Usefulness of fructosamine for monitoring outpatients with diabetes.

BACKGROUND: Measurements of total glycohemoglobin (glycoHb) or hemoglobin A1c are routinely used to evaluate intermediate-to-long term glycemic control in patients with diabetes. However, despite the recent availability of more rapid methods for glycohemoglobin determination, it remains difficult in many institutions to obtain same-day glycoHb determinations in time to assist physicians with management of outpatients with diabetes. Hence, we investigated whether fructosamine, which reflects very recent (2 to 3 weeks) glycemic control and which can be assayed more rapidly in our laboratory, could serve as a useful adjunct to glycoHb for management of these patients. METHODS: Diabetes control in outpatients managed using fructosamine, fasting serum glucose, and glycoHb (concentrations from the prior visit) was compared with that for outpatients monitored using fasting serum glucose and prior glycoHb alone. The relative usefulness of fructosamine, current and prior glycoHb, and "fasting" serum glucose for evaluation and management of outpatients with diabetes was compared. In addition, the acceptance of fructosamine by physicians was evaluated by a questionnaire. RESULTS: Same-day fructosamine concentrations correlated better with current glycoHb than did either prior glycoHb or current fasting serum glucose concentrations. However, the availability of same-day fructosamine results did not objectively improve diabetes control compared with that obtained using only fasting serum glucose values and prior glycoHb concentrations. Nonetheless, most examining physicians stated that same-day fructosamine concentrations helped them significantly with diabetes management, primarily because many patients do not adequately monitor home blood glucose levels. CONCLUSIONS: Fructosamine may be a useful adjunctive test for management of outpatients with diabetes in situations where it is not practical to obtain same-day glycoHb concentrations, for patients less compliant with home glucose monitoring, or where recent changes in insulin dose or clinical presentation might not be reflected in the glycoHb levels.

Multicenter clinical and analytical evaluation of the AxSYM troponin-I immunoassay to assist in the diagnosis of myocardial infarction.

We evaluated the AxSYM troponin I (cTnI) immunoassay for assisting in the detection of acute myocardial infarction (AMI). At four sites, the total imprecision (CV) over 20 days was 6.3-10.2%. The minimum detectable concentration was 0.14 +/- 0.05 microgram/L. Comparison of cTnI measurements between the AxSYM and Stratus (n = 406) over the dynamic range of the AxSYM assay demonstrated good correlation, r = 0.881, with a proportional bias: AxSYM cTnI = 3.50(Stratus cTnI) - 1. 10. The confidence intervals (95%) for the slope and intercept were 3.39-3.64 and -1.32 to -0.95, respectively. The expected cTnI concentration in healthy individuals was /=96%, in skeletal muscle injury, chronic renal disease, and same-day noncardiac surgery patients.

Stability of milrinone lactate in the presence of 29 critical care drugs and 4 i.v. solutions.

The stability of milrinone lactate in the presence of 29 critical care drugs during simulated Y-site injection and in 4 i.v. solutions was studied. Ten milliliters of milrinone 400 microg/mL (as the lactate salt) was combined with 10 mL of each of 29 commonly used critical care drugs in 5% dextrose injection. Also, mixtures containing milrinone 400 microg/ mL in lactated Ringer's injection, 5% dextrose injection, 0.45% sodium chloride injection, and 0.9% sodium chloride injection were prepared. All mixtures were prepared in triplicate and stored at 22-23 degrees C in glass containers or polyvinyl chloride bags under fluorescent light. Samples were withdrawn zero, one, two, and four hours after mixing for each milrinone-secondary drug mixture and at intervals up to seven days for each milrinone-i.v. diluent mixture. Samples were examined visually and analyzed by high-performance liquid chromatography, enzymatic assay, or fluorescence polarization immunoassay. No precipitation or substantial pH change was observed in any of the mixtures. In all the mixtures, milrinone retained more than 96% of its initial concentration, and the other drugs retained more than 97% of their initial concentrations. Milrinone 400 microg/mL in 5% dextrose injection and 29 critical care drugs were stable for four hours at 22-23 degrees C during simulated Y-site administration. Milrinone 400 microg/mL was stable in lactated Ringer's injection, 5% dextrose injection, 0.45% sodium chloride injection, and 0.9% sodium chloride injection for seven days at 22-23 degrees C.

The diagnostic accuracy of bedside and laboratory coagulation: procedures used to monitor the anticoagulation status of patients treated with heparin.

We evaluated the diagnostic accuracy of three bedside coagulation procedures, the Hemochron activated whole-blood clotting time (ACT) (International Technidyne, Edison, NJ), the CoaguChek Plus (Boehringer Mannheim, Indianapolis, Ind) activated partial thromboplastin time (APTT) and the TAS (Cardiovascular Diagnostics, Raleigh, NC) APTT, before removal of arterial sheaths, in patients who received heparin therapy during percutaneous coronary angioplasty. As part of the postprocedure care, nurses performed bedside coagulation tests, removed the sheaths when appropriate coagulation criteria were met, and collected samples for laboratory APTT determinations and heparin assays performed with an automated chromogenic anti-Xa assay. Patients with heparin concentrations of 0.3 U/mL or more were classified as anticoagulated and those with concentrations less than 0.3 U/mL, as not anticoagulated. Analysis of the receiver operator characteristic (ROC) curve was used to rank the performance of the methods. Areas under the ROC curves +/- SE for the laboratory APTT, CoaguChek Plus APTT, Hemochron ACT, and TAS APTT were 0.978 +/- 0.016, 0.872 +/- 0.044, 0.797 +/- 0.039, and 0.795 +/- 0.048, respectively. At cutoff values for the tests that provide greatest safety for the patients (no false-negative results), the false-positive rates for the laboratory, CoaguChek Plus, Hemochron, and TAS methods were 15%, 27%, 62%, and 100%, respectively. The laboratory APTT demonstrated the highest diagnostic accuracy in this application; however, turnaround time for the test (50% of the results were reported in excess of 77 minutes) was inadequate for clinical decision making. To meet this requirement, we developed a point-of-care program using the whole blood APTT performed on the CoaguChek Plus analyzer.

Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients.

The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.

Association of busulfan area under the curve with veno-occlusive disease following BMT.

Busulfan pharmacokinetics, specifically area under the concentration curve (AUC), have been correlated with the occurrence of veno-occlusive disease (VOD) following BMT. To evaluate the risk of VOD, we studied 66 patients who received pharmacotherapeutically monitored busulfan regimens in combination with CY, etoposide (VP16) and/or Ara-C in preparation for BMT. These patients received a total of 16 doses of busulfan dosed as 1 mg/kg/dose q 6 h beginning at 09.00 (n = 39), 18.00 (n = 2), 21.00 (n = 1) or 24.00 (n = 24) h. With the first dose, blood samples were obtained at baseline, every 15-30 min for 2 h, then every 1-2 h for 4 h. Blood was analyzed for busulfan concentration by high performance liquid chromatography and AUC calculated by the trapezoidal rule. Seventeen patients (25.8%) were not evaluable for AUC calculation due to slow absorption and/or elimination: 13 of 27 (48.1%) received the first dose between 18.00-24.00 vs four of 39 (10.2%) patients who received the first dose at 09.00 (P < 0.001). Eighteen of 51 (35.3%) evaluable patients had an AUC > 1500 mumol x min/l; 10 of whom received doses reduced proportionally to achieve an AUC = 1200 mumol x min/l starting with the 10th to 15th dose. Six of 18 (33.3%) patients with an initial AUC > 1500 mumol x min/l developed VOD vs one of 33 (3.0%) patients with an initial AUC < 1500 mumol x min/l (relative risk = 11.1; P = 0.0056). Other pharmacokinetic parameters, age, gender, type of BMT, previous therapy or pre-transplant liver function tests were not predictive of VOD. A higher incidence of VOD occurred in patients receiving BUCY (4 of 10) compared to those receiving BUCYAra-C (1 of 18) or BUCYVP16 (7 of 38), which could not be attributed to increased busulfan exposure in the BUCY patients. Routine pharmacotherapeutic monitoring of busulfan is recommended with further study to evaluate the impact of earlier and greater overall dose reduction in patients with high initial busulfan exposures.

Vancomycin redistribution: dosing recommendations following high-flux hemodialysis.

Although increased vancomycin clearance has been reported with highly permeable hemodialysis membranes (such as polysulfone), failure to consider post-dialysis redistribution could lead to unnecessary dosage supplementation. In protocol 1, twelve hemodialysis patients admitted for vascular access thrombectomy received 15 mg/kg of vancomycin as surgical prophylaxis. Post-operatively, patients underwent high-flux hemodialysis (HFHD) for two hours using a Fresenius F-80 polysulfone dialyzer (QB = 417 +/- 49, QD = 800 ml/min). Vancomycin's intradialytic clearance increased 13-fold compared to the patient's endogenous clearance (120 +/- 59 vs. 9 +/- 8 ml/min, respectively) yet dialysate recovery indicated that only 17% of body stores were removed (179 +/- 70 mg). Although serum vancomycin levels decreased 33% during HFHD, vancomycin levels increased in all patients following dialysis and the post-rebound values reached 87% of the pre-dialysis concentration. In protocol 2, eight outpatients receiving maintenance HFHD with a F-80 dialyzer (Kt/V = 1.29 +/- 0.08) were given 20 mg/kg of vancomycin immediately following dialysis on Monday; pre- and post-levels were measured during the next three dialysis treatments. The predialysis serum vancomycin levels were > 7.5 micrograms/ml (9.7 +/- 1.0 micrograms/ml; range 8.0 to 11.0) in all patients the following Monday. Thus, vancomycin clearance is increased during HFHD, but redistribution post-HD minimizes changes in serum levels. We recommend a 20 mg/kg i.v. loading dose and subsequent doses of 15 mg/kg every seven days; to account for individual variability, weekly vancomycin levels should be drawn before dialysis.

Analyses of plasma for metabolic and hormonal changes in rats flown aboard COSMOS 2044.

Plasma samples from rats flown aboard COS-MOS 2044 were analyzed for the levels of key metabolites, electrolytes, enzymes, and hormones. The major differences between the flight group and the synchronous control were elevations in glucose, cholesterol, phosphate, creatinine, blood urea nitrogen, lactate dehydrogenase, and aspartate amino-transferase and decreased levels of thyroxine. Most of these differences were not mimicked by tail suspension of ground-based rats; however, both flight and suspended rats exhibited inhibited testosterone secretion. Corticosterone, immunoreactive growth hormone, and prolactin showed inconsistent differences from the various control groups, suggesting that the levels of these hormones were not due to actual or simulated microgravity.

Differences in glycogen, lipids, and enzymes in livers from rats flown on COSMOS 2044.

Livers from rats flown aboard COSMOS 2044 were analyzed for protein, carbohydrate (glycogen), and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. The major differences between the flight group and the synchronous control were elevations in microsomal protein, liver glycogen content, tyrosine aminotransferase, and tryptophan oxygenase and reductions in sphingolipids and the rate-limiting enzyme of heme biosynthesis, delta-aminolevulinic acid synthase. These results provide further evidence that spaceflight has pronounced and diverse effects on liver function; however, some of the results with samples from COSMOS 2044 differed notably from those from previous spaceflights. This may be due to conditions of spaceflight and/or the postflight recovery period for COSMOS 2044.

Functional differences in human neutrophils isolated pre- and post-prandially.

Activated polymorphonuclear leukocytes have been associated with neoplasia, atherogenesis and reperfusion injury. Since some of these conditions are also correlated with dietary fat, we examined the functional characteristics of leukocytes isolated from subjects before and after consumption of a lipid-rich meal. There was up to 2-fold greater superoxide generation in response to agonists in leukocytes obtained post-prandially; the maximum increase was observed about 4 h after eating and followed the peak (2-4 h) in serum triglycerides. Neutrophils isolated post-prandially also exhibited impaired chemotaxis and defective bacterial killing, but normal phagocytosis. These findings provide a new variable that should be considered in studies of leukocytes.

Stability of ceftazidime and amino acids in parenteral nutrient solutions.

The stability of ceftazidime was studied under conditions simulating administration via a Y-injection site into a primary infusion of parenteral nutrient (PN) solution; the stabilities of ceftazidime and amino acids when the drug was added directly to PN solutions were also studied. Three PN solutions containing 25% dextrose were used; the amino acid contents were 0, 2.5%, and 5%. Ceftazidime with sodium carbonate was used to prepare stock solutions of ceftazidime 40 mg/mL in both 0.9% sodium chloride injection and 5% dextrose injection; to simulate Y-site injection, samples were added to the three PN solutions to achieve ceftazidime concentrations of 10 and 20 mg/mL, or 1:1 and 1:3 ratios of drug solution to PN solution. Samples of these admixtures were assayed by high-performance liquid chromatography (HPLC) initially and after room-temperature (22 degrees C) storage for one and two hours. Additional solutions were prepared by adding sterile water for injection to ceftazidime with sodium carbonate; drug solutions were added to each PN solution in polyvinyl chloride bags to achieve ceftazidime concentrations of 1 and 6 mg/mL. The samples were assayed by HPLC for ceftazidime concentration after storage at 22 degrees C for 3, 6, 12, 24, and 36 hours and at 4 degrees C for 1, 3, 7, and 14 days. Amino acid stability was analyzed in admixtures containing 5% amino acids and ceftazidime 6 mg/mL after 24 and 48 hours at 22 degrees C and after 7 and 10 days at 4 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of home glucose monitoring with determinations of hemoglobin A1c, total glycated hemoglobin, fructosamine, and random serum glucose in diabetic patients.

We compared four objective measures of glycemic control (fructosamine, total glycated hemoglobin, hemoglobin A1c, and random serum glucose) with home glucose monitoring records in 17 diabetic patients followed up prospectively for 4 months. There was good overall correlation between all of these objective measures and weekly mean capillary glucose values. However, considerable scatter was seen in the data such that none of the glycated protein measurements was an ideal predictor of home glucose values. For example, all markedly elevated home glucose levels (greater than 11.1 mmol/L) were associated with elevated glycated protein levels, but moderately high blood glucose levels (8.3 to 11.1 mmol/L) were associated with one or more normal glycated protein values in some patients. Similar correlations were obtained whether glycemia was estimated by 1-week or 6-week home averages. Random serum glucose level also correlated with average home glucose level; however, there was wide fluctuation within individual subjects. All three glycated protein measurements (hemoglobin A1c, glycated hemoglobin, and fructosamine) appear equally useful as a supplement to home glucose monitoring in the assessment of glycemic control. Of the three types of glycated protein assays, fructosamine, with its advantage of speed and simplicity, may offer a more cost-effective alternative.

Early postoperative intraperitoneal chemotherapy as an adjuvant therapy to surgery for peritoneal carcinomatosis from gastrointestinal cancer: pharmacological studies.

Gastrointestinal malignancy may spread to peritoneal surfaces in the absence of lymphatic or hematogenous metastases. To treat peritoneal carcinomatosis, a uniformly lethal disease process, extensive cytoreductive surgery and i.p. chemotherapy were combined. Early postoperative i.p. chemotherapy was instilled in the first few days after the surgical procedure in an attempt to treat anatomic sites that would be sealed off by postoperative adhesions. Mitomycin C was given on the first postoperative day at two doses, 10 and 12 mg/m2. 5-Fluorouracil was given on postoperative days 2-5 at 15 and 20 mg/kg, respectively. Median area under the curve ratio i.p./i.v. was 117 for 5-fluorouracil and 21.6 for mitomycin C. Elevated intraportal levels of drug were observed for i.p. 5-fluorouracil but not for mitomycin C. The marked pharmacokinetic advantage of postoperative i.p. suggests that this treatment strategy should be considered in a clinical trial in patients at risk for progression of peritoneal carcinomatosis.

Expanding clinical pharmacy services in a VA hospital.

The pharmacy staff at the VA Medical Center, Biloxi, Mississippi, has increased direct patient care activities for the Medical Center's inpatients by converting 139 beds from a manual system of unit dose to a computerized unit dose distribution system. Expanded clinical programs were primarily developed, implemented, and operated by staff pharmacists.

Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887.

To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer.

A new concept in the natural history of gastrointestinal (GI) cancer suggests that recurrence of this malignancy can be separated into two types. Hematogenous and lymphatic metastases occur before surgical removal of the primary cancer. The spread of cancer to the resection site and to peritoneal surfaces occurs at the time of surgical removal of the primary tumor. Surgical trauma leads to a dispersal of malignant tumor emboli, which then implant within the raw tissue surfaces of the resection site and abraded peritoneal surfaces. Instillation of chemotherapy directly into the peritoneal cavity, as part of GI surgery, provides cytotoxic levels of drug that may change the natural history of GI cancer. The most common sites of disease recurrence have been, in the past, at the resection site and on peritoneal surfaces. With the optimal use of intraperitoneal chemotherapy, these sites of surgical treatment failure should no longer occur. Early phase I and II and pharmacologic studies suggest that an effective dose and schedule have been achieved, that toxicity is at reasonable levels, and that responses with small volumes of intra-abdominal cancer are exceptionally high. Chemotherapy that has an impact on the surgical event by decreasing cancer spread to the resection site and to peritoneal surfaces may significantly improve survival and quality of life in patients with GI cancer.

Modulation of the free sphingosine levels in human neutrophils by phorbol esters and other factors.

Because free long-chain bases have been recently found to have potent pharmacological effects when added to neutrophils (Wilson, E., Olcott, M. C., Bell, R. M., Merrill, A. H., Jr., and Lambeth, J. D. (1986) J. Biol. Chem. 261, 12616-12623) and other cell types, the levels in human neutrophils were measured by high-performance liquid chromatography. Sphingosine was the major free long-chain base in freshly isolated cells and ranged from 13 to 101 pmol/10(7) cells for different donors (mean +/- S.E. of 50 +/- 5, n = 17). Upon incubation at 37 degrees C, there was a time-dependent increase in free sphingosine (57 +/- 8% in 1 h, n = 17), but no change was seen at 4 or 25 degrees C. The sphingosine was apparently derived from more complex sphingolipids because little (less than 1%) could be accounted for by new synthesis from [14C]serine. Greater increases in free sphingosine were obtained when neutrophils were incubated with serum, plasma, or serum lipoproteins (about 2-fold higher than for cells incubated alone). In contrast, agonists such as phorbol 12-myristate 13-acetate, A23187, arachidonic acid, low concentrations (10 nM) of N-formyl-methionyl-leucyl-phenylalanine, and opsonized zymosan either decreased the amount of free sphingosine or blunted the time-dependent increase. This may be due to enhanced removal of free sphingosine because phorbol 12-myristate 13-acetate-treated cells exhibited an increased conversion of exogenously added [3H]sphinganine to ceramides. Endogenous sphingosine was approximately one-tenth the level found in neutrophils when exogenous long-chain bases were added to inhibit protein kinase C. Hence, depending on the subcellular localization of the endogenous versus exogenous long-chain bases, the amounts of free sphingosine in neutrophils might be sufficient to affect the function of these cells.

Quantitation of free sphingosine in liver by high-performance liquid chromatography.

Conditions were established for the extraction of free sphingosine from liver and the separation and quantitation of this and other long-chain (sphingoid) bases (e.g., sphingosine, sphinganine, phytosphingosine, and homologs) by reverse-phase high-performance liquid chromatography (HPLC). The long-chain bases were extracted with chloroform and methanol and then treated with base to remove interfering lipids. After preparation of the o-phthalaldehyde derivatives, the long-chain bases could be separated using C18 columns eluted isocratically with methanol:5 mM potassium phosphate, pH 7.0 (90:10). The HPLC analyses took 15 to 20 min per sample and had lower limits of detection in the picomole range. Quantitation was facilitated by using a 20-carbon long-chain base homolog as an internal standard. The utility of the method was demonstrated with rat liver, providing the first quantitation of free sphingosine in this tissue of approximately 7 nmol/g wet wt.

Ion transport mediated by copolymers composed of polyoxyethylene and polyoxypropylene.

Block copolymers composed of polyoxyethylene and polyoxypropylene were found to increase the influx of Na+ and the efflux of K+ from human erythrocytes. They were, however, ineffective at promoting the transport of Ca2+. The size of the ion fluxes induced by the copolymers correlated with their efficacy in stimulating inflammation. These compounds were also found to induce conductance increases in planar lipid bilayers in a nonvoltage dependent and nonstepwise manner. In both experimental systems, ion transport was facilitated only under temperature and ionic-strength conditions in which the polymers form aggregates in aqueous solution. In neither system did the concentration dependence of transport activity exhibit a pronounced cooperativity. These observations are consistent with the view that aqueous monomers of these surface active agents partition into the membrane, where they facilitate the conductive movement of monovalent cations by means of a carrier type mechanism. As a novel class of ionophores, these substances are of practical interest because they can be water soluble and are potentially reversible.