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Biomedical subjects

S S Davis

Publications and source records attributed to S S Davis.

At least 73 records · Page 4Linked to original sources
PubMed1998

Resorbable lamellar particles of polylactide as adjuvants for influenza virus vaccines.

Lamellar particles and microspheres were produced by precipitation from solutions of resorbable, biocompatible, semi-crystalline poly(L-lactide)[PLA] and amorphous poly(DL lactide co-glycolide)[PLG] copolymer, respectively, to investigate their adjuvanticity towards adsorbed influenza virus. Both types of substrate were capable of adsorbing large quantities of virus (> 15% w/w) and retaining virus (> 60% of the initial load) over an 8 week time scale in-vitro. Potent immune responses were obtained in mice after the intra-muscular injection of adsorbed vaccine systems. The response to virus adsorbed on PLA lamellar particles was almost five times that obtained using PLG microspheres and fourteen times that using aqueous vaccine. The lamellar forms of PLA may function as an immunomodulator enhancing phagocytic activity due to their irregular shape and may be useful in improving the immune response to a variety of protein and viral antigens.

Adjuvants, Immunologic↗
PubMed1998

Stimulation of mucosal and systemic antibody responses against Bordetella pertussis filamentous haemagglutinin and recombinant pertussis toxin after nasal administration with chitosan in mice.

Mice were intranasally immunised with a mixture of Bordetella pertussis filamentous haemagglutinin (FHA) and recombinant pertussis toxin, PT-9K/129G (rPT) in combination with chitosan. For both antigens, this formulation induced systemic responses as measured by serum IgG and also mucosal responses as measured by secretory IgA in lung lavage and nasal washes. Immunosorbant assays were used to measure these responses. Both the systemic and mucosal responses were considerably higher than those produced when a mixture of rPT and FHA was administered nasally without chitosan. In comparison, intraperitoneally administered rPT/FHA adsorbed to Alhydrogel elicited only a systemic response, and nasal chitosan solution produced neither systemic nor mucosal response. This study clearly demonstrated that chitosan potentiated the serum and mucosal immune responses to nasally administered FHA and rPT in mice. Hence, this nasal chitosan delivery system has potential as a new non-injectable vaccine for the prophylaxis of whooping cough.

Adhesins, Bacterial↗
PubMed1998

Intranasal absorption of granulocyte-colony stimulating factor (G-CSF) from powder formulations, in sheep.

Granulocyte-colony stimulating factor (G-CSF) was administered to sheep in three different nasal formulations and as a subcutaneous injection. The nasal formulations were: a solution containing L-alpha-lysophosphatidylglycerol (LPG), a powder formulation comprising small starch microspheres (SSMS) and a powder formulation comprising SSMS and LPG. Absorption of G-CSF was assessed directly by quantitation in plasma and indirectly by measurement of the pharmacodynamic response in terms of leucocyte and neutrophil counts. After the nasal delivery of the G-CSF powder formulation containing SSMS and LPG the absorption of G-CSF was significantly higher (P<0.01) than that from the simple nasal solution or the powder without the enhancer, but the resulting pharmacological response was not significantly different. The bioavailability of G-CSF from the powder formulation containing SSMS and LPG relative to the subcutaneous injection was 8.4% (+/-3.4). We also found that at the respective G-CSF doses investigated, the pharmacodynamic response of this nasal formulation, was similar to that obtained after the subcutaneous administration. The study indicates that the powder formulation containing enhancers could offer an alternative delivery route for G-CSF in the form of intranasal administration.

Administration, Intranasal↗
PubMed1998

Is the pig a good animal model for studying the human ileal brake?

This study was designed to investigate the existence of an ileal brake mechanism in the pig model. The test substances used (oleic acid, deoxycholic acid, taurocholic acid) had all been previously shown to affect the ileal brake mechanism in other species including man. The substances were infused directly into the terminal ileum of surgically modified pigs, 45 min after the pigs had ingested a meal containing a drug marker. The marker used was sulfasalazine, which is cleaved to form a metabolite, sulfapyridine, when it reaches the colon. The subsequent HPLC analysis of collected blood samples allowed the appearance of sulfapyridine in the plasma and hence the arrival of sulfasalazine in the colon to be determined. Any differences in transit between control and test could be evaluated from a profile of plasma concentrations and corresponding values of AUC. The findings from this study show that the various substances did not affect transit of a test meal in the pig and suggest that it is not possible to use this pig model to make predictions about the human ileal brake.

Animals↗
PubMed1998

In vitro displacement by rat serum of adsorbed radiolabeled poloxamer and poloxamine copolymers from model and biodegradable nanospheres.

Poloxamer 407 and poloxamine 908 have been used by many research groups to modify the surface of both model latex and biodegradable nanospheres, thereby producing nanospheres that have shown reduced protein adsorption in vitro and extended circulation times in vivo. A potential limitation of such systems is the desorption of the copolymer coating layer. We describe a two-stage process to radiolabel poloxamer 407 and poloxamine 908 that has facilitated an investigation into this potential desorption, in vitro. The first stage of the labeling procedure involved the substitution of the terminal hydroxyl groups in each poly(ethylene oxide) (PEO) chain of poloxamer 407 and poloxamine 908 with an amino group. The aminated copolymers were then radiolabeled with 125Iodine Bolton-Hunter reagent. The efficiency of labeling was calculated to be approximately 20% for the tetramine poloxamine 908 and approximately 33% for the diamine poloxamer 407. Remaining free amino groups were then either acetylated, using acetic anhydride, or left in the free amino form. Covalent linkage of the radiolabel to the copolymer was confirmed by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The stability of the link between radiolabel and copolymer to hydrolysis was also confirmed; <4% loss of radiolabel occurred from poloxamine 908 after incubation in phosphate-buffered saline (PBS) at 37 degrees C for 8 days. The radiolabeled copolymers (with the free amino groups acetylated) were then used in experiments that have given the first direct evidence that adsorbed copolymers can be displaced by serum proteins in significant amounts from the surface of model and biodegradable nanospheres. The displacement was highly dependent on copolymer-nanosphere compatibility, with up to 78% of 125I tetramine poloxamine 908 being displaced from poly(lactide-co-glycolide) (PLGA) nanospheres in 24 h, compared with 20% displacement of 125I tetramine poloxamine 908 in 24 h from polystyrene nanospheres. These results have direct implication for the future design of drug delivery systems based on coated nanospheres.

Animals↗
PubMed1998

Modification of the copolymers poloxamer 407 and poloxamine 908 can affect the physical and biological properties of surface modified nanospheres.

PURPOSE: To investigate the effects of the modification of the copolymers poloxamer 407 and poloxamine 908 on the physical and biological properties surface modified polystyrene nanospheres. METHODS: A method to modify poloxamer 407 and poloxamine 908, introducing a terminal amine group to each PEO chain has been developed. The aminated copolymers can be subsequently radiolabelled with Iodinated (I125) Bolton-Hunter reagent. The aminated copolymers were used to surface modify polystyrene nanospheres. The physical and biological properties of the coated nanospheres were studied using particle size, zeta potential, in vitro non-parenchymal cell uptake and in vivo biodistribution experiments. RESULTS: The presence of protonated amine groups in the modified copolymers significantly affected the physical and biological properties of the resulting nanospheres, although the effects were copolyme specific. The protonated surface amine groups in both copolymers reduced the negative zeta potential of the nanospheres. Acetylation of the copolymer's free amine groups resulted in the production of nanospheres with comparable physical properties to control unmodified copolymer coated nanospheres. In vivo, the protonated amine groups in the copolymers increased the removal of the nanospheres by the liver and spleen, although these effects were more pronounced with the modified poloxamer 407 coated nanospheres. Acetylation of the amine groups improved the blood circulation time of the nanospheres providing modified poloxamine 908 coated nanospheres with comparable biological properties to control poloxamine 908 coated nanospheres. Similarly, modified poloxamer 407 coated nanospheres had only slightly reduced circulation times in comparison to control nanospheres. CONCLUSIONS: The experiments have demonstrated the importance of copolymer structure on the biological properties of surface modified nanospheres. Modified copolymers, which possess comparable properties to their unmodified forms, could be used in nanosphere systems where antibody fragments can be attached to the copolymers, thereby producing nanospheres which target to specific body sites.

Animals↗
PubMed1997

Lymph node localisation of biodegradable nanospheres surface modified with poloxamer and poloxamine block co-polymers.

Studies were performed to develop a sub-100 nm biodegradable colloidal system for the efficient delivery of drugs and diagnostic agents to the lymphatic system. Nanospheres of poly(lactide-co-glycolide) were prepared by interfacial polymer deposition. The nanospheres were coated with block co-polymers in order to modify their surface characteristics. Radiolabelling of the nanospheres for in vivo tracing was achieved by the incorporation of the lipophilic complex 111In-oxine during nanosphere preparation. In vitro stability of the radiolabelled nanospheres was determined in rat serum at 37 degrees C. The lymphatic distribution of the nanospheres was determined after subcutaneous administration to the rat. Lymphatic uptake of all coated systems was enhanced compared to the uncoated nanospheres, and a maximal uptake of 17% of the administered dose in the regional lymph nodes was achieved. These observations suggest that the nanospheres are suitable for diagnostic and therapeutic applications in clinical and experimental medicine.

Animals↗
PubMed1997

Preparation of surface-modified albumin nanospheres.

Surface-modified human serum albumin (HSA) nanospheres with a size of around 100 nm in diameter were prepared from poly(amidoamine)-poly(ethylene glycol) copolymer grafted human serum albumin (HSA-PAA-PEG) and poly(thioetheramido acid)-poly(ethylene glycol) copolymer grafted human serum albumin (HSA-PTAAC-PEG). The nanospheres were produced using a pH-coacervation method and cross-linked with glutaraldehyde. The cross-linking efficiency was affected by the type of albumin conjugate used. The zeta potential of the surface-modified nanospheres was significantly lower than that of unmodified particles. The existence of a hydrated steric barrier surrounding the nanospheres was confirmed by electrolyte- and pH-induced flocculation tests. The surface-modified nanospheres showed a reduced plasma protein adsorption on the particle surface compared with unmodified particles.

Adsorption↗
PubMed1997

Biodegradable polymeric microparticles for drug delivery and vaccine formulation: the surface attachment of hydrophilic species using the concept of poly(ethylene glycol) anchoring segments.

Poly(ethylene glycol)-dextran (PEG-DEX) conjugates have been used as a combined stabilizer and surface modifier to produce resorbable poly(DL-lactide-co-glycolide) (PLG) microparticles by an emulsification/solvent evaporation technique. The use of PEG or dextran polymers alone was incapable of producing microparticles. Particle size measurements revealed smaller mean particle sizes (480 nm) and improved polydispersity when using a 1.2% PEG substituted conjugate relative to a 9% substituted material (680 nm). PLG microparticles modified by post-adsorbed PEG-DEX conjugates flocculated in 0.01 M salt solutions, whereas PLG microparticles prepared using PEG-DEX as a surfactant were stable in at least 0.5 M NaCl solutions. Surface modification of PLG microparticles was confirmed by zeta potential measurements and surface analysis using X-ray photoelectron spectroscopy. The presence of surface exposed dextran was confirmed by an immunological detection method using a dextran-specific antiserum in an enzyme-linked immunosorbent assay. The findings support a model in which the PEG component of the PEG-DEX conjugate provides an anchor to the microparticle surface while the dextran component extends from the particle surface to contribute a steric stabilization function. This approach offers opportunities for attaching hydrophilic species such as targeting moieties to biodegradable microparticles to improve the interaction of drug carriers and vaccines with specific tissue sites.

Biocompatible Materials↗
PubMed1997

Long circulating biodegradable poly(phosphazene) nanoparticles surface modified with poly(phosphazene)-poly(ethylene oxide) copolymer.

The biodistribution of biodegradable poly(organo phosphazene) nanoparticles surface modified by adsorption of a novel poly(organo phosphazene)-poly(ethylene oxide) copolymer with a 5000 M(W) PEO chain (PF-PEO[5000]), following intravenous administration in rats and rabbits, is described. The data are compared to the biodistribution of poly(organo phosphazene) and poly(lactide-co-glycolide) nanoparticles coated with a tetrafunctional copolymer of poly(ethylene oxide)-poly(propylene oxide) ethylenediamine, commercially available as Poloxamine 908. This copolymer has a PEO chain of the same size as the poly(organo phosphazene)-PEO derivative used. The results in the rat model reveal that poly(organo phosphazene) nanoparticles with a Poloxamine 908 coating were mainly captured by the liver, although a retardation in clearance from the systemic circulation was seen. In contrast, the poly(organo phosphazene) nanoparticles coated with PF-PEO(5000) showed a prolonged blood circulating profile, with only a small amount of the nanoparticles sequestered by the liver. This indicates the importance of the nature of both the anchoring group and the particle surface on the biological performances of the system. Study of the biodistribution of the PF-PEO(5000)-coated poly(organo phosphazene) nanoparticles in the rabbit model also indicated a prolonged systemic circulation lifetime and reduced liver uptake, whereby a significant amount of the administered nanoparticles was targeted to the bone marrow.

Animals↗
PubMed1997

Biomedical applications of nanotechnology--implications for drug targeting and gene therapy.

Colloidal particles in the nanometre size range (less than 1 micron in diameter) can be engineered to provide opportunities for the site-specific delivery of drugs after injection into the general circulation or lymphatic systems. Targets include the liver (both Kupffer cells and hepatocytes), endothelial cells, sites of inflammation and lymph nodes. The size and surface of the particle are crucial factors in targeting, and the attachment of cell-specific ligands can lead to increased selectivity. The applications of such particle engineering are discussed in relation to conventional drugs as well as the emerging area of gene therapy.

Animals↗
PubMed1997

The immune response to a model antigen associated with PLG microparticles prepared using different surfactants.

The effect of different surfactants on the surface characteristics of poly(D,L-lactideco-glycolide) microparticles prepared by the emulsification/solvent evaporation technique was investigated and the immune response to a protein antigen (OVA) associated with these microparticles was measured. Three surfactants--polyvinyl alcohol (PVA, a conventional stabilizer of PLG microparticles), the non-ionic surfactant, poly(oxyethylene glycerol mono-oleate) [Tagat] and Bile salts (a natural emulsifer)--were used to produce OVA-loaded PLG microparticles. Antigen was detected at the surface of all three types of OVA-loaded microparticles, in amounts in excess of 40% of the total protein load. The levels of specific serum IgG antibody elicited to OVA were significantly higher (P < 0.05) after a single subcutaneous administration of antigen associated with the Bile salts and Tagat formulations compared to the PVA formulation. A strong correlation was revealed between the levels of antibody measured and the magnitude of negative surface charge of the particulate carrier. The pattern of the IgG antibody response to OVA was similar in all three cases, indicating that the degradation rate of the PLG polymer determined the duration of the response. The results demonstrate the potential of using different surfactants to produce PLG microparticles with increased adjuvant activity.

Animals↗
PubMed1997

Spreading and retention of vaginal formulations in post-menopausal women as assessed by gamma scintigraphy.

PURPOSE: In this paper we report on the first scintigraphic evaluation of vaginal dosage forms in post-menopausal women. To date, almost nothing is known about the in vivo performance of pharmaceutical formulations in the human vagina, which is a major deficiency in the rational design of drug delivery systems for both existing and new indications. METHODS: The vaginal spreading and clearance of a radiolabelled pessary formulation and Replens (polycarbophil) gel, was assessed in six healthy, post-menopausal female volunteers over a six hour period using the technique of gamma scintigraphy. RESULTS: In five out of the six subjects studied, clearance of the two formulations exhibited very little intra-subject variation. However, there was considerable inter-subject variability in clearance; in Subject 5 circa 80% of the products were retained whilst in Subject 2 less than 2% was present at the end of the six hour imaging period. Importantly, there was no evidence to suggest that either of the formulations dispersed material beyond the cervix, into the uterus, in any of the subjects studied. CONCLUSIONS: The lack of significant retention of these products in most of the volunteers has obvious implications for the delivery of therapeutic agents. This study shows that gamma scintigraphy is an invaluable technique with which to assess novel formulations aimed at optimising retention in the vagina for topical or systemic drug delivery.

Administration, Intravaginal↗
PubMed1997

Preparation of biodegradable, surface engineered PLGA nanospheres with enhanced lymphatic drainage and lymph node uptake.

PURPOSE: Nanospheres can be utilised for the targeting of drugs and diagnostic agents to the regional lymph nodes. The surface modification of model polystyrene, (PS), and poly(lactide-co-glycolide),(PLGA), nanospheres by poly(lactide)-poly(ethylene glycol), (PLA:PEG), copolymers has been assessed by in vitro characterisation and in vivo biodistribution studies following subcutaneous administration of the nanospheres to the rat. METHODS: Three PLA:PEG copolymers were investigated, with PEG chain lengths of 750, 2000 and 5000 Da. The PLA:PEG copolymers were either coated onto the surface of PS and PLGA nanospheres or used as a co-precipitate in the formation of PLGA-PLA:PEG nanospheres. Coating of the nanospheres was confirmed by an increase in their particle size and a corresponding decrease in the surface potential. The kinetics of injection site drainage and lymph node retention was determined over a 24 hour time course for naked, coated and co-precipitated nanosphere systems. RESULTS: Dependent on the surface characteristics, the distribution of the nanospheres can be significantly modified and the lymph node localisation dramatically enhanced by coating their surfaces with PLA:PEG copolymers or by producing co-precipitate nanospheres of PLGA and PLA:PEG. CONCLUSIONS: A fully biodegradable nanosphere system has been developed with excellent lymph node targeting characteristics.

Animals↗
PubMed1997

Activation of the mononuclear phagocyte system by poloxamine 908: its implications for targeted drug delivery.

PURPOSE: To investigate the effect of poloxamine 908 on the MPS activity and the importance of its mode of presentation to the immune system. METHODS: Solutions of endotoxin free poloxamine 908 were injected daily intravenously to rats, and the effect on the degree of sequestration by the liver of I125 labelled, poloxamine 908-coated 60 nm polystyrene particles was investigated by studying effect of dosing regimen(s) and assessment of opsonic activity. RESULTS: After 3 or 4 days repeated dosing with poloxamine 908 (0.7 mg) in solution, the poloxamine 908-coated polystyrene particles (60 nm) were rapidly cleared from the circulation. The increase sequestration of the particles by the liver lasted for more than 7 days after last dosing with the poloxamine 908 solution. In subsequent studies, it was found that a single dose of poloxamine 908 (0.7 mg) in solution was sufficient to activate the MPS 4 days after the injection. The increased uptake was found not be mediated by a serum component, nor was it due to proliferation of the Kupffer cells in the liver. CONCLUSIONS: The results provide evidence that a solution of endotoxin-free poloxamine 908 activates the MPS so that 4 days after injection otherwise long-term circulating poloxamine 908-coated particles are sequestered by the liver. This finding has implications for use of such coated systems in therapeutic situations.

Animals↗
PubMed1996

Nasal administration of morphine-6-glucuronide in sheep--a pharmacokinetic study.

The pharmacokinetics of morphine-6-glucuronide (M6G) after both intravenous dosing and nasal administration were studied in sheep. The nasal formulation consisted of M6G in combination with an absorption promoting delivery system in the form of chitosan. The mean half-life of M6G after intravenous administration was 51.0 +/- 8.2 min and that after intranasal dosing was 45.0 +/- 5.5 min. M6G clearance and volume of distribution were 5.4 +/- 1.5 mL min-1 kg-1 and 0.4 +/- 0.1 L kg-1 respectively. The plasma profile after nasal administration demonstrated rapid absorption of M6G. The bioavailability of M6G in the chitosan formulation was found to be 31.4%. These results suggest that M6G administered in combination with the chitosan delivery system may be considered as a suitable non-parenteral means of administering this analgesic.

Absorption↗