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Validation of volume kinetic analysis of glucose 2.5% solution given by intravenous infusion.

BACKGROUND: The distribution and elimination of glucose solutions can be analysed by means of a volume kinetic model, but the ability of the model to predict plasma dilution ('model linearity') has not been evaluated. METHODS: Six male volunteers received four separate infusions of glucose 2.5%: 10 ml kg(-1) and 15 ml kg(-1) over 30 min, and 15 ml kg(-1) and 25 ml kg(-1 )over 60 min. The kinetic model was fitted to measurements of plasma glucose concentration and haemodilution. RESULTS: The mean volume of distribution for the glucose was 9.2 (SEM 0.4) litres while the infused fluid expanded a central body fluid space (V(1)) of 3.1 (0.3) litres. Increasing the amount of infused fluid, but not the infusion rate, resulted in a proportional increase in the area under the curve for plasma glucose and plasma dilution, the only confounder being glycosuria. The bias of computer simulation was slightly increased by rebound hypoglycaemia, which could occur with the highest infusion rates, but the accuracy was almost identical regardless of whether the kinetic parameters from all 24 experiments or from any of the subgroups were used. CONCLUSION: The volume kinetic model for glucose 2.5% is linear and can therefore be used for computer simulation as long as marked glycosuria does not occur.

Adult↗

Cerebral and lung kinetics of morphine in conscious sheep after short intravenous infusions.

BACKGROUND: The analgesic effects of morphine are delayed relative to its concentration in blood. The rate of equilibration of morphine between blood and brain may contribute to this delay, but the kinetics of this process have not been modelled. This was determined in conscious instrumented sheep. The lung kinetics of morphine were also determined given their importance in defining systemic kinetics after i.v. bolus administration. METHODS: Sheep were given short i.v. infusions of morphine (30 mg over 4 min). Cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. These data were fitted to flow- and membrane-limited models of the kinetics in each organ. RESULTS: Morphine had minimal cardiovascular effects, did not alter cerebral blood flow and caused insignificant respiratory depression. Lung kinetics were best described by a single distribution volume (2036 ml) with a first-order loss (1370 ml min(-1)), which was attributed to deep distribution. The cerebral kinetics of morphine were characterized by a significant permeability barrier. Permeability across the barrier (7.44 ml min(-1)) was estimated with good precision, and was approximately one-fifth of the nominal cerebral blood flow. The distribution volume of morphine in the brain was estimated with less precision, but was described by a brain:blood partition coefficient of approximately 1.4. The time required for 50% equilibration between brain and blood concentrations was approximately 10.3 min. CONCLUSION: The cerebral equilibration of morphine was relatively slow, and was characterized by significant membrane limitation.

Analgesics, Opioid↗

Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn.

The combination of sulbactam and ampicillin was administered to 16 newborn infants, 15 preterm and one term, who required umbilical arterial or venous catheterization and prophylactic antibiotics. The aims were to determine an appropriate dosage regimen and to study the pharmacokinetics. Satisfactory plasma concentrations were achieved with administration of a bolus injection of 50 mg of each drug/kg every 12 hr (mean concentrations: sulbactam, 110 mg/liter; ampicillin, 87 mg/liter 3 hr after dosing; and sulbactam, 105 and 135 mg/liter; ampicillin, 320 and 310 mg/liter 30 min after dosing in two infants. Mean elimination half-lives were longer than those in adults (sulbactam, 7.9 hr; ampicillin, 9.4 hr), and urinary excretion over 12 hr varied considerably (range: sulbactam, 7%-91%; ampicillin, 5%-132%), rates reflecting the immature renal function in the newborn and the relative oliguria characteristic of preterm infants with idiopathic respiratory distress syndrome. There was little evidence of accumulation of either drug, and both were well tolerated. This combination and dosage should be suitable for a trial of therapy for infection in the newborn.

Ampicillin↗

Acute effects of intravenous infusions of alcohol on baroreceptor sensitivity in essential hypertension.

To assess the acute effects of alcohol on baroreceptor reflex in moderate and heavy drinkers with essential hypertension and in healthy subjects who drank moderately, four groups of age and sex matched subjects were studied. Group 1 consisted of 10 healthy subjects (age range 21-50 (mean 37.4(10.5) years), who usually drank less than 200 g of alcohol per week; group 2 patients (age range 21-50 (mean 37.4(10.3) years) with mild or moderate essential hypertension and whose weekly alcohol consumption was less than 200 g; and groups 3 and 4 patients with mild or moderate hypertension (age range 21-50 (mean 37.2(10.2) years and 21-52 (mean 38.1(10.4) years respectively), who usually drank greater than 700 g of alcohol per week. In groups 1-3 an infusion of alcohol (7 mg.kg-1.min-1) in 500 ml of 5% glucose was administered for 1 h to keep blood concentrations constant (6-7 g.litre-1), whereas in group 4 the dose was doubled (blood concentration 10-11 g.litre-1). Baroreceptor sensitivity was measured by the phenylephrine method before and after alcohol infusion and one or two days later before and after infusion of 500 ml of 5% glucose. In healthy subjects and in moderate drinkers with hypertension the alcohol reduced baroreflex sensitivity significantly (from 17.5(9.5) to 13.8(8.4); p less than 0.01 and from 15(10) to 10.5(6.7) ms.mmHg-1, p less than 0.01 respectively), whereas in the heavy drinkers with hypertension it was significantly reduced only at the highest dose of alcohol (from 12.5(6) to 7.9(3.5) ms.mmHg-1; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Rapid intravenous infusion of d-1 sotalol: time to onset of effects on ventricular refractoriness, and safety.

d-1 sotalol is one of the most effective antiarrhythmic agents currently available for ventricular tachyarrhythmias, but the recommended infusion rate of 10-20 min is too slow for rapid pharmacological termination of sustained ventricular tachycardia (VT) or for use during cardiac arrest. The safety of the drug and time lag from its rapid administration to onset of significant effects on ventricular refractoriness is unknown. One hundred and nine patients with a history of spontaneous and inducible sustained ventricular tachyarrhythmias were studied. d-1 sotalol (1.5 mg.kg-1) was infused over 5 min in the first 57 patients (mean age 61 +/- 13 years, mean ejection fraction 37 +/- 15%, range 15-70%). d-1 sotalol was then given over 1 min in the next 52 patients (mean age 61 +/- 12 years, mean ejection fraction 35 +/- 11%, range 18-58%). The time course of change in right ventricular effective refractory period (RVERP) was measured in 15 consecutive patients following the 5 min infusion and in all 52 patients following the bolus injection. Following the 5 min infusion, RVERP increased rapidly from a baseline of 231 +/- 17 ms, reaching a plateau of 268 +/- 23 ms at 10 min. Following the 1 min injection, RVERP increased virtually immediately from a baseline of 237 +/- 25 ms to reach a plateau of 271 +/- 31 ms at 5 min. Two patients (one in each group) developed symptomatic hypotension; both responded to volume replacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Intravenous infusion of erythromycin inhibits CXC chemokine production, but augments neutrophil degranulation in whole blood stimulated with Streptococcus pneumoniae.

Macrolides may influence the inflammatory response to an infection by mechanisms that are unrelated to their antimicrobial effect. Indeed, erythromycin and other macrolides inhibit cytokine production and induce degranulation of neutrophils in vitro. CXC chemokines are small chemotactic cytokines that specifically influence neutrophil functions. To determine the effect of a clinically relevant dose of erythromycin on the production of CXC chemokines and neutrophil degranulation, six healthy humans received a 30 min iv infusion of erythromycin (1000 mg). Whole blood obtained before and at various times after the infusion was stimulated ex vivo with heat-killed Streptococcus pneumoniae. Ex vivo production of the CXC chemokines interleukin 8 (IL-8) and epithelial cell-derived neutrophil attractant 78 (ENA-78), in whole blood obtained after erythromycin infusion, was lower than that in blood drawn before erythromycin infusion (maximum inhibition post-infusion: 32.9 +/- 6.5% and 35.2 +/- 12.6% decrease in production, respectively, expressed as percentage change relative to production before infusion of erythromycin, both P < 0.05). In contrast, infusion of erythromycin was associated with an enhanced capacity of whole blood to release the neutrophil degranulation products bactericidal/permeability increasing protein (BPI), human neutrophil elastase (HNE) and human lactoferrin (HLF) upon stimulation with S. pneumoniae. Effects of erythromycin were greatest 4 h after infusion was stopped, when BPI, HNE and HLF concentrations were increased by +107.6 +/- 33.5%, +134.7 +/- 34.8% and +205.9 +/- 55.9 %, respectively (expressed as percentage change relative to production before infusion of erythromycin) (all P < 0. 05). These results indicate the ability of erythromycin to reduce CXC chemokine production and to enhance neutrophil degranulation in human blood.

Adult↗

Intravenously infused 13C-leucine is retained in fasting healthy adult men.

We have proposed a leucine requirement of 40 mg/(kg. d) in adults, based on 24-h direct amino acid balance (24-h DAAB) studies in which leucine intake is calculated as the sum of diet and tracer intake. However, it is possible that the tracer intake that is given during the fasting state in the 24-h studies is oxidized, thereby not contributing to the effective daily leucine intake and thus lowering the intake and, consequently, the requirement estimate. We assessed the fasting state leucine oxidation with different leucine infusion rates ( approximately 2.5-5% of the leucine flux rate) in well-nourished Indian men. Healthy subjects (n = 10) in a fasting state were studied during three randomly administered infusions of different, known amounts of leucine, supplying 4.1, 6.6 or 8.3 mg/(kg. 12 h) during the 12-h fast. Mean 12-h leucine oxidation rate and leucine flux for the different levels of leucine infused did not change significantly (P > 0.1) for the three leucine infusion rates. The plasma leucine concentrations increased significantly after 12 h of leucine infusion, rising from between 20 and 50 micromol/L by the end of the infusions over the range of tracer input. We conclude that tracer leucine infused in the fasting state does not measurably increase leucine oxidation at the doses studied. Thus, tracer intake during the 12-h fast contributes to the effective leucine intake in 24-h DAAB studies.

Adult↗

Differential biliary excretion of genistein metabolites following intraduodenal and intravenous infusion of genistin in female rats.

The purpose of this study was to determine whether bioflavonoid glucoside O-conjugates are absorbed from the intestine in the intact form or as their aglycones following hydrolysis by intestinal beta-glucosidases. In this study, the intestinal absorption of genistin, the beta-glucoside of the isoflavone genistein, was examined in anesthetized, adult female rats fitted with indwelling biliary cannulas. To first establish whether genistein, once absorbed, was converted into unique metabolites, genistin was infused into the femoral or portal veins and bile samples quantitatively collected. Analysis of bile samples by HPLC-mass spectrometry revealed that almost full recovery of the genistein component occurred in the form of unreacted genistin ( approximately 20%) and genistein 7beta-O-glucuronide ( approximately 80%). However, when genistin was infused into the upper small intestine, only genistein 7beta-O-glucuronide and the aglycone genistein appeared in the bile. There was no evidence for any biliary secretion of the unreacted genistin, thereby excluding its uptake in the intact form from the small intestine in this animal model.

Animals↗

Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.

Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.

Adolescent↗

Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

Aged↗

Renal haemodynamic changes, renal tubular function, sodium and water homeostatic hormones in patients with chronic glomerulonephritis and in healthy humans after intravenous infusion of amino acids.

To determine whether renal reserve capacity was preserved in patients with chronic glomerulonephritis with well-preserved kidney function, and how sodium was handled in proximal and distal tubules, 13 healthy control subjects and 13 patients with biopsy-verified chronic glomerulonephritis were studied before and during a continuous 120-min amino-acid infusion. Glomerular filtration rate (GFR), renal plasma flow (RPF), and tubular function evaluated by the lithium clearance method, were determined during six clearance periods of 30 min each. Plasma concentrations of angiotensin II, atrial natriuretic peptide (ANP), aldosterone, arginine vasopressin (AVP), glucagon, amino acid and serum osmolality were determined before, 60, and 120 min after infusion. GFR and RPF increased about 10% in both groups; filtration fraction (FF) was unchanged. Proximal tubular reabsorption of sodium and water decreased, and distal tubular reabsorption of sodium and water increased, and thus the net excretion of sodium and water was unchanged. Angiotensin II and aldosterone were reduced in control subjects, but not in the patients. ANP and glucagon increased equally in both groups. Most amino acids increased two- or threefold. It is concluded that renal reserve capacity and glomerulotubular balance are intact in patients with chronic glomerulonephritis with well-preserved renal function, but there is an abnormal lack of suppression of the renin-angiotensin-aldosterone system in response to an amino acid infusion in these patients.

Adult↗

Acral erythrodysesthesia syndrome caused by intravenous infusion of docetaxel in breast cancer.

Docetaxel-induced skin reactions include hypersensitivity, edema, skin toxicity with erythrodysesthesia syndrome, infusion site reactions, alopecia, nail onycholysis, nail pigmentation, photosensitivity, scleroderma, and others, for example, stomatitis and paresthesias. However, of all reported effects, the acral erythrodysesthesia syndrome has only rarely been described in the literature. We report on two female patients with breast cancer who on treatment with docetaxel developed acral erythrodysesthesia syndrome. It presented as bizarrely shaped, burning skin reactions at their hands and feet. Histology of skin biopsies revealed microscopic damages to the eccrine sweat glands in both patients. Skin patch testing with docetaxel was negative. None of the reports dealing with side effects of docetaxel chemotherapy has described acral erythrodysesthesia syndrome with the histologic features of syringo-squamous metaplasia and eccrine neutrophilic hidradenitis. We propose here that these characteristic histologic features are essential in the differentiation from fixed drug eruption and localized graft-versus-host disease.

Antineoplastic Agents↗

Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery.

UNLABELLED: We analyzed morphine clearance values in infants receiving the drug by continuous i.v. infusion for analgesia after surgery, because we found lower steady-state morphine concentrations than we expected from our previous studies. Infants received morphine after a loading dose of 0.05 mg/kg and continuous infusion calculated to reach a steady-state concentration of 20 ng/mL. Blood was sampled twice on Postoperative Day 1 at times separated by at least 2 h, and morphine and morphine-6-glucuronide (M-6-G) concentrations were determined by high-performance liquid chromatography. Clearance of morphine was calculated as infusion rate divided by the steady-state morphine concentration. Morphine given to 26 infants by continuous i.v. infusion after major noncardiac surgery has rapidly increasing clearance values, from a median value of 9.2 mL x min(-1) x kg(-1) in infants 1-7 days old, 25.3 in infants 31-90 days old, and 31.0 in infants 91-180 days old to 48.9 in infants 180-380 days old. Adult clearance values are reached by 1 mo of age, more quickly than in infants of the same age previously studied who received morphine after cardiac surgeries. M-6-G was measured in all infants. The ratio of M-6-G to morphine concentrations was 1.9-2.1 in these infants, which is lower than ratios reported in older infants or adults by others, but higher than those reported in newborns. Infants with normal cardiovascular systems undergoing surgery clear morphine more efficiently than infants of the same age undergoing cardiac surgery. IMPLICATIONS: Morphine removal from the body is slow in newborns but increases to reach adult values in the first months of life. Calculating the clearance of morphine from blood samples drawn during continuous i.v. infusions after surgery shows that this maturation occurs more quickly in infants undergoing noncardiac surgery (by 1-3 mo of age) than in those receiving morphine after cardiac surgery (by 6-12 mo of age).

Age Factors↗