Gastrointestinal transit of Sinemet CR in healthy volunteers.

The gastrointestinal transit and systemic absorption of Sinemet CR (50/200) and standard Sinemet (25/100) have been studied in fasting and "fed" healthy human subjects. Both formulations were labeled with a gamma-emitting radionuclide, and their gastric emptying, colon arrival, and in vivo dissolution profiles were monitored using gamma scintigraphy. The standard dosage forms were found to disperse soon after administration and to empty rapidly from both the fasting and the "fed" stomach. The erosion of the controlled-release (CR) system was independent of food. Dosing after a light breakfast altered the gastric emptying profile of the CR formulation and led to significant differences in the plasma levels of levodopa.

A comparison of some psychological and physiological effects exerted by zetidoline (DL308) and by oxazepam.

In a double-blind, balanced crossover study, eight healthy male volunteers ingested either DL-308 (10 mg), DL-308 (20 mg), oxazepam (30 mg) or placebo. Subjective estimates of coordination and anxiety, objective performance measurements and cardiovascular measurements were taken at 1, 3, 5 and 8 h after ingestion. DL-308 (20 mg) exerted a strong sedative effect as judged by self-reported coordination scores and performance on logical reasoning and reaction time tests. The effect was evident almost immediately and, on the coordination and reasoning tests, lasted up to 8 h following ingestion. Attention is drawn to the need to extend performance testing in order to maximise test sensitivity. No drug had any consistent or strong influence on cardiovascular measures.

Characterisation of the in vivo behaviour of a controlled-release formulation of levodopa (Sinemet CR).

The gastrointestinal transit and systemic absorption of Sinemet CR (50-200) controlled-release tablets and standard Sinemet (25-100) immediate-release (IR) tablets have been studied in fasted and fed healthy human subjects. Both formulations were labelled with a gamma-emitting radionuclide and their gastric emptying, colon arrival and in vivo disintegration profiles monitored using gamma scintigraphy. The IR dosage forms were found to disperse soon after administration and to empty rapidly from both fasted and fed stomachs. Erosion of the CR system was independent of food or stomach pH. The CR tablet was observed to disintegrate fully in the gastrointestinal (GI) tract, resulting in complete release of levodopa over a 3-4 h time period. Considerable intersubject variation was found to exist for levodopa absorption. Absorption was more protracted with Sinemet CR than with standard Sinemet, due to the controlled release characteristics of the tablet matrix. There was no rapid initial absorption phase and instead, a gradual build-up in the absorption profile occurred.

In-vitro enhancement of cholesterol dissolution by commonly used drugs.

A rotating disc apparatus was used to study the dissolution of cholesterol in sodium cholate solutions and ox bile. Drugs with structures that render them capable of lowering interfacial resistance were tested and shown to increase cholesterol dissolution rates in both systems. In sodium cholate solutions, loperamide (3 X 10(-4)M) increased the rate of dissolution by over six times, and a similar effect was observed with amitriptyline (3 X 10(-3)M), diphenhydramine (3 X 10(-3)M), dicyclomine (3 X 10(-3)M) and propantheline (3 X 10(-3)M). These drugs are as effective as benzalkonium chloride at these concentrations. Amitriptyline, propantheline, dicyclomine and diphenhydramine also increased cholesterol dissolution rates into ox bile. If these drugs are excreted into human bile in sufficient quantities and in an active form they may be able to enhance the speed of cholesterol gallstone dissolution therapy.

The inhibitory effect of phlorhizin and phloretin on hexose transport in the liver.

The inhibitory effect of phlorhzin on renal tubular glucose absorption has been known for a long time now. But its aglycone, phloretin is almost completely devoid of such an action in the kidney although it is more active than phlorhzin on sugar transport mechanism in human erythrocytes. The present investigation was designed to find out the effects of these two chemically related substances on hexose transport in the liver. The effect of 1mM phlorhzin or ImM phloretin on the transport of D-stereoisomers of glucose, galactose and fructose using the first pass extraction technique. It was found that phloretin was a better inhibitor of hexose transport in the liver. The difference between the effect of phlorhizin, and the phloretin was highly significant. The inhibitory pattern of the two chemical substances on the three hexoses indicate a discrimination between galactose transport and glucose or fructose transport in the liver.

How to :use games in medical education.

There is tremendous scope for greater use of games in medical education. In this introductory article, the authors explain what sets games apart from other learning activities, discuss the place of games in the curriculum, and list sources of information for interested teachers. This paper will be followed, in the next issue, by a detailed description of three examples of learning through games in biochemistry, physiology and pharmacology.

Interactions between monosaccharides and disaccharides during uptake by the perfused liver of rat.

The extractions of D-glucose, L-glucose, D-fructose and D-galactose by the isolated liver of rat perfused at constant flow were estimated by paired tracer dilution. The effects on these of 25 mM concentrations of these monosaccharides, of alpha-methyl-glucoside and of the disaccharides sucrose, maltose, and lactose were measured. Inferences were drawn from these data about the transport of monosaccharides at the sinusoidal surface of the liver cells. The hepatic clearances of the isomeric monosaccharides consistently ranked D-glucose (at 5.5 X 10(-3) M) greater than D-galactose (2.5 X 10(-5) M) greater than D-fructose (3.2 X 10(-7) M) much greater than L-glucose (2 X 10(-6) M). This implies at least that there are membrane transport mechanisms with distinctly lower affinity for the other sugars than for D-glucose. Glucose entry was stereoselective, and interactions amongst some of the sugars were demonstrated. A reproducible pattern of differential inhibition of D-glucose entry by the competing sugars at 25 mM was found. The consistent lack of effect of sucrose excluded a mere osmotic effect. The pattern of inhibition of D-fructose entry by the same sugars was qualitatively similar to that of D-glucose, whereas that of D-galactose was distinctive. The disaccharide competitors, lacking cell entry, can exert their effects only at the external surface. These markedly discriminate between D-glucose and D-galactose. The penetrating sugars, however, show mutual competition.(ABSTRACT TRUNCATED AT 250 WORDS)

The hepatocellular uptake of glucose, galactose and fructose in conscious sheep.

1. Surgical techniques for chronic catheterization of hepatic and portal veins in the sheep are described. These catheters remained usable for 2-6 months and did not alter hepatic morphology. 2. Hepatocellular uptake of monosaccharides was estimated from their ability to pass the boundaries of the sucrose space in a double indicator dilution procedure in conscious fed sheep. 3. A large proportion (81%) of D-glucose carried in the portal blood was found to enter an hepatic cellular compartment. 4. The radioactive label of D-glucose infused in the portal vein remained associated with D-glucose in hepatic venous blood samples during the experimental period. 5. A large proportion (74%) of an infused trace of D-galactose, a smaller proportion (33%) of D-fructose, and negligible amounts of L-glucose were taken up in a single passage through the liver. 6. Raised blood concentrations of sucrose or of methyl-alpha-D-glucoside (Me-alpha-DG) significantly diminished the proportional uptake of D-glucose. Raised blood concentrations of glucose, galactose or Me-alpha-DG diminished the proportional uptake of D-galactose. Raised blood concentrations of fructose diminished the proportional uptake of fructose. 7. Neither total hepatic blood flow changes nor competitive effects within the cell could account for these findings. 8. It is concluded that these monosaccharides enter the liver cell by facilitated diffusion, and share at least some of the membrane elements that mediate this process. It seems likely that only a proportion of the glucose-transporting apparatus is accessible to galactose.

A new method for measuring power output in a single leg extension: feasibility, reliability and validity.

A method is described for measuring the explosive power of the leg in extension which has been found safe and acceptable for all age groups and levels of physical capability. The extension movement takes 0.25-0.40 s in a push through 0.165 m against a flat pedal. At the end of the push the leg is fully extended. The movement is made seated so that the forces are contained between the buttocks and the foot. The seat position is adjusted for leg length and the push is transmitted by a lever and chain to spin a flywheel. The gearing is such that resistance to the movement remains velocity of the flywheel is measured by an optoswitch and used to calculated the average leg extensor power (LEP) in the push. The reliability of the power measurement was evaluated in 46 subjects ranging in age from 20 to 86 years; they included medical students and geriatric day patients. They were tested on two occasions separated by a week. The maximal values on the first occasion (best of at least five trials) ranged from 30 to 300 W (mean +/- 1 SD = 154 +/- 88 W). There was no significant difference on re-test and the coefficient of variation was 9.4%. In a subgroup of 9 non-naive subjects who were measured by an experienced observer it was 6.3%. As expected, power was lower in women than in men and declined sharply with age. The sex difference was less when the values were expressed as power per body mass; a sharp age-related decline remained.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in drug metabolism with increasing age: 1. warfarin binding and plasma proteins.

1 A decrease was found in the binding capacity of elderly people for warfarin. 2 The decrease in binding correlated with a fall in plasma albumin concentrations. 3 No changes in the association constant were observed.

Changes in drug metabolism with increasing age: 2. phenytoin clearance and protein binding.

1 Comparison of phenytoin clearance showed a marked increase in people over 65 years of age compared with people under 45 years of age. 2 This difference was apparent if phenytoin was given orally or intravenously. 3 Phenytoin clearance correlated inversely with phenytoin binding and plasma albumin, both of which were found to be reduced in the elderly.

Blood pressure reduction in elderly: a randomised controlled trial of methyldopa.

A total of 123 out of 549 elderly residents of local authority welfare homes in Nottinghamshire were found at screening to have a standing or lying diastolic blood pressure of 100 mm Hg or more. These 123 subjects were randomly allocated to simple observation or to treatment with methyldopa. The cumulative mortality was similar in the observed and treated groups and in the normotensive group from which the subjects had been separated. Thus moderate hypertension, whether treated or not, was not a major risk predictor in the elderly population studied.

Glucose carriers at maternal and fetal sides of the trophoblast in guinea pig placenta.

Trophoblast uptake and unidirectional influx of 3H-labeled hexoses were measured relative to L-[14C]glucose (extracellular marker) using a single-circulation, paired-tracer dilution technique. Successive runs were performed in the fetal and maternal circulations of isolated dually perfused guinea pig placentas, obtained from anesthetized dams and perfused for 60--140 min. The leakiness, estimated from the percentage of the L-glucose dose that crossed the trophoblast, varied (25 +/- 3% (SE), n = 28). On the injection side the maximal sugar uptake (Umax) was measured from early venous concentration ratios, since rapid tracer backflux occurred: Umax = (1 -- 3H/14C) x 100. Umax was independent of the leakiness. In all 14 placentas studied, stereospecific saturable transport of D-glucose was demonstrated at fetal (Umax = 56 +/- 4% (SE), n = 14) and maternal (62 +/- 1% (SE), n = 14) surfaces. The mean unidirectional influxes were 3.3 and 3.5 mumol.min-1.g-1, respectively. Uptakes were inhibited by phloretin and less effectively by phlorizin. D-glucose, 3-O-methylglucose, D-mannose and D-galactose had similar Umax values, about four times that of D-fructose. Tracer backflux and transplacental flux were also equal from both sides. It is concluded that similar hexose carriers, which resemble the human erythrocyte carrier, exist at the membrane on both sides of the trophoblast. The nondestructive technique employed characterizes carriers and receptors at the blood side of cells and could be applied to the placenta or other organs in the intact animal.

Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man.

1. The present experiment was undertaken to investigate the influence of oral creatine supplementation, shown previously to increase the total creatine content of human skeletal muscle (Harris RC, Soderlund K, Hultman E. Clin Sci 1992; 83: 367-74), on skeletal muscle isokinetic torque and the accumulation of plasma ammonia and blood lactate during five bouts of maximal exercise. 2. Twelve subjects undertook five bouts of 30 maximal voluntary isokinetic contractions, interspersed with 1 min recovery periods, before and after 5 days of placebo (4 x 6 g of glucose/day, n = 6) or creatine (4 x 5 g of creatine plus 1 g of glucose/day, n = 6) oral supplementation. Muscle torque production and plasma ammonia and blood lactate accumulation were measured during and after exercise on each treatment. 3. No difference was seen when comparing muscle peak torque production during exercise before and after placebo ingestion. After creatine ingestion, muscle peak torque production was greater in all subjects during the final 10 contractions of exercise bout 1 (P < 0.05), throughout the whole of exercise bouts 2 (P < 0.01), 3 (P < 0.05) and 4 (P = 0.057) and during contractions 11-20 of the final exercise bout (P < 0.05), when compared with the corresponding measurements made before creatine ingestion. Plasma ammonia accumulation was lower during and after exercise after creatine ingestion. No differences were found when comparing blood lactate levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycogen resynthesis in human muscle fibre types following exercise-induced glycogen depletion.

1. Studies investigating muscle glycogen resynthesis in man have usually examined mixed-fibred biopsies or have used histochemical methods to estimate single fibre resynthesis. Since the accuracy of the latter is open to debate, this study investigated glycogen resynthesis in type I and II fibres using biochemical methods of analysis. 2. Seven subjects performed one-legged cycling exercise to exhaustion. During the initial 2 h of recovery, subjects consumed 3 g of glucose (kg body mass (BM))-1, and a high carbohydrate diet thereafter. Muscle biopsy samples were obtained from both legs at exhaustion, and from the exercised leg after 3, 10 and 24 h of recovery. 3. In the initial 3 h of recovery, there was a 25 +/- 8% higher rate of resynthesis in type I compared with type II fibres (41 +/- 3 and 31 +/- 4 mmol glucosyl units (kg dry mass (DM))-1 h-1, respectively; P < 0.05). Between 3 and 10 h of recovery, resynthesis in type I fibres declined by 60 +/- 13% to 15 +/- 4 mmol glucosyl units (kg DM)-1 h-1 (P < 0.01), whilst the rate in type II fibres was maintained. Good agreement was found when relating the mixed-fibred muscle glycogen concentration to the mean concentration found in type I and type II fibres (r = 0.96). 4. A discrepancy was found to exist with histochemically derived data reported in the literature. The higher initial glycogen resynthesis rate in type I fibres may be attributable to fibre-type differences in glucose uptake and disposal.(ABSTRACT TRUNCATED AT 250 WORDS)