Structural modifications of human albumin in diabetes.

AIM: Albumin, a major protein in the blood circulation, can undergo increased glycation in diabetes. From recent studies, it has become evident that glycation has important implications for albumin actions and impact on cell functioning. This study compares the structural and functional properties of albumin glycated by glucose and methylglyoxal (MGO) with those of albumin purified from diabetic patients. METHODS: Human serum albumin (HSA) was purified from diabetic patients and control subjects using affinity chromatography, and oxidation parameters in various albumin preparations were determined. Tryptophan and 1-anilino-8-naphthalene sulphonic acid (ANSA) probe fluorescence, redox state, antioxidant and copper-binding capacities of the different preparations of albumin were also determined and compared. RESULTS: Occurrence of oxidative modifications was enhanced in albumin whether purified from diabetic patients, or glycated by glucose or MGO, after determination of their fructosamine and free thiol and amino group contents, carbonyl content and antioxidant activities. Whereas more quantitative changes in oxidative and structural parameters were observed in the glucose- and MGO-modified albumins, significant impairment of albumin function (free-radical-scavenging and copper-binding capacities) were demonstrated in the HSA purified from diabetics. These findings reveal different structural and functional features of diabetic HSA compared with in vitro models. CONCLUSION: This study provides new information supporting albumin as an important biomarker for monitoring diabetic pathophysiology. In addition, it reconfirms the influence of experimental conditions in which advanced glycation end-products (AGEs) are generated in tests designed to mimic the pathological conditions of diabetes.

Effect of buflomedil on in vitro prostacyclin and endothelin synthesis by vascular (rat and human) and penile (rat) tissue and calcium uptake by isolated human platelets.

The effect of buflomedil, a vasodilator, on: (a) in vitro prostacyclin (PGI2) synthesis by the rat aorta and penis, human cultured endothelial cells (HUVECs) and human iliac artery, (b) endothelin synthesis by HUVECs and (c) 45Ca2+ uptake by isolated human platelets was investigated. Buflomedil had no effect on PGI2 synthesis by rat aorta, iliac artery or HUVECs (short or long-term incubations). However, buflomedil inhibited noradrenaline- (but not arachidonate- or ionophore A23187-) stimulated PGI2 synthesis. Buflomedil had a weak stimulatory effect on PGI2 synthesis by the isolated rat penis, but this was not inhibited by cholinergic antagonists. Buflomedil (except at supra-therapeutic concentrations) exerted no effect on endothelin release by HUVECS. Buflomedil inhibited 45Ca2+ uptake by human platelets when stimulated with collagen and adrenaline, but not when stimulated with calcium ionophore A23187. These data demonstrate that buflomedil has no deleterious effect on the enzymes that control vascular PGI2 synthesis. The data also adds to the evidence that buflomedil is an alpha-adrenoceptor blocker and has stimulatory effects on penile PGI2 synthesis. Both of these properties may prove useful in the treatment of impotence. The specific inhibition of 45Ca2+ uptake consolidates that buflomedil has some calcium-channel-blocking properties which may explain, at least in part, its vasodilator and antiplatelet properties. Buflomedil may prove beneficial in the treatment of impotence via three mechanisms: (a) stimulation of penile PGI2 synthesis (b) alpha-adrenoceptor blockade and (c) calcium-mobilization-blocking properties.

Pretreatment with buflomedil enhances ventricular function by reducing the dysfunctional area after transient coronary artery occlusion.

OBJECTIVE: The aim was to evaluate whether buflomedil (a drug used to treat peripheral vascular disease and which has a number of pharmacological actions potentially beneficial to dysfunctional myocardium) would preserve myocardial function after transient coronary artery occlusion followed by reperfusion. METHODS: The physiological response to a 15 min balloon occlusion of the left anterior descending coronary artery followed by 1 h of reperfusion was monitored in 17 placebo treated dogs and compared with that of 15 dogs which received 10 mg.kg-1 of buflomedil. Buflomedil or its vehicle were given intravenously. Myocardial blood flow was assessed with radiolabelled microspheres and cardiac function was evaluated with quantitative contrast left ventriculography. RESULTS: Buflomedil did not affect baseline haemodynamic variables or contractile function. At the end of occlusion, there was no difference between dogs receiving vehicle compared with those receiving drug with respect to ejection fraction [33(SD 11)% v 34(11)%] or transmural blood flow [0.23(0.11) v 0.28(0.14) ml.g-1 x min-1]. However, at 30 min after reperfusion, ejection fraction was 89% of normal in the buflomedil group compared with 69% of normal in the placebo group (p < 0.03). This difference was sustained 60 min after reperfusion, and was due in part to slightly enhanced flow during reperfusion and a decrease in the dysfunctional area (16 compared with 28 chords lower than -2 SD from the mean, p < 0.04) in the hearts of dogs receiving buflomedil. Areas at risk were equivalent (15.9% and 15.8% of the left ventricle, respectively). CONCLUSIONS: The results suggest that buflomedil and agents with similar modes of action may be beneficial in preserving ventricular function after transient ischaemia followed by reperfusion.

A review of long-term safety data with buflomedil.

Tolerance of long-term buflomedil was assessed by compiling safety data (adverse effects, vital signs and clinical laboratory results) from three multicentre clinical trials in patients with intermittent claudication or Alzheimer's disease-type senile dementia. The three studies were similar in design: open placebo lead-in; double-blind, placebo-controlled treatment; and open long-term treatment. Patients were randomly assigned to receive 600 mg/day buflomedil given orally for 3 or 6 months (n = 297) or placebo (n = 298). Buflomedil was continued for a further 6-12 months in 193 patients and for 12 months or more in 99 patients. Side-effects occurred in 20.5% and 18.1% of buflomedil- and placebo-treated patients, respectively, with discontinuation in 14.5% and 13.1%, respectively. In the open phase, 10.9% experienced side-effects, with 1.5% of patients discontinuing treatment. Mean changes in vital signs and laboratory tests were occasionally statistically, but not clinically, significant. Overall long-term tolerance was excellent.

An experimental overview of a new vasoactive drug: buflomedil HCl.

A brief review of the pharmacology, pharmacokinetics, and metabolism of buflomedil-HCl is presented providing a pharmacologic basis for buflomedil therapy of ischemia associated with peripheral vascular disease. Buflomedil is readily absorbed in the gastrointestinal tract and has a plasma half-life of approximately 2-3 hours. The para-desmethyl derivative of buflomedil has been identified as a urinary metabolite. Pharmacologically, buflomedil increases perfusion to impaired vascular beds of the microcirculation, increases arterial perfusion with minimal effects on central hemodynamics, exhibits apparent oxygen "sparing" effects in animal experiments, demonstrates inhibitory effects on platelet aggregation, and, in preliminary experiments, appears to improve deformability of erythrocytes with abnormal fluidity. A nonspecific alpha-receptor blocking activity appears to be involved, at least in part, in these pharmacologic effects. The relative importance of these mechanisms/effects in the treatment of symptoms of vascular disease is unknown.

Erythromycin succinate in the treatment of acute exacerbations of chronic bronchitis.

In 20 patients with an acute exacerbation of chronic respiratory tract infection the effectiveness of oral erythromicin succinate 3 X 500 mg daily has been tested. The duration of treatment was 10 days in all cases. The criteria of success, in addition to the clinical findings, were the results of bacteriological investigations and assessment of the appearance of the sputum. In all patients sputum and serum concentrations or erythromicin were determined. All pathogens isolated from the sputum of the patients were erythromicin-sensitive. One instance of development of resistance was observed. The drug was well tolerated.

An international haematological survey.

Haematological surveys of adult population samples were conducted simultaneously in 12 countries, all but one of which are in Europe. Haematological estimations on samples from nine of the countries were made in one central laboratory. Differences between countries in the mean levels of haemoglobin (and haematocrit and red cell count) were found to be relatively small, and the prevalence of levels below the arbitrary WHO levels for anaemia were, on the whole, low. In males, the evidence suggests a fall in haemoglobin level throughout adult life, which increases slightly in advanced age. In females, there is no evidence of any important relationship between age and haemoglobin level.