Biomedical subjects

J L Ford

Publications and source records attributed to J L Ford.

At least 19 recordsLinked to original sources

PubMed2005

The killing effect of cryptolepine on Staphylococcus aureus.

AIM: This study was undertaken to further examine the antimicrobial actions of the alkaloid cryptolepine. METHODS AND RESULTS: The minimum inhibitory concentration (MIC) of cryptolepine against Staphylococcus aureus was determined using the broth dilution method. Time-kill kinetics and scanning electron microscopy (SEM) techniques were employed to monitor the survival characteristics and the changes in morphologies respectively of staphylococci in the presence of cryptolepine. A notable antistaphylococcal activity was recorded for cryptolepine (MIC against S. aureus NCTC 10788=5 microg ml(-1)). Cryptolepine appears to have a lytic effect on S. aureus as seen in SEM photomicrographs following 3, 6 or 24 h treatment with 4X MIC, i.e. 20 microg ml(-1) of cryptolepine. The surface morphological appearance of the staphylococcal cells was also altered. The lytic effect appeared to coincide with low viable counts recorded in survival curves following treatment with cryptolepine. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings demonstrate that lysis occurs when susceptible organisms are exposed to cryptolepine.

Alkaloids↗

PubMed2004

An assessment of dose-uniformity of samples delivered from paediatric oral droppers.

BACKGROUND AND OBJECTIVES: To assess the accuracy and precision of delivery from containers containing oral drops, both under optimal laboratory conditions and during use by volunteers using a variety of real pharmaceutical products and specially prepared fluids. METHODS: The effects of the physical properties (viscosity, surface tension, fluid density) of fluids and the angle of a dropper upon the accuracy and precision of dispensing were investigated under standard laboratory conditions. Dose delivery was then assessed using a number of volunteers who were either given no instructions on the use of containers or were instructed to hold the droppers vertically. RESULTS: Viscosity, surface tension, fluid density and residual volume had little or no effect upon the volume of liquid delivered by a dropper clamped in the vertical position. However, when the angle of the dropper was moved towards 45 degrees from the vertical, the volume dispensed declined and became more variable to a point where the requirements of the European Pharmacopoeia were no longer fulfilled. This finding applied to a variety of products. When volunteers used the same droppers manually, the mean volumes dispensed were lower than when the droppers were vertically clamped and the variability was greater. It appeared that these problems were associated with volunteers failing to hold the dropper vertically and the precision and accuracy were indeed increased if the volunteers were instructed as to how the dropper should be held. The results from volunteers were more precise and accurate with the most viscous of the fluids tested and it was speculated that this may have been because the volunteers could more easily use the droppers vertically as there was less fear of dispensing too many drops. CONCLUSIONS: The key factor in achieving satisfactory dispensing from droppers is to ensure that the dropper is held vertically and this should form the basis of instructions to patients. Formulators should consider increasing the viscosity of prepared dropper solutions to reduce further errors in dose.

Administration, Oral↗

PubMed2002

Characterisation of water behaviour in cellulose ether polymers using low frequency dielectric spectroscopy.

The behaviour of water in hydroxypropylmethylcellulose (HPMC) K100LV, K4M, K15M, K100M, E4M, F4M and HPC polymers was characterised using low frequency dielectric spectroscopy (LFDS). Dielectric responses of 25% (w/w) HPMC K15M gels and deionised water were found to be similar at +22 and 0 degrees C. However, at -30 degrees C, a dielectric response typical of a solid was apparent. The melting of frozen water within gels was detected as increases in the magnitude of the dielectric response with increase in temperature. More than one phase transition was visible in the majority of gels studied which may be related to the presence of different states of water melting at different temperatures. In addition to polymer concentration, both polymer molecular weight and substitution level influenced the nature of the transitions. The magnitude of the dielectric response was increased in all HPMC gel systems in comparison to the response seen in deionised water. Drug addition affected the transitions occurring during the melting of ice in the gels. This may be related to the presence of ionic species in the systems. LFDS studies on cellulose ether gels have provided some interesting evidence for the existence of more than one state of water within such gel systems. The results are in good agreement with thermal analysis findings in similar gel systems.

Cellulose↗

PubMed2002

Cellularity of human annulus tissue: an investigation into the cellularity of tissue of different pathologies.

AIMS: To investigate the cells of the inner annulus and to demonstrate that differences in disc pathology can be identified at the cellular level. METHODS AND RESULTS: Annulus tissue taken from scoliotic, degenerate and prolapsed human disc tissue was processed for histology and transmission electron microscopy. Ki67 antibody was used to identify cells in the active part of the cell cycle and cell surface receptors for the matrix-degrading enzyme urokinase were immunolocalized. More chondron clusters were observed in tissue from prolapsed discs than in degenerate and scoliotic discs. Positive Ki67 staining was detected in cells within chondron clusters. Most cells observed from scoliotic and prolapsed annulus contained distinctive nuclei and organelles, whereas cells from degenerate discs contained very few well-defined organelles but abundant glycogen deposits. Immunolocalization identified urokinase receptors on the surface of cells from degenerate discs but not in the other pathologies. CONCLUSIONS: Cellular differences appear to underlie different types of disc pathology. The annulus tissue taken from prolapsed discs appeared to contain more chondron clusters and more active cells than scoliotic and degenerative tissue, suggesting a possible wound repair response. In contrast, cell and matrix degeneration appeared to be the most significant underlying processes in degenerate discs.

Adolescent↗

PubMed2001

Effect of nicotinamide on the properties of aqueous HPMC solutions.

The effect of nicotinamide on the properties of aqueous hydroxypropylmethylcellulose (HPMC) solutions was studied. Rheological studies showed that solutions of HPMC of concentration less than 3.0 w/v.% did not form gels and exhibited Newtonian flow patterns at 25 degrees C. The inclusion of nicotinamide increased the viscosity of HPMC solutions, which indicates that nicotinamide expanded the HPMC coils in aqueous solution. When the temperature of the solutions was raised, they formed gels that were detected by viscometry and oscillation tests as abrupt increases in viscosity, storage modulus and loss modulus and an abrupt decrease in loss angle. Nicotinamide exhibited a salting in effect on the HPMC solutions resulting in an increase in gelation temperatures and cloud points. These effects are considered to be due to the hydrogen-bonding of nicotinamide to HPMC molecules, which was suggested by a shift to a longer wavelength of the UV spectra of aqueous nicotinamide solutions by the addition of HPMC. These results suggested that nicotinamide has affinity with the hydrophilic groups of HPMC.

Drug Storage↗

PubMed2001

Structure prediction and active site analysis of the metal binding determinants in gamma -glutamylcysteine synthetase.

gamma-Glultamylcysteine synthetase (gamma-GCS) catalyzes the first step in the de novo biosynthesis of glutathione. In trypanosomes, glutathione is conjugated to spermidine to form a unique cofactor termed trypanothione, an essential cofactor for the maintenance of redox balance in the cell. Using extensive similarity searches and sequence motif analysis we detected homology between gamma-GCS and glutamine synthetase (GS), allowing these proteins to be unified into a superfamily of carboxylate-amine/ammonia ligases. The structure of gamma-GCS, which was previously poorly understood, was modeled using the known structure of GS. Two metal-binding sites, each ligated by three conserved active site residues (n1: Glu-55, Glu-93, Glu-100; and n2: Glu-53, Gln-321, and Glu-489), are predicted to form the catalytic center of the active site, where the n1 site is expected to bind free metal and the n2 site to interact with MgATP. To elucidate the roles of the metals and their ligands in catalysis, these six residues were mutated to alanine in the Trypanosoma brucei enzyme. All mutations caused a substantial loss of activity. Most notably, E93A was able to catalyze the l-Glu-dependent ATP hydrolysis but not the peptide bond ligation, suggesting that the n1 metal plays an important role in positioning l-Glu for the reaction chemistry. The apparent K(m) values for ATP were increased for both the E489A and Q321A mutant enzymes, consistent with a role for the n2 metal in ATP binding and phosphoryl transfer. Furthermore, the apparent K(d) values for activation of E489A and Q321A by free Mg(2+) increased. Finally, substitution of Mn(2+) for Mg(2+) in the reaction rescued the catalytic deficits caused by both mutations, demonstrating that the nature of the metal ligands plays an important role in metal specificity.

Amino Acid Sequence↗

PubMed2001

Characterization of the hydroxypropylmethylcellulose-nicotinamide binary system.

The effect of hydroxypropylmethylcellulose (HPMC) on the thermal behaviour of nicotinamide was studied. Binary mixtures of nicotinamide and HPMC, composed of various weight fractions of HPMC (X(HPMC)), were heated, cooled and subsequently re-heated. HPMC dissolved in fused nicotinamide at 140 degrees C. The binary mixture at compositions 0<==X(HPMC)<==0.3 formed a film structure on cooling. At X(HPMC)>==0.4, the molten nicotinamide at 140 degrees C was saturated with HPMC. These heated mixtures did not form a homogeneous film by cooling to ambient temperature. At X(HPMC)<0.4, differential scanning calorimetry peaks originating from recrystallization and melting of nicotinamide were observed in the cooling and re-heating scans, respectively. These peaks became smaller with increase in X(HPMC) and disappeared at X(HPMC) approximately 0.4. Decrease in crystallinity with increase in X(HPMC) was confirmed by X-ray diffraction. The glass transition temperature of the cooled mixture (T(g)) increased with increase in X(HPMC). When the enthalpy of melting of nicotinamide and 1/T(g) were plotted against X(HPMC), inflections were observed at similar X(HPMC) values, 0.37-0.38. Dissolution of HPMC in molten nicotinamide was accompanied by hydrogen bond formation, which was confirmed by infrared studies.

Algorithms↗

PubMed2001

Study of drug release from pellets coated with Surelease containing hydroxypropylmethylcellulose.

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n approximately 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (approximately 1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolution-controlled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.

Algorithms↗

PubMed2001

Effect of compression force, compression speed, and particle size on the compression properties of paracetamol.

The compression characteristics of two particle size fractions (< 90 microm, 105-210 microm) of paracetamol were examined. Each fraction produced extremely weak tablets and displayed a high tendency to cap. Low correlation coefficients of the initial parts of the Heckel plots, a low strain rate sensitivity, and an increase in mean yield pressure (from 34.2 to 45.5 MPa) with decrease in particle size all confirmed that the main mechanism during the compaction of paracetamol was fragmentation. The 105-210-microm particles underwent more fragmentation than the less than 90-microm powder. Heckel analysis confirmed that the larger size fraction of paracetamol produced denser compacts than the smaller fraction. The 105-210-microm fraction resulted in tablets with lower elastic recoveries and elastic energies. The elastic, plastic energy ratios indicated that the majority of energy involved during the compaction of paracetamol was utilized as elastic energy, indicative of massive elastic deformation of paracetamol particles under pressure.

Acetaminophen↗

PubMed2000

Highly compressible paracetamol: I: crystallization and characterization.

It was found that polyvinylpyrrolidone (PVP) is an effective additive during crystallization of paracetamol and significantly influenced the crystallization and crystal habit of paracetamol. These effects were attributed to adsorption of PVP onto the surfaces of growing crystals. It was found that the higher molecular weights of PVP (PVP 10000 and PVP 50000) were more effective additives than lower molecular weight PVP (PVP 2000). Paracetamol particles obtained in the presence of 0.5% w/v of PVP 10000 or PVP 50000 had near spherical structure and consisted of numerous rod-shaped microcrystals which had agglomerated together. Particles obtained in the presence of PVP 2000 consisted of fewer microcrystals. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XPD) experiments showed that paracetamol particles, crystallized in the presence of PVP, did not undergo structural modifications. By increasing the molecular weight and/or the concentration of PVP in the crystallization medium the amount of PVP incorporated into the paracetamol particles increased. The maximum amount of PVP in the particles was 4.32% w/w.

Acetaminophen↗

PubMed2000

Highly compressible paracetamol - II. Compression properties.

Paracetamol particles crystallized in the presence of polyvinylpyrrolidone (PVP) exhibited an obvious improvement in their compression properties compared to untreated paracetamol. Paracetamol particles crystallized in the presence of 0.5% w/v PVP 10000 or PVP 50000 produced tablets with improved crushing strength with no tendency to cap even at high compression speeds. The very low values of strain rate sensitivity (SRS) and the lack of reduction in crushing strength with increasing compression speed for these particles, were indicative of a high degree of fragmentation during compression. The results of elastic recoveries and elastic energies of tablets were indicative of much less elastic behaviour of these particles than untreated paracetamol. The low elastic energy/plastic energy (EE/PE) ratio for paracetamol crystallized in the presence of PVP indicated that, contrary to untreated paracetamol, a minor portion of compression energy was utilized as elastic energy.

Acetaminophen↗

PubMed2000

Comparative study of drug release from pellets coated with HPMC or Surelease.

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Effects of intramuscular administration of low doses of medetomidine and medetomidine-butorphanol in middle-aged and old dogs.

OBJECTIVE: To determine effects of low doses of medetomidine administered with and without butorphanol and glycopyrrolate to middle-aged and old dogs. DESIGN: Prospective randomized clinical trial. ANIMALS: 88 healthy dogs > or = 5 years old. PROCEDURE: Dogs were assigned randomly to receive medetomidine (2, 5, or 10 micrograms/kg [0.9, 2.3, or 4.6 micrograms/lb] of body weight, i.m.) alone or with glycopyrrolate (0.01 mg/kg [0.005 mg/lb], s.c.), medetomidine (10 micrograms/kg) and butorphanol (0.2 mg/kg [0.1 mg/lb], i.m.), or medetomidine (10 micrograms/kg), butorphanol (0.2 mg/kg), and glycopyrrolate (0.01 mg/kg). Anesthesia was induced with thiopental sodium and maintained with isoflurane. Degree of sedation and analgesia were determined before and after medetomidine administration. Respiratory rate, heart rate, and mean arterial blood pressure were determined 10 and 30 minutes after medetomidine administration. Adverse effects and amounts of thiopental and isoflurane used were recorded. RESULTS: Sedation increased after medetomidine administration in 79 of 88 dogs, but decreased in 7 dogs that received 2 or 5 micrograms of medetomidine/kg. Mean postsedation analgesia score and amounts of thiopental and isoflurane used were less in dogs that received medetomidine and butorphanol, compared with other groups. Respiratory rate, heart rate, and blood pressure were not different among groups. Significantly more adverse effects developed in dogs that did not receive glycopyrrolate. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of medetomidine (10 micrograms/kg, i.m.) and butorphanol (0.2 mg/kg, i.m.) induced sedation and analgesia and reduced amounts of thiopental and isoflurane required for anesthesia in middle-aged and old dogs. Glycopyrrolate decreased frequency of medetomidine-associated adverse effects.

Adjuvants, Anesthesia↗

PubMed1999

Formation and compression characteristics of prismatic polyhedral and thin plate-like crystals of paracetamol.

Prismatic polyhedral crystals of paracetamol were prepared by cooling an aqueous saturated solution of paracetamol from 65 to 25 degrees C. Thin plate-like crystals were prepared by adding a concentrated solution of paracetamol in hot ethanol to water at 3 degrees C. Infrared (IR), X-ray powder diffraction (XPD) and differential scanning calorimetry (DSC) studies confirmed that these two forms of crystals were structurally similar, therefore polymorphic modifications were ruled out. The crystal habit influenced the compression properties during axial compression of paracetamol at different constant rates in a compaction simulator, the Heckel plots and their associated constants being dependent on the habits. The correlation coefficient of the initial part of the Heckel plots, and also the values of strain rate sensitivity (SRS), were lower for thin plate-like crystals, indicative of greater fragmentation for the thin plate-like as compared to polyhedral crystals. Compacts made from thin plate-like crystals exhibited higher elastic recoveries and elastic energies indicating that these crystals underwent less plastic deformation during compression than the polyhedral crystals.

Acetaminophen↗

PubMed1999

Thermal analysis of hydroxypropylmethylcellulose and methylcellulose: powders, gels and matrix tablets.

This review focuses on the thermal analysis of hydroxypropylmethylcellulose (HPMC) and methylcellulose. Differential scanning calorimetry (DSC) of their powders is used to determine temperatures of moisture loss (in conjunction with thermogravimetric analysis) and glass transition temperatures. However, sample preparation and encapsulation affect the values obtained. The interaction of these cellulose ethers with water is evaluated by DSC. Water is added to the powder directly in DSC pans or preformed gels can be evaluated. Data quality depends on previous thermal history but estimates of the quantity of water bound to the polymers may be made. Water uptake by cellulose ethers may be evaluated by the use of polymeric wafers and by following loss of free water, over a series of timed curves, into wafers in contact with water. Cloud points, which assess the reduction of polymer solubility with increase of temperature, may be assessed spectrophotometrically. DSC and rheometric studies are used to follow thermogelation, a process involving hydrophobic interaction between partly hydrated polymeric chains. The advantages and disadvantages of the various methodologies are highlighted.

Calorimetry, Differential Scanning↗

PubMed1999

Influence of drug:hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets.

This study evaluates the relationship and influence of formulation and technological factors such as drug:hydroxypropylmethylcellulose (HPMC) ratio, particle size of the drug, particle size of HPMC and compression force, on drug release from matrices containing HPMC and diclofenac sodium as a model drug. The influence of these variables was assessed by multi-way analysis of variance. The results of the present study point out that the rate and mechanism of diclofenac sodium release from HPMC K15M matrices are mainly controlled by the drug:HPMC ratio. The drug and HPMC particle size also influence the drug release parameters, although to a lesser extent. Finally, the independence of the drug release from matrix tablets with respect to the compression force is reported.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Water distribution studies within cellulose ethers using differential scanning calorimetry. 1. Effect of polymer molecular weight and drug addition.

Differential scanning calorimetry (DSC) was employed to characterize the distribution of water in gels produced from a series of hydroxypropylmethylcelluloses (HPMC, Methocel K-series) of different molecular weights (i.e., different viscosity grades). The presence of loosely bound water was characterized as pre-endothermic events occurring at temperatures below the main melting endotherm of free water. Both the magnitude and occurrence of these pre-endothermic events were affected by polymer molecular weight and gel storage time. In addition, the amount of water bound to the polymer depended on polymer molecular weight and gel storage time. The temperature at which frozen water melted within the gels was dependent on polymer concentration, with a depression of extrapolated endothermic melting peak onset occurring with an increase in polymer concentration. The addition of propranolol hydrochloride or diclofenac sodium, as model drugs, affected both the occurrence of pre-endothermic events and the distribution of water within the gels.

Calorimetry, Differential Scanning↗

PubMed1999

Water distribution studies within cellulose ethers using differential scanning calorimetry. 2. Effect of polymer substitution type and drug addition.

The distribution of water within gels composed of a range of cellulose ether polymers of similar molecular weights (viscosity grades of 4000-6000 cP) but varying substitution types and levels was assessed by differential scanning calorimetry (DSC). Water loosely bound to the polymer was detected as one or more events appearing at the low-temperature side of the main endotherm for the melting of free water in DSC scans. Polymer substitution types and levels, and added drugs (50 mM propranolol hydrochloride or 50 mM diclofenac sodium) influenced the appearance of these melting events. Hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC F4M) gels showed behavior different to that of the other polymers studied. It is thought that any water binding to HPC gels is tightly attached and is not visible as pre-endothermic events on DSC scans. The amount of water bound per polymer repeating unit (PRU) was influenced by and related to the degree of hydrophilic and hydrophobic substitution on the polymer backbone and by the inclusion of either drug. HPC gels had the highest bound water content after 96 h and this was probably related to the high percentage of hydrophilic hydroxypropoxyl substitutions in this polymer. In contrast, methylcellulose (MC A4M) had the lowest bound water content after 96 h storage, and this was explained by the lack of hydrophilic hydroxypropoxyl substitutions in the polymer.

Calorimetry, Differential Scanning↗