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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 109 records · Page 6Linked to original sources
PubMed1995

The role of potassium channels in excitable cells.

Potassium (K) channels regulate cellular excitability. Their opening hyperpolarises the membrane potential and induces quiescence whereas their closure produces depolarisation and excitation. One K-channel superfamily includes the delayed rectifier (KV), the A-type (KA) and the large conductance, Ca-sensitive (BKCa) channels. These serve to terminate excitatory events and consist of a tetramer of alpha-subunits each comprising six transmembrane-spanning segments including a voltage-sensor. Additional beta-subunits which modify inactivation and voltage sensitivity may also be present. Channels in the second superfamily include the inward rectifiers (KIR) and the ATP-sensitive K-channel (KATP). Their tetrameric assembly of alpha-subunits contains only two transmembrane-spanning segments and lacks a voltage sensor. KATP is associated with a sulphonylurea binding site belonging to the ATP-binding cassette family. Although KIR conducts poorly at potentials positive to EK, both it and KATP do conduct over the physiological potential range. K-channel modulators are important in determining channel function. These include drugs like tetraethylammonium and 4-aminopyridine and more recently-discovered selective agents active at KATP and BKCa. These are typified by diazoxide, levcromakalim and glibenclamide and by NS1619, iberiotoxin and penitrem A, respectively.

Animals↗
PubMed1995

A 3-year epidemiological review of burn unit admissions in Dublin, Ireland: 1988-91.

A retrospective multifactorial epidemiological study of all patients admitted to the Burns Unit, St James's Hospital, Dublin during a 3-year period from January 1988 to December 1990 was undertaken. One hundred and twenty patients were admitted. All patients were aged over 14 years. The mean patient age was 48.2 years. Males accounted for 56 per cent of admissions. The mean percentage body surface area (%BSA) burned was 24.9 per cent. Flame was the cause of burns in 60 per cent of cases and produced the most extensive lesions. The home was the most common site of injury. Almost half the patients admitted from residential institutions sustained their burns in hot baths. Those aged over 60 years sustain smaller burns but are at increased risk from thermal injury. Twenty-one per cent of burns were caused by open fires used for heating the home. The mean time in hospital was 49.9 days. Twenty-three per cent of patients died as a result of their injuries. We have identified those living in residential institutions to be at increased risk from scald burns and suggest methods by which they may be protected.

Adolescent↗
PubMed1995

Signalling in extracellular-matrix-mediated control of epithelial cell phenotype.

Interactions with an appropriate ECM are crucial for normal cell behaviour. The basement membrane contributes to both the tissue-specific lactational function and survival of mammary epithelial cells, possibly through a similar beta 1-integrin-dependent mechanism. Of current interest is whether the downstream intracellular signals diverge, with milk expression regulated through cell shape and the Jak-Stat pathway and survival mediated through controls on the Bcl-2/Bax and Ice checkpoints.

Animals↗
PubMed1995

Marked variation in pyrimethamine disposition in AIDS patients treated for cerebral toxoplasmosis.

We have characterized the disposition of pyrimethamine in 20 adults with advanced AIDS. After the first dose, the area under concentration versus time curves (corrected for dose-size) varied 13-fold. This marked variation in drug levels was also noted during accumulation towards steady-state: pyrimethamine levels were consistently below the suggested lower end of the therapeutic range (750 mg/L) in three severely ill patients with perturbed consciousness (two of whom received the drug by nasogastric tube). Possible mechanisms for these observations are discussed. Pyrimethamine levels may be an important determinant of the rate of response to treatment by AIDS patients with toxoplasmosis: therapeutic drug monitoring may have a role.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide-resistant, ATP-sensitive potassium current.

1. The effects of the benzopyran K-channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly-isolated single cells derived from these tissues. 2. BRL55834 (3 nM-1 microM) produced a concentration-dependent relaxation of bovine trachealis precontracted with 100 microM histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1-10 microM) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis. 3. BRL55834 (10 nM-10 microM) did not relax segments of bovine trachealis precontracted with 80 mM KCl. 4. In some freshly-isolated single cells from bovine trachealis held at -10 mV, BRL55834 (3 microM) induced a time-independent outward K-current which was partially resistant to inhibition by glibenclamide (10 microM). In other cells, a very noisy, outwardly-rectifying and charybdotoxin-sensitive current developed in the presence of BRL55834 (3 microM) and in time-matched control cells. 5. In freshly-isolated single cells from rat portal vein held at -10 mV, BRL55834 (3 microM) induced a time- and calcium-independent outward K-current which was partially resistant (approximately 25% inhibition at +40 mV) to subsequent inhibition by glibenclamide (10 microM). In contrast, levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 microM. 6. With the non-hydrolysable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at +40 mV) whereas the effects of 10 microM levcromakalim were totally inhibited. 7. The glibenclamide-resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 microM), a concentration that had no effect on the peak current (IBK(Ca)) induced by NS1619 (33 microM). 8. Stationary fluctuation analysis of the noise associated with the glibenclamide-insensitive K-current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKCa. 9. It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K-channels. These are probably identical to the ATP-sensitive K-channel opened by levcromakalim, although the involvement of an additional K-channel cannot be excluded. The reduced sensitivity of the BRL55834-induced changes to glibenclamide and toAMP-PCP may result from avid binding of BRL55834 to its site of action.

Adenosine Triphosphate↗
PubMed1995

Evaluation of suramin, ivermectin and CGP 20376 in a new macrofilaricidal drug screen, Onchocerca ochengi in African cattle.

To aid the development of a macrofilaricidal agent for Onchocerca volvulus, the African bovine parasite, O. ochengi, was evaluated as a drug screen by testing three known filaricidal drugs. Groups of five Zebu cattle, naturally infected with more than 15 palpable O. ochengi nodules in the ventral skin, were treated with either suramin (10 mg/kg/day i.v. for 6 days), ivermectin (200 micrograms/kg, s.c.), CGP 20376 (20 mg/kg orally) or left untreated as controls and examined at intervals up to 137 days post-treatment (d.p.t.). After ivermectin treatment, microfilarial densities in the skin decreased within one week to virtually zero and remained at a very low level. A similar rapid and profound reduction was seen after CGP 20376 treatment, but by 137 d.p.t. microfilarial skin densities were approaching pre-treatment levels. With suramin, skin microfilarial densities fell to very low levels after 12 weeks but rose slightly by 137 d.p.t. Effects on the macrofilariae were assessed by sequential nodulectomies at -3 and 28, 84 and 137 d.p.t. By 137 d.p.t. embryogenesis was almost completely interrupted in the CGP 20376 and ivermectin treated animals, although not in the suramin treated group, but in all three groups the majority of remaining intrauterine microfilariae were pathologically altered. Degenerating intrauterine microfilariae accumulated in the ivermectin and in the CGP 20376, but not in the suramin treated worms. The motility of male and female worms was not reduced by any treatment except for female worms at 84 d.p.t. with CGP 20376. Viability of the worms as indicated by the MTT-formazan reduction assay was not reduced in any of the treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Africa↗
PubMed1994

Tissue ablation by a free-electron laser tuned to the amide II band.

Efforts to ablate soft tissue with conventional lasers have been limited by collateral damage and by concern over potential photochemical effects. Motivated by the thermal-confinement model, past infrared investigations targeted the OH-stretch mode of water with fast pulses from lasers emitting near 3,000 nm (refs 1, 7-9). What does a free-electron laser offer for the investigation of tissue ablation? Operating at non-photochemical single-photon energies, these infrared sources can produce trains of picosecond pulses tunable to the vibrational modes of proteins, lipids and/or water. We report here that targeting free-electron laser radiation to the amide II band of proteins leads to tissue ablation characterized by minimal collateral damage while maintaining a substantial ablation rate. To account for these observations we propose a novel ablation mechanism based on compromising tissue through resonant denaturation of structural proteins.

Amides↗
PubMed1994

Ferriprotoporphyrin catalysed decomposition of artemether: analytical and pharmacological implications.

The ability of the products of erythrocytic haemolysis and ferriprotoporphyrin (FP-IX)-containing substances of facilitate the decomposition of the antimalarial drug artemether has been evaluated in vitro. The products of haemolysis accelerate the degradation of artemether to unidentified compounds which are undetectable by currently available HPLC methods. This decomposition is temperature dependent and occurs after relatively brief artemether (ARM)-catalyst contact. Using radiolabelled [16-14C]ARM, we have demonstrated that the extractability of total radioactivity into the organic phase diminishes with increasing FP-IX concentration with an appreciable reduction in the organic extractability as ARM in the presence of FP-IX and associated increase in water solubility of radioactivity when the concentration of FP-IX increases from 0 to 7.7 mM. This effect appears to be temperature dependent for incubations with haematin. Characterisation of the organically extractable radioactivity from incubations of [16-14C]ARM with FP-IX has shown a loss of ARM and the formation of two radioactive products which occurs in proportion to the concentration of FP-IX. We believe these findings are of particular relevance to the determination of plasma concentrations of ARM and dihydroartemisinin (DHA) in malaria patients where extensive haemolysis and the presence of breakdown products of haemoglobin may contribute to a reduction in the circulating concentration of these substances. In these circumstances, measurement of ARM and DHA by conventional methods may be meaningless.

Antimalarials↗
PubMed1994

Treatment with coumarin to prevent or delay recurrence of malignant melanoma.

Both coumarin (1,2-benzopyrone) and warfarin (4-hydroxycoumarin) have been shown to prevent the recurrence of malignant melanoma. Their action is macrophage-dependent and the dosage is critical. In 1984 a multicentre, prospective, randomised, double-blind trial of coumarin, given as a daily 50-mg dose for 2 years after surgery in patients with high-risk melanoma, was started. the patients had lesions greater than 1.70 mm thick and TNM stage IB or stage II disease. To date there are 4 recurrences in the coumarin-treated group of 13 patients, and 10 recurrences in the placebo-treated group of 14 patients (P < 0.01). There were no toxic effects.

Chemotherapy, Adjuvant↗
PubMed1994

Measurement of artemisinin and its derivatives in biological fluids.

The development of selective analytical methods for the determination of artemisinin and its analogues and metabolites in biological fluids poses challenging problems. All are thermally labile, lack ultraviolet (u.v.) absorbent or fluorescent chromophores and do not possess functional groups for derivatization. Two chemical approaches have been used; acid (or alkali) catalysed decomposition to u.v. absorbing compounds followed by high-performance liquid chromatography (HPLC) of the decomposition products, and HPLC with reductive electrochemical detection. Each has its difficulties. The first, although sensitive, may lack specificity if drug metabolities are also converted to identical products, but a recently developed method surmounts this problem. The second, while providing good sensitivity and specificity, requires rigorous deoxygenation of the sample and mobile phase and an electrochemical detector, which is expensive, and may prove difficult to operate under field conditions. As an alternative to a chemical method, a bioassay may be suitable for plasma level monitoring in such circumstances. However its lack of selectivity means it is of questionable value in the determination of the pharmacokinetic parameters for individual drug-related species.

Antimalarials↗
PubMed1994

D.L. Davies and 'Normal drinking in recovered alcohol addicts': the genesis of a paper.

This paper explores the genesis of D.L. Davie's 1962 paper on 'Normal drinking in recovered alcohol addicts' in terms of the background and training of its author and the institutional context within which he worked. Davies was born in 1911 and died in 1982. Alter a brilliant undergraduate medical career and war service in command of a military hospital, Davies joined the staff of the Maudsley Hospital in 1946 and was exposed to the intellectual influence of Aubrey Lewis. The research tradition to which he was introduced emphasised case description. The 1962 paper radically challenged perceived wisdom by purporting to describe 7 'alcohol addicts' who had achieved sustained, controlled drinking over a 7-11 year period. A subsequent follow-up of these cases suggested that Davies had been substantially mislead, and the paradox exists that a widely influential paper which did much to stimulate new thinking was based on faulty data. Some possible explanations for the occurrence of such a scientific accident are considered and the relevance of this story for the present day.

Alcohol Drinking↗