Pharmacokinetics and pharmacodynamics of BB-10153, a thrombin-activatable plasminogen, in healthy volunteers.

BACKGROUND: BB-10153 is an engineered variant of human plasminogen that is activated to plasmin by thrombin. Thrombus-selective induction of reperfusion and prevention of reocclusion have been demonstrated following bolus administration in animal models of thrombosis. OBJECTIVE AND METHODS: The objective of the study was to examine the pharmacokinetics and pharmacodynamics of BB-10153 administered as an intravenous bolus to healthy male human volunteers. Cohorts of four were dosed with BB-10153 (n = 3) or placebo (n = 1). In total, placebo was received by eight volunteers and 0.08, 0.2, 0.6, 1.2, 1.8, 2.4, 3.6 and 4.8 mg kg(-1) BB-10153 by three volunteers each. RESULTS: There was a linear relationship between AUC/Cmax and dose. The half-life of BB-10153 was approximately 3-4 h and all the BB-10153 in the circulation retained the ability to be activated by thrombin. There was a dose-related increase in plasma fibrin D-dimers. Ex vivo plasma clot lysis was observed at doses of 3.6 and 4.8 mg kg(-1), whereas lysis of clots formed from euglobulin-fractionated plasma was first evident at 0.6 mg kg(-1) and activity increased with dose. This activity decreased with time in line with the half-life. BB-10153 had no effect on plasma alpha2-antiplasmin or fibrinogen levels, coagulation assays or bleeding time. An increase in plasminogen was observed as BB-10153 was detected by the enzyme-linked immunosorbent assay (ELISA) for human plasminogen. CONCLUSIONS: BB-10153 was well tolerated and had a 3-4-h plasma half-life. Fibrinolytic activity was demonstrated by dose-related ex vivo clot lysis and in vivo production of fibrin D-dimers. These effects were not accompanied by consumption of alpha2-antiplasmin or fibrinogen.

Combination treatment with cholestyramine and bezafibrate for heterozygous familial hypercholesterolaemia.

Cholestyramine and bezafibrate were compared individually and in combination in the treatment of 18 patients with heterozygous familial hypercholesterolaemia. The study used a double blind, placebo controlled block design with a placebo run in period of two months followed by three phases of active treatment, each of two months' duration. Patients were randomly allocated to one of the six possible sequences of medication so that three patients would be treated with each sequence. Two patients withdrew from the study before completion. The median concentration of total cholesterol decreased from 9.65 mmol/l (interquartile range 8.62 to 8.72) to 7.24 mmol/l (6.70 to 7.52) with cholestyramine, to 8.09 mmol/l (7.18 to 8.68) with bezafibrate, and to 6.31 mmol/l (5.84 to 7.27) with the combination. This fall was due almost entirely to a decrease in the low density lipoprotein cholesterol concentration, and the combination was significantly more effective than either drug alone. The 98% confidence intervals for the median differences between the combination and cholestyramine and the combination and bezafibrate were 0.04 to 1.49 mmol/l and 0.51 to 2.18 mmol/l respectively. These results suggest that this combination is an effective and useful treatment in heterozygous familial hypercholesterolaemia.

Arterial oxygen desaturation following intravenous injection of midazolam.

The water soluble benzodiazepine derivative, midazolam, is used almost exclusively at our institution to produce sedation for numerous surgical procedures. Mild arterial oxygen desaturation has been reported in patients who have received as little as .04 mg/kg. A time series design study was undertaken to determine if there was any correlation between the decline in arterial oxygen percent saturation (SaO2) and the time at which sedation occurred and to establish the presence of any statistical significance in this decline. Thirty-one ASA I and II patients consisting of 8 females and 23 males requiring various minor orthopedic and general surgical procedures were studied. The total mean age of the population was 32.29 +/- 12.43 years (mean +/- SD). Fourteen patients had a smoking history, while 15 patients did not (2 patients were eliminated from the study for failure to demonstrate sedation, as characterized by either Verrill's sign or thickened speech following intravenous administration of midazolam). All patients arrived in the operating room unpremedicated and were administered .04 mg/kg midazolam intravenously. Arterial oxygen saturation was measured over a 10-minute period using pulse oximetry. Results were analyzed using regression analysis, a t-test for independent groups, and a one-way analysis of variance. There was no statistically significant difference in the decline in SaO2 between smokers and nonsmokers. Our study has shown that the mean onset of sedation using a dose of .04 mg/kg occurred between 3 and 4 minutes, with the peak fall in SaO2 occurring at the 3-minute interval irrespective of smoking history. The greatest mean drop in SaO2 was 95.84%. Midazolam, like its parent drug, diazepam, alters ventilatory mechanics.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and laboratory responses to niceritrol in the treatment of hypercholesterolaemia.

Twenty-five hypercholesterolaemic patients from three centres in the UK were investigated in an open study of the efficacy and side effects of niceritrol. Five patients dropped out of the study at an early stage and had insufficient data for analysis. There were 13 males and 7 females (mean age 49.2 years, range 18-69). Fourteen patients had heterozygous familial hypercholesterolaemia, and six polygenic hypercholesterolaemia. Niceritrol was started at a dose of 750 mg/day and this was increased at weekly intervals over 4 weeks to the maximum tolerated dosage up to 3 g/day. This was then maintained for a further 8 weeks. There were statistically significant decreases in total plasma cholesterol, total triglyceride, LDL cholesterol and VLDL triglyceride; HDL cholesterol remained unchanged after 12 weeks of treatment (Wilcoxon matched pairs, signed ranks test). The 14 patients with familial hypercholesterolaemia showed a 13.9% fall in total cholesterol and a 19.8% fall in LDL cholesterol. All patients reported flushing and some had gastrointestinal symptoms but 19 would have been prepared to continue with the therapy at doses up to 3 g/day. Thus niceritrol has been found to be beneficial in the treatment of both familial and polygenic hypercholesterolaemia.

Measurement of platelet aggregation in diabetics using the new electronic platelet aggregometer.

Platelet function has been studied in diabetic subjects using a new electronic platelet aggregometer which enables platelet aggregation to be studied in whole blood. This may be a more physiological approach to the assessment of platelet behaviour as centrifugation is avoided and platelets are studied in the presence of other blood elements which may be important modulators of platelet function in vivo. Twenty insulin-dependent diabetic subjects were studied along with 20 age and sex-matched controls. Platelet aggregation to collagen (1 microgram/ml) and arachidonic acid (1 mM) was significantly increased in the diabetic group. In addition the sensitivity of diabetic platelets to the antiaggregatory effects of prostacyclin was significantly reduced. A significant inverse correlation was found between platelet sensitivity to prostacyclin and glycosylated haemoglobin concentration in the diabetic group. It is unlikely that the platelet abnormalities in this diabetic group are due to underlying vascular disease as none of the patients had evidence of diabetic complications. These findings may have important implications for the development of vascular disease in diabetics.

The distribution of catecholamines between platelets and plasma in normal human subjects.

We have used high-performance liquid chromatography with electrochemical detection to measure content of adrenaline and noradrenaline in platelets in 13 normal subjects at rest. Subjects were exercised to raise plasma catecholamine levels and promote the platelet release reaction. There was a significant positive correlation between plasma noradrenaline concentrations and platelet noradrenaline content. Platelet/plasma concentration ratios were 1855 for noradrenaline and 268 for adrenaline at rest and 473 and 152 respectively after exercise. Plasma noradrenaline levels positively correlated with age. Determination of platelet factors released to the plasma showed increases of beta-thromboglobulin and platelet factor 4 with exercise, whereas thromboxane B2 remained unchanged. No change in platelet catecholamine levels occurred with exercise and no correlations were observed between platelet catecholamines and released platelet factors. These data suggest that plasma catecholamine levels influence platelet content and that noradrenaline and adrenaline are concentrated in platelets.

Glycaemic control in diabetic patients transferred from therapy with animal insulins to human crystalline zinc insulin of recombinant DNA origin: a multicentre study.

87 stable insulin-dependent diabetic patients from 6 diabetic clinics within the UK were transferred from their existing once or twice daily regimen of subcutaneous animal insulin to a similar regimen of human insulin of recombinant DNA origin in neutral soluble and crystalline zinc suspension formulations. Seven point blood glucose profiles, glycosylated haemoglobin concentrations and insulin dose were examined, in each patient, before and after 6 weeks therapy with human insulins. The 67 patients on twice daily insulin showed no significant change in mean blood glucose values or glycosylated haemoglobin but required a significantly higher dose of human crystalline zinc suspension than their previous long-acting animal insulin. In contrast the 17 patients on a once daily regimen experienced a significant deterioration in glycaemic control without a significant change in insulin dose or glycosylated haemoglobin. Three patients on twice daily insulin withdrew shortly after transfer to human insulin. The combination of human soluble and crystalline zinc suspension appears to be a more satisfactory substitute for animal insulin when used in a multi-dose regime rather than on a once daily basis.

Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis.

BACKGROUND: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. FINDINGS: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. INTERPRETATION: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis