Neuropeptide levels in Dercum's disease (adiposis dolorosa).

Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), ß-endorphin-like immunoreactivity (ß-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin-like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), γ2-melanocyte-stimulating hormone-like immunoreactivity (γ2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease.

End-organ damage in treated severe hypertension: close relation to nocturnal blood pressure.

In an attempt to improve therapeutic decision-making in severe hypertension, different blood pressures (BP) were correlated with target organ damage in a cross-sectional study of 20 asymptomatic patients. Casual BP was 197/117 (s.d. 31/10) mmHg despite therapy. Each subject was assigned an end-organ score on the basis of the number of silent cerebrovascular damages detected by magnetic resonance imaging, funduscopic retinopathy, cardiac hypertrophy by echocardiography, and renal involvement evaluated by isotopic renography. The pooled scores for target organ damage showed significant correlations with an elevated asleep mean ambulatory (amb-) brachial systolic (r = 0.84) and diastolic BP (r = 0.88) but not with either awake amb-BP (means or peak values), causal BP or invasive radial BP at the clinic. Night-time amb-DBP increased with age in contrast to the daytime DBPs. Furthermore, the nocturnal fall in mean arterial amb-BP was significantly less in patients aged > or = 60 years, average 5%, than in patients < 60 years, 16%. This may have prognostic implications even if, after age adjustment, the inverse relation (r = -0.78) between the end-organ scores and the dip in BP did not reach independent significance. The close association of cardiovascular complications with night-time rather than daytime BP emphasises the importance of making a prospective study in this field, trying to optimise the nocturnal BP in severe hypertension.

Efficacy and tolerability of felodipine ER and diltiazem SR as monotherapy in primary hypertension: a double-blind randomized study.

PURPOSE: Efficacy, tolerability, and optimal doses of felodipine ER (FER) and diltiazem SR (DSR), given as monotherapy, were evaluated in patients with mild or moderate primary hypertension. METHODS: This was a multicenter, double-blind, parallel-group study of 98 hypertensive patients. Following a 4 weeks placebo run-in period, patients were randomized to either FER 5 mg once daily (qd) or DSR 90 mg twice daily (bid). If supine DBP was > 90 mmHg after 2 and 4 weeks treatment, the dose was increased to 10 mg FER qd or 120 mg DSR bid plus 20 mg FER qd or 180 mg DSR bid, respectively. The double-blind treatment lasted 8 weeks. RESULTS: After 8 weeks FER treatment 70% of the patients responded (DBP < or = 90 mmHg or DBP decrease > or = 10 mmHg) and 50% became normotensive (DBP < or = 90 mmHg); the corresponding figures for DSR were 63% and 37%, respectively. No statistical significant differences in BP reduction and HR were found between the two compounds. HR did not change during the study. Seven patients discontinued due to adverse events (AEs). Five patients received FER and two patients received DSR. The AEs were similar in the two groups and generally mild. CONCLUSIONS: At the highest dose levels of FER and DSR, no further BP reduction was observed, but there was a tendency to report more AEs. Both FER and DSR can be used as first-line therapy in hypertension.

Long-term effects of ticlopidine on lower limb blood flow, ankle/brachial index and symptoms in peripheral arteriosclerosis. A double-blind study. The STIMS Group in Lund. Swedish Ticlopidine Multicenter Study.

The aim was to test within a randomized double-blind trial whether the platelet inhibitor ticlopidine might improve peripheral blood flow and distal pressures in patients with aortofemoral arteriosclerosis. One hundred and one patients with intermittent claudication were studied after one year, after two to three years, and after five years of treatment with ticlopidine, 500 mg/day, or placebo. Analysis was performed according to years on treatment. Baseline flow values as assessed by venous occlusion plethysmography were significantly and similarly deranged in the ticlopidine and placebo groups as compared with a reference group of healthy subjects. Ankle/brachial index was unrelated to either leg blood flow variables or walking distance. After five years of treatment (median follow-up time) a slight tendency to a slower progression of disease was observed in the ticlopidine group as compared with placebo. However, intergroup differences were not significant. Therefore, the potential benefit of ticlopidine in this respect is from a clinical point of view certainly only marginal. Minor increases in claudication distances were found with no difference between groups. Smoking habits and lipoproteins were mainly unaltered at the end of the study. It is concluded that platelet inhibition for up to five years has no clear beneficial effect on leg blood flow variables, ankle/brachial index, or walking distances and probably no clinically relevant retarding effect on the slow progression of atherosclerosis. This lack of influence must be distinguished from the antithrombotic effect of ticlopidine, shown as a decreased incidence of acute cardiovascular events and mortality in the authors' multicenter study, STIMS (the Swedish Ticlopidine Multicenter Study).

Direct and indirect blood pressure in normotensive and hypertensive subjects.

OBJECTIVES: To compare intrabrachial blood pressure (I-BP) with simultaneously measured contralateral auscultatory (A-)BP in hypertensive and normotensive subjects. The question was whether differences between direct and indirect BP are influenced by the BP levels. SUBJECTS: Hypertensive subjects treated with either placebo (n = 10) or metoprolol (n = 8) and age-matched normotensive subjects (n = 15), selected from a defined patient population waiting for cholecystectomy or hernia repair. Measurements were performed pre-induction of anaesthesia. RESULTS: In the hypertensive subjects, cuff systolic BP (SBP) was lower than I-BP by an average of 8 mmHg (placebo-) and 7 mmHg (metoprolol-treated), whereas diastolic A-BP (A-DBP) was 3 and 7 mmHg higher, respectively. In the normotensive subjects, mean A-SBP and I-SBP agreed closely, whereas A-DBP was 11 mmHg higher. Thus, SBP differences (i.e. indirect-direct BP) were significantly less and DBP differences significantly greater in the normotensive than in the hypertensive subjects (P < 0.05). Plasma renin activity and adrenalin showed better correlations with A-MBP than with I-MBP. CONCLUSIONS: The drift of cuff systolic readings fell progressively below the intrabrachial values when BP increased, whilst diastolic cuff values approached the direct pressures. Since A-MBP did not significantly differ from I-MBP in any group, one must ask whether hypertension would be more correctly defined according to MBP criteria.

Training after myocardial infarction: lack of long-term effects on physical capacity and psychological variables.

This study evaluated long-term effects of 12 weeks of supervised training, of at least 45 minutes duration with two sessions per week, on physical performance and psychological well-being after myocardial infarction (MI). Sixty-nine patients were randomized to either an exercise or a nonexercise group. Maximum exercise capacity 6 weeks post-MI was inversely related to the acute peak aspartate aminotransferase values in serum, as an index of infarct size. One year post-MI, the increase in level of fitness (10%) in the training group did not significantly exceed (p = .10) that of the controls (2%). No intergroup differences were registered in self-rated psychological well-being and physical scores or in the return to work rate. In the training group, but not in the controls, the change in perceived dyspnoea at leisure-time activities was positively related to the objectively measured peak exercise capacity. We conclude that after MI only marginal improvements in physical performance are achieved 6 months after training is finished, with no long-term psychological benefits apparent versus a usual care program. The adaptive implications of supervised conventional exercise programs post-MI are therefore questioned.

Effect of erythropoietin on muscle metabolic rate, as measured by direct microcalorimetry, and ATP in hemodialysis patients.

Ten anemic hemodialysis patients were treated for 6-14 months with human recombinant erythropoietin (EPO). The mean hemoglobin level significantly increased by 42%. Pretreatment skeletal muscle heat production rate at rest, as determined by direct microcalorimetry, was lower than normal (p < 0.03), indicating decreased metabolic activity. ATP levels in muscle were inversely correlated (rs = -0.66, p < 0.05) with the heat production values. The latter significantly increased by about 40% and were almost normalized by the therapy, whereas a decline in the mean ATP level was seen, from 14.8 to 13.2 mumol g-1 of muscle (p = 0.06). We hypothesize that the lowered ATP concentration in muscle after treatment might have been due to an enhanced ATP consumption in parallel with improved muscle strength. Alternatively, since acidosis prior to treatment might have altered the equilibrium state of the creatine kinase reaction towards ATP production, it is possible that the improved oxygenation after EPO had increased pH in the muscle and catalyzed the transfer of phosphate from ATP to PCr. It is concluded that EPO treatment can almost normalize the decreased muscle metabolic rate in hemodialysis patients, and that the anemia per se seems to be an important cause of the deranged metabolism in striated muscle.

Effects of terbutaline on basal thermogenesis of human skeletal muscle and Na-K pump after 1 week of oral use--a placebo controlled comparison with propranolol.

1. A double-blind placebo-controlled study was conducted on the effects of oral terbutaline (beta 2-adrenoceptor agonist) and propranolol (beta 1 beta 2-adrenoceptor antagonist) on basal heat production of skeletal muscle, measured ex vivo by direct microcalorimetry. Terbutaline slow-release 7.5 mg, propranolol 80 mg, and matching placebo were randomly administered twice daily for 1 week to 15 healthy males, using a cross-over design. 2. Resting heat production in biopsied vastus lateralis was lowered by median 27% (P < 0.01) after terbutaline medication as compared with placebo. The cause of this hypometabolism at the cellular level is obscure but may possibly be explained by desensitization of beta 2-receptors. 3. Propranolol decreased the metabolic rate by 17% (P > 0.3); this might imply that the sympathetic nervous system is playing only a minor role in the regulation of basal metabolic rate in muscle, or that up-regulation of beta-receptors had influenced the decline. 4. The muscle utilized about 6% of its total energy for the Na-K pump as assessed after inhibition by ouabain. 5. Serum potassium was significantly lowered by terbutaline and slightly increased by propranolol with no relationship between changes in extracellular levels and muscle content of potassium under resting conditions. Energy values for the Na-K pump in muscle after 1 week of terbutaline or propranolol medication were similar to placebo. The results are not consistent with the hypothesis that decreased serum potassium during continuous beta 2-adrenoceptor agonist treatment is due to a chronically activated Na-K pump, at least not in resting muscle.

Blood viscosity during long-term treatment with ticlopidine in patients with intermittent claudication. A double-blind study.

The aim was to test within a randomized, double-blind trial whether the antiaggregant drug ticlopidine might reduce blood viscosity as has been claimed. Sixteen patients with intermittent claudication were studied before and after three years of treatment with ticlopidine, 500 mg/day, or placebo. At baseline, the viscosity values were significantly higher as compared with a reference group of healthy subjects. Whole-blood viscosity, measured at four different shear rates at hematocrit adjusted to a standard 40%, decreased significantly at follow-up, with no difference between ticlopidine treatment and placebo. Hematocrit showed a slight increase in the placebo group. The viscosity parameters were unrelated to lower limb blood flow variables, ankle/brachial index, and walking distances. The mechanism behind the overall decrease in whole-blood viscosity is obscure but could possibly be explained by lifestyle changes. Smoking habits were, however, unaltered. Since plasma viscosity remained increased, it might indicate that some erythrocyte factor, notably red cell aggregability and deformability, had improved. It is concluded that ticlopidine had no long-term effect on blood viscosity.

Cerebral blood flow in patients with severe hypertension, and acute and chronic effects of felodipine.

OBJECTIVES: To evaluate whether a spontaneous increase in cerebral blood flow (CBF) could be observed in subjects with severe hypertension and to study the effect of a calcium antagonist, felodipine, on blood pressure and CBF after acute and chronic administration. DESIGN: Patients with severe hypertension were recruited at the emergency ward. Patients with previous treatment with calcium antagonists, women of child-bearing potential, severe uraemia, nephrotic syndrome, heart failure, manifest cerebrovascular lesions and pathological liver function tests were excluded. METHODS: CBF was measured by single-photon emission computed tomography after intravenous administration of xenon-133 before (CBF1) and after intravenous infusion of felodipine, 0.01 mg/min during 40-60 min (CBF2) in 12 patients aged 25-67 years with no antihypertensive treatment except for beta-blockers in four patients and beta-blockers plus a diuretic in one patient. CBF was repeated after 3 weeks of oral therapy with felodipine, 5-10 mg twice a day with the addition of beta-blockers in 10/12 patients (CBF3). RESULTS: During the felodipine infusion blood pressure decreased. There were no neurological symptoms or signs before or during the felodipine administration. CBF1 was within normal limits with no significant differences between previously treated and untreated patients. There was a non-significant tendency to increase in global CBF after felodipine administration, associated with a significant reduction in the physiological side differences in blood flow. CONCLUSIONS: In spite of the initially very high blood pressure, no general or focal hyperaemia was observed, and thus no evidence for a 'breakthrough' of the cerebral autoregulation. Felodipine gives a smooth blood pressure reduction with a maintained CBF.

Lack of influence of short-term treatment with propranolol and terbutaline on metabolism and energy expenditure of the Na-K pump in human erythrocytes evaluated by microcalorimetry.

A double blind placebo-controlled study was conducted of the effects of oral propranolol (beta 1 beta 2-adrenoceptor antagonist) and terbutaline (beta 2-adrenoceptor agonist) on erythrocyte heat production, measured by direct microcalorimetry under static conditions at 37 degrees C and pH 7.4. Propranolol 80 mg and terbutaline slow-release 7.5 mg were randomly administered twice daily for one week to 15 healthy males, using a cross-over design. No thermogenic difference was detected. Serum potassium was significantly decreased by terbutaline but was only slightly increased by propranolol, but no relationship was found between changes in the extra- and intracellular levels. In the placebo group, 10% of total cell energy was consumed by the Na-K pump, as assessed by ouabain inhibition, and this value was not significantly affected by the treatments. Thus, it seems unlikely that there is a clinically relevant influence on the Na-K pump in erythrocytes during continuous terbutaline or propranolol medication. It is concluded that short term medication with propranolol and terbutaline in therapeutic doses has almost no thermal or metabolic effect on human erythrocytes. The results indirectly imply that no clinically relevant beta-adrenoceptor effects are mediated in erythrocytes and this may also be true with regard to the 'membrane effect' of propranolol.

Fat-cell heat production, adipose tissue fatty acids, lipoprotein lipase activity and plasma lipoproteins in adiposis dolorosa.

1. Gluteal adipose tissue was examined in 13 patients with generalized adiposis dolorosa, a clinical condition characterized by painful adiposity with a chronic intractable course. The total metabolic activity of fat cells, isolated by collagenase and suspended in Krebs-Ringer bicarbonate buffer with glucose and insulin, was assessed by the measurement of heat production at 37 degrees C using microcalorimetry. 2. Fat cells were markedly enlarged; their metabolic activity expressed in terms of microW/g, but not in pW/cell, was significantly decreased when compared with both lean and weight-matched non-painful subjects. Both mean values were, however, significantly higher than in grossly obese subjects with similar mean cell size. Heat production as expressed per g of tissue, but not per cell, was inversely correlated with body mass index. One additional patient had unilateral disease, and fat cells from the painful side had a lower heat production than cells from the unaffected side. 3. The fatty acid composition of adipose tissue, as determined by g.c., revealed a significantly increased proportion of monounsaturated (18:1 and 16:1) at the expense of saturated (14:0 and 18:0) fatty acids compared with healthy control subjects. The activity of adipose tissue lipoprotein lipase was slightly, but not significantly, decreased. 4. It is concluded that a metabolic pathogenetic factor cannot be ruled out in adiposis dolorosa. As the results do not explain the nature of the diffuse pain, further studies need to be performed.

Antihypertensive efficacy and tolerability of enalapril and slow-release verapamil in essential hypertension: a double-blind, cross-over study.

The antihypertensive efficacy and tolerability of enalapril (E) and slow-release verapamil (V) were compared in a 2-month double-blind cross-over study in 22 patients with mild to moderate essential hypertension. After 1 month, significantly lower systolic (P less than 0.01) and diastolic (P less than 0.02) blood pressures (BP) were achieved with E, 20 mg d-1, compared with V, 240 mg d-1. After 2 months of treatment, BP reductions were similar after E, 40 mg d-1, and V, 240 mg twice a day. The fall in supine mean BP after 2 months of treatment with V was significantly greater in patients aged greater than or equal to 50 years of age (P = 0.02) (median 18 mmHg) than in patients aged less than 50 years (10 mmHg). E showed similar effectiveness in both age groups. Statistical group analysis of a quality-of-life questionnaire showed no significant differences between the active drugs and the placebo. It is concluded that E and V are equally effective as antihypertensive agents, and that both drugs are well tolerated.

Effects of verapamil and atenolol on exercise tolerance in 5,000 m cross-country running: a double-blind cross-over study in normal humans.

The effects on exercise tolerance of 7-day treatment with a calcium channel blocker, verapamil 160 mg twice daily (b.i.d.), and a beta 1-selective blocker, atenolol 50 mg b.i.d., were compared in 10 healthy and physically active young subjects in 5,000-m cross-country running at high intensity. The study was a double-blind cross-over trial. Comparison was made with a single-blind placebo as well. Performance time was measured every 1,000 m in seven 5,000-m runs, in which subjects were instructed to keep to a constant fatigue perception (Borg scale rating). Both drugs significantly (p = 0.001) increased the performance time over the first 1,000 m as compared with placebo. However, running time after 1,000, 2,000, and 3,000 m was prolonged significantly less (p less than 0.05) by verapamil than by atenolol. For the entire 5,000-m run, atenolol caused a significant increase (p = 0.001) in mean running time by 1 min 34 s (i.e., 7.5%; 95% confidence interval 48 s to 2 min 21 s) as compared with placebo, whereas verapamil caused no significant change (+46 s).

Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study.

The Swedish Ticlopidine Multicentre Study (STIMS) was a double-blind placebo-controlled trial designed to determine whether ticlopidine, a platelet antiaggregatory agent, reduces the incidence of myocardial infarction, stroke and transitory ischaemic attacks in patients with intermittent claudication. A total of 687 patients was monitored for a minimum of 5 years or until an end-point was reached. The number of end points (99 vs. 89), analysed according to the intention-to-treat principle, was 11.4% lower in the ticlopidine group (P = 0.24). The mortality rate was 29.1% lower in the ticlopidine group (64 vs. 89, P = 0.015); this observation could be accounted for by a reduced mortality from ischaemic heart disease. On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group (47 vs. 76, P = 0.017). Diarrhoea was the most common side-effect. Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine. It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine.

Renal and endocrine effects of long-term converting enzyme inhibition as compared with calcium antagonism in essential hypertension.

In a double-blind, double-dummy, placebo-controlled crossover design, the renal hemodynamic and tubular effects of 2-month specific vasodilation with a converting enzyme inhibitor (enalapril, 40 mg once daily) was compared with that of a calcium antagonist (verapamil slow release, 240 mg twice daily) in 15 patients with established essential hypertension. Enalapril and verapamil treatment induced a 9% reduction in mean blood pressure (BP). Heart rate (HR) was similar after placebo (66 beats/min), enalapril (63 beats/min), and verapamil (63 beats/min). Plasma norepinephrine (P-NE) was unaltered after enalapril and verapamil as compared with placebo (0.92, 0.88, and 1.33 nM, respectively). Plasma angiotensin II and aldosterone decreased and plasma renin activity (PRA) increased after enalapril but were unaltered after verapamil. Glomerular filtration rate (51Cr-EDTA) was not altered by either enalapril or verapamil, whereas renal blood flow (125I-hippurate) was reduced 9% by verapamil. Renal vascular resistance (RVR) was unchanged after enalapril as well as verapamil. Fractional excretion of electrolytes and diuresis were unaltered and body weight was similar after enalapril, verapamil, and placebo (81.0, 82.5, and 80.2 kg, respectively). Long-term treatment with enalapril and verapamil had a comparable antihypertensive effect. Neither enalapril nor verapamil appeared to induce reflex activation of the sympathetic nervous system. Renal hemodynamic and tubular function was well preserved with both drugs without signs of sodium and water retention.

Antihypertensive and renal effects of enalapril and slow-release verapamil in essential hypertension. A double-blind, randomized study.

The renal, metabolic and antihypertensive effects of enalapril (E) and slow-release verapamil (V) were compared in a 2-month double-blind crossover trial in 22 patients with newly discovered essential hypertension. The glomerular filtration rate and renal vascular resistance were unaltered: renal blood flow was slightly decreased by V. Serum Ca2+ increased and Na+ excretion declined after V. Serum lipids, glucose, and erythrocyte electrolytes were unchanged. Blood pressure (BP) was lower with E after half the maximum dosage compared with V, but similar BP reductions were obtained after 2 months with the maximum dosage.

Acute massive pulmonary embolism treated with streptokinase during labor and the early puerperium.

Acute massive pulmonary embolism occluding 60-70% of the pulmonary circulation occurred in a young primipara during the 28th week of pregnancy. She was critically ill despite 40 h of heparin infusion and thrombolytic therapy with streptokinase was initiated. After a 10-h infusion she went into labor and streptokinase treatment was stopped. One hour later she gave birth spontaneously to a preterm infant in footling breech delivery. The infant did well neonatally. Streptokinase infusion was recommenced 8 h after delivery. Because of increasing blood loss on the second day after delivery, streptokinase was withdrawn after a total treatment time of 29 h. Total hemorrhage amounted to 8.9 litres. Serial perfusion lung scans showed complete resolution of the emboli and normal lung function was restored.