Biomedical subjects

D Attwood

Publications and source records attributed to D Attwood.

At least 19 recordsLinked to original sources

PubMed2003

The influence of surface modification on the cytotoxicity of PAMAM dendrimers.

The influence of surface modification on the cytotoxicity of PAMAM dendrimers was examined using Caco-2 cells. Dendrimers were modified by conjugating either lauroyl chains or polyethylene glycol (PEG) 2000 onto the surface of cationic PAMAM dendrimers (G2, G3, G4). The cytotoxicity of unmodified dendrimers towards Caco-2 cells was appreciably higher for cationic (whole generation) compared with anionic (half generation) dendrimers and for both types increased with increasing size (generation) and concentration. A marked decrease in the cytotoxicity of cationic PAMAM dendrimers was noted when the surface was modified, with the addition of six lauroyl or four PEG chains being particularly effective in decreasing cytotoxicity. This decrease in cytotoxicity is thought to be due to a reduction/shielding of the positive charge on the dendrimer surface by the attached chains. The cytotoxicity of dendrimer-based delivery systems is likely to be very different from the parent dendrimer.

Caco-2 Cells↗

PubMed2002

Percutaneous absorption of non-steroidal anti-inflammatory drugs from in situ gelling xyloglucan formulations in rats.

The potential of gels formed in situ by dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed as sustained release vehicles for percutaneous administration of non-steroidal anti-inflammatory drugs has been assessed by in vitro and in vivo studies. Chilled aqueous solutions of xyloglucan that had been partially degraded by beta-galactosidase formed gels at concentrations of 1-2% w/w when warmed to 37 degrees C. The in vitro release of ibuprofen and ketoprofen at pH 7.4 from the enzyme degraded xyloglucan gels and the subsequent permeation of these fully ionized drugs through cellulose membranes followed root-time kinetics over a period of 12 h after an initial lag period. Diffusion coefficients were appreciably higher when the drugs were released from 1.5% w/w xyloglucan gels than when released from 25% w/w Pluronic F127 gels formed in situ under identical conditions. The difference in release rates was attributed to differences in the structure of the gels. The permeation rate of ibuprofen through excised skin was higher than that of ketoprofen when released from both gels, but of similar magnitude through cellulose membranes. Plasma concentrations of ibuprofen and ketoprofen from gels formed in situ following topical application of chilled aqueous solutions of xyloglucan and Pluronic F127 to the abdominal skin of rats were compared. The bioavailabilities of ibuprofen and ketoprofen were significantly higher when released from xyloglucan gels compared to Pluronic F127 gels. Occlusive dressing techniques had a greater enhancing effect on the bioavailability of ibuprofen when released from Pluronic gels.

Administration, Cutaneous↗

PubMed2002

Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayers and everted gut sacs.

This study explores the potential of the monoglyceride monocaprin as an enhancer of the epithelial permeability of the beta(3)-adrenoceptor agonist BTA-243, as an approach to improving the bioavailability of this drug. The permeabilities of BTA-243 and mannitol (paracellular marker) in Caco-2 cell monolayer and everted gut sac models in aqueous buffer (pH 6.8) in the presence of 1.3 and 2.0 mM monocaprin were compared with control (monocaprin-free) solutions over a period of 1 h. The transepithelial electrical resistance (TEER) of the Caco-2 cell monolayers was measured at regular time intervals throughout the experiment and after a recovery period of 30 h. Toxicological damage to the biological models associated with exposure to monocaprin was assessed by scanning electron microscopy and by the measurement of lactate dehydrogenase (LDH) release from everted gut sacs. The permeability of BTA-243 in epithelial monolayers was enhanced in the presence of 1.3 and 2.0 mM monocaprin. Measurements of TEER and mannitol permeability showed partial recovery of barrier properties after a 30 h period following exposure to 1.3 mM monocaprin. No structural damage was evident in these monolayers. Enhancement of Caco-2 permeability to BTA-243 by 2.0 mM monocaprin was significantly greater than by 1.3 mM but was irreversible; monolayers failed to recover their barrier properties after 30 h and changes in their gross morphology were observed. The mucosal to serosal transfer of BTA-243 in everted gut sac was enhanced but to a lesser extent than in the Caco-2 model. LDH release from everted gut sacs exposed to monocaprin was significantly less than that after exposure to Triton X-100, a nonionic surfactant known to cause membrane disruption.

Animals↗

PubMed2002

Do triglycerides modulate the effectiveness of clozapine?

We describe a case in which a patient's clinical response to clozapine appears to correlate positively with his serum triglyceride concentrations. We propose that the observed clinical response may partly be the result of the physical interaction of clozapine with the very low-density lipoproteins. We base this supposition on our previous in-vitro study showing that the plasma distribution of clozapine is significantly altered by increases in plasma triglyceride concentrations. Although this case only represents one patient, it highlights the possibility that serum lipids may be potential contributors to the clinical effectiveness of clozapine.

Adult↗

PubMed2001

In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride.

Thermoreversible gels formed in situ by aqueous solutions of an enzyme-degraded xyloglucan polysaccharide were evaluated as sustained release vehicles for the ocular delivery of pilocarpine hydrochloride. In vitro release of pilocarpine from gels formed by warming xyloglucan sols (1.0, 1.5 and 2.0% w/w) to 34 degrees C followed root-time kinetics over a period of 6 h. The miotic responses in rabbit following administration of xyloglucan sols were compared with those from in situ gelling Pluronic F127 sols and from an aqueous buffer solution containing the same drug concentration. Sustained release of pilocarpine was observed with all gels, the duration of miotic response increasing with increase of xyloglucan concentration. The degree of enhancement of miotic response following sustained release of pilocarpine from the 1.5% w/w xyloglucan gel was similar to that from a 25% w/w Pluronic F127 gel.

Animals↗

PubMed2001

Adsorption of an amphiphilic penicillin onto human serum albumin: characterisation of the complex.

The complex formed by the interaction of the amphiphilic penicillin drug nafcillin and human serum albumin (HSA) in water at 25 degrees C has been characterised using a range of physicochemical techniques. Measurements of the solution conductivity and the electrophoretic mobility of the complexes have shown an ionic adsorption of the drug on the protein surface leading to a surface saturation at a nafcillin concentration of 0.012 mmol kg(-1) and subsequent formation of drug micelles in solutions of higher nafcillin concentration. Measurements of the size of the complex and the thickness of the adsorbed layer by static and dynamic light scattering have shown a gradual change in hydrodynamic radius of the complex with increasing drug concentration typical of a saturation rather than a denaturation process, the magnitude of the change being insufficient to account for any appreciable extension or unfolding of the HSA molecule. The interaction potential between the HSA/nafcillin complexes, and the stability of the complexes were determined from the dependence of diffusion coefficients on protein concentration by application of the DLVO colloidal stability theory. The results indicate decreasing stability of the colloidal dispersion of the drug/protein complexes with an increase in the concentration of added drug.

Adsorption↗

PubMed2001

Comparison of in situ gelling formulations for the oral delivery of cimetidine.

Three liquid formulations with in situ gelling properties have been assessed for their potential for the oral delivery of cimetidine. The formulations were dilute solutions of: (a) enzyme-degraded xyloglucan, which form thermally reversible gels on warming to body temperature; (b) gellan gum and; (c) sodium alginate both containing complexed calcium ions that form gels when these ions are released in the acidic environment of the stomach. The in vitro release of cimetidine from gels of each of the compounds followed root-time kinetics over a period of 6 h. Plasma levels of cimetidine after oral administration to rabbits of each of the formulations were compared with those resulting from administration of a commercial cimetidine/alginate suspension with an identical drug loading. In vivo release characteristics of each of the in situ gelling formulations were similar to those of the commercial preparation.

Absorption↗

PubMed2001

Magnetic domains in nanostructured media studied with M-TXM.

Combining X-ray magnetic circular dichroism (X-MCD) with a transmission X-ray microscope (TXM) allows to image element-specifically magnetic domain structures with 25nm lateral resolution. Both in-plane and out-of-plane systems can be studied in applied magnetic fields. Thus field-dependent parameters, as individual nucleation fields in magnetic nanostructures can be deduced and related to morphology. Images of thermomagnetically written bits in magneto-optical TbFeCo media proof the reliability of the writing process and the importance of an exact thermal design of the systems. Domains observed at corresponding Co L edges proof the chemical sensitivity of M-TXM and its potential to image few monolayer systems.

Journal Article↗

PubMed2001

Physicochemical and biopharmaceutical characterization of BTA-243, a diacidic drug with low oral bioavailability.

This investigation has examined possible causes of the poor bioavailability of the beta(3)-adrenoceptor agonist BTA-243. The aqueous solubility of BTA-243 is pH dependent with a solubility minimum at pH 1.5. However, the dissolution rate of the disodium salt of BTA-243 is similar at both pH 2.0 and 7.4 indicating that dissolution rate is unlikely to be the controlling factor in the absorption of BTA-243. The apparent permeability coefficient of BTA-243 across Caco-2 monolayers at pH 6 was lower than that of mannitol and therefore the epithelial permeability of the molecule in vivo is predicted to be very low and potentially bioavailability limiting. Apparent permeability coefficients were not dependent on BTA-243 concentration over the concentration range 0.5 to 12 mM, indicating that epithelial transport is unlikely to occur via a saturable mechanism. They were of similar magnitude in both directions across the monolayers, indicative of no significant effluxing of BTA-243 by components of the cell membrane. Apparent octanol/water distribution coefficients increased with decrease of pH between 2 and 6; the relatively low values at pH 4 and 6 suggest that the limited intestinal absorption predicted in vivo will occur predominantly via paracellular passive diffusion. Everted gut sac experiments performed at pH 2.0 and 6.8 suggest that at pH 2.0 a significant proportion of the BTA-243 transport occurs via the transcellular route confirming that the ionization state of the BTA-243 molecule influences the route and rate of epithelial permeability.

Adrenergic beta-Agonists↗

PubMed2001

Physicochemical consequences of the perdeuteriation of glutathione S-transferase from S. japonicum.

Glutathione S:-transferase (GST) from Schistosoma japonicum has been prepared in both normal protiated (pGST) and fully deuteriated (dGST) form by recombinant DNA technology. Electrospray mass spectrometry showed that the level of deuteriation in dGST was 96% and was homogeneous across the sample. This result is attributed to the use of a deuterium-tolerant host Escherichia coli strain in the preparation of the protein. 10 heteroatom-bound deuteriums (in addition to the carbon-bound deuteriums) were resistant to exchange when dGST was incubated in protiated buffer. The physicochemical and biological properties of the two proteins were compared. dGST was relatively less stable to heat denaturation and to proteolytic cleavage than was pGST. The midpoint transition temperature for pGST was 54.9 degrees C, whereas that for dGST was 51.0 degrees C. Static light-scattering measurements revealed that the association behavior of dGST is also different from that of pGST. The perdeuteriated enzyme shows a tendency to associate into dimers of the fundamental dimer. This is in contrast with results that have been obtained for other perdeuteriated proteins in which perdeuteriation has been shown to promote dissociation of aggregates. dGST showed a similar K(m) to pGST; similar results had been obtained previously with bacterial alkaline phosphatase. However, whereas the alkaline phosphatase showed a reduced rate of catalysis on deuteriation, dGST exhibited a slightly higher rate of catalysis than pGST. It is clear that the bulk substitution of deuterium for protium has significant effects on the properties of proteins. Until many more examples have been studied, it will be difficult to predict these effects for any given protein. Nevertheless, deuteriation represents an intriguing method of preparing functional analogs of recombinant proteins.

Animals↗

PubMed2001

Oral sustained delivery of theophylline from thermally reversible xyloglucan gels in rabbits.

Thermally reversible gels formed in-situ following the oral administration of dilute aqueous solutions of an enzyme-degraded xyloglucan to rabbits were evaluated as sustained-release vehicles for the delivery of theophylline. In-vitro release of theophylline from gels formed by warming xyloglucan sols (0.5, 1.0 and 1.5% w/w) to 37 degrees C followed root-time kinetics over a period of 4 h. Gels formed after oral administration to rabbits of chilled 1.5% w/w aqueous solutions of xyloglucan containing dissolved drug showed sustained-release characteristics with a maximum plasma concentration at 4.5 h. The theophylline bioavailability from a 1.5% w/w xyloglucan gel was 1.7-2.5 times that of commercial oral sustained-release liquid dosage forms containing an identical theophylline concentration. It was concluded that dilute solutions of the enzyme-degraded xyloglucan had suitable rheological properties and in-situ gelling characteristics for use as sustained-release vehicles for oral drug delivery. The in-vivo release characteristics of theophylline in a rabbit model suggested the potential for the use of these vehicles in humans for the oral delivery of this drug.

Administration, Oral↗

PubMed2000

Oral mucosal bioadhesive tablets of pectin and HPMC: in vitro and in vivo evaluation.

The potential of tablets containing 1:4, 1:1 and 4:1 weight ratios of pectin and hydroxypropyl methylcellulose (HPMC) for the sustained release of diltiazem by sublingual administration has been investigated. Measurements of maximum adhesive force to rat peritoneal membrane indicated a satisfactory bioadhesive strength. An in vitro sustained release of diltiazem over 5 h was achieved with bilayer tablets composed of a drug-free ethylcellulose layer in addition to the pectin/HPMC layer containing drug. Plasma concentration-time curves obtained following sublingual administration to rabbits of single and bilayer tablets with 1:1 weight ratios of pectin and HPMC showed evidence of sustained release of diltiazem. Bioavailability of diltiazem was 2.5 times that achieved by oral administration for single layer tablets and 1.8 times for the bilayered tablets.

Adhesives↗

PubMed2000

A Calorimetric Study of the Influence of Temperature on the Self-Association of Amphiphilic Antidepressant Drugs in Aqueous Solution.

Relative apparent molar enthalpies have been determined as a function of concentration (0.0001 to 0.2 mol kg(-1)) by heat conduction calorimetry for aqueous solutions of the structurally related antidepressant drugs imipramine and clomipramine in water over the temperature range 288 to 308 K. Critical concentrations determined from inflections in these plots for both drugs had minimum values at 298 K. The concentration dependence of the relative apparent molar enthalpy could be quantitatively described using a mass action model of association based on the Guggenheim equations for the activity coefficients of mixed electrolytes. Derived values of the monomer-counterion interaction coefficient for imipramine became increasingly negative with an increase in temperature over the temperature range 293 to 303 K, indicative of an increasing degree of premicellar association. In contrast, negative monomer-counterion interaction coefficients were obtained for clomipramine at only 303 and 308 K, suggesting an absence of premicellar association at lower temperatures. Values derived for the molar enthalpy of micellization of both drugs from the mass action model indicate an increasingly exothermic process with increase in temperature; positive values at 288 and 293 K arise from hydrophobic interactions while the negative values at higher temperatures suggest the importance of London dispersion interactions as the major driving force for aggregation. Copyright 2000 Academic Press.

Journal Article↗

PubMed2000

Oral sustained delivery of theophylline using in-situ gelation of sodium alginate.

Gels formed in situ following oral administration of aqueous solutions of sodium alginate (1.0-2.0%w/v) to rats were evaluated as sustained release vehicles for the delivery of theophylline. The liquid formulation contained calcium ions in complexed form, the release of which in the acidic environment of the stomach caused gelation of the alginate. Bioavailability of theophylline from alginate gels formed by in situ gelation in the rat stomach was increased by 1.3-2-fold in rats for alginate concentrations of 2.0 to 1.0%w/v respectively compared with that from a proprietary oral sustained release formulation containing an identical drug concentration. There was no significant difference in the mean residence times of theophylline when administered by these two vehicles.

Administration, Oral↗

PubMed2000

Light Scattering Study of the Effect of n-Butanol on the Micellar Properties of Undecylammonium Chloride in Aqueous Electrolyte Solutions.

Light scattering measurements have been performed on aqueous solutions of undecylammonium chloride in the presence of 0 to 0.2 mol dm(-3) NaCl and 0 to 0.5 mol dm(-3) n-butanol at 25 degrees C. The critical micelle concentration (CMC), aggregation number, and degree of dissociation of the micelles have been determined. The observed decrease of the CMC with the increase of the n-butanol concentration was explained by the effect of the n-butanol on water structure and by the selective solvation of the micelles with n-butanol, which counteract the decrease of the polar character of the solvent caused by n-butanol addition. An observed increase in the degree of dissociation of the micelles and a decrease in the aggregation number following alcohol addition have been explained by considering the effect of this additive on the electrostatic and other interactions involved in free energy of micellization. Our results support the concept of opposing effects between n-butanol and NaCl on the cooperativity in the micellization process of this surfactant, with the n-butanol disfavoring micellar growth. Copyright 2000 Academic Press.

Journal Article↗

PubMed2000

Polyamidoamine Starburst dendrimers as solubility enhancers.

The solubility of the hydrophobic drug ibuprofen has been compared in an aqueous solution of polyamidoamine (PAMAM) G4 dendrimer and sodium dodecyl sulphate (SDS). The PAMAM G4 dendrimer solution significantly enhanced the solubility of ibuprofen compared to 2% SDS solution. It was found that the solubility of ibuprofen in dendrimer solution was directly proportional to dendrimer concentration and inversely proportional to temperature. The influence of dendrimer solution pH on the solubility enhancement of ibuprofen suggests that it involves an electrostatic interaction between the carboxyl group of the ibuprofen molecule and the amine groups of the dendrimer molecule.

Dendrimers↗

PubMed2000

Thermodynamics of Association of Structurally Related Amphiphilic Penicillins.

Critical micelle concentrations (CMCs) of the penicillins cloxacillin and dicloxacillin in water were determined by conductivity measurements over the temperature range 288.15 to 313.15 K. Both penicillins showed minimum CMCs at temperatures close to 298.15 K. Thermodynamic parameters of aggregate formation were derived from the variation of the CMC with temperature using a modified form of the mass action model applicable to systems of low aggregation number. Values for the enthalpy of aggregate formation, DeltaH(0)(m), calculated by this method showed that the aggregation of both cloxacillin and dicloxacillin became increasingly exothermic with increase in temperature. The predicted DeltaH(0)(m) at 298.15 K was in good agreement with the value determined experimentally by calorimetry for each drug. Copyright 2000 Academic Press.

Journal Article↗

PubMed2000

The release of 5-fluorouracil from microspheres of poly(epsilon-caprolactone-co-ethylene oxide).

The purpose of this study was to evaluate the in vitro release of 5-fluorouracil from microspheres prepared using a novel triblock copolymer of epsilon-caprolactone and ethylene oxide as the encapsulating material. Microspheres of poly(epsilon-caprolactone-co-ethylene oxide) were prepared by employing the "hot-melt" method of microencapsulation. Microspheres were sized using sieve analysis and scanning electron microscopy (SEM). Release studies were performed using a custom-made rotating paddle dissolution apparatus. Copolymer microspheres, fabricated by the hot melt method were shown by electron microscopy to have smooth, nonporous surfaces. Drug-loaded microspheres were found to have a broad distribution of sizes, which was thought to be a consequence of the wide range of crystal sizes of the encapsulated unmilled drug. Nonlinear release kinetics were observed from microspheres in the size fraction 75-250 microns, with a pronounced "burst release" associated with the presence of drug at the surface of the microspheres. A specific delineation of the drug release mechanism was not possible due to rapid gelation, swelling, and subsequent dissolution of the microspheres that occurred on hydration. This work describes the preparation of microspheres that swell rapidly and coalesce together on hydration, accompanied by rapid drug release and copolymer dissolution over a 2-hr period.

Algorithms↗