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Biomedical subjects

M Williams

Publications and source records attributed to M Williams.

At least 505 records · Page 28Linked to original sources
PubMed1990

CGS 19755: a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist with anticonvulsant, anxiolytic and anti-ischemic properties.

CGS 19755 is a potent and selective competitive antagonist at NMDA receptors in the brain. In preclinical animal tests, the compound produces anticonvulsant, anxiolytic and anti-ischemic effects. CGS 19755 is not very active when administered orally, and intravenous administration is the most practical for clinical application. The anti-ischemic potential of CGS 19755 provides the most attractive application for clinical investigation.

Animals↗
PubMed1990

In vitro antiplaque effects of a triclosan/copolymer mouthrinse.

The influence of a mouthrinse containing 0.03% triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) and 0.25% copolymer (polyvinylmethylether maleic acid copolymer), compared to a matching placebo rinse, on in vitro plaque formation was assessed in two dynamic plaque model systems. In the controlled saliva flow cell system, the triclosan-containing rinses significantly reduced total plaque compared to the placebo rinse, with no significant differences when copolymer was removed from the active rinse formula. In the continuous culture system (chemostat flow cell model), the mean plaque was significantly reduced when compared with placebo. The results of these studies indicate that a triclosan mouthrinse, in the presence or absence of copolymer, is effective in reducing plaque in vitro.

Bacteria↗
PubMed1990

Antiplaque effects of dentifrices containing triclosan/copolymer/NaF system versus triclosan dentifrices without the copolymer.

A dentifrice containing triclosan/PVM/MA, Colgate Gum Protection Formula Toothpaste (GPF), was found to be highly effective against oral bacteria with minimal inhibitory concentration ranging from 0.3 to 5.35 micrograms/ml. A variety of in vitro model systems simulating oral environment were used to compare dentifrices containing triclosan/PVM/MA versus the dentifrices containing triclosan without PVM/MA, such as Crest Gum Health Toothpaste (CGH) and Neo-Mentadent P Toothpaste (N-MP). The uptake of triclosan on saliva-coated hydroxyapatite (HA) disks and buccal epithelial cells was significantly higher from the GPF versus the other dentifrices. Uptake on HA disks was 132 micrograms/disk versus 11 micrograms/disk from CGH; on buccal epithelial cells the uptake was 59 micrograms/2 x 10(5) cells with GPF versus 30.0 micrograms with CGH per same number of cells. The retained triclosan on the surfaces provided a sustained and higher antibacterial effect up to 4 hours post-treatment with GPF, but not with N-MP and CGH. In dynamic plaque model systems such as the chemostat or the controlled saliva flow system, GPF was significantly (P = 0.05) more effective than N-MP or CGH in reducing plaque thickness, protein and carbohydrate contents of plaque films. Collectively, the results of these microbiological and biochemical investigations indicate that the GPF has the potential to provide superior clinical efficacy versus the dentifrices without the copolymer.

Dental Plaque↗
PubMed1990

[Imaging of the temporomandibular joint].

The recent advances in imaging of the temporomandibular joint (TMJ), especially the introduction of MR imaging and surface colls allowing precise visualization of superficial structures led us to reconsider the different techniques used in this very complex anatomical region, due to both its morphology and function. We also tried to determine their respective role, especially in the study of TMJ dysfunction syndromes, that represent the most frequent pathology of this region. Conventional radiography allows us to appreciate the overall amplitude of the joint movements, and to study bone abnormalities, but CT is much more precise in the study of cortical bone. In TMJ dysfunction, the joint itself is studied by either arthrography or MRI, but both techniques have their limitations and remain complementary in some aspects, which are detailed here, so that the choice between them depends on availability and therapeutic indications.

Arthrography↗
PubMed1990

Interhospital referral of high-risk newborns in a rural regional perinatal program.

In light of increased competition for patients among hospitals, a trend toward deregionalization for perinatal programs and expansion of level II hospital neonatal intensive care services has been noted. This study investigates the determinants of the decision to transport very low birthweight (VLBW) babies born live at primary care community hospitals to a regional tertiary NICU or to a level II hospital in a semirural regional perinatal program. Data were collected from medical records of mothers and their newborns at 18 level I hospitals (primary care only), three level II hospitals (intermediate care), and the one tertiary hospital in the region. The sample includes all newborns with birthweights between 500 g and 1750 g born in 1983 (299). Despite dramatic increases in the proportion of very low birthweight deliveries at the tertiary center in the past decade, one third of the VLBW babies continue to be delivered at community hospitals in the study region. Although 25% of all transports from level I are to level II hospitals rather than to the level III hospital, birthweight and need for assisted ventilation were statistically significant determinants of transport of newborns from level I to level III hospitals rather than to a level II hospital. While both level I and level II hospitals are likely to transport newborns who need assisted ventilation to the level III hospital, the odds of transport are significantly higher for newborns born at level I as opposed to level II hospitals. Nontransported babies who were born at very low birthweight (less than 1000 g) died within 24 hours. The nontransported babies who survived had birthweights of greater than 1000 g, and fewer required assisted ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Is it possible to "achieve a balance" and meet the "safety net"? Paediatric Advisory Subcommittee to the North West Thames Regional Health Authority.

The government's document Hospital Medical Staffing--Achieving a Balance--Plan for Action introduced the concept of a "safety net"--that is, a minimum safe level of staffing--of junior doctors in the acute specialties. The North West Thames Paediatric Advisory Group has therefore reviewed the implications and consequences of implementing the safety net in respect of children's services. The group found that if a reasonable safety net was to be provided that enabled the services to stay within the projected junior staffing levels, maintain a balance, meet training needs, and reduce junior doctors' hours of work, then changes in the organisation of the services would be required. Examining the options available showed that to achieve a safety net within the projected numbers of junior staff at least six paediatric units in the region would have to close. It is doubtful if there is the political will to support the very radical changes that would be needed in the distribution of services if the government's recommendations in Achieving a Balance were to be implemented. The profession, the Department of Health, and the public must be made aware that the proposed changes in medical staffing will cause a fundamental change in the traditional pattern of delivery of health care.

Child↗
PubMed1989

Direct autoradiographic localization of adenosine A2 receptors in the rat brain using the A2-selective agonist, [3H]CGS 21680.

The regional distribution of adenosine A2 receptors in the rat brain was determined using the A2-selective agonist ligand [3H](2-p-carboxyethyl)phenylamino)-5'-N-carboxamidoadenosine (CGS 21680) by quantitative receptor autoradiography. [3H]CGS 21680 binding was highly localized in the striatal region of the rat brain with the greatest density of binding found in the caudate-putamen, nucleus accumbens and olfactory tubercle. Additionally, lower levels of binding were also found in the globus pallidus. No significant amounts of [3H]CGS 21,680 binding were detected in other brain regions. This localization of brain adenosine A2 receptors was markedly different from the known regional distribution of A1 receptors which are highly concentrated in cerebellum, hippocampus, thalamus and cortex. The present results provide further evidence for a specific contribution of adenosine in the modulation of central neurotransmission.

Adenosine↗
PubMed1989

Autoradiographic characterization of high-affinity adenosine A2 receptors in the rat brain.

Binding of the non-selective adenosine receptor agonist, [3H]NECA (5'-N-ethylcarboxamidoadenosine) was evaluated in sections of rat brain using quantitative receptor autoradiography. [3H]NECA bound specifically to a variety of different brain regions including striatum, cerebellum and thalamus. In the presence of the selective adenosine A1 receptor agonist, cyclopentyladenosine (CPA: 50 nM), [3H]NECA binding was exclusively localized to the striatum and olfactory tubercle. Binding in rat striatum occurred at a single site (Kd = 9 nM) with limited capacity (apparent Bmax = 230 fmol/mg tissue). Competition experiments in both striatum and olfactory tubercle with various adenosine agonists and antagonists indicated that the sites labeled by [3H]NECA in the presence of 50 nM CPA were A2 in nature, the rank order of activity for agonists being NECA greater than 2-chloroadenosine (2-CADO), greater than R-N6-phenylisopropyladenosine (R-PIA) greater than CPA greater than S-N6-phenylisopropyladenosine (S-PIA). For xanthine antagonists the order was greater than 1,3-dipropyl-8(2-amino-4-chloro)phenylxanthine (PACPX) greater than xanthine amino acid congener (XAC) greater than xanthine carboxylic acid congener (XCC) greater than 1,3-diethyl-8-phenylxanthine (DPX). The localization of A2 receptors to discrete regions of rat brain indicates that the purine may have a selective role in modulating basal ganglia function.

Adenosine↗
PubMed1989

Agonist derived molecular probes for A2 adenosine receptors.

The adenosine agonist 2-(4-(2-carboxyethyl)phenylethylamino)-5'-N- ethylcarboxamidoadenos ine (CGS21680) was recently reported to be selective for the A2 adenosine receptor subtype, which mediates its hypotensive action. To investigate structure/activity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p-hydroxyphenylpropionic, 2-thiophenylacetic, and p-aminophenylacetic acids were prepared. The latter derivative (PAPA-APEC) was iodinated electrophilically using [125I]iodide resulting in a radioligand which was used for studies of competition of binding to striatal A2 adenosine receptors in bovine brain. A biotin conjugate and an aryl sulfonate were at least 350-fold selective for A2 receptors. For spectroscopic detection, a derivative of the stable free radical tetramethyl-1-piperidinyloxy (TEMPO) was prepared. For irreversible inhibition of receptors, meta- and para-phenylenediisothiocyanate groups were incorporated in the analogs. We have demonstrated that binding at A2 receptors is relatively insensitive to distal structural changes at the 2-position, and we report high affinity molecular probes for receptor characterization by radioactive, spectroscopic and affinity labelling methodology.

Adenosine↗
PubMed1989

Molecular cloning of human myelin-associated glycoprotein.

The nucleotide sequence for human myelin-associated glycoprotein (MAG) and its deduced amino acid sequence, obtained by analysis of two overlapping cDNA clones isolated from a human brain cDNA library, is presented and compared to that reported for rat MAG. The sequence provides an open reading frame of 1,878 nucleotides encoding a peptide of 626 amino acids with a calculated molecular weight of 69.1 kD. It is 89% homologous in nucleotide sequence to the large isoform of rat MAG, with 95% homology in the amino acid sequence. It contains 9 potential glycosylation sites, one more than in rat, and shares other key features with rat MAG, including 5 immunoglobulin-like regions of internal homology, an RGD sequence, and potential phosphorylation sites. Its structure appears to be highly conserved in evolution, possibly suggesting a close interdependence between its structure and function. The human gene is located on the proximal long arm of chromosome 19 (19q12----q13.2).

Amino Acid Sequence↗
PubMed1989

Specificity of human anti-neurofilament autoantibodies.

The specificities and isotypes of human antibodies that react with neurofilament (NF) proteins were examined by Western blot analysis. Two-thirds of the subjects tested had antibodies to the 200 kDa high molecular weight neurofilament protein (NF-H), and fewer had antibodies to the low and middle molecular weight neurofilament proteins (NF-L and NF-M respectively). Human autoantibodies bound to both native and dephosphorylated NF-H, but some antibodies bound to dephosphorylated NF-H only, indicating the presence of at least two target epitopes. They also recognized a fusion protein containing a segment of the NF-H protein produced by a cDNA clone in Escherichia coli, indicating that they bind to unmodified peptide epitopes. The anti-NF-H antibodies were mostly IgG, but were frequently complexed to IgA or IgM antibodies, possibly with rheumatoid factor or anti-idiotypic activity. These characteristics of anti-NF-H antibodies are most consistent with a secondary immune response that is antigen driven and T-cell dependent.

Adult↗
PubMed1989

2H-[1]benzopyrano[3,4-b]pyridines: synthesis and activity at central monoamine receptors.

Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.

Animals↗
PubMed1989

Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides.

A series of azaspiro[4.5]decanyl amides were prepared by a novel cyclization route and examined for opiate receptor binding and antinociceptive activity. Selected tertiary amides in this series showed potent selective mu-receptor binding and antinociceptive activity, in contrast to the less conformationally restricted secondary amides, which showed relatively weak activity. Although structurally similar to the kappa-agonist U-50488H (1), these compounds showed virtually no tendency to bind to the kappa-receptor. An X-ray crystal structure of compound (21) confirms that the spirocyclic amine does not cause distortion away from the chair conformation of the cyclohexane ring. Either this receptor has very specific requirements for the orientation of the two nitrogens of these compounds or this ring system fills a portion of space more readily tolerated by the mu- and delta-receptors.

Analgesia↗
PubMed1989

4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors, and anticonvulsant activity.

A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.

Animals↗
PubMed1989

Benzofuro[2,3-c]pyridin-6-ols: synthesis, affinity for opioid-receptor subtypes, and antinociceptive activity.

A general synthetic approach to a novel series of cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols is described together with their receptor-binding profile on opioid-receptor subtypes (mu, kappa, delta). In addition, their in vivo antinociceptive activity was assessed. A number of the analogues synthesized showed potent affinity for opioid receptors and have potent antinociceptive activity in a mouse phenylquinone abdominal stretching model. In addition, the SAR for nitrogen substitution in the above series is explored with respect to the overall opioid receptor subtype binding profile. In general it was found that substituents which enhanced mu and kappa binding affinity in the benzomorphan series had a similar effect in the benzofuropyridine series described in this manuscript. An overlap hypothesis topologically connecting the benzomorphan nucleus to the cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine nucleus is also presented.

Analgesics↗