Biomedical subjects

A T Florence

Publications and source records attributed to A T Florence.

At least 73 records · Page 4Linked to original sources

PubMed1989

The effect of hydrotropic agents on the heat coagulation of bovine serum albumin.

The effect of two hydrotrophic solubilizers on the heat coagulation of bovine serum albumin (BSA) has been investigated. Photon correlation spectroscopy indicated possible unfolding of BSA molecules in solutions of sodium benzoate and sodium salicylate at 25 degrees C. The effect of these hydrotropes on the heat coagulation of BSA was concentration-dependent. Relatively low concentrations stabilized the protein structure as indicated by the increase in the transition temperature(Tm) and induced gelation at temperatures and BSA concentrations lower than those required in the absence of hydrotropes. Higher concentrations of the hydrotropes considerably reduced Tm and inhibited gelation of BSA, the effect of sodium salicylate being more pronounced, as was the lower aggregation rate of BSA. The behaviour of these hydrotropes as protein denaturants differs from that of neutral electrolytes but is similar to that of concentrated solutions of urea.

Benzoates↗

PubMed1989

Biodegradation rate of embolized protein microspheres in lung, liver and kidney of rats.

The targeting and sustained release characteristics of cytotoxic drug-loaded protein microspheres may prove useful in the therapeutic chemoembolization of solid tumours. Because biodegradation rate of embolized particles will influence rate of incorporated drug release and duration of exposure, this parameter was studied for microspheres (10-30 microns mean diam.) prepared from the proteins albumin and casein, that we have previously used as carriers for doxorubicin. As a measure of microsphere loss in-vivo the radionuclide 125I was chosen because it can be covalently bound to proteins and also homogeneously distributed throughout the matrix. Radiolabelled microspheres were administered to rats both intravenously (lung as target organ, 1.4-2.2 mg/100 g) and via the hepatic artery (liver as target organ, 0.4-0.8 mg/100 g). In both cases it was observed that the casein system biodegraded more slowly than the albumin in-vivo. Thus, time taken for loss of 50% of embolized microspheres from lung was: albumin 2.0 days; casein 3.5 days and from liver:albumin 3.6 days; casein 6.8 days. Microsphere "debris" did not markedly accumulate in other organs. In-vitro experiments showed that microspheres were stable in serum and that albumin microspheres were not innately more sensitive to enzymic digestion than casein. The results may be useful in estimating duration of exposure of target organs to drug-loaded microsphere systems prepared from these proteins.

Animals↗

PubMed1988

Antitumour activity and pharmacokinetics of niosome encapsulated adriamycin in monolayer, spheroid and xenograft.

Niosomes are multilamellar vesicles formed from nonionic surfactants of the alkyl or dialkyl polyglycerol ether class and cholesterol. Adriamycin has been trapped within vesicles prepared from a monoalkyl triglycerol ether and its activity compared with adriamycin solution in human lung tumour cells grown in monolayer and spheroid culture and in tumour xenografted nude mice. The activity of the encapsulated adriamycin in vitro is maintained with similar clonogenic survival curves following treatment of monolayers and identical growth delays following spheroid exposure. The pharmacokinetics of adriamycin are altered in vivo in human lung tumour-bearing nude mice, when it is administered in niosomal form. There is prolonged release of drug from the plasma compartment with significantly lower peak levels; lower peak cardiac adriamycin concentrations with a shorter tissue half-life and decreased cardiac AUC and a greater degree of hepatic metabolism to inactive 7-deoxyaglycones. The tumour peak drug level and AUC was similar irrespective of the mode of administration of adriamycin. The growth delay (i.e. the time taken for the tumour volume to double) was significantly longer for adriamycin (15 days) and niosomal adriamycin (11 days) than for control (5.8 days). It is possible that the therapeutic ratio of adriamycin could be enhanced by administration in niosomal form.

Animals↗

PubMed1988

The distribution of doxorubicin in mice following administration in niosomes.

Large multilamellar non-ionic surfactant vesicles (niosomes) with diameters of around 800-900 nm prepared from a C16 triglyceryl ether with and without cholesterol and containing doxorubicin (Adriamycin) were administered to S180 tumour-bearing NMRI mice by bolus injection. Although in-vitro drug release from cholesterol-containing niosomes is delayed, in-vivo there was little difference between the two preparations when plasma levels were compared. As previously observed, half-lives of the drug were prolonged compared with free solution profiles. Liver uptake was not significantly affected by niosome encapsulation of doxorubicin. There is minor accumulation of drug in the lung, perhaps because of aggregation of the vesicles and their physical entrapment. Tumour levels of drug were higher following administration of cholesterol-containing niosomes and this was reflected in the more effective reduction in tumour growth. Metabolism of doxorubicin is altered by niosomal administration, but more studies are required before the significance of the metabolic data can be assessed.

Animals↗

PubMed1987

The effect of the non-ionic surfactant Brij 30 on the cytotoxicity of adriamycin in monolayer, spheroid and clonogenic culture systems.

The effects of a non-ionic polyoxyethylated lauryl ether surfactant (Brij 30) on monolayer uptake and spheroid penetration of adriamycin have been studied. Co-incubation of adriamycin with Brij 30 increases intracellular adriamycin levels by 2-3-fold. Although, in the concentrations used, Brij 30 alone is not cytotoxic, adriamycin and Brij 30 mixtures are significantly more cytotoxic (monolayer ID90 = 0.6 microgram/ml; disaggregated spheroid ID50 = 1.9 micrograms/ml) and induce significantly longer spheroid growth delay than adriamycin alone (monolayer ID90 = 2.1 micrograms/ml; disaggregated spheroid ID50 = 3.3 micrograms/ml). Adriamycin is equally cytotoxic to mouse normal granulocytes and chronic myeloid leukaemic (M1 cell line) cells in agar clonogenic cultures. The addition of Brij 30 appears to enhance preferentially the activity of adriamycin against these tumour cells relative to the normal granulocytes.

Animals↗

PubMed1987

Characterization of in-vitro drug release and biological activity of methotrexate-bovine serum albumin conjugates.

Two series of methotrexate (MTX)-bovine serum albumin (BSA) conjugates have been prepared containing either 96 +/- 16 mg (mean +/- s.d.) or 32 +/- 13 mg of MTX per gram of conjugate. The conjugates released MTX in-vitro in a biphasic manner, the release rate being dependent on the quantity of MTX in the conjugate and on the pH of the release medium. An initial rapid release over 6 h appears to be due to physically adsorbed MTX with the slower secondary release due to covalently bound drug. The conjugates retain a degree of antineoplastic activity in-vitro, but this might be related to the small fraction of MTX that is tightly physically bound.

Animals↗

PubMed1987

Comparison of albumin and casein microspheres as a carrier for doxorubicin.

Doxorubicin (Adriamycin)-loaded casein and albumin microspheres, with diameters between 14 and 38 micron (50% weight average) were prepared by glutaraldehyde stabilization of the aqueous phase (containing protein and drug) of a water in oil emulsion. Physical properties, drug loading characteristics and release rates from microspheres in-vitro have been compared and correlated with effects on tumour growth when injected intratumourally in rats. Compared with albumin, the surface charge of the casein system was more negative and the microspheres exhibited a slower release of drug in-vitro. Both observations could be explained by the lower drug content of the casein system. There was evidence for the formation of a doxorubicin complex in the microspheres, the significance of which is not yet known. Casein microspheres containing 11 micrograms of doxorubicin had a similar inhibitory effect on tumour growth (growth delay = 20.7 days) to 85 micrograms of drug incorporated into albumin microspheres (growth delay = 18.6 days). The absence of a simple dose-response relationship shows that carrier matrix can influence potency of incorporated drug. The results are consistent with release rate of the drug from microspheres (obversely, rate of drug delivery to the tumour), being a determinant of potency in these systems.

Albumins↗

PubMed1986

Skin reflectance measurements of patch test responses.

Skin reflectance values were used as an objective measure of skin haemoglobin content at patch test sites to facilitate quantification of the erythematous response to contact allergens in patients with allergic contact dermatitis. Reflectance measurements of patch test responses correlated well with the clinical scoring and provided a numerical measure of reaction severity. Experimental contact allergen formulations were also evaluated by this method.

Color↗

PubMed1986

The nature of the oil phase and the release of solutes from multiple (w/o/w) emulsions.

The effect of the nature of the oil phase of w/o/w emulsions stabilized by interfacial complexation between span 80 (sorbitan mono-oleate) and albumin has been studied. The long-term stability of the systems has been assessed by photomicrography and by measuring the quantity of an internal marker (NaCl) remaining entrapped with time. The number of multiple oil drops and the diameters of the internal aqueous droplets were determined over 6 weeks, and the amounts of NaCl entrapped over the same period were followed. There were no significant changes in w/o/w emulsions prepared with a range of hydrocarbons (octane, dodecane, hexadecane, toluene and cyclohexane), indicating stable multiple emulsions. The release of NaCl and 5-fluorouracil (5-FU) separately entrapped in the internal aqueous phase of w/o/w emulsions was measured. Diffusion of the un-ionized species of 5-FU across the oil phase or through localized thin oil lamellae is the primary transport mechanism. In the presence of surface active agents, water is solubilized in inverse micelles which would possess the ability to solubilize other water-soluble components, such as NaCl and 5-FU. The mixed inverse micellar units of Span 80 and polysorbate (Tween) 80 therefore act as solute carriers across the liquid hydrocarbon membrane separating the two aqueous phases of the emulsions. The main factor in determining the differences in rates of release from the hydrocarbon emulsions appears to be the droplet size of the internal aqueous phase.

Chemical Phenomena↗

PubMed1985

The distribution and elimination of methotrexate in mouse blood and brain after concurrent administration of polysorbate 80.

This paper describes further exploration of the effect of polysorbate 80 on the absorption, distribution, and elimination of methotrexate (MTX). This study has confirmed the earlier finding that polysorbate 80 could increase the absorption of MTX from the mouse gastrointestinal tract and enhance the drugs uptake into the brain. The experiments reported here suggest that polysorbate 80 has a direct effect on the blood-brain barrier leading to the increased uptake of MTX, which is evident following IV administration. Measurements of MTX excreted in the urine and faeces confirmed the role of polysorbate 80 in facilitating the excretion of MTX into the bile and urine. Polysorbate 80 administered PO did not cause any reduction of plasma volume, thus excluding the possibility that the higher MTX concentrations measured in mice after concurrent administration of polysorbate PO might result from a reduction in blood volume due to osmotic effects. At the doses given, polysorbate 80 appeared not to have a damaging effect on the gastrointestinal mucosa.

Animals↗

PubMed1985

A low density lipoprotein-methotrexate covalent complex and its activity against L1210 cells in vitro.

Low-density lipoprotein particles are potential drug carriers, but only lipophilic drug species partition into the core of the system. In this paper the polar drug methotrexate has been coupled to the exterior protein of low density lipoprotein (LDL) particles using the reagent 1-ethyl-3(3'-dimethylaminopropyl) carbodiimide HCl. The coupled system was sized by photon correlation spectroscopy and the in vitro activity of the complex determined against L1210 cells maintained in medium supplemented with fetal calf serum. The reaction between methotrexate and low density lipoprotein is variable but quantifiable, about ten drug molecules being attached to each LDL particle, resulting in an increase in the radius and polydispersity of the particles. The activity of the complex against L1210 murine leukaemia cells has been demonstrated in vitro, but it is 30 times less active than free drug.

Animals↗

PubMed1985

Patch testing for nickel allergy. The influence of the vehicle on the response rate to topical nickel sulphate.

A group of 43 patients with a clinical history of nickel allergy who exhibited an equivocal or no allergic reaction to a patch test at 48 h were further challenged using several different formulations of nickel sulphate. This experimental test battery comprised aqueous, dimethyl sulphoxide (DMSO) and propylene glycol (PG) solutions of nickel sulphate, and nickel sulphate incorporated into cetomacrogol cream and yellow soft paraffin (PMF). Although some of these vehicles were irritant, a formulation-dependent test response was observed, such that in terms of the number of responses per unit weight of nickel sulphate applied to the skin, the vehicles could be ranked: DMSO greater than PG greater than aqueous solution greater than cetomacrogol cream greater than PMF preparations. This ranking could be correlated with the relative ease with which nickel sulphate could be dialysed from each vehicle in vitro. This study demonstrates that for nickel sulphate, the vehicle can influence the outcome of patch testing apparently by modifying the quantity of nickel released into the skin for elicitation of the allergic response.

Dermatitis, Atopic↗

PubMed1985

The preparation and properties of niosomes--non-ionic surfactant vesicles.

Vesicles were prepared on hydration of a mixture of a single or double alkyl-chain, non-ionic surfactant with cholesterol. These vesicles, or 'niosomes', are capable of entrapping and retaining water soluble solutes such as carboxyfluorescein, are osmotically active and can be formulated to release entrapped solute slowly. The physical characteristics of the vesicles were found to be dependent on the method of production and three such methods, based on liposome technology, are described. The vesicles have been characterized by photon correlation spectroscopy, freeze fracture electron micrography, measurement of solute entrapment efficiency, and solute release rates. Vesicular forms of the single chain surfactant which could be formed under certain conditions in the absence of cholesterol are also described.

Buffers↗

PubMed1985

The effect of non-ionic surfactant vesicle (niosome) entrapment on the absorption and distribution of methotrexate in mice.

Non-ionic surfactant vesicles (niosomes) prepared from a non-ionic surfactant, cholesterol and dicetyl phosphate and containing methotrexate (MTX) have been administered to mice. Given intravenously the niosomes prolong the levels of MTX in the blood, large amounts of the drug being taken up by the liver. There was also an increased uptake of MTX into the brain, perhaps due to an effect of the niosome components on the permeability of the blood brain barrier. Absorption of the drug from the gastrointestinal tract following oral ingestion, appeared to be increased at some doses; most of the entrapped MTX was taken up by the liver, but uptake of MTX into the brain was also increased. The metabolic profile of the drug is altered by the niosomes which appear to prevent the rapid formation of 7-hydroxy methotrexate.

Administration, Oral↗

PubMed1983

Interactions of ionic and non-ionic surfactants with plasma low density lipoprotein.

Surfactants might be useful in facilitating the replacement of the interior of low density lipoprotein (LDL2) (p = 1.02-1.063 g ml-1) with drug molecules. We have used photon correlation spectroscopy, supported by sedimentation velocity measurements to study the effects of surfactants on LDL2. Sodium dodecyl sulphate, cetrimide, and all non-ionic surfactants studied caused rapid increases of ca 50% in the Stokes' radius up to surfactant/LDL2 molar ratios of ca 1000:1. This was interpreted as due to partial unfolding of the LDL2 protein and intercalation of surfactant with the LDL2 surface layer. At higher concentrations, ionic surfactants and non-ionics with HLB values less than 14.6 decreased the Stokes' radius due to delipidation of LDL2. These interactions are similar to those between surfactants and biological membranes, thus LDL2 might be a useful model system to study surfactant structure-activity relationships.

Adult↗

PubMed1982

Effects of polysorbate 80 on the absorption and distribution of oral methotrexate (MTX) in mice.

This study is part of a programme of work aimed at improving the bioavailability of oral methotrexate (MTX). In preliminary experiments no significant effect of non-ionic surfactant polysorbate 80 (Tween 80) on absorption of 0.5 mg MTX X kg-1 in NMRI mice was observed except when the drug was given together with 6% polysorbate 80 in solution. Absorption from a higher dose of 3 mg MTX X kg-1 was increased when the drug was administered with 2% or 6% polysorbate 80. Plasma MTX measurements confirmed the significantly higher levels of MTX with 6% polysorbate 80 PO. In subsequent experiments, when Porton mice were used and 4 mg MTX X kg-1 was administered PO, higher plasma and brain levels of MTX were measured in animals given the drug with 6% polysorbate 80, suggesting the enhancement of MTX uptake by this non-ionic surfactant. Although the amount of MTX in the liver and kidney of mice given MTX with polysorbate 80 were not significantly different from the amounts in mice given MTX alone, the lower observed levels suggested that polysorbate 80 perhaps facilitates the elimination of the drug from these organs. The amount of plasma MTX in mice measured 1 h after oral administration of various MTX doses in the presence of 6% polysorbate 80 were significantly higher than the levels in mice given the drug without surfactant, but the significantly higher amounts of MTX in the brain were only observed following the doses of 2 and 6 mg MTX X kg-1.

Administration, Oral↗

PubMed1982

Medication problems of rheumatic patients assessed by domicillary visits by pharmacists.

A pilot scheme of domicillary visits to thirty-three rheumatic patients attending either a specialized clinic or general practitioners was undertaken. Patients' understanding of their therapy and compliance with prescribed regimens was assessed, and a comparison made between specialized medical records and actual medications found in the home. A number of cases are discussed in detail to highlight some of the problems uncovered. It is suggested that the visits by pharmacists were sufficiently useful to extend the scheme.

Arthritis, Rheumatoid↗

PubMed1982

Stabilization of water/oil/water multiple emulsions by polymerization of the aqueous phases.

In order to improve the stability of w/o/w multiple emulsions which have isopropyl myristate as the non-aqueous 'oil' phase, either the internal aqueous phase of the multiple system or the secondary (outer or continuous) aqueous phase can be gelled. Production, by gamma-irradiation, or cross-linked polyacrylamide or poloxamer gels in the aqueous phases of the emulsions leads to systems which have a greater intrinsic stability than untreated multiple emulsions. If the internal aqueous phase is gelled this prevents coalescence. When the continuous outer phase is gelled an opaque emulsion is produced in which the disperse w/o droplets are held in a hydrophilic polymer network from which the droplets are released on contact with water.

Chemical Phenomena↗