Antianginal efficacy of the combination of felodipine-metoprolol 10/100 mg compared with each drug alone in patients with stable effort-induced angina pectoris: a multicenter parallel group study. The TRAFFIC Study Group.

OBJECTIVE: The primary objective of this randomized, double-blind, parallel group trial was to compare the antianginal and antiischemic efficacy of a combination tablet of felodipine-metoprolol 10/100 mg once daily with both drugs given separately once daily in patients with stable effort-induced angina pectoris. The secondary objective was to compare the tolerability of the 3 treatments. METHODS: The main criteria for inclusion were stable effort-induced angina pectoris for at least 2 months before the enrollment and a positive bicycle exercise test result. Patients were allocated to once-daily treatment with either felodipine-metoprolol 10/100 mg, felodipine 10 mg, or metoprolol 100 mg. The duration of active double-blind treatment was 4 weeks. There were 3 primary efficacy variables in the study; time until end of exercise, time until onset of chest discomfort, and time until 1-mm ST depression during a standardized exercise test. RESULTS: The number of patients randomized was 397. There was a statistically significant improvement in time until end of exercise with felodipine-metoprolol 10/100 mg compared with metoprolol 100 mg (P =.04) and felodipine 10 mg compared with metoprolol 100 mg ( P =.03). However, for time until onset of pain or time until 1-mm ST-depression there were no significant differences among the treatment groups. At highest comparable workload, ST depression was less pronounced with felodipine-metoprolol than with metoprolol alone (P =.04), and the rate-pressure product was significantly lower in the groups receiving felodipine-metoprolol and metoprolol than in the group receiving felodipine alone. The combination and metoprolol were better tolerated than felodipine alone. CONCLUSIONS: In stable angina pectoris, the combination felodipine-metoprolol 10/100 mg and felodipine 10 mg alone increased exercise time compared with metoprolol 100 mg. The combination tablet and metoprolol 100 mg alone showed a more favorable tolerability profile than felodipine 10 mg alone.

Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4.

To test the hypothesis that interaction between genetic, immunological, clinical and metabolic risk factors influences the outcome of Type II (non-insulin-dependent) diabetes mellitus, we examined which of the above factors present at baseline were associated with mortality in 134 Type II diabetic patients followed for 9 years. Thirty-eight patients (29%) died during the follow-up period; the majority of whom (68%) died from cardiovascular disease. At baseline, the deceased patients had higher HbA1c values (p = 0.002), higher LDL-triglycerides (p = 0.007), lower HDL-cholesterol (p = 0.007), higher non-esterified fatty acid (NEFA) concentrations (p = 0.014), and higher albumin excretion rate (p < 0.0001) than the patients who survived. In addition, the frequency of HLA-DR4 (21 vs 39%, p = 0.048) and of parietal cell antibodies (5 vs 14%, p = 0.016) were decreased in the deceased as compared to the living patients. Patients who died during follow-up also had more retinopathy (42 vs 16%, p = 0.002), neuropathy (57 vs 23%, p < 0.001), microalbuminuria (45 vs 6%, p < 0.0001), coronary heart disease (50 vs 13%, p < 0.0001), and peripheral vascular disease (27 vs 9%, p = 0.005) at baseline than patients who survived. In a multiple logistic regression analysis macroangiopathy (p = 0.004), neuropathy (p = 0.007), HbA1c (p = 0.018) and albumin excretion rate (p = 0.016) were independent risk factors for death. In patients free of cardiovascular disease at baseline, conventional risk factors such as LDL-cholesterol (p = 0.005) and age (p = 0.003) were associated with subsequent development of cardiovascular disease. In conclusion, in addition to coexisting macroangiopathy, increased albumin excretion rate, poor glycaemic control and neuropathy are risk factors for cardiovascular mortality in patients with Type II diabetes. The presence of HLA-DR4 and signs of autoimmunity may be associated with decreased risk of cardiovascular disease.

Predictors of progression from normoalbuminuria to microalbuminuria in NIDDM.

OBJECTIVE: Our objective was to establish the clinical, genetic, metabolic, and immunologic risk factors for the progression of the albumin excretion rate (AER) in normoalbuminuric NIDDM patients. RESEARCH DESIGN AND METHODS: We recruited 108 NIDDM patients with normal AER after a diabetes duration of 9 years to participate in a prospective 9-year follow-up. In addition to conventional clinical and metabolic variables, we assessed microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (coronary heart disease, peripheral vascular disease) diabetic complications, genetic markers (HLA genotypes), and organ-specific autoimmune markers, including islet cell antibodies. Multiple logistic regression was used to determine independent predictors of progression of AER. RESULTS: A total of 21 patients (19%) died during the follow-up. There was an overrepresentation of men (61 vs. 39%; P = 0.044) and smokers (55 vs. 27%; P = 0.01) in patients who progressed to micro- or macroalbuminuria versus those who did not progress. In addition, progressors had higher fasting plasma glucose (P = 0.002) and HbA1 (P = 0.0002) concentrations at baseline than did nonprogressors. Neuropathy was more often seen in progressors than in nonprogressors at baseline (53 vs. 16%; P = 0.0004). Frequency of HLA genotypes and autoimmune markers did not differ between progressors and nonprogressors. In a multiple logistic regression analysis, HbA1 (P = 0.0005) and a history of smoking (P = 0.011) were independent predictors of progression of AER. CONCLUSIONS: This study reemphasizes the importance of poor glycemic control and smoking as independent risk factors for progression of AER. Furthermore, development of micro- or macroalbuminuria in NIDDM was associated with neuropathy and male sex.

Tolerability to high doses of formoterol and terbutaline via Turbuhaler for 3 days in stable asthmatic patients.

This randomized, double-blind, crossover study in two parts compared tolerability to high doses of formoterol (Oxis Turbuhaler) with that of high doses of terbutaline (Bricanyl Turbuhaler). After Holter monitoring at home, 12 patients were treated with 4+4+4 doses of formoterol Turbuhaler, 6 microg x dose(-1), (total daily metered dose 72 microg) or 4+4+4 doses of terbutaline Turbuhaler, 0.5 mg x dose(-1) (daily dose 6 mg) given in the morning, after lunch and in the evening, for 3 consecutive days. After a one week washout period at home, patients received the alternative treatment. Thereafter, 15 other patients received 8+6+6 doses of formoterol Turbuhaler (total daily metered dose 120 microg) or 8+6+6 doses of terbutaline Turbuhaler (daily dose 10 mg). Pulse, cardiac frequency, blood pressure, serum potassium, electrocardiogram and forced expiratory volume in one second (FEV1) were registered at regular intervals and Holter monitoring was applied during all 4 treatment days. Terbutaline 6 mg showed significantly greater systemic effects than formoterol 72 microg on pulse, blood pressure, cardiac frequency and QTc (QT interval corrected for heart rate). Terbutaline 10 mg had significantly greater effects than formoterol 120 microg on serum potassium levels, pulse, cardiac frequency and QTc. No differences in FEV1 levels were found. Both drugs were safe and generally well tolerated on both dose levels. In conclusion, high doses of formoterol Turbuhaler over 3 days were generally safe and well tolerated. Daily doses of 6 mg and 10 mg terbutaline Turbuhaler were systemically more potent than 72 microg and 120 microg formoterol, respectively. The safety margin thus appears to be wide if patients happen to use extra doses of formoterol in addition to those prescribed for regular use.

Thrombosed coronary artery fistula as a cause of paroxysmal atrial fibrillation and ventricular arrhythmia.

This case report presents a 68-year-old woman with a symptomatic coronary artery fistula. Usually these rare congenital malformations are symptom-free but in this patient the fistula began to cause various arrhythmias after it thrombosed. Her symptoms resolved completely after connective surgery.

Lack of association between the apolipoprotein B gene 3' hypervariable region alleles and coronary artery disease in Finnish patients with angiographically documented coronary artery disease.

Previous studies have suggested that some apolipoprotein B (apoB) 3' variable number of tandem repeats (3'VNTR) locus alleles are associated with coronary artery disease (CAD). We examined the possible association between the apoB 3'VNTR alleles and CAD in 387 Finnish subjects. Using the polymerase chain reaction and polyacrylamide gel electrophoresis, the 3'VNTR genotype was determined in 187 individuals with severe CAD confirmed by coronary angiography (patients), in 121 individuals with normal coronary angiograms (controls), and in 79 apparently healthy subjects (normals). In contrast to previous reports from other populations, the larger apoB 3'VNTR alleles were not significantly more frequent among CAD patients than among controls or normals. In addition, there was no significant association between the 3'VNTR alleles and serum lipid levels in this Finnish population.

Sick sinus syndrome as a complication of mediastinal radiation therapy.

A 33-year-old man who had received mediastinal radiation therapy for Hodgkin's disease 12 years earlier developed a symptomatic sick sinus syndrome requiring the implantation of a permanent pacemaker. The sick sinus syndrome and a finding of an occult constrictive pericarditis were considered to be due to the previous mediastinal irradiation. A ventricular pacemaker was chosen because mediastinal radiotherapy also increases the risk of developing atrioventricular conduction defects.

Serum amyloid A protein, apolipoprotein A-I, and apolipoprotein B during the course of acute myocardial infarction.

Serum amyloid A protein (SAA), apolipoprotein A-I (apoA-I), apolipoprotein B (apoB) concentrations, and creatine kinase (CK)-MB isoenzyme activity were serially measured in 10 patients during the course of acute myocardial infarction. Pronounced increases in SAA concentrations were observed in all patients during infarction. The highest SAA values were observed, on average, 67 hours after the onset of chest pain. After infarction both apoA-I and apoB concentrations decreased. The reduction in apoA-I concentration 67 to 72 hours after the onset of chest pain was (31%) (p less than 0.01) and the reduction in apoB concentration 55 to 60 hours after the onset of pain was (34%) (p less than 0.01). Negative correlations were found between the concentrations of SAA and apoproteins A-I and B; this inverse relation was stronger between SAA and apoB than between SAA and apo-AI.

Hemodynamic effects of alpha-human atrial natriuretic peptide in healthy volunteers.

The hemodynamic effects of synthetic alpha-human atrial natriuretic peptide (alpha-hANP) were evaluated in a double-blind, placebo-controlled study with echocardiography and systolic time intervals in 11 healthy volunteers. During an infusion of alpha-hANP for 30 min, when plasma ANP concentration increased to a peak level of approximately 300 pg/ml, an increase occurred in diuresis (+174%, p less than 0.01 vs. placebo) and natriuresis (+148%, p less than 0.05). Heart rate increased (+10%, p less than 0.05), but the mean arterial pressure remained unchanged. The left ventricular end-diastolic diameter was reduced (-3%, p less than 0.01), as was the left ventricular end-systolic diameter (-11%, p less than 0.001). Total peripheral resistance (-12%, p less than 0.05) and midsystolic circumferential wall stress (-16%, p less than 0.05) decreased, while cardiac output increased (+15%, p less than 0.05), as did fractional shortening (+15%, p less than 0.001). Within 30 min postinfusion, all differences between the ANP and placebo treatments had disappeared. No significant difference between the treatments was observed in preejection period or preejection period/left ventricular ejection time ratio. In conclusion, when administered as a short infusion, alpha-hANP causes peripheral arterial vasodilation and thus, by reducing left ventricular afterload, improves the pump function of the heart. Venous vasodilating effect of alpha-hANP may contribute to the decrease in left ventricular preload, but a diuresis-induced reduction in circulating intravascular volume may also be influenced.

Effects of the combination of insulin and glibenclamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents.

The effects of combined insulin and sulfonylurea therapy on glycaemic control and B-cell function was studied in 15 Type 2 (non-insulin-dependent) diabetic patients who had failed on treatment with oral hypoglycaemic agents. The patients were first treated with insulin alone for four months. Five patients were given two daily insulin doses and ten patients one dose. During insulin treatment the fasting plasma glucose fell from 14.5 +/- 0.8 to 8.8 +/- 0.4 mmol/l and the HbA1 concentration from 12.6 +/- 0.4 to 9.2 +/- 0.2%. This improvement of glycaemic control was associated with a suppression of basal (from 0.31 +/- 0.04 to 0.10 +/- 0.02 nmol/l) and glucagon-stimulated (from 0.50 +/- 0.08 to 0.19 +/- 0.04 nmol/l) C-peptide concentrations. Four months after starting insulin therapy the patients were randomised to a four-month double-blind cross-over treatment with insulin combined with either 15 mg glibenclamide per day or with placebo. Addition of glibenclamide to insulin resulted in a further reduction of the fasting plasma glucose (7.9 +/- 0.5 mmol/l) and HbA1 (8.3 +/- 0.2%) concentration whereas the basal (0.21 +/- 0.03 nmol/l) and glucagon-stimulated C-peptide concentrations (0.34 +/- 0.06 nmol/l) increased again. Addition of placebo to insulin had no effect. The daily insulin dose could be reduced by 25% after addition of glibenclamide to insulin, while it remained unchanged when insulin was combined with placebo. The fasting free insulin concentration did not differ between the glibenclamide and placebo periods (28 +/- 6 vs 30 +/- 5 mmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of pharmacokinetics, metabolic effects and mechanisms of action of glyburide and glipizide during long-term treatment.

Fourteen non-insulin-dependent diabetic (NIDDM) patients continued their previous medication (7 on glyburide, 7 on glipizide) for 6 mo, after which they switched to the alternate treatment for another 6 mo. The treatment periods were followed by 1 mo of placebo. The sulfonylurea dose was increased to achieve fasting plasma glucose levels less than 9 mM or to a total maximum daily dose of 25 mg. The mean final doses of glyburide (14.7 +/- 2.4 mg/day) and glipizide (15.2 +/- 2.2 mg/day) were similar. Postprandial (postdose) glipizide levels were higher than those of glyburide, whereas fasting (predose) glyburide concentrations were higher than those of glipizide. Both treatments improved glucose control by 25% compared with placebo. Glipizide therapy evoked higher postprandial insulin concentrations than did glyburide, whereas basal insulin concentrations were higher during glyburide. Insulin sensitivity, assessed by an insulin tolerance test, was more improved with glyburide than with glipizide. In conclusion, overall glucose control is similarly improved by glyburide and glipizide. However, glipizide amplifies the plasma insulin response to meals more than glyburide, whereas glyburide enhances basal insulin secretion more than glipizide. Both pharmacokinetic and pharmacodynamic factors may contribute to these differences.

The effect of dexamethasone on the enteroinsular axis.

In order to examine whether hyperinsulinaemia induced glucocorticoid therapy involves alterations of the enteroinsular axis glucose, insulin, C-peptide, glucagon and GIP responses to a test meal with and without prior intake of dexamethasone (2 + 2 mg) in 13 healthy subjects were measured. Dexamethasone caused impaired glucose tolerance, which was associated with an exaggerated insulin (0.61 +/- 0.05 vs. 0.38 +/- 0.05 nmol/l; p less than 0.001). C-peptide (0.97 +/- 0.08 vs. 0.71 +/- 0.06 nmol/l; p less than 0.001) and glucagon response to a test meal. In contrast, the GIP response to the test meal was blunted after dexamethasone (126 +/- 17 vs. 177 +/- 23 pmol/l; p less than 0.001). It therefore follows that alterations in the enteroinsular axis, that is, GIP secretion, cannot be responsible for the enhancement of insulin secretion observed after dexamethasone. The mechanism(s) for the decreased GIP response after dexamethasone could involve (1) a direct inhibitory effect on GIP secretion by dexamethasone, and/or (2) a negative feedback of elevated glucose and insulin levels on GIP secretion.

AA amyloidosis in systemic lupus erythematosus.

A 37-year-old woman with longstanding systemic lupus erythematosus developed cardiac insufficiency, nephrotic syndrome, and azotemia. The findings at echocardiography and cardiac scintigraphy suggested amyloidosis, which was confirmed by rectal biopsy and fine needle biopsy of subcutaneous abdominal fat. Postmortem examination revealed systemic amyloidosis with massive deposits in the heart, spleen and kidneys. She had persistently increased concentration of serum amyloid A protein during the last 4 years of her life, and her amyloidosis was of the secondary (AA) type, as shown by immunohistochemical studies.

Late cardiac effects of mediastinal radiotherapy in patients with Hodgkin's disease.

Twenty-eight patients younger than age 40 years, treated for Hodgkin's disease with mediastinal irradiation, were examined no less than 5 years after the irradiation in order to evaluate the frequency of cardiac abnormalities. Twelve patients (43%) had had some pericardial event after radiation: a diagnosed pericarditis, remarkably increased heart volume, or a conspicuous change of cardiac silhouette, suggesting pericardial fluid. On evaluation, 50% of the patients complained of symptoms, and 13 patients had to stop the exercise test on a low level because of chest pain, dyspnea, or general fatigue. In 13 patients some of the following abnormalities in the electrocardiogram (ECG) was found: right bundle branch block (four), first-degree atrioventricular block (four), abnormal P terminal force (five), or a low voltage (two). In ten patients (38%) an increase of the pericardial fluid was seen in the echocardiogram, and in nine patients the right ventricle wall thickness had increased. In two patients a severe coronary artery disease was found. One died suddenly after an acute myocardial infarction (AMI), and the other had a large anterior AMI. Two patients with chronic pericardial fluid underwent partial pericardectomy. Two cases of mild pulmonary valve stenosis, one pulmonary subvalvular stenosis and two aortic valve deformities were discovered. Eight patients went through cardiac catheterization, and in all but one case the pressures were slightly elevated suggesting diminished diastolic compliance. In summary, 19 of 28 patients had some abnormal cardiac findings, but only three of them were serious ones.

Plasma atrial natriuretic peptide in health and disease.

The plasma concentration of atrial natriuretic peptide (ANP) in 16 healthy subjects on a free diet was 41 +/- 23 pg ml-1 (mean +/- SD) when upright and 58 +/- 27 pg ml-1 in the supine position (P less than 0.05), which confirms the concept that the supine position raises plasma ANP. Water immersion to the neck for 2 h caused a brisk diuresis, natriuresis and raised plasma ANP in 8 healthy subjects, suggesting that ANP is a mediator of diuresis and natriuresis during immersion. Dynamic exercise (50-200 W per 4 min) on a bicycle ergometer caused a gradual increase in plasma ANP in 6 healthy males, with a close correlation between the increases in plasma ANP and heart rate (r = 0.96). Thus, plasma ANP levels are increased in healthy subjects by stimuli causing an increased preload and possibly by tachycardia itself. Markedly raised plasma levels of ANP were found in patients with congestive heart failure, and upright posture caused a further rise of plasma ANP which correlated with the increase in heart rate (r = 0.87). High plasma ANP concentrations were also found in 25 patients with end-stage renal failure maintained on haemodialysis. When these patients were subdivided into those with concomitant heart failure and those with normal cardiac function, changes in plasma ANP correlated with predialysis weight gain and weight loss during dialysis, but only in patients without heart failure. In 9 infants treated by operative or pharmacological closure of persistent ductus arteriosus, high pre-treatment plasma ANP values were lowered by successful therapy, and plasma ANP correlated with the degree of left atrial distension.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphate binding by a myeloma protein.

A patient with IgG kappa myeloma had markedly elevated serum phosphate concentrations but no clinical features of hyperphosphataemia. The hyperphosphataemia was due to a high phosphate per protein unit than normal IgG.

Relationship between changes in GIP concentrations and changes in insulin and C-peptide concentrations after guar gum therapy.

In order to elucidate the mechanisms of the action of gel-forming fibre in diabetes, we measured insulin, C-peptide and GIP responses to meals during treatment with guar gum and placebo in normal and non-insulin-dependent diabetic (NIDD) subjects. Dietary supplementation with guar gum caused a sustained reduction of the GIP response in normal and diabetic subjects (p less than 0.05), but did not influence insulin responses. On the other hand, guar gum increased the C-peptide response to meals in normal subjects (p less than 0.05) resulting in a 40% decrease of the insulin/C-peptide ratio (p less than 0.01). Assuming that the insulin/C-peptide ratio reflects the hepatic extraction of insulin, this would be compatible with increased hepatic removal of insulin. The change in insulin/C-peptide ratio was positively correlated with the change in GIP response after guar gum (r = 0.75; p less than 0.001) and this correlation was strengthened in normal subjects (r = 0.91; p less than 0.001). Our data thus suggest that guar gum stimulates rather than suppresses insulin secretion. The apparent insulinotropic action of GIP may partly be explained by a reduced hepatic extraction of insulin.