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Biomedical subjects

L Illum

Publications and source records attributed to L Illum.

At least 73 records · Page 4Linked to original sources
PubMed1995

Measurement of nasal mucociliary transport rates on the isolated human inferior turbinate.

The mucociliary transport rate was measured using sequential images of graphite particles moving on 17 isolated human inferior turbinates. These had been removed from 13 patients who had normal saccharin clearance tests on the day of surgery. The initial mean mucociliary transport rate was found to be 4.1 mm/min rising to 5.0 mm/min 2 h after harvesting. After 4 h it fell to 3.7 mm/min. Where the rate was measured at two different sites on the same turbinate (n = 4), there was a close correlation over 6 h (r = 0.95, P < 0.001). When the turbinates were exposed to an aqueous solution of adrenaline (1:10,000) or a 2.5% cocaine solution, the rate increased or decreased respectively by 100% and 58% but returned to within 10% of the initial level within 2 h. We believe that the isolated inferior turbinate can be considered a useful model for the study of mucociliary clearance and agents that may influence it.

Cocaine↗
PubMed1994

Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes.

The concept of steric stabilization as used in colloid science is applied to carefully manipulate the drainage and lymphatic distribution of subcutaneously administered model polystyrene nanospheres. A wide range of synthetic polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymers of poloxamine and poloxamer series have been used to produce sterically stabilized nanospheres. We have found a correlation between the length of the stabilizing POE chains of the block co-polymers and nanosphere drainage and passageway across tissue lymph interface in dermal lymphatic capillaries in the rat footpads; the longer the POE chains, the faster the particle drainage. Nanospheres conditioned with block co-polymers of POE chains of 5-15 ethylene oxide units are effectively opsonized in lymphatics; a process which dramatically enhances sequestration (up to 40% of the administered dose) by macrophages of the regional lymph nodes. If the dimensions of the stabilizing POE chains of the poloxamines and poloxamers exceed the range of the Van der Waals force of attraction, opsonization fails to occur and rapidly drained engineered vehicles escape clearance by macrophages of the regional nodes, reach the systemic circulation and remain in the blood for prolonged periods. These observations suggest that a lymphatic delivery composition based on polymer-coated particles will be advantageous for many applications in clinical and experimental medicine.

Animals↗
PubMed1994

Resorbable polymeric microspheres for drug delivery--production and simultaneous surface modification using PEO-PPO surfactants.

Poly(oxyethylene)-poly(oxypropylene) (PEO-PPO) co-polymers have been used as surfactants to produce resorbable poly(DL-lactide co-glycolide) (PLG) microspheres in the 500 nm-1 micron size range by an emulsification/solvent evaporation technique based on acetone-dichloromethane mixtures. The high polydispersity of microspheres could be reduced by using low PLG concentrations of 1% (w/v). Surface analysis by static secondary ion mass spectroscopy revealed the presence of PEO-PPO at the microsphere surface after cleaning by centrifuging and resuspension in water, and after further cleaning by dialysis. Physical entrapment of PEO-PPO chains in the particle surface is indicated due to rapid collapse of the solvent swollen PLG network as acetone is extracted from the suspended droplets. Opportunities are presented for simultaneous manufacture and surface modification of microspheres.

Chemistry, Pharmaceutical↗
PubMed1994

Chitosan as a novel nasal delivery system for peptide drugs.

A nasal solution formulation of the cationic material chitosan was shown to greatly enhance the absorption of insulin across the nasal mucosa of rat and sheep. The absorption promoting effect was concentration dependent with the optimal efficacy obtained for concentrations higher than 0.2% and 0.5% in rats and sheep, respectively. The absorption promoting effect was reversible with time in a "pulse-chase" study. Histological examination of the nasal mucosa of rats exposed to a chitosan solution for 60 minutes showed little change.

Absorption↗
PubMed1994

Polystyrene-poly (ethylene glycol) (PS-PEG2000) particles as model systems for site specific drug delivery. 2. The effect of PEG surface density on the in vitro cell interaction and in vivo biodistribution.

The effect of differing densities of poly (ethylene glycol-2000) (PEG2000) at the particle surface of polystyrene-poly (ethylene glycol-2000) (PS-PEG2000) particles was assessed in terms of hydrophobic interaction chromatography (HIC) and the in vitro and in vivo behaviour of the particles. The particles, with different surface densities of PEG, were prepared by varying the copolymerizing reaction of styrene with a PEG macromonomer. There is a clear relationship between the surface density of PEG as determined by X-ray photoelectron spectroscopy and surface hydrophobicity as assessed by hydrophobic interaction chromatography (HIC). Similarly, the interaction of the particles with non-parenchymal liver cells in in vitro studies was shown to decrease as the surface density of PEG increases. The in vivo study investigating the biodistribution of the PS-PEG particles after intravenous injection into rats reveals that a relationship exists between the surface density of PEG and the extent to which the particles remain in the circulation, avoiding recognition by the reticuloendothelial system. Particles with the higher surface densities show increased circulatory times which compared well with data for particles prepared with the surface adsorbed PEO-PPO block copolymer, Poloxamine 908.

Animals↗
PubMed1994

Preparation of sterically stabilized human serum albumin nanospheres using a novel Dextranox-MPEG crosslinking agent.

Human serum albumin (HSA) nanospheres with a size less than 200 nm in diameter were prepared using a modified coacervation method and crosslinking with methyl polyethylene glycol modified oxidized Dextram (Dextranox-MPEG) which created a sterically stabilizing polyethylene oxide surface layer surrounding the nanospheres. The crosslinking efficiency and the surface characteristics of glutaraldehyde and Dextranox-MPEG crosslinked HSA nanospheres were determined and compared. The zeta potential of the Dextranox-MPEG crosslinked particles was significantly lower than that of glutaraldehyde stabilized particles. The existence of a hydrated steric barrier surrounding the nanospheres was confirmed by an electrolyte and pH induced flocculation test. The Dextranox-MPEG crosslinked nanospheres showed a significantly reduced plasma protein adsorption on the particle surface compared with glutaraldehyde crosslinked nanospheres.

Chemistry, Pharmaceutical↗
PubMed1994

Nasal absorption in the rat. III. Effect of lysophospholipids on insulin absorption and nasal histology.

The intranasal absorption enhancing and histological effects of a range of lysophospholipids has been investigated in the rat. Blood glucose levels fell rapidly following the administration of insulin (8 IU/kg) in combination with lysophosphatidylcholines (LPC; 0.625% w/v) which had ten or more carbon groups in their fatty acid chain. The effect of the LPC-caproyl (C6) was comparable to that of an unenhanced insulin formulation; the enhancing effect of LPC-decanoyl (C10) was similar to that of an LPC-palmitoyl/stearoyl (C16/C18) for similar concentrations. The effect of LPC-decanoyl was reduced with concentration but was still significant at 0.2% w/v (5mM). Lysophosphatidylglycerol (LPG) had a marked insulin absorption enhancing effect even at 0.0625% w/v. The histological effects of LPC-caproyl were similar to those of an unenhanced insulin formulation, while co-administration of LPC-decanoyl resulted in evidence of epithelial interaction. LPG (0.5% w/v) resulted in similar histological changes as LPC (0.625% w/v) (1), but at 0.0625% w/v no significant changes in epithelial integrity were observed. The length of the fatty acid residue of lysophospholipids was identified as an important factor for intranasal absorption enhancing activity. The nature of the polar head group may also have an influence. Increased insulin absorption was not necessarily accompanied by severe disruption of the nasal epithelium. Careful selection of lysophospholipid type and concentration may enable therapeutic drug levels to be achieved via the nasal route without prohibitive toxic effects.

Absorption↗
PubMed1994

Nasal absorption of desmopressin in rats and sheep. Effect of a bioadhesive microsphere delivery system.

The nasal absorption of desmopressin was studied in two animal models, the rat and the sheep. The bioavailability after nasal administration was found to be 13 times higher in the rat model. This discrepancy is suggested to be due to the impaired mucociliary clearance mechanism in the rat model and possibly differences in enzymatic degradation and elimination rates of the drug. The effect of the addition of L-alpha-lysophosphatidylcholine (LPC) to the formulations as an absorption enhancer was most pronounced in the sheep model. The use of the bioadhesive starch microsphere delivery system, especially in combination with LPC, had a profound effect on the absorption of desmopressin in sheep, with bioavailabilities reaching nearly 10% compared with 1.2% for a simple nasal solution of desmopressin.

Absorption↗
PubMed1993

Coating particles with a block co-polymer (poloxamine-908) suppresses opsonization but permits the activity of dysopsonins in the serum.

The surfaces of polystyrene microspheres (60 nm in diameter) and colloidal gold particles (17 nm in diameter) were coated with a polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymer; poloxamine-908. The polymer adsorb strongly to the microspheres via its relatively hydrophobic POP segments. This leaves the POE chains in a mobile state as they extend outward from the surface and thereby provide stability to the particle suspension by suppressing aggregation. The blood clearance and biodistribution of uncoated vs. poloxamine-908-coated 125I-labelled polystyrene microspheres were compared 1 h after intravenous administration into rats. Poloxamine coating dramatically reduced liver accumulation of microspheres and kept them within the systemic circulation. These observations were further confirmed by electron microscopy, demonstrating that Kupffer cells were loaded with uncoated latex but had ingested few if any of the poloxamine-908-coated particles. The interaction of uncoated and poloxamine-coated gold particles with freshly isolated rat liver sinusoidal cells was examined by electron microscopy. The accumulation in Kupffer cells of gold particles after opsonization with autologous plasma was in accordance with previous observations where the dominant opsonizing activity had been identified as fibronectin. In contrast, coating of gold particles with poloxamine-908 prior to plasma opsonization prevented the adsorption of fibronectin onto their surface. Simultaneously, Kupffer cells failed to recognize poloxamine-908-coated gold particles before and after opsonization. Unlike Kupffer cells, liver endothelial cells endocytosed poloxamine-908-coated gold particles prior to opsonization but failed to recognize them after the opsonization process. This was taken as an indication of the presence of dysopsonic activity in plasma. This dysopsonic activity was studied using polystyrene latex microspheres, where the uptake of such particles by phagocytes is known to be independent of opsonization. The coating of 125I-labelled polystyrene microspheres with poloxamine-908 dramatically reduced their interaction with liver sinusoidal cells. This interaction was further reduced in the presence of either autologous plasma or serum. A heat-stable (60 degrees C for 15 min) serum component of molecular mass > 100 kDa was found to mediate this suppressive effect. Thus, we demonstrate that organ-specific receptors, opsonin activities and plasma dysopsonins regulate the in vivo clearance of particulate materials from the circulation. Poloxamine-908 coating modulates particle clearance by effectively blocking opsonization but still allowing for dysopsonization.

Animals↗
PubMed1993

An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen.

Earlier we demonstrated that coating the surface of large model polystyrene microspheres (220-300 nm in diameter) with the block co-polymer polyoxyethylene/polyoxypropylene poloxamine-908 triggered their accumulation in the rat spleen by a filtration mechanism following intravenous administration [Moghimi, S.M., Porter, C.J.H., Muir, I.S., Illum, L. and Davis, S.S. (1991) Biochem. Biophys. Res. Commun. 177, 861-866]. We have now demonstrated that the macrophages of the red-pulp can effectively phagocytose the filtered poloxamine-coated microspheres 24 h post-administration. This could be the result of either the loss of the surface absorbed poloxamine, and hence the steric barrier, or 'neutralization' of the effect of the anti-phagocytic material poloxamine-908 within the spleen. In order to assess the capacity of the splenic uptake mechanism(s), rats received daily intravenous administration of unlabelled large poloxamine-908 coated microspheres (220 nm in diameter) for 4 days (daily-dosed animals). Control rats received daily saline injection. On the fifth day all animals were injected with either radiolabelled large (220 nm) or small (60 nm in diameter) poloxamine-coated polystyrene microspheres. Predosing dramatically decreased the splenic uptake of the large test microspheres but had no effect on the uptake of small test-microspheres. The failure of the spleen to take up particles was not associated with an increased circulatory level of microspheres. Surprisingly, both small and large coated microspheres were sequestered by the liver and accumulated in Kupffer cells as demonstrated by electron microscopy in daily-dosed animals. In contrast, the liver of control animals did not effectively sequester poloxamine-coated microspheres. Here, microspheres predominantly remained in blood. Sequestration of poloxamine-908 coated microspheres by Kupffer cells of the liver of daily-dosed animals was the result of opsonization by an unknown serum component.

Animals↗
PubMed1993

Mice are protected against Bordetella pertussis infection by intra-nasal immunization with filamentous haemagglutinin.

Intra-nasal immunization of mice with purified Bordetella pertussis filamentous haemagglutinin (FHA) or a crude cell sonicate was shown to protect against subsequent B. pertussis aerosol challenge. Immunization with FHA was found to be the most effective and resulted in complete clearance of the bacterial infection from the lungs within 14 days. Serum IgG and lung IgA anti-FHA antibodies were detectable within 4 weeks of the first immunization and anamnestic responses were seen following secondary immunization and subsequent challenge with B. pertussis. Nasal administration of pertussis antigens is a route which induces good systemic serum, as well as local secretory, antibody responses.

Adhesins, Bacterial↗
PubMed1993

In vivo evaluation of protein adsorption to sterically stabilised colloidal carriers.

A diffusion chamber implanted intraperitoneally in the rabbit was employed as an in vivo model to evaluate the interaction of peritoneal proteins with block copolymer (poloxamer and poloxamine)-coated polystyrene microspheres (PS). Using a desorption technique followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, six proteins of 94, 86, 66, 53, 40, and 20 kDa were desorbed from the carrier systems after incubation with peritoneal fluid in vitro. The 40- and 20-kDa proteins dominated the protein profile. A similar pattern was observed when proteins were desorbed from PS microspheres removed after 24-h implantation in chambers in the peritoneal cavity, although the protein profile was dominated by the 94- and 53-kDa proteins. In general, coating of PS with block copolymers reduced the amount of protein bound to the microspheres in vitro and in vivo but did not change the types of proteins bound.

Adsorption↗
PubMed1993

Enhanced hepatic clearance of intravenously administered sterically stabilized microspheres in zymosan-stimulated rats.

The blood clearance and organ deposition of sterically stabilized (poloxamine-908 coated) polystyrene microspheres of two different sizes (60 and 220 nm in diameter) were compared in control and zymosan-stimulated rats 3 h after intravenous administration. Poloxamine coating dramatically decreased the uptake of 60-nm microspheres by organs of the reticuloendothelial system and, concomitantly, kept microspheres in the blood. Large poloxamine-coated microspheres (220 nm) initially remained in the blood, but eventually a large fraction of these microspheres was filtered by the spleen. Daily administration of zymosan produced a marked increase in the intravascular clearance of the large, but not the small, poloxamine-coated microspheres. The enhanced intravascular clearance of large poloxamine-coated microspheres in zymosan-treated rats was the result of hepatic sequestration. On the other hand, the splenic filtration of these microspheres was depressed by 225% below the control values, despite the dramatic increase in spleen size of zymosan-treated rats. Preincubation of large poloxamine-coated microspheres in serum derived from both the control and zymosan-treated animals suggested that the enhanced hepatic uptake of large sterically stabilized microspheres following zymosan stimulation was not the result of "specific opsonization" processes. Instead, the changes in the proliferative as well as the phagocytic response of Kupffer cells appeared to be responsible for these observations. The preferred hepatic uptake of large poloxamine-coated microspheres, as opposed to smaller particles, is suggested to be due to differences in surface characteristics and the properties of microspheres. These may include differences in polymer density and the surface conformation of the polyoxyethylene segments of the polymer in the biological environment and the way they interact with both plasma components and the macrophage surface. These observations could be of importance in the use of sterically stabilized drug carriers for delivery of therapeutic agents to sites other than the reticuloendothelial system in clinical conditions associated with globally or regionally enhanced reticuloendothelial activity.

Animals↗
PubMed1993

Hydrodynamic characterization of chitosans varying in degree of acetylation.

The molecular weights and gross aqueous solution conformation of two chitosans of different degrees of acetylation, 'Sea Cure +210' (11% acetylated) and KN50 (58% acetylated) were characterized by viscometry, analytical ultracentrifugation and dynamic light scattering. The hydrodynamic parameters obtained were used to determine both the molecular weights and the gross solution conformation of the two chitosans. Using the Wales-Van Holde ratio of sedimentation coefficient concentration regression coefficient (ks) to intrinsic viscosity [eta], the Sea Cure +210 chitosan, which is much less acetylated than the KN50, is highly asymmetric in conformation. This, in conjunction with the charge on the molecule, would suggest a rod-like conformation in solution. The two largest KN50 chitosans have widely differing values for the Wales-Van Holde ratio, suggesting different solution conformation. However, when the series is examined as a whole using the Mark-Houwink-Kuhn-Sakurada relationships relating molecular weight to both intrinsic viscosity and translational diffusion coefficient, then a more spheroidal structure, approximating to a random coil, is predicted.

Acetylation↗
PubMed1993

Influence of block copolymers on the adsorption of plasma proteins to microspheres.

SDS-PAGE in combination with densitometry has been used to evaluate the adsorption of plasma and serum proteins to polystyrene microspheres (PS) coated with block copolymers of the poloxamer and poloxamine series. The protein-resistant nature of coated PS was demonstrated for these systems when incubated in dilutions of plasma and serum. The total amount of protein and the type of proteins adsorbed were dependent on the plasma and serum incubation concentration used. At 0.3% serum concentrations the total amount of protein adsorbed was found to be related to the polyoxyethylene (PEO) chain length of the block copolymer, whilst at 0.3% or 50% plasma concentrations a relationship was shown between the polyoxypropylene (PPO) chain and the plasma protein adsorption for the range of block copolymers studied. Immunoblotting studies revealed the adsorption of immunoglobulin G, complement C3, transferrin and fibronectin to all microspheres previously incubated in 50% serum and plasma, whilst fibrinogen was also adsorbed after incubation in 50% plasma; with similar quantities of each protein adsorbed to PS and block copolymer-coated PS.

Adsorption↗
PubMed1993

Intravaginal immunization in sheep using a bioadhesive microsphere antigen delivery system.

An enzymatically cleaved glycoprotein fragment (amino acids 28-328: 40 kDa) from influenza virus haemagglutinin (TOPS) was used to assess an intravaginal antigen delivery system, comprising lysophosphatidylcholine (LPC) and degradable starch microspheres (DSM). Three groups of three sheep received intravaginal immunization with TOPS as follows: group 2, TOPS in solution; group 3, TOPS and DSM/LPC as a powder formulation and group 4, TOPS and LPC in solution. A fourth group, group 1, received intramuscular immunization with TOPS adsorbed to aluminium hydroxide gel (Alugel). Intravaginal immunizations were repeated on two consecutive days. Two weeks later, booster doses of the same formulations were administered on two consecutive days to each group. Group 1 sheep were boosted with a single injection, 2 weeks after the single primary immunization. The serum and vaginal wash IgA and IgG antibody responses were compared among the four groups of sheep at days 15, 30 and 45 after the booster immunizations. At day 45, the serum IgG and the vaginal wash IgA antibody responses induced by TOPS and DSM/LPC (group 3), were significantly greater than the responses induced by intravaginal immunization with TOPS (group 2). However, the highest levels of antibodies in serum and vaginal wash samples were induced by intramuscular immunization with TOPS and Alugel (group 1). Intravaginal immunization with TOPS and LPC (group 4) did not result in the induction of enhanced levels of antibodies in serum or vaginal wash samples.

Administration, Intravaginal↗
PubMed1993

Effect of splenic congestion associated with haemolytic anaemia on filtration of 'spleen-homing' microspheres.

1. The surface of large model 125I-labelled polystyrene microspheres (220 nm in diameter) was coated with the polyoxyethylene/polyoxypropylene block co-polymer poloxamine-908. The coated microspheres were injected intravenously into rats. Up to 40% of the administered dose had accumulated in the spleen by a filtration mechanism, as compared with 5% for uncoated microspheres, at 3 h after administration. The enhanced splenic sequestration of microspheres was accompanied by a decrease in the liver uptake. In contrast, smaller poloxamine-908-coated microspheres (60 nm in diameter) effectively avoided uptake by both the liver and the spleen and remained in systemic circulation. 2. The effect of splenic congestion, associated with phenylhydrazine-induced haemolytic anaemia, on filtration of poloxamine-908-coated microspheres was studied. The enlarged spleen of the anaemic rats was incapable of efficiently filtering large poloxamine-908-coated microspheres when compared with the spleen of normal animals. This was suggested to be the result of extensive 'clogging' of the red pulp by damaged erythrocytes. However, the splenic filtration of large coated microspheres was still five-fold higher than that of uncoated microspheres of similar size in anaemic animals. 3. The potential use of large sterically stabilized colloids and drug carriers for selective spleen scanning and splenic drug delivery in pathological conditions, where anaemia prevails, is discussed. 4. Sterically stabilized microspheres may have potential for re-examining the microcirculatory pathways in healthy spleen and various splenomegalies.

Anemia, Hemolytic↗