Six-hour Infusion Research Articles

Albumin and fibrinogen kinetics in sepsis: a prospective observational study

BackgroundThe measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects.MethodsWith the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-2H5]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-2H5]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured.ResultsMean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR.ConclusionsWhile septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production.Trial registration: ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015).

Midazolam Promotes the Mobilization of Endothelial Progenitor Cells and Increases the Plasma Concentration of VEGF in Rats with Myocardial Ischemia Treated with G-CSF

Background: Midazolam is commonly used during the perioperative period in patients with cardiac operations, especially in the patients with myocardial ischemia (MI). Some studies have demonstrated that midazolam stimulates vascular endothelial growth factor (VEGF) release in aortic smooth muscle cells. As we all know, VEGF is a hypoxia-inducible factor, which enhances vascular permeability, promotes angiogenesis, and appears to play an important role in the mobilization of endothelial progenitor cells (EPCs). The aim of this study was to evaluate the effects of midazolam on both VEGF release and the mobilization of EPCs in rats with myocardial ischemia treated with granulocyte colony-stimulating factor (G-CSF).Methods: Thirty-six rats with myocardial ischemia were randomly divided into three groups (n=12): control group, G-CSF alone-group and G-CSF plus midazolam group (control group, G-CSF group and midazolam group), pretreated with G-CSF for five days, and followed by continuous infusion of saline and midazolam into the veins for six hours on the sixth day. The number of CD34+ mononuclear cells (MNCs) and EPCs, and the plasma concentrations of VEGF and C-reactive protein (CRP) were measured at the end of the six-hour infusion. Left ventricular end-diastolic pressure (LVEDP), and maximal and minimal rates of rise of pressure in the left ventricle (dp/dtmax and dp/dtmin, respectively) were measured with a modified non-circulating Langendorff apparatus.Results: Compared to the control group, rats in the G-CSF group had a higher concentration of VEGF and increased levels of CD34+ MNCs and EPCs (P<0.05). Whereas compared to the G-CSF group, the concentrations of VEGF and the number of CD34+ MNCs and EPCs in the midazolam group were significantly higher (P<0.05). The LVEDP of the rats in both the midazolam and G-SF groups were significantly lower than that of the control group (P<0.05); while the dp/dtmin of the rats in both the midazolam and G-CSF groups were significantly higher than that of the control group, and the dp/dtmin in the midazolam group was higher than that of the G-CSF group (P<0.05).Conclusions: G-CSF can increase VEGF concentration and promote EPC mobilization in rats with myocardial ischemia. Midazolam reinforces the above effects and increases vascular dilation. Citation: Ting-Ting Chen, Wei-Dong Mi, Gang Wang, Li-Bing Li. Midazolam promotes the mobilization of endothelial progenitor cells and increases the plasma concentration of VEGF in rats with myocardial ischemia treated with G-CSF. J Anesth Perioper Med 2016; 3: 119-124. doi: 10.24015/JAPM.2016.0016This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Introduction: Amid PK changes and emerging multi-drug resistant pathogens, prolonged-infusion beta-lactam dosing strategies have been recommended to achieve optimal PD targets, but actual PK data in critically ill patients are limited. This study describes PK and PD profiles in critically ill trauma and medical patients receiving twice-daily prolonged-infusion cefepime. Methods: This prospective, clinical PK study included adult critically ill multiple trauma and medical patients with suspected ventilator-associated pneumonia (VAP) and normal renal function receiving cefepime 2 g IV every 12 hours with a six-hour infusion. Six unbound cefepime serum concentrations (drawn 0, 3, 6, 8, 10 and 12 hours post-dose) were assessed after the third dose and measured using reverse-phase high-performance liquid chromatography. PK parameters were determined by fitting data to a linear, one-compartment, first-order elimination model. Results: Four patients (trauma = 3; medical = 1) were enrolled. Trauma patients were younger (47 ± 11 vs. 68 ± 0 years) and had higher estimated creatinine clearance (133.4 ± 21.2 vs. 104.0 ± 0.0 mg/dL) than the medical patient. All patients had microbiologically confirmed VAP. Between groups, the medical patient had higher Cmax (61.4 ± 0.0 vs. 34.8 ± 6.4 mg/L), Cmin (23.6 ± 0.0 vs. 1.3 ± 0.5 mg/L), and VD (24.7 ± 0.0 vs. 22.3 ± 1.7 L), as well as lower clearance (63.3 ± 0.0 vs. 131.4 ± 9.3 mL/min) compared to the trauma patients. The dosing strategy provided > 60% free time above the MIC for the medical patient up to an MIC of 32 mcg/mL, but only up to 8 mcg/mL for the trauma patients. Using the most optimal PD endpoint of Cmin > 4 times the MIC, only for MICs of < 0.25 mcg/mL did 100% of patients meet the PD goal, well below the current FDA-defined susceptibility breakpoint of 8 mcg/mL for most Gram-negative rods. Conclusions: Variability in cefepime PK and ability to achieve recommended PD targets was noted among critically ill patients receiving prolonged-infusion. Larger studies are needed to better characterize inter-critically ill population differences in PK/PD to optimize cefepime dosing strategies.

Chest and back pain associated with a six-hour infusion of liposomal daunorubicin

Chest and back pain associated with a six-hour infusion of liposomal daunorubicin

Pharmacodynamic and Safety Results of PEG-Hirudin in Healthy Volunteers

PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of action than non-conjugated recombinant hirudin permitting once daily subcutaneous administration. A series of placebo-controlled, randomized, Phase I clinical trials were conducted in 75 healthy volunteers to investigate the anticoagulant effects, safety and pharmacodynamics of PEG-Hirudin when administered intravenously as a bolus injection, infusion, and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa activity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 micrograms/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 micrograms/ml and 0.77 micrograms/ml, respectively, at the end of a six-hour infusion period without having reached steady state at this time. After termination of the infusion, anticoagulant activity displayed an immediate exponential decrease. The anticoagulant activities of single subcutaneous doses of 0.05 to 0.6 mg/kg were studied in a further series of investigations and slow increases and prolonged durations of anti-IIa activity and APTT prolongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg for five days resulted in dose-dependent prolongations of APTT and increases in anti-IIa activity without completely reaching steady state conditions. In a further study, 0.3 mg/kg of PEG-Hirudin was given as an i.v. bolus injection followed by three repeated single daily s.c. injections. In this trial, the APTT was shorter than expected from previous studies; therefore, a direct comparison of various APTT reagents was made in the intravenous infusion trial. Of the APTT reagents tested, BioMérieux Silimat and IL-ellagic acid proved to be the most sensitive to PEG-Hirudin. The hirudin derivative PEG-Hirudin was tolerated very well without immuno-allergic side effects. In view of the significantly prolonged anticoagulant efficacy in comparison to non-conjugated r-hirudin, PEG-Hirudin is a promising compound especially for repeated once daily subcutaneous administration.

Phase I Evaluation of Crisnatol (BWA770U Mesylate) on a Monthly Extended Infusion Schedule

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.

Beneficial Effect of a New Prostacyclin Derivative on the Walking Capacity in Patients with Peripheral Arterial Insufficiency

The efficacy, tolerance and safety of iloprost, a stable analogue of carbaprostacyclin, were evaluated in 7 patients with peripheral arterial insufficiency at stage II of Fontaine's classification. After washout, placebo was infused intravenously for seven days, then iloprost was given by a six-hour intravenous infusion of 1 ng/kg/min over the next seven days. At the end of each period, the initial (ICD) and the absolute (ACD) claudication distance were measured by treadmill. The ankle/arm systolic blood pressure ratio (WI) was also assessed, at rest and ten minutes after exercise. As compared with placebo, ICD increased from 98 +/- 60 to 137 +/- 91 meters (p less than 0.05) and ACD from 151 +/- 76 to 210 +/- 95 meters (p less than 0.05). Similarly, WI rose from 0.44 +/- 0.14 to 0.52 +/- 0.18 (p less than 0.05) at rest and from 0.40 +/- 0.13 to 0.48 +/- 0.20 (p less than 0.05) ten minutes after treadmill exercise. Owing to the spontaneous fluctuation in walking distance experienced by such patients, an increase in ACD greater than or equal to 50% was considered as clinically relevant. In 3 patients, who experienced such an improvement, iloprost continued to be infused at the same dosage as before, for an additional seven days. In the remaining 4 patients (nonresponders), the dose was increased to 2 ng/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral Blood Leukocyte Kinetics Following In Vivo Lipopolysaccharide (LPS) Administration to Normal Human Subjects

Lipopolysaccharide (LPS, endotoxin) administration to human subjects elicits significant elevations in plasma cachectin/TNF, epinephrine, and cortisol. This study examined the temporal relationship between changes in blood leukocyte subsets and plasma mediators following endotoxin administration to normal human subjects. A five-minute intravenous infusion of purified LPS (20 units/kg Escherichia coli) was administered to 12 healthy volunteers. Blood samples were obtained at varying intervals after infusion and analyzed for differential cell counts and lymphocyte subsets (CD2, CD3, CD4, CD8, CD20, and HLA-DR) by flow microfluorimetry, and also assayed for plasma cachectin/TNF, epinephrine, and cortisol. Plasma cachectin/TNF was significantly elevated at 75 and 90 minutes after infusion with a peak concentration of 261 +/- 115 pg/ml noted 75 minutes after infusion. A significant plasma epinephrine elevation of 181 +/- 75 pg/ml was demonstrated one hour after infusion, while significant elevations in plasma cortisol were noted from one to five hours after infusion with a peak level of 34 +/- 3 micrograms/dl three hours after infusion. A profound monocytopenia (p less than 0.01) was noted one hour after infusion. Temporally associated with the rise in plasma cortisol was a reversal of the early granulocytopenia to a significant granulocytosis (p less than 0.01 versus preinfusion mean), whereas a marked lymphocytopenia (p less than 0.01) was observed from one to six hours after infusion. During the period of hypercortisolemia, CD2, CD3, and CD4 lymphocyte percentages were decreased (p less than 0.01) while CD20 and HLA-DR lymphocyte percentages were increased (p less than 0.01). There was a small percentage decrease in CD8 lymphocytes from one to 24 hours after infusion (p less than 0.01), although relative to the one-hour nadir, there was a significant rise in the percentage during the time of elevated plasma cortisol concentrations. A six-hour infusion of epinephrine (30 ng/kg/min) administered to six healthy volunteers resulted in a monocytosis (p less than 0.05) and granulocytosis (p less than 0.01) without a change in lymphocyte number or lymphocyte subset percentage. Previous reports have shown that in vivo corticosteroid infusion causes a prominent granulocytosis, monocytopenia, and lymphocytopenia with a decrease in the percentages of CD3 and CD4 lymphocytes. The peripheral blood leukocyte dynamics documented in the current study are similar to patterns observed following in vivo corticosteroid administration. This study suggests that the acute adrenocortical response to endotoxemia primarily mediates the subsequent changes in leukocyte subsets.

Effects of the infusion with ACTH or crh on the secretory activity of RAT adrenal cortex

Six-hour infusion with ACTH or CRH induced a dose-dependent rise in the plasma concentrations of ACTH, corticosterone (B) and aldosterone (A). Positive linear correlations between the plasma levels of ACTH and B or A were found in both ACTH- or CRH-infused animals. Regression curves for B were similar in both groups of animals, while the regression line for A was significantly ( P < 0.05) steeper in CRH- than in ACTH-treated rats. These findings suggest that, in the rat, the mechanism underlying the CRH-induced stimulation of A secretion does not exclusively involve the enhancement of ACTH release.

Elevated aluminum persists in serum and tissues of rabbits after a six-hour infusion

The half-life of aluminum was estimated in selected tissues and fluids in a representative mammal, the rabbit. After a single iv aluminum infusion, half-lives were determined by serial killing of rabbits and aluminum quantitation in selected tissues and fluids by electrothermal atomic absorption spectroscopy. Tissues and fluids demonstrating a significant increase 4 hr after the 200 μmol/kg aluminum dose were the bile, kidney, liver, lung, serum, and spleen. Aluminum concentration did not significantly increase above control in the adrenal gland, bone, heart, muscle, testis, thyroid gland, or selected central nervous system regions. Biliary aluminum concentration returned to control within 12 hr after infusion. Estimated half-lives were 113 days in spleen, 74 days in liver, 44 days in lung, 42 days in serum, 4.2 days in kidney cortex, and 2.3 days in kidney medulla. The kidney also demonstrated another half-life greatly exceeding 100 days. The results demonstrate that aluminum persists in various tissues and fluids for different lengths of time. The calculated half-life of aluminum in these tissues is substantially longer than previously estimated half-lives based on serum aluminum determination. The persistence of aluminum in the liver and other tissues may serve as a source of continous aluminum exposure for sensitive target organs such as the brain. These calculated half-lives establish the normal rate of aluminum elimination from tissues. Furure studies could determine the influence of factors such as uremia or chelation therapy on the rate of aluminum elimination from storage sites as well as serum.

Stability of Liposyn II fat emulsion in total nutrient admixtures

Compatibility and safety of a safflower oil-soybean oil lipid emulsion (Liposyn II, Abbott) with amino acids and dextrose in total nutrient admixtures (TNAs) were studied. Sixty-two admixtures representing 31 different combinations of fat emulsion, amino acid injection, and dextrose injection were tested. Both 10% and 20% concentrations of the fat emulsion and three concentrations each of amino acid injection and dextrose injection were used; the core admixture components were placed in empty flexible plastic bags in three different sequences: fat, amino acids, dextrose; fat, then dextrose and amino acids simultaneously; and amino acids and dextrose simultaneously, then fat. One of two mixtures of electrolytes and trace metals was added to each sample at the end of mixing. Six samples were tested after one day at 25 degrees C, 35 after two days at 5 degrees C plus one day at 30 degrees C, and 21 after nine days at 5 degrees C plus one day at 25 degrees C. Multivitamin injections were added to each TNA just before the 24-hour room-temperature storage. pH, emulsion particle size, and zeta potential (electrostatic surface charge of lipid particles) were measured after visual inspection of each sample. Amino acids were separated by high-performance liquid chromatography and measured. Dextrose was measured by size-exclusion chromatography. In a controlled study of 24 dogs, six-hour infusions of TNAs containing Liposyn II 20% were administered for 14 days, after which all major organs and tissues were studied microscopically. At all storage times in the compatibility study, all TNAs retained a uniform, milk-like appearance.(ABSTRACT TRUNCATED AT 250 WORDS)

4'Epidoxorubicin (epirubicin): activity in hepatocellular carcinoma.

Doxorubicin provides the most consistent response rate in hepatocellular carcinoma. We therefore initiated a trial with its analog 4'epidoxorubicin. Eighteen patients, all without prior treatment, were given the drug as a single agent every 3 weeks with dose escalation whenever possible. Five patients were treated by six-hour infusion and 13 by intravenous (IV) bolus injection, with the median dose being 90 mg/m2. The patients were of diverse ethnic background and included some with underlying cirrhosis and hepatitis B surface antigenemia. Three patients had partial remissions (6, 12, 48 weeks) for a response rate of 17%. Four patients also had prolonged stable disease (14, 26, 27, 38 weeks). Toxicity was mild, although cardiac toxicity developed in three patients at 685, 825, and 1,460 mg/m2 cumulative dose. The response to 4'epidoxorubicin in this study appears to be equivalent to the reported response rates for doxorubicin, with decreased toxicity.

Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast

In order to test the possible cardiac-sparing effect of doxorubicin admininstered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall In resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m 2 was 0.06 (p <0.005); at 301 to 449 mg/m 2 it was 0.09 (p <0.0005); and at 450 mg/m 2 or greater it was 0.15 (p <0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the “normal range” (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 n M. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus Infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should Include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to Include deteriorations In function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage.

The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate.

The pharmacokinetics of high-dose methotrexate (MTX, 5-15 g/m2) were evaluated in 11 children and adolescents who had previously received two to eight doses of cisplatin (90 mg/m2) in the treatment of malignant solid tumors. The half-life for disappearance of MTX from serum during the first 24 hours after infusion was determined from serum samples obtained at the end of a six-hour infusion and six, 12, and 24 hours after infusion. These values were compared to a mean half-life of 2.83 (+/- 0.34) hours following 489 courses administered to 71 patients who had not received cisplatin. Stepwise multiple linear regression analysis of patient variables revealed cumulative cisplatin dosage and time from last cisplatin dose as the best predictors of MTX half-life (r2 = 65.4%, p less than 0.001). The best predictors of 24-hour serum concentration were cumulative cisplatin dosage and MTX dosage (r2 = 54.2%, p less than 0.001) in the multiple linear regression model. Patients with delayed MTX clearance received additional leucovorin and experienced no severe toxicity. Patients receiving up to 270 mg/m2 of cisplatin appear to have minimal increases in MTX half-life, while the likelihood of delayed clearance increases in patients who have received 360 mg/m2 or more of cisplatin. All patients who have previously received cisplatin should be treated cautiously with high-dose MTX and prospective pharmacokinetic monitoring should be routinely performed.

Intravenous gamma globulin treatment for chronic idiopathic thrombocytopenic purpura in children

Six children, five to 16 years of age, with the chronic, autoimmune form of idiopathic thrombocytopenic purpura were given intravenous gamma globulin (Gamimune, Cutter Biological, Berkeley, California) in a dose of 400 mg/kg per day for five consecutive days as six-hour infusions. Two of the six children had undergone splenectomy but the other four had not. Three of six children had a good or excellent response to the first five-day course of intravenous gamma globulin. The peak platelet count occurred within 12 days of the start of therapy in all. All three have required booster doses of intravenous gamma globulin to maintain platelet counts at a safe level. All children had marked increases in serum IgG following intravenous gamma globulin, except one who had undergone splenectomy and who had chronic idiopathic thrombocytopenic purpura with high baseline levels of immunoglobulin G (IgG). The significance of the observed increase in platelet-associated IgG during treatment is not clear. No untoward reactions necessitating cessation of therapy were encountered during this study. Our short-term observations in six children with chronic idiopathic thrombocytopenic purpura indicate that high-dose intravenous gamma globulin is an effective form of treatment for certain children with this condition.

Secretory bursts of growth hormone secretion in the dog may be initiated by somatostatin withdrawal.

In 28 6-h experiments on 10 conscious resting trained male dogs, plasma growth hormone (GH) was determined at 5-min intervals by radioimmunoassay. For all experiments, the basal GH concentration in plasma was 0.80 +/- 0.06 ng mL-1. In each experiment, 1-3 secretory bursts of GH occurred, raising plasma GH 2.4 to 15.3 times basal concentrations (for all 43 bursts, 6.6 +/- 0.4 times the basal value). Metabolic clearance rates (MCR) and apparent distribution volumes (V) were determined, using stepwise infusions of canine GH. The MCR (3.99 +/- 0.30 mL kg-1 min-1) and V (57.9 +/- 5.5 mL kg-1) were used to transform the GH concentration versus time data into GH secretion rates, using a single compartment approach. Basal GH secretion rates for all 28 experiments were 3.12 +/- 0.24 ng kg-1 min-1. The secretory bursts yield peak GH secretion rates of 9.4 +/- 0.8 times basal secretion and these steep-sloped bursts last 25.1 +/- 1.2 min. Six-hour infusions of 0.15 microgram kg-1 min-1 of somatostatin (SRIF) abolished all secretory bursts but did not lower basal secretion rates. In five of seven SRIF infusion experiments in which samples were taken after the infusion ceased a secretory burst was seen in the hour following cessation of infusion (in four cases within 10 min). These secretory bursts lasted 23.0 +/- 2.9 min and were similar to those seen in control experiments. Infusions of SRIF at 0.05 microgram kg-1 min-1 had no effect. These results imply that during basal GH secretion, a surfeit of SRIF impinges on the somatotrophs, as extra SRIF does not further lower basal secretion. However, during secretory bursts, very little SRIF must be present, as exogenous SRIF blocks these bursts. The bursts are similar in duration to overshoots provoked in perifused dispersed rat somatotrophs by removal of an SRIF signal. It seems likely that their cause in vivo is similar. (All values are means +/- SEM.)

Amino Acid Absorption following Intraperitoneal Administration in CAPD Patients

Six non-diabetic CAPD patients were infused over six hours with two litres of a dialysis solution containing 2 g/ dl amino acids (a mixture of essentials and non-essentials). The osmolality of the solution and the amount of ultrafiltration it induced were simiiar to that of a 4.25 g% dextrose Dianeal solution (control), suggesting that an amino acid solution is an efficient osmotic agent. By the end of the six-hour infusion, 80 to 90% of the amino acids present in the dialysis solution had been absorbed. One hour after the infusion was instituted, plasma amino acid levels increased threefold and subsequently decreased to near the initial value by the sixth hour. The amino acid solution was as effective as the dextrose solution in removing urea nitrogen, creatinine and potassium. Our data indicate that intraperitoneal administration of amino acids is effective and well-tolerated in patients on CAPD. We believe further work should be done to determine whether long-term administration of amino acids by this route will improve the nutritional status of these patients and prevent the side effects of daily absorption of large amounts of glucose.

Long-term Intravenous Drug Therapy

To the Editor.— Medications requiring daily intravenous (IV) administration for weeks or months present the difficult task of maintaining IV access while avoiding infectious, metabolic, and sociologic complications. At our institution, we have been using a new protocol for long-term IV therapy of systemic mycoses that has proved very successful. The method is as follows. Four patients have been treated for four to eight weeks with daily infusions of amphotericin B. Each day a new steel scalp-vein needle is inserted into a vein in an upper extremity. Immediately after completing a sixhour infusion, the needle is removed. For three fourths of each day, patients are free to ambulate, feed themselves, and bathe without hindrance. Despite daily therapy with a drug known to cause phlebitis, central venous catheters or cut-downs have not been required. Patients are not required to receive unnecessary IV fluids and electrolytes to keep the line open. Our system requires that

Degradation and clearance of methotrexate in children with osteosarcoma receiving high‐dose infusion

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.

Use of Plasma Pharmacokinetics to Predict and Prevent Methotrexate Toxicity

To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48 hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean +/- 2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10(-7) M. In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.