The differential effect of aspirin on human platelet activation in aspirin-sensitive asthmatics and normal subjects.

1. The in vitro effect of aspirin on platelet aggregation and ATP release induced by platelet activating factor (PAF), arachidonic acid (AA) and collagen (COL) was assessed in 10 aspirin-sensitive (ASP+) asthmatic patients and 10 normal subjects. 2. For PAF, but not AA or COL, both the baseline EC50 and minimum concentration required to produce a maximum response for aggregation were significantly increased in ASP+ asthmatics compared with normal subjects (P < 0.05). Maximum ATP released was greater in ASP+ patients for all agonists but the difference was most significant for PAF (P < 0.025). 3. In ASP+ asthmatics COL induced, but not AA induced, aggregation was less sensitive to inhibition by aspirin compared with normals (P < 0.01). Similarly, analysis of the area under the percent inhibition concentration-response curve showed aspirin to be less effective in inhibiting platelet aggregation induced by PAF in ASP+ asthmatics than in normal subjects (normal subjects: 155 +/- 11 mg% ml-1, ASP+ asthmatics: 115 +/- 19 mg% ml-1; P < 0.05). 4. Regression analysis showed a poor correlation (r = 0.25, P < 0.4933) between the degree of aspirin induced inhibition of ATP release and platelet aggregation induced by PAF in ASP+ asthmatics. 5. The significant differences observed in platelet responses to PAF, COL and to aspirin in ASP+ asthma patients further suggests an abnormality in platelet function exists in this syndrome.     

Action of probucol in arteries from normal and hypercholesterolaemic rabbits.

1. The effect of probucol on the vascular reactivity of different arteries isolated from rabbits was studied as well as its effects on the development of atherosclerosis in a cholesterol-fed rabbit model. 2. Probucol 10(-6)-5 x 10(-4)M produced a concentration-dependent inhibition of the contractile responses induced by KCI (80 mM), the sequence for the IC50 was: mesenteric artery (5th branch, 4.8 +/- 2.6 x 10(-5) M) > aorta (8.2 +/- 2.3 x 10(-5) M) > femoral artery (> 5 x 10(-4) M). The response to noradrenaline was: mesenteric artery (5th branch, 4.2 +/- 1.3 x 10(-5) M) > aorta (3.2 +/- 3.0 x 10(-4) M) > femoral (> 5 x 10(-4) M). 3. In the aorta, probucol (10(-5)-10(-4) M) shifted the concentration-response curves to Ca2+ downward and to the right. 4. Probucol at 5 x 10(-5) M and 5 x 10(-4) M showed a reduction in the 45Ca2+ uptake in resting, non-stimulated aortic rings as well as the uptake induced by both noradrenaline 10(-6) M and KCI 80 mM. 5. In experiments in vivo, probucol did not affect lipid profiles; however, drug-treatment significantly decreased the cholesterol content of aortic tissue and the extent of intimal surface covered with atherosclerotic lesions. 6. The vascular reactivity was recovered in femoral arteries from rabbits on the atherogenic diet plus probucol. 7. It is concluded that the effect of probucol in vascular smooth muscle can be attributed to an inhibition of Ca2+ entry through both potential- and receptor-operated pathways. Moreover our findings suggest that the effects of probucol on movement of calcium in vascular smooth muscle may play an important role in the mechanism of antiatherogenic properties of this drug.     

The effect of age on theophylline clearance in normal subjects.

Dose-interval AUC and clearance of theophylline at steady-state were determined in healthy male subjects in each of three age groups (18-35, 36-54 and 55-70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.     

The addition of oatbran to a low fat diet has no effect on lipid values in hypercholesterolaemic subjects.

AIMS: to assess the hypocholesterolaemic effect of adding 50 g of oatbran to the diet of hypercholesterolaemic subjects already prescribed a diet with less than 30% of energy from fat. METHODS: twenty-nine volunteers aged 21-67 years with total serum cholesterol levels 5.59-8.5 mmol/L prescribed a diet containing less than 30% of energy intake as fat, and with a body mass index between 19.8 and 29.3, were enrolled in a crossover study to assess the effect of the addition to the diet of 50 g daily of oatbran. After six weeks of an oat-free control diet, subjects were randomised to eat 50 g daily of oatbran or to continue on the oat-free diet. Six weeks later the subjects crossed to the alternative diet for a further six week period. Lipid levels were assessed in weeks five and six of each study period. RESULTS: twenty-four subjects completed the study consuming 51.7 (SD 15.5) g of oatbran daily during the treatment phase. No significant difference was seen between the oatbran and control diet periods in body mass index, energy or fat intake, or in total cholesterol, LDL and HDL fractions, apolipoprotein A1 and B levels, or triglyceride levels. Considerable variation was observed between the paired lipid results. CONCLUSIONS: ingestion of 50 g of oatbran daily by hypercholesterolaemic subjects on a low fat diet showed no influence on serum lipid levels. The importance of using at least duplicate samples in assessing changes in lipid values is emphasised.     

A comparison of the effect of salmeterol and salbutamol in normal subjects.

1. The effects of salmeterol hydroxynaphthoate (50 micrograms, 8.3 x 10(-8) M) and salbutamol (200 micrograms, 3.5 x 10(-7) M) on sGaw were compared in a double-blind, placebo-controlled, randomised study in 10 normal subjects. 2. SGaw increased by 29% (14-43) (mean (CI)), 5 min after salmeterol and by 35% (19-51) at 15 min compared with an increase of 32% (14-51) and 37% (10-63) after salbutamol and 4% (-3-11) and 8% (0-16) after placebo. 3. The mean area under the sGaw-time curve (AUC480) after salmeterol inhalation was 22,500 kPa-1 (10,100-39,500) compared with 14100 kPa-1 (8020-24,500) after salbutamol and 5300 kPa-1 (1500-10,400) after placebo. 4. Salmeterol produced a significantly prolonged bronchodilator effect compared with salbutamol in normals.     

Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects

In the present study we have investigated the cAMP-dependent phosphorylation system in platelets of euthymic bipolar patients and healthy volunteers before and after 15 days of lithium treatment. The results showed that 15 days of lithium treatment enhanced the basal and the cAMP-stimulated ³²P incorporation in the 22 and 38 kDa phosphoproteins in bipolar patients, but not in healthy subjects. Moreover, we provided further evidence of increased phosphorylation in the 22 kDa platelet phosphoprotein in untreated euthymic bipolar patients when compared with controls. Overall, these findings suggest an implication of protein phosphorylation in the biochemical action of lithium and in the pathophysiology of bipolar disorder. Received: 9 April 1996/Final version: 1 September 1996     

Lack of effect of terfenadine on theophylline pharmacokinetics and metabolism in normal subjects.

The pharmacokinetics of oral theophylline (250 mg) and the production of its metabolites (3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid) were studied before and after the administration of oral terfenadine (120 mg twice daily for 16 days) in 10 healthy volunteers. Comparison of volumes of distribution, elimination half-lives, areas under the plasma concentration-time curves, plasma clearance of theophylline and elimination of theophylline metabolites indicated that terfenadine had no significant effect on theophylline pharmacokinetics and metabolism.     

Iloprost binding and inhibition of aggregation in platelet rich plasma. Differences between normal and type IIa hypercholesterolemic subjects

Platelets from type IIa hypercholesterolemic subjects have been previously shown to be less sensitive than normal platelets to the antiaggregatory effect of PGI2. We demonstrate here that these platelets display a reduced response to iloprost, a chemically stable analogue of PGI2, as well. In fact, the concentration of iloprost yielding 50% inhibition of PRP aggregation was higher in type IIa patients (0.77 +/- 0.08 nM) than in controls (0.51 +/- 0.06 nM, P less than 0.01). In addition, an inverse relationship existed between the threshold aggregatory concentration for collagen and the concentration of iloprost yielding 50% inhibition of PRP aggregation, both in type IIa and normal individuals. In order to elucidate the mechanism of the different sensitivity of platelets to prostacyclin and its analogue, we characterized the binding of 3H-iloprost to platelet rich plasma from single individuals. The binding was rapid, reversible, inhibited by iloprost, PGI2 and PGE1 (Kd = 50.7; 346.2 and 7500 nM, respectively); no heterogeneity of sites could be demonstrated in the PRP from a single individual. When binding studies were carried out in PRP of type IIa patients and controls, it appeared that the amount of 3H-iloprost bound at a fixed (300 nM) concentration was significantly lower in platelets from type IIa individuals (0.94 +/- 0.17 vs. 1.77 +/- 0.27 fmol/10(6) platelets, for patients and controls, respectively). It is concluded that such difference in binding might represent the mechanism underlying the reduced response to PGI2 and iloprost observed in platelets from type IIa patients.     

The effect of salbutamol on mood in normal subjects

The beta-2-adrenoceptor agonist salbutamol, widely used in the treatment of asthma, is thought to have antidepressant activity and possibly an abuse liability. In order to examine the mood-altering potential of this drug, a placebocontrolled, double-blind crossover trial was conducted in 21 psychiatrically normal subjects. The Profile of Mood States (POMS) was used to assess mood at baseline, after six weeks of placebo and salbutamol treatment (in either order), and after a four-week washout period in between treatments. The results showed little difference between treatments, apart from a tendency for salbutamol to worsen subjective mood relative to placebo during the first treatment phase only. In conclusion, the blinded, placebo-controlled administration of salbutamol gives no evidence of mood-elevating or addictive properties in psychiatrically normal individuals.     

Differential effect of phosphodiesterase 4 inhibitors on the proliferation of human peripheral blood mononuclear cells from normals and subjects with atopic dermatitis.

1. The aims of this study were to compare the effects of selective inhibitors of the type 3, type 4 and type 5 phosphodiesterase (PDE) isoenzymes on the phytohaemagglutinin (PHA)-stimulated proliferation of human peripheral blood mononuclear cells (HPBM) from normals and subjects with atopic dermatitis (AD). 2. Mononuclear cells were isolated from peripheral venous blood of normals and subjects with AD. A concentration-response curve was carried out with PHA (0.5-5 micrograms ml-1) and a concentration which produced a submaximal stimulation of proliferation (2 micrograms ml-1) was selected for further experiments. HPBM (10(5) cells per well) were stimulated with PHA (2 micrograms ml-1) in the absence or presence of PDE inhibitor (0.01 microM-10 microM) and 24 h later [3H]-thymidine (0.1 microCi per well) was added. Cells were incubated for an additional 24 h period and [3H]-thymidine incorporation measured. 3. The type 4 PDE inhibitors (rolipram, RO 20-1724 and denbufylline) produced a concentration-related inhibition of proliferation of HPBM from normal and AD subjects. The IC50 for rolipram was significantly (P < 0.05) lower in HPBM from AD patients 0.28 microM (95% confidence limits (CL): 0.158-0.499, n = 5) vs normal subjects 2.6 microM (95% CL: 0.867-7.05, n = 5, P < 0.05) as were the IC50 values for denbufylline: 0.26 microM (95% CL: 0.152-0.440, n = 5) vs 1.84 microM (95% CL: 0.467-7.23, n = 5, P < 0.05) respectively and RO 20-1724: 1.49 microM (95% CL: 0.61 microM-3.64 microM) vs 6.46 microM (95% CL: 2.03 microM-20.46 microM), respectively. 4. The mixed type 3/4 inhibitors (zardaverine and benzafentrine) produced a concentration-related inhibition of proliferation of HPBM from normal and AD subjects. The IC50 value for zardaverine in HPBM from normal subjects: 1.8 microM (95% CL: 0.43 microM-7.85 microM, n = 4) was similar to that in AD subjects: 1.03 microM (95% CL: 0.48 microM-2.28 microM) as was the IC50 value for benzafentrine in normal 3.8 microM (95% CL: 2.45 microM-5.9 microM) and atopic 5.5 microM (95% CL: 3.84 microM-7.78 microM) HPBM. The type 5 PDE inhibitor, zaprinast was ineffective at inhibiting the proliferation of normal HPBM. The type 3 PDE inhibitor, siguazodan only inhibited [3H]-thymidine incorporation at a concentration of 10 microM. 5. These results show that combined inhibition of the type 3 and 4 PDE isoenzymes in HPBM from normal subjects has a greater antiproliferative effect than inhibition of the type 4 isoenzyme alone. In addition these data indicate that the proliferative response of HPBM from AD subjects is more sensitive to PDE 4 inhibition than the proliferation of HPBM from normals.     

Cyclosporin-erythromycin interaction in normal subjects.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.     

Cardiovascular effect and simultaneous pharmacokinetic and pharmacodynamic modeling of pimobendan in healthy normal subjects.

Pimobendan is a new inotropic agent with vasodilator properties. We have reported the pharmacokinetics of enantiomers of pimobendan in healthy humans. The present report focuses on the pharmacodynamic effect of pimobendan and a simultaneous pharmacokinetic-pharmacodynamic modeling. Eight normal healthy volunteers were studied with oral administration of 7.5 mg and i.v. administration of 5 mg of racemic pimobendan. Concentrations of enantiomers of pimobendan were determined by high performance liquid chromatography. Cardiovascular effects of pimobendan were evaluated by echocardiography. Oral pimobendan significantly reduced 29.0% and 16.5% of the left ventricle end-systolic dimension (LVESD) and end-diastolic dimension, respectively. The mean velocity of circumferential fiber shortening, ejection fraction, and fractional shortening significantly increased 105.9%, 29.8%, and 46% from their baseline values, respectively. The cardiovascular effects of i.v. pimobendan were similar but to a lesser extent. Plots of effect versus plasma concentration (Cp) showed counterclockwise hysteresis loops. A hypothetical effect compartment was established and incorporated into a sigmoid Emax model to describe the time courses of Cps of pimobendan and effects on LVESD. The maximal changes (Emax) in LVESD would be 2.60 +/- 0.51 cm and 2.30 +/- 0.13 cm as estimated from plasma data of (+)- and (-)-pimobendan, respectively. The estimated effect-site concentrations corresponding with 50% of the maximal effect (Ce50) were 6.54 +/- 1.35 and 6.64 +/- 1.35 ng/ml for (+)- and (-)-pimobendan, respectively. A simultaneous pharmacokinetic-pharmacodynamic model could be established to suppress the hysteresis loop and to predict the pharmacological effect based on Cp.     

Effects of single doses of tranylcypromine on platelet mao and amine uptake in normal subjects

Twelve normal volunteers were administered single doses of dl-tranylcypromine, 10 and 20 mg, and placebo under double-blind conditions using a balanced cross-over design. Blood samples were taken pretreatment and at intervals thereafter and assayed for platelet MAO activity and platelet uptake of 5HT, dopamine and metaraminol. Platelet MAO activity was markedly and significantly decreased after both doses of tranylcypromine and remained low for at least 24 hr. By contrast, amine uptake into the subject's platelets was slightly but not significantly reduced. In vitro studies yielded parallel results, tranylcypromine being much more potent in inhibiting platelet MAO than platelet amine uptake. Therefore, it seems unlikely that the antidepressive activity of the MAOI's might correlate more closely with their ability to inhibit catecholamine uptake than with their power to inhibit MAO, as has been suggested.     

Chronopharmacokinetics of paracetamol in normal subjects.

The chronopharmacokinetics of paracetamol was studied in six male volunteers. Serum concentrations of paracetamol were determined after a single oral dose of 1 g, on three occasions, spaced at least 1 week apart. Plasma drug concentration vs time curves were obtained after dosage at 08.00 h (Day 1), 14.00 h (Day 2) and 20.00 h (Day 3), under standardized conditions. Pharmacokinetic parameters compared were t1/2,alpha, t1/2,Z, tmax, Cmax and AUCpo. No statistically significant differences were found.     

The effect of food on ciramadol bioavailability in normal subjects

Eleven healthy volunteers completed a study to compare the relative bioavailability to orally administered ciramadol in a fasting versus postprandial state. A single oral dose of 30 mg of ciramadol was administered on two separate occasions, 2 weeks apart, in a randomized crossover study. A mono- or biexponential pharmacokinetic equation with first-order absorption was applied to analyse the serum data for each subject. Significant differences were found in peak time (tmax) and absorption time (tabs) whereas the mean AUCs for the two modes of administration were not significantly different. The relative bioavailability (F) of the drug when administered in the postprandial state with respect to the fasting state was 96 per cent. It is thus concluded that ingestion of food has no effect on the extent of absorption of ciramadol; however, food may alter its rate of absorption.     

The effect of acute alcohol intoxication on psychometric testing and 5-HT-induced platelet aggregation in normal subjects; modulatory role of evening primrose oil

Groups of university students were exposed acutely to alcohol (100 ml vodka) and their performance in the Bexley Maudsley Automated Psychological Screening Tests (BMAPS) was assessed. Blood samples were also taken to assess platelet aggregation to 5-HT challenge. After 1 week administration of Evening Primrose Oil (EPO) or placebo under double-blind conditions the students were re-assessed. No mean difference was found in the psychometric testing of any of the groups either before or after the administration of EPO; however 5-HT-induced platelet aggregation was significantly potentiated in those groups exposed to alcohol, and was further increased in the group receiving EPO. These results suggest that platelet aggregation in response to 5-HT is more sensitive than psychometric tests commonly used to assess alcoholism in detecting changes due to acute alcohol intoxication.     

The effect of acute alcohol intoxication on psychometric testing and 5-HT-induced platelet aggregation in normal subjects: Modulatory role of evening primrose oil

Groups of university students were exposed acutely to alcohol (100 ml vodka) and their performance in the Bexley Maudsley Automated Psychological Screening Tests (BMAPS) was assessed. Blood samples were also taken to assess platelet aggregation to 5-HT challenge. After 1 week's administration of evening primrose oil (EPO) or placebo under double-blind conditions the students were re-assessed. No mean difference was found in the psycho-metric testing of any of the groups either before or after the administration of EPO. However 5-HT-induced platelet aggregation was significantly potentiated in those groups exposed to alcohol, and was further increased in the group receiving EPO. These results suggest that platelet aggregation in response to 5-HT is more sensitive than psychometric tests commonly used to assess alcoholism in detecting changes due to acute alcohol intoxication.