Biomedical subjects
G G Graham
Publications and source records attributed to G G Graham.
Application of a simplified method to determine bioavailability of an oral dose of phenytoin.
The bioavailability of capsules of phenytoin was determined by two methods: a method involving the numerical integration of the Michaelis-Menten equation and an alternative method involving fitting the time course of plasma concentrations, following the administration of the reference intravenous dosage, to an empirical quadratic function of time. The latter procedure requires much simpler computations. The two methods yielded very similar estimates of the rate and extent of absorption of phenytoin. Total absorption was 0.90 +/- 0.05 and 0.89 +/- 0.05 (mean +/- SE, n = 6) using the methods of numerical integration and quadratic curve fitting, respectively. Both methods indicated that the rate of absorption of phenytoin was inconsistent and slow. Half the total absorption of phenytoin occurred over 2.5 +/- 0.3 hr but the remainder was absorbed very slowly over a period of about 30 hr. Empirical functions may be more generally useful in the determinations of the bioavailability of drugs, particularly if some aspects of the disposition are saturable.
Pharmacokinetics of tiaprofenic acid in normal rabbits and rabbits subjected to joint immobilisation.
In a previous study, tiaprofenic acid (TA) was administered daily over a 30-day period at 5 and 10 mg/kg of body weight subcutaneously (s.c.) to animals with arthritis induced by immobilisation. The 10 mg/kg dose exacerbated the loss of proteoglycan from joint cartilage but the 5 mg/kg dose showed protective effects on articular cartilage. These results led us to investigate the concentration of TA achieved in synovial fluid of both the immobilised and non-immobilised rabbit joints after single s.c. doses of 5 or 10 mg/kg. The half-lives of elimination of TA from the synovial fluids of the immobilised joints were 1.27 and 1.07 h after the 5 and 10 mg doses, respectively, and 0.66 and 0.39 h in the non-immobilised contralateral joints. Clearances from synovial fluid to plasma were found to be 0.41 and 0.55 ml/h/kg from the immobilised joints after the 5 and 10 mg doses, respectively, and 0.11 and 0.25 ml/h/kg from the non-immobilised contralateral joints. The peak concentration of TA achieved in synovial fluid of immobilised knee joints after a single s.c. injection of 10 mg/kg was approximately two times greater than the concentrations achieved after administration of 5 mg/kg by the same route and two to six times greater than the levels achieved after oral administration of TA at 600 mg/day in humans.
Third World conference on variability in response to anti-rheumatic drugs, Singapore, July 22-24, 1992.
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Quality-protein maize with a high fat content as a weaning food.
Few advances would contribute more to the growth and well-being of infants and children in the developing world than the making available of acceptable staple foods that are easy to grow and process, nutritionally complete enough to serve as the major weaning food, and safe without refrigeration. High-fat quality-protein maize (QPM), grown in Mexico, had > 10% of its energy as well-balanced protein and > 15% as fat. When it was fed to six recovering malnourished infants to provide 85-88% of dietary energy, all of 9.8% protein calories, and all of 13.5% fat calories, it was easily consumed and tolerated. In comparison with a fiber-free, casein-based diet, fecal wet and dry weights of children consuming two varieties of high-fat QPM were three to four times greater, and apparent digestibilities of energy were 86 +/- 3 and 86 +/- 4 versus 97 +/- 1%, of carbohydrate 88 +/- 3 and 89 +/- 5 versus 100%, and of nitrogen (N) 77 +/- 4 and 75 +/- 4 versus 89 +/- 2% of intake. High "biological values," 43 +/- 10 and 46 +/- 13 versus 43 +/- 10% of absorbed N, led to comparable apparent N retentions: 33 +/- 8 and 35 +/- 9 versus 38 +/- 9% of intake. Results were similar to those from earlier studies with Peruvian QPM with a typical fat content. Fat absorptions from QPMs were nearly complete, equal to those from separated vegetable oils in the casein diet. Breath H2s were suggestive of significant colonic salvage of incompletely digested maize carbohydrates.
[Peruvian corn of high protein quality. Digestibility and use in malnourished children].
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Medicinal chemistry of gold.
In order to determine the mechanism of action of the anti-arthritic gold complexes, it is necessary to understand the physicochemical properties of these complexes and the exchange of ligands which may occur under physiological conditions, since these factors control the cellular uptake and effects of the gold complexes. Present leads to the forms of gold which may be taken up by cells include the metabolism of the injectable complexes to aurocyanide which is quite a potent inhibitor of the oxidative burst of neutrophils and an even more potent inhibitor of the proliferation of lymphocytes. Further metabolism of aurocyanide to Au(III) complexes is also possible. The orally active complex, auranofin, is active in various cellular systems but the relevance of its in vitro actions to its clinical effects is not known, in part, due to its unknown metabolism. A potentially active derivative of auranofin is a presumed metabolite which can be transferred from plasma to red blood cells. If this metabolite is taken up by red blood cells, then it may be taken up by target cells with consequent pharmacological activity.
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.
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.
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.
Tryptophan, tube-feeding, and hypoalbuminemia.
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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.
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.
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.
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.
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.