Combined Infusion Research Articles

202 Phase I study of paclitaxel (P) over 1 hr infusion in combination with vinorelbine (V) in advanced non small cell lung cancer (NSCLC)

202 Phase I study of paclitaxel (P) over 1 hr infusion in combination with vinorelbine (V) in advanced non small cell lung cancer (NSCLC)

178 Paclitaxel by 96-hour continuous infusion in combination with cisplatin: Preliminary results of a phase II trial in patients with advanced non-small cell lung cancer (NSCLC)

178 Paclitaxel by 96-hour continuous infusion in combination with cisplatin: Preliminary results of a phase II trial in patients with advanced non-small cell lung cancer (NSCLC)

The effect of stevioside on glucose metabolism in rat

This study was conducted to determine the effect of stevioside (SVS) on glucose metabolism. The experiments were performed in male Wistar rats treated with SVS either by intravenous infusion or feeding. SVS infusion (150 mg/mL) was carried out in doses of 0.67, 1.00, and 1.33 mL.kg-1 body weight.h-1. The plasma glucose level significantly increased both during and after SVS infusion, whereas it was not affected by SVS feeding (13.3 mL.kg-1 body weight). The glucose turnover rate (GTR) of [14C(U)]glucose and [3(-3)H]glucose was not significantly different between control and SVS infusion animals. Percent glucose carbon recycling and glucose clearance were reduced from 28.7 +/- 1.3 to 23.0 +/- 1.6% (p < 0.05) and from 6.46 +/- 0.34 to 4.99 +/- 0.20 mL.min-1.kg-1 body weight (p < 0.01), respectively. The plasma insulin level did not change, whereas the plasma glucose level significantly increased from 120.3 +/- 5.9 to 176.8 +/- 10.8 mg% (p < 0.01) during SVS infusion. Animals pretreated with angiotensin II and arginine vasopressin showed no significant effect, while animals pretreated with prazosin had an attenuated hyperglycemic effect of SVS infusion. Pretreatment with indomethacin or N omega-nitro-L-arginine methyl ester (L-NAME) alleviated the plasma glucose level during the second period of SVS infusion. Pretreatment with the combination infusion of indomethacin and L-NAME reduced the plasma glucose level from 117.0 +/- 1.8 to 109.0 +/- 1.7 mg% (p < 0.001), and normalized the plasma glucose level in the second period of SVS infusion. Insulin infusion inhibited the hyperglycemic effect of SVS infusion. The present results show that the elevation of the plasma glucose level during SVS infusion is not due to the reduction of the insulin level. It is probably the effect of SVS on glucose transport across the cell. Insulin response to a high plasma glucose level is suppressed during SVS infusion. Several interactions among norepinephrine, prostaglandin, and nitric oxide are involved in modulating the hyperglycemia during SVS infusion.

Intrathecal infusion of bupivacaine with or without morphine for postoperative analgesia after hip and knee arthroplasty

Postoperative pain after major orthopaedic operations can be controlled by continuous intrathecal administration of opioids or local anaesthetics. Effective intrathecal analgesia can be achieved through synergism of low doses of the two analgesic drugs and, possibly, less drug-related adverse effects. Therefore, we have evaluated the usefulness of a combined low-dose bupivacaine and morphine infusion in patients undergoing hip and knee arthroplasty. Spinal anaesthesia was induced in 55 ASA I-III patients with 0.5% bupivacaine 2 ml via a 28-gauge spinal catheter (L3-4 interspace) and 0.5-ml increments were given if needed. Intrathecal 24-h infusions consisted of bupivacaine 2 mg h-1 alone (n = 18), bupivacaine 1 mg h-1 alone (n = 18) or bupivacaine 1 mg h-1 combined with morphine 8 micrograms h-1 (n = 19). The interview after 3, 6, 12 and 24 h included assessment of pain at rest and on movement (VAS scale), occurrence of sensory and motor block and nausea/vomiting. Bupivacaine 1 mg h-1 combined with an infusion of morphine provided as good postoperative analgesia as bupivacaine 2 mg h-1, but motor block disappeared earlier (P = 0.01). Patients in the bupivacaine 1-mg h-1 group required more supplementary doses of oxycodone i.m. than the other groups (P = 0.04). Time to first oxycodone dose from the start of intrathecal infusion did not differ between groups. The frequency of nausea and vomiting was similar in all groups. In spite of this, antiemetic medication was required more often in the bupivacaine 1-mg h-1 group (possible because of opioid rescue medication). On the ward, one patient in the bupivacaine 2-mg h-1 group experienced a new increase in sensory block with concomitant hypotension. One patient in the same group had minor decubitus on the heel of the operated leg, probably because of prolonged motor block. We conclude that intrathecal infusion of a combination of bupivacaine 1 mg h-1 and morphine 8 micrograms h-1 produced adequate postoperative analgesia. Unfortunately, postoperative nausea and vomiting was a frequent disturbing adverse effect.

Chemotherapy

Chemotherapy

Blockade of serotonin-2C receptors by mesulergine reduces ocular dominance plasticity in kitten visual cortex.

We have investigated the role of serotonin-2C (5-HT2C) receptors in modulation of ocular dominance plasticity in kitten visual cortex. A small quantity of the 5-HT2C receptor blocker, mesulergine, was infused into the visual cortex of one hemisphere of 5- to 7-week-old kittens using osmotic minipumps, while the control hemisphere received vehicle solution. At the same time, one eyelid of the experimental animals was sutured shut. The ocular dominance distributions in the visual cortex (area 17) were assessed using extracellular recording methods after 1 week of combined mesulergine infusion and monocular deprivation. We found that the majority of the neurons remained binocularly responsive in the mesulergine-treated hemisphere, while most of the neurons recorded were either unresponsive or only weakly responsive to the deprived eye in the control hemisphere. Local infusion of mesulergine into the kitten visual cortex thus reduced the shift of ocular dominance that normally occurs in animals of these ages following monocular deprivation. The blocking effect seems to be distance-dependent and therefore dose-dependent: the farther away the recording sites were from the injection site, the fewer binocularly responsive cells were found. These results are relevant to previous findings indicating transient overexpression of 5-HT2C receptor in visual cortex of kittens at these ages. The data suggest that the 5-HT2C receptor system may be involved in the formation and modification of ocular dominance columns in the developing visual cortex.

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer.

To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.

Endogenous nitric oxide buffers blood pressure variability between 0.2 and 0.6 Hz in the conscious rat.

Shear stress is a potent stimulus for the formation and release of nitric oxide (NO). It seems, therefore, possible that a short-term increase in arterial blood pressure (ABP), which leads to a concomitant rise in endothelial shear stress, enhances NO release. The latter elicits a relaxation of vascular smooth muscle cells that, in turn, counteracts the initial rise in blood pressure (BP). Thus this chain of events may constitute a negative feedback loop reducing BP variability (BPV). To test this hypothesis, BP-time series were determined via telemetry in freely moving conscious Sprague-Dawley rats. Because it was reported recently that NO effects on ABP are more pronounced in females, the experiments were performed on 2 groups consisting of 10 female and 11 male animals. This was done under control conditions and after fixing NO plasma levels via an intravenous bolus of 15 mg/kg body wt N(G)-nitro-L-arginine methyl ester together with a continuous infusion of nitroprusside (15 +/- 0.8 microg/min). This combined infusion maintained mean ABP and heart rate at physiological levels, thus avoiding as much as possible interferences with other reflexes, e.g., the baroreflex. To quantitate BPV, fast Fourier transforms of the BP-time series were determined. The absolute power in the frequency range below 1 Hz increased during fixed NO to approximately 350% vs. control animals (female control, 2.1 x 10(9) +/- 1.5 x 10(8) mmHg2 vs. fixed NO, 8.0 x 10(9) +/- 1.3 x 10(9) mmHg2, P < 0.005; male control, 3.4 x 10(9) +/- 4.6 x 10(8) mmHg2 vs. fixed NO, 8.3 x 10(9) +/- 2.0 x 10(9) mmHg2, P < 0.05). This was mainly caused by a substantial rise in the power ranging from 0.2 to 0.6 Hz, which increased roughly fourfold in both females and males. It is concluded that the NO system is a potent buffer of spontaneous BP oscillations in the freely moving rat. This system is most efficient in buffering frequencies within the range of 0.2-0.6 Hz and shows no gender-specific differences with respect to its BP buffering capacity.

Stress echocardiography using adenosine combined with nitroglycerin-dobutamine in the detection of viable myocardium in patients with previous myocardial infarction.

The aim of this study was to assess the value of adenosine (A) and the combination of nitroglycerin (N) with dobutamine (D) stress echocardiography (SE) in the identification of viable myocardium. The clinical and electrocardiographic (ECG) effects of both tests were also evaluated. Fifty-two coronary artery disease patients, aged 56.4 +/- 8 years, with left ventricular dysfunction due to a previous myocardial infarction (mean ejection fraction: 49 +/- 8%) were included in the study. Cardiac catheterization was performed in all patients before A (140 micrograms/kg/minute for five minutes) and the combination of N with D (5-10 micrograms/kg/minute) stress echocardiography. On the echocardiogram, the left ventricle was divided into 16 segments and wall motion was graded semiquantitatively from 1 (normal) to 4 (dyskinesia). The echocardiographic index was also estimated. A segment was considered viable during A infusion when resting asynergy showed deterioration of one grade or more. In contrast, segmental viability was considered to be present during the combination of N with D infusion when resting asynergy showed improvement of one grade or more. A thallium 201 single photon emission computed tomography (SPECT) with reinjection was performed as reference standard for the identification of viable myocardium. Stress echocardiography during infusion of A was associated with short-duration angina attacks in 3 (5.8%) patients and transient complete atrioventricular (AV) block in 1 (1.9%), whereas during the combination of N with D infusion, 6 (11.5%) patients experienced ventricular bigeminy lasting for a short period. ST segment elevation greater than 1 mm was recorded in those leads having a Q wave, in 19 (36.5%) patients. In 10 of these 19 (52.6%), viable myocardium was present in SPECT, as it was in 33 patients (63.5%) having no ST segment elevation (P = NS). Of a total of 832 segments that were graded during A-SE, 276 exhibited resting asynergy and the remaining 556 had normal motion and thickening at rest. The echocardiographic index during A infusion increased from 1.52 +/- 0.22 to 1.71 +/- 0.24 (P < 0.001), whereas during D and N infusion it decreased from 1.53 +/- 0.31 to 1.30 +/- 0.42 (P < 0.001). With SPECT considered as the gold standard for the identification of viable myocardium, sensitivity, specificity, and positive and negative predictive values of A-SE in detecting viable myocardium were 54%, 86%, 65% and 80%, respectively. The respective values for the combination of nitroglycerin with D-SE were 91%, 89%, 78%, and 96%, respectively. Stress echocardiography during A, and the combination of N with D, constitute safe methods in the identification of viable myocardium. The detection of ST segment elevation in the ECG leads with a Q wave during the combined infusion of nitroglycerin and dobutamine is not related to the presence of viable myocardial tissue. The A-SE provide moderate diagnostic accuracy, while the combination of N with D during SE is much superior in detecting viable myocardium.

Effect of enterostatin and kappa-opioids on macronutrient selection and consumption.

Enterostatin, the activation peptide of pancreatic procolipase, suppresses consumption of high-fat diets and selectively suppresses fat consumption over carbohydrate consumption. Kappa-opioid subtype agonists stimulate feeding whereas antagonists suppress feeding. We investigated the effects of enterostatin, the kappa-opioid agonist U50488, and the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) on macronutrient selection and food consumption in rats adapted to choose between a high-fat (HF) diet or a low-fat-high-carbohydrate (LF) diet. In fasted rats, lateral cerebro-ventricular injection (LV) of enterostatin selectively suppressed consumption of the HF diet, with no effect on LF diet consumption. Nor-BNI also selectively suppressed consumption of the HF diet without affecting LF diet consumption. Additionally, U50488 prevented the suppression of consumption of the HF diet in response to enterostatin. In food-sated rates, U50488 preferentially increased consumption of the HF diet and had no effect on consumption of the LF diet. Combined infusions of subthreshold doses of enterostatin and nor-BNI also inhibited consumption of the HF but not the LF diet, whereas combined infusions of maximal doses of enterostatin and nor-BNI had no additive effects. Collectively, these data suggest that a kappa-opioid pathway modulates selection and consumption of diets high in fat and that enterostatin modulates consumption of dietary fat by interacting with this pathway.

Renal functional reserve in pigs: renal haemodynamics, renal tubular function and salt and water homeostatic hormones during amino acid and dopamine stimulation.

The purpose of the study was to evaluate renal functional reserve [RFR is the difference between glomerular filtration rate (GFR) at rest and maximal GFR after stimulation] in a controlled study in normal pigs. Our basic hypothesis was that a decreased RFR may be used as an early indicator of renal deterioration, i.e. a test to disclose significant obstruction as opposed to simple dilatation in hydronephrosis. During various forms of stimulation (amino acids, captopril and dopamine), we measured changes in GFR, renal plasma flow (RPF), tubular reabsorption of sodium and water, net uptake from plasma to the kidney of three salt and water homeostatic hormones (angiotensin II, aldosterone and atrial natriuretic peptide) and of glucagon, which is thought to play a key role as mediator of the GFR increase during amino acid infusion. We found the largest GFR increase during combined infusion of amino acids and dopamine (+13%), but compared with a non-stimulated control group, the GFR increase was statistically non-significant. RPF increased by 57% during stimulation with amino acids plus dopamine (P < 0.001), while tubular reabsorption of sodium and water, and renal uptake of angiotensin II, aldosterone and atrial natriuretic peptide showed no significant differences between control and stimulation groups. The renal uptake of glucagon increased significantly during amino acid stimulation with no concomitant GFR increase. We conclude that in this experimental, non-obstructed model, RFR is a very insensitive measure, which cannot be used to discriminate between obstruction and simple dilatation in hydronephrosis. Further, our study does not support the hypothesis that glucagon is involved in GFR changes after amino acids.

Does free fatty acid infusion impair insulin action also through an increase in oxidative stress?

In vitro studies have demonstrated that free fatty acids (FFA) may enhance oxidative stress. In contrast, no in vivo studies have addressed such a relationship. This four-part study aims at investigating the association between FFA and oxidative stress in healthy volunteers. The following experimental procedures were carried out: 1) determination and simple correlations among fasting plasma FFA, glucose, insulin, plasma thiobarbituric acid-reactive substance (TBARS), the ratio of reduced glutathione (GSH) to oxidized GSH, and lipid hydroperoxide (n = 30); 2) time-dependent effect of FFA on plasma TBARS concentrations and GSH/oxidized GSH ratio (n = 10); 3) dose-dependent effect of FFA on plasma TBARS concentrations (n = 9); and 4) relationship among plasma FFA concentrations, plasma TBARS concentrations, and insulin action (n = 11). The results demonstrate that fasting plasma FFA concentrations correlated with fasting plasma TBARS concentrations (r = 0.65; P < 0.001) and lipid hydroperoxide (r = 0.79; P < 0.001). The correlation between plasma FFA and TBARS remained significant even after adjustment for age, sex, body mass index, and fasting and 2-h plasma glucose concentrations (r = 0.43; P < 0.01). In the time-dependent study, plasma TBARS concentrations increased with the rise in plasma FFA concentrations. In the dose-response study, a progressive increase in fasting plasma FFA concentrations was achieved by varying the Intralipid infusion rate, which also caused plasma TBARS concentrations to increase progressively until they reached a plateau between the last two infusion rates (0.3 and 0.4 mL/min). A euglycemic hyperinsulinemic glucose clamp (insulin infusion rate, 10.2 pmol/kg min for 360 min) was also performed. Simultaneous 10% Intralipid (0.4 mL/min) infusion significantly enhanced plasma TBARS concentrations and inhibited insulin-stimulated whole body glucose disposal (WBGD). GSH infusion (15 mg/min for 360 min) had opposite effects on plasma TBARS concentrations and WBGD. A combined infusion of 10% Intralipid and GSH was associated with a stimulation of WBGD with a magnitude midway between that of 10% Intralipid and GSH infused separately. In conclusion, fasting plasma FFA seems to enhances oxidative stress, which might contribute to the disruptive effects of plasma FFA on insulin-mediated glucose uptake.

Does free fatty acid infusion impair insulin action also through an increase in oxidative stress?

In vitro studies have demonstrated that free fatty acids (FFA) may enhance oxidative stress. In contrast, no in vivo studies have addressed such a relationship. This four-part study aims at investigating the association between FFA and oxidative stress in healthy volunteers. The following experimental procedures were carried out: 1) determination and simple correlations among fasting plasma FFA, glucose, insulin, plasma thiobarbituric acid-reactive substance (TBARS), the ratio of reduced glutathione (GSH) to oxidized GSH, and lipid hydroperoxide (n = 30); 2) time-dependent effect of FFA on plasma TBARS concentrations and GSH/oxidized GSH ratio (n = 10); 3) dose-dependent effect of FFA on plasma TBARS concentrations (n = 9); and 4) relationship among plasma FFA concentrations, plasma TBARS concentrations, and insulin action (n = 11). The results demonstrate that fasting plasma FFA concentrations correlated with fasting plasma TBARS concentrations (r = 0.65; P < 0.001) and lipid hydroperoxide (r = 0.79; P < 0.001). The correlation between plasma FFA and TBARS remained significant even after adjustment for age, sex, body mass index, and fasting and 2-h plasma glucose concentrations (r = 0.43; P < 0.01). In the time-dependent study, plasma TBARS concentrations increased with the rise in plasma FFA concentrations. In the dose-response study, a progressive increase in fasting plasma FFA concentrations was achieved by varying the Intralipid infusion rate, which also caused plasma TBARS concentrations to increase progressively until they reached a plateau between the last two infusion rates (0.3 and 0.4 mL/min). A euglycemic hyperinsulinemic glucose clamp (insulin infusion rate, 10.2 pmol/kg min for 360 min) was also performed. Simultaneous 10% Intralipid (0.4 mL/min) infusion significantly enhanced plasma TBARS concentrations and inhibited insulin-stimulated whole body glucose disposal (WBGD). GSH infusion (15 mg/min for 360 min) had opposite effects on plasma TBARS concentrations and WBGD. A combined infusion of 10% Intralipid and GSH was associated with a stimulation of WBGD with a magnitude midway between that of 10% Intralipid and GSH infused separately. In conclusion, fasting plasma FFA seems to enhances oxidative stress, which might contribute to the disruptive effects of plasma FFA on insulin-mediated glucose uptake.

Dopaminergic Control of Prolactin Secretion in the Turkey

The stimulatory and inhibitory effects of dopamine (DA) upon avian prolactin (PRL) secretion suggest that, in birds, these actions are mediated by multiple DA receptors. To test this hypothesis, combined intracranial infusions of DA and selective D1or D2DA receptor blockers, plus electrical stimulation (ES) of the brain and vasoactive intestinal peptide (VIP) immunoneutralization, were used to characterize the actions of DA on PRL secretion in the turkey. Blockade of D1DA receptors prevented the increase in circulating PRL observed in response to infusion of stimulatory concentrations of DA or to ES. Stimulatory infusions of DA also failed to increase circulating PRL in birds immunized against VIP. Results from infusion of the D2DA receptor antagonist were unclear. Low concentrations had no effect, while the highest concentration (100 nmol/min) produced an increase in plasma PRL. At the high concentration the drug may be affecting PRL secretion by (1) acting nonspecifically, (2) acting as a partial DA agonist on D1DA receptors, or (3) diffusion to the pituitary and blockade of D2receptors there. These data suggest that avian PRL secretion is mediated by D1DA receptors within the brain and that the stimulatory effect of DA upon PRL secretion requires an intact VIPergic system.

Deficiency in nitric oxide bioactivity in epicardial coronary arteries of cigarette smokers

This study sought to examine nitric oxide-mediated regulation of epicardial coronary arterial tone in cigarette smokers. Cigarette smoking is a major risk factor for coronary artery disease and is highly prevalent in patients with coronary spastic angina. Long-term exposure to cigarette smoking has been recently reported to suppress endothelium-dependent arterial relaxation in vivo humans. Responses of epicardial coronary artery diameter to single or combined infusion of acetylcholine and NG-monomethyl-L-arginine (L-NMMA) into the left main coronary artery were examined in 11 current smokers and 17 nonsmokers using quantitative coronary angiography. Acetylcholine dilated one-third of the proximal segments and most of the distal segments of coronary arteries in nonsmokers, whereas it constricted most of the proximal and distal segments in smokers. L-NMMA decreased the basal diameter of coronary arteries in nonsmokers but had minimal effect on the basal diameter in smokers. L-NMMA abolished the dilator response to acetylcholine in the coronary arteries of nonsmokers but had minimal effect on the constrictor response to acetylcholine in the arteries of smokers. The dilator response to nitroglycerin was significantly increased in the coronary arteries of smokers compared with in those of nonsmokers. The constrictor response to L-NMMA at rest was significantly correlated with the dilator response to nitroglycerin and with the diameter changes to acetylcholine in both smokers and nonsmokers. Nitric oxide bioactivity at rest and at acetylcholine-stimulated conditions in smokers was decreased, leading to the supersensitivity of the artery to the dilator effect of nitroglycerin as well as the constrictor effect of acetylcholine in smokers. Cigarette smoking affects nitric oxide-mediated regulation of coronary artery tone.

Preoperative treatment of patients with locally advanced unresectable rectal adenocarcinoma utilizing continuous chronobiologically shaped 5-fluorouracil infusion and radiation therapy.

This study was designed to determine the efficacy and maximally tolerated dose of 5-fluorouracil when administered by chronobiologically shaped prolonged infusion in combination with radiation therapy in patients with both locally advanced and unresectable rectal carcinoma. Eighteen sequential patients determined clinically to have either locally advanced or unresectable rectal carcinoma were treated by 4500 centigray (cGy) or 5580 cGy, respectively, combined with continuous chronobiologically modulated 5-FU infusion starting at 250 mg/m2/day, with the dose escalating in each cohort of 5 patients if no Grade 3 or higher toxicity was observed in each cohort. Imaging studies were obtained prior to and after completion of treatment. All 18 patients completed the full course of radiation therapy and all were subsequently resectable for potential cure. The maximum tolerated dose of 5-FU was 275/m2/day for 5 weeks. Seven patients had a sphincter-sparing procedure, and ten patients underwent an abdominoperineal resection, all with clear margins. Five complete pathologic responses (28%) were obtained. The average follow-up time was 12 months with a range of 6 to 37 months. With the exception of two patients, one of whom declined surgery and one of whom died of widespread disease, all of the patients have remained free of disease. The combination of radiation therapy and continuous chronobiologically shaped 5-FU infusion at a dose of up to 275/m2/day is well tolerated and appears to be more effective in downsizing and possibly downstaging locally advanced and unresectable rectal carcinoma than radiation therapy alone. Longer follow-up will determine whether ultimate disease free and overall survival are improved by this method.

Response of phenylalanine and leucine kinetics to branched chain- enriched amino acids and insulin in patients with cirrhosis

BACKGROUND & AIMS: We tested the effects of branched chain-enriched, aromatic-deficient amino acids with insulin to correct the altered protein turnover as well as phenylalanine (Phe) and leucine (Leu) rate of appearance in compensated cirrhotics and controls. METHODS: Phe and Leu tracers were infused both before and following intravenous amino acid administration with insulin and euglycemic clamp. RESULTS: In cirrhosis, fasting whole-body protein synthesis and protein degradation were normal; Phe rate of appearance was greater (P<0.05), whereas Leu rate of appearance/Phe rate of appearance ratio was approximately 35% less than in controls (P<0.001). Following the infusion, protein synthesis did not increase (+1% +/ 5% [NS] vs. +21% +/- 5% [P<0.05] in controls); protein degradation was more suppressed, whereas protein balance increased normally. Total Phe rate of appearance (0.91 +/- 0.13 micromol x kg-1 x min-1) and Leu/Phe disposal ratio (3.53 +/- 0.36) were nearly normalized (fasting controls, 0.68 +/- 0.07 micromol x kg-1 x min-1 and 2.87 +/- 0.14 micromol x kg-1 x min-1, respectively; P>0.05). However, Leu/Phe endogenous rate of appearance ration remained approximately 50% less (1.56 +/- 0.31 vs. 2.87 +/- 0.14; P<0.004) than in controls. CONCLUSIONS: Following this combined infusion in cirrhosis, net protein deposition increased normally despite a blunted response of protein synthesis. Phe and Leu to Phe peripheral disposal were near normalized; however, the exaggerated endogenous Phe production was not corrected entirely. (Gastroenterology 1996 Jul;111(1):127-37)

Role of cortisol in the metabolic response to stress hormone infusion in the conscious dog

The role of cortisol in directing the metabolic response to a combined infusion of glucagon, epinephrine, norepinephrine, and cortisol (stress hormones) was investigated. Chronically catheterized, conscious fasted dogs were studied before hormone infusion and after a 70-hour stress hormone infusion containing glucagon, epinephrine, norepinephrine, and cortisol (n = 11) or containing all these hormones except cortisol (n = 5). Combined stress hormone infusion increased arterial plasma glucagon, cortisol, epinephrine, and norepinephrine approximately sixfold. Whole-body glucose production (R a), glycogenolysis, and gluconeogenesis were assessed using tracer and arteriovenous-difference techniques. The absence of an increase in cortisol during stress hormone infusion attenuated the increase in arterial plasma glucose concentration and R a (Δ 81 ± 16 v 24 ± 3 mg/dL and 1.7 ± 0.3 v 0.8 ± 0.4 mg/kg/min, respectively). However, it did not alter the increase in net hepatic glucose output (Δ 0.7 ± 0.3 v 0.8 ± 0.4 mg/ kg/ min). When the increase in cortisol was absent, the increase in net hepatic gluconeogenic precursor uptake was attenuated (Δ 0.7 ± 0.3 v 0.1 ± 0.3 mg glucose/kg/min) due to a decrease in gluconeogenic precursor levels. The efficiency of gluconeogenesis increased to a greater extent (Δ 0.19 ± 0.07 v 0.31 ± 0.11) when cortisol was not infused. The absence of an increase in cortisol also led to marked glycogen depletion in the liver (10 ± 4 v 55 ± 10 mg/g liver). Cortisol thus plays a pivotal role in the metabolic response to stress hormone infusion by sustaining gluconeogenesis through a stimulatory effect on hepatic gluconeogenic precursor supply and by maintaining hepatic glycogen availability.

Effects of infusion of combinations of adrenocorticosteroids on systemic and regional haemodynamics in conscious sheep

To compare the cardiovascular, metabolic and endocrine responses to infusions of two combinations of adrenocorticosteroids and to determine their contribution to the haemodynamic effects of corticotrophin. The effect of 5 day's infusion of combinations of seven corticosteroids (aldosterone, cortisol, corticosterone, 11-deoxycorticosterone, 11-deoxycortisol, 17 alpha-hydroxyprogesterone and 17 alpha-hydroxy-20 alpha-dihydroprogesterone and five corticosteroids (17 alpha-hydroxyprogesterone and 17 alpha,20 alpha-hydroxyprogesterone omitted) on arterial pressure, cardiac output (measured using electromagnetic flow probes) and regional blood flows (measured using transit-time flow probes) was determined in conscious sheep. Combined infusion of seven steroids increased mean arterial pressure from 79 +/- 2 to 91 +/- 2 mmHg (day 5). Cardiac output increased from 5.42 +/- 0.22 to 6.55 +/- 0.41 l/min owing to an increase in stroke volume. Mesenteric conductance fell from 6.3 +/- 0.4 to 5.4 +/- 0.5 ml/min per mmHg, and renal conductance increased from 3.1 +/- 0.1 to 4.0 +/- 0.1 ml/min per mmHg, resulting in no change in total peripheral conductance. There were only minor effects on the coronary and iliac vascular beds. Infusion of five steroids caused similar changes in mean arterial pressure (from 78 +/- 1 to 89 +/- 2 mmHg on day 5), cardiac output and regional blood flows. The cardiovascular, fluid, electrolyte and endocrine responses to both steroid treatments were similar to those with corticotrophin. Infusion of combinations of seven or five adrenocortical steroids reproduced the cardiovascular actions of corticotrophin, namely increases in arterial pressure, and cardiac output, mesenteric vasoconstriction and renal vasodilation. This contrasts with previous studies in which only an infusion of steroids including 17 alpha-hydroxyprogesterone and 17 alpha,20 alpha-OHP reproduced the pressor effect of corticotrophin fully, possibly because in these sheep, as has been proposed to be the case in humans, the dose-response curves for the hypertensinogenic, mineralocorticoid and glucocorticoid actions overlap.

GLUCOSE AND PROTEIN METABOLISM IN NEWBORNS UNDERGOING EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO). ▴ 1820

To determine to what extent glucose homeostasis, proteolysis, and essential amino acid loss is altered in infants undergoing ECMO for persistent pulmonary hypertension, stable isotope tracer infusions were used to measure endogenous glucose production, phenylalanine (PHE) rates of appearance (Ra), and PHE hydroxylation (PHE-OH) in 7 neonates on ECMO (birth weight 3.5±0.9kg, 40±2 wks gestation, 3±1 days old) and in 10 normal newborn controls (birth weight 3.3±0.5kg, 39±1 wks gestation, 2.4±1.4 days old). ECMO infants and controls were both studied during a 7 mg/kg/min glucose infusion. In addition, to determine the effect of a combined glucose (7 mg/kg/min) and amino acid (AA) infusion (1.5 g/kg/day, 16.2μmol/kg/hr PHE) on proteolysis and PHE balance in ECMO patients, the same measurements were made in 8 ECMO patients receiving the combined infusion.