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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
PubMed1990

Testicular endocrine effects of alkane methanesulphonates related to the Leydig cell cytotoxic compound, EDS.

A series of compounds structurally similar to the specific Leydig-cell-cytotoxic substance ethane-1,2-dimethanesulphonate (EDS) were examined for Leydig cell toxicity in the rat. Within 48 h of a single injection of butane-2,3-dimethanesulphonate (BDS), propan-1,3-dimethanesulphonate (P-1,3-DS) or propan-1-chloro-2,3-DS (PCDS) there was a reduction in serum and testicular testosterone levels. The serum luteinizing hormone (LH) concentration was reduced following BDS or P-1,3-DS, and Leydig-cell LH receptors (measured by 125I-labelled hCG binding) were reduced by less than 15%, from which it is concluded that these compounds are not selectively toxic to Leydig cells. However, PCDS reduced human chorionic gonadotropin (hCG) binding by greater than 70% and could be considered to be a potential toxin. The effects of hydroxy-ethanemethane-sulphonate (HEMS), 1,5,2,4-dioxadithiepane-2,2,4,4-tetraoxide (cyclic SOSO), PCDS, propan-2,3-DS, alpha-chlorohydrin and cyclohexane-1,2-dimethane-sulphonate were compared with the effects of EDS 7 days after injection. Systemic toxicity, indicated by a loss of body weight, was associated with cyclic SOSO, PCDS and EDS, although only EDS and PCDS reduced both testicular hCG binding and serum and testis testosterone levels consistent with Leydig-cell toxicity. Further studies indicated that the potency of PCDS in reducing testicular hCG binding and serum and intratesticular testosterone levels was similar to that of EDS. However, unlike EDS, PCDS was systemically toxic and also reduced LH, which could at least in part account for changes in testosterone secretion. The experiments confirm the unique cytotoxicity of EDS. Loss of specific Leydig-cell cytotoxicity and an increase in systemic toxicity occurred when the EDS molecule was altered, even if the distance between the alkylating centres was maintained. The mechanism of action of EDS remains elusive.

Animals↗
PubMed1990

Potassium channel openers and vascular smooth muscle relaxation.

Potassium channel openers comprise a diverse group of chemical agents which open plasma-lemmal K-channels. They show selectivity for smooth muscle, although K-channels in cardiac and skeletal muscle, neurones and the pancreatic beta-cell are also affected at relatively high concentrations. In addition, at least one endogenous K-channel opener of vascular origin--endothelium-derived hyperpolarizing factor--exists and in man plays a role in modulating blood vessel tone. The type of K-channel involved in the actions of both exogenous and endogenous K-channel openers is still uncertain, although a prime candidate in smooth muscle seems similar to the [ATPi]-modulated K-channel in the pancreatic beta-cell. This review focuses attention on the action of these agents in vascular smooth muscle and on the possible clinical exploitation of their powerful vasorelaxant properties.

Animals↗
PubMed1990

Structure-activity relationships of K+ channel openers.

Seven groups of synthetic agent, distinguished by a combination of their chemical and pharmacological characteristics exert some or all of their effects by opening plasmalemmal K+ channels primarily in smooth muscle. Progress over the past two years now allows broad structure-activity relationships to be formulated within many of the individual groups of agent. Gillian Edwards and Arthur Weston review the historical basis of these discoveries and comment on the significance of new developments. They focus on the search for tissue and channel selectivity, two factors likely to be important for the successful clinical deployment of these substances as antihypertensive and bronchodilator agents.

Animals↗
PubMed1990

Withdrawal symptoms and alcohol dependence: fruitful mysteries.

Five types of question are posed around withdrawal symptoms. (1) The reasons for the fluctuations over time in medical awareness of alcohol's capability to produce withdrawal symptoms. (2) What type of drinking schedules instigate withdrawal experience? (3) Do withdrawal phenomena get worse over time? (4) The 'addiction memory' question; and lastly (5) Is withdrawal a reinforcer for drinking behaviour? These issues point to a need for a renascence in the kind of research which is based on clinical observation and on listening to what patients have to tell, with such lines of work brought into much closer contact than before with corresponding laboratory investigation.

Alcohol Drinking↗
PubMed1990

The disposition of amodiaquine in Zambians and Nigerians with malaria.

1. Oral amodiaquine (AQ) has been used to treat patients with symptomatic malaria in Zambia (n = 14) and Nigeria (n = 5). Clinical cure was obtained in all patients and no serious adverse drug reactions were seen. 2. As in healthy subjects, AQ achieved low plasma concentrations. Plasma concentration vs time profiles of desethylamodiaquine (AQm) from the present study did not differ from those obtained from healthy subjects. 3. In contrast to previous results from healthy subjects, the mean ratio of red cell (RBC): plasma AQm concentration in the present study was 0.80: 1 at the start of the study and rose in a linear manner (r = 0.873; P less than 0.01) to 3.04: 1 by the end (n = 10; P less than 0.01). The final mean value was similar to that seen in healthy subjects. 4. These data show that there are differences in the disposition of orally administered AQ between healthy subjects and patients with clinical malaria. The relevance of this observation to the frequency of adverse reactions to AQ in these two groups is not established.

Administration, Oral↗
PubMed1990

The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism.

1. Based on the ratio of drug to active metabolite excreted in urine approximately 3% of a healthy Caucasian population showed a reduced ability to convert proguanil to cycloguanil. 2. Pharmacokinetic analysis showed that this observation resulted from a reduced oral clearance of proguanil in these individuals (245, 534 and 552 ml min-1) compared with the rest of the population (858 +/- 482 ml min-1). 3. Peak plasma concentrations of active metabolite were significantly lower in these subjects (54.2, 26.8 and 51.7 ng ml-1) compared with the rest of the population (141 +/- 45.2 ng ml-1). 4. The observed variability may result from the polymorphic metabolism of proguanil in man.

Biotransformation↗
PubMed1990

The action of diazoxide and minoxidil sulphate on rat blood vessels: a comparison with cromakalim.

1. The actions of diazoxide and minoxidil sulphate have been compared with those of cromakalim in rat aorta and portal vein. 2. Diazoxide and minoxidil sulphate hyperpolarized the rat portal vein in a similar manner to cromakalim. 3. Cromakalim, diazoxide and minoxidil sulphate increased 42K and 86Rb efflux from rat portal vein, although minoxidil sulphate had only a small effect on 86Rb efflux. 4. Cromakalim, diazoxide and minoxidil sulphate increased 42K efflux from rat aorta but only cromakalim and diazoxide increased 86Rb efflux from this tissue. 5. Glibenclamide inhibited the relaxant actions of cromakalim, diazoxide and minoxidil sulphate on rat aorta and the increase in 42K efflux produced by these agents in this tissue. 6. Diazoxide relaxed an 80 mM KCl-induced contraction of rat aorta, whilst cromakalim and minoxidil sulphate were without effect. 7. Cromakalim, diazoxide and minoxidil sulphate had no effect on cyclic AMP or cyclic GMP concentrations in rat aorta. 8. It is concluded that diazoxide and minoxidil sulphate like cromakalim exhibit K+ channel opening properties in vascular smooth muscle. Diazoxide exerts an additional inhibitory action not related to the production of cyclic AMP or cyclic GMP. The action of minoxidil sulphate may be primarily located at a K+ channel which is relatively impermeable to 86Rb.

Animals↗
PubMed1990

Flurbiprofen in human crevicular fluid analyzed by high-performance liquid chromatography.

The aim of this study was to determine whether the non-steroidal anti-inflammatory drug, flurbiprofen, which has been shown to be an inhibitor of alveolar bone loss in human periodontal disease, is present in human crevicular fluid (CF) following oral dosing. A method is described whereby routine high-performance liquid chromatography is used to detect the drug in only 20 microliters of CF. 5 volunteers abstained from toothbrushing for 21 days to induce experimental gingivitis and increase the resting flow of CF. 100 mg of flurbiprofen was taken by each volunteer on d 21-28. On d 21 and 28, serum and CF samples were taken prior to dosing and afterwards at 1, 2, 4 and 6 hours. On d 21 the mean peak concentration of the drug in serum was about 11 micrograms/ml and was found between 1-2 h after dosing. The respective values for CF (d 21) were 0.32 micrograms/ml and 4 h. On d 28 flurbiprofen was detected in both fluids prior to dosing. The mean peak concentrations after dosing had increased to 13.13 micrograms/ml (serum) and 0.46 micrograms/ml (CF) although the levels of the drug in CF remained relatively constant throughout the observation period on d 28. The results indicate that flurbiprofen may be detected in human CF after oral administration and that the levels are in excess of the plasma level, which in beagles has been shown to inhibit alveolar bone loss in periodontal disease.

Administration, Oral↗
PubMed1990

The effect of malaria infection on the disposition of quinine and quinidine in the rat isolated perfused liver preparation.

The effect of malaria on the disposition of quinine and quinidine was studied in livers isolated from young rats infected with merozoites of Plasmodium berghei, a rodent malaria model, and non-infected controls. Following bolus administration of quinine (1 mg) or quinidine (1 mg) to the 100 mL recycling perfusion circuit, perfusate was sampled (0-4 h) and plasma assayed for quinine and quinidine by HPLC. Higher quinine (AUC:6470 +/- 1101 vs 3822 +/- 347 ng h mL-1, P less than 0.001) and quinidine (AUC: 6642 +/- 1304 vs 4808 +/- 872 ng h mL-1, P less than 0.05) concentrations were observed during malaria infection (MI). MI resulted in decreased quinine clearance (CL) (0.33 +/- 0.08 vs 0.64 +/- 0.09 mL min-1 g-1, P less than 0.001) and volume of distribution (Vd) (53.0 +/- 13.3 vs 81.2 +/- 23.7 mL g-1, P less than 0.05) but no significant change in elimination half-life (t1/2) (1.93 +/- 0.6 vs 1.37 +/- 0.25 h, P greater than 0.05). With quinidine, however, MI resulted in decreased CL (0.38 +/- 0.16 vs 0.64 +/- 0.09, P less than 0.05) with no change in Vd and a significant increase in t1/2 (1.62 +/- 0.42 vs 0.88 +/- 0.22, P less than 0.01). In summary, the hepatic disposition of quinine and quinidine is altered in the malaria-infected rat.

Animals↗
PubMed1990

The potassium channel openers: a new class of vasorelaxants.

Cromakalim, pinacidil, nicorandil, diazoxide and RP-49356 belong to the class of drugs termed potassium channel openers. In rat portal vein diazoxide, like cromakalim, abolished spontaneous mechanical and electrical activity and in rat aorta caused an increase in 86Rb efflux and inhibited KCl(20 mM)-induced contractions. However, in contrast to cromakalim, diazoxide (greater than 100 microM) also inhibited mechanical responses evoked by 80 mM KCl in rat aorta suggesting that it possesses pharmacological properties in addition to K channel opening. Since glibenclamide can attenuate the effects of cromakalim and diazoxide in vascular tissues, it is possible that a channel resembling the ATP-sensitive K channel found in pancreatic beta-cells may be involved in the vasorelaxant effects of these agents. However, differences exist in the order of potency of cromakalim and diazoxide for producing smooth muscle relaxation and for decreasing insulin secretion in pancreatic beta-cells. Furthermore galanin (which opens ATP-sensitive K channels in beta-cells) increases mechanical activity in rat portal vein. It is anticipated that new chemical developments will produce K channel opening molecules with greater potency and tissue selectivity.

Animals↗
PubMed1990

The chemotherapy of onchocerciasis. XIV. Studies with mebendazole citrate.

Twenty patients from an area of vector control in the savannah region of northern Ghana with moderate to heavy infection with Onchocerca volvulus were randomised to receive two priming doses of levamisole 150 mg on two occasions followed either by mebendazole-citrate (500 mg) given daily or twice daily for 14 days. The two dose levels produced a similar effect on skin microfilariae (80-88% reduction) with a very mild systemic clinical reaction: low levels were maintained over 42 weeks. Both regimes were embryotoxic for O. volvulus; an effect which was transient in the single dose group but persisted for more than three months in the twice daily dose group. Mebendazole-citrate appeared to be absorbed more predictably than has been observed previously for mebendazole. The degree of systemic exposure as determined by measurement of AUC (0-24 h) was 2.5 times greater for the twice daily dose as compared to the single dose and this fact was reflected in the efficacy of the two dose regimes against the adult female worms at three months.

Adult↗
PubMed1989

Determination of artelinic acid in blood plasma by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method is described for the analysis of the new antimalarial drug artelinic acid in blood plasma. The influence of mobile phase composition, pH and type of mobile phase modifier on the retention of artelinic acid on the reversed-phase column is reported. Linear calibration curves were obtained in the range 0-500 ng/ml artelinic acid. Intra-assay and inter-assay variability in the analysis of plasma samples spiked with the drug were less than or equal to 15%. Plasma samples of the drug were found to be unstable when stored at -20 degrees C, the concentration of the drug decreasing by over 50% within three days. Plasma samples stored at -70 degrees C remained stable for at least two weeks. Initial pharmacokinetic studies in the rat showed that following intravenous administration, plasma concentrations of artelinic acid declined mono-exponentially. The relatively short elimination half-life (17 +/- 5 min) of artelinic acid is consistent with what is known for qinghaosu and its derivatives.

Animals↗
PubMed1989

Determination of arteether in blood plasma by high-performance liquid chromatography with ultraviolet detection after hydrolysis acid.

A reversed-phase high-performance liquid chromatographic method is described for determination of the antimalarial agent arteether in blood plasma based on its decomposition in acidic medium and measurement of the major decomposition product, which has been identified as an alpha,beta-unsaturated decalone. Linear calibration curves were obtained in the range 0-250 ng/ml arteether and the recovery of the drug from plasma was found to be quantitative. There is no interference from desoxyarteether, the putative major metabolite of arteether. The method has been applied to the measurement of arteether in the plasma of rats given 110 mg/kg by intramuscular injection of the drug as a solution in sunflower oil.

Animals↗
PubMed1989

Blasted with ennui.

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3,4-Methylenedioxyamphetamine↗