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Biomedical subjects

J S Fleming

Publications and source records attributed to J S Fleming.

At least 91 records · Page 5Linked to original sources
PubMed1991

Imidazoquinoline derivatives: potent inhibitors of platelet cAMP phosphodiesterase which elevate cAMP levels and activate protein kinase in platelets.

Compounds containing the imidazoquinoline nucleus are a new class of potent, broad-spectrum inhibitors of platelet aggregation. This report describes studies with a simply-substituted imidazoquinoline (BMY 20844) and several new ether-linked side chain derivatives (BMY 21638 and BMY 43351). These compounds are potent inhibitors of platelet cAMP phosphodiesterase (IC50 values: BMY 20844, 1.3 X 10(-8); BMY 21638, 2 X 10(-10); and BMY 43351, 1 X 10(-10) M, measured using 0.15 microM cAMP) but have little effect on platelet homogenate cGMP phosphodiesterase (IC50 greater than 10(-5) M). Inhibition of different cAMP phosphodiesterase isozymes was tested to determine if the compounds inhibited similar isozymes in other tissues. Rabbit heart cAMP phosphodiesterase isozymes were resolved by ion-exchange chromatography and three peaks of activity were obtained. BMY 20844 inhibited only fraction III (a "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase) with an IC50 value of 5 X 10(-8) M. These compounds also inhibited canine cardiac sarcoplasmic reticulum membrane-bound "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase with virtually the same potency as inhibition of cAMP phosphodiesterase in platelet homogenate. In washed platelets these compounds elevated cAMP levels and activated the platelet cAMP dependent protein kinase. Activation of cAMP-dependent protein kinase was determined by cAMP-dependent protein kinase ratio measurements and phosphorylation of intracellular proteins. These studies suggest that this potent new class of agents inhibits platelet phosphodiesterase activity in intact platelets causing an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and stimulate protein phosphorylation. This mechanism is, at least in part, responsible for the ability of these compounds to prevent platelet aggregation and thrombosis in experimental animal models.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

The effect of acute hypoxia on right ventricular function in healthy adults.

Right ventricular ejection fraction and right ventricular volumes were derived in 12 healthy male subjects using krypton-81m equilibrium radionuclide ventriculography whilst subjects breathed 30% (high inspired oxygen) and then 8-12% oxygen in nitrogen mixture (hypoxia). 'Physiological' tricuspid valve regurgitation was identified in 7 of the subjects by Doppler echocardiography, and right ventricular peak systolic pressure was estimated during high inspired oxygen and during hypoxia. Mean right ventricular peak systolic pressure was 24.1 +/- 3.3 mmHg during high inspired oxygen and increased to 41.3 +/- 8.4 mmHg during hypoxia (P less than 0.01). Mean right ventricular ejection fraction was 0.612 +/- 0.075 during high inspired oxygen and was unchanged at 0.590 +/- 0.073 during hypoxia. There was no significant change in right ventricular end-diastolic volume or stroke volume in response to hypoxia. The systolic performance of the normal right ventricle is well-maintained during an acute rise in afterload induced by hypoxia.

Acute Disease↗
PubMed1991

1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation.

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives was synthesized and evaluated as inhibitors of cAMP hydrolysis by a crude human platelet phosphodiesterase preparation and as inhibitors of ADP- and collagen-induced aggregation of rabbit blood platelets. The parent structure 7a, demonstrated potent inhibitory activity that was enhanced by the introduction of alkyl, alkoxy, or halogen substituents at the 5-, 6-, 7-, and 8-positions. Methylation at N-1 or N-3 produced weaker inhibitors of cAMP PDE and platelet aggregation. 1,3,9,9a-Tetrahydro-2H-imidazo[4,5-b]quinolin-2-ones (6) were found to be equipotent with their fully oxidized congeners (7). On the basis of platelet inhibitory properties in vitro, efficacy at preventing thrombus formation in animal models of thrombosis, and a favorable hemodynamic profile, 1,3-dihydro-7,8-dimethyl-2H- imidazo[4,5-b]quinolin-2-one (7o, BMY 20844) was selected for advancement into toxicological evaluation and clinical trial. An efficient synthesis of 7o is described.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Measurement of glomerular function during cisplatin therapy.

1. Creatinine-based methods for measuring glomerular filtration rate (GFR) were compared with the plasma clearance of 99mTc DTPA as an accurate index of GFR in patients prior to and during cisplatin therapy. 2. Measured creatinine clearances using either unsupervised 24 h or supervised 4 h collections correlated less well with the reference GFR than did predicted creatinine clearances derived from serum creatinine using formulae or a nomogram. 3. Predicted creatinine clearance appears to be at least as sensitive as measured creatinine clearance for screening GFR in patients receiving cisplatin. However, owing to the inherent inaccuracy in any creatinine-based method, if the prediction is within 20% of the value at which dose reduction of cisplatin is considered, an isotopically determined GFR should be carried out to optimise dosage adjustments.

Adolescent↗
PubMed1991

The accuracy of creatinine clearance with and without urine collection as a measure of glomerular filtration rate.

Conventional creatinine clearances involving urine collections over 2, 4 and 24 hours and creatinine clearance predicted from plasma creatinine concentrations without urine collection were compared to glomerular filtration rate (GFR) estimated by 99mTc DTPA clearance in 171 patients with a wide range of GFR. All creatinine clearance methods involving urine collection had standard errors of the estimate of GFR greater than predictions from formulae. Predictions of creatinine clearance by formulae had coefficients of variation of the estimate of approximately 23% when compared to isotopically determined GFR. Creatinine clearances determined by these equations in patients with stable renal function are an easier and at least as accurate a guide to GFR as methods involving urine collection.

Body Weight↗
PubMed1991

Clinical experience with heparin-coated cardiopulmonary bypass circuits.

The extensive area of contact between blood and synthetic surfaces during cardiopulmonary bypass results in the activation of the kallikrein, the complement and the clotting and fibrinolytic systems. This results in white cell activation and a whole body inflammatory response. Pulmonary neutrophil sequestration is also known to occur during cardiopulmonary bypass and has been associated with pulmonary damage. This has been previously demonstrated using the technique of differential neutrophil counts in simultaneous venous and left atrial samples. The efficacy of retinal fluorescein angiography as an indicator of cerebral microembolism has also been proved in previous studies. The objectives of this study were to determine whether heparin precoating with Duraflo II reduced pulmonary neutrophil sequestration, retinal microembolism and postoperative blood loss. Fourteen patients were randomized into two groups using either heparin-coated or nonheparin-coated cardiopulmonary bypass circuits. The preliminary results suggest a reduction in pulmonary neutrophil sequestration (p greater than 0.05) and the generation of thrombin antithrombin complexes (p less than 0.05). Retinal microembolism was not significantly different in the two groups nor was the postoperative blood loss. Thus, heparin-coated cardiopulmonary bypass circuits do not reduce pulmonary neutrophil sequestration, retinal microembolism or postoperative blood loss.

Biocompatible Materials↗
PubMed1991

Automated measurement of tumour extent in patients with colorectal liver metastases from X-ray computed tomography.

Tumour burden is a significant prognostic factor in patients with colorectal liver metastases, and can be staged according to percentage hepatic replacement (PHR), but accurate measurements of PHR are difficult to obtain. We have used an automated computerized technique to isolate tumour and measure PHR from computed tomography images of 22 patients. Tumour identification was achieved by establishing local histogram-based thresholds at liver-tumour boundaries displaying clear bimodal histogram distributions. There was a significant association between measured PHR and independent visual estimates of PHR stage defined in quartiles (p less than 0.001). When the measured value of PHR differed from the PHR stage, the visual estimate was always higher. The accuracy of PHR measurement was assessed on stimulated liver computed tomography images. It seems likely that visual estimates of PHR from computed tomography images tend to overestimate tumour extent. The automated technique is probably more accurate and will be useful for assessing and monitoring patients.

Colorectal Neoplasms↗
PubMed1990

81mKr equilibrium radionuclide ventriculography for the assessment of right heart function.

Right heart 81mKr equilibrium radionuclide ventriculography was used to derive right ventricular ejection fraction (RVEF) in 12 healthy male volunteers. Anatomical lung subtraction using 99mTc-MAA perfusion scintigraphy was compared with conventional background correction and the effect of imaging projection on the techniques of image analysis evaluated. Both intra and inter observer variability were reduced by anatomical lung subtraction when compared to conventional background correction. In the right anterior oblique (RAO) projection, background corrected RVEF was lower than lung subtracted RVEF - 0.544 +/- 0.05 and 0.612 +/- 0.08 (mean +/- SD) (P less than 0.02). Lung subtracted RVEF in the anterior projection was lower than that with background correction (P less than 0.05) and lower than lung subtracted RVEF in the RAO projection (P less than 0.001). We conclude that optimal separation of right heart structures is achieved in the RAO projection and that reproducibility of the analytical technique is improved by anatomical lung subtraction.

Adult↗
PubMed1990

A comparison of three indices of relative hepatic perfusion derived from dynamic liver scintigraphy.

Data from dynamic radiocolloid liver scintigraphy (DLS) have been analysed to calculate three indices of relative arterial to total hepatic perfusion. Ninety subjects have been studied, comprising 21 normals, 62 patients with metastatic liver disease and 7 patients with cirrhosis. Correlation coefficients above 0.81 were found in all patient groups between an index based on rates of liver uptake (the hepatic perfusion index, HPI) and a method based on quantitative liver uptake (the mesenteric fraction, MF). A further method employing the spleen to model arterial inflow (hepatic arterial ratio, HAR) had less agreement with both HPI and MF, with correlation coefficients below 0.76. Posterior images have previously been used to calculate HAR, and greater errors are expected in HAR from the anterior images acquired in this study. Receiver operating characteristic analysis showed that the diagnostic performance of HPI and MF indices in metastatic disease were not significantly different. For anterior image data analysis both HPI and MF were superior to HAR.

Humans↗
PubMed1990

Regional indices of relative hepatic arterial perfusion from dynamic liver scintigraphy: the variability of indices and the use of parametric imaging.

Regional indices of relative arterial hepatic perfusion have been studied in 21 control subjects following dynamic radiocolloid scintigraphy of the liver (DLS). Three different indices have been calculated: the hepatic perfusion index (HPI); the hepatic arterial ratio (HAR) and the mesenteric fraction (MF). Three regions were defined in the upper, mid and lower right hepatic lobes and the three indices were calculated for each region. There was reasonable agreement between regional values of the same index with inter-regional correlation coefficients above 0.7 and standard errors in straight line fits of less than 0.093. There were significant regional differences for (1-MF) and HPI indices, but not for HAR. The index (1-MF) was calculated for each pixel and presented as a parametric image in 16 control subjects. The parametric images indicated the raised regional arterial indices due to overlying lung, right kidney and aorta. Parametric images may be of value to show the hepatic area free of significant overlying tissue and therefore available for analysis by DLS. However, the results suggest that the observed variability of single pixel indices limit the potential of parametric imaging for the localization of small focal lesions.

Humans↗
PubMed1990

Technique for the use of standard outlines for attenuation correction and quantification in SPECT.

A technique is described for using a set of standard outline images for attenuation correction and quantification in SPECT. The effectiveness of the method was investigated using an anatomical phantom and in a series of 123I-mIBG patient imaging studies. In the latter measurements the ability of the technique to quantify the activity of various features in the images was compared to the use of CT images for attenuation correction. The mean difference between the two measurements was 4.4%.

Humans↗
PubMed1990

Effect of food and activity on the reproducibility of isotopic GFR estimation.

The reproducibility of the plasma clearance of 99Tcm DTPA was studied in 26 patients under standardized conditions with the subject fasting and at rest. The coefficient of variation of duplicate measurements in patients with glomerular filtration rates (GRF's) ranging from 11-103 ml min-1 was 8%. Mean GFR following a breakfast containing 670 kcal and 31 g protein was increased significantly from 40.7 +/- 28.1 ml min-1 to 43.6 +/- 30.8 ml min-1. When fasted but permitted free exercise there was no consistent trend in GFR but the coefficient of variation of duplicate estimates increased significantly to 12.1%. It is recommended that routine GFR measurement should be carried out fasting or following a light diet with restricted activity.

Food↗
PubMed1990

The influence of levodopa on gastric emptying in man.

1. Simultaneous radioisotopic (99Tc-DTPA) gastric emptying measurements and paracetamol pharmacokinetic studies were performed in eight healthy male volunteers with and without levodopa (125 mg orally). 2. In the absence of levodopa gamma camera imaging showed rapid mono or biexponential emptying in all subjects and the plasma concentration-time curves for paracetamol displayed a single major peak. 3. In the presence of levodopa the time to 90% emptying was prolonged from 32 +/- 24 min to 81 +/- 20 min (P less than 0.01). Gastric emptying was interrupted by a plateau phase in six subjects and this pattern of emptying was associated with double peaks in the plasma concentration-time curves of both levodopa and paracetamol. The time to the end of the plateau phase of emptying correlated with the time to the trough plasma concentrations of paracetamol and levodopa. 4. There was excellent agreement between the plasma concentration-time curves of levodopa and paracetamol, i.e. time to initial peak, r = 0.946, P less than 0.001; time to trough concentration r = 0.943, P less than 0.01; time to second peak r = 0.974, P less than 0.001. 5. The results indicate that levodopa inhibits gastric emptying and thus influences its own absorption. Temporary inhibition of gastric emptying by levodopa (or a metabolite) is the cause of the multiple plasma peaks commonly observed following oral levodopa.

Acetaminophen↗
PubMed1990

The Booroola F gene mutation in sheep is not located close to the FSH-beta gene.

A cDNA probe for the beta subunit of bovine FSH (FSH-beta) detects multiple restriction fragment length polymorphisms (RFLPs) in sheep genomic DNA consistent with an insertion/deletion polymorphism around the FSH-beta locus. The presence of the insertion/deletion was confirmed by screening over 100 individuals with two restriction enzymes detecting RFLPs. All individuals showed the same patterns of fragments with both enzymes. A partial restriction map of the FSH-beta gene in sheep suggests that the insertion/deletion is approximately 2 kb in size and located downstream from the third exon. Individual DNA samples were analysed from two flocks where the Booroola F gene is known to be segregating. Individuals that were heterozygous for the F gene were shown to be homozygous for one or other of the two alleles. Genetic recombination between the FSH-beta locus and the F gene was observed in four pedigrees and there was no evidence that the insertion/deletion is closely linked genetically to the Booroola F gene. A major gene transcript of 2.2-2.3 kb was detected on Northern blots of sheep RNA. Neither the insertion/deletion polymorphism nor the presence of the F gene appeared to influence the size of the FSH-beta gene transcript.

Alleles↗
PubMed1990

Octimibate inhibition of platelet aggregation: stimulation of adenylate cyclase through prostacyclin receptor activation.

Octimibate inhibited ADP- and collagen-induced platelet aggregation in human, rabbit and rat platelet-rich plasma. Washed human platelets treated with octimibate had elevated cyclic AMP (cAMP) levels and cAMP-dependent protein kinase activity. When whole platelets were incubated with radiolabeled phosphate, octimibate produced an increase in the phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. This pattern of protein phosphorylation is identical to that observed when the platelets were treated with forskolin, phosphodiesterase inhibitors or other compounds that elevate platelet cAMP levels. Octimibate also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets, which is consistent with octimibate's ability to elevate platelet cAMP levels. When isolated platelet plasma membranes were treated with octimibate, adenylate cyclase activity was stimulated, reaching maximal activation at 1 microM octimibate. (The maximal activation of adenylate cyclase observed with octimibate is 70-75% of that observed with 10 microM PGE1.) This stimulation of platelet adenylate cyclase activity was enhanced by GTP. Octimibate competed for radiolabeled prostaglandin E1 and lloprost binding to isolated platelet membranes at submicromolar concentrations, but did not compete with radiolabeled prostaglandin D2 binding. These studies suggest that octimibate inhibits platelet aggregation by activating platelet adenylate cyclase through stimulation of platelet prostacyclin receptors.

Adenylyl Cyclases↗
PubMed1989

Pharmacology of a potent, new antithrombotic agent, 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (BMY-20844).

The effects of 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (BMY-20844) on platelet function and experimental thrombosis were evaluated in a series of in vitro, ex vivo and in vivo experiments. The compound inhibited platelet aggregation in vitro in platelet rich plasma obtained from humans, rats and rabbits with EC50s of less than 1 microgram/ml when aggregation was induced by ADP, collagen or thrombin. Supra-additive interaction against ADP aggregation was also observed when BMY-20844 was combined with prostacyclin. BMY-20844 was orally active with an ex vivo ED50 in the rat of 3.2 mg/kg vs ADP. Significant antithrombotic activity was observed in two animal models (laser induced thrombosis in the microcirculation of the rabbit ear and coronary artery thrombosis in the dog). Inhibitions of 52% at 3 mg/kg p.o. in the laser model and 100% at 1 mg/kg i.d. in the coronary artery thrombosis model were obtained. Modest inotropic and hemodynamic effects were observed in ferrets and dogs. BMY-20844 was found to be a potent, specific inhibitor of platelet low Km cyclic AMP phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

An association between parameters of liver blood flow and percentage hepatic replacement with tumour.

The extent of hepatic replacement with tumour is a significant prognostic factor in patients with liver metastases. Measuring the percentage hepatic replacement (PHR) accurately is difficult, but is important for both patient management and clinical trial evaluation. This study correlates haemodynamic indices obtained by dynamic liver scintigraphy (DLS) with estimates of PHR made from isotope scan, ultrasound, CT scan and laparotomy in 45 patients with established colorectal liver metastases and 21 controls who also underwent DLS. There was a significant reduction in the mesenteric fraction (MF) in the group of patients with metastases compared to the controls (P less than 0.001), and also a significant trend for progressive reduction in the MF with increasing PHR. A significant rise in an index of total hepatic arterial blood flow was also demonstrated with increasing PHR. These results are important with current interest in regional hepatic arterial therapy, and may prove of clinical value for prediction or monitoring of response to therapy.

Colorectal Neoplasms↗