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Biomedical subjects

G G Graham

Publications and source records attributed to G G Graham.

At least 19 recordsLinked to original sources
PubMed1992

Gold complexes and activation of human polymorphonuclear leukocytes. Dissociation of changes in membrane potential and oxidative burst.

The effects of the gold compounds on the alteration of membrane potential of polymorphonuclear leukocytes (PMN) in response to various stimulants have been compared with their effects on the oxidative burst. The present studies have shown that gold complexes [auranofin (AF), aurothiomalate (Autm), aurocyanide (Au(CN)2-)] have contrasting effects on the membrane potential of 3,3'-dipentyloxacarbocyanine [di-O-C5(3)] loaded PMN. Au(CN)2- at concentrations which inhibit the oxidative burst of PMN did not affect the membrane depolarization after activation of PMN by phorbol myristate acetate (PMA) and N-formyl-methionyl-leucyl phenylalanine (FMLP); Autm slightly stimulated the oxidative burst but had no effect on the depolarization of PMN. In contrast, AF inhibited the depolarization of stimulated PMN to an extent depending upon the concentration of AF, the time of preincubation and the stimulus. The membrane depolarization of PMN caused by PMA, FMLP and concanavalin A (ConA) was inhibited by AF (5 microM) but the depolarization induced by calcium ionophore (A23187) was not affected. AF at the same conditions inhibits the oxidative burst of PMN induced by all these single stimuli including the calcium ionophore. Dissociation of membrane depolarization and superoxide generation caused by AF was also seen in PMN activated by two stimuli. AF (5 microM) had little initial inhibitory effect on the oxidative burst of PMN stimulated by combinations of PMA and ConA or PMA and FMLP whereas it almost totally blocked the depolarization caused by these combinations. Preincubation of cells with 5 microM AF for less than 5 min prior to the addition of PMA allowed membrane depolarization which was followed rapidly by repolarization. None of the gold complexes studied had any effect on the resting membrane potential of PMN.

Auranofin↗
PubMed1992

Effect of aspirin on ulcer site blood flow in cat stomachs.

Radioactive microspheres were used to measure blood flow in the cat stomach during exposure to saline, 0.075 M HCl, and then 15 and 30 min after exposure to 20 or 40 mM aspirin in HCl. At the end of the experiment, the stomach wall was divided into ulcerated regions and adjacent nonulcerated areas. When exposed to saline, both regions had similar blood flow: 27 +/- 5 and 25 +/- 5 ml.min-1.100 g-1 (means +/- SE). Addition of acid caused a significant increase in blood flow to 41 +/- 7 ml.min-1.100 g-1 only at those sites that eventually ulcerated in the presence of aspirin. In the adjacent nonulcerated regions, blood flow was 31 +/- 5 ml.min-1.100 g-1 and was not significantly greater than the flow recorded during saline exposure. Aspirin caused ulcer site blood flow to increase dramatically to 89 +/- 12 and 122 +/- 18 ml.min-1.100 g-1 after 15 and 30 min, whereas the adjacent nonulcerated tissue rose to 40 +/- 6 and 44 +/- 5 ml.min-1.100 g-1, respectively. The ulcer site hyperemia with acid alone suggests higher mucosal permeability in these regions allowing back-diffusion of acid and injurious agents. The present data obtained in the cat do not support the notion that ischemia plays a role in initiating nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, but rather that acute NSAID ulcers are associated initially with a hyperemia.

Animals↗
PubMed1991

Auranofin inhibits the activation pathways of polymorphonuclear leukocytes at multiple sites.

In order to characterize the mechanism by which the anti-rheumatic gold complex auranofin (AF) affects the functions of resting and activated polymorphonuclear leukocytes (PMN) the following studies were performed: (1) The effect of AF on the major processes involved in the respiratory burst of PMN: glucose transport and phosphorylation; hexose monophosphate (HMP) shunt activity in intact cells and in a cell-free system; superoxide production by particulate fractions and intact PMN measured as lucigenin-dependent chemiluminescence. (2) A comparison of the effects of AF added to the PMN before, at the time of, or subsequent to the stimulants [N-formyl-methionyl-leucyl phenylalanine (FMLP), concanavalin A (ConA), calcium ionophore (A23187) and phorbol myristate acetate (PMA)]. (3) The effect of AF on PMN activated by two stimulates (PMA, ConA) added sequentially. AF (0.1-10 microM) caused a dose-dependent inhibition of lucigenin-dependent chemiluminescence regardless of the activator (FMLP, ConA, A23187, PMA) when AF was added before the activator. In contrast, when AF was added to PMN after stimulation, it inhibited only the chemiluminescence of PMN stimulated by PMA. Furthermore, the chemiluminescence was largely unaffected by AF in sequentially activated PMN. The relative sensitivity to AF of the various processes studied indicates that blockade of the activation signal appears to be responsible for inhibition of the respiratory burst of PMN.

Auranofin↗
PubMed1991

Effect of dietary fiber and starch on fecal composition in preschool children consuming maize, amaranth, or cassava flours.

Metabolic balance studies were carried out in young children fed diets based on maize, amaranth, or cassava flours and in corresponding casein controls. Dietary fiber intakes were 22.2, 20.5, and 9.0 g/day for the maize, amaranth, and cassava groups, respectively. Fecal energy losses at least doubled in all test diets when compared with the corresponding controls and could generally be accounted for by recovered fiber in the feces. Fecal starch was also a significant contributor to fecal energy in the cassava group. All cassava fiber was recovered in the feces, whereas only 48.4 and 16.3% were recovered from ingested maize and amaranth. 2,6-Diaminopimelic acid (DAPA), an indicator of bacterial mass, was highest in the cassava group. Expired breath hydrogen was highest for those consuming maize or cassava. Resistant starch may have been responsible for the high DAPA and breath hydrogen values in the cassava group.

Breath Tests↗
PubMed1991

Stress in mice increases intrinsic pentobarbitone sensitivity by a predominantly pharmacodynamic mechanism.

1. Mice were swum for 3 min at room temperature. 2. After this stress 'sleeping time' in response to pentobarbitone was increased by over 70%. 3. Loss of 'righting reflex' occurred in these stressed animals at brain concentrations of pentobarbitone which were 40% lower than those needed for 'sleep' in the unstressed mice, indicating a true increase in sensitivity to the drug. 'Waking' (the return of the righting reflex) occurred at identical levels in both groups. 4. Kinetic analysis showed that the rates of absorption, elimination and transfer between plasma and brain were slower in the swum than in the unswum mice, probably because of the reduced body temperatures produced by the swimming.

Animals↗
PubMed1991

The effect of aurothiomalate on the oxidative burst of polymorphonuclear leukocytes varies with the quantity of drug in myocrisin ampoules.

The antirheumatic drug, sodium aurothiomalate (GSTM), is not a well defined substance and chemical changes occur in the heat sterilization of the commercial ampoules (Myocrisin). In a comparison of the pharmacological properties of Myocrisin with freshly prepared solutions of GSTM, their effects on the chemiluminescence of polymorphonuclear leukocytes (PMN) activated by phorbol myristate acetate (PMA) were studied. Chemiluminescence was measured in the presence of GSTM from solid material and from Myocrisin ampoules. Myocrisin from 1 and 5 mg ampoules and GSTM in fresh solutions heated at 95 degrees C for 30 min inhibited chemiluminescence, whereas Myocrisin from the higher strength (10-50 mg) ampoules and GSTM in unheated solutions showed no effect at low concentrations and enhancement of chemiluminescence at higher concentrations. Since the gold complexes present in the different strength Myocrisin ampoules do not have identical biological effects, the use of GSTM in investigational studies should involve consideration of its source.

Capsules↗
PubMed1990

The activation of gold complexes by cyanide produced by polymorphonuclear leukocytes--I. The effects of aurocyanide on the oxidative burst of polymorphonuclear leukocytes.

It has been suggested that the antiarthritic gold complex, aurothiomalate (Autm), is activated by its conversion to aurocyanide by polymorphonuclear leukocytes (PMN) which generate cyanide from thiocyanate. In an examination of this hypothesis, a study has been conducted on the effects of aurocyanide on the oxidative burst of polymorphonuclear leukocytes (PMN) and monocytes activated by phorbol myristate acetate (PMA). Aurocyanide produced delayed inhibition of the oxidative burst as shown by its effect on both lucigenin and luminol-dependent chemiluminescence and on the production of superoxide. It was a more potent inhibitor of luminol-dependent chemiluminescence than free thiomalate and other by-products of the reaction between Autm and cyanide. Aurocyanide had a biphasic effect on the PMA-stimulated hexose monophosphate shunt of PMN, with enhancement at 0.1 microM and inhibition at 10 and 100 microM. The activity of aurocyanide was also compared with that of auranofin, an orally active gold complex, which inhibits a variety of functions of PMN and monocytes. At low concentrations, auranofin produced delayed inhibition of chemiluminescence in a similar fashion to aurocyanide but at high concentrations was an immediate inhibitor of the oxidative burst.

Auranofin↗
PubMed1990

The activation of gold complexes by cyanide produced by polymorphonuclear leukocytes--II. Evidence for the formation and biological activity of aurocyanide.

Experiments have been conducted to investigate a possible mechanism which might explain why aurothiomalate (Autm), a gold complex used in the treatment of rheumatoid arthritis, is active in vivo but not in vitro, by testing the hypothesis that Autm is converted to aurocyanide by activated polymorphonuclear leukocytes (PMN) which generate cyanide from thiocyanate, an anion which is present in plasma at concentrations ranging from 20 to 200 microM. Two-stage experiments were conducted in which PMN, in the first stage, were activated by opsonized zymosan in the presence of Autm both with and without thiocyanate. Then, in the second stage, the effect of the drugs on superoxide (O2-) production stimulated by a further addition of zymosan was measured. Autm at concentrations of 10 and 100 microM decreased O2- production if thiocyanate was present, but not if it was absent. By contrast, preformed aurocyanide at 10 and 100 microM decreases O2- production by PMN stimulated by opsonized zymosan both in the presence and absence of thiocyanate. Changes in the ultraviolet spectra of the supernatants of PMN indicated that aurocyanide was formed by activated PMN in the presence of thiocyanate but not in its absence.

Cyanates↗
PubMed1990

Stereoselective disposition of ibuprofen and flurbiprofen in rats.

(R)-2-Arylpropionates are often inverted to the pharmacologically active S-enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)- or (S)-ibuprofen (20 mg/kg), (R,S)-ibuprofen (40 mg/kg), (R)- or (S)-flurbiprofen (10 mg/kg), or (R,S)-flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two-compartment open model with conversion of the R- to S-enantiomers in the central compartment. There was 50 +/- 4% inversion of (R)-ibuprofen, a figure similar to that observed in man and (R)-ibuprofen had a higher clearance (12.6 +/- 1.3 ml/min/kg) than (S)-ibuprofen (7.7 +/- 0.7 ml/min/kg; P less than 0.01). The clearance of (R)-flurbiprofen after racemate (2.3 +/- 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 +/- 0.2 ml/min/kg; P less than 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)-flurbiprofen as determined by area analysis (4.5 +/- 1.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The gold complexes.

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Arthritis, Rheumatoid↗
PubMed1990

A simplified approach to the effect kinetics of atracurium.

The combination of the Hill equation, which describes the concentration-effect relation, with the monoexponential function for the terminal decline of plasma concentration, yields a compound time constant, T beta s1/2. This constant is a combination of the terminal elimination half-life (T beta 1/2) and the exponent (s) of the Hill equation and may be used to describe the time course of recovery from neuromuscular block. The constant may be estimated by non-linear curve fitting to f, the effect expressed as fraction of maximal effect, or by linear regression of the logit function of f. The methods were validated using plasma concentration and effect data from seven patients administered atracurium. The two methods utilizing effect data alone yielded values of 4.2 (0.7) min and 4.3 (0.5) min (mean (SEM)), respectively, for T beta s1/2 compared with 4.1 (0.6) min when the constant was calculated using plasma concentration data for T beta 1/2 and curve fitting to the concentration-effect data to determine s. These methods offer an objective measure of the rate of recovery and a means of testing if redistribution or elimination is the primary process in the termination of drug effect.

Atracurium↗
PubMed1990

The nutritional value of oat flour for very young children.

Whole groat flour was consumed by nine infants and young children as 22.5, 45, or 67% of total diet energy (one half of 6.4%, all of 6.4%, or all of 9.6% protein energy). Isonitrogenous and isoenergetic casein control diets were given. Apparent absorption of oat nitrogen (N) was consistently around 75% of intake (casein, 87%), but absorptions of oat energy, carbohydrate, and fat, as percentages of intake, decreased disproportionately as oat flour intake was doubled and then tripled. Apparent retentions were 39 +/- 5% of mixed oat-casein protein intake in the 22.5% diet, the preceding and following casein controls being 38 +/- 8% (NS) and 44.4% (p less than 0.05) of the intakes; 32 +/- 6% from oats in the 45% diet, controls 38 +/- 5 and 46 +/- 5% (both p less than 0.05), and 33 +/- 11% from oats in the 67% diet, controls, 36 +/- 9% (NS). Fasting plasma free total essential amino acid (TEAA) levels of children consuming 45% oats were low (562 +/- 119 mumol of TEAA/L) and did not change significantly after meals. Fasting molar proportions of individual essentials (millimoles of EAA per mole of TEAA) were similar to those from milk protein diets and did not vary significantly 3 and 4 h after feeding, suggesting that no individual amino acid, but rather protein digestibility, was first limiting to N retention. Oats are a satisfactory source of energy, protein, and fat for very young children and many infants.

Amino Acids, Essential↗
PubMed1990

Acceptability, tolerance, and nutritional value of a rice-based infant formula.

An infant formula based on high protein rice flour, with added lysine and threonine, was evaluated in recovering malnourished infants. Acceptability, tolerance, and the digestibility of most major nutrients (energy 93.9 +/- 0.7%, fat 96.9 +/- 0.3%, carbohydrate 96.8 +/- 0.6% of intake) were excellent. Digestibility of protein, as with all rice products, was moderately low (80.1 +/- 3.3%), but its high biological value made N retention equal to that from casein. Plasma-free amino acids were consistent with the low essential/total amino acids ratio found in cereals, with slower absorption, and with the possibility that leucine was the first-limiting amino acid. Absorptions of Ca, Mg, PO4, and Zn were considered satisfactory. Energy costs of weight gain and the estimated percentage N in the weight gained during 14 days were comparable to those attained with the highest quality cow's milk-derived formulas in children of similar ages and nutritional status.

Diarrhea, Infantile↗
PubMed1990

Neuromuscular sensitivity to atracurium in humans.

The relation between plasma concentration and the effects of atracurium was studied in seven patients anaesthetised with thiopentone, fentanyl and nitrous oxide-oxygen. The response to train-of-four stimulation at ten-second intervals with tetanic stimuli applied every five minutes were recorded. The first sign of transmission returning after complete blockade was usually the post-tetanic facilitated twitch, which was noted when the mean atracurium concentration was 1.15 mg 1(-1) (SD 0.77). The most sensitive parameter was the train-of-four ratio, which recovered to 0.5 when the concentration was 0.217 mg 1(-1) (SD 0.56), compared with a concentration of 0.271 (SD 0.85) at 50% recovery for twitch height, 0.221 (SD 0.029) for tetanic peak and 0.231 (SD 0.079) for tetanic fade. The value for the train-of-four ratio differed significantly (P less than 0.05) from that for the twitch height, but other differences were not significant. Once recovery commenced, these four parameters recovered at similar rates, with recovery indices (25 to 75% responses) of 14.8 (SD 1.7), 14.0 (SD 1.0), 14.3 (SD 1.8) and 13.7 (SD 2.1) minutes respectively. Post-tetanic facilitation was most marked during severe but incomplete blockade and tetanic stimulation temporarily reversed the atracurium-induced decrease in train-of-four ratio. Clinically, the use of tetanic stimulation did not improve the sensitivity of neuromuscular monitoring, but post-tetanic count may be useful where monitoring of profound relaxation is required.

Atracurium↗
PubMed1990

Quality-protein maize as the sole source of dietary protein and fat for rapidly growing young children.

Earlier studies demonstrated that quality protein maize (QPM), with increased lysine and tryptophan and decreased leucine contents, was more digestible and supported 45% greater nitrogen retention than common maize. Ten recovering malnourished children (ages 13 to 29 months, height-ages 5 to 15 months, weight-ages 3 to 11 months) have now received 90% of their diet energy and 100% of protein and fat from QPM. Energy intake was adjusted to allow them to reach the 50th centile of weight-for-length (according to the National Center for Health Statistics) in 90 days (two completed 60 days only). Growth was compared with that of 10 children receiving modified cow's milk formula (CMF). Energy intakes (QPM 110 +/- 15, CMF 106 +/- 12, corrected for absorption to 94 and 97 kcal/kg.d), crude energy costs of gain (43 +/- 9 and 40 +/- 10, corrected to 37 and 37 kcal/g), linear growth (1.23 +/- 0.24 and 1.33 +/- 0.26 cm/mo), gains in height-age (3.1 +/- 0.7 and 3.3 +/- 1.2 mo), weight gain (2.6 +/- 0.6 and 2.6 +/- 0.8 g/kg.d), and final sums of fat folds (24.3 +/- 3.5 and 27.2 +/- 2.9 mm) were not different. Gains in weight-age were greater (7.5 +/- 2.3 vs 5.4 +/- 1.6 months, P less than .05) and serum albumin decreased (4.10 +/- 0.24 to 3.77 +/- 0.31 g/dL, P less than .01) during QPM feeding. Plasma-free total essential amino acids and ratio of these to total essential amino acids were less after QPM than after CMF diets. Equal growth rates with QPM and CMF diets offer great potential for developing- and developed-country children.

Animals↗
PubMed1990

Post-prandial plasma aminograms in the assessment of protein quality for young children: maize and grain amaranth, alone and combined.

Post-prandial (p.p.) changes in plasma free amino acid (AA) concentrations of children consuming a single source of protein at critical levels are determined by its digestibility and total essential AA/total AA ratios; the molar proportion of the limiting EAA (EAA/TEAA), if any, will fall significantly in plasma as it is utilized more completely than others. Grain amaranths (Am), reputedly rich in lysine (Lys) and tryptophan (Trp), but moderately deficient in leucine (Leu), should be ideal complements to Lys and Trp-poor, Leu-rich maize (M). Most animal studies confirm this. In children, 20, 30 and even 50 per cent replacement of M proteins with toasted Am proteins had failed to show any gains over M or Am alone: heat losses of Lys were suspected. Plasma obtained during the above studies, before and 3 h and 4 h after the first meal of the last day of consuming Am alone, three M-toasted Am mixtures, or M alone, were analysed for free AAs. Toasted, popped or flaked Am consumption caused significant p.p. falls in molar proportions of Leu from 99 to 85, 88 to 82, and 92 to 75, and of threonine (Thr) from 118 to 108 (popped) and 109 to 97 (flaked) mmol/mol TEAA, suggesting that these were first- and second-limiting EAAs. Post-prandial fall in Lys proportion was questionably significant. The M diet produced highly significant 3-h Leu elevation from 132 to 187, Lys fall from 167 to 135, and Trp fall from 62 to 46 mmol/mol TEAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗