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Biomedical subjects

J T DiPiro

Publications and source records attributed to J T DiPiro.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a widely used therapy for neonates with respiratory failure. Because of sepsis, many of these infants require antibiotics like vancomycin during ECMO treatment. ECMO transiently alters renal function and increases the circulating blood volume by 75%. Initial vancomycin pharmacokinetics were determined in 12 infants undergoing ECMO to determine an adequate drug administration regimen. Vancomycin dosage was based on current recommendations for weight and gestational age. Pharmacokinetic parameters were determined by fitting the data to a two compartment model. This study yielded a mean steady-state volume of distribution of 1.1 +/- 0.5 (range, 0.6 to 2.1) liters/kg and a mean vancomycin clearance of 0.78 +/- 0.19 (range, 0.49 to 1.07) ml/min/kg. The mean vancomycin half-life was 16.9 +/- 9.5 (range, 8.8 to 42.9) h. Nomogram-calculated creatinine clearance was a significant predictor of vancomycin terminal rate constant and clearance. These data suggest alterations in the pharmacokinetics of vancomycin in infants on ECMO. With the goal of achieving vancomycin concentrations in serum above the MIC for the offending pathogen while using the least amount of the drug necessary, new administration guidelines for term infants without renal impairment undergoing ECMO should be 20 mg of vancomycin per kg at an interval of 24 h. With significant renal impairment, the interval should be extended on the basis of concentrations in serum. In comparison with previously published data, the neonates undergoing ECMO in our study demonstrated a much larger volume of distribution, a lower clearance, and consequently a longer vancomycin half-life.

Anti-Bacterial Agents↗
PubMed1995

Association of interleukin-4 plasma levels with traumatic injury and clinical course.

OBJECTIVES: To determine if interleukin-4 (IL-4) could be detected in plasma of trauma patients and if IL-4 activity is associated with patterns of clinical events, complications, or outcomes. METHODS: A prospective case series conducted in a tertiary care referral center with a level I trauma center. One hundred patients admitted to the trauma intensive care unit for at least 3 days were included. Plasma concentrations of IL-4 and IgE were determined from admission to intensive care unit discharge. Data on clinical outcome were collected, including death, sepsis, severe sepsis, adult respiratory distress syndrome, pneumonia, and renal dysfunction. RESULTS: Interleukin-4 was detected in the plasma of 87 patients. Patients with an Injury Severity Score of greater than 25 had higher admission IL-4 levels (P = .03) and greater maximal IL-4 levels (P < .001). Admission hypotension (P = .04) and age 30 years or younger (P < .001) were also associated with higher admission IL-4 levels. Increases in IL-4 levels were significantly greater for patients in whom sepsis, severe sepsis, or pneumonia developed (P < .05). A low admission IL-4 level was associated with a greater incidence of nosocomial pneumonia (P < .001). Additional indirect evidence of IL-4 activation included increased plasma IgE levels. CONCLUSIONS: Anti-inflammatory cytokine mechanisms are activated after injury and are associated with the development of infectious complications (sepsis, severe sepsis, and pneumonia). Exogenous administration of interleukin-4 should be evaluated as an experimental therapeutic approach after trauma and associated sepsis.

Adult↗
PubMed1995

Antipyrine pharmacokinetics in the tail-suspended rat model.

As space flight becomes more commonplace, the influence of physiologic changes associated with the microgravity environment become of greater concern. Exposure to weightlessness has been shown to have numerous effects on body composition and organ function in animals and humans. However, studies examining possible alterations in drug metabolism and pharmacokinetics are not readily available. Antipyrine is a marker of hepatic oxidative function and total body water. The purpose of our study was to examine the effects of simulated weightlessness on the pharmacokinetics of antipyrine. Weightlessness was simulated through the use of the tail-suspended rat model. Rats were suspended for a total of 7 days. During the study period, antipyrine pharmacokinetics, after a single 20 mg/kg i.v. or p.o. dose, were evaluated at base line (day-1) and 1, 3 and 7 days after the initiation of suspension. Total body clearance was significantly elevated in the tail suspended rats from both the i.v. and p.o. dosing groups after 3 and 7 days of simulated weightlessness. In addition, clearance was elevated after 1 day of tail-suspension in the p.o. dosing group. Steady-state volume of distribution was not statistically different over the entire study period in either dosing group. Data from the present study suggest that brief periods of tail-suspension may markedly alter the pharmacokinetics of drugs in the rat and that more studies are required in models of weightlessness and actual space flight to understand the complex interaction between microgravity and hepatic metabolic activity.

Administration, Oral↗
PubMed1994

Reconstituted high density lipoprotein inhibits physiologic and tumor necrosis factor alpha responses to lipopolysaccharide in rabbits.

OBJECTIVE: To determine the effect of reconstituted human high density lipoprotein (rHDL) on physiologic and cytokine responses to infusion of lipopolysaccharide. DESIGN: A blinded, randomized trial of three preparations of a purified human rHDL with apolipoprotein A-I-phosphatidyl choline-cholesterol molar ratios of 1:100:10, 1:150:10, and 1:200:0 and placebo in a rabbit lipopolysaccharide intravenous infusion model. INTERVENTIONS: Groups of six New Zealand white rabbits received either placebo or one of the three human rHDL preparations above as a single, 75-mg/kg (apolipoprotein A-I equivalent) dose intravenously over 10 minutes ending 5 minutes before the start of a 3-hour infusion of lipopolysaccharide. MAIN OUTCOME MEASURES: Mean arterial pressure, base excess, and plasma tumor necrosis factor alpha (TNF-alpha) production were determined. RESULTS: The human rHDL suppressed TNF-alpha production with the products having the highest fraction of phosphatidyl choline producing the greatest suppression of TNF-alpha production. The human rHDL 1:200:0 group maintained a low, near-baseline TNF-alpha concentration and minimal decline in mean arterial pressure and base excess throughout the lipopolysaccharide infusion in contrast to the placebo group. CONCLUSION: Reconstituted human high density lipoprotein appears to be useful in inhibiting the physiologic effects and cytokine release associated with endotoxemia and may provide adjunctive treatment for patients with gram-negative sepsis.

Acidosis↗
PubMed1994

Lipopolysaccharide-reactive immunoglobulin E is associated with lower mortality and organ failure in traumatically injured patients.

Antilipopolysaccharide (anti-LPS) immunoglobulin G (IgG) and IgM have been associated with protection from LPS effects in vivo. We investigated the presence of IgE and anti-LPS in 32 patients that had experienced severe traumatic injury and in 35 healthy volunteers; we also investigated whether IgE anti-LPS was associated with important clinical events. Plasma samples were collected daily from patients in the intensive care unit and on one occasion from volunteers; the samples were assayed for IgE anti-LPS. IgE anti-LPS was assayed by enzyme-linked immunosorbent assay with monoclonal anti-human IgE as the capture antibody. Detection was accomplished with biotin-labeled LPS (Escherichia coli J5 mutant) followed by streptavidin-peroxidase with 2,2'-azino(3-ethylbenzthiazoline)sulfonic acid as the substrate. The assay was demonstrated to be specific for IgE and LPS-biotin by nonreactivity of control sera with high-titer anti-LPS IgG and IgM and by inhibition with unlabeled LPS. IgE anti-LPS was detected in 1 of 35 healthy controls (2.9%) and 25 of 32 traumatically injured patients (78%) (P < 0.001). The presence of IgE anti-LPS was associated with a lower incidence of death (P = 0.026) and of renal failure (P = 0.0012). There was no apparent temporal relationship between detection of IgE anti-LPS and clinical events. IgG anti-LPS was detected more frequently in patients that were positive for IgE anti-LPS (P = 0.06) but was not associated with clinical events. The inability to detect IgE anti-LPS may be related to adverse clinical events through depletion of specific IgE due to LPS exposure after trauma or through saturation of the assay by IgE with other specificities. We have reported increased total IgE concentrations in these patients. (J.T. DiPiro, R.G. Hamilton, T. R. Howdieshell, N. F. Adkinson, and A. R. Mansberger, Ann. Surg. 215:460-466, 1992).

Acute Kidney Injury↗
PubMed1993

Serum antipyrine concentrations determined by micellar electrokinetic capillary chromatography.

We developed an assay for antipyrine in serum using micellar electrokinetic capillary chromatography. A capillary electrophoresis system with a 70-cm fused-silica capillary and pH 8.2 borate-sodium dodecyl sulfate buffer was used. Standard curves ranging from 0.5 microgram/ml to 25 micrograms/ml were analyzed. The resulting electropherograms showed no interfering endogenous peaks and the assay was linear in the range of concentrations analyzed. The intra-day and inter-day relative standard deviations ranged from 0.7 to 5.2% and 1.7 to 8.1%, respectively. Analytical recovery of antipyrine ranged from 78.2 to 105.0%. The theoretical plate number for antipyrine was calculated to be 561,000 +/- 79,000 plates/m.

Acetaminophen↗
PubMed1993

Combination antibiotic therapy in the management of intra-abdominal infection.

Combination antimicrobial regimens consisting of an agent with activity against gram-negative bacilli (an aminoglycoside) plus an agent with anaerobic activity (usually clindamycin or metronidazole) have traditionally been accepted as the standards for the treatment of intra-abdominal infection. Because of the problems of nephrotoxicity and ototoxicity in patients treated with aminoglycosides, clinical trials have been conducted using alternative combination therapy (e.g., aztreonam plus clindamycin) or single beta-lactam antimicrobial agents. Most clinical trials of intra-abdominal infections have been conducted in relatively small patient populations with a variety of low- and high-risk patients. The newer regimens have demonstrated efficacy equivalent to traditional combination therapy in selected patient populations. When selecting an antimicrobial regimen for treatment of intra-abdominal infection, multiple issues should be considered, including demonstrated efficacy in clinical trials, potential for adverse effects, and cost.

Abdomen↗
PubMed1993

In vitro protein binding of cefonicid and cefuroxime in adult and neonatal sera.

The levels of in vitro protein binding of cefonicid and cefuroxime in human adult and neonatal sera were compared. Binding parameters for each drug were determined within the concentration range of 25 to 3,000 micrograms/ml. Cefonicid exhibited concentration-dependent protein binding in both types of sera, with more extensive binding in adult serum at all concentrations. Two classes of binding sites were found: a high-affinity, saturable site and a low-affinity, nonspecific site. Cefuroxime also showed two-class, concentration-dependent protein binding in adult serum, but binding in neonatal serum was to a single class and was independent of drug concentration. Parameters for class 1 binding sites for cefonicid indicated one binding site per albumin molecule in both adult and neonatal sera, with association constants of 7.0 x 10(4) and 1.3 x 10(4) M-1, respectively. These parameters were also derived for cefuroxime in adult serum and were 0.15 and 7.1 x 10(4) M-1, respectively. In neonatal serum, the combined value (number of binding sites per molecule x equilibrium association constant) was similar to combined values calculated for class 2 binding sites for cefuroxime in adult serum and for cefonicid in neonatal serum (287 versus 195 and 261 M-1, respectively). Cephalosporins have been shown to compete with bilirubin for albumin binding sites. Lower levels of protein binding of cefuroxime in the therapeutic range may mean a lower potential for drug displacement of bilirubin in neonates, on the basis of these results. It may be prudent to select less highly protein-bound agents when treating neonatal infections.

Adult↗
PubMed1993

Facilitation of penicillin haptenation to serum proteins.

Traditionally, penicillin binding to serum proteins was believed to be a passive chemical process; however, it appears to be facilitated by serum factors. The objectives of this in vitro investigation were to examine facilitated penicillin haptenation, to study the kinetics of haptenation, and to determine the nature of haptenation-facilitating factors. The model involved addition of [3H]benzylpenicillin to serum or albumin solutions (at pH 7.3 to 7.4) and incubation at 37 degrees C for up to 72 h. The extent of penicillin binding to proteins in serum was found to be four- to fivefold higher than with solutions having comparable concentrations of purified albumin, total protein, or total immunoglobulin. Ultrafiltration of serum reduced penicillin binding to serum proteins substantially. An ultrafiltrable haptenation-facilitating factor(s) was found to be less than 0.5 kDa but was not calcium or magnesium. Finally, the extent of penicillin binding was related to albumin purity, as binding substantially increased with albumin purity. These findings suggest that there is a factor(s) in serum that facilitates covalent binding of penicillin to serum proteins. The factor(s) can be removed and then restored to increase penicillin binding to albumin. It appears that at least one component of the facilitation factor is less than 0.5 kDa, which suggests that it is not a peptide and that it is some simple serum component other than calcium or magnesium.

Adult↗
PubMed1993

Buprenorphine versus morphine for patient-controlled analgesia after cholecystectomy.

Buprenorphine is an opioid agonist-antagonist that has emerged as an option for postoperative analgesia. We compared the postoperative hospital course of patients undergoing open cholecystectomy who received buprenorphine hydrochloride with those who received morphine sulfate. Patients in both groups administered the analgesic using a patient-controlled analgesia infusion device. Comparison of the two groups demonstrated no difference with respect to clinical indicators of intestinal motility, visual analog pain scores and hospitalization period. Postoperative nausea occurred more frequently in the buprenorphine group, but the difference was not significant. We concluded that the patient-controlled analgesia device is a valuable tool for comparing different analgesics. Both analgesics tested provide adequate analgesia with a similar postoperative course.

Adolescent↗
PubMed1992

Novel drug-delivery systems for hypertension.

Although novel controlled-release drug-delivery systems have been used in other areas of medicine, their application in the treatment of hypertension has been relatively recent. Biotechnical use of chemical-dispensing systems has been applied to propranolol, clonidine (the transdermal therapeutic system), nifedipine (the gastrointestinal therapeutic system), verapamil (the sodium alginate and spheroidal oral-delivery absorption system), felodipine (the hydrophilic gel principle), metoprolol succinate (the multiple-unit pellet system), and diltiazem (one system comprising sustained-release beads and the other utilizing the patented Geomatrix extended-release system). Oral drug-delivery systems allow antihypertensive agents that previously had to be administered two to four times daily to be administered once each day. Potential disadvantages of the oral controlled-release products include delayed attainment of pharmacodynamic effect, unpredictable or reduced bioavailability, enhanced first-pass hepatic metabolism, dose dumping, sustained toxicity, dosing inflexibility, and increased cost. Potential advantages include reduced dosing frequency, enhanced compliance and convenience, reduced toxicity, stable drug levels, uniform drug effect, and decreased total dose. Although skin reactions are common, the transdermal drug delivery of clonidine provides another innovative approach to supplying transcutaneous, controlled, continuous delivery of drug for 7 days. It is possible that future research will prove that the agents that provide complete 24-hour control may reduce the cardiovascular events associated with the early-morning blood pressure surge. This evolution in antihypertensive therapy to achieve once-daily dosing may prove to be of great value to both physicians and patients in the 1990s.

Administration, Cutaneous↗
PubMed1992

Novel antibody drug products.

Recent developments in protein and genetic engineering methods have allowed the production of antibody-derived molecules that have important potential as therapeutic agents. Although monoclonal antibodies of murine origin have been used for therapeutic purposes, limitations due to anti-antibody responses and suboptimal effectiveness for some indications, such as tumor cell killing, have led to the development of human monoclonal antibodies, chimeric and complementarity determining-region grafted antibodies, immunotoxins, and other engineered products. These novel antibodies are being tested for the treatment and prevention of infectious diseases and for the diagnosis and treatment of cancers, as well as for indications considered nontraditional for antibodies (e.g., as antithrombotics or inhibitors of neutrophil adherence). The availability of antibody drug products raises a number of issues for clinicians. Among these are new patterns of adverse effects, immunogenicity (development of anti-antibody response), important questions regarding administration and dosage, and substantial cost implications.

Antibodies↗
PubMed1992

Total IgE in plasma is elevated after traumatic injury and is associated with sepsis syndrome.

Gamma E immunoglobulin (IgE) is associated with allergic reactions, but has not been described as being activated after trauma or sepsis. Total plasma IgE concentrations were determined in 32 patients with major traumatic injury, 29 patients undergoing elective abdominal operations, and 30 healthy volunteers. Mean total IgE concentrations were 271.7 ng/mL, 52.3 ng/mL, and 41.3 ng/mL, respectively (p less than 0.01 for each comparison with the trauma group). Total IgE concentrations in trauma patients at the time of admission were not significantly different from elective surgical controls, and tended to increase during the intensive care unit stay. In the trauma group, total IgE concentration was significantly greater in the 18 patients that developed sepsis syndrome compared with those that did not (p = 0.034). These data suggest that allergic mechanisms may be involved in the physiologic response to major traumatic injury and sepsis syndrome, or that other cells known to be involved in the immune responses to trauma and sepsis (macrophages, platelets, and B lymphocytes) may become activated by IgE-dependent mechanisms.

Acute Kidney Injury↗
PubMed1992

Effect of experimental hemorrhagic shock on hepatic drug elimination.

OBJECTIVE: Exogenous substrates were used to measure hepatic function for the purposes of determining organ dysfunction and to evaluate the effect of experimental hemorrhagic shock with resuscitation on hepatic drug elimination. DESIGN: Prospective, controlled, non-randomized crossover trial. INTERVENTIONS: Eleven chronically instrumented immature swine were studied using a fixed-volume hemorrhage model (45 mL/kg blood removal over 15 mins) followed by resuscitation with lactated Ringer's solution at three times the volume of shed blood. One week before and immediately after hemorrhage and resuscitation, hepatic function markers (indocyanine green and antipyrine) were simultaneously administered intravenously. MEASUREMENTS: Physiologic data and blood samples were collected over 12 hrs after drug administration. Drug clearances, volumes of distribution, and half-lives were determined. MAIN RESULTS: For indocyanine green, there was no substantial change in pharmacokinetics from preshock to postshock, suggesting minimal change in hepatic blood flow. For antipyrine, clearance was decreased by 30% after shock and resuscitation (p = .05), suggesting that oxidative metabolism was acutely impaired. CONCLUSIONS: The information indicates that hepatic oxidative drug metabolism may be impaired early after hemorrhagic shock and that dosages of drugs in this class should be carefully examined when administered to patients who have sustained injury with hemorrhagic shock.

Animals↗
PubMed1991

Aminoglycoside combinations versus beta-lactams alone for penetrating abdominal trauma: a meta-analysis.

Despite several small comparative clinical trials, controversy persists over the best choice of antimicrobial therapy for penetrating abdominal trauma. Some still question whether single drug regimens are as effective as the traditional combinations containing an aminoglycoside. A meta-analysis was performed to address this issue. Meta-analysis is a relatively new statistical tool whereby data from a number of clinical trials is analyzed and pooled to produce useful and more reliable data. In this study, a meta-analysis of 17 published randomized trials was performed to assess the effectiveness of single beta-lactam antimicrobials versus combinations containing aminoglycoside when used for penetrating abdominal trauma. The overall summary odds ratio of the pooled results of these trials was 0.96 (p = 0.833) with a 95% confidence interval of 0.30-3.05. Since not significantly different from unity (1.0), we conclude that single beta-lactam antimicrobials are as effective as traditional combinations containing aminoglycoside in this setting.

Abdominal Injuries↗
PubMed1990

Blood kinetics, tissue distribution, and radioimaging of anti-common chronic lymphatic leukemia antigen (cCLLa) monoclonal antibody CLL2 in mice transplanted with cCLLa-bearing human leukemia cells.

The blood kinetics and biodistribution of anti-common chronic lymphatic leukemia antigen (cCLLa) monoclonal antibody (MoAb) CLL2 were assessed in mice bearing cCLLa+ tumors. The cCLLa is a 69-Kd glycoprotein antigen expressed selectively by malignant B cells in human CLL, hairy cell leukemia (HCL), and prolymphocytic leukemia. Immunoreactive 125I-CLL2 (5 micrograms/mouse, specific activity 4.3 microCi/micrograms) was injected intravenously in mice bearing HCL-derived EH xenografts, and blood kinetics and biodistribution were ascertained up to 16 days postinjection. Radioimages were also obtained up to 72 hours after injecting 10 micrograms/mouse (specific activity 50.1 microCi/micrograms) of 125I-CLL2. Distinct 125I-CLL2 blood kinetics were observed in EH engrafted compared with tumor-free mice including: a longer 125I-CLL2 T 1/2 (153 hours v 72 hours), and a considerably greater blood clearance (173 mg/h v 54.7 mg/h) with biexponential rather than monoexponential configuration; and a greater volume of antibody distribution (31,483 mg v 5,729 mg). These data suggest more rapid tissue uptake by grafted tumours. Preferential 125I-CLL2 uptake by EH tumours relative to normal tissues was observed beginning 24 hours postinjection (mean ratio, 4.2) with average peak tumor 125I-CLL2 levels of 428.7 pg/mg. 125I-CLL2 uptake selectivity by EH tumor cells was also supported by: (1) negligible 125I-CLL2 uptake by cCLLa- Molt-4 xenografts (average 29.1 pg/mg 24 hours postinjection); (2) background uptake of cCLLa-irrelevant MoAb 131I-LEU1 by CD5- EH xenografts (average 31.4 pg/mg 48 hours postinjection); and (3) by scintigraphy. The EH xenograft mouse model might be useful to ascertain preclinically the anti-tumor effect of anti-cCLLa MoAbs and of their conjugated derivatives.

Animals↗