Budesonide versus prednisone in the treatment of active Crohn's disease. The Israeli Budesonide Study Group.

BACKGROUND & AIMS: Budesonide (BUD) is a potent steroid that undergoes extensive first-pass metabolism. BUD incorporated in a pH-dependent formulation has been proposed as an alternative treatment for Crohn's disease (CD). The aim of this study was to compare the efficacy and safety of BUD and prednisone (PRED) in the treatment of active CD involving the terminal ileum and/or the colon. METHODS: Patients with mild to moderately active CD were included in a randomized, double-blind, double-dummy controlled trial. Patients received either 9 mg BUD once daily for 8 weeks or 40 mg PRED once daily for the first 2 weeks tapered gradually to 5 mg/day by the end of the study. Disease activity, quality of life, and laboratory parameters were recorded. RESULTS: One hundred patients received BUD, and 101 patients received PRED. By intention-to-treat analysis, treatment efficacy defined as Crohn's Disease Activity Index of <150 at completion was 51% and 52.5% for the BUD and PRED groups, respectively. Twice as many responded to treatment with no side effects in the BUD compared with the PRED group (30% vs. 14%) (P = 0.006). Most of the decrease in CDAI scores occurred during the first 2 weeks. CONCLUSIONS: BUD is as effective as PRED in the treatment of CD involving the terminal ileum and right colon. BUD has significantly fewer steroid-related adverse reactions.

Prevention of coronary platelet aggregation with a phosphodiesterase inhibitor RX-RA 69.

The formation and prevention of coronary platelet thrombi (CPT) was studied in a modified Folts model in 23 anaesthetized dogs. The left circumflex coronary artery was acutely damaged and narrowed until resting flow started to fall. Spontaneous sharp decrease of flow indicated the acute formation of CPT. Intravenous infusion of 30 ng/kg/min of PGI2 prevented the formation of CTP. The effect lasted 3-7 min after termination of the infusion. RX-RA 69 a potent inhibitor of platelet phosphodiesterase (IC50 of 1 X 10(-9) mol/1) inhibited the formation of CPT for 9 and 18 min when 60 and 120 micrograms/kg were administered i.v. The results demonstrate that platelet aggregation induced by acute damage of the vascular wall can be inhibited by a potent PDE inhibitor.

Morphologic investigation of coronary arteries subjected to hypertension by experimental supravalvular aortic stenosis in dogs.

A sustained and gradual development of hypertension in coronary arteries of 16 foxhounds was induced by afterload stress with supravalvular aortic stenosis. Dogs were perfusion fixed after 4 months and 1 year of stenosis for morphologic analysis of coronary arteries with scanning electron microscopy, transmission electron microscopy, and light microscopy. Mean prestenotic pressures and SD standard deviations in millimeters of mercury for perfusion-fixed foxhounds after 4 months were systolic 141 +/- 14, mean arterial 101 +/- 8, and diastolic 81 +/- 7, and after 1 year systolic 182 +/- 31, mean arterial 128 +/- 22, and diastolic 101 +/- 16. Scanning electron microscopy results of coronary arteries subjected to 4 months of hypertension show little change from normal coronary arteries. Only isolated cases of desquamating endothelial cells were seen directly proximal to ostia of coronary arteries. Transmission electron microscopy showed no ultrastructural changes in this banding group. In four of six foxhounds subjected to 1 year of hypertension, scanning electron microscopy observations of coronary arteries revealed one to five areas of endothelial denudation, typically oriented parallel to the longitudinal axis of the artery, a few cell diameters wide and 100 to 300 microns in length. These lesions were often seen to form narrow channels between two or more branching points, either in a continuous or in series fashion. Platelets, lymphocytes, granulocytes, and monocytes adhered to the subendothelial surface. Occasional denudations were oriented transversely to the longitudinal axis. Denudations were restricted to arteries greater than 1.2 mm in diameter. In the vicinity of denudation lesions, lymphocytes and monocytes adhered to endothelium showing alterations in cell size and shape. Transmission electron and light microscopy of this banding group showed breaks and duplication of the internal elastic lamina and smooth muscle proliferation in the intima. Focal areas of intimal inflammatory reactions, sometimes superimposed upon intimal proliferative changes, were noted in those areas exhibiting luminal cell adherence to endothelium. The results indicate that the morphologic equivalent of hypertension varies depending on the manner in which it is experimentally produced. The findings of intimal proliferation and late endothelial denudation give support to the response-to-injury hypothesis for the pathogenesis of atherosclerosis and suggest a mechanism for the role of hypertension as a risk factor.(ABSTRACT TRUNCATED AT 400 WORDS)

[The "spill-over" method for flow measurements]. / Die Spillover-Flussmessung.

"Spill-over" measurement is a simple method for estimating arterial blood flow during selective angiography. It depends on a direct comparison between a known contrast flow rate and the unknown blood flow in the aortic branch that is being examined. The criterion crucial to the measurement is the back-flow of contrast into the aorta. By means of model and animal experiments, it has been established why back-flow occurs and which factors favour or retard back-flow and thereby falsify the results. The results of "spill-over" measurements were compared with electro-magnetic measurements. A modification of the "spill-over" method is described, which makes it suitable for routine use in visceral angiography.

Effects of acute vagally-mediated bradycardia on systemic hemodynamics and coronary blood flow before and after coronary stenosis.

The effects of short episodes (1 min) of vagally-mediated bradycardia were studied in 9 anesthetized dogs utilizing vagal stimulation and slow atrial pacing (120 and 80 beats/min) before and after graded coronary constriction of the left anterior descending (LAD) and the left circumflex (CCA). In the presence of 90% LAD stenosis, bradycardia tended to restore both the elevated total LAD coronary vascular resistance (CVR-LAD) and the reduced, total CVR-CCA towards control levels obtained at corresponding slow rates in the absence of coronary stenosis; as a result, LAD coronary flow (F-LAD) was relatively less reduced and the accessory rise of F-CCA disappeared. In the presence of combination of 90% LAD plus 70% CCA stenosis, the effects of bradycardia on total CVR-LAD and F-LAD were similar to those obtained with single 90% LAD stenosis, but the accessory flow through the CCA was abolished resulting in no significant difference of the rate-dependent alterations of total CVR-CCA and F-CCA as compared with those observed in the absence of coronary stenosis. In the presence of single or combined coronary stenosis, bradycardia restored the depressed aortic pressure and cardiac output towards control values obtained at comparable slow rates before coronary stenosis. The results support the concept that in the presence of 90% LAD stenosis vagally-mediated bradycardia 1) decreases the tension-time index (myocardial nutritional demand) shifting cardiac performance to less expensive "flow work" and 2) facilitates antegrade flow through the highly stenotic LAD thereby inhibiting accessory flow through the nonstenotic CCA.

Effect of brief periods of paced ventricular tachycardia on coronary blood flow in dogs before and after graded coronary stenosis.

The effect of short bouts (1 min) of electrically induced ventricular tachycardias (VT) of increasing rates (160-240/min) was studied in 8 anesthetized dogs before and after graded constrictions of the left anterior descending (LAD) and the circumflex (CCA) coronary arteries. In the absence of coronary stenosis, paroxysmal VT caused a significant decrease in tension-time index (TTI), coronary blood flow (CBF) and coronary vascular resistance (CVR). Single and combined coronary stenosis caused relatively small alterations of the VT-induced depression of the systemic hemodynamics but reversed the effect of paroxysmal VT on the CVR. In the presence of single 90% LAD stenosis, VT resulted in an increase in CVR-LAD and a decrease in F-LAD associated with a fall in CVR-CCA and a rise in F-CCA. Combination of 90% LAD plus 70% CCA stenosis abolished the compensatory fall of CVR-CCA resulting in a pronounced reduction of F-CCA during VT. The results support the concept that in the presence of severe coronary stenosis brief paroxysmal ventricular tachycardias do increase myocardial nutritional demand but rather decrease nutritional supply.

Postischemic liver damage in rats: amino acid analysis and morphometric studies.

Normothermic, temporary, total ischemia of the liver was produced for 60-225 min under transient portal decompression with a by-pass between the mesenteric and the femoral vein. Total amino acids in the liver tended to increase after an ischemic period of more than 120 min without reperfusion as compared with control with increasing trends in most of the individual amino acids. In a group undergoing 120 min of ischemia and 60 min of reperfusion, total amino acids and individual amino acids tended to decrease. Total plasma amino acids significantly increased after ischemia of more than 120 min. Without reperfusion, elevations of almost all amino acids except for branched chain amino acids were found, whereas after reperfusion most of the individual amino acids also increased including branched chain amino acids. Molar ratios of branched chain amino acids to tyrosine and phenylalanine decreased only after more than 120 min ischemia without reperfusion. Volume ratios of organelle disintegration on electron micrographs such as mitochondrial degradation and autophagic vacuoles were moderately increased after 90 min ischemia with a further steep rise after more than 120 min ischemia. The survival rates of the animals after 60, 90 and 120 min ischemia were 35% (6/17), 27% (3/11) and 25% (3/12), respectively. The following conclusions were obtained: 1) Pre-necrosis of the hepatocytes with simultaneous protein degradation started after ischemia for about 2 hr. The survival rates of the animals after 60 and 90 min ischemia were very low despite of mild necrosis of the liver. 2) Most of the amino acids in the liver were washed out into the plasma to cause an abnormal plasma amino acid pattern in the acute state. However, the molar ratio of branched chain amino acids to aromatic group was not reduced, in contrast to the ischemic group without reperfusion.

Postischemic liver damage in rats: effect of some therapeutic interventions on survival rate.

The aim of this paper is to elucidate the cause of death after 90 min of normothermic partial (2/3) ischemia of the liver and to examine the effects of glucagon, somatostatin, insulin, prednisolone and oral administration of polymyxin B (PB). The animals 24 hr after partial ischemia for 90 min were divided into two groups; namely, animals with normal appearance and those with moribund state. There were no significant differences in the plasma level of S-GOT, S-GPT, amino acids, NH3 or insulin, or in morphometrically estimated volume ratio of necrotic hepatocytes between the two groups of rats. The blood glucose level, however, was significantly decreased (31 +/- 28 mg/100 ml, n = 6) in the moribund rats with a higher incidence of positive Limulus gelation tests as compared with the rats with normal appearance (149 +/- 19, n = 5). The 1-day and 1-week survival rates of the animals were 42/62 (69%) and 32/61 (53%), respectively. A glucagon injection (1.5 mg/kg, after ischemia) was effective to elevate the 1-day survival rate (14/14), but failed to increase the 1-week survival rate (11/14). On the other hand, a somatostatin injection (100 micrograms/kg, after ischemia) or PB treatment (15 mg/kg/day x 5-9, before ischemia) succeeded to increase the 1-week survival rate (20/22 p less than 0.01 and 17/17 p less than 0.01, respectively), although no significant amelioration in transaminase levels or volume ratio of necrosis was demonstrated. It could be seen that a moribund state after partial ischemia was accompanied by severe hypoglycemic shock, and that the injection of somatostatin after ischemia or the annihilation of gram-negative bacteria by means of oral administration of polymyxin B before ischemia prevented the occurrence of the hypoglycemic shock.

Haemodynamics and myocardial metabolism of phosphorus depleted dogs: effects of catecholamines and angiotensin II.

The responses of arterial pressure and myocardial contractile force (VPM) to infusion of angiotensin II, noradrenaline and orciprenaline were examined in twelve dogs during a control phase, after 30 days of dietary phosphorus deprivation and after 21 days of phosphorus repletion. In the phosphorus depletion period, animals had low skeletal and heart muscle Pi content, low magnesium, ATP and creatine phosphate in skeletal and heart muscle with no change of ADP, AMP or energy charge. In the basal state, VPM was diminished with no change of end-diastolic and systolic pressure. Infusion of angiotensin II caused a significantly smaller rise of arterial pressure (angiotensin II resistance), and the stimulatory effect of noradrenaline and orciprenaline on VPM was diminished (catecholamine resistance). These effects were reversible with Pi repletion. In phosphorus depletion, arterial concentrations were increased for lactate, unchanged for FFA and decreased for acetoacetate/beta-hydroxybutyrate. Unchanged myocardial extraction of lactate or beta-hydroxybutyrate and preserved cell Pi uptake for glycogenolysis were observed. The initial rate of uptake of calcium and concentrating ability of myocardial sarcoplasmic reticulum were unchanged.

Contralateral renal function following unilateral renal artery constriction.

The acute (0.5-3.0 h) response of the contralateral kidney to unilateral renal artery constriction was studied in 7 pentobarbital-anesthetized dogs. Within 30 min after unilateral renal artery constriction to a pressure of about 60 mm Hg, contralateral vascular resistance, sodium excretion and filtration fraction increased significantly while glomerular filtration rate, blood flow and plasma flow did not change. Renin secretion decreased dramatically within 30 min, demonstrating a negative venous minus arterial plasma renin activity in some dogs. Unilateral renal artery constriction did not change the rate of angiotensin II extraction across the contralateral kidney or the urinary renin activity (measured in 4 dogs). These results indicate that the acute response of the contralateral kidney to unilateral renal artery constriction is somewhat different from that seen in the chronic state.

Effect of neurotensin on exocrine pancreatic secretion in dogs.

The effects of various doses of synthetic neurotensin on exocrine pancreatic secretion were investigated in dogs prepared with pancreatic fistulae. Increasing doses of neurotensin infused intravenously caused a dose-dependent stimulation of exocrine pancreatic secretion. Plasma neurotensin levels determined with a radioimmunoassay kit for neurotensin were significantly correlated to the amount of neurotensin infused. Significant stimulation of exocrine pancreatic secretion was observed when 2.5 pmol kg-1 min-1 neurotensin were infused. This dose resulted in neurotensin plasma levels comparable to those observed after a meal. Combined infusions of neurotensin and the cholecystokinin analogue cerulein had synergistic effects on pancreatic bicarbonate output and raised the HCO-3:protein ratio. These observations suggest that neurotensin may play a role in the early phase of postprandial stimulation of exocrine pancreatic function.

[Haemodynamic effects of intraarterial contrast injections (author's transl)]. / Hämodynamische Effekte der intraarteriellen Kontrastmittelinjektion.

Intra-arterial contrast injections have well known systemic and pulmonary vascular effects; in addition there are local haemodynamic changes which begin immediately after the injection and last for several seconds. Three phases can be recognised: Phase 1 Increased flow, pressure and turbulence due to transmission of kinetic energy from the contrast medium to the vessel contents. Phase 2 Reduced flow due to the high viscosity of the contrast medium. Phase 3 Increased flow, probably a pharmacological results produced by contrast (osmolarity). The effects of contrast injection can be altered by changes to the catheter or to the properties of the contrast medium. This has practical consequences for injection techniques and for flow measurements. While assessing the clinical usefulness of the "spill over" flow measurements described by Olin and Redman in 1966, we concluded that the haemodynamic effects of the contrast lead to significant falsification of the measurements, and this also has some significance for the performance of angiography. We have therefore studied this phenomenon, its causes and the factors which influence it, on a model and in animal experiments. In order to quantify changes in flow caused by the injection during animal experiments, a study was carried out on the effects of contrast media on electromagnetic measurements.

[Standardized experimental coronary stenosis. Reduction of diameter and cross-sectional area following eccentric narrowing]. / Standardisierte Coronarstenosierung im Tierexperiment. Reduktion von Durchmesser und Querschnittsfläche bei exzentrischer Einengung. Methodische Mitteilung.

The hemodynamic relevance of a coronary stenosis depends essentially upon the reduction of the cros-sectional area of the coronary lumen. However, the extent of experimental coronary narrowing is measured generally by determining the coronary diameter. In a series of experiments, the relationship between diameter and cross-sectional area (d/a) was determined using a micrometer constrictor and four different silastic tubings the size of which reflected actual coronary diameters as measured in coronary casts of German shepherd dogs. The d/a relationship was linear over a range of diameter reductions from 50 to 90%. A "physiologic" wall of thickness of 0.3-0.4 mm had no major influence on the d/a relationship. However, identical reductions of diameters and cross-sectional areas could only be achieved with the tubing fitting exactly into the curvature of the coronary constrictor.

Effect of neurotensin on regional intestinal blood flow in the dog.

The effects of various doses of synthetic neurotensin on regional blood flow in different tissue layers of the stomach, small bowel, colon, pancreas, brain, kidneys, adrenal gland, and heart of six dogs was studied using an isotope microsphere technique. Infusion of high doses (20, 40 pmol/kg . min(-1)) of exogenous synthetic neurotensin caused an increase of blood flow in the "muscularis" of duodenum, jejunum, ileum, and colon. Neurotensin infused in a dose (2.5 pmol/kg . min(-1)) raising neurotensin plasma levels to concentrations comparable to those observed after a meal caused an increase of blood flow in the muscular layer in ileum. Our results suggest that one of the physiologic actions of neurotensin may be the regulation of blood flow in the muscular layer of the ileum.

Efficiency of cardioplegia in the presence of coronary occlusion.

Myocardial tissue pH and temperatures (MT) were continuously measured in dogs on total cardio-pulmonary bypass (CPB) after acute distal coronary artery occlusion. Measurements were performed in a collateralized area with myocardial blood flow (MBF) ranging from 20 to 80 ml/100 g-min (microspheres). Immediately after coronary artery occlusion the aorta was clamped and the heart perfused with a cardioplegic solution (Bretschneider HP, 41 ml/kg, 4 degrees C). Prolonged regional fibrillation was observed and MT fell to 20 degrees C in 10 min in the low perfusion area (LPA) and in 2 min in the control area (CA). Whereas MTs were practically identical 15 min after termination of cardioplegic perfusion the magnitude of H+ accumulation continued to be greater in the LPA. During blood reperfusion with the coronary snare released MBF was significantly lower in the LPA as opposed to the CA indicating a microcirculatory derangement. Accordingly the bipolar ECG revealed signs of regional ischemia even after 30 min of reperfusion. We conclude that myocardial protection may be inadequate in areas located distal to coronary occlusion. This is true not only in cases of acute severe ischemia but also when collateral resistance is sufficiently high to impede the flow of cold viscous cardioplegic solutions. Results derived from intermittent MT measurements may be erroneous because intramyocardial heat equilibration may mask the inhomogeneous cardioplegic perfusion.

Myocardial flow reserve in experimental cardiac hypertrophy.

The distribution of myocardial blood flow (MBF) was evaluated in pressure-induced LV hypertrophy of foxhounds. At the early stage of developing hypertrophy, i.e., 3 months after aortic banding (+ 53% LV weight) resting MBF and flow reserve were not significantly different from control hearts. One year after banding (+94% LV weight) myocardial flow reserve had clearly decreased. Acute coronary stenosis of 60 and 70% cross-sectional area resulted in a moderate fall of flow reserve in controls and hearts with early hypertrophy. In hearts with extensive hypertrophy the drop of poststenotic MBF was considerably greater affecting preferentially the subendocardium. The data suggest that myocardial blood flow was impaired before any signs of heart failure were observed. Furthermore a decrease of MBF may not be confined to forms of hypertrophy induced by renal and idiopathic hypertension.

[Long-term observation of pulmonary water and protein extravasation in traumatic-hemorrhagic shock (author's transl)]. / Verlauf des pulmonalen Wasser- und Eiweissaustritts im protrahierten traumatisch-hämorrhagischen Schock.

Eleven mongrel dogs were observed for 72 h following a standardized traumatic hemorrhagic shock. The decrease of plasma albumin concentration and blood 125-I-albumin activity with a concomitant increase in lung I-albumin content is possibly caused by capillary leakage. A rise in the extravascular lung water content was measured by a gravimetric postmortem method. An in vivo double indicator technique, however, failed to document these findings.

[Effects of various forms of myocardial protection on cardiac function, metabolism, and blood flow (author's transl)]. / Funktion, Stoffwechsel und Durchblutung des Myokards bei verschiedenen Formen des Myokardschutzes.

The myocardial protective effect of two cardioplegic solutions was studied after an ischemic period of 2 h in eight dogs. Group I received a high potassium solution (St. Thomas Hospital) and group II a sodium withdrawal solution with high colloid osmotic pressure (Eppendorf solution). With the exception of a prolonged myocardial K+ washout (10 min) in group I, which was presumably responsible for fibrillation in the early reperfusion period, no major metabolic or perfusion differences between the two groups were observed. After 30 min of reperfusion, postischemic LV function (-43%) and O2 uptake (-43%) were equally reduced in both groups.