24-h Continuous Intravenous Infusion Research Articles

Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia.

To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient. A prospective study was developed in 50 children (1-15years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX. A two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model. The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.

Effects of low-molecular-weight heparin and unfractionated heparin on patients with exertional heat stroke with thrombocytopenia: A prospective study

Background: Thrombocytopenia often occurs in patients with exertional heat stroke (EHS). We aimed to investigate the effect of low-molecular-weight heparin sodium (LMWH) and unfractionated heparin (UFH) on coagulation and prognosis in the treatment of EHS with thrombocytopenia. Methods: In a prospective cohort study, 64 patients admitted to the emergent intensive care unit (ICU) were studied between July 2015 and October 2018. Patients were randomized to receive LMWH or UFH. Thirty-three patients were given LMWH 4000 IU twice a day for 5 days, by subcutaneous injection. Thirty-one patients were given UFH 5–10 U/kg × h for 5 days, by 24-h continuous intravenous infusion. Demographic and clinical data (platelets [PLTs] counts, activated partial thromboplastin time [aPTT], prothrombin time [PT], fibrinogen [FIB], D-dimer, presence of diffuse intravascular coagulation [DIC]), and mortality in the ICU were recorded along with the 28-day survival rate. The acute physiology and chronic health evaluation (APACHE) II score was calculated within 24 h of admission and used to indicate the severity of disease. Results: There were no significant differences in sex, age, APACHE II score, and core temperature between the two groups (P > 0.05). PLT and FIB were significantly increased after treatment in both groups (P 0.05), but the incidence of bleeding in the LMWH group was significantly lower than in the UFH group (P 0.05). Conclusions: The results of this study support that the efficacy of LMWH and UFH in the prevention of thrombosis is equivalent. However, the incidence of bleeding was lower in LMWH group. LMWH and UFH had statistically similar rates of ICU mortality, 28-day mortality, and incidence of DIC. Our results suggest that LMWH may be safer than UFH for use in patients with EHS with thrombocytopenia.

Superselective Intra-arterial Infusion Chemotherapy with Nedaplatin for Oral Cancer: A Pharmacological Study of the Dose Clearance.

Nedaplatin (cis-diammine-glycolate platinum) is a new anticancer agent developed in Japan. It is especially designed to reduce adverse side effects of CDDP such as renal toxicity and neurotoxicity. We used nedaplatin as a superselective intra-arterial infusion chemotherapy for oral cancers and carried out a pharmacological study of the dose clearance of nedaplatin based on renal function as well as evaluating its efficacy, including hematological side effects. Typical regimens of this chemotherapy consisted of 5-days straight of 24-h continuous intravenous infusion of 5-Fu with a single shot of nedaplatin via transfemoral artery on day 4. The dose of nedaplatin was calculated based on the 24-h creatine clearance. A total of 37 patients who had oral cancer and had received 68 courses (total) of chemotherapy were found to be eligible for this study. Total and free platinum concentrations in the plasma were measured at each of the time points, and the area under the curve (AUC, measured in units of µgh/ml) was calculated based on the platinum concentration with the following formula: CL (clearance of free platinum: l/h)=0.042×CCr (ml/min)+5.84. The response rate was 70.1% (in CR 51%, in PR 19%). Histological CR was seen in 28.6% of surgical specimens. Moderate hematological side effects were seen. However, severe adverse events were not observed, including those associated with cannulation of the femoral artery. The dose-clearance formula that was established by our study can most likely be utilized to accurately predict the optimal administered dose of nedaplatin for arterial infusion chemotherapy.

Effect of additional preoperative administration of the neutrophil elastase inhibitor sivelestat on perioperative inflammatory response after pediatric heart surgery with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) elicits a systemic inflammatory response. Our previous reports revealed that prophylactic sivelestat administration at CPB initiation suppresses the postoperative acute inflammatory response due to CPB in pediatric cardiac surgery. The purpose of this study was to compare the effects of sivelestat administration before CPB and at CPB initiation in patients undergoing pediatric open-heart surgery. Twenty consecutive patients weighing 5-10 kg and undergoing ventricular septal defect closure with CPB were divided into pre-CPB (n = 10) and control (n = 10) groups. Patients in the pre-CPB group received a 24 h continuous intravenous infusion of 0.2 mg/kg/h sivelestat starting at the induction of anesthesia and an additional 0.1 mg/100 mL during CPB priming. Patients in the control group received a 24-h continuous intravenous infusion of 0.2 mg/kg/h sivelestat starting at the commencement of CPB. Blood samples were tested. Clinical variables including blood loss, water balance, systemic vascular resistance index, and the ratio between partial pressure of oxygen and fraction of inspired oxygen (P/F ratio) were assessed. White blood cell count and neutrophil count as well as C-reactive protein levels were significantly lower in the pre-CPB group according to repeated two-way analysis of variance, whereas platelet count was significantly higher. During CPB, mixed venous oxygen saturation remained significantly higher and lactate levels lower in the pre-CPB group. Postoperative alanine aminotransferase and blood urea nitrogen levels were significantly lower in the pre-CPB group than in the control group. The P/F ratio was significantly higher in the pre-CPB group than in the control group. Fluid load requirement was significantly lower in the pre-CPB group.Administration of sivelestat before CPB initiation is more effective than administration at initiation for the suppression of inflammatory responses due to CPB in pediatric open-heart surgery, with this effect being confirmed by clinical evidence.

A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors

To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent. In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg. Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses. When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.

Preclinical toxicity and toxicokinetics of GTI-2040, a phosphorothioate oligonucleotide targeting ribonucleotide reductase R2

GTI-2040, a 20-mer phosphorothioate oligonucleotide, was designed to hybridize to the mRNA sequence of human ribonucleotide reductase R2. GTI-2040 has been shown to inhibit human cancer cell proliferation by downregulation of R2 expression in vitro and to significantly inhibit tumor growth in xenograft models of human cancer in mice. As part of the safety evaluation for human clinical trials, the toxicity and toxicokinetics of GTI-2040 were determined in Sprague-Dawley rats and rhesus monkeys. GTI-2040 was administered to rats at 2, 10, and 50mg/kg/day by bolus intravenous injection every second day for 21days with a 21-day recovery. In monkeys, an acute study was performed with single, escalating doses of GTI-2040 ranging from 10 to 80mg/kg given as a 24-h continuous intravenous infusion. As well, a 21-day, continuous intravenous infusion study with GTI-2040 was conducted in monkeys at 2, 10, and 50mg/kg/day, with a 3-week recovery. Blood sampling was done to measure GTI-2040 plasma concentrations, metabolites, and pharmacokinetic parameters, and tissues were collected to assess the distribution of GTI-2040 and/or metabolites. The toxicities of GTI-2040 in both rats and monkeys were typical for the phosphorothioate oligonucleotide class of compounds. In monkeys, there was a dose-related increase in GTI-2040 plasma levels with concomitant increase in complement activation and prolongation of activated partial thromboplastin time. In both rats and monkeys, the tissues having the highest concentrations of GTI-2040 (kidney, liver, spleen) had the largest dose-related toxic effects. Adverse effects were diminished or absent in the recovery animals. GTI-2040 was well tolerated when infused over 24h at doses up to 80mg/kg in monkeys. In rats and monkeys, GTI-2040 was reasonably well tolerated and showed reversible toxicities when administered at doses up to 50mg/kg/day for 21days. The no observed adverse effect dose level for GTI-2040 in both animal species was 2mg/kg/day. There were no apparent sequence-specific effects related to the interaction of GTI-2040 with the R2 component of the mRNA expressing ribonucleotide reductase.

Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457. MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria. A 100-mg oral dose was administered to seven patients 48 h prior to the CIV infusion dose of 64 mg/m(2)/h. Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m(2)/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m(2)/h. The most common adverse events were nausea, vomiting, diarrhea, and fatigue. Pharmacokinetic analyses revealed that CIV infusion MK-0457 had an estimated mean terminal half-life of approximately 6.6-10.2 h and that end-of-infusion concentrations and mean AUCs were approximately dose proportional. The estimated mean oral bioavailability of MK-0457 was 7.9%. One patient with advanced ovarian cancer attained prolonged stable disease for 11 months. MK-0457 was well tolerated in this schedule. Almost half the patients attained stable disease. Further development of this class of agents will likely occur in combination with other anti-cancer treatments.

Effectiveness of preoperative concurrent chemoradiation therapy (CCRT) for locally advanced adenocarcinoma of cervix

Aim To determine the efficacy of preoperative concurrent chemoradiation therapy (CCRT) to improve the prognosis of locally advanced adenocarcinoma of the uterine cervix. Methods Twenty-five patients with clinical stage IB2–IVB adenocarcinoma of the cervix were received preoperative CCRT. The CCRT protocol included: external radiotherapy to the pelvis: 39.6 Gy; intra-arterial or intravenous infusion of 70 mg/m 2 cisplatin, days 1 and 22; 24-h continuous intravenous infusion of 700 mg/m 2 5-FU, days 1–4 and 22–25. Two weeks after the end of CCRT, patients underwent restaging followed by appropriate surgery with pelvic lymphadenectomy. Results The overall clinical response rate was 96% (24/25), with a complete response (CR) in 12/25 patients and partial response (PR) in 12/25. On pathological examination, 5 of 19 patients (26%) undergoing surgery showed a pathological CR, 13 patients showed a PR, and 1 patient no change (NC) in their disease. Grade 3 or 4 hematological toxicity was observed in 15 patients. Grade 3 gastrointestinal toxicity was observed in 8 patients. The median follow-up period was 34 months (range, 6–69). The 5-year overall survival (OS) rate was 84%, and the progression-free survival (PFS) rate was 76%. Conclusions Preoperative CCRT improves the survival of patients with locally advanced adenocarcinoma of the cervix, with manageable toxicities.

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer. Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m(2), respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m(2) to the MTD. A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m(2). All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3-4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6-46%). This rate increased to 39% (95% CI: 12-66%) in 13 chemotherapy-naïve patients. A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m(2) of docetaxel, 30 mg/m(2) of cisplatin and 1,500 mg/m(2) of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.

A phase II study of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin (IFLUX) for advanced, previously untreated colorectal cancer

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m with a combination of 120 mg/kg floxuridine and 500 mg/m leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest. Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.

Aluminum load in ICU patients during stress ulcer prophylaxis

Background Accumulating evidence has linked high aluminum (Al) levels with toxicity and disease. Our objective was to evaluate the Al exposure of ICU patients receiving stress ulcer prophylaxis with sucralfate and ranitidine. Methods Within a large prospective, randomized study, a subgroup of 30 critically ill, renally intact patients on prolonged mechanical ventilation who were being treated in intensive care units (ICU) of a university hospital were allocated to two prophylaxis subgroups: enteral sucralfate, 1 g six times daily by gastric tube (n = 15), or intravenous ranitidine, 200 mg daily by 24-h continuous intravenous infusion (n = 15). The Al content of large and small-volume parenterals was measured and Al intake calculated for each patient and day. Aluminum levels in serum and 24-h urine were monitored every 2 days during the 16-day observation period (days 0–15). Results Mean daily parenteral Al exposure ranged from 101.3 to 158.7 μg/day for sucralfate and ranitidine patients, respectively. In both groups, Al serum levels increased from baseline on days 1–13 and on days 3–7 in the sucralfate and ranitidine groups, respectively. From days 3–13, Al serum levels were significantly higher with sucralfate than with ranitidine ( P < 0.05). On days 7–13, 24-h urinary Al excretion was also significantly higher in the sucralfate than in the ranitidine group ( P < 0.05). Conclusion In ICU patients, only approximately 50% of parenterally administered Al is eliminated renally. Sucralfate additionally increases patients exposure to Al. In ICU patients, the mean absorption of enteral Al from sucralfate is only 0.019%.

Phase II trial of nolatrexed dihydrochloride [ThymitaqTM, AG 337] in patients with advanced hepatocellular carcinoma

To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma. Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced > or = grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method. Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1-12). The mean dose intensity was 700 mg/m(2)/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22-37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (C (max)) was 14.20 microg/mL (range 1.41 to 119 microg /mL) with no accumulation observed between cycles 1-6. This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.

A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer

Yondelis® (trabectedin, ET-743) is a novel marine-derived anticancer compound found in the ascidian Ecteinascidia turbinata. It is currently under phase II/III development in breast cancer, hormone refractory prostate cancer, sarcomas and ovarian cancer. Activity in breast cancer experimental models has been reported, and preliminary evidence of activity in this setting during the phase I programme has also been observed. The present study assessed the activity and feasibility of trabectedin in women with advanced breast cancer previously treated with conventional therapies. Patients with advanced disease previously treated with at least one but not more than two regimens that included taxanes or anthracyclines as palliative therapy were eligible. Trabectedin 1.5 mg m−2 was administered as a 24-h continuous infusion every 3 weeks. Patients were kept on therapy until disease progression, unacceptable toxicity or patient refusal. Twenty-seven patients were included between April 1999 and September 2000. Their median age was 54 years (range: 36–67) and 63% of them had two metastatic sites. Twenty-two patients were performance status 1. All patients had previously received anthracyclines, and 23 out of 27 patients had received taxanes. Of 21 patients with measurable disease, three confirmed partial responses, one unconfirmed partial response and two minor responses (49 and 32% tumour shrinkage) were observed; six patients had stable disease. Median survival was 10 months (95% confidence interval: 4.88–15.18). Transient and noncumulative transaminitis was observed in most of the patients. The pharmacokinetic profile of trabectedin in this patient's population is in line with the overall data available with this schedule. The policy of dose adjustments based on the intercycle peaks of bilirubin and alkaline phosphatase appears to have a positive impact in the therapeutic index of trabectedin. Trabectedin can induce response and tumour control in previously treated advanced breast cancer, with manageable toxicity, thus warranting further development as a single agent or in combination regimens.

A phase II study of ET-743/trabectedin (`Yondelis') for patients with advanced gastrointestinal stromal tumours

Primary or secondary resistance to imatinib may occur in patients with gastrointestinal stromal tumours (GISTs) while these tumours have repeatedly been shown to be highly resistant to conventional doxorubicin- and ifosfamide-containing regimens. The investigation of new drugs is therefore warranted in GIST. A phase II study was conducted between May 1999 and November 2000 in eight centres of the EORTC STBSG group to establish the efficacy and safety of ET743 (`Yondelis') in GIST previously untreated with cytotoxic chemotherapy before the imatinib era. ET-743 was given was given at 1.5 mg/m 2 per course as a 24-h continuous intravenous infusion every 3 weeks. Twenty-eight patients were included, 16 males and 12 females. Median age was 54 years (range 25–73 years). Median performance status was 0 (range 0–1). 17 (63%), 4 (12%) and 7 (25%) patients, received 0–2, 3–5, and ⩾6 courses of ET-743, respectively. The best response was stable disease in 9 (33%) patients, and disease progression in 18 patients (67%), with a median time to disease progression and overall survival of 51 days and 589 days, respectively. The treatment was well tolerated: there were grades 3–4 neutropenia, thrombocytopenia, and transaminase increases in 13 (48%), 1 (4%) and 16 (59%) patients, respectively. There were no toxic deaths. ET-743 at this dose and schedule is not an effective treatment for advanced GIST.

L-Arginine supplementation in pigs decreases liver protein turnover and increases hindquarter protein turnover both during and after endotoxemia

Accumulating evidence suggests that L-arginine, under conditions of septicemia, not only enhances immune function but also improves protein metabolism. Because the effect of L-arginine administration on the protein metabolism of different organs is unknown, the aim of the study was to elucidate the effects of exogenous supplementation of L-arginine during endotoxemia on the in vivo protein metabolism of individual organs and at the whole-body level. Female pigs were cannulated with catheters in the aorta and the splenic, caval, portal, hepatic, and renal veins, enabling measurements across the hindquarter, portal-drained viscera, liver, and kidneys. Endotoxemia was induced by a 24-h continuous intravenous infusion of endotoxin (3 microg x kg body wt(-1) x h(-1)). At 8 h, an intravenous infusion of L-arginine was started (n = 8). Control pigs (n = 6) received L-alanine. At 24 h, blood was sampled. After cessation of the endotoxin infusion, L-arginine and L-alanine infusions were continued as a supplement in the enterally infused diet. At 48 h, blood samples were obtained during the postendotoxemic and nutritionally supported conditions. Stable isotopes were used to assess protein metabolism and phenylalanine hydroxylation. Both during and after the endotoxin challenge, L-arginine administration enhanced protein synthesis and degradation across the hindquarter and simultaneously reduced protein synthesis and degradation in the liver at equal rates. Protein turnover across the kidneys and portal-drained viscera remained unaffected. After endotoxemia, L-arginine infusion decreased whole-body protein turnover without affecting the net protein balance. L-Arginine administration affects protein turnover of the muscle area and the liver oppositely.

Rates of Urea Production and Hydrolysis and Leucine Oxidation Change Linearly over Widely Varying Protein Intakes in Healthy Adults

The quantitative relationships between nitrogen (N) intake, urea production, excretion and amino acid oxidation are currently a matter of debate. Some investigators have proposed that urea production is essentially constant over a wide range of N intakes and that urea hydrolysis is regulated according to the N needs of the organism. We have assessed this proposal by compiling results from four separate experiments in healthy young adults (n = 34) carried out in our laboratories and all at the end of the respective diet periods using an identical 24-h continuous intravenous infusion of [(15)N, (15)N]urea and L-[1-(13)C]leucine. The N intakes were: expt. 1; protein-free diet for 5 d; expt. 2; N at 44 mg N. kg(-1). d(-1) from a balanced L-amino acid mixture for 13 d; expt. 3; N at 161 mg. kg(-1). d(-1) from egg protein for 6 d; expt. 4 -one group received 157 mg. kg(-1). d(-1) and the other 392 mg. kg(-1). d(-1) from milk-protein-based diets for 6 d. Urea production and excretion were linearly correlated with N intake (r = 0.98 and 0.94, respectively; P < 0.01). Urea hydrolysis increased linearly with N intake (r = 0.7; P < 0.05), with considerable variation in the rate among individuals, especially at the N intake of approximately 160 mg N. kg(-1)d(-1). These findings are consistent with the generally accepted view that a control of body N balance is via a regulation of urea production. They do not support the concept that urea hydrolysis is the more important site in the control of body N loss.

Effect of protein intake and physical activity on 24-h pattern and rate of macronutrient utilization.

Effects of moderate physical activity (90 min at 45-50% of maximal O2 uptake 2 times daily) and "high" (2.5 g protein. kg-1. day-1, n = 6) or "normal" protein intake (1.0 g protein. kg-1. day-1, n = 8) on the pattern and rate of 24-h macronutrient utilization in healthy adult men were compared after a diet-exercise-adjustment period of 6 days. Energy turnover (ET) was determined by indirect and direct (suit) calorimetry, and "protein oxidation" was determined by a 24-h continuous intravenous infusion of [1-13C]leucine. Subjects were in slight positive energy balance during both studies. Protein contributed to a higher (22 vs. 10%) and carbohydrate (CHO) a lower (33 vs. 58%) proportion of total 24-h ET on the high- vs. normal-protein intake. The highest contribution of fat to ET was seen postexercise during fasting (73 and 61% of ET for high and normal, respectively). With the high-protein diet the subjects were in a positive protein (P < 0.001) and CHO balance (P < 0.05) and a negative fat balance (P < 0.05). The increased ET postexercise was not explained by increased rates of urea production and/or protein synthesis.

The 24-h pattern and rate of leucine oxidation, with particular reference to tracer estimates of leucine requirements in healthy adults

Daily leucine oxidation and derived values for whole-body leucine balance, obtained by continuous measurement throughout a 24-h period, were compared with those predicted from short-term measurements during fasted and fed states in five healthy adults studied during two 6-d experimental diet periods, each immediately followed by a 24-h continuous intravenous tracer infusion of L-[1-13C]leucine. Leucine intake was either 14 or 38.3 mg.kg-1.d-1. Mean measured daily leucine oxidation (mg leucine.kg-1.d-1) was 27.8 and 45.2 for the 14- and 38.3-mg intakes, respectively. Oxidation rates predicted by extrapolation of rates measured during the final hour of fasting (15 h after last meal) and the 5th h of feeding were approximately 12% higher (P < 0.01) than measured rates for both diets. For the prediction based on the 12th h of fasting and 5th h of feeding, it was 4% higher or 0.4% lower than measured rates for the 38.3- and 14- mg intakes, respectively. Hence, relatively small differences exist between measured vs predicted estimates of daily leucine oxidation and balance. These studies support previous conclusions that the current, international requirement value for leucine in healthy adults is far too low.

Phase II Trial of Recombinant DNA ?? -Interferon in Advanced Colorectal Cancer: A Southwest Oncology Group Study

Fifty evaluable patients with advanced colorectal cancer, but without prior chemotherapy or immunotherapy, were randomized to one of two schedules of recombinant gamma-interferon (rGIFN). Twenty-four evaluable patients received rGIFN as a 2-h intravenous infusion daily x 5 every other week at a starting dose of 4.0 x 10(6) IU/m2/day (arm I). Twenty-six evaluable patients received rGIFN as a 24-h continuous intravenous infusion daily x 5 every month at a starting dose of 2.6 x 10(6) IU/m2/day (arm II). Toxicities on both schedules included flu-like symptoms, fevers/rigors, nausea/vomiting, hypotension, leukopenia, hepatotoxicity, nephrotoxicity, diarrhea, anemia, confusion, and ileus. Toxicity appeared to be more severe on arm I. No antitumor responses were observed, with 95% confidence intervals of 0 to 14% for arm I and 0 to 13% for arm II.

Interleukin-2 Lymphokine-Activated Killer Cell Therapy of Non-Hodgkinʼs Lymphoma and Hodgkinʼs Disease

We conducted a phase II study utilizing interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells as therapy for non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). IL-2 was given at a fixed dose of 3 x 10(6) U/m2/day administered as a 24-h continuous intravenous infusion with LAK cells. Nineteen extensively treated patients were entered and 15 were evaluable. In general, this regimen was reasonably well tolerated with mild toxicities that were rapidly reversible. Patients who completed therapy did so without dose attenuations. However, discontinuation of therapy was necessary in four patients due to atypical toxicities that were not clearly dose related. Two patients (one NHL and one HD) had partial remissions of brief duration, four had disease stabilization, and seven had progressive disease. While there were not sufficient numbers to evaluate critically any NHL or HD subtype, this regimen does not appear to have significant activity for either disease.