Pharmacologic and biochemical profiles of new venous antithrombotic beta-D-xyloside derivatives: potential antiathero/thrombotic drugs.

Following a screening program for orally active antithrombotic drugs, it was found that a series of thioxyloside compounds presented with good venous antithrombotic properties. Of more than 500 compounds, LF 09-0055, LF 04-0212, and LF 05-0030 were the most active at inhibiting venous thrombus formation in the rat and rabbit Wessler model after intravenous and oral dosing. LF 05-0030 showed the greatest activity with an ED80 value of 6 mg/kg on oral administration in rats. This activity was maintained in several different models of venous thrombosis and shown to be devoid of anticoagulant effects or hemorrhage. Kinetic studies have demonstrated that maximal levels of activity, following either intravenous or oral dosing, occurred between 2 and 4 hours after administration. This may reflect the type of mechanism involved, since it has been well documented in the literature that xylosides are capable of initiating glycosaminoglycan (GAG) synthesis. Moreover, in vitro galactosyltransferase 1 (the second enzyme involved in GAG polymerization) enzymic assays showed that these thioxyloside derivatives were good acceptors for galactose transfer and therefore at initiating GAG formation. Further in vivo experimentation demonstrated that after treatment by these molecules an important elevation in circulating GAG occurred, with LF 05-0030 presenting the greatest activity, being five times higher than control levels. In addition it was found that dermatan sulfate levels, expressed as antithrombin activity by heparin cofactor II, were significantly increased over control values. As such, this dermatan sulfate moiety is believed to support the antithrombotic activity observed. Studies are underway to investigate the activity of these interesting molecules in atherosclerosis and other vessel wall diseases.

NCI's cancer information systems--bringing medical knowledge to clinicians.

The National Cancer Institute's computerized information systems have been designed to help physicians cope with the information explosion by translating the medical literature into usable forms. Systems developed by the NCI's International Cancer Information Center provide access to a comprehensive source of bibliographic citations on cancer research (the CANCERLIT database) and to current, peer-reviewed syntheses of state-of-the-art clinical information on cancer (the PDQ database). This article describes how the PDQ databases were developed and are kept up-to-date, and how physicians and other health professionals can access PDQ and other NCI information by computer and fax.

The effect of interleukin-4 on tumour necrosis factor-alpha induced expression of tissue factor and plasminogen activator inhibitor-1 in human umbilical vein endothelial cells.

The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is able to alter the haemostatic balance of human umbilical vein endothelial cells (HUVECs) towards that of a procoagulant and anti-fibrinolytic state. Treatment of HUVECs in culture with human recombinant TNF-alpha (0.5-50 U/ml; 6 h) significantly increased total cell expression of tissue factor (TF) 10-fold from 40 mU/well to 400-500 mU/well. Levels of plasminogen activator inhibitor-1 (PAI-1) antigen secreted from HUVECs also increased up to 2-fold in concentration-dependent fashion following addition of TNF-alpha (10-100 U/ml; 24 h). TNF-alpha induced total and cell surface expression of TF on HUVECs was significantly inhibited when the cells were pre-incubated with interleukin-4 (IL-4; p < 0.001). This effect was time and concentration dependent. Pretreatment of HUVECs with IL-4 for 4 h had no significant effect, but increasing inhibition of total TF expression occurred after 8 and 16 h pre-incubations. Treatment with IL-4 at 20 and 200 U/ml significantly inhibited cell surface TF responses induced by TNF-alpha, whereas a low concentration (0.2 U/ml) was without effect. In contrast, the production of PAI-1 from HUVECs stimulated by TNF-alpha (50 U/ml) was unaffected by the presence and/or prior incubation with 200 U/ml IL-4. Thus, IL-4 may regulate the pro-coagulant but not the antifibrinolytic effects of TNF-alpha at sites of vascular inflammation.

Effects of propranolol and pindolol on cardiac output during extended periods of low-intensity physical activity.

The effects of a nonselective beta-adrenergic blocking agent with (pindolol) and without (propranolol) intrinsic sympathomimetic activity properties, compared with placebo-controlled conditions, on metabolic and cardiorespiratory function during long-duration (2 hours) physical activity were examined. After initial cardiorespiratory testing, subjects performed 2-hour walks at 25 and 45% of maximal oxygen consumption (VO2max) under each of the following 3 treatments: pindolol, propranolol and placebo. Medication distribution was randomized and double-blinded. A supine resting blood pressure and electrocardiogram were obtained before each exercise trial. Oxygen consumption, heart rate, stroke volume, cardiac output and blood pressure were determined after 5 minutes of quiet sitting and every 30 minutes during each 2-hour exercise trial. Cardiac output was not significantly different at rest or during exercise, comparing pindolol and propranolol with placebo conditions. Cardiac output tended to decrease over time earlier during propranolol treatment for the 25% VO2max trials in trained normotensive subjects than for the other treatments. Cardiac output decreased at approximately the same time across treatments during the 45% VO2max trials in trained normotensive and untrained hypertensive groups. Finally, owing to the observation that a reduction in cardiac output was delayed or prevented in trained normotensive subjects when compared with that in untrained hypertensives while exercising at 25% VO2max, developing a subject's cardiovascular fitness level may be important in the maintenance of cardiac output during extended periods of low-to-moderate physical activities while under the influence of beta-adrenergic blockade.

Protein metabolism during sexual maturation in female Atlantic salmon (Salmo salar L).

Body composition and fractional rates of protein synthesis (percentage of the protein mass synthesized per day) were determined in female Atlantic salmon returning to the River Tay, Scotland in July and in October after a 95 day period without food, during which time the animals became sexually mature. During the 95 day period of starvation/sexual maturation the ventricle and red muscle remained as a constant proportion of fresh weight whereas the liver, gill and ovary increased and the stomach and white muscle decreased. Fractional rates of protein synthesis increased markedly in the liver, stomach and ovary during the period of starvation/sexual maturation. In the gill, ventricle and white muscle fractional protein synthesis rates increased slightly or remained constant. From the estimated rates of protein loss or gain in the various tissues it is concluded that there is considerable protein turnover and repartitioning of amino acids during the period of starvation and sexual maturation. The absolute rate of protein synthesis rates in the ovary indicates that this tissue made the largest contribution to the energy and amino acid demands of the fish, whilst most of the amino acids required for maturation of the ovary were derived from white muscle, principally as the result of increased muscle protein degradation.

Stroke volume during submaximal exercise in endurance-trained normotensive subjects and in untrained hypertensive subjects with beta blockade (propranolol and pindolol).

The effect of beta-adrenergic blockade on stroke volume (SV) at increasing submaximal exercise intensities was studied in 12 endurance-trained normotensive and 12 untrained hypertensive (diastolic blood pressure greater than 95 mm Hg) men, aged 18 to 34 years. Subjects were assigned to each of 3 treatments in a double-blind, randomized order: placebo, propranolol (80 mg twice daily) and pindolol (10 mg twice daily) for 10 days, with a period of 48 to 60 hours from the initial dose to the first treadmill test and a 4-day washout period between drugs. Cardiac output was measured using the carbon dioxide rebreathing method and SV was calculated from cardiac output and heart rate as follows: SV = cardiac output/heart rate. Cardiac outputs were estimated at rest and while walking on a treadmill at 25, 45, 60 and 75% of the subject's previously determined maximal oxygen uptake (VO2max). No significant differences were found in cardiac output between either of the drugs and placebo at rest, or at any of the 4 rates of work. Propranolol significantly increased SV above placebo values (p less than 0.05) for both trained and untrained groups at the intensities of 45, 60 and 75%. Significant differences in SV were found between pindolol and placebo only at the intensities of 60 and 75% in the trained group. Contrary to expectations, SV showed no indication of a plateau with propranolol in the trained subjects throughout the 4 different exercise intensities, whereas a plateau was established under placebo conditions by 45% of VO2max in both trained and untrained subjects. These results suggest that both trained and untrained hypertensive persons can exercise with beta-adrenergic blockade at submaximal levels without compromised cardiac function.

Changes in plasma free fatty acids and glycerols during prolonged exercise in trained and hypertensive persons taking propranolol and pindolol.

The extent to which lipolysis is attenuated during prolonged submaximal exercise during beta blockade was determined in 12 normotensive endurance-trained and 12 hypertensive sedentary men using nonselective drugs with and without intrinsic sympathomimetic activity (ISA). Initially, subjects performed a graded treadmill test to determine maximal oxygen uptake (VO2max). This was followed by 2-hour walks at 25 and 45% of the subject's VO2max under each of 3 treatments: pindolol (ISA), propranolol (non-ISA) and placebo. The distribution of medication was randomized and double blinded. Blood samples taken at rest and every 30 minutes during the 2-hour walks were analyzed to determine the concentrations of free fatty acids (FFA) and glycerol. On the basis of the respective changes in FFA, glycerols and the respiratory exchange ratio, beta-adrenergic blockade did not attenuate lipolysis in the untrained hypertensive subjects when compared with the placebo administration. However, beta blockade did demonstrate a tendency to attenuate lipolysis in the trained, normotensive subjects when compared with results after placebo administration. This was particularly evident at 30 minutes of exercise, when both glycerol and FFA concentrations were not increased above resting values under both conditions of beta blockade. No differences between pindolol and propranolol were observed. Therefore, a beta-blocking agent with ISA properties appears to have no clear benefit with respect to lipid metabolism during low and moderate intensity exercise. Furthermore, these data demonstrate that beta blockade does not inhibit exercise-induced lipolysis at low and moderate intensities of exercise as formerly believed, and is unlikely to be the cause of fatigue normally observed during work in patient populations taking beta-blocking medication.

Comparison of the effects of pindolol and propranolol on exercise performance in young men with systemic hypertension.

To determine the effect of intrinsic sympathomimetic activity (ISA) on exercise performance during beta blockade, 12 hypertensive men were studied. The subjects underwent graded treadmill testing while taking pindolol (a beta blocker with ISA), propranolol (a beta blocker without ISA) and placebo, in a double-blind, crossover fashion. Blood pressure, heart rate, oxygen consumption (VO2), cardiac output and stroke volume were determined at 25, 45, 60 and 75% of each subject's VO2 max. Heart rate was significantly lower with pindolol compared with placebo at all stages of exercise, but significantly higher compared with propranolol at all stages of exercise except at 75% of VO2 max and at VO2 max (no significant differences between the 2 beta blockers were recorded at these stages). Mean arterial pressure was statistically equivalent with pindolol and propranolol at all stages of exercise and significantly lower while beta-blocked compared with placebo conditions at 45, 60 and 75% of VO2 max. Cardiac output and VO2 were statistically equivalent across all 3 treatments at all submaximal levels of exercise. It was concluded that, although heart rate was significantly higher with pindolol compared with propranolol at the 3 lower rates of work, cardiac output and VO2 were not different between the drugs, thus making little impact on exercise performance.

The Physician Data Query (PDQ) cancer information system.

PDQ is an online database that provides information about the prognosis and treatment of all major types of cancer. It represents a major effort by the NCI to communicate advances in cancer treatment using computer technology, and serves as a major component of the Institute's program to reduce cancer mortality nationwide. PDQ utilizes a modern large-scale computer to provide processing speed, a general purpose database management system to provide retrieval and display functions, and commercial telecommunication networks to provide online access to up-to-date information on cancer treatment. A series of user-friendly menus allow searching, browsing, and displaying without having to learn a specialized search language. PDQ is accessible through the National Library of Medicine's computer system via a computer terminal or personal computer and is available to the medical community at over 2000 medical libraries and centers and through individual access codes. PDQ is also available as an online database under a special license agreement with NCI through two medical information systems produced by commercial database vendors: BRS/Saunders' COLLEAGUE and Mead Data Central's MEDIS.

Effect of antibody concentration on opsonic requirements for phagocytosis in vitro of Streptococcus pneumoniae types 7 and 19.

We investigated the effect of the concentration of type-specific antibody to pneumococcal polysaccharide (PPS) on opsonic requirements for phagocytosis in vitro of Streptococcus pneumonia types 7 and 19. We measured the uptake by human neutrophils of radiolabeled S. pneumoniae opsonized with either complement-intact, complement-depleted (by heat inactivation), or alternative complement pathway-activated (by magnesium dichloride-ethylene glycol tetraacetic acid (MgEGTA) chelation) immune sera with varying concentrations of antibody from individuals immunized with polyvalent PPS vaccine. Increased opsonization was found with increasing concentrations of type-specific antibody in the sera. Higher concentrations of antibody were required to opsonize type 7 than type 19 bacteria, both in the presence and absence of complement activity. Type 19 bacteria were more efficiently opsonized via the alternative complement pathway than type 7. For both types, antibody and the alternative complement pathway provided most of the opsonic activity in sera with lower concentrations of type-specific antibody. At high antibody concentrations, effective opsonization occurred in heat-activated sera, indicating the requirement for complement could be overcome with sufficient amounts of antibody alone.