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G Edwards

Publications and source records attributed to G Edwards.

At least 109 records · Page 6Linked to original sources
PubMed1994

Clinical pharmacokinetics in the treatment of tropical diseases. Some applications and limitations.

In recent years major advances have been made in the clinical pharmacology of many drugs used for the treatment of tropical diseases, particularly in the design and development of dosage regimens for the treatment of severe malaria. For example, by careful manipulation of its rate of administration, chloroquine has been shown to be well tolerated when used for treatment of severe disease caused by susceptible parasites. Similarly, important advances have been made in the rational design of quinine dosage regimens for patients in South East Asia and Africa. Investigation of the pharmacokinetics of mefloquine has drawn attention to the problems associated with its administration as combination therapy with pyrimethamine and sulfadoxine in Thailand. Similarly, evaluation of the pharmacokinetic properties of halofantrine has led to the demonstration that poor and erratic absorption could be just as likely to explain therapeutic failure as resistance of the parasite to effects of this drug. Disposition of the antimalarial biguanides has highlighted the role of host-related effects in the determination of drug response. For example, a small percentage of individuals are unable to convert proguanil (chloroguanide) to its active triazine metabolite, cycloguanil. Finally, agents that reverse chloroquine resistance are currently under development for the treatment of malaria. The importance of assessing the clinical pharmacokinetic properties of potential resistance reversers must be recognised. While limited success has been achieved in antifilarial chemotherapy, other parasitic diseases have been largely neglected with advances in the laboratory still awaiting full recognition of their clinical application. For example, clinical pharmacokinetic concepts may be used to improve the therapy of human hydatid disease. We believe that clinical management of tropical diseases can be improved by the application of clinical pharmacokinetic principles. However, this may not be universally advantageous. For example, the artemisinin (qinghaosu) derivatives are among the most recently developed antimalarials that have great therapeutic promise. Recent evidence suggests that pharmacokinetic data would be of limited value in the design and optimisation of dosage regimens because of its chemical reactivity and the unusual mechanism by which these drugs kill parasites. Similar limitations may apply to the microfilaricidal drug, ivermectin.

Chloroquine↗
PubMed1994

Effect of malaria infection on the pharmacokinetics of paracetamol in rat.

1. Paracetamol (P; 50 and 300 mg/kg i.v.) was administered to the control and malaria-infected (MI) male Wistar rat in order to assess the effect of MI on the metabolism of paracetamol to its glucuronide (PG) and sulphate (PS) conjugates and their excretion in urine. 2. At a dose of 50 mg/kg, neither total clearance (ClT) (controls, 20.3 +/- 0.5; MI, 19.9 +/- 0.9, ml/min/kg; mean +/- SD, p > 0.05) nor the renal clearance of P (ClR) were affected by MI. Although the formation clearance of PG (Clf PG) was decreased by about 40% (controls, 6.6 +/- 1.1; MI, 3.9 +/- 0.9, ml/min/kg, p < 0.05), the formation clearance of PS (Clf PS) was increased by 30% in the MI rat (controls, 8.8 +/- 0.9; MI, 11.2 +/- 1.7, ml/min/kg, p < 0.05), and therefore Clm (controls, 19.7 +/- 0.5; MI, 19.2 +/- 0.8, ml/min/kg, p > 0.05) was unchanged by MI. 3. At a dose of 300 mg/kg, MI produced a significant decrease in the total clearance of P (ClT) (controls, 16.9 +/- 1.0; MI, 11.9 +/- 0.9, ml/min/kg, p < 0.05), metabolic clearance (Clm) (controls, 15.9 +/- 1.4; MI, 11.3 +/- 0.9, ml/min/kg, p < 0.05) and the formation clearance of PG (Clf PG) (controls, 7.9 +/- 1.3; MI, 4.7 +/- 1.5, ml/min/kg, p < 0.05) without affecting Clf PS and ClR of P. 4. These findings indicate that MI impairs the glucuronidation of paracetamol in rat in vivo at both the low and high doses of P. Increased sulphate formation appeared to compensate for decreased glucuronidation at the lower dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1994

Effect of an experimental malaria infection on the metabolism of phenacetin in the rat isolated perfused liver.

1. The effect of infection with the rodent malaria parasite Plasmodium berghei on the metabolism of phenacetin has been investigated in a rat isolated perfused liver preparation. 2. A bolus dose of phenacetin (10 mg) was introduced into the perfusate reservoir of both control (n = 4) and malaria-infected (n = 4) liver preparations, and samples of bile and perfusate were collected (0-4 h) for hplc analysis of phenacetin, paracetamol and its phase II metabolites. 3. Whereas malaria had no effect on the hepatic clearance of phenacetin (control: 0.64 +/- 0.15 versus malaria: 0.66 +/- 0.14 ml min-1), there was a significant reduction in the hepatic clearance of generated paracetamol (control: 1.22 +/- 0.15 versus malaria: 0.41 +/- 0.08 ml min-1) and the total recovery in bile and perfusate of paracetamol glucuronide (control: 1.18 +/- 0.44 versus malaria: 0.29 +/- 0.20 mg). There was no significant change during malaria infection in the total recovery of either phenacetin (control: 1.30 +/- 0.73 versus malaria: 0.79 +/- 0.36 mg) or paracetamol sulphate (control: 0.81 +/- 0.25 versus malaria: 0.74 +/- 0.16 mg),

Acetaminophen↗
PubMed1994

Carriers of healthcare's load of information.

As the market for telemedicine products and services expands, many long distance telecommunications carriers and regional Bell operating companies developed strategies for meeting healthcare's needs. Some initiated projects to display their capabilities or to receive returns on investments in telecommunications infrastructures. Their capabilities and use of advanced technologies vary. The level of their healthcare commitment and involvement also varies. Regional Bell companies compete fiercely with each other and with national carriers for consulting and implementation contracts, unrestricted by service area boundaries. On the following pages, representatives from most of the major telecommunications carriers express their firms' healthcare strategies and offer synopses of their notable healthcare projects. For many, their resources are vast, their expertise undisputed. Access to high-quality healthcare services stands to benefit from their involvement.

Health Services Needs and Demand↗
PubMed1994

The chemotherapy of onchocerciasis XVII. A clinical evaluation of albendazole in patients with onchocerciasis; effects of food and pretreatment with ivermectin on drug response and pharmacokinetics.

Three pharmacokinetic studies were conducted in Ghanaian patients in support of investigations of albendazole and its combination with ivermectin in the treatment of onchocerciasis. These included dose-finding studies, investigations into the influence of a fatty meal on the relative bioavailability of albendazole as assessed by the measurement of concentrations of albendazole sulphoxide and the effect of prior treatment with ivermectin on antiparasitic efficacy and plasma concentrations of albendazole suphoxide. Increasing the dose of albendazole from 800 mg x 3 daily to 1200 mg x 3 daily produced no additional antiparasitic effects although plasma concentrations of albendazole sulphoxide were increased in proportion to dose size. Moreover, the plasma concentration vs time profiles suggest that most of the effects observed may have been due to the first 800 mg dose. Administration of ivermectin had no effect on the pharmacokinetics of albendazole sulphoxide and there was no additive effect on the parasite. Albendazole was well tolerated and its administration 5-7 days after ivermectin produced little additional reaction. Although it is not macrofilaricidal, it does possess important chemosterilant properties which are enhanced by its administration with a fatty breakfast. Under these conditions, the relative bioavailability of albendazole is increased four-fold. These studies support further work with albendazole administered with food either as a single dose, as multiple single doses repeated at intervals of several months and its coadministration with ivermectin. They also encourage the belief that a more potent and bioavailable benzimidazole may be macrofilaricidal or a permanent chemosterilant for Onchocerca volvulus on single dosage.

Adolescent↗
PubMed1993

Transcription factor E2F binds DNA as a heterodimer.

E2F is a mammalian transcription factor that appears to play an important role in cell cycle control. DNA affinity column-purified E2F from HeLa cells reproducibly exhibits multiple protein bands when analyzed by SDS/PAGE. After electrophoretic purification, electroelution, and refolding of the individual protein components, the E2F DNA binding activity of the individual proteins was poor. However, upon mixing the individual components together, a dramatic (100- to 1000-fold) increase in specific DNA binding activity was observed. The five protein bands isolated can be separated into two groups based on apparent molecular mass. Optimal reconstitution of activity requires one of the two proteins found in the group of larger molecular mass (approximately 60 kDa) and one of the three proteins in the smaller-sized group (approximately 50 kDa). The reconstituted heterodimer is identical to authentic affinity-purified E2F by three criteria: DNA-binding specificity, DNA pattern, and binding to the retinoblastoma gene product. A recently cloned protein with E2F-like activity, RBP3/E2F-1, is related to the protein components of the group of larger molecular mass, as determined by Western blot analysis and reconstitution experiments. These data suggest that E2F, like many other transcription factors, binds DNA as an oligomeric complex composed of at least two distinct proteins.

Adenoviruses, Human↗
PubMed1993

Effect of malaria infection and endotoxin-induced fever on phenacetin O-deethylation by rat liver microsomes.

We have investigated the effect of malaria infection with the rodent parasite Plasmodium berghei and fever induced by Escherichia coli endotoxin on the metabolism of phenacetin to paracetamol by rat liver microsomes from young (4 weeks old) male Wistar rats (N = 5 in control and fever groups; N = 10 in malaria-infected group). Following determination of % parasitaemia, the malaria-infected group was divided into a low parasitaemia subgroup (N = 5; mean % parasitaemia = 9.87 +/- 2.6) and a high parasitaemia subgroup (N = 5; mean % parasitaemia = 36.6 +/- 8.1). The control group received normal saline. Total microsomal protein was not significantly affected by fever or malaria infection while cytochrome P450 levels were reduced by approximately 50% in the high parasitaemia subgroup, 20% in the low parasitaemia subgroup and 20% in the endotoxin-treated group. Phenacetin-O-deethylation kinetics were biphasic in both control and malaria-infected rats, but monophasic in endotoxin-treated rats. Total apparent intrinsic clearance (CL(int),total; calculated as Vmax/Km; Vmax is maximum velocity, Km is Michaelis constant) of phenacetin was reduced approximately 6-fold in low parasitaemia, 30-fold in high parasitaemia and 35-fold in fever. There was a poor correlation between CL(int),total and % parasitaemia (r = -0.6). However, log CL(int),total correlated inversely with % parasitaemia (r = -0.9), suggesting that Cl(int),total decreased exponentially with an increase in % parasitaemia. Phenacetin O-deethylation is a marker for cytochrome P4501A2 activity and the results of the present study suggest that both malaria infection and fever might specifically reduce P4501A2 activity in the rat.

Acetaminophen↗
PubMed1993

Effect of malaria infection and endotoxin-induced fever on the metabolism of antipyrine and metronidazole in the rat.

Antipyrine and metronidazole were administered as a cocktail to young (4 weeks old) male Wistar rats (N = 12 for each treatment) to investigate the effect of malaria infection due to the rodent parasite Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of the two compounds in vivo. Control rats received normal saline. Antipyrine and metronidazole clearances were estimated from a single saliva sample while the formation clearances of their metabolites (in malaria-infected and control rats) were estimated from the product of clearance of parent drug and the fraction of the administered dose excreted as metabolites in urine in 24 hr. Rats treated with endotoxin produced no urine during this period. Malaria infection had no effect on clearance of antipyrine or on formation clearance of any of its metabolites. However, the clearance of metronidazole was reduced by approximately 20% compared with controls as a result of decreased formation of hydroxymetronidazole. Fever decreased clearance of both antipyrine and metronidazole by approximately 36% and 23%, respectively. These results demonstrate that both malaria infection and fever can influence P450-dependent drug metabolism and the effects seen appear to be isozyme-selective.

Animals↗
PubMed1993

Bupivacaine and Kaltostat reduces post-operative donor site pain.

A prospective double blind controlled trial was carried out to examine the differences in post-operative split skin graft donor site pain between sites dressed with three differently treated types of dressing; a dry calcium alginate dressing (Kaltostat Britcair), a saline moistened Kaltostat dressing and a bupivacaine hydrochloride (0.5%) moistened Kaltostat dressing. There was a significant reduction in post-operative pain in the Kaltostat and bupivacaine group (group 3) at 24 and 48 h when compared to the other two groups (p < 0.04). There was no difference in ease of removal of dressings or the quality of wound healing on day 10 between the three groups. This study demonstrates a significant reduction in post-operative pain in bupivacaine soaked Kaltostat without reducing the beneficial effects of Kaltostat on donor site healing and we recommend its use in clinical practice.

Adult↗
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↗