Comparison of native E. coli and PEG asparaginase pharmacokinetics and pharmacodynamics in pediatric acute lymphoblastic leukemia.

Asparaginase (ASP) is used routinely in frontline clinical trials for the treatment of childhood acute lymphoblastic leukemia (ALL). The goals of this study were to assess the pharmacokinetics and pharmacodynamics of ASP and to mathematically model the dynamics between ASP and asparagine (ASN) in relapsed ALL. Forty children were randomized to receive either native or polyethylene glycolated (PEG) Escherichia coli ASP during reinduction therapy. Serial plasma ASP and ASN, cerebrospinal fluid (CSF) ASN, and serum anti-ASP antibody samples were collected. The ASP clearance was higher (P = 0.001) for native vs. PEG ASP. Patients with antibodies to PEG ASP had faster PEG ASP clearance (P = 0.004) than did antibody-negative patients. Patients who were positive for antibodies had higher CSF ASN concentrations than did those who were negative (P = 0.04). The modeling suggests that by modifying dosages, comparable ASN depletion is achievable with both preparations. At relapse, there were significant pharmacokinetic and pharmacodynamic differences attributable to ASP preparation and antibody status.

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia.

Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (+/-s.d.) CSF asparagine (0.29+/-0.63, n=9) than those who received PEG (0.77+/-0.82, n=4) (P=0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients.

To evaluate how well antibodies to one asparaginase preparation predict or correlate with antibodies to another preparation in acute lymphoblastic leukemia (ALL) and lymphoma patients who did and did not have hypersensitivity reactions during chemotherapy. In all, 24 children with newly diagnosed ALL or lymphoma, who received Escherichia coli asparaginase 10 000 IU/m(2) IM thrice weekly for nine doses as part of multiagent induction and reinduction chemotherapy, and seven monthly doses during the first 7 months of continuation treatment, were studied. Plasma samples were collected at postinduction and at postreinduction. Six of 24 patients had no overt clinical reactions (nonreacting) and received only the E. coli preparation. Of these, 18 patients who had allergic reactions were switched to Erwinia asparaginase. A total of 18 patients had an anaphylactoid reaction to Erwinia asparaginase and were switched to receive polyethylene glycol (PEG) asparaginase. Antibody levels were measured by enzyme-linked immunoadsorbent assay against all the three asparaginase preparations. At postinduction, antibodies against E. coli were higher in reacting patients (0.063+/-0.066) than in nonreacting patients (0.019+/-0.013) (P=0.03). At postreinduction, anti-Erwinia antibodies were significantly higher in reacting patients (0.431+/-0.727) than in nonreacting patients (0.018+/-0.009) (P=0.007). Anti-E. coli antibodies correlated with anti-PEG antibodies at postinduction (r=0.714, P<0.001) and at postreinduction (r=0.914, P<0.001), but did not correlate with anti-Erwinia antibodies at postinduction (r=0.119, P=0.580) and at postreinduction (r=0.078, P=0.716). The results indicate a crossreactivity between patient antibodies raised against natural E. coli and PEG asparaginase but not Erwinia asparaginase.

Effect of pentoxifylline on nitrogen balance and 3-methylhistidine excretion in parenterally fed endotoxemic rats.

Pentoxifylline interrupts early gene activation for tumor necrosis factor, interleukin-1, and interleukin-6 production and improves survival from experimental sepsis. These effects can alter nitrogen loss during critical illness. To determine the dose-dependent influence of pentoxifylline on nitrogen loss, 44 male Sprague-Dawley rats (220 to 265 g) were randomized to receive parenteral nutrition only (PN), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide (LPS) at 9 mg x kg(-1) x d(-1), or PN plus LPS plus a continuous infusion of pentoxifylline at either 25 (PEN25) or 100 mg x kg(-1) x d(-1) (PEN100) for 48 h. Before randomization, all animals underwent intravenous cannulation and 40 h of PN adaptation. All animals received isocaloric, isonitrogenous PN (160 kcal x kg(-1) x d(-1) and 1.0 gN x kg(-1) x d(-1)) and were kept nil per os except for water ad libitum. Administration of LPS significantly worsened nitrogen balance for all three groups compared with PN control; however, pentoxifylline only modestly improved nitrogen balance compared with LPS (206 +/- 255, -497 +/- 331, -332 +/- 329, and -310 +/- 383 mg/48hr for the PN, LPS, PEN25, and PEN100 groups, respectively; P < 0.001). Pentoxifylline did not significantly change 3-methylhistidine urinary excretion compared with LPS (573 +/- 180, 705 +/- 156, 780 +/- 326, and 683 +/- 266 microg/48 h for the PN, LPS, PEN25, and PEN100 groups, respectively, P not significant). Pentoxifylline, given in therapeutic doses after an endotoxin challenge, modestly, but not significantly, improved nitrogen balance. Urinary 3-methylhistidine excretion was not influenced by pentoxifylline. A dose-dependent effect by pentoxifylline on these markers was not evident.

Pharmacokinetics of naratriptan in adolescent subjects with a history of migraine.

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.

Sequential group trial to determine gastrointestinal site of absorption and systemic exposure of azathioprine.

Azathioprine (AZA) is used in the treatment of patients with refractory inflammatory bowel disease; however, its use is limited because of systemic toxicity associated with long-term use. Ileocecal delivery of AZA might be advantageous if local intestinal therapeutic effects could be provided with decreased systemic side effects. Decreased cecal systemic absorption would allow higher dosages of AZA to be administered. A two-phase study was performed to compare the systemic exposure of AZA and 6-mercaptopurine (6-MP) following administration of AZA into the stomach, jejunum, and cecum and to compare the systemic exposure to AZA and 6-MP following administration of three different dosages of AZA into the cecum. In phase I, six healthy male volunteers received three 50 mg sequential doses of AZA via an oral tube directly placed into the stomach, jejunum, and cecum, respectively. In phase II, six healthy male volunteers received three different dosages (50, 300, 600 mg of AZA) into the cecum. Plasma concentrations of AZA and 6-MP at various times were quantified and area under the plasma concentration-time curve (AUC) and mean residence time (MRT) were determined. No significant differences in the AUC of AZA were seen at the different sites. The AUC of 6-MP following administration of AZA into the jejunum (67.0 +/- 30.1 ng x hr/ml) was higher compared to the stomach (39.9 +/- 38.1 ng/hr/ml) and cecum (29.2 +/- 10.9 ng x hr/ml). Jejunal absorption was 68% higher than absorption from the stomach and 129% higher than that of the cecum. Gastric absorption was 27% higher than that of the cecum. Increased dosages given into the cecum resulted in increased AUCs of AZA and 6-MP. The AUCs of AZA following 50, 300, and 600 mg dosages were 16.9 +/- 7.4, 52.3 +/- 67.2, and 132 +/- 151 ng x hr/ml, respectively, and the AUCs of 6-MP were 22.2 +/- 14.9, 63.4 +/- 50.6, and 104 +/- 115 ng x hr/ml, respectively. Systemic exposure to 6-MP is reduced following administration of AZA into the cecum, most likely secondary to reduced absorption of 6-MP from the colon. Higher dosages of AZA presented to the cecum do result in increased systemic absorption, but may still allow more drug to be administered with less toxicity than the same dose received orally.

ELISA to evaluate plasma anti-asparaginase IgG concentrations in patients with acute lymphoblastic leukemia.

The development of antibodies to asparaginase may attenuate the pharmacologic effect of asparaginase treatment, may be associated with hypersensitivity reactions, and may necessitate switching to a different commercial asparaginase preparation for current or future therapy. Thus, development of an ELISA for measurement of anti-asparaginase antibody levels is important in the clinical setting. An anti-asparaginase antibody reference was established by screening 65 plasma samples from six patients with acute lymphoblastic leukemia (ALL) who had recently developed a hypersensitivity reaction to Escherichia coli or Erwinia chrysanthemi asparaginase therapy. Twenty-one plasma samples were selected for the anti-asparaginase antibody reference pool. Five micrograms per milliliter of commercial E. coli and Erwinia asparaginase and 10 microg/ml of E. coli asparaginase conjugated with polyethylene glycol (PEG asparaginase) were found to be optimal as coating antigen concentrations. Anti-asparaginase antibody concentrations were determined using a commercial polyclonal goat anti-human IgG horseradish peroxidase conjugate. The antibody reference curves were linear in a range of absorbance from 0.1 to 1. 5 O.D. units for dilutions from 1:1600 to 1:51,200. Inter-assay coefficients of variation were 9.04, 14.7 and 13.0%, and intra-assay coefficients of variation were 1.44, 4.43 and 3.28% for antibodies against E. coli, Erwinia, and PEG L-asparaginase, respectively. The cut-off for positivity in plasma was determined as mean+2 S.D. of the optical density values for plasma from untreated healthy volunteers. Measurement of specific IgG by this ELISA allows for the evaluation of plasma anti-asparaginase antibody concentrations in patients receiving one or more of the multiple commercial L-asparaginase preparations.

Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia.

PURPOSE: Development of antibodies and hypersensitivity to asparaginase are common and may attenuate asparaginase effect. Our aim was to determine the relationship between antiasparaginase antibodies or hypersensitivity reactions and event-free survival (EFS). PATIENTS AND METHODS: One hundred fifty-four children with acute lymphoblastic leukemia received Escherichia coli asparaginase 10,000 IU/m(2) intramuscularly three times weekly for nine doses during multiagent induction and reinduction phases and for seven monthly doses during continuation treatment. Erwinia asparaginase was used in case of clinical hypersensitivity to E coli but not for subclinical development of antibodies. Plasma antiasparaginase antibody concentrations were measured on day 29 of induction in 152 patients. RESULTS: Antibodies were detectable in 54 patients (35.5%), of whom 30 (55.6%) exhibited hypersensitivity to asparaginase. Of the 98 patients who had no detectable antibodies, 18 (18.4%) had allergic reactions. Patients with antibodies were more likely to have a reaction than those without antibodies (P <.001). Among the 50 patients who experienced allergic reactions (including two for whom antibodies were not measured), 36 (72.0%) were subsequently given Erwinia asparaginase; seven (19.4%) reacted to this preparation. EFS did not differ among patients who did and did not have antibodies (P =.54), with 4-year EFS (+/- 1 SE) of 83% +/- 6% and 76% +/- 5%, respectively. Similarly, EFS did not differ among patients who did and did not develop allergic reactions (P =.68), with 4-year estimates of 82% +/- 6% and 78% +/- 5%, respectively. CONCLUSION: In this setting, in which most patients with allergy were switched to another preparation, there was no adverse prognostic impact of clinical or subclinical allergy to asparaginase.

Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia.

PURPOSE: The CNS is an important sanctuary site in childhood acute lymphoblastic leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic pharmacodynamics. We evaluated the time course of CSF asparagine depletion in children with ALL during and after a course of Escherichia coli asparaginase. PATIENTS AND METHODS: Thirty-one children (24 newly diagnosed and seven at relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for six and nine doses, respectively, as part of multiagent induction chemotherapy. CSF asparagine levels were measured before, during, and after asparaginase dosing. RESULTS: The percentage of patients with undetectable (< 0.04 micromol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9% (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8% (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21) more than 30 days after asparaginase therapy. The proportion of patients with depleted CSF asparagine was higher during asparaginase therapy than at baseline (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase therapy (P < .001). Median CSF asparagine concentrations were 4.42 micromol/L before, less than 0.04 micromol/L during, and less than 0.04 micromol/L at 1 to 5 days, 1.63 micromol/L at 6 to 10 days, 1.70 micromol/L at 11 to 30 days, and 5.70 micromol/L at more than 30 days after asparaginase therapy, respectively. CSF depletion was more common in patients with low baseline CSF asparagine concentrations (P = .003). CONCLUSION: CSF asparagine concentrations are depleted by conventional doses of E coli asparaginase in the majority of patients, but they rebound once asparaginase therapy is completed.

Measured energy expenditure of tube-fed patients with severe neurodevelopmental disabilities.

OBJECTIVE: To determine measured resting energy expenditure (REE) of nonambulatory tube-fed patients with severe neurological neurodevelopmental disabilities. METHODS: Twenty patients were prospectively studied. Only steady state indirect calorimetry measurements were taken. All measurements were conducted using a canopy system. Nutritional needs were met entirely by enteral feedings via a permanent ostomy. RESULTS: REE was widely distributed from 16 kcals/kg/day to 39 kcals/kg/day. The mean REE (888+/-176 kcals/day) of the patients was significantly (p<0.01) lower than predicted as estimated by the Harris-Benedict equations (1081+/-155 kcals/day) and World Health Organization equations (1194+/-167 kcals/day). Fat-free mass (FFM) was the best parameter for predicting REE. Two predictive equations were developed that are not significantly biased and more precise (< or =15% error) than conventional predictive formulas. CONCLUSION: Conventional formulas for estimating energy expenditure are inaccurate and generally overestimate measured energy expenditure of nonambulatory patients with severe developmental disabilities.

Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia.

Asparaginase is an effective antileukemic agent and is included in most front-line protocols for pediatric acute lymphoblastic leukemia (ALL) worldwide; however, allergic reactions to asparaginase may be dose-limiting. We evaluated plasma anti-asparaginase antibody concentrations in a cohort of children with newly diagnosed ALL, who did and who did not exhibit clinical hypersensitivity, after Escherichia coli (E. coli) asparaginase therapy. Thirty-five children who received asparaginase 10000 IU/m2 i.m. three times weekly for nine doses as part of both multiagent induction and reinduction chemotherapy, and seven monthly doses during the first 7 months of continuation treatment, were studied. Twenty-two patients experienced initial allergic reactions to asparaginase during continuation (n=20) or reinduction (n=2) phases and 13 children did not exhibit any reaction. An enzyme-linked immunosorbent assay (ELISA) was used to measure anti-asparaginase antibodies in plasma samples, diluted 1:3200, using E. coli asparaginase as the antigen. The median anti-asparaginase antibody concentration (OD at 1:3200 dilution) increased from 0.039 at induction to 0.506 at reinduction in patients who exhibited clinical hypersensitivity (P = 0.0002). By comparison, median antibody level increased from 0.011 to 0.032 OD at identical time points in patients who did not react to asparaginase (P = 0.02). Both post-induction and post-reinduction anti-asparaginase antibody levels were higher in reacting than in nonreacting patients (P = 0.004 and P = 0.01, respectively). Antibody levels were inversely related to the time elapsed between the reaction and sampling (P = 0.011). Although anti-asparaginase antibody levels increased from the post-induction plasma sample to the post-reinduction sample in 28 of 35 patients regardless of whether they exhibited clinical hypersensitivity, patients with hypersensitivity reactions had higher antibody levels than did identically treated control patients at comparable time points in therapy. Therefore, antibody analysis may be of clinical value in predicting future hypersensitivity.

Alterations in N-acetylation of 3-methylhistidine in endotoxemic parenterally fed rats.

N-methylhistidine (3-meH) is endogenously released during muscle catabolism and serves as a marker of protein turnover. In rats > 85% of 3-meH is excreted in the urine as the N-acetyl derivative. It has been reported that the percent of non-acetylated 3-meH (NA-3-meH) varies minimally with stress. To further evaluate these reports we randomized 39 male Sprague-Dawley rats (157-213 g) to receive parenteral nutrition only (PN) or PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 (LPS-6) or 12 (LPS-12) mg.kg-1.d-1 for 48 h. All animals received isocaloric and isonitrogenous PN 24 h before and throughout the study with water ad libitum. Total 3-meH excretion was significantly increased (P < 0.05) in the LPS-6 (470 +/- 136 micrograms/48 h) and LPS-12 (557 +/- 171 micrograms/48 h) groups versus the PN (331 +/- 126 micrograms/48 h) group. NA-3-meH differed significantly between the LPS-12 (218 /+- 89 micrograms/48 h, LPS-6 (94 +/- 48 micrograms/48 h), and PN (39 +/- 12 micrograms/48 h) groups (P < 0.05). Percent NA-3-meH increased significantly from 12.7 +/- 3.9% in the PN group to 19.8 +/- 8.0 and 39.9 +/- 12.8% in the LPS-6 and LPS-12 groups, respectively (P < 0.05). No significant changes in acetyl 3-meH were found between groups. These data suggest that either saturation or inhibition of acetylation pathways occurs with increasing levels of stress. Due to the disproportionate increases in NA-3-meH and percent NA-3-meH during endotoxemia, only total 3-meH should be used as an indicator of protein turnover in rats.

Effect of sustained endotoxemia on alpha1-adrenergic responsiveness in parenterally fed rats.

We investigated the effect of endotoxemia on alpha1-adrenergic receptor-mediated smooth muscle contraction as measured by mean arterial pressure (MAP) in response to incremental doses of a vasopressor. Twelve male Sprague-Dawley rats were randomized to receive parenteral nutrition alone (PN) or in combination with a continuous infusion of endotoxin (PN-LPS) for 48 hours. Incremental doses of phenylephrine were given and peak MAP response was recorded. The endotoxin group had a decreased rise in MAP with the same dose of phenylephrine compared with the control group (59 +/- 14 and 99 +/- 12 mm Hg, respectively, p<0.001). However, the baseline MAP was higher in the endotoxin group (102 +/- 18 and 71 +/- 7 mm Hg, respectively, p<0.002). The overall maximum effect was the same for both groups (161 +/- 16 and 170 +/- 8 mm Hg, respectively, p=NS). These data indicate that sustained endotoxemia does not result in desensitization of alpha1-adrenergic responsiveness. Other mechanisms are responsible for the ineffectiveness of vasopressors during advanced sepsis.

The effect of alpha-adrenergic antagonism upon nitrogen loss during endotoxemia.

Sixty male Sprague-Dawley rats were randomized to receive parenteral nutrition (PN) only; PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide (PN + LPS) at 6 mg.kg-1.d-1; or PN plus LPS plus a continuous infusion of the alpha-adrenergic antagonist phentolamine (PN + LPS + PHEN) at 5 mg.kg-1.d-1 or 20 mg.kg-1.d-1 for 48 h. All animals received isocaloric, isonitrogenous PN. LPS significantly lowered nitrogen balance (mmol/48 h) from PN control; however, addition of PHEN substantially worsened nitrogen balance compared with LPS (14.2 +/- 3, 2.4 +/- 5.2, -1.6 +/- 4.5, -0.8 +/- 5.4, for the PN, PN + LPS, PN + LPS + PHEN5 and PN + LPS + PHEN20 groups, respectively; P < 0.0001). Urinary 3-methylhistidine/creatinine ratio (3-meH/creat) paralleled the nitrogen balance data (0.30 +/- 0.09, 0.45 +/- 0.12, 0.51 +/- 0.14, 0.60 +/- 0.12, respectively; P < 0.0001). The high-dose PHEN resulted in 82 +/- 9% blockade. To ascertain if any beneficial effect upon body protein loss is achieved during severe stress, 30 rats were given PN + LPS at 12 mg.kg-1.d-1 or PN + LPS12 + PHEN20. These data showed similar changes in nitrogen balance and 3-methylhistidine/creatinine with the use of PHEN during severe endotoxemia. alpha-adrenergic antagonism with PHEN worsens body protein loss as measured by nitrogen balance and 3-methylhistidine/creatinine in PN-fed endotoxemic rats.

Recovery from ischemic acute renal failure is improved with enteral compared with parenteral nutrition.

OBJECTIVE: To compare measurements of renal function after acute ischemic renal failure in rats fed enterally or parenterally. DESIGN: Prospective, randomized, animal trial. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats (n = 21). INTERVENTIONS: Animals were randomized to receive isocaloric (160 nonprotein kcal/kg/day), or isonitrogenous (1.4 g of nitrogen/kg/day [100 mmol/kg/day]) enteral (n = 10), or parenteral nutrition (n = 11) through either a gastrostomy tube or a catheter placed in the jugular vein. After the animals received 7 days of assigned feedings, baseline blood samples were collected. A right nephrectomy and 45-min left renal pedicle occlusion were then performed. One hour after the ischemic injury, assigned feedings were resumed and continued for 3 days. After ischemic injury, daily blood samples were obtained and 24-hr urine collections were performed. On day 11, animals were killed and the kidney was harvested and fixed for subsequent microscopic examination. MEASUREMENTS AND MAIN RESULTS: Urine was analyzed for concentrations of total urea nitrogen, creatinine, protein, and calcium. Serum was analyzed for creatinine and urea nitrogen concentrations. Fixed kidney sections were examined for mitotic figures, tubular calcifications, and casts using light microscopy by an investigator blinded to the nutritional regimen. Data are presented as mean +/- SD or median (range). Percent increase in creatinine clearance from the nadir on day 9 to day 11 was approximately 2.5-fold greater in the enteral compared with the parenteral nutrition group (490 +/- 221% vs. 208 +/- 130%; p = .003). Histologic evaluation demonstrated greater dystrophic tubular calcifications per ten high-power fields in the parenteral compared with the enteral nutrition group (50 [four to 85] vs. three [0 to 37]; p = .001). No differences in urine calcium concentration or 24-hr calcium excretion were seen. CONCLUSION: Rats given continuous enteral nutrition 7 days before and for 3 days after ischemic acute renal failure have improved renal function compared with rats given parenteral nutrition.

Impact of a pharmacist-based consult service on nutritional rehabilitation of nonambulatory patients with severe developmental disabilities.

A pharmacist consult service was developed to evaluate the appropriateness of enteral feeding through a permanent ostomy in 24 nonambulatory patients with severe developmental disabilities. Several problems with enteral nutrition were identified. Policies to improve them were instituted, and several educational presentations were made. Pharmacists' actions were implemented, including assessment of energy needs by indirect calorimetry and rearrangement of enteral feeding schedules to achieve optimal nutrition support and pharmacotherapy administration. By the fourth month of the consult service, body weight in these patients increased from 101 +/- 6% of baseline to 109 +/- 7% (p<0.05). Weight continued to increase through the seventh month of the consult service to 116 +/- 12% of baseline (p<0.0001). Measured resting energy expenditure for the group was 889 +/- 170 kcal/day compared with the predicted 1055 +/- 163 kcal/day.

Octreotide and potassium homeostasis.

Somatostatin infusion causes hyperkalemia in healthy subjects and in some animal models. The purpose of this investigation was to determine what effect octreotide has on potassium homeostasis during serious illness and if there is a dose-response relationship. Sixty-six male Sprague-Dawley rats (185-225 g) were randomized to receive parenteral nutrition (PN) only, PN plus continuous infusion of Escherichia coli lipopolysaccharide (LPS), or PN plus LPS plus octreotide 10, 100, or 1000 micrograms/kg/day for 48 hours. Before randomization all animals received isocaloric, isonitrogenous, isokalemic PN. A 24-hour urine was collected and a blood sample was taken at the end of the study immediately before euthanization. Data were analyzed by ANOVA and Duncan's multiple range test. Nonhemolyzed serum samples from 50 rats were available for study. Serum potassium concentrations were in the normal range for rats and did not differ significantly among the groups: 5.97 +/- 0.86, 5.96 +/- 1.58, 5.78 +/- 1.48, 5.79 +/- 1.67, 5.35 +/- 0.78 mEq/L, respectively. No differences among groups were found for fractional excretion of potassium or serum creatinine concentration. Octreotide administration in escalating dosages does not cause hyperkalemia in endotoxemic rats given intravenous potassium at a constant rate by PN.

Dose-dependent effect of octreotide on nitrogen retention and glucose homeostasis in response to endotoxemia in parenterally fed rats.

OBJECTIVE: This study compared the effect of different doses of octreotide on glucose and protein homeostasis in rats receiving concomitant lipopolysaccharide and parenteral nutrition infusions. METHODS: Sixty-six male Sprague Dawley rats (185 to 220 g) were randomized to receive parenteral nutrition only (PN), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), PN plus LPS plus octreotide at 10 micrograms/kg/day (LPS + Oct 10), 100 micrograms/kg/day (LPS + Oct 100), or 1000 micrograms/kg/day (LPS + Oct 1000) for 48 hours. Prior to randomization all animals received isocaloric and isonitrogenous PN (170 kcal/kg/day as glucose and 1.1 g N/kg/day) and were kept nil per os except for water ad libitum. Nitrogen balance, urinary 3-methylhistidine/creatinine ratio, serum glucose concentration, and incidence of glycosuria were compared between groups. Serum urea nitrogen (SUN) changes were incorporated into the cumulative 48 hour nitrogen balance. ANOVA, Duncan's multiple range test, and Fisher's Exact Test were used for statistical analysis. RESULTS: Nitrogen balance (mg/48 hours) was significantly lower in all four groups receiving LPS +/- Oct when compared to the control group receiving PN alone. SUN (mg/dL) was significantly higher in all four groups receiving LPS +/- Oct when compared to control. There were no statistically significant differences in nitrogen balance or SUN among the four groups receiving LPS +/- Oct. The ratio of urinary 3-methylhistidine/ creatinine was significantly higher in the LPS + Oct 1000 group compared to the PN group (0.77 +/- 0.37 vs. 0.42 +/- 0.24, p < 0.05). Serum glucose concentrations and incidence of glycosuria among the five groups were not significantly different. CONCLUSIONS: Endotoxin significantly reduces nitrogen balance compared to controls fed PN. Octreotide does not significantly improve nitrogen retention or glucose homeostasis in endotoxemic parenterally fed rats.