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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 73 records · Page 4Linked to original sources
PubMed2000

Disposition of intravenous pyrimethamine in healthy volunteers.

A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustain low plasma pyrimethamine concentrations during oral treatment, possibly because of incomplete and variable bioavailability. We wanted to develop a safe, practicable intravenous (i.v.) formulation of pyrimethamine and characterize its disposition in healthy volunteers. A neutral, aqueous, sterile solution of pyrimethamine was produced and presented in sealed glass ampoules. Pyrimethamine (1 mg/kg) was given to eight healthy male volunteers by i.v. infusion over 2 h, and blood was sampled over a 2 week period. Pyrimethamine levels in plasma were measured by high-performance liquid chromatography. The drug was well tolerated by all volunteers, and there were no changes in vital signs, electrocardiogram, hematology, or biochemical parameters. The maximum pyrimethamine concentration of 2,089+/-565 ng ml(-1) (mean +/- standard deviation) was achieved shortly after the end of the infusion; thereafter, concentrations declined in a log-linear manner, with a half-life of 140+/-31 h.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Biliary metabolites of beta-artemether in rats: biotransformations of an antimalarial endoperoxide.

beta-Artemether (AM), the O-methyl ether prodrug of dihydroartemisinin (DHA), is an endoperoxide antimalarial. The biliary metabolites of AM in adult male Wistar rats were characterized with particular reference to potential antimalarial compounds and stable derivatives of free radical intermediates. [13-(14)C]-AM (35 micromol kg(-1), i.v.) was administered to anesthetized rats. Within 0 to 3 h, 38.6 +/- 4.8% (mean +/- S.D., n = 6) of the radiolabel was recovered in bile; the 0- to 5-h recovery was 42.3 +/- 4.3%. The major metabolites (0-3 h) were the glucuronides of 9alpha-hydroxyAM (33.4 +/- 6.8% biliary radioactivity) and alpha-DHA (22.5 +/- 4.4%); four stereochemically unassigned monohydroxyAM glucuronides (II, 3.1 +/- 0.9; IV, 4.4 +/- 1.7%; V, 21.4 +/- 3.0%; VI, 3.0 +/- 1.1%) and a dihydroxyAM glucuronide (6.0 +/- 2.1%) were also identified. A sixth monohydroxyAM glucuronide (VIIa) and desoxyDHA glucuronide were detected in trace amounts. The furano acetate isomer of DHA glucuronide, indicative of the formation of a radical intermediate, was also found in trace amounts. O-methyl substitution of DHA favors ring hydroxylation in vivo. However, the principal hydroxylated metabolite, 9alpha-hydroxyAM, is unlikely to possess significant antimalarial activity.

Animals↗
PubMed1999

Simultaneous determination of artemether and its major metabolite dihydroartemisinin in plasma by gas chromatography-mass spectrometry-selected ion monitoring.

A sensitive, selective, and reproducible GC-MS-SIM method was developed for determination of artemether (ARM) and dihydroartemisinin (DHA) in plasma using artemisinin (ART) as internal standard. Solid phase extraction was performed using C18 Bond Elut cartridges. The analysis was carried out using a HP-5MS 5% phenylmethylsiloxane capillary column. The recoveries of ARM, DHA and ART were 94.9 +/- 1.6%, 92.2 +/- 4.1% and 81.3 +/- 1.2%, respectively. The limit of quantification in plasma was 5 ng/ml (C.V. < or = 17.4% for ARM and 15.2% for DHA). Calibration curves were linear with R2 > or = 0.988. Within day coefficients of variation were 3-10.4% for ARM and 7.7-14.5% for DHA. Between day coefficients of variations were 6.5-15.4% and 7.6-14.1% for ARM and DHA. The method is currently being used for pharmacokinetic studies. Preliminary data on pharmacokinetics showed Cmax of 245.2 and 35.6 ng/ml reached at 2 and 3 h and AUC0-8 h of 2463.6 and 111.8 ngh/ml for ARM and DHA, respectively.

Adult↗
PubMed1999

Type IV collagen and laminin regulate glomerular mesangial cell susceptibility to apoptosis via beta(1) integrin-mediated survival signals.

Postinflammatory scarring is characterized by changes in extracellular matrix (ECM) composition and progressive loss of normal resident cells. In glomerular inflammation there is now evidence that unscheduled apoptosis (programmed cell death) of mesangial and other resident cells may mediate progression to irreversible glomerulosclerosis. In the current study we examined the hypothesis that ECM components may differ in their capacity to support mesangial cell survival by suppression of apoptosis. Using a well-established in vitro model of mesangial cell apoptosis, we found that collagen IV and laminin, components of normal mesangial ECM, protected rat mesangial cells from apoptosis induced by serum starvation and DNA damage, by a beta(1) integrin-mediated, but arg-gly-asp (RGD)-independent mechanism. In contrast, collagen I, fibronectin, and osteonectin/SPARC, which are overexpressed in diseased glomeruli, failed to promote rat mesangial cell survival. However, the survival-promoting effect of collagen IV and laminin was not associated with changes in cellular levels of apoptosis regulatory proteins of the Bcl-2 family. These experiments demonstrate that glomerular mesangial cell survival is dependent on interactions with ECM and provide insights into potential mechanisms by which resident cell loss may occur during acute inflammation and postinflammatory scarring of the kidney and other organs.

Animals↗
PubMed1999

Further investigation of endothelium-derived hyperpolarizing factor (EDHF) in rat hepatic artery: studies using 1-EBIO and ouabain.

1. The characteristics of endothelium-dependent hyperpolarization in rat hepatic artery have been further investigated in the presence of inhibitors of cyclo-oxygenase and nitric oxide synthase. 2. Using sharp micro-electrodes, the smooth muscle hyperpolarization induced by acetylcholine, KCl or 1-ethyl-2-benzimidazolinone (1-EBIO) in intact hepatic arteries was abolished by 30 micronM barium plus 500 nM ouabain. 3. In vessels without endothelium, the smooth muscle hyperpolarization induced by KCl was not reduced by 30 micronM barium alone. However, in the presence of barium the effects of KCl were partially inhibited by 100 nM ouabain and essentially abolished by 500 nM ouabain. 4. Using sharp micro-electrodes, the hyperpolarization of both the smooth muscle and the endothelium induced by 1-EBIO or by acetylcholine was unaffected by 100 nM iberiotoxin. However, in the presence of 100 nM charybdotoxin, the effects of 1-EBIO were abolished whereas those of acetylcholine were only partially reduced. The hyperpolarization induced by levcromakalim was unaffected by either charybdotoxin or iberiotoxin. 5 Under whole-cell patch-clamp recording conditions, 1-EBIO induced a voltage-insensitive, charybdotoxin-sensitive K+ current in cultured endothelial cells but was without effect on K+ currents in smooth muscle cells isolated from hepatic arteries. 6 It is concluded that the endothelium-dependent hyperpolarization of smooth muscle induced by either acetylcholine or by 1-EBIO in rat hepatic artery is initially associated with the opening of endothelial calcium-sensitive K+-channels insensitive to iberiotoxin. The resulting accumulation of K+ in the myoendothelial space activates an isoform of Na+/K+-ATPase which is sensitive to low concentrations of ouabain.

Acetylcholine↗
PubMed1999

Role of gap junctions in the responses to EDHF in rat and guinea-pig small arteries.

1. In guinea-pig internal carotid arteries with an intact endothelium, acetylcholine (10 microM) and levcromakalim (10 microM) each hyperpolarized the smooth muscle whereas a 5 mM elevation of extracellular K(+) was without effect. 2. Incubation of the carotid artery with the gap junction inhibitors carbenoxolone (100 microM) or gap 27 (500 microM) essentially abolished the hyperpolarization to acetylcholine but it was without effect on that to levcromakalim. Carbenoxolone had no effect on the acetylcholine-induced endothelial cell hyperpolarization but inhibited the smooth muscle hyperpolarization induced by the endothelial cell K(+) channel opener, 1-ethyl-2-benzimidazolinone (600 microM). 3. In rat hepatic and mesenteric arteries with endothelium, carbenoxolone (100 or 500 microM) depolarized the smooth muscle but did not modify hyperpolarizations induced by KCl or levcromakalim. In the mesenteric (but not the hepatic) artery, the acetylcholine-induced hyperpolarization was inhibited by carbenoxolone. 4. Phenylephrine (1 microM) depolarized the smooth muscle cells of intact hepatic and mesenteric arteries, an effect enhanced by carbenoxolone. Gap 27 did not have a depolarizing action. In the presence of phenylephrine, acetylcholine-induced hyperpolarization of both hepatic and mesenteric artery myocytes was partially inhibited by each of the gap junction inhibitors. 5. Collectively, the data suggest that gap junctions play some role in the EDHF (endothelium-derived hyperpolarizing factor) response in rat hepatic and mesenteric arteries. However, in the guinea-pig internal carotid artery, electrotonic propagation of endothelial cell hyperpolarizations via gap junctions may be the sole mechanism underlying the response previously attributed to EDHF.

Acetylcholine↗
PubMed1998

K+ is an endothelium-derived hyperpolarizing factor in rat arteries.

In arteries, muscarinic agonists such as acetylcholine release an unidentified, endothelium-derived hyperpolarizing factor (EDHF) which is neither prostacyclin nor nitric oxide. Here we show that EDHF-induced hyperpolarization of smooth muscle and relaxation of small resistance arteries are inhibited by ouabain plus Ba2+; ouabain is a blocker of Na+/K+ ATPase and Ba2+ blocks inwardly rectifying K+ channels. Small increases in the amount of extracellular K+ mimic these effects of EDHF in a ouabain- and Ba2+-sensitive, but endothelium-independent, manner. Acetylcholine hyperpolarizes endothelial cells and increases the K+ concentration in the myoendothelial space; these effects are abolished by charbdotoxin plus apamin. Hyperpolarization of smooth muscle by EDHF is also abolished by this toxin combination, but these toxins do not affect the hyperpolarizaiton of smooth muscle by added K+. These data show that EDHF is K+ that effluxes through charybdotoxin- and apamin-sensitive K+ channels on endothelial cells. The resulting increase in myoendothelial K+ concentration hyperpolarizes and relaxes adjacent smooth-muscle cells by activating Ba2+-sensitive K+ channels and Na+/K+ ATPase. These results show that fluctuations in K+ levels originating within the blood vessel itself are important in regulating mammalian blood pressure and flow.

Acetylcholine↗
PubMed1998

Orthodontic auxiliaries--a pilot project.

AIM: To undertake a pilot study to determine a possible training programme for orthodontic auxiliaries. DESIGN AND SETTING: Trainee hygienists who had been accepted onto a 2-year programme were asked to attend the Bristol Dental School well before their course was due to begin in order to participate in a pilot orthodontic assistant auxiliary training programme. METHODS: A modular course of one month's duration was constructed based on the programme at the University of British Columbia. This aimed to teach skills such as impression taking, bond placement, debracketing, band cementation as well as core knowledge relevant to these procedures. RESULTS: At the end of the course all participants were judged to be performing the tasks they had been taught competently and safely. CONCLUSION: UK dental nurses can be trained to fill the role of an orthodontic auxiliary. It would appear that an introductory clinical skills course of one week followed by an orthodontic skills training of three weeks is sufficient for a qualified dental nurse of above average abilities such as typifies those who are currently applying for places on UK dental hygiene courses. It is estimated that a further period of nine months supervised training will be necessary for those who have successfully completed such a training to develop clinically useful speeds when delivering these skills.

Cementation↗
PubMed1998

Endothelium-derived hyperpolarizing factor--a critical appraisal.

Endothelium-derived hyperpolarizing factor is defined as that substance which produces vascular smooth muscle hyperpolarization which cannot be explained by nitric oxide or by a cyclo-oxygenase product such as prostacyclin. The possibility that the factor is an epoxyeicosatrienoic acid or a cannabinoid agonist such as anandamide continues to be investigated, but definitive evidence in favour of either is lacking. The sensitivity of EDHF-mediated responses to charybdotoxin, to apamin or to mixtures of these two toxins may indicate the opening of more than one smooth muscle K-channel, but the possibility that these are located on the vascular endothelium is discussed.

Animals↗