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Constant-rate intravenous infusion methods for estimating steady-state volumes of distribution and mean residence times in the body for drugs undergoing reversible metabolism.

Equations for the steady-state volumes of distribution (Vss) and the mean residence times in the body (MRT) are derived for a drug and its metabolite subject to reversible metabolism and separately infused intravenously at a constant rate to steady state of both compounds. The Vss and MRT parameters are functions of the integrals of plasma concentrations, plasma concentrations at steady state, and times to reach steady state of both drug and metabolite. In addition, the MRT values are functions of the infusion rates. These equations were validated by computer simulations and comparison with IV bolus dose parameters. These relationships extend the ability to assess the pharmacokinetics of linear reversible metabolic systems.

Infusions, Intravenous↗

Intravenously infused substance P enhances basal and growth hormone (GH) releasing hormone-stimulated GH secretion in normal men.

The effect of synthetic substance P (SP), infused intravenously (IV) in doses of 0.5, 1, or 1.5 pmol/kg-1/min-1 over 60 min, on GH secretion was evaluated in seven healthy men. Substance P tests and a control test with normal saline were randomly performed at weekly intervals. No untoward side effects or changes in blood pressure were observed during SP infusions. Serum GH concentrations did not change when normal saline, the lowest dose, or the middle dose of SP were infused. In contrast, GH levels rose significantly when the highest dose of SP was given, with a mean peak two times higher than baseline. Further studies were performed to test the possible influence of SP on the GH response to GH-RH. For this purpose, seven other healthy men were tested with GH-RH (1 micrograms/kg body weight in an IV bolus) during saline or SP (1.5 pmol/Kg-1/min-1 x 60 min) infusion. The GH-RH induced a significant GH rise, with a mean peak seven times higher than baseline. When subjects were infused with SP, the GH response to GH-RH was greatly enhanced, with a mean peak 12 times higher than baseline. These results demonstrate for the first time in humans that the systemic infusion of SP stimulates GH secretion, and suggest that SP might interact with GH-RH in the stimulation of GH secretion.

Adult↗

Intravenous infusion of cereport increases uptake and efficacy of acyclovir in herpes simplex virus-infected rat brains.

The outcome of herpes simplex virus (HSV) infections manifesting as encephalitis in healthy or immunocompromised individuals is generally very poor with mortality rates of about 8 to 28% with treatment. The long-term prognosis of survivors is often problematic, posing the need for alternative treatments that may decrease the mortality and morbidity associated with herpes encephalitis. This study addresses one such approach that includes a temporary permeabilization of the blood-brain barrier during treatment with acyclovir (ACV). In these studies we utilized a synthetic bradykinin analog, Cereport (RMP-7), in conjunction with ACV to treat HSV infection of the brain in a rat model. Cereport, infused intravenously via the jugular vein, was shown to increase [(14)C]ACV uptake in both the HSV-1-infected and -uninfected rat brain by approximately two- to threefold, correlating with enhanced efficacy of ACV in various brain compartments. In another series of experiments to determine efficacy, various doses of unlabeled ACV were administered during infusion with RMP-7. The decrease in viral titers in the temporal regions of the brain after 5 days of treatment suggested that this approach enhanced the efficacy of ACV treatment. These data indicated that Cereport infused with ACV enhances both the penetration and efficacy of this drug in the treatment of an experimental HSV-1 infection of the rat brain.

Acyclovir↗

Pharmacokinetics and effects of intravenous infusion of somatostatin in normal subjects--a two-compartment open model.

A direct radioimmunoassay of plasma somatostatin-like immunoreactivity (SRIF-LI) was developed and validated. The sensitivity was 16.0 pg/ml, and the specificity was good. The recovery of plasma SRIF-LI was 98.8 +/- 6.3%. The Scatchard plot of the antiserum binding data revealed a straight line, with a binding affinity of 3.52 X 10(-12) M and a binding capacity 4.06 X 10(-10) M. Synthetic SRIF (Stilamin), 250 micrograms, was infused intravenously over a 30-min period in 9 healthy volunteers. Plasma glucose, insulin (IRI), glucagon (IRG) and SRIF-LI were measured. A two-compartment open model was adopted to analyze the pharmacokinetic data of SRIF-LI. The results showed that plasma SRIF-LI rose from 192.2 +/- 16.2 pg/ml to a plateau of 2,129.8 +/- 288.2 pg/ml within 5-10 min after starting the infusion. The half disappearance time from plasma (Ta1/2) was 1.36 +/- 0.18 min, the half disappearance time from the 'remote' compartment (Tb1/2) was 49.6 +/- 10.9 min and the net half disappearance time from the two compartments together (Tn1/2) was 9.19 +/- 1.49 min. The metabolic clearance rate was 50.3 +/- 7.0 ml/kg/min. The plasma IRI, IRG and the IRI/IRG molar ratio were all suppressed during the infusion period. The recovery time of plasma IRG was mildly delayed in comparison to that of IRI. This indicates that there are dissociations between IRI and IRG in the extent and the duration of suppression caused by somatostatin infusion.

Adult↗

Local venomotor response to intravenous infusion of substance P and glyceryl trinitrate in systemic sclerosis.

Endothelial injury has been shown in ultrastructural studies in systemic sclerosis (SSc). In the present study, we tested the functional response of the endothelium in the early phase of the disease and at a more advanced stage. Substance P (SP) (25 and 50 ng) and glyceryl trinitrate (GT) (100 and 200 ng) were infused intravenously in 6 control subjects and in 6 female patients affected with early systemic sclerosis (SSc) to verify whether or not a lack of endothelial function could be detected. Venous compliance was assessed with a linear variable differential technique. Endothelial injury was evaluated by the von Willebrand Factor Antigen (vWF:Ag) plasma level and platelet aggregation by the platelet aggregate ratio (PAR). Endothelial-mediated response to SP was deficient in SSc patients in comparison with controls, whereas endothelium independent vasodilation was detected after the infusion of GT both in patients and controls. All vWF:Ag levels were in the normal range while in vivo platelet aggregation was increased as demonstrated by the PAR levels in the SSc subjects. The experiment was repeated in the same patients when the clinical status worsened and the levels of vWF:Ag were noted to rise: the endothelium dependent vasodilatory response to SP was still deficient as before and a decrease in vasodilatory response to GT was noted. vWF:Ag levels were significantly increased and the PAR still demonstrated an increased platelet aggregation. These data clearly indicate that an early functional deficit of the endothelial function is present before the onset of extensive visceral and skin involvement. The mechanism that provokes the impairment of the endothelial function need further investigation.

Female↗

Selective down-regulation of AT2 receptors in uterine arteries from pregnant ewes given 24-h intravenous infusions of angiotensin II.

Previously, we showed that uterine arteries from late gestation pregnant ewes infused intravenously with angiotensin II (Ang II) for 24 h, displayed heightened responsiveness to Ang II in vitro. Furthermore, we found that a small population of ewes with a "preeclampsia-like" disorder also displayed this. Therefore, we have investigated the density and affinity of Ang II receptor subtypes in the uterine arteries from these groups. Ang II receptor binding was measured using 125I [Sar1Ile8] Ang II. Proportions of AT1 and AT2 receptors were determined by inhibiting 125I [Sar1Ile8] Ang II with losartan (AT1 antagonist) or PD 123319 (AT2 antagonist). Uterine arteries from 24-h Ang II-infused ewes had a lower proportion of AT2 receptors (56.2+/-2.3%) than control (saline-infused) ewes (84.1+/-1.0%; P<0.05). The density of AT2 receptors was reduced (P<0.05) while the density of AT1 receptors was not different. Thus, 24-h infusions of Ang II selectively down-regulated AT2 receptors in the uterine artery, resulting in heightened Ang II reactivity. By contrast, the binding properties of Ang II receptor subtypes in uterine arteries from ewes with the "preeclampsia-like" disorder were not different from control ewes.

Angiotensin II↗

Expirograms of O2, CO2 and intravenously infused C2H2 and Freon-22 during panting in dogs.

To study pulmonary gas transport in panting, expirograms of several inert and respiratory gases were simultaneously measured in panting dogs. The experiments were performed on 5 conscious dogs (mean body weight 34.4 kg) provided with a chronic tracheostomy. Panting at a mean frequency of 312/min (5.2 Hz) was induced by elevated room temperature (mean 28.1 degrees C). Isotonic saline equilibrated with 50% acetylene and 50% Freon-22 was infused intravenously at a constant rate (4 ml/min). Fractional concentrations in the tracheostomy tube were measured by a respiratory mass spectrometer, using a special sampling system designed for quasi-continuous analysis of rapidly changing gas concentrations. Air flow was monitored by an ultrasonic transit-time flowmeter. A tracing of expired gas concentrations versus expired volume showed no alveolar plateau, displaying a steep increase of Freon-22, acetylene and CO2 (decrease of O2) up to the onset of inspiration. The small but statistically highly significant differences between the expirograms of CO2 and O2, and of Freon-22 and acetylene, could be qualitatively explained by ventilation-perfusion inequalities with sequential emptying, by Taylor dispersion and by reversible solution in airway mucosa in the course of the respiratory cycle.

Acetylene↗

Effects of intravenous infusions of noradrenaline on renal function in chronically catheterised fetal sheep.

To determine the effects of circulating noradrenaline on fetal renal function noradrenaline was infused intravenously into 7 chronically catheterised fetal sheep (127-138 days) at a dose (1 microgram/kg/min) which resulted in plasma levels similar to those which occur during hypoxia. Fetal mean arterial pressure increased by approximately 14 mmHg (p < 0.001) and haematocrit rose (p < 0.005). Glomerular filtration rate rose from 3.85 +/- 0.47 (SEM) to 4.70 +/- 0.50 ml/min (p < 0.05) during the first hour and fractional reabsorption of sodium by the proximal tubule fell (p < 0.05) during the second hour. Urine flow rate increased from 0.61 +/- 0.13 to 1.18 +/- 0.24 ml/min (p < 0.001) and osmolar excretion increased from 78 +/- 15 to 153 +/- 36 mu osm/min (p < 0.005). By contrast lung liquid flow fell (p < 0.05), but the increase in urine flow was much greater than the decline in lung liquid. These findings suggest that during hypoxia, noradrenaline may play an important role in the maintenance of urine flow and consequently amniotic fluid volume and, as suggested by others, in the distribution of fluid between the vascular and interstitial compartments.

Absorption↗

Continuous intravenous infusion of deleted form of hepatocyte growth factor attenuates hepatic ischemia-reperfusion injury in rats.

BACKGROUND/AIMS: Although beneficial roles of hepatocyte growth factor (HGF) and its variants on several hepatic disorders have been reported, their effects on hepatic ischemia-reperfusion (IR) injury remain undetermined. We investigated the action of a deleted form of HGF (dHGF) on hepatic IR injury in rats. METHODS: dHGF or phosphate-buffered saline was continuously infused intravenously for 20 h prior to a 20-min occlusion of hepatic vessels. Samples were taken before and after IR, for measurement of serum dHGF and released enzymes, liver gamma-glutamylcysteinyl glycine (GSH) level, as well as histological and immunohistochemical examinations. RESULTS: After reperfusion, histological injury, as well as increase in the serum activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase-BB were significantly attenuated in the dHGF-treated rats. dHGF maintained a high GSH level and suppressed oxidative stress and intercellular adhesion molecule-1 (ICAM-1) expression on sinusoidal endothelial cells (SECs), on which c-Met was not detected. IR caused activation of c-Met expression, which was milder in the dHGF-treated group, in hepatocytes at the pericentral region. CONCLUSIONS: dHGF attenuated liver injury after IR. It also maintained a higher GSH level, depressed oxidative stress and inhibited ICAM-1 expression on c-Met negative SECs, suggesting a paracrine effect of dHGF.

8-Hydroxy-2'-Deoxyguanosine↗

Influence of renal failure on the disposition of morphine, morphine-3-glucuronide and morphine-6-glucuronide in sheep during intravenous infusion with morphine.

The influence of experimentally induced renal failure on the disposition of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was examined in seven sheep infused intravenously with morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. Morphine, M3G and M6G were determined in plasma and urine by high-performance liquid chromatography. Constant concentrations of morphine, but not of M3G and M6G, were achieved in plasma between 5 and 6 hr. Significant (P < .001) extraction of morphine by the liver (0.72 +/- 0.05) and kidney (0.42 +/- 0.15) occurred. Compared with sheep with normal kidneys (Milne et al., 1995), renal failure did not alter (P = .11) the mean total clearance of morphine (1.5 +/- 0.3 liters/min); clearance by the kidney was less (P < .001). However, a paired comparison using sheep common to this study and from the study when their kidneys were normal revealed a significant reduction in mean total clearance of 25%. The renal extraction of M3G and M6G and urinary recovery of the dose as summed morphine, M3G and M6G were reduced by renal failure. The kidney metabolized morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.

Animals↗

Pharmacokinetics and pharmacodynamics of nitroglycerin and its dinitrate metabolites in conscious dogs: intravenous infusion studies.

Intravenous infusions of nitroglycerin (GTN), 1,2-glyceryl dinitrate (1,2-GDN), and 1,3-glyceryl dinitrate (1,3-GDN) were given to four conscious dogs at 10 micrograms/min, 30 micrograms/min, 50 micrograms/min, and 70 micrograms/min of GTN and 20 micrograms/min and 100 micrograms/min of GDNs. The steady state plasma concentrations (Css) of GTN were reached after about 60 min whereas for 1,2-GDN and 1,3-GDN the Css were reached at about 150 min after the infusion began. Except for one dog, the Css of GTN were not proportional to infusion rate, however, all dogs together showed a good linear relationship between Css of GTN and infusion rates with an average correlation coefficient of 0.917 +/- 0.102. Large variability in GTN clearance after various infusion rates was observed in all dogs. The Css ratios of 1,2-GDN/GTN and 1,3-GDN/GTN yield overall averages of 31.5 +/- 17.2 and 5.47 +/- 3.19, respectively. Average Css ratios of metabolites 1,2-GDN/1,3-GDN were 5.78 +/- 1.23. This ratio is different from those obtained after iv bolus and oral dosing indicating that the biotransformation of GTN to 1,2-GDN and 1,3-GDN differs for each dosing route. The clearances for 1,2-GDN and 1,3-GDN were not changed over the dose range of 20 micrograms/min to 100 micrograms/min. Terminal half-lives of 1,2-GDN and 1,3-GDN postinfusion were similar to those values obtained after a single bolus dose (45 min). It appears that all the GTN dose at steady state can be accounted for by the formation of measurable 1,2-GDN and 1,3-GDN. Large intra- and interdog variations in systolic blood pressure decrease (SPD) following infusions of GTN were observed, however, all dogs showed a clear systolic blood pressure decrease when the highest infusion rate (70 micrograms/min) was given. No significant systolic blood pressure drop was detected following 20 micrograms/min infusions of 1,2-GDN or 1,3-GDN. It was clear that systolic blood pressure in all dogs decreased following 100 microgram/min infusions of 1,2-GDN or 1,3-GDN. When SPD values were plotted vs. log GTN concentrations following the infusion of 70 micrograms/min of GTN in all four dogs, a counterclockwise hysteresis was observed indicating the significant contribution of the active dinitrate metabolites to GTN pharmacodynamics.

Animals↗

Plasma angiotensin II levels at moment of drinking during angiotensin II intravenous infusion.

Angiotensin II (ANG II) was infused intravenously within an apparent physiological dose range of 10-200 ng.kg-1.min-1 to induce a drinking response in rats. To determine the plasma ANG II level at the moment of drinking, blood samples were collected from the femoral artery at the onset of the drinking response. Control blood samples were obtained in a similar way before infusion. The lowest dose of ANG II did not evoke drinking. Variable water intake in response to 25, 50, and 75 ng ANG II.kg-1.min-1 after a relatively long latency to drink (40-65 min) was observed. All animals showed a drinking response when 100 ng ANG II.kg-1.min-1 or higher doses of ANG II were infused. The latencies to drink were inversely correlated to the dose of ANG II and were as short as 8 min with 200 ng ANG II.kg-1.min-1. Measurement of ANG II in the plasma of drinking rats showed that all concentrations were similar with an average of 458 +/- 58.1 pg/ml. This dipsogenic plasma ANG II level is equivalent to plasma ANG II after 48 h of dehydration. The results show that drinking in response to exogenous intravenous ANG II requires a threshold level to be reached that is equivalent to levels produced by the endogenous renin-angiotensin system when dehydration is prolonged. This suggests that intravenous ANG II is not involved in moment-to-moment fluid homeostasis but operates only when dehydration is severe.

Angiotensin II↗

Biodistribution of 111indium-labeled macrophages infused intravenously in patients with renal carcinoma.

PURPOSE: We have previously reported a clinical trial on the intravenous injection of autologous activated macrophages (AAM) in 15 patients with renal carcinoma. The present paper concerns scintigraphic investigations performed in 11 of these patients after injection of 111indium oxinate-radiolabeled AAM. METHODS: AAM were prepared from mononuclear cells (MNC) collected by apheresis from patients treated simultaneously with granulocyte-macrophage colony-stimulating factor (GM-CSF). MNC were cultured for 6 days in the presence of GM-CSF and exposed for 18 h to gamma-interferon, the AAM were then separated by elutriation and injected. RESULTS: After intravenous infusion, radiolabeled AAM were transiently retained in the lungs, where they predominated in the first hour. Later on, radioactivity accumulated in liver and spleen and then decreased from the first and second day, respectively. In one patient, two foci of radioactivity were detected in the lungs 1 h after injection, and persisted thereafter. Their association with tumor lesions was uncertain. This observation possibly resulted from the presence of granulocytes in the radiolabeled AAM populations of this patient. It seems that MNC collected from GM-CSF-treated patients and cultured in the presence of GM-CSF enables the differentiation of granulocytes. CONCLUSIONS: A series of 11 investigations confirms the previously reported distribution pattern of intravenously injected AAM. It is possible that in patients treated with hematopoietic cell-mobilizing agents, granulocytes develop in cultures designed to produce monocyte-derived antigen-presenting cells.

Carcinoma, Renal Cell↗

Effect of intravenous infusion of Intralipid, cholesterol, and plant sterols on hepatic cholesterogenesis.

Male Wistar rats were infused intravenously with various amounts (2-20 mL/24 h) of Intralipid or Intralipid containing cholesterol or plant sterols (5-100 mg/24h), and hepatic cholesterogenesis was monitored by measuring the incorporation of [1-14C]acetate into the nonsaponifiable sterols of liver slices. It was observed that the infusion of Intralipid alone resulted in a hypercholesterolemia that varied with the amount of Intralipid administered and that it was accompanied by up to a threefold increase in hepatic cholesterogenesis. Inclusion of cholesterol in the Intralipid at 5 mg/mL prevented the increase in hepatic cholesterol biosynthesis, while an inhibition of up to 95% of control synthesis was achieved when a total of 33 mg of cholesterol in 20 mL Intralipid was infused over a 24-h period. It is concluded that the feedback regulation of cholesterol biosynthesis is operative even when the entry of cholesterol bypasses the intestine and the lipoprotein synthesis taking place there and that Intralipid is a suitable medium for the intravenous introduction of a large mass of metabolically active cholesterol molecules. Similar infusions of mixed plant sterols failed to prevent the activation or inhibition of cholesterol biosynthesis, but the administration of much larger doses of plant sterols (100 mg) brought about a partial inhibition of hepatic cholesterogenesis. It is concluded that the presence of an alkyl group in the side chain prevents the plant sterols from an effective interaction with the critical sites of the feedback regulatory system of cholesterogenesis. The effects of the larger doses of plant sterols were attributed to the displacement of increasing amounts of free cholesterol from the vascular tissues, which resulted in an effective elevation of plasma cholesterol levels. The infusion of either cholesterol or plant sterols over the 24-h period did not appear to have a consistent effect upon the composition or secretion of biliary bile acids.

Acetates↗

Transplacental, amniotic, urinary, and fetal fluid dynamics during very-large-volume fetal intravenous infusions.

With rapid intravenous infusion of very large volumes of isotonic saline solutions into the fetus, the fluid could stay within the fetal body, thereby creating hydrops fetalis, be transferred into the amniotic fluid through the fetal kidneys, thereby creating polyhydramnios, or be transferred across the placenta into the maternal circulation. This study was designed to explore these possibilities. After a 1-hour control period, 10 near-term chronically catheterized ovine fetuses were infused intravenously with 4 L (greater than 100% of fetal weight) of either isotonic saline solution or lactated Ringer's solution over 4 hours. Fetal arterial pressure was significantly elevated by 7 mm Hg throughout the infusion (p less than 0.00001). Venous pressure underwent a transient rise (4.8 mm Hg) at 20 minutes of infusion and remained elevated (2.7 mm Hg) during the rest of the infusion (p less than 0.00001). Fetal urine flow increased by an average of 5.7 +/- 0.4 ml/min throughout the infusion (p less than 0.00001) and accounted for 34.1% +/- 2.6% of the infused volume. Estimated fetal extracellular fluid volume increased by 17.7% +/- 1.8% of the infused volume. Because fetal fluid retention, urine flow, and amniotic fluid volume changes accounted for only half of the infused fluid, the remainder of the infused volume must have crossed the placenta and entered the maternal circulation. Given the above changes in vascular pressures, this requires a filtration coefficient of the placenta 50 to 100 times the previously reported values. Thus we conclude that relatively small changes in fetal vascular pressures dramatically alter the filtration capacity of the ovine placenta and transplacental volume flow.

Amniotic Fluid↗

Effects of intravenous infusions of prostaglandin D2 in man.

Prostaglandin D2 (PGD2) was infused intravenously into normal male volunteers. Seven subjects received infusions of 16, 32, 64 ng/kg/min and six of these a further dose of 128 ng/kg/min. Each individual's maximum dose was limited by discomfort caused by intense facial flushing and nasal congestion. At these doses there was no significant effect on systolic or diastolic blood pressure nor on spirometric measurements. There was a small but statistically significant tachycardia at 64 and 128 ng/kg/min. Collagen- and adenosine diphosphate (ADP)-induced platelet aggregation ex vivo was not affected at any of the infusion rates. Infused PGD2 is unlikely to be a useful antithrombotic agent.

Adenosine Diphosphate↗

Effects of continuous long-term intravenous infusion of long-chain fatty acids on feeding behaviour and blood components of adult sheep.

Albumin complexes of palmitic, stearic and oleic acids were continuously infused intravenously into adult sheep to investigate their effects on feeding behaviour and blood components. They were compared with saline infusions as during a preliminary test albumin alone showed no influence on voluntary food intake. Oleic and palmitic acid infusions induced a significant decrease of the voluntary food intake, relative to saline infusion. Food intake also decreased in experimental sheep when stearic acid was used, though not significantly. For all the tested fatty acids, blood beta-hydroxybutyrate and acetoacetate concentrations, plasma lipid content and the distribution of fatty acids in triacylglycerol remained unchanged. Oleic acid infusion induced the following significant changes of blood composition between control and experimental sheep: increased free fatty acid (FFA) concentration, increased oleic acid and decreased palmitic acid proportions in FFA and an increased amount of oleic acid balanced by a decreased linoleic acid content in phospholipids and cholesteryl esters. The only significant changes observed with the palmitic acid infusion were: decreased linoleic acid content in phospholipids and cholesteryl esters and increased oleic acid content in cholesteryl esters. The stearic acid infusion induced a decrease of stearic acid quantity in phospholipids and a corresponding increase in oleic acid in phospholipids and cholesteryl ester. It is suggested that these long-chain fatty acids might affect the long-term control of voluntary food intake in ruminants.

3-Hydroxybutyric Acid↗

Abnormal suppression of plasma cortisol during the intravenous infusion of dexamethasone to alcoholic patients.

In some cases the oral administration of dexamethasone to alcoholic patients has failed to cause a normal depression of plasma cortisol levels. Although alcoholics often show signs of intestinal malabsorption, the possibility that the dexamethasone was not fully absorbed has not previously been considered. To eliminate any question of malabsorption, ten male alcoholic patients were infused intravenously with dexamethasone (1 mg/h). The plasma cortisol levels in blood samples withdrawn at half-hourly intervals during a 2-h infusion were compared with the values found in ten normal subjects similarly infused. Four of the alcoholics failed to show normal suppression of plasma cortisol levels, thus confirming that in some alcoholics there is a disturbance of pituitary-adrenal function similar to that found in Cushing's disease. In only one of the four cases was failure to suppress normally associated with the presence of clinical signs of Cushing's disease.

Adult↗