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Biomedical subjects

S T Hall

Publications and source records attributed to S T Hall.

At least 19 recordsLinked to original sources
PubMed2000

The measurement of IgA and IgG transglutaminase antibodies in celiac disease: a comparison with current diagnostic methods.

Celiac disease (CD) is an inflammatory disorder of the small intestine induced by cereal prolamins. The demonstration of IgA endomysial antibodies (EMA) is currently the most reliable serological screen for CD. The antigenic target is transglutaminase. The aim of this study was to develop an ELISA assay for the detection of antibodies to transglutaminase (TGA), and to assess the sensitivity and specificity of TGA for the detection of celiac disease against the benchmarks of jejunal biopsy, antigliadin antibodies (AGA) and EMA. Sera from 57 patients with celiac disease were tested for IgA and IgG TGA, IgA EMA, IgA and IgG AGA, and the total IgA level. The sensitivity, specificity, predictive value and concordance of AGA, EMA and TGA were assessed against the gold-standard biopsy result. IgG plus IgA TGA offered 100% sensitivity in CD patients for whom no dietary intervention had been commenced, with a specificity of 61%. The sensitivity of TGA dropped from 100 to 79% after dietary restriction. In patients on no gluten restriction, there was 100% agreement between TGA and EMA, and 100% agreement between TGA and AGA for the IgA isotype. The false-positive rate for TGA was 53% in Down's syndrome patients and 25% in patients with systemic autoimmune disorders. We conclude that testing for TGA is a reliable diagnostic serology for celiac disease, with improved sensitivity compared with established methods. The results suggest that serial TGA measurements may be a more and accurate marker for dietary compliance than AGA, but prospective studies are required.

Autoantibodies↗
PubMed1999

Salivary IgA subclasses and infection risk in elite swimmers.

The concentrations of total IgA, IgA1 and IgA2 were measured in saliva collected from 25 elite swimmers in the early and late phases of a 7 month training season and compared with the number of respiratory infections during the season. The IgA1 concentrations in the early phase of the training season were significantly associated (P = 0.01) with the number of respiratory infection episodes during the training season. The lower the concentration of IgA1, the greater the number of infection episodes. Swimmers with four or more infections during the training season had significantly lower salivary IgA1 concentrations than those with less than four infection episodes (P = 0.01). The proportion of IgA1 in the saliva of the elite swimmers (80%) was higher than for normal non-exercising adults (60%). A small proportion of athletes had salivary IgA2 concentrations below the detection limit of the assay and the mean concentration of IgA2 was significantly lower than the concentrations for a normal adult population (P = 0.01). This study suggests that measurement of IgA subclasses, in particular IgA1, at the commencement of a training season may predict infection risk in elite swimmers.

Adolescent↗
PubMed1998

Expression of substrate-specific transporters encoded by Plasmodium falciparum in Xenopus laevis oocytes.

When the malarial parasite Plasmodium falciparum multiplies in erythrocytes it dramatically increases uptake of essential metabolic precursors (nucleosides, nucleobases and glucose) and export of lactic acid by undefined mechanisms. The first evidence is provided here, by a detailed study in Xenopus laevis oocytes, that several specific nutrient transporters are the product of P. falciparum genes. We report the expression of nucleoside, nucleobase, hexose and monocarboxylate transport systems in Xenopus oocytes when injected with mRNA isolated from asexual stages of developing P. falciparum parasites. Their properties are distinct from transport events occurring at the infected erythrocyte membrane or the electrophysiologically identified channel localised to the parasitophorous vacuolar membrane. These novel transporters are substrate-specific and stereoselective, and represent a key regulatory step in the acquisition and export of metabolites by intraerythrocytic P. falciparum.

Adenosine↗
PubMed1998

Crithidia luciliae: functional expression of nucleoside and nucleobase transporters in Xenopus laevis oocytes.

The expression of purine-specific nucleoside and base transporters of Crithidia luciliae has been demonstrated in Xenopus laevis oocytes. Poly(A)+-mRNA from C. luciliae, cultured in either purine-replete or purine-starved conditions, was microinjected into X. laevis oocytes. For "purine-replete" mRNA, expression of adenosine and hypoxanthine uptake in microinjected X. laevis oocytes was increased on average 9- and 3-fold above water-injected controls, respectively. Expression of adenosine and hypoxanthine uptake in oocytes microinjected with "purine-starved" mRNA was 8 and 3-fold above water-injected controls, respectively. Substrate competition indicated an adenosine/deoxyadenosine transporter and a separate base transporter specific for hypoxanthine. In contrast to C. luciliae in vivo, where the level of activity of adenosine and hypoxanthine transport was regulated by the level of purines in the medium, the heterologous expression of these transporters (from both purine replete and deplete cultures) in X. laevis oocytes was independent of the extracellular purine concentration. These results may suggest that the presence of specific transporter message is independent of the extracellular purine content, indicating that the regulation of activation and expression of these transporters in C. luciliae may not be under transcriptional control.

Adenosine↗
PubMed1997

Stimulated transport of adenosine, guanosine and hypoxanthine in Crithidia luciliae: metabolic machinery in which the parasite has a distinct advantage over the host.

Nutritional insufficiency is a common environmental extreme to which parasitic protozoa are routinely exposed. In this study of purine salvage mechanisms we illustrate some successful adaptations of the parasite Crithidia luciliae to its environment, particularly in the case of purine stress. In purine-depleted conditions, the insect trypanosome C. luciliae has the ability to increase the rates of transport of adenosine, guanosine and hypoxanthine and the activity of the exoenzyme 3'nucleotidase (3'NTase) during the growth cycle. The dramatic increase in these activities appears after a 72-h period in culture. The increased activity of the purine transporters and 3'NTase could be suppressed by addition to the medium of a purine supplement such as adenosine or hypoxanthine (100 microM). Under conditions where the concentration of purines in the medium could be closely regulated, C. luciliae grown in purine-replete medium (> or = 75 microM purine) exhibited low rates of purine transport and activity of 3'NTase. In comparison, parasites transferred to medium with a low purine source (< or = 7.5 microM adenosine) had levels of adenosine, guanosine and hypoxanthine transport elevated 25-40-fold. The results link the simultaneous increase in activity of the nucleoside and base transporters, 3'NTase activity and a general increase in the purine salvage of C. luciliae to the concentration of purines available at any time to the parasite.

Adenosine↗
PubMed1996

Crithidia luciliae: regulation of purine nucleoside transport by extracellular purine concentrations.

During the growth cycle of the protozoan parasite Crithidia luciliae, there was a dramatic concomitant increase in the rate of adenosine and guanosine transport and 3' nucleotidase (3'NTase) activity after 72-94 hr. The simultaneous increased activities of the nucleoside transporters and 3'NTase could be suppressed by addition to the medium of a purine supplement such as adenosine (100 microM). C. luciliae grown in purine-replete medium (> or = 75 microM adenosine) exhibited low rates of adenosine and guanosine transport whilst parasites transferred to a defined serum-free medium containing < or = 7.5 microM adenosine demonstrated elevated levels of both adenosine and guanosine transport up to 25- to 40-fold. The increased activity of the nucleoside transporters was inhibited by cycloheximide (10 microM). Under conditions of purine depletion 3'AMP and 3'GMP inhibited the adenosine and guanosine transporters, respectively. However, in the presence of a purine supplement (100 microM), neither 3'AMP nor 3'GMP was an effective inhibitor of nucleoside transport. Our results link the increased activity of the nucleoside transporters to the increased activity of the 3'NTase, indicating the activation of a purine salvage system not previously reported in other organisms.

Adenosine↗
PubMed1996

Volume-regulatory amino acid release from the protozoan parasite Crithidia luciliae.

The unicellular protozoan parasite, Crithidia luciliae, responded to osmotic swelling by undergoing a regulatory volume decrease. This process was accompanied by the efflux of amino acids (predominantly alanine, proline and glycine). The relative loss of the electroneutral amino acids proline, valine, alanine and glycine was greater than that for the anionic amino acid, glutamate; there was negligible loss of the cationic amino acids, lysine, arginine and ornithine. The characteristics of amino acid release were investigated using a radiolabeled form of the nonmetabolized alanine analogue alpha-aminoisobutyrate. alpha-Aminoisobutyrate efflux was activated within a few seconds of a reduction of the osmolality, and inactivated rapidly (again within a few seconds) on restoration of isotonicity. The initial rate of efflux of alpha-aminoisobutyrate from cells in hypotonic medium was unaffected by the extracellular amino acid concentration. Hypotonically activated alpha-aminoisobutyrate efflux (as well as the associated regulatory volume decrease) was inhibited by the sulfhydryl reagent N-ethylmaleimide but was not inhibited by a range of anion transport blockers. As in the efflux experiments, unidirectional influx rates for alpha-aminoisobutyrate increased markedly following reduction of the osmolality, consistent with the swelling-activated amino acid release mechanism allowing the flux of solutes in both directions. Hypotonically activated alpha-aminoisobutyrate influx showed no tendency to saturate up to an extracellular concentration of 50 mM. The functional characteristics of the amino acid release mechanism are those of a channel, with a preference for electroneutral and anionic amino acids over cationic amino acids. However, the pharmacology of the system differs from that of the anion-selective channels that are thought to mediate the volume-regulatory efflux of organic osmolytes from vertebrate cells.

Amino Acids↗
PubMed1995

Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine.

Lamivudine is a novel cytosine nucleoside analog, reverse transcriptase inhibitor that has shown activity against human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B virus in vitro. This study was conducted to compare the absolute bioavailability, pharmacokinetics, and absorption characteristics of oral solution, 100-mg capsule, and 100-mg tablet formulations of lamivudine with those of intravenous lamivudine. Twelve patients with HIV were enrolled in a single-center, randomized, open-label, four-way cross-over study. Treatment arms consisted of 100 mg intravenous lamivudine (administered over 1 hour), 100 mg oral lamivudine (1 mg/mL), a 100-mg capsule, and a 100-mg tablet, each followed by a 3- to 14-day washout period. Serial blood samples over 24 hours were obtained after each dose administration. Serum concentration data were analyzed to determine pharmacokinetic parameter estimates including area under the curve (AUC), terminal half-life (t1/2), mean residence time (MRT) for each formulation, systemic clearance, oral clearance, and apparent volume of distribution (Vd). Absolute bioavailability and in vivo mean absorption time (MAT) and mean dissolution time (MDT) were calculated for the oral formulations. Deconvolution techniques were used to calculate the input rate for the oral solution, capsule, and tablet. The two one-sided t test was used to determine bioequivalency among oral formulations with respect to logarithmic transformed estimates of AUC and maximum peak concentration (Cmax). Mean (CV) systemic clearance and Vdss after intravenous administration of lamivudine were 22.6 L/h (15%) and 99 L (28%), respectively; mean t1/2 ranged from 8.41 to 9.11 hours for all formulations; and MRT ranged from 4.42 to 5.77 hours for all formulations. Mean absolute bioavailability ranged from 86% to 88% for the oral solution, capsule, and tablet. All oral formulations were considered bioequivalent for AUC and Cmax. The MAT was 1.32 hour for the oral solution, and MDT was 0.03 and -0.11 hours for the capsule and the oral solution, respectively. The oral formulations of lamivudine examined in this study demonstrated acceptable bioavailability for oral administration. The solid oral formulations (capsule and tablet) show rapid dissolution properties with an absorption rate similar to or exceeding those observed with the oral solution. This suggests that dissolution is not an important factor for the rate of absorption of lamivudine. The use of deconvolution techniques using PCDCON provides valuable insight into the absorption characteristics of lamivudine.

Absorption↗
PubMed1994

Interspecies scaling and pharmacokinetic parameters of 3TC in humans.

3TC is a dideoxy-nucleoside analogue that has demonstrated in-vitro activity against human immunodeficiency virus (HIV). 3TC concentrations in humans were predicted before the initiation of clinical trials by interspecies scaling of pharmacokinetic parameters observed in animal species. Clearance and volume of distribution were estimated for humans using linear regression on a log-log scale of each parameter versus body weight for rats and dogs. The concentration-time profile and the average serum concentration at steady state after various dosage regimens were estimated as a basis for initial dose selection for clinical trials. The predicted parameters (clearance of 16.3 L/hr and volume of distribution of 40 L for a 70-kg man) were compared with that observed (mean clearance of 24 L/hr and mean volume of distribution of 96 L, mean weight of 74 kg) in 20 asymptomatic, HIV positive, volunteers after single intravenous doses of 3TC. Interspecies scaling was applied prospectively as a rationale for dose selection of 3TC in clinical trials.

Animals↗
PubMed1994

An assessment of lacidipine and atenolol in mild to moderate hypertension.

1. The aim of this randomised, double-blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post-dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/- 3/3 mmHg; 142/89 +/- 5/3 mmHg; and 154/98 +/- 5/3 mmHg respectively; P < 0.001). Co-administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/- 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/- 1 beats min-1 and 74 +/- 2 beats min-1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/- 1 beats min-1 and 86 +/- 1 beats min-1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co-dosing (120/82 +/- 10/2 mmHg) compared with lacidipine (140/92 +/- 5/3 mmHg) and atenolol (146/90 +/- 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/- 8 beats min-1; 65 +/- 4 beats min-1 and 75 +/- 7 beats min-1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co-administration of both lacidipine and atenolol.

Adult↗
PubMed1993

Nucleoside transport in Crithidia luciliae.

Nucleoside transport was evaluated in the trypanosomatid Crithidia luciliae by a rapid sampling technique. C. luciliae was shown to possess two independent nucleoside transporters, one which transported adenosine, deoxyadenosine, tubercidin, sangivamycin and the pyrimidine nucleoside thymidine, while the second was specific for guanosine, inosine and deoxyguanosine. The rapid influx occurred by a process of facilitated transport. The apparent Km values for adenosine and guanosine were 9.34 +/- 1.30 and 10.6 +/- 2.60 microM, respectively. The pyrimidine nucleoside thymidine was transported at a rate approximately 50% lower than the purine nucleosides, whilst uridine, deoxyuridine and deoxycytidine were not transported. The optical isomer, L-adenosine entered the organism by simple diffusion rather than by facilitated transport. In contrast to mammalian cells, neither of the nucleoside transporters in C. luciliae were inhibited by nitrobenzylthioinosine, dilazep, or dipyridamole, potent inhibitors of nucleoside transport in mammalian cells, whilst p-chloromercuribenzoate sulphonate inhibited both nucleoside transporters in C. luciliae.

Animals↗
PubMed1992

The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a phase I study.

OBJECTIVE: To determine the safety and pharmacokinetics of the nucleoside analogue, 3TC. DESIGN: A Phase I, open-label, single-centre study. METHODS: Twenty asymptomatic, HIV-infected male patients with CD4 lymphocyte counts < 500 x 10(6)/l who had not received previous antiretroviral therapy completed the study. Each patient received a single intravenous dose followed by a single oral dose of 3TC. Four patients were dosed at each of five dose levels (0.25, 1.0, 2.0, 4.0 and 8.0 mg/kg). RESULTS: The most commonly reported adverse event was headache, which was generally reported to be mild. The mean bioavailability of 3TC was 82% following oral administration. The majority of the dose (approximately 70%) was excreted unchanged in the urine. CONCLUSIONS: Overall, 3TC was well tolerated following dosing, and there were no significant changes in the safety parameters measured. Phase I/II clinical trials with 3TC are ongoing to evaluate its safety, pharmacokinetics and preliminary activity.

Administration, Oral↗
PubMed1991

A study to evaluate the effect of ondansetron on psychomotor performance after repeated oral dosing in healthy subjects.

The aim of the study was to determine the effect of repeated oral administration of ondansetron, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, on psychomotor performance. The study was of a randomised, double-blind, four-way, cross-over design in 12 healthy subjects, with 1 mg and 8 mg ondansetron, placebo and 2 mg lorazepam evaluated. Each subject received five administrations per treatment period. Ondansetron, 1 mg and 8 mg, and placebo were given as twice daily dosing for 2 1/2 days. Lorazepam was administered as a 2 mg single oral dose which was taken as the fifth administration; placebo was given for the remaining four doses. Within each treatment period, subjects underwent a baseline (pre-dose) assessment of psychomotor performance using four commonly used and validated psychomotor tests, and were then re-assessed after the fifth and final dose over a 7-h, post-dose period. Following dosing with lorazepam, statistically significant changes were seen in five of the six test variables compared with placebo. Ondansetron, at both the 1 mg and the 8 mg doses, did not produce a statistically significant effect on any measure of psychomotor performance compared with placebo.

Adult↗
PubMed1991

The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers.

The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of lacidipine (by 38% and 42%, respectively) whereas lacidipine significantly increased the Cmax and AUC of propranolol (by 35% and 26%, respectively); neither the time to maximum plasma concentration (tmax) nor the terminal half-life (t 1/2) were affected. With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension.

Administration, Oral↗
PubMed1991

Clinical pharmacology of lacidipine.

The safety and tolerability of lacidipine was assessed in a volunteer population, and its pharmacodynamic and pharmacokinetic profiles evaluated. In normotensive subjects, single oral doses of 3-5 mg of lacidipine produced a dose-related fall in peripheral vascular resistance. This was accompanied by reflex-mediated increases in heart rate and cardiac output to maintain blood pressure. Adverse events were those typically related to the vasodilatory action of lacidipine, such as flushing and headache. A 4-mg dose of lacidipine elicited a cardiovascular response equivalent to that with 10 mg of nifedipine, given as a single oral dose. Lacidipine did not affect sinoatrial or atrioventricular conduction in the healthy subjects studied. Two specialized electrophysiologic studies in patients confirmed that lacidipine does not affect pacemaker tissue and that it exhibits relative selectivity for the vascular smooth muscle. Lacidipine is eliminated primarily by hepatic metabolism, and extensive first-pass loss occurs after oral dosing. Absolute bioavailability is less than 10%. The systemic availability of lacidipine was increased in healthy elderly subjects and in patients with impaired hepatic function, but not in patients with impaired renal function.

Adolescent↗
PubMed1990

Early clinical testing of cognition enhancers: prediction of efficacy.

The major problem in predicting clinical efficacy from animal experimental results and phase I data is the lack of resemblance between the models used and the clinical condition. This problem is complicated by the diversity of the potential mechanisms of action of new compounds. A further question is whether Phase I studies should be used as predictors of clinical efficacy at all. Should they be used simply for determining pharmacologically active dose ranges and tolerance? If used as predictors should drug development stop if negative results are obtained? These questions were not resolved. It was nonetheless suggested that some human models (e.g. scopolamine-induced amnesia, hypoxia-induced performance deficits) were indeed potential predictors of clinical response and, in addition, were analogous to similar models in animals. On the other hand characterisation of quantified EEG (QEEG) profiles remained controversial.

Alzheimer Disease↗
PubMed1986

Effect of pregnenolone carbonitrile, promethazine and antipyrine pretreatment on antipyrine metabolite formation in rats.

The effect of three inducers of cytochrome P-450-mediated drug oxidations (Pregnenolone carbonitrile, promethazine and antipyrine) on antipyrine metabolite kinetics has been investigated using the urinary metabolite pattern and 14CO2 exhalation rate (CER)-time profile following [N-methyl-14C]antipyrine administration. The CER-time profiles showed the characteristic changes associated with induction, namely, increased maximum CER and decreased half-life, previously observed in phenobarbitone and beta-naphthaflavone-induced rats. Calculation of formation rate constants based on urinary recovery of 3-hydroxymethyl-, 4-hydroxy- and nor-antipyrine indicated no clear selectivity of induction by any pretreatment. However, the percentage increase of the latter two metabolites was two- to four-fold greater than for the former metabolite. The use of the metabolite ratio (3-hydroxymethylantipyrine/norantipyrine) is proposed to assess the qualitative nature of induction of antipyrine metabolism.

Animals↗