and central organs, such as the heart. Adverse effects of colloid fluids include anaphylactic reactions, which occur in 1 out of 500 infusions. The possibility that hydroxyethyl starch causes kidney injury in patients other than those with sepsis is still unclear. For both crystalloid and colloid fluids, coagulation becomes impaired when the induced haemodilution has reached 40%. Coagulopathy is aggravated by co-existing hypothermia. Although oedema can occur from both crystalloid and colloid fluids, these differ in pathophysiology. To balance fluid-induced adverse effects, this review suggests that a colloid fluid is indicated when the infused crystalloid volume exceeds 3-4 litres, plasma volume support is still needed, and the transfusion of blood products is not yet indicated.

Chitosan Tethered Colloidal Gold Nanospheres for Drug Delivery Applications.

Gold Nanospheres (AuNS) have been widely explored as an emerging system for various biomedical applications including drug delivery, bioimaging and photomedicine. However, method of synthesizing nanoparticles and its toxicity including bioaccumulation has been a problem of concern. In the present study, we explored the appropriateness of 12.0 ±1.99 nm chitosan reduced AuNS in vivo models with respect to its bioavailability and toxicity against various concentrations (2.5-7.5 mg/kg). Administration of AuNS did not show any signs of morbidity. Inductively coupled plasma optical emission spectrometry (ICP-OES) analysis of blood (0.156 ± 0.154), urine (0.084 ± 0.08) and tissues indicates gradual dissipation and obligatory clearance within 24 h time interval. Nevertheless, pres- ence of AuNS in blood after 24 h confirms the bioavailability of AuNS demonstrating the evidence for no immune clearance and efficient tissue uptake. Further, brain shows the lowest quantity of injected AuNS. From this result, we determine this chitosan monolayer protected AuNS could cross the blood brain barrier and enter to the neural tissues. Interestingly there was no evidence of toxicity in any of the organs. In conclusion, our data suggest that AuNS injected though tail vain were easily taken up by tissues and does not produce sub-acute physiological damage even at high concentrations tested, supporting chitosan reduced AuNS as biocompatible, nontoxic nanoconjugates for targeted drug delivery and other biomedical applications.

Modeled Analysis of Entrance of Colloid Suspensions into the Middle Ear Cavity.

Otic suspensions have a positive effect on the duration of otorrhea in children with a tympanostomy tube. It is still questionable how eardrops reach the middle ear. We hypothesized that otic suspensions do not pass the tympanostomy tube if the middle ear is dry but pass by diffusion when wet. The median concentration of Evans blue (colorant) in the middle ear was <15.6 mg/mL (lower limit of quantification) when diffusion was impossible but 45.3 µg/mL when diffusion was possible (P = .01). When the outward flow was increased to 0.1 mL/h, the concentration of Evans blue in the middle ear increased significantly (P = .03). With further-increasing outward flows, the concentration of Evans blue decreased linearly (ß = -144, P < .001, R (2) = 0.44). We conclude that diffusion is the mechanism by which otic suspensions enter the middle ear in children with tympanostomy tubes and otorrhea.

Natural colloidal P and its contribution to plant P uptake.

Phosphorus (P) bioavailability depends on its concentration and speciation in solution. Andisols and Oxisols have very low soil solution concentration of free orthophosphate, as they contain high concentrations of strongly P-sorbing minerals (Al/Fe oxyhydroxides, allophanes). Free orthophosphate is the form of P taken up by plants, but it is not the only P species present in the soil solution. Natural colloidal P (P associated with Al, Fe, and organic matter of sizes ranging from 1 to 1000 nm) constitutes an important fraction of soil solution P in these soils; however, its availability has not been considered. We measured the uptake of P by wheat (Triticum aestivum) from radiolabeled nonfiltered (colloid-containing) and 3-kDa filtered (nearly colloid-free) soil-water extracts from Andisols and Oxisols. In the Andisol extracts, P uptake was up to 5-fold higher from the nonfiltered solutions than the corresponding 3-kDa filtered solutions. In the Oxisol extract, no difference in P uptake between both solutions was observed. Also the diffusional flux of P as measured with the DGT technique was larger in the nonfiltered than in the 3-kDa filtered solutions. Our results suggest that colloidal P from Andisols is not chemically inert and contributes to plant uptake of P.

Patient-specific dosimetry for intracavitary 32P-chromic phosphate colloid therapy of cystic brain tumours.

PURPOSE: (32)P-chromic phosphate colloid treatments of astrocytoma and craniopharyngioma cystic brain tumours in paediatric patients are conventionally based on a sphere model under the assumption of uniform uptake. The aims of this study were to determine the distribution of the absorbed dose delivered by (32)P on a patient-specific basis and to evaluate the accuracy with which this can be predicted from a pretherapy administration of (99m)Tc-Sn colloid. METHODS: Three patients were treated with (32)P-chromic phosphate colloid following (99m)Tc-Sn colloid administrations. Convolution dosimetry was performed using pretherapy and posttherapy sequential SPECT imaging, and verified with EGSnrc Monte Carlo radiation transport simulations. Mean absorbed doses to the cyst wall and dose-volume histograms were also calculated and compared with those obtained by the sphere model approach. RESULTS: Highly nonuniform uptake distributions of both the (99m)Tc and (32)P colloids were observed and characterized by dose-volume histograms to the cyst wall. Mean absorbed doses delivered to the cyst wall, obtained with the convolution method, were on average 21 % (SD 18 %) and 50 % (SD 30 %) lower than those predicted by the (99m)Tc distribution and the uniform assumption of the sphere model, respectively. CONCLUSION: Absorbed doses delivered to the cyst wall by (32)P are more accurately predicted from image-based patient-specific convolution dosimetry than from simple sphere models. These results indicate the necessity to perform personalized treatment planning and verification for intracavitary irradiation of cystic brain tumours treated with radiocolloids. Patient-specific dosimetry can be used to guide the frequency and levels of repeated administrations and would facilitate data collection and comparison to support the multicentre trials necessary to progress this therapy.

Does increased tumor burden of sentinel nodes in breast cancer affect detection procedure?

Numerous studies have shown that sentinel lymph node biopsy (SLN) has a high level of detection sensitivity. Successful detection procedure depends on the amount of radioactivity and accumulation of blue dye in the SN. Our aim was to relate the differences observed in intraoperative SN presentation to tumor burden, characteristics of the primary tumor and patient attributes. Our retrospective analysis included 369 patients undergoing SLN in the Department of Gynecology of the University Hospital of Zurich within five years. Data was collected from the patients (age, BMI), the primary tumor (size, grading, hormone receptors, HER2 status) and the SNs removed (counts per second [cps], blue dye, size of nodular metastasis, extracapsular involvement, number of SNs excised). Because patients typically had more than one SN, a linear mixed-effects model was used to account for the clustering within one patient. SNs presented with significantly lower radioactivity in elderly (-1.8%/year, p < 0.001) and obese patients (-3.9%/kg/m2, p = 0.006) as well as in G3 primary tumors (p = 0.002). Radiocolloid accumulation decreased with increasing metastasis size (-6.1%/mm, p = 0.006). In conclusion the detection procedure of SNs is mainly affected by the patient's age and BMI and by nodular metastasis' size. Phagocytotic activity in the lymph node may increase radiotracer accumulation, showing the highest tracer signals in micrometastatic SNs. In large SN metastasis the lymph flow appears obstructed, reducing the axillary drainage and therefore making detection procedure difficult.

Development and evaluation of colloidal modified nanolipid carrier: application to topical delivery of tacrolimus, Part II--in vivo assessment, drug targeting, efficacy, and safety in treatment for atopic dermatitis.

In atopic dermatitis (AD), topical anti-inflammatory therapy with skin barrier restoration to prevent repeated inflammatory episodes leads to long-term therapeutic success. Tacrolimus, although effective against AD, is a challenging molecule due to low solubility, low-penetration, poor-bioavailability, and toxicity. Part I of this paper, reported novel modified nanolipid carrier system for topical delivery of tacrolimus (T-MNLC), offering great opportunity to load low-solubility drug with improved entrapment efficiency, enhanced stability and improved skin deposition. Present investigation focused on restoration of skin barrier, site-specific delivery, therapeutic effectiveness, and safety of novel T-MNLC. T-MNLC greatly enhanced occlusive properties, skin hydration potential and reduced transepidermal water loss. This might help to reduce the number of flares and better control the disease. Cutaneous uptake and drug deposition in albino rats by HPLC and confocal laser scanning microscopy revealed prominently elevated drug levels in all skin strata with T-MNLC as compared to reference. T-MNLC demonstrated efficient suppression of inflammatory responses in BALB/c mice model of AD. Safety assessment by acute and repeated-dose dermal toxicity demonstrated mild keratosis and collagenous mass infiltration at the treatment area with repeated application of reference. Interestingly, T-MNLC showed no evident toxicity exhibiting safe drug delivery. Thus, novel T-MNLC would be a safe, effective, and esthetically appealing alternative to conventional vehicles for treatment for AD.

Development and characterization of colloidal soft nano-carriers for transdermal delivery and bioavailability enhancement of an angiotensin II receptor blocker.

The purpose of this study was to develop and characterize a successful colloidal soft nano-carrier viz. microemulsion system, for the transdermal delivery of an angiotensin II receptor blocker: olmesartan medoxomil. Different microemulsion formulations were prepared. The microemulsions were characterized visually, with the polarizing microscope, and by photon correlation spectroscopy. In addition, the pH and conductivity (σ) of the formulations were measured. The type and structure of microemulsions formed were determined using conductivity measurements analysis, Freezing Differential Scanning Calorimetry (FDSC) and Diffusion-Ordered Spectroscopy (DOSY). Alterations in the molecular conformations of porcine skin were determined using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) biophysical assessment. Olmesartan medoxomil delivery from the investigated formulations was assessed across porcine skin ex-vivo using Franz diffusion cells; the drug was analyzed by liquid chromatography mass spectroscopy (LC/MS/MS). A comparative pharmacokinetic study was done on healthy human subjects between the selected microemulsion and the commercial oral tablets. The physico-chemical and spectroscopic methods revealed the presence of water-in-oil and bicontinuous structures. Biophysical assessment demonstrated various stratum corneum (SC) changes. Olmesartan medoxomil was delivered successfully across the skin with flux achieving 3.65µgcm(-2)h(-1). Higher bioavailability compared to commercial oral tablets with a more sustainment behavior was achieved.

Effect of chitosan chain architecture on gene delivery: comparison of self-branched and linear chitosans.

Chitosan possesses many characteristics of an ideal gene delivery system. However, the transfection efficiency of conventional chitosans is generally found to be low. In this study, we investigated the self-branching of chitosans as a strategy to improve its gene transfer properties without compromising its safety profile. Self-branched (SB) and self-branched trisaccharide-substituted (SBTCO) chitosans with molecular weights of 11-71 kDa were synthesized, characterized, and compared with their linear counterparts with respect to transfection efficiency, cellular uptake, formulation stability, and cytotoxicity. Our studies show that in contrast with unmodified linear chitosans that were unable to transfect HeLa cells, self-branched chitosans mediated high transfection efficiencies. The most efficient chitosan, SBTCO30, yielded gene expression levels two and five times higher than those of Lipofectamine and Exgen, respectively, and was nontoxic to cells. Nanoparticles formed with SBTCO chitosans exhibited a higher colloidal stability of formulation, efficient internalization without excessive cell surface binding, and low cytotoxicity.

A comparison of the effects of preanesthetic administration of crystalloid versus colloid on intrathecal spread of isobaric spinal anesthetics and cerebrospinal fluid movement.

BACKGROUND: Movement of the cerebrospinal fluid (CSF) is one of the most important factors in determining the intrathecal spread of isobaric spinal anesthetics. Preanesthetic administration of either crystalloid or colloid immediately before spinal anesthesia (preload) may result in different CSF pulsatile movement because of their different physical properties. We examined whether preload of crystalloid versus colloid may have different effects on the intrathecal spread of isobaric spinal anesthetics as a result of their different CSF dynamics regarding its pulsatile movement. METHODS: In a clinical study of isobaric spinal anesthesia, patients were allocated into 1 of 2 groups according to preload with either crystalloid (n = 30) or colloid (n = 30) before spinal anesthesia with 0.5 isobaric tetracaine. The pulsatile movements of CSF at the L2-3 intervertebral space and midportion of the aqueduct of Sylvius were also examined by magnetic resonance images in healthy volunteers (n = 23) at 0, 30, and 60 minutes after administering either crystalloid or colloid. RESULTS: In the clinical study, the time to reach the peak sensory block level was delayed significantly in the crystalloid preload group (27.2 ± 17.8 minutes; P < 0.01) compared with the colloid preload group (13.9 ± 7.0 minutes). The median sensory block levels of the crystalloid preload group at 15 minutes (T10, P < 0.05) and 20 minutes (T9.5, P < 0.05) were significantly lower than those (T8, T7, respectively) of the colloid preload group. In the magnetic resonance imaging study, cranially directed CSF pulsatile movement decreased significantly at the L2-3 intervertebral intrathecal space at 30 minutes after crystalloid administration, but not after colloid administration. The CSF production rate significantly increased at 30 minutes (637 µL/min, P < 0.05) after crystalloid preload compared with the baseline measurement (448 µL/min), and then slightly decreased (609 µL/min) at 60 minutes. In the colloid preload group, the CSF production rate was not statistically significant compared with the baseline measurement (464, 512, and 542 µL/min at baseline, 30, and 60 minutes, respectively). CONCLUSIONS: Compared with a colloid preload, which may be comparable to the no-preload condition, crystalloid preload prolonged the time to reach the peak sensory block level in isobaric spinal anesthesia, which might have been caused by a significant decrease in CSF pulsatile movement. This attenuated CSF pulsatile movement in the crystalloid preload group might have resulted from significant increases of CSF production.

Colloidal DNA carriers for direct localization in cell compartments by pH sensoring.

Multifunctional colloidal microparticles allow the integration of various active agents as well as reporter molecules into one system without interfering combining delivery and sensing functions. In this study, calcium carbonate particles were functionalized with fluorescein isothiocyanate-labeled poly(allylamine hydrochloride) (FITC-PAH) allowing particle localization in cell compartments of different pH. Plasmid DNA (pEGFP-C1 and pDsRed1-N1) as a reporter agent for drug release in the cytoplasm and rhodamine-B-isothiocyanate-labeled protamine (RITC-PRM) were integrated into biocompatible and biodegradable PRM/DXS multilayers. The uptake and processing of the particles by HEK293T/17 cells were investigated via flow cytometry and confocal laser scanning microscopy. The presented data show a clear correlation between the fluorescence intensity of the FITC-labeled core, that is, the particle localization after cellular uptake, and the expression of fluorescent proteins by the cells without further cell staining. In conclusion, this particle design allows the simultaneous study of particle location and processing to monitor the transport and release of active agents and should thus be an invaluable tool for the study and design of nano- and microcarrier systems.

Skin efficacy and biophysical assessment of glycerol-containing hydrocolloid patches.

Hydrocolloid patches are developed with 10, 20 and 30% (w/w) glycerol as the main active ingredient. By making use of two experimental forearm models, skin efficacy and its dependency on the glycerol concentration applied were compared with a blank reference patch, a commercialized protective patch and a cosmetic barrier cream. Skin hydration and transepidermal water loss measurements were combined with skin erythema assessments. After a single application to healthy skin, a clear concentration-dependent effect of glycerol-containing patches was observed with - for the highest glycerol content - a 31% increase in skin hydration and an improvement in skin barrier properties of 15%. This glycerol-containing patch also accelerated barrier recovery of mechanically irritated skin after stripping with cyanoacrylate tape. After 7 days of repetitive application, a significantly hydrating effect of the 30% glycerol-containing patch was observed, which was of the same order of magnitude as observed for the cosmetic barrier cream, the latter being applied twice daily. The effects seen were maximal after 3 days of patch application.

A combined crystalloid and colloid pd solution as a glucose-sparing strategy for volume control in high-transport apd patients: a prospective multicenter study.

BACKGROUND: Evidence is accumulating that the continuous exposure to high glucose concentrations during peritoneal dialysis (PD) is an important cause of ultrafiltration (UF) failure. The cornerstone of prevention and treatment of UF failure is reduction of glucose exposure, which will also alleviate the systemic impact of significant free glucose absorption. The challenge for the future is to discover new therapeutic strategies to enhance fluid and sodium removal while diminishing glucose load and exposure using combinations of available osmotic agents. OBJECTIVES: To investigate in patients on automated PD (APD) with a fast transport pattern whether there is a glucose-sparing advantage to replacing 7.5% icodextrin (ICO) during the long dwell with a mixed crystalloid and colloid PD fluid (bimodal UF) in an attempt to promote daytime UF and sodium removal while diminishing the glucose strength of the dialysate at night. DESIGN: A 2 parallel arm, 4 month, prospective nonrandomized study. SETTING: PD units or university hospitals in 4 French and Belgian districts. RESULTS: During the 4-month intervention period, net UF and peritoneal sodium removal during the long dwell when treated by bimodal UF was about 2-fold higher than baseline (with ICO). The estimated percent change (95% confidence interval) from baseline in net daytime UF for the bimodal solution was 150% (106% - 193%), versus 18% (-7% - 43%) for ICO (p < 0.001). The estimated percent change from baseline in peritoneal sodium removal for the bimodal solution was 147% (112% - 183%), versus 23% (-2% - 48%) for ICO (p < 0.001). The estimated percent change from baseline in UF efficiency (24-hour net UF divided by the amount of glucose absorbed) was significantly higher (p < 0.001) when using the bimodal solution was 71%, versus -5% for ICO. CONCLUSION: Prescription of bimodal UF during the day in APD patients offers the opportunity to optimize the long dwell exchange in a complete 24-hour APD cycle. The current study demonstrated that a bimodal solution based on the mixing of glucose (2.6%) and icodextrin (6.8%) achieved the double target of significantly improving UF and peritoneal sodium removal by exploring a new concept of glucose-sparing PD therapy.

Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia.

OBJECTIVE: To compare crystalloid and colloid fluids in their effect on pulmonary edema in hypovolemic septic and nonseptic patients with or at risk for acute lung injury/acute respiratory distress syndrome. We hypothesized that 1) crystalloid loading results in more edema formation than colloid loading and 2) the differences among the types of fluid decreases at high permeability. DESIGN, SETTING, AND PATIENTS: Prospective randomized clinical trial on the effect of fluids in 24 septic and 24 nonseptic mechanically ventilated patients with clinical hypovolemia. INTERVENTIONS: Patients were assigned to NaCl 0.9%, gelatin 4%, hydroxyethyl starch 6%, or albumin 5% loading for 90 minutes according to changes in filling pressures. MEASUREMENTS AND MAIN RESULTS: Twenty-three septic and 10 nonseptic patients had acute lung injury/acute respiratory distress syndrome (p < 0.001). Septic patients had greater pulmonary capillary permeability, edema, and severity of lung injury than nonseptic patients (p < 0.01), as measured by the pulmonary leak index (PLI) for Gallium-labeled transferrin, extravascular lung water (EVLW), and lung injury score (LIS), respectively. Colloids increased plasma volume, cardiac index, and central venous pressure (CVP) more than crystalloids (p < 0.05), although more crystalloids were infused (p < 0.05). Colloid osmotic pressure (COP) increased in colloid and decreased in crystalloid groups (p < 0.001). Irrespective of fluid type or underlying disease, the pulmonary leak index increased by median 5% (p < 0.05). Regardless of fluid type or underlying disease, EVLW and LIS did not change during fluid loading and EVLW related to COP-CVP (rs = -.40, p < 0.01). CONCLUSIONS: Pulmonary edema and LIS are not affected by the type of fluid loading in the steep part of the cardiac function curve in both septic and nonseptic patients. Then, pulmonary capillary permeability may be a smaller determinant of pulmonary edema than COP and CVP. Safety factors may have prevented edema during a small filtration pressure-induced rise in pulmonary protein and thus fluid transport.

In vivo uptake of inhaled particles by airway phagocytes is enhanced in patients with mild asthma compared with normal volunteers.

BACKGROUND: The uptake of inhaled particulate matter by airway phagocytes is an important defence mechanism contributing to the clearance of potentially toxic substances, including aeroallergens, from the lung. Since airway monocytes and macrophages can also function as antigen presenting cells, their ability to engulf materials deposited on the airway surface is of particular interest in patients with allergic asthma. To determine whether airway mononuclear phagocytes of patients with allergic asthma might have enhanced phagocytic activity, the in vivo uptake of inhaled radiolabelled particles was compared in 10 patients with mild allergic asthma and 8 healthy (non-allergic) individuals. METHODS: Phagocyte function was assessed by quantifying the proportion of radioactivity associated with cellular and supernatant fractions of induced sputum 2 h after inhalation of radiolabelled sulfur colloid particles. All subjects were pretreated with albuterol before sputum induction. A standardised breathing pattern was used to target aerosol deposition in the bronchial airways. RESULTS: In vivo particle uptake by airway cells was significantly greater in patients with asthma than in healthy volunteers (57.2% (95% CI 46.5% to 67.9%) vs 22.3% (95% CI 4.9% to 39.6%), p<0.01), as was in vitro phagocytosis of opsonised zymosan-A bioparticles. There was also a significant correlation (r = 0.85, p<0.01) between the percentage of sputum mononuclear phagocytes and the percentage uptake of particles in the patients with asthma but not in the control subjects. CONCLUSIONS: In vivo particle uptake by airway macrophages is enhanced in persons with mild asthma. Enhanced uptake and processing of particulate antigens could contribute to the pathogenesis and progression of allergic airways disease and may contribute to the increased risk of disease exacerbation associated with particulate exposure.

Chapter 1 - Drug delivery to the brain using colloidal carriers.

Many neurodegenerative diseases, cancer, and infections of the brain become more prevalent as populations become older. Despite major advances in neuroscience, the blood-brain barrier (BBB) ensures that many potential therapeutics cannot reach the central nervous system (CNS). The BBB is formed by the complex tight junctions between the endothelial cells of the brain capillaries and their low endocytic activity. It results in the capillary wall that behaves as a continuous lipid bilayer and prevents the passage of polar substances. Drug delivery to the brain has remained one of the most vexing problems in translational neuroscience research, because of the difficulties posed by the BBB. Several strategies for delivering drugs to the CNS have been developed. This review rationalizes the strategies to target drugs to the brain by using different colloids.