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G Edwards

Publications and source records attributed to G Edwards.

At least 37 records · Page 2Linked to original sources
PubMed1991

The effect of malaria infection on paracetamol disposition in the rat.

The effect of Plasmodium berghei infection, a rodent malarial model, on the disposition of paracetamol (50 mg/kg, i.v.) was investigated in rats. Malaria infection (MI) resulted in a significant decrease in clearance (control: 21.6 +/- 5.5 vs test: 11.8 +/- 2.9 mL/min/kg, P less than 0.005) with no change in volume of distribution and a significant prolongation of the elimination half-life (control: 30.7 +/- 6.3 vs 53.3 +/- 12.1 min, P less than 0.005) of paracetamol in malaria infected rats. These changes were not related to the severity of MI. Malaria infection also decreased biliary clearance of paracetamol (64%) but not its glucuronide and sulphate conjugates in the bile compared with controls. In addition, glutathione conjugates were not detected in bile samples of malaria infected rats. These data suggest that important pathways of drug detoxification may be compromised by MI in a relatively selective fashion and the relevance of these findings to the clinical use of drugs eliminated by these pathways merits further study.

Acetaminophen↗
PubMed1991

Rapid and sensitive method for the determination of albendazole and albendazole sulphoxide in biological fluids.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of albendazole and its active metabolite albendazole sulphoxide in plasma has been developed. It involves single-step extraction of plasma with dichloromethane, evaporation of the solvent and chromatography on a muBondapak phenyl column with a mobile phase of water containing 1% (v/v) triethylamine-methanol-acetonitrile (70:10:20, v/v) at pH 3.1. Run time is 12 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies and possesses important advantages, notably speed and expense, over current methods.

Adult↗
PubMed1991

The effect of malaria infection on antipyrine metabolite formation in the rat.

We have shown that malaria infection can impair selectively the formation of antipyrine metabolites in the rat. During malaria, a significant increased urinary levels of unchanged antipyrine was observed (control: 1.7 +/- 0.4 vs test: 8.1 +/- 1.1% of dose, P less than 0.001). This was associated with significantly decreased excretion of 3-hydroxymethylantipyrine (control: 24.5 +/- 1.2 vs test: 21.4 +/- 0.7%, P less than 0.001) and 4-hydroxyantipyrine (control: 20.1 +/- 0.9 vs test: 15.5 +/- 1.3%, P less than 0.001) but not norantipyrine compared to control. Following treatment of the malaria infection with halofantrine, only the formation of 3-hydroxymethylantipyrine (control: 25.2 +/- 0.9 vs test: 24.1 +/- 0.6%, P less than 0.05) is impaired. The implications of these findings in relation to metabolism of other antimalarial drugs during malaria remains to be elucidated. Further work is needed to determine the changes in the pharmacokinetics of AP and its metabolites before, during and after MI in the rat in order to give a better insight into the effect of MI on hepatic drug metabolism.

Animals↗
PubMed1991

The practical business of treatment--15. The alcoholism treatment service at the Maudsley Hospital, London.

This article describes the linked clinical, research and teaching functions of the Maudsley's Alcoholism Treatment service. Emphasis is placed on the heterogeneity of the patients who are seen. Therapy must therefore always be patient-specific and the Procrustean insistence that patients should fit the programme rather than the programme fit the patients should be resisted. Within the diversity of approaches which are employed some important common elements can though be identified: detailed case assessment as the necessary basis for everything else, goal setting, a flexible intensity of response, networking with other treatment resources, and attention to methods of patient recruitment. The relationship between outpatient and inpatient services is discussed: about 80% of all new referrals are treated entirely on an outpatient basis. The clinical setting provides a teaching base for the Diploma in Addiction Behaviour. There is a close link between this clinical service and the Addiction Research Unit; issues of clinical and research collaboration and the interpretation and clinical application of research findings are considered. Whatever the theories in which a team believes or the techniques which it practices, the nurturing of hope is the vital essence of the practical business of treatment.

Alcoholism↗
PubMed1991

Addiction as an occupational hazard: 144 doctors with drug and alcohol problems.

Information was abstracted from the hospital notes of 144 doctors who had received treatment for drug and alcohol dependency. These problems affect those in every specialty, and at all degrees of seniority. Over half came into treatment following medical referral. Social morbidity was an important contributory reason for seeking help. The mean age at presentation was 43.1 years; the mean duration of problematic use prior to this was 6.4 years for drug misusers and 6.7 years for alcohol misusers. Alcohol was the current problem for 41.6% and drug misuse for 26.4%; 31.3% were misusing both alcohol and drugs at presentation. Of the 83 subjects who were misusing drugs, only four had ever used blackmarket supplies. Psychotropic agents are readily available to doctors, but the consequences of this are not addressed. Those who develop dependency suffer a delay of years before reaching help.

Adult↗
PubMed1991

Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha 1-acid glycoprotein and the binding of quinine in Malawian children.

1. We have measured plasma concentrations of alpha 1-acid glycoprotein (AGP) in 18 healthy children and 85 children with falciparum malaria in Malawi. In addition, we determined the degree of protein binding of quinine (QN) in the plasma of 52 of the patients and each of the healthy controls. 2. The mean plasma AGP concentration was higher in patients than in controls (P less than 0.0001) and remained elevated 3 weeks after complete resolution of malaria infection. 3. The mean unbound QN fraction was significantly less (P less than 0.00001) in patients with malaria (0.128 +/- 0.037) than in controls (0.193 +/- 0.051) and significantly higher (P = 0.02) in convalescence (0.153 +/- 0.067) than during acute illness. 4. There were highly significant negative correlations between plasma AGP concentration and the free QN fraction in spiked plasma samples (r = -0.534, P less than 0.0001, n = 93) and in clinical samples (r = -0.484, P less than 0.00001, n = 225). There was a significant positive correlation between plasma concentrations of AGP and another acute phase reactant, C reactive protein (P less than 0.001).

Animals↗
PubMed1991

Pharmacokinetics of halofantrine in Thai patients with acute uncomplicated falciparum malaria.

Twelve patients with acute uncomplicated falciparum malaria were admitted to the Hospital for Tropical Diseases for 42 days. The patients were treated with halofantrine 500 mg 6 hourly for three doses and halofantrine and its desbutyl metabolite were analysed in plasma by h.p.l.c. Cmax values of halofantrine and desbutylhalofantrine (n = 12) were 1192 +/- 410 (mean +/- s.d.) and 397 +/- 160 ng ml-1 with tmax values of 16 +/- 2 and 55 +/- 26 h, respectively. AUC was 60.6 +/- 23.9 and 48.5 +/- 22.2 mg l-1 h, respectively, for halofantrine and its metabolite. Halofantrine cured 83% of the patients but in two patients a reduction only in asexual parasitaemia was seen and no overall parasite clearance occurred. One of these, however had relatively low plasma concentrations of both halofantrine and its desbutyl metabolite and it appeared to be a case of inadequate treatment rather than true resistance. We suggest that the large intersubject variability in plasma drug concentrations may relate in part to its poor and inconsistent bioavailability and this rather than true resistance might be responsible for some of the treatment failures.

Acute Disease↗
PubMed1991

Differences between the effects of cromakalim and nifedipine on agonist-induced responses in rabbit aorta.

1. The effects of cromakalim on endothelium-denuded rabbit aortic strips were compared with those of the calcium (Ca2+) entry blocking agent, nifedipine. 2. Pre-incubation with cromakalim or nifedipine had no significant effect on the initial phasic component of noradrenaline (NA)-induced responses. 3. Cromakalim (0.3-10 microM), but not nifedipine, inhibited the maintained tonic contractions produced by NA. The effects of cromakalim were antagonized by raising extracellular [K+] or by glibenclamide. 4. Nifedipine inhibited contractions produced by KCl (40 mM) whereas cromakalim had no effect. 5. In Ca2(+)-free physiological salt solution (PSS), cromakalim produced a significant inhibition of both the refilling of and the release of Ca2+ from NA-releasable Ca2+ stores, whereas nifedipine was ineffective. 6. In tissues preloaded with 42K+ cromakalim (0.3-10 microM) produced a concentration-dependent increase in the 42K+ efflux rate coefficient. NA (0.3 microM) also produced an increase in the rate of efflux of 42K+, an effect which was not antagonized by nifedipine (0.3 microM). 7. When microelectrodes were used, cromakalim (1-10 microM) produced a maintained concentration-dependent membrane hyperpolarization. However, low concentrations of cromakalim (less than 1 microM) which relaxed the aorta had no effect on membrane potential. NA had no significant effect on membrane potential. 9. It is concluded that the ability of cromakalim to relax NA-induced contractions in rabbit aorta is not exerted by the indirect closure of nifedipine-sensitive Ca2+ channels. Instead, cromakalim may exert a direct inhibitory action on Ca2+ uptake into and release from Ca2+ stores and additionally inhibit the pathway through which Ca2+ passes from the extracellular fluid to intracellular Ca2+ stores.

Animals↗
PubMed1991

Comparison of the effects of several potassium-channel openers on rat bladder and rat portal vein in vitro.

1. The ability of several K-channel openers to inhibit KCl-induced contractions of rat bladder detrusor and spontaneous mechanical activity in rat portal vein was examined. 2. Lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 dose-dependently relaxed rat detrusor, precontracted with 20 mM KCl. With the exception of pinacidil, concentrations of these agents below 30 microM did not inhibit 80 mM KCl-included contractions. Pinacidil (10 microM) produced a small, but significant (P < 0.05) relaxation of 80 mM KCl-induced mechanical activity. Minoxidil sulphate and BRL 38226 produced some relaxation of 20 mM but not 80 mM KCl-induced contractions. 3. Glibenclamide (0.3-3 microM) antagonized the relaxant effects of lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 in a competitive manner (pA2 values 6.3-6.6). The effects of minoxidil sulphate and BRL 38226 were fully antagonized by 3 microM glibenclamide. 4. Lemakalim, pinacidil, S 0121, BRL 38226 and minoxidil sulphate were each approximately 8 times more potent as inhibitors of the spontaneous contractions of rat portal vein than KCl-induced contractions of the rat detrusor. Minoxidil sulphate was approximately 30 times more potent in the rat portal vein than in the bladder. This may indicate that either minoxidil sulphate is acting at different recognition sites in these two tissues, or that this compound has an additional mechanism of action in the portal vein. 5. With the exception of minoxidil sulphate, all the compounds tested stimulated 86Rb efflux and 42K efflux from preloaded rat detrusor strips. The stimulated 86Rb efflux was qualitatively but not quantitatively similar to the stimulated 42K efflux. Minoxidil sulphate stimulated 42K efflux from rat portal vein but not from rat bladder. 6. It is concluded that all the compounds tested cause relaxation of rat detrusor predominantly by Kchannel opening. Selectivity for bladder rather than vascular smooth muscle was not shown by any compound.

Animals↗
PubMed1991

The effect of fever on quinine and quinidine disposition in the rat.

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.

Animals↗
PubMed1991

The influence of alpha 1-acid glycoprotein on quinine and quinidine disposition in the rat isolated perfused liver preparation.

We have studied the effect of 0.5 and 2.0 g L-1 of alpha 1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2.0 g L-1) resulted in a significant decrease in clearance [quinine study (control: 9.6 +/- 2.9 vs test: 3.1 +/- 1.2 mL min-1); quinidine study (control: 9.8 +/- 2.4 vs test: 3.5 +/- 1.1 mL min-1]) and volume of distribution [quinine study (control: 1198 +/- 416 vs test: 466 +/- 95 mL); quinidine study (control: 1352 +/- 459 vs test: 317 +/- 24 mL]) but not the elimination half-life compared with control. At the lower concentration (0.5 g L-1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0.5 to 2.0 g L-1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0.5 g L-1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.

Animals↗
PubMed1991

Who was Jellinek?

Explore the source record for details and available documents.

Alcoholism↗
PubMed1991

Latest developments in K-channel modulator pharmacology.

Synthetic modulators of smooth muscle potassium (K) channels now comprise a large number of chemically-diverse molecules which possess either K-channel-opening or K-channel-blocking properties. First-generation openers are typified by the benzopyran, BRL38227 which exhibits little tissue selectivity in vivo or in vitro. Under current development are second-generation molecules such as the benzopyran, HOE234, and the guanidine, LY211808, both of which exhibit some tissue selectivity. Until recently, tetraethylammonium, the aminopyridines and the sulphonylureas like glibenclamide were the most important types of synthetic K-channel blocker available. Recent work has now identified several novel K-channel blockers active in smooth muscle. These include the bradycardic agents tedisamil and alinidine and the anorectic agent ciclazindol. The effects of K-channel openers on transmitter release are now under detailed study. Although postganglionic neuroeffector transmission in blood vessels seems little affected, transmitter release in bronchial, gastrointestinal and genitourinary preparations is reduced. Whether these effects are primarily pre- or post-ganglionic is unclear. Transmitter release is also reduced in certain areas of the CNS. No clear picture of the type of smooth muscle K-channel with which the openers interact has yet emerged. The ability of glibenclamide to antagonise the effects of K-channel openers apparently favours the involvement of KATP, although the selectivity of glibenclamide and the existence of KATP in smooth muscle remain to be firmly established.

Angina Pectoris↗
PubMed1990

Specialist versus general practitioner treatment of problem drinkers.

The efficacy of specialist versus general practitioner (GP) treatment of problem drinkers was assessed in a randomised controlled trial. 40 problem drinkers referred consecutively to a specialist alcohol clinic by their GP were, after assessment, randomly allocated to either GP or specialist clinic treatment groups. All subjects received initial advice and counselling in the clinic about their drinking. The specialist clinic group received continued care from the clinic including, if necessary, admission to hospital. Patients in the GP group were returned to the care of the GP who was contacted and supported by the specialist. After 6 months of follow-up, there were significant reductions in alcohol consumption and alcohol-related problems in both groups. No significant difference was found between the two groups with respect to the main outcome measures. No differential treatment effect was found with the more severely dependent drinkers. The findings show that after an initial detailed assessment and advice session, the treatment provided by GPs is at least as effective as that from a specialist clinic with respect to improvements in drinking behaviour and alcohol-related problems. After initial assessment and advice, specialist clinics should encourage GPs to become more involved in the subsequent care of problem drinkers. Such a practice should be based on the individual patient's needs and the adequacy of support offered to GPs.

Adult↗
PubMed1990

Lack of effect of halofantrine on hepatic drug metabolism in the rat in vivo and in vitro.

The effect of the antimalarial drug halofantrine (Hf) on hepatic drug metabolism in the rat has been studied in vivo and in vitro using different model drug substrates. Hf in vitro produced no significant effect on the values of Km and Vmax for aminopyrine N-demethylation or 7-ethoxycoumarin O-dealkylation in microsomes incubated with Hf (0.01-0.1 mM) or on the rate of N-demethylation of aminopyrine or O-dealkylation of Ec in microsomes produced from rats dosed chronically with Hf (200 mg/kg) for 4 days. The disposition of antipyrine (Ap) was investigated in the isolated perfused rat liver preparation (IPRL). Following the administration of bolus doses of Hf (0.5, 2.5 and 5.0 mg) no significant changes were observed in the half-life (t1/2), clearance (Cl) or apparent volume of distribution (Vd) for Ap compared with controls. Pentobarbitone induced sleeping time was also assessed in mice. No significant difference was determined in time to recovery of the righting reflex for mice receiving Hf as single oral doses or chronically over 4 days when compared with appropriate controls. The potential for selective isoenzyme effects was studied in vivo. The three principal urinary metabolites of Ap, norantipyrine (Np), 3-OH and 4-OH Ap were measured in rat urine, with no significant change in urinary recovery of Ap or any of the metabolites in the presence of Hf (1.25 mg/kg i.p.) compared with controls. These results suggest that Hf is not, in contrast to many commonly used quinoline antimalarials, a potent or specific inhibitor of drug metabolism in vitro or in vivo.

Animals↗