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  • 1
    ISSN: 1420-908X
    Keywords: Key words: Neutrophils — PDE type IV inhibitors — Adeno-sin — TNF — Degranulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Objective and Design: In the present work, we studied the role of cell-derived adenosine in both the physiologic regulation and pharmacologic control of the exocytosis of azurophilic granules of neutrophils exposed to tumor necrosis factor alpha (TNF) and stimulated with some chemoattractants.¶Material and Methods: Human neutrophils were pre-incubated in the absence or presence of TNF. Thereafter, the appropriate chemoattractant was added to the cells. After incubation, the cell-free supernatant was collected for testing elastase activity and intracellular cAMP levels. Results, expressed as mean ±1SD, were evaluated by unpaired, two-tailed Student's t-test and by analysis of variance followed by Student-Newman-Keuls multiple comparisons test.¶Results: Neutrophil incubation with 10 ng/ml TNF or 0.1 μmol/l N-formyl-met-leu-phe (fMLP) failed to release elastase activity (NE) (NE in absence of stimulus: 23.1 ± 5.7 nmol/h; TNF-induced NE: 26.4 ± 14.4 nmol/h; fMLP-induced NE: 27.0 ± 9.9 nmol/h). Neutrophils, pre-exposed to various amounts of TNF, released elastase in response to 0.1mmol/l fMLP in a dose-dependent manner (NE in presence of 10 ng/ml TNF and 0.1 mmol/l fMLP: 133.7 ± 24.0 nmoles/h). As compared with fMLP, C5a had lower activity (NE in presence of 10 ng/ml TNF and 0.1 mmol/l C5a: 66.4 ± 25.1 nmoles/h), whereas interleukin-8, platelet activating factor and leukotriene B4 were ineffective. The secretory response of TNF-primed neutrophils to fMLP was inhibited by adenosine in a dose-dependent manner (IC50 = 5.18 ± 7.1 mmol/l). The addition of adenosine deaminase (ADA) to TNF-primed neutrophils resulted in increased secretory response to fMLP (NE in absence and presence of 0.25 U/ml ADA: 71.5 ± 11.0 and 107.3 ± 18.6 respectively, P = 0.060). Moreover, two inhibitors of phosphodiesterase type IV (RO 20-1724 and nimesulide) reduced the elastase release only in the absence of ADA (RO 20-1724: percent inhibition in absence or presence of ADA = 20.2 ± 15.0 and 4.4 ± 5.1 respectively; nimesulide: percent inhibition in absence or presence of ADA = 22.2 ± 19.6 and 0.8 ± 3.0 respectively). Similarly, RO 20-1724 and nimesulide increased intracellular cAMP levels only in absence of ADA (RO 20-1724: percent cAMP increment in absence or presence of ADA = 215.4 ± 97.5 and 47.3 ± 53.3 respectively; nimesulide: percent cAMP increment in absence or presence of ADA = 177.7 ± 19.0 and 19.5 ± 29.3 respectively).¶Conclusions: Endogenous adenosine down-regulates the cell secretory response and is instrumental in uncovering the susceptibility of azurophilic granule exocytosis to control by inhibitors of phosphodiesterase type IV.
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  • 2
    ISSN: 1432-0428
    Keywords: Lipoproteins ; VLDL subfractions ; diabetes mellitus ; lipid composition ; lipolytic enzymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Very low density lipoproteins (VLDL) have an abnormal lipid composition in Type 1 (insulin-dependent) diabetic patients. Since VLDL represent a heterogeneous lipoprotein class, this might be due either to a shift in the distribution or to an abnormal composition of VLDL subclasses or both. In order to investigate these possibilities and to evaluate possible pathogenetic mechanisms, lipid composition (non-esterified and esterified cholesterol, triglycerides, phospholipids) of four VLDL subfractions of decreasing size (A: Svedberg flotation unit [Sf]〉400, B: Sf, 175–400, C: Sf 100–175, D: Sf 20–100), isolated by density gradient preparative ultracentrifugation, and plasma post-heparin lipolytic activity (lipoprotein lipase and hepatic lipase) were evaluated in 13 male normolipidaemic insulin-dependent diabetic patients in good glycaemic control (HbA1c 6.9±0.5%) (mean±SEM) and 9 male control subjects matched for age, body mass index and plasma lipid values. Compared to control subjects, diabetic patients showed a reduced total lipid concentration of VLDL of intermediate size (B and C) reaching statistical significance only for VLDL C (0.16±0.02 vs 0.24±0.03 mmol/l; p 〈0.05). Expressing each VLDL subfraction as percent of the total VLDL lipid concentration, a significant decrease in particles of intermediate size (C) (20.5±1.6 vs 27.9±1.5%; p 〈0.005) was present, which was compensated by an increase in the smallest ones (D) (50.5±2.7 vs 37.4±3.1%; p 〈0.05). VLDL of smaller size were also the only particles with an abnormal composition consisting of a significant increase in esterified cholesterol (12.2±0.8 vs 8.7±1.2%, p 〈0.01). Post-heparin hepatic lipase activity was significantly reduced in diabetic patients as compared to control subjects (232.9±27.9 vs 332±42.3 mU/ml; p 〈0.05) while post-heparin lipoprotein lipase activity was similar in the two groups. Furthermore, hepatic lipase activity was inversely related to the percentage of smaller VLDL (D)(r=−0.72; p 〈0.01) in diabetic patients and this relationship was independent of changes in intermediate VLDL (VLDL C). In conclusion the data suggest that Type 1 diabetic patients, although normolipidaemic and in good blood glucose control, show a shift in the distribution of VLDL subclasses toward VLDL of a smaller size which also have an abnormal composition. The different distribution of VLDL subfractions seems to be related to a reduced hepatic lipase activity.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 29 (1986), S. 717-719 
    ISSN: 1432-1041
    Keywords: sulphinpyrazone ; oxprenolol ; antihypertensive activity ; cyclo-oxygenase ; prostaglandins ; drug interaction ; drug metabolizing enzymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interfering effect of sulphinpyrazone, a uricosuric agent which reduces the activity of cyclo-oxygenase, with the antihypertensive activity of oxprenolol, a non-cardioselective beta-blocker with sympathomimetic activity, has been evaluated. Ten patients with primary arterial hypertension of mild to moderate degree entered a randomized doubleblind cross-over study versus placebo. They were given oxprenolol + placebo or oxprenolol + sulphinpyrazone for 15 days, and then the treatments were crossed-over for a further 15 days. Oxprenolol significantly reduced blood pressure (161±3/101±1 vs 149±4/96±2 mmHg) and heart rate (72±3 vs 66±3 beats/min). During administration of the combination with sulphinpyrazone the blood pressure increased to its pretreatment level (156±5/101±2 mmHg). The effect of oxprenolol on heart rate was not influenced by the combined treatment (67±6 beats/min). The results may be explained by 1) sulphinpyrazone-induced inhibition of prostaglandin synthesis, which could interfere with the antihypertensive activity of oxprenolol, or 2) sulphinpyrazone-induced acceleration of the metabolism of oxprenolol.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1041
    Keywords: nicardipine ; insulin ; glucose ; diabetes ; hypertension ; metabolic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Certain acute and chronic metabolic effects of nicardipine have been studied in 20 patients with non-insulin dependent diabetes (NIDD). An intravenous glucose tolerance test (i.v. GTT, glucose 0.33 g/kg as a bolus) and the corresponding insulin response were assessed at the end of a 4 week placebo period, after the first dose and on administration for 12 weeks of nicardipine 20 mg t.i.d. The glucose and insulin responses to the i.v. GTT, evaluated as incremental AUCs, did not change significantly (glucose 30.5 mg/dl·90 min on placebo, 33.1 mg/dl·90 min acutely and 31.4 mg/dl·90 min on chronic administration of nicardipine; insulin 2.08 µU/ml·90 min on placebo, 1.87 µU/ml·90 min acutely and 1.93 µU/ml·90 min after chronic nicardipine). Glucose removal rate (KG) following the i.v. GTT was 0.73%/min on placebo 0.75%/min on acute administration and 0.8%. min−1 with chronic nicardipine. Active treatment produced a significant reduction of blood pressure (from 187/96 mm Hg on placebo to 166/89 mm Hg acutely and 152/83 mm Hg after 12 weeks of nicardipine treatment). It is concluded that the calcium antagonist nicardipine was an effective antihypertensive drug, and that it did not cause deterioration of metabolic control in hypertensive patients with NIDD.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 38 (1990), S. 393-395 
    ISSN: 1432-1041
    Keywords: Insulin ; propranolol ; sympathetic stimulus ; heart rate increase ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acute hyperinsulinaemia in the absence of changes in blood glucose increases heart rate in man. Animal studies have suggested that beta-adrenergic blockade does not prevent the insulin-induced increase in heart rate. The aim of the present study was to investigate the acute effect of insulin on heart rate and blood pressure in non diabetic subjects and, in particular, to determine whether beta-adrenergic receptor blockade would significantly influence the effect. On separate days 9 healthy young volunteers were pretreated with either 80 mg propranolol or placebo p.o. After a 60–90 min period of heart rate and blood pressure stabilization, a placebo injection was given intravenously and heart rate and blood pressure were then monitored every 5 min. After 30 min insulin Actrapid MC 0.2 IU/kg body weight was given i.v. A 20% glucose infusion was given to maintain blood glucose at its fasting level. After insulin administration, a rapid and statistically significant increase in heart rate was observed when the patients were pretreated with placebo; pretreatment with propranolol completely prevented this effect. Serum insulin levels were significantly higher than baseline at all times and there was no significant change in blood glucose. The results are consistent with the hypothesis that the insulin-induced increase in heart rate in man may result from stimulation of cardiac sympathetic activity.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 28 (1985), S. 241-244 
    ISSN: 1432-1041
    Keywords: muzolimine ; hydrochlorothiazide + amiloride ; antihypertensive treatment ; hypertensive patients ; side-effects ; serum potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thiazide therapy is a widely used first line treatment for arterial hypertension. Its useful value, particularly in mild or moderate hypertension, is sometimes reduced by metabolic side-effects, as hypokalaemia and hyperuricaemia. In the present study the antihypertensive efficacy of a new, non-sulphonamide diuretic Bay g 2821 (muzolimine) was evaluated in comparison with the combination of hydrochlorothiazide-amiloride over a period of 4 weeks. A highly significant decrease in systolic and diastolic blood pressures was produced by both treatments. No decrease in serum potassium nor an increase in cholesterol, triglycerides, uric acid or glucose was detected during the 4 week treatment period. Subjective side-effects, such as headache and dizziness, were very rarely observed during Bay g 2821 treatment. The new diuretic appears, therefore, to be effective in the treatment of arterial hypertension without untoward side-effects.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1041
    Keywords: muzolimine ; chlorthalidone ; hypertension ; serum electrolytes ; potassium ; ion transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous short-term studies of muzolimine (a diuretic with frusemide-like activity) had shown that it did not induce a significant change in the serum potassium concentration. In the present study sodium and potassium handling and other metabolic variables have been compared during 16 weeks of therapy with muzolimine and chlorthalidone, a thiazide-like diuretic. During muzolimine treatment, plasma and red cell potassium concentrations remained unchanged, while a significant fall in potassium occured with chlorthalidone. Neither drug affected the activity of sodium-potassium cotransport or sodium-lithium countertransport in red cells in vitro. Muzolimine and chlorthalidone had similar effects on arterial pressure and on the other metabolic variables tested.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 26 (1984), S. 331-334 
    ISSN: 1432-1041
    Keywords: metoprolol ; oxprenolol ; hypertension ; beta-blockers ; HDL-cholesterol ; intrinsic sympathomimetic activity ; cardioselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of the present study was to evaluate whether a reduction in HDL-cholesterol is peculiar to non cardioselective beta blockers or whether it is also produced by cardioselective beta1-blockers. 16 patients with primary arterial hypertension on a balanced isocaloric diet were given oxprenolol 120 to 240 mg/day or metoprolol 100 to 200 mg/day in a random cross-over study. No significant change was observed after either treatment in fasting blood glucose, serum total cholesterol and triglycerides. HDL-cholesterol concentration was significantly decreased on metoprolol, from 41 to 36 mg/dl (p〈0.05), while oxprenolol did not affect it at all. The difference might depend on intrinsic sympathomimetic activity which is possessed by oxprenolol and which metoprolol lacks.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1041
    Keywords: beta-adrenoreceptor blockers ; normoglycaemia ; glucose tolerance ; insulin secretion and -sensitivity ; hypertension ; propranolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of 3 weeks of treatment with the beta-receptor blocking agent propranolol and a placebo on glucose tolerance, insulin secretion and peripheral insulin sensitivity have been evaluated in 7 normoglycaemic hypertensive patients by an oral glucose tolerance test and the insulin clamp technique. Significant changes in systolic and diastolic blood pressure and heart rate were observed at the end of propranolol treatment, but there were no associated changes in glucose tolerance, insulin secretion or peripheral insulin sensitivity. No difference was observed in glucagon, growth hormone and free fatty acids between propranolol and placebo treatment. The results support the view that the hypothetical pancreatic glucoreceptor, at least in non-acute studies, is not affected by beta blockade. In addition, there was no effect on tissue sensitivity to insulin.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1041
    Keywords: chlorthalidone ; nifedipine ; left ventricular mass ; slow-release nifedipine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The presence of a possible correlation between changes in left ventricular mass of hypertensive patients and the degree of blood pressure reduction with different antihypertensive drugs has been investigated in 40 outpatients by M-mode echocardiography. Ten of these, with blood pressure in normal limits with different antihypertensive treatment had their therapy changed in chlorthalidone 25 mg/day without any run-in (Group A); other 30 patients, with a previously uncontrolled blood pressure, after a 14 day run-in, were randomly allocated to chlorthalidone 25 mg/day (Group B), slow release nifedipine 20 mg/day (Group C) or placebo (Group D). At the end of the eight week treatment period a further decrease in systolic blood pressure was observed in Group A without changes in ventricular mass; an highly significant decrease in both systolic and diastolic blood pressure was observed in B and C but only patients on chlorthalidone changed their ventricular mass; no change in both blood pressure and ventricular mass was observed on placebo. As changes in ventricular mass are not correlated with blood pressure reduction, we conclude that other, not well defined factors, apart from the decrease in duration and degree of left ventricular systolic wall tension, may be responsable for reversal of left ventricular hypertrophy.
    Type of Medium: Electronic Resource
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