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A C Williams

Publications and source records attributed to A C Williams.

At least 91 records · Page 5Linked to original sources
PubMed1999

Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies.

Deformable vesicles and traditional liposomes were compared as delivery systems for oestradiol to elucidate possible mechanisms of drug delivery through human skin. Accordingly, epidermal permeation of oestradiol from optimized deformable vesicles and traditional liposome formulations was studied under low dose non-occluded conditions. Five mechanisms were investigated. A free drug mechanism compared low-dose permeation through skin with drug release determined after separation of the free drug. Penetration enhancement was researched by studying skin pretreatment with empty vesicles. Improved drug uptake by skin was monitored by dipping stratum corneum into different formulations for 10 min and determining drug uptake. The possibility that intact vesicles permeate through the epidermis was tested by comparing permeation from 136-nm vesicles with that from >500-nm vesicles, assuming that penetration depends on vesicle size. The possibility that different entrapment efficiencies in alternative formulations could be responsible for the difference in delivery was also evaluated. Lipid vesicles improved the skin delivery of oestradiol compared with delivery from an aqueous control. Maximum flux (Jmax) was increased 14- to 17-fold by use of deformable vesicles and 8.2- to 9.8-fold by use of traditional liposomes. Deformable vesicles were thus superior to traditional liposomes. Drug release was negligible over the period during which skin flux was maximum. Pretreatment with empty vesicles resulted in an enhancement ratio of 4.3 for pure phosphatidylcholine (PC) vesicles but the enhancement ratio ranged from only 0.8 to 2.4 for other formulations. Vesicles increased drug uptake into the stratum corneum 23- to 29-fold. Relative flux values obtained from small and large vesicles were similar. No correlation was found between entrapment efficiency and skin delivery. The results showed no evidence of a free drug mechanism, but revealed a possible penetration-enhancing effect for pure PC vesicles, although this was not the only mechanism operating. The positive uptake suggested that lipid vesicles increased drug partitioning into the skin. The data provided no evidence for in-vitro liposome penetration through skin as distinct from vesicle penetration into the stratum corneum.

Aged↗
PubMed1998

A direct correlation between nicotinamide N-methyltransferase activity and protein levels in human liver cytosol.

Phenotypic differences in nicotinamide N-methyltransferase (NNMT, E. C. 2.1.1.1) activity may be due to a genetic polymorphism. We report the characterisation of the hepatic NNMT activity in cytosol from normal human livers, enzyme protein levels determined by Western blotting and ELISA and mRNA levels determined by SDS-PAGE/Northern blotting. Subjects with high NNMT activity had high levels of NNMT protein and NNMT mRNA levels in hepatic cytosol and the converse was true for individuals with low NNMT activity. No differences in sequences were seen when cDNAs of individuals with high and low NNMT activity were compared. Thus phenotypic differences in the general population are due to differences in steady-state mRNA levels and not because of a polymorphism in the coding region of the NNMT gene.

Adolescent↗
PubMed1998

Cysteine dioxygenase: regional expression of activity in rat brain.

The levels of expression of cysteine dioxygenase (CDO) protein and activity were investigated in nine functionally distinct regions of the rat brain before and after induction with methionine by Western analysis and an activity assay. Activity expression ranged from no activity in the brain-stem to high activity expression in the olfactory bulb and basal ganglia. Upon exposure to 400 mg/l methionine for 5 days, significant induction of expression was observed in the basal ganglia, brain-stem, cerebellum, hippocampus, midbrain and olfactory bulb. Protein expression appeared to correlate with activity expression when levels before and after induction were compared. This non-uniformity of expression may reflect different physiological functions of CDO in these areas.

Animals↗
PubMed1998

Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen.

The formation of eutectic systems between ibuprofen (ibu) and seven terpene skin penetration enhancers was studied and, by using the eutectic systems as donors, the effects of melting point depression of the delivery system on transdermal delivery were investigated. A range of ibu:terpene binary mixtures were melted together, cooled, and recrystallised. Composition/melting point phase diagrams were determined by DSC and FT-IR analysis was used to investigated the nature of the interaction. Permeation of ibu across human epidermal membrane from the eutectic system was measured and compared to the flux from a saturated aqueous solution across skin and skin pretreated with the terpenes. The eutectic, i.e. minimum, melting points of these systems ranged from 32 degrees C for ibu:thymol 40:60 (% w/w) to -13 degrees C for ibu:1,8-cineole 40:60 (% w/w) compared to 76 degrees C for ibu alone. FT-IR studies indicated that only the terpenes which formed hydrogen bonds with ibu produced eutectic systems. Each set of ibu:terpene eutectic systems produced a significant (t-test, p = 0.05) increase in flux compared to a saturated aqueous solution applied to untreated and to terpene pretreated skin. For example, ibu:thymol 40:60 (% w/w) produced a flux of 150 micrograms/cm2/h, 5.9 times the flux from a saturated aqueous solution with thymol pretreated skin and 12.7 times the flux from a saturated aqueous solution across non-pretreated skin. In conclusion, a hydrogen bonding interaction is the primary mechanism by which some terpenes form binary eutectic mixtures with ibu. The resultant melting point depression of the delivery system is correlated with a significant increase in transdermal permeation.

Administration, Cutaneous↗
PubMed1998

Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache.

Plasma amino acids were analysed in patients with migraine with (9) and without (80) aura, in patients with tension headache (14) and in controls (62). The neuroexcitatory amino acids glutamic acid, glutamine, glycine, cysteic acid and homocysteic acid were elevated in migraine patients while total thiols (cysteine/cystine) were reduced. Patients with tension headache had values which were similar to those of controls. Tryptophan was elevated in migraine patients without aura only. Studies on two patients showed that the raised resting excitatory amino acid levels became still further elevated during a migraine attack. These results show that high concentrations of neurotransmitter amino acids occur normally in migraine patients and suggest that this profile may be a contributory factor in migraine attacks. Tension headache, however, has different biochemical parameters.

Adult↗
PubMed1998

Hepatic localisation of rat cysteine dioxygenase.

BACKGROUND/AIM: Cysteine dioxygenase (CDO, E.C. 1.13.11.20) is the main catabolic enzyme of cysteine, metabolising cysteine to cysteinesulphinic acid. CDO abnormality has been implicated in a number of neurological and non-neurological diseases, with CDO deficiency possibly leading to excitotoxic damage to the brain and impaired Phase II metabolism in the liver. METHODS: Two novel anti-CDO antibodies raised against linear synthetic peptides corresponding to two distinct epitopes on the 22 kDa gene product of the CDO-I gene were used for immunohistochemistry and Western blotting. These antibodies were characterised by their ability to both block and precipitate CDO enzyme activity as well as the ability of the respective antigenic peptides to absorb the antibodies and prevent the immunodetection of CDO. RESULTS: The antibodies were found to detect the presence of a 68 kDa protein, which was subsequently shown to be CDO. Distribution was found to be centrilobular and did not alter when CDO was induced with cysteine or methionine; however, the intensity of staining increased, indicating an increase in the levels of CDO in that region. CONCLUSIONS: These results suggest that the 68 kDa Type II is the predominant isoform in vitro and in vivo and that its centrilobular localisation may allow CDO to initiate the production of sulphate and taurine for Phase II conjugation in the liver.

Animals↗
PubMed1998

Thermally induced molecular disorder in human stratum corneum lipids compared with a model phospholipid system; FT-Raman spectroscopy.

The molecular basis of lipid packing in human stratum corneum and a model phospholipid system has been studied as a function of temperature using Fourier Transform (FT) Raman spectroscopy. Thermally induced molecular rearrangements of the model lipid system, dipalmitoylphosphatidyl choline (DPPC), and stratum corneum were investigated using FT Raman spectroscopy coupled to a heating chamber. Spectra were recorded for a range of sample temperatures and the results for the two systems were compared, producing previously unreported information of the thermal behaviour for the different systems. Discrete thermal events were recorded for both systems by plotting band separation of the lipid v(CH2) symmetric and asymmetric stretching modes against temperature. The main thermal events observed for DPPC included a 'pre-melting' between 37 and 39 degrees C, the main transition observed between 41 and 42 degrees C, a 'post-transition' between 42 and 43 degrees C and three minor transitions at 58-60, 65-70 and 75-80 degrees C. No evidence was found for the pre-transition of DPPC, previously observed at 34-35 degrees C. The main transitions for human stratum corneum were observed at 35-45, 55, 72 and 83 degrees C, measured from lipid CH2 stretching and bending vibrations. The keratin thermal transition at about 100 degrees C exerted little effect on the lipid bands and no characterisable structural changes were reflected in the keratotic bands.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Intracellular or intercellular localization of the polar pathway of penetration across stratum corneum.

A pharmacokinetic hypothesis of stratum corneum with two parallel pathways, lipophilic and porous hydrophilic, is not well documented yet. Still questionable is the localization of the pores, and the present experiments were designed to elucidate the contribution of extracellular lipids and intracellular keratin to the structure of this pathway. Percutaneous penetration of baclofen, a model zwitterion, was studied in vitro using human cadaver skin. Aqueous or ethanolic saturated solutions of the drug (Cs = 4.6 and 0.4 mg/mL, respectively) were applied on the skin that was pretreated with: methanol/chloroform (Me/Ch) or acetone-chloroform (Ac/Ch) (1:1) mixtures, or with these solvents followed by 0.2% solution of sodium lauryl sulfate (SLS). As controls, baclofen penetration through the intact full-thickness skin was determined, and the fluxes were 0.18 +/- 0.08 and 0.14 +/- 0.07 microg/cm2/h for aqueous and ethanolic solutions, respectively. When Me/Ch was used for 1 h, an expected increase of the penetration was observed, but the lag time, Tlag, was still nearly 20 h. When the less polar mixture, Ac/Ch, was used, no flux enhancement was observed, and with ethanol as the vehicle, decreased penetration was even noted. No effect on baclofen penetration was observed when SLS was used for 1 h after delipidization of the skin was done with either the Me/Ch or Ac/Ch mixture. The results suggest that the polar pathway may be located intercellularly and comprises aqueous regions surrounded by polar lipids, which create the walls of such microchannels.

Baclofen↗
PubMed1998

Particle size dependent molecular rearrangements during the dehydration of trehalose dihydrate in situ FT-Raman spectroscopy.

PURPOSE: (1) To characterise the different phases of trehalose using FT-Raman spectroscopy. (2) To monitor the changes in the structure of trehalose dihydrate on isothermal heating at 80 degrees C. METHODS: Different phases of trehalose were prepared and FT-Raman spectra obtained. Trehalose dihydrate was sieved to < 45 microns and > 425 microns particle size fractions and FT-Raman spectra were obtained at various time intervals during heating at 80 degrees C. RESULTS: During heating at this temperature, the spectra of a < 45 microns particle size fraction showed a loss of peak resolution with time and after 210 minutes resembled the spectrum of amorphous trehalose prepared by lyophilisation, indicating that the material was rendered amorphous by heating. In contrast, spectra obtained from a > 425 micron particle size fraction altered with time and became characteristic of the crystalline anhydrate. The approximate kinetics of this transformation to the anhydrate were monitored by analysis of peak intensity ratios with time. A two state rearrangement was indicated; some functional groups appeared to manoeuvre into the spatial arrangement found in the anhydrate initially before the rest of the ring structure relaxed into this conformation. This may be due to some parts of the molecule being immediately affected by the loss of the water molecules on dehydration prior to the subsequent reorientation of the entire molecule into the anhydrate crystal lattice. CONCLUSIONS: The < 45 micron particle size fraction becomes disordered on dehydration induced by heating at 80 degrees C whilst the > 425 micron particle size fraction crystallises to the anhydrate under the same conditions.

Calorimetry, Differential Scanning↗
PubMed1998

Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach.

5-Fluorouracil permeates the stratum corneum through the intercellular pathway. 5-Fluorouracil is hydrophilic and, therefore, its partitioning from the aqueous region into the hydrocarbon interior of stratum corneum lipids is expected to be an important stage of its permeation and a target for some permeation enhancers. It has also been reported that complexation plays a role in the enhancement effect of some accelerants. These mechanisms have been investigated. For partitioning-permeation studies, isooctane was chosen as a model of the hydrocarbon interior of stratum corneum lipid bilayers and the effects of 26 different terpene enhancers on the solubility of 5-fluorouracil in isooctane were measured. Results were then compared with the effects of the same enhancers on the permeation of 5-fluorouracil through the epidermis in man. The stoichiometry of interaction of cineole and limonene with 5-fluorouracil were also studied to reveal possible complex formation. Solubility studies revealed good correlation between solubility and enhancement ratios for the majority of terpenes, indicating that one mechanism by which terpenes increase permeation of the stratum corneum by 5-fluorouracil is by improvement of partitioning. Stoichiometry studies showed that cineole can form 1:1 or higher complexes with 5-fluorouracil. With limonene, only a weak 1:1 complex was indicated. Data obtained using epidermis from man show that the enhancement effect of cineole toward 5-fluorouracil is much higher than that of limonene. These data reveal that terpenes might increase the permeation of 5-fluorouracil through the stratum corneum as a result of complex formation and a form of facilitated transport.

Antimetabolites↗
PubMed1998

Cytochrome P450 1B1 mRNA in the human central nervous system.

AIMS: To study the expression of CYP1B1 in a variety of human and rat cell lines as a means of identifying a new tool for the investigation of gene regulation. In addition, to identify the expression of cytochrome P450 1B1 (CYP1B1) in different regions of the central nervous system (CNS). METHODS: Reverse transcription-polymerase chain reaction followed by cloning and sequencing were used to detect the expression of CYP1B1 in human cell lines. Poly A+ mRNA from the human spinal cord and from different brain regions was analysed using a CYP1B1 probe labelled with 32PdCTP. RESULTS: Expression of CYP1B1 was shown in a human astrocytoma cell line (MOG-G-CCM). CYP1B1 mRNA was expressed in a variety of regions of the CNS but with a distinct regional specificity. Expression was highest in the putamen. CONCLUSIONS: The expression of CYP1B1 in a human astrocytoma enables this cell line to be used in further studies of regulation and function of this gene. The demonstration that CYP1B1 mRNA is expressed in a variety of regions of the CNS suggests a role for this gene in brain and spinal cord metabolism. The regional specificity of expression might explain the focal damage of certain human neurodegenerative diseases.

Animals↗
PubMed1998

Direct genetic evidence for involvement of tau in progressive supranuclear palsy. European Study Group on Atypical Parkinsonism Consortium.

OBJECTIVE: To confirm whether a dinucleotide repeat sequence in an intron of the microtubule-associated protein tau is associated with progressive supranuclear palsy (PSP) in an independent study population and to establish an improved methodology for allelotyping. BACKGROUND: It has recently been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in PSP patients when compared with control subjects. METHODS: In a multicenter study, the authors examined the allelic distribution of this dinucleotide repeat marker in a set of clinically ascertained PSP patients (n = 30), multiple system atrophy (MSA) patients (n = 35), and matched control subjects (n = 70). Individuals were allelotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The A0 allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%; p = 0.0067; odds ratio [OR] = 4.33; 95% confidence interval [CI], 1.36 to 13.60), but not in the MSA patients. Likewise, A0 homozygotes were overrepresented in the PSP group (86.7% versus 61.1%; p = 0.02; OR = 4.14; 95% CI, 1.19 to 14.48) compared with control subjects. CONCLUSIONS: The findings of this study, which is the largest to date, support those of a previous investigation that used pathologically confirmed PSP patients. These data provide additional strong evidence that genetic variation at or near the tau gene plays an important role in the pathogenesis of PSP.

Aged↗
PubMed1998

Interaction of salicylic acid with verrucae assessed by FT-Raman spectroscopy.

FT-Raman spectroscopy has been used to investigate treated verrucae (warts from the sole of the foot) with a local application of a salicylic acid paint. Differences in the molecular structure of the stratum corneum across the verruca sample were observed, and by comparison with normal and hyperkeratotic skin it was concluded that the tissue around the edges of the verrucae was typically hyperkeratotic skin. In the centre of the verruca, the molecular structure of the skin was altered showing evidence of the interaction with salicylic acid. Salicylic acid was not observed in its characteristic dimerised acid structure, but spectroscopic evidence suggested that fission of the intermolecular H-bonding essentially cleaved the dimer. Observed changes in the v(CCO) stretching mode of the carboxyl and hydroxyl groups indicate the inter H-bonds have broken. These spectral changes are believed to be more consistent with salicylic acid bonding within the human papillomavirus-containing verruca tissue rather than simple acid dissociation upon dissolution in water within the tissue. No evidence for the presence of the other paint components, lactic acid and flexible collodion, was found in the verrucae spectra. This Raman approach may help to elucidate the molecular basis for therapeutic agents interacting with diseased skin.

Humans↗
PubMed1998

Transdermal permeation modulation by cyclodextrins: a mechanistic study.

The purpose of this study was to investigate permeation modulation by beta- and 2-hydroxypropyl-beta-cyclodextrins (beta-CD and HP-beta-CD, respectively) alone and complexed with penetration enhancers for the test drugs 5-fluorouracil and estradiol through human skin, and to probe the value of the CDs in a barrier cream against toluene exposure. Methods include phase solubility studies, permeation experiments, and thermal analysis of stratum corneum; inclusion complexes were characterized by Karl Fischer titrimetry, infrared spectroscopy, and thermal analysis. Results show that complexes of terpenes or toluene with beta-CD were insoluble, whereas those with HP-beta-CD were soluble. The CDs did not enhance flux of either the polar or lipophilic drugs through skin; estradiol permeation was reduced following membrane pretreatment with either CD. Complexation of the lipophilic terpenes with the CDs reduced enhancer efficacy. When formulated into a barrier ointment both CDs, but particularly beta-CD, retarded toluene permeation through the skin and delayed the onset of maximum flux. It is concluded that the CDs themselves are not penetration enhancers for 5-fluorouracil or estradiol in human skin, and that they may be usefully incorporated into a barrier formulation to reduce percutaneous absorption of toxic materials on occupational exposure.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

Guidelines for the management of Parkinson's disease. The Parkinson's Disease Consensus Working Group.

Parkinson's disease is a chronic and disabling illness and there is currently wide variation in its management. This article presents the first UK-specific guidelines for the management of Parkinson's disease and it contains a treatment decision free to aid the physician in deciding when and how to treat patients. We hope this document will prove useful to all those involved in the planning and delivery of care to patients with Parkinson's disease.

Aged↗
PubMed1997

Modulation of p53 expression in cultured colonic adenoma cell lines by the naturally occurring lumenal factors butyrate and deoxycholate.

The high incidence of colorectal cancer in Western society is believed to be strongly related to diet. Mutation of the p53 gene is a late event in colorectal carcinogenesis, and thus, the majority of pre-malignant adenomas express wild-type p53. As loss of p53 protein function is an important step in colorectal carcinogenesis, we investigated whether naturally occurring lumenal factors can modulate the expression of p53 in non-tumorigenic human colonic adenoma cell lines. Levels of p53 protein and mRNA were measured in adherent cells which had been incubated with growth-inhibitory concentrations of sodium butyrate (a by-product of dietary fibre fermentation) or sodium deoxycholate (a bile acid) for up to 48 hr. We report that both butyrate and deoxycholate can down-regulate the expression of wild-type and mutant p53. In contrast, incubation for 48 hr with the endogenous inhibitory growth factor TGFbeta1 did not alter p53 protein expression. Thus, in addition to cellular mechanisms which regulate p53 function, such as post-translational stabilisation, nuclear exclusion, negative feedback inhibition of p53 mRNA translation or binding of p53 by cellular proteins, p53 protein levels also may be regulated by changes in the level of p53 gene transcription. Furthermore, we show that lumenal factors are able to affect directly the expression of p53 protein in colonic epithelial cells.

Adenoma↗