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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 55 records · Page 3Linked to original sources
PubMed1993

Doctors and substance misuse: types of doctors, types of problems.

The casenotes of 144 doctors who had received treatment for substance misuse were analysed. There were no differences between general practitioners (n = 61) and hospital doctors (n = 58) in terms of their substance misuse histories or the problems they incurred. Differences emerged between the consultant (n = 24) and the non-consultant (n = 34) grades of hospital doctor. The consultants were older at onset of problematic use (42.6 +/- 8.6 vs. 29.9 +/- 9.8 years); they suffered fewer career problems and misused fewer substances. The most frequent pathways into substance use were personality difficulties (76 subjects, 52.8%) and anxiety or depression (46 subjects, 31.9%). A history of depression (n = 36) was associated with perceived stress at work (p = 0.014), and at home (p = 0.06). Past neurotic disturbances (n = 20) were associated with personality difficulties (p = 0.035), anxiety or depression (p = 0.004), and with an earlier onset of problematic substance use (30.2 +/- 8.3 vs. 36.5 +/- 9.8 years, p = 0.014). Principal components of possible antecedents yielded one major component on which all elements loaded; this was labelled the 'disturbance score'. This score showed a reduction with increasing age of onset of problematic substance use.

Adult↗
PubMed1993

The multiple dose pharmacokinetics of proguanil.

Proguanil, a prophylactic antimalarial agent, is metabolised by the polymorphic isoenzyme CYP2Cmep in man. In this study the multiple dose pharmacokinetics of proguanil were investigated in subjects who were phenotyped previously as extensive (n = 6) or poor (n = 2) metabolisers of the drug. Steady-state plasma concentrations of proguanil were achieved within 48 h in extensive metaboliser subjects and chronic administration of the drug did not appear to alter the disposition of proguanil or that of its active metabolite, cycloguanil. The currently recommended dosage regimen appears to be appropriate for extensive metabolisers of proguanil. Poor metabolisers of proguanil had significantly lower plasma concentrations of the active metabolite cycloguanil compared with extensive metabolisers. Thus, even on multiple dose administration these subjects may not achieve adequate plasma concentrations of cycloguanil. Deficient metabolism of proguanil to cycloguanil leads to an increased appearance of the N-dealkylated metabolite p-chlorphenylbiguanide in the urine of poor metabolisers.

Adult↗
PubMed1993

Interactions among primaquine, malaria infection and other antimalarials in Thai subjects.

1. The pharmacokinetics of rac-primaquine (45 mg base) and its principal plasma metabolite, carboxyprimaquine have been investigated in healthy Thai adults prior to and following a single oral dose of mefloquine (10 mg kg-1). 2. Primaquine was rapidly absorbed, attaining peak plasma concentrations (median and range) of 167 (113-532) micrograms l-1 in 2 (1-4) h. Thereafter, concentrations declined rapidly with an apparent terminal half-life of 6.1 (1.7-16.1) h and an oral clearance (CLpo) of 33.1 (17.6-49.3) l h-1. Administration of mefloquine had no effect on the values of any of these parameters at the 5% level of significance [Cmax 229 (114-503) micrograms l-1; tmax 3 (2-4) h; t1/2,z 3.9 (1.7-13.5) h; CLpo 34.0 (21.7-49.0) l h-1]. 3. The carboxylic acid metabolite of primaquine achieved maximum concentrations (median and range) of 890 (553-3634) micrograms l-1 at 6 (3-16) h. Thereafter, plasma concentrations of carboxyprimaquine declined to 346 (99-918) micrograms l-1 at 24 h. AUC (0,24 h) was 12737 (6837-27388) micrograms l-1 h. Administration of mefloquine had no effect on the plasma concentrations of this metabolite [Cmax 1035 (174-3015) micrograms l-1; tmax 8 (2-24) h; AUC(0,24) 13471 (2132-17863) micrograms l-1 h]. 4. The effect of falciparum malaria and treatment with quinine (10 mg salt kg-1 p.o.) on the pharmacokinetics of primaquine (45 mg base p.o.) has been investigated in adult Thai patients during and after infection with falciparum malaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Effects of P1060 and aprikalim on whole-cell currents in rat portal vein; inhibition by glibenclamide and phentolamine.

1 Smooth muscle cells of the rat portal vein were dispersed by enzymatic treatment and recordings of whole-cell currents were made by the voltage-clamp technique. The effects of the potassium (K) channel openers, P1060 (0.3-10 microM) and aprikalim (3-30 microM) on these currents were investigated. Antagonism of these agents by glibenclamide and phentolamine was also studied. 2 When cells were clamped at -10 mV, P1060 (1 microM) and aprikalim (3 microM) each induced a slowly-developing K-current (IKCO), the noise of which gradually increased. The rate of onset of IKCO was greater for P1060 than for aprikalim. Current-voltage plots showed that P1060 and aprikalim each caused an approximately 25 mV negative shift of the reversal potential at zero current. 3 P1060 (1 microM) and aprikalim (3 microM) each inhibited the slowly activating, slowly inactivating delayed rectifier current, ITO. 4 Addition of MgATP (5 mM) to the recording pipette inhibited the generation of IKCO by P1060 (1 microM) and reduced the accompanying inhibition of ITO. 5 Stationary fluctuation analysis of the current noise associated with IKCO induced by P1060 (1 microM) or aprikalim (3 microM) at a holding potential of -10 mV indicated that the unitary conductance of the underlying K-channels was 10.5 pS at 0 mV under the quasi-physiological conditions of the experiment. 6 In the absence of K-channel openers, neither phentolamine (30-100 microM) nor glibenclamide (1 microM) affected the magnitude of control non-inactivating currents. However, phentolamine (30-100 microM), but not glibenclamide (1 microM) inhibited the control delayed rectifier current ITO. 7. After induction of IKCO by P1060 (1 microM) or aprikalim (3 microM), subsequent exposure to glibenclamide(1 microM) or phentolamine (30 microM) inhibited this current. After aprikalim-induced reduction of ITO had developed, subsequent exposure to glibenclamide was able partially to reverse the inhibition of ITO whereas phentolamine was without effect. Pre-exposure to glibenclamide (1 microM) prevented both the generation of IKCO by aprikalim (3 microM) and the inhibitory effect of this agent on ITO.8. It is concluded that P1060 and aprikalim each induce the current IKCO by opening the same small conductance, ATP-sensitive K-channel (KATP), an effect which can be inhibited by glibenclamide orphentolamine. The opening of KATP by both P1060 and aprikalim probably involves competition between these agents and ATP for the ATP-control site associated with the channel. Inhibition of the delayed rectifier current, ITO, by P1060 and aprikalim was glibenclamide-sensitive and may be caused by the induction of a state of run-down in the channel which underlies this current.

Adenosine Triphosphate↗
PubMed1993

Levcromakalim may induce a voltage-independent K-current in rat portal veins by modifying the gating properties of the delayed rectifier.

1. Smooth muscle cells of the rat portal vein were dispersed by enzymatic treatment and recordings of whole-cell currents under calcium-free conditions were made by the voltage-clamp technique. The effects of the potassium (K)-channel opener, levcromakalim, on K-currents were compared with those of agents which modify protein phosphorylation. 2. Levcromakalim (1-10 microM) added to the extracellular (bath) fluid caused the development of a non-inactivating current (IK(ATP)) and simultaneously inhibited the delayed rectifier current (IK(V)) in a concentration-dependent manner. On prolonged exposure to levcromakalim (10 microM), IK(ATP) declined and IK(V) was further diminished. 3. Addition to the pipette (intracellular) solution of the selective inhibitor of protein kinase C, calphostin C, itself had no effect on K-currents and did not modify the induction of IK(ATP) or the simultaneous inhibition of IK(V) produced by 1 microM levcromakalim. 4. Addition of the protein kinase inhibitor (PKI(6-22)amide, 1 microM) to the pipette solution caused the production of a glibenclamide-sensitive, non-inactivating current and inhibited IK(V). 5. In an assay system, levcromakalim (10 microM) did not inhibit the activity of purified protein kinase A (Type 1 or Type 2). 6. Addition to the pipette solution of the phosphatase inhibitor, okadaic acid (1 microM), did not itself modify K-currents and had little effect on the simultaneous induction of IK(ATP) and inhibition of IK(V) by levcromakalim (1 microM). 7. When the pipette solution contained 1 mM MgATP (but was depleted of substrates for ATP production), a non-inactivating, glibenclamide-sensitive K-current developed spontaneously in 5 out of 11 cells with the simultaneous reduction of IK(V). In 3 of the 6 remaining cells, addition of the dephosphorylating agent, butanedione monoxime (5 mM) to the bath inhibited IK(V) and stimulated a glibenclamide-sensitive non-inactivating current. 8. Depletion of intracellular Mg2+ slightly enhanced IK(V). Under these conditions, levcromakalim (1 microM and 10 microM) did not significantly induce IK(ATP) or inhibit IK(V). 9. It is concluded that the effects of levcromakalim on K-currents can be mimicked by procedures designed to reduce channel phosphorylation. The results are consistent with the view that levcromkalim dephosphorylates the delayed rectifier channel, KV, which becomes converted into a voltage-independent, non-inactivating form known as KATP. The possible mechanisms which underlie this interconversion are discussed.

Animals↗
PubMed1993

Induction of a glibenclamide-sensitive K-current by modification of a delayed rectifier channel in rat portal vein in insulinoma cells.

In insulinoma cells (RINm5F), the glibenclamide-sensitive K-current (IK(ATP)) which developed spontaneously or after exposure to levcromakalim or to butanedione monoxime was always accompanied by a reduction in the delayed rectifier current (IK(V)). At potentials over which IK(V) was fully activated, the total outward current remained constant. In rat portal vein, the delayed rectifier channel inhibitor, margatoxin, reduced the combined induction of IK(ATP) and inhibition of IK(V) by levcromakalim. These data suggest that the ATP-sensitive K-channel, K(ATP), is a voltage-insensitive state of the delayed rectifier, KV.

Animals↗
PubMed1993

Antagonism of levcromakalim by imidazoline- and guanidine-derivatives in rat portal vein: involvement of the delayed rectifier.

1. In rat whole portal veins, guanabenz (100 nM to 10 microM) and antazoline (100 nM to 100 microM) each increased the amplitude, frequency and duration of spontaneous contractions. In addition, guanabenz (30 microM) and antazoline (30 microM) each antagonized the ability of levcromakalim (3 nM to 10 microM) to inhibit the spontaneous contractions of this tissue. 2. Whole-cell voltage-clamp recordings were made from freshly-isolated rat portal vein cells dispersed by a collagenase/pronase enzyme treatment. The ability of several agents (antazoline, cirazoline, clonidine, guanabenz and phentolamine, each containing an imidazoline or guanidine moiety), to modulate potassium (K) currents and to inhibit the actions of levcromakalim was investigated. 3. Antazoline, cirazoline, clonidine, guanabenz and phentolamine (each at a concentration of 30 microM) had little effect on control non-inactivating currents but inhibited the delayed-rectifier current, IK(V). 4. Levcromakalim (1 microM) induced a non-inactivating current, IK(ATP), and also inhibited the delayed rectifier current, IK(V). 5. Glibenclamide (1 microM) had no effect on control delayed rectifier or non-inactivating currents, but it inhibited the simultaneous induction of IK(ATP) and reduction of IK(V) produced by levcromakalim (1 microM). 6. Antazoline, cirazoline, clonidine and guanabenz (each at a concentration of 30 microM) prevented the induction of IK(ATP) by levcromakalim (1 microM). Phentolamine (30 microM) and clonidine (30 microM) each inhibited the IK(ATP) generated by levcromakalim (1 microM). 7. It is concluded that a variety of agents which possess either an imidazoline (antazoline, cirazoline, clonidine and phentolamine) or a guanidine (guanabenz) moiety within their structure inhibit the delayed rectifier current, IK(V). This action may thus be mediated via a so-called non-adrenoceptor imidazoline binding site. Furthermore, the ability of these ligands to inhibit IK(V) and to antagonize both the induction of IK(ATP) and the vasorelaxation produced by levcromakalim is consistent with the view that the channel (KATP) which underlies IK(ATP) is a voltage-insensitive state of the delayed rectifier K-channel (Kv).

Animals↗
PubMed1993

Flurbiprofen in the prevention and treatment of experimental gingivitis.

A clinical trial was undertaken to examine the effects of a potent cyclooxygenase inhibitor, flurbiprofen, on both developing and established gingivitis in humans. 21 subjects with healthy gingiva abstained from all oral hygiene procedures for 21 days. 7 subjects were prescribed flurbiprofen, 50 mg b.d. beginning from baseline and a control group (Cl, n = 14) were given placebo. Gingival redness and bleeding on probing were assessed at baseline, 7, 14 and 21 days. Crevicular fluid (GCF) samples were also taken to determine concentrations of PGE2, TxB2 and LTB4 at baseline and at 21 days. Results show that flurbiprofen significantly inhibited the development of redness and bleeding (p < 0.001) effects which were associated with a significant inhibition of TxB2 (p < 0.05). There were no apparent flurbiprofen effects on GCF-PGE2 or GCF-LTB4 during this 21-day gingivitis, model To assess the effects of flurbiprofen on established experimental gingivitis, the model was extended to 28 days. On day 21, the Cl group was subdivided into 2 groups of 7 subjects. One group was prescribed flurbiprofen (50 mg b.d.) for 7 days and controls (C2) continued to take placebo. All subjects continued to abstain from tooth cleaning. Pretreatment (day 21) and post-treatment (day 28) comparisons showed that flurbiprofen again significantly inhibited bleeding (p < 0.001), but did not affect redness. Control subjects demonstrated a significant elevation in gingival bleeding on day 28, and this was associated with significant rises in GCF-PGE2 (p < 0.001), GCF-TxB2 (p < 0.01) and GCF-LTB4 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Protein domains governing interactions between E2F, the retinoblastoma gene product, and human papillomavirus type 16 E7 protein.

Human papillomaviruses (HPVs) are the etiological agents for genital warts and contribute to the development of cervical cancer in humans. The HPV E7 gene product is expressed in these diseases, and the E7 genes from HPV types 16 and 18 contribute to transformation in mammalian cells. Mutation and deletion analysis of this gene suggests that the transforming activity of the protein product resides in the same domain as that which is directly involved in complex formation with the retinoblastoma gene product (pRB). This domain is one of two conserved regions (designated CRI and CRII) shared by E7 and other viral oncoproteins which bind pRB, including adenovirus E1A protein. Binding of HPV type 16 E7 protein to pRB has previously been shown to affect pRB's ability to bind DNA and to form complexes with other cellular proteins. In the current study, we map the functional interaction between E7 protein and pRB by monitoring the association between a 60-kDa version of the pRB, pRB60, and the cellular transcription factor E2F. We observe that CRII of E7 (amino acids 20 to 29), which completely blocks binding of full-length E7 protein, is necessary but not sufficient to inhibit E2F/pRB60 complex formation. While CRI of E1A (amino acids 37 to 55) appears to be sufficient to compete with E2F for binding to pRB60, the equivalent region of E7 is neither necessary nor sufficient. Only E7 fragments that contained both CRII and at least a portion of the zinc-binding domain (amino acids 60 to 98) inhibited E2F/pRB60 complex formation. These results suggest that pRB60 associates with E7 and E2F through overlapping but distinct domains.

Amino Acid Sequence↗
PubMed1993

Effect of acute resistance exercise on postexercise energy expenditure and resting metabolic rate.

Two separate experiments were performed to determine the effect of acute resistive exercise on postexercise energy expenditure in male subjects previously trained in resistive exercise. In experiment 1, after measurement of their resting metabolic rate (RMR) at 0700 h and their ingestion of a standardized meal at 0800 h, seven subjects (age range 22-40 yr) beginning at 1400 h completed a 90-min weight-lifting protocol. Postexercise metabolic rate (PEMR) was measured continuously for 2 h after exercise and compared with a preexercise baseline. RMR was measured the following morning 15 h after completion of the workout. In experiment 2, six different men (age range 20-35 yr) completed a similar experimental protocol as well as a control condition on a separate day in which metabolic rate was measured for 2 h after a period of quiet sitting. For both experiments, PEMR remained elevated for the entire 2-h measured recovery period, with the average oxygen consumption for the last 6 min elevated by 11-12%. RMR measured the morning after exercise was 9.4% higher in experiment 1 and 4.7% higher in experiment 2 than on the previous day. In experiment 2, the postabsorptive respiratory exchange ratio was significantly lower the morning after the exercise bout. Strenuous resistive exercise may elevate PEMR for a prolonged period and may enhance postexercise lipid oxidation.

Adult↗
PubMed1993

PEIRS: a pathologist-maintained expert system for the interpretation of chemical pathology reports.

Provision of a comprehensive interpretative service is an important challenge facing chemical pathologists. Attempts to automate report interpretation using expert systems have been limited in the past by the difficulties of rule base maintenance. We have applied a novel knowledge acquisition technique, ripple down rules, in the development of PEIRS (Pathology Expert Interpretative Reporting System), a user-maintained expert system for automating chemical pathology report interpretation. We created over 950 rules for thyroid function tests, arterial blood gases and other test sub-groups in 9 mths of operation. A staff pathologist performed all maintenance tasks as part of his routine duties without any need for computer programming skills. No clerical staff involvement was required. Duplication of rule addition for reports requiring multiple comments was the only limitation to coverage of other high volume test groups. PEIRS is the first expert system for the automated interpretation of a range of chemical pathology reports which operates in routine use without extra staffing requirements. PEIRS does not require "knowledge engineering" expertise. Thus, the knowledge base is flexible and can be easily maintained and updated by the pathologist. Expert systems based on ripple down rules should enable pathologists to provide a comprehensive automated interpretative service within the context of the total testing process.

Chemistry, Clinical↗
PubMed1993

Metabolism of caffeine and theophylline in rats with malaria and endotoxin-induced fever.

1. The effects of malaria infection due to Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of orally-administered caffeine (CA: 10 mg/kg) to its primary metabolites (theobromine (TB), paraxanthine (PX) and theophylline (TH)) were studied in 5-week-old male Wistar rats (n = 5 for each treatment). In separate experiments, the effects of malaria and endotoxin-induced fever on the clearance of i.v.-administered theophylline (TH; 15 mg/kg) were studied in another group of rats. 2. The ratios of CA to the three primary metabolites (TB/CA, PX/CA, PH/CA) determined in a single plasma sample obtained 3 h after CA administration were significantly reduced (p < 0.05) both by malaria and fever compared with control (saline) treatment. The clearance of TH determined from the concentration of TH in a single plasma sample obtained 6 h after TH administration was significantly reduced (p < 0.05) by fever but not malaria (4.0 +/- 0.7 ml/min/kg in controls; 4.2 +/- 0.5 in malaria; 2.4 +/- 0.4 in fever). 3. These results suggest that malaria and fever have different effects on CA and TH metabolism in vivo, probably as a result of different effects on the hepatic isozymes involved.

Administration, Oral↗
PubMed1992

Selective determination, in plasma, of artemether and its major metabolite, dihydroartemisinin, by high-performance liquid chromatography with ultraviolet detection.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of artemether and its major metabolite dihydroartemisinin in plasma has been developed. It involves extraction of plasma with dichloromethane, solid-phase separation of the two analytes and acid decomposition prior to chromatography on a C18 Spherisorb column with a mobile phase of acetonitrile-water (50:50, v/v). Run time is 30 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies.

Artemether↗
PubMed1992

The effect of malaria infection on 3'-azido-3'-deoxythymidine and paracetamol glucuronidation in rat liver microsomes.

The effect of malaria infection on UDP-glucuronosyltransferase (UDPGT) activity was investigated in rat liver microsomes using 3'-azido-3'-deoxythymidine and paracetamol. The Michaelis-Menten parameters, Km and Vmax were calculated and intrinsic clearance values were estimated for normal and infected livers. The results show that malaria infection alters the activity of UDPGT.

Acetaminophen↗
PubMed1992

Recent progress in potassium channel opener pharmacology.

Potassium (K) channel openers comprise a diverse group of molecules capable of opening K channels in excitable cells. These agents exhibit their greatest potency in the smooth muscle system but K channels in cardiac muscle, neurones and in secretory cells are also affected. The development of tissue selectivity is currently one major focus of research and evidence is starting to emerge that this can be achieved. The profound effects of the K channel openers in vivo has led to the suggestion that an endogenous K channel opener might exist and exert an important role in blood pressure homeostasis. The discovery of such a substance--endothelium-derived hyperpolarizing factor--has many implications and its role in cardiovascular regulation is currently under investigation. In vivo, initial studies with the K channel openers emphasized their antihypertensive properties. However, later studies have concentrated on the improvement to coronary blood flow produced by these substances together with their protective effect on the ischaemic myocardium, the basis of which is not fully understood. In spite of great efforts, the K channel which forms the target of these agents in smooth muscle is a matter of controversy. The ability of glibenclamide to antagonize the actions of the K channel openers initially led to the suggestion that an ATP-dependent K channel was their site of action in smooth muscle although the most recent data have implicated a smaller conductance K channel.

Animals↗
PubMed1992

Cocaine in perspective.

In a medical text published in 1883, Dr Benjamin Ward Richardson FRS denounced the evils of tea drinking, suggesting that it commonly gave rise to an 'Extremely nervous semi-hysterical condition'. That this distinguished Victorian physician could take such a view invites a sensitivity toward the perspective within which any debate on drugs is conducted--the historical, cultural and professional assumptions which will colour views as to what needs to be explained and how explanation is to be accomplished. The reality and significance of 'perspective' is further illustrated by examples drawn from contemporary literature which contrast the laboratory and social science approaches to study of cocaine. No one narrow disciplinary perspective on the cocaine problem will suffice; the challenge is to build bridges.

Animals↗
PubMed1992

Role of immersion refractometry for investigating laser-induced effects in cells.

The broad background of scattered light observed in spectra of cell suspensions is reduced by factors of up to 20 by immersion refractometry allowing for improved spectroscopic determination of the absorption properties of cells in the 325-820 nm range. Refractive-index matched spectra of E. coli C1a exhibit a set of resonant features near 422, 561, and 582 nm. Exposure wavelengths are chosen based on this spectrum and cell viability is investigated in E. coli suspensions exposed to 350, 400, 422, 440, and 700 nm radiation delivered in nanosecond pulses with total doses from 500 millijoules to 60 Joules. We observe a loss in cell viability for doses greater than 1 Joule at 422 nm and for all doses at other wavelengths; exposures of less than 1 Joule at 422 nm enhance growth. Excluding exposures at wavelengths within the resonant feature, longer wavelengths are less effective at reducing the viability of E. coli C1a. This indicates the occurrence of at least two absorption processes.

Absorption↗