Search PubMed⌕ Search

Biomedical subjects

D J Roberts

Publications and source records attributed to D J Roberts.

At least 127 records · Page 7Linked to original sources
PubMed1989

The influence of structure on the accumulation of caffeine induced by methyl xanthine derivatives.

In rats given caffeine (25 mg kg-1 p.o.) and 1,3,8-trisubstituted xanthine (1,3,8-TSX) derivatives (10 mg kg-1 p.o.) the accumulation of the former in plasma was 300% higher than that in control animals given caffeine alone. The effect on caffeine accumulation appears to be independent of the nature of the N3 substituent and its absence in rats given 1,3-disubstituted xanthines (1,3-DSX) instead of 1,3,8-TSX suggests that the presence of the C8-methyl group in the latter compounds is responsible for the accumulation phenomenon. The results of our previous work imply that these observations in this rat model can be extrapolated to man.

Animals↗
PubMed1989

The polarization of fibroblasts in early primary cultures is independent of microtubule integrity.

Fibroblasts in culture apparently require an intact system of microtubules in order to adopt and maintain a polarized morphology. In contrast, the polarization of a number of epithelial cell types has been shown to be microtubule-independent. Reconciliation of these apparently contradictory data is difficult, however, because the epithelial cells were studied in short-term primary cultures while the fibroblasts were studied in secondary or longer-term cultures. To clarify the situation we have examined the effects of the microtubule-disrupting drugs, colcemid and nocodazole, on the polarization of a single cell type, the chick heart fibroblast (HF), maintained in both primary (1 degree) and secondary (2 degree) cultures. Immunofluorescence observations of both types of culture showed that in control medium the cells contained abundant microtubules, which were absent if the cells were cultured in medium containing either colcemid or nocodazole. The effects of microtubule-disrupting drugs on the polarization of the cells were quantified using two measures of cell shape, elongation and dispersion, both of which increase with increasing polarization. The results show that microtubule-disrupting drugs do not have a significant effect on the polarization of HF spreading in 1 degree culture but significantly reduce the polarization of HF spreading in 2 degree cultures. The effects of microtubule disruption on HF that had been maintained in 1 degree culture for 6 h, 24 h or 48 h were also quantified.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The shape of cultured epithelial cells does not depend on the integrity of their microtubules.

Fibroblasts are thought to require an intact system of cytoplasmic microtubules in order both to adopt and to maintain a polarized morphology in culture, but whether the same is true for epithelial cells is not clear. We therefore compared the effects of the microtubule-disrupting drugs, colcemid and nocodazole, on the morphology of isolated embryonic chick heart fibroblasts (HF), corneal epithelial (CE) and epidermal epithelial (EE) cells. Immunofluorescence observations showed that all three cell types contained abundant microtubules when cultured in control medium and that these were absent from cells cultured in medium containing either colcemid or nocodazole. Qualitative observations suggested that these drugs inhibited the polarization of spreading HF but had no effect on the morphology of either of the epithelial cell types. We confirmed this observation quantitatively using two measures of cell shape, elongation and dispersion, both of which increase with increasing polarization. Our measurements show that microtubule-disrupting drugs significantly reduce both the elongation and dispersion of spreading HF but do not have a significant effect on either of these measures for the epithelial cell types. We quantified in a similar way the effects of microtubule-disrupting drugs on the morphology of all three cell types that had previously spread in control medium. We found that transferring spread HF to colcemid-containing medium significantly reduced both the elongation and dispersion of these cells but that the same treatment had no effect on these measures for either of the epithelial cell types. Our observations suggest that, unlike the fibroblasts, the epithelial cell types we have studied do not require microtubules either to adopt or to maintain a polarized morphology.

Animals↗
PubMed1988

Potentiation of the gastric antisecretory activity of histamine H2-receptor antagonists by clebopride.

The substituted benzamide, clebopride, at doses (0.03-3 mg kg-1 i.p.) that were without effect per se on the secretion of gastric acid in pylorus ligated (Shay) rats, potentiated the antisecretory effects of the histamine H2 receptor antagonists cimetidine and ranitidine in this model but not those of the muscarine receptor antagonist pirenzepine nor those of the proton pump inhibitor omeprazole. By contrast, clebopride was without influence on the inhibitory effects of cimetidine on pentagastrin-induced secretion in perfused stomach (Ghosh and Schild) preparations in anaesthetized rats. The significance of these findings is discussed in relation to the previously described potentiating effects of clebopride on the anti-ulcer activity of cimetidine in various experimental models, and the potential beneficial effects of such combined therapy in the clinic.

Animals↗
PubMed1987

Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To compare the effects of intravenous dobutamine and milrinone on right ventricular (RV) systolic function, 14 patients with severe congestive heart failure underwent simultaneous radionuclide-hemodynamic study. Patients were randomized to receive intravenous milrinone (50 micrograms/kg bolus then 0.5 microgram/kg/min) or dobutamine (2.5 to 15 micrograms/kg/min) to achieve equal increases in cardiac output. Both drugs significantly improved cardiac performance, with identical 24% increases in mean cardiac index (p less than 0.05 vs baseline; difference not significant for milrinone vs dobutamine) and no change in heart rate. Neither drug substantially altered RV preload, as reflected by mean right atrial pressure and RV end-diastolic volume. Both drugs caused similar increases in RV ejection fraction (mean +/- standard deviation; dobutamine: 0.32 +/- 0.09 to 0.40 +/- 0.11; p less than 0.05; milrinone: 0.35 +/- 0.19 to 0.43 +/- 0.21; p less than 0.05) resulting from reductions in RV end-systolic volume. RV afterload reduction contributed substantially to drug effect on RV systolic performance in patients treated with milrinone but not those treated with dobutamine. With doses effecting equal increases in cardiac index and RV systolic performance, pulmonary artery end-systolic pressure was significantly reduced by milrinone (40 +/- 12 to 33 +/- 12 mm Hg; p less than 0.05), but not by dobutamine. Thus, in patients with congestive heart failure milrinone's effect on RV systolic function is explainable, at least in part, by RV afterload reduction, whereas RV inotropic augmentation contributed more strongly to dobutamine's effect.

Adult↗
PubMed1987

Sister chromatid induction by beta-irradiation from incorporated 3H-thymidine: a paradox explained.

Sister chromatid exchanges (SCE's) induced by [3H]thymidine (3HdT) of increasing specific activities incorporated over one cycle and 5-bromodeoxyuridine (BrdUrd) over the two following cycles were investigated in synchronised Chinese hamster ovary (CHO) cells. SCEs induced during the first cycle on a T.T template (SCE 1) show little increase with dose compared with those induced in the second cycle on a 3HT.T template (SCE 2) where the linear increase with dose reflects that seen after X irradiation. During the third cycle, SCEs 3.1 and 3.2 are induced on unlabelled T.B or labelled 3HT.B templates respectively. These templates are theoretically present in a 1:1 ratio after random segregation at second metaphase. Over practically the entire dose range however, the ratio 3.1/3.2, which decreased with dose, was greater than 1.0 and similar to the high values obtained by other workers. At increasing times after BrdUrd introduction, the ratio decreased from greater than 1.0 to less than 1.0. Measurements showed that the expected 50% level of labelled chromosomes at metaphase in the samples could vary between 42%-59%. Cells with greater than 50% labelled chromosomes were more delayed in the cell cycle due to the 3H-irradiation than those with less than 50%. Early fixations therefore favoured SCE 3.1 while late favoured SCE 3.2. SCEs due to BrdUrd in 3HT.B and T.B templates showed no synergistic interaction with irradiation-induced SCEs. When these BrdUrd-induced SCEs were removed from the totals then the 3H-induced SCE levels in 3HT.T, and 3HT.B templates (SCE 2 and 3.2) were similar and increased at a similar rate with dose. This was 2-3 times faster than in SCE 1 and 3.1 where the SCE levels due to irradiation were again similar but lower than for 2 and 3.2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Accumulation of caffeine in healthy volunteers treated with furafylline.

The pharmacokinetics and tolerance of repeated oral doses of furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg). The half-life of elimination was less when the plasma concentration was lower than 600 ng ml-1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of furafylline appeared to be associated with the onset of adverse xanthine-like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half-life of some 50 h and an abrupt decrease in metabolite levels. The furafylline-induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity.

Administration, Oral↗
PubMed1987

Adenylate cyclase regulation in intact cultured myocardial cells.

To examine the coupling of cardiac cell-surface beta-adrenergic receptors to adenylate cyclase activation and contractile response, we studied this receptor-effector response system in monolayers of spontaneously contracting chick embryo ventricular cells under physiological conditions. The hydrophilic ligand 3H-CGP12177 identified uniformly high-agonist affinity beta-adrenergic receptors (isoproterenol KD = 15 +/- 9 nM). Isoproterenol-stimulated cyclic AMP (cAMP) accumulation with 50% effective concentration at (EC50) = 12.1 nM and augmented contractile response with EC50 = 6 nM under identical conditions. One micromolar isoproterenol induced receptor loss from the cell surface with t1/2 = 13.2 min; under identical conditions cAMP content declined with t1/2 = 13.5 min and contractile response with t1/2 = 20.7 min. After agonist removal cAMP response recovered with t1/2 = 15.7 min and receptors with t1/2 = 24.7 min. Sixty minutes after agonist removal there was recovery of 52% of maximal cAMP responsiveness and 82% of the initial number of receptors; receptor occupancy was associated with 78% of initial contractile response. Agonist affinity for cell-surface receptors was changed only modestly by agonist exposure. We conclude that for this system there is relatively close coupling between high-affinity receptors, adenylate cyclase stimulation, and contractile response.

Adenylyl Cyclases↗
PubMed1987

An animal model for the detection of drug-induced inhibition of caffeine metabolism.

Plasma levels of caffeine are increased more than 400% in rats given furafylline (10 mg kg-1 p.o.) and caffeine (25 mg kg-1 p.o.) as compared to rats given caffeine alone. In rats given idrocilamide (100 mg kg-1 p.o.) and caffeine (25 mg kg-1 p.o.) accumulation of xanthine is higher than 600%. The chromatographic separation and analysis of plasma extracts indicates that the N3-demethylation pathway is inhibited. Since furafylline and idrocilamide have been shown to increase blood levels of caffeine by the same mechanisms in humans and to give rise to adverse reactions, the rat would appear to be a suitable model to detect and study the inhibition of the metabolism of caffeine by such drugs and could be usefully included in the usual series of drug interaction studies done routinely during drug development.

Animals↗
PubMed1986

Neuromuscular blockade for critical patients in the emergency department.

This retrospective study examines the indications and the effects of 119 doses of succinylcholine or pancuronium given in the emergency department during a 24-month period to patients considered to have immediately life-threatening emergencies. The most common indication for succinylcholine was to accomplish tracheal intubation (20 of 25 patients). Indications for pancuronium included computerized tomography of the head (60 of 94), control of agitation (40 of 94), facilitation of tracheal intubation (20 of 94), control of ventilation (12 of 94), and control of seizure unresponsive to anticonvulsants (4 of 94). Deterioration following succinylcholine occurred in three cases. These included two involving bradycardia and one involving ventricular tachycardia. Major complications following pancuronium included four incidences of ventricular arrhythmias. Intubation failure requiring surgical airway occurred in one patient given succinylcholine, two patients given pancuronium, and one patient who received both succinylcholine and pancuronium. Inadequate documentation of neurological examination prior to blockade was noted in six of 25 succinylcholine and nine of 94 pancuronium cases. Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses. Neuromuscular blocking agents facilitate expeditious management of selected critical patients in the ED. Their prudent use requires anticipation of potential complications, preparation for surgical airway should intubation fail, documentation of physical examination before paralysis, and prior sedation when the patient responds to pain.

Adolescent↗
PubMed1986

Prevention of transcoronary macromolecular leakage after ischemia-reperfusion by the calcium entry blocker nisoldipine. Direct observations in isolated rat hearts.

Coronary microvascular damage appears to play a role in reperfusion injury after myocardial ischemia. This study was designed to afford direct viewing of the effects of myocardial ischemia-reperfusion on the coronary microcirculation and to determine whether pretreatment with the calcium blocker nisoldipine would attenuate any microvascular damage during reperfusion. Four groups of isolated rat hearts were perfused with a solution that contained red cells and fluorescent albumin, but was essentially free of platelets and leukocytes. Group I served as a nonischemic control. Group II hearts were subjected to 30 minutes of no-flow ischemia followed by reperfusion. Group III hearts were pretreated with nisoldipine (1 microgram/min) for 5 minutes before ischemia, and group IV hearts were treated with nitroglycerin (93 micrograms/min) before and after ischemia to mimic the vasodilation caused by nisoldipine. Perfused coronary capillarity and transcoronary extravasation of plasma albumin were measured by direct visualization techniques before and after ischemia. For group I, there was no significant change in coronary resistance, perfused capillarity, or transcoronary extravasation with time. For both groups II and IV, ischemia-reperfusion caused no increase in coronary resistance, but a significant decrease in perfused capillarity and a marked increase in transcoronary extravasation of fluorescent albumin (P less than 0.05). The nisoldipine group (group III) demonstrated a similar decrease in perfused capillarity but no increase in protein extravasation during reperfusion. These results indicate that, in the heart, platelets and/or leukocytes are not absolutely necessary to induce either the no-reflow phenomenon or the permeability damage observed during reperfusion after ischemia. The protective effect of treatment with nisoldipine appeared to be independent of vasodilation. We speculate that this calcium blocker reduced endothelial uptake of calcium during reperfusion, preventing endothelial deformation and formation of interendothelial gaps.

Animals↗
PubMed1986

Synergistic interactions between piracetam and dihydroergocristine in some animal models of cerebral hypoxia and ischaemia.

In pharmacological screening tests for activity against the cerebral insults of hypoxia and ischaemia induced by MgCl2 or decapitation in mice, the combination of piracetam and dihydroergocristine has been shown to produce synergistic effects in prolonging the survival time. This was not the case in the model of histiocytic anoxia induced by KCN. Using an optimal combination of piracetam and dihydroergocristine (533:1, Diemil) significant increases in cerebral resistance to hypercapnic anoxia and reductions in the duration of the ensuing electrical silence on the electrocorticogram have been demonstrated in the rat. The same combination was also effective in antagonizing the memory ablating effects of anoxia in rats subjected to electric footshocks during a standard passive avoidance response. The absence of clear effects on gross cerebral blood flow and metabolism, together with considerations of the known pharmacological properties of the two components of the combination and the effects of standard drugs in the models used, lead to the conclusion that the explanation of the observed synergism probably lies in complimentary actions at the level of the cerebral neurones and is independent of simple vasodilation.

Anesthesia↗