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Biomedical subjects

J J Zimmerman

Publications and source records attributed to J J Zimmerman.

At least 19 recordsLinked to original sources
PubMed1996

Pharmacokinetics of prednisolone during administration of sirolimus in patients with renal transplants.

The pharmacokinetic interaction of multiple oral doses of sirolimus (rapamycin) and prednisone were evaluated in 40 stable patients with renal transplants receiving concomitant multiple doses of cyclosporine. Nine sirolimus dosage levels from 1 mg/m2/day to 13 mg/m2/day were studied and compared with placebo. Plasma concentrations of prednisone, prednisolone, and cortisol were measured by high-performance liquid chromatography and analyzed by noncompartmental methods. Mean pharmacokinetic values of prednisolone found before sirolimus administration were as follows: peak plasma concentration (Cmax) was 187 ng/mL; time to peak plasma concentration (tmax) was 2.03 hours; rate of reaching peak plasma concentration (Cmax divided by the area under the concentration-time curve [AUC]) was 0.149 hour-1; terminal half-life (t1/2) was 3.60 hours; AUC was 1206 ng.hour/mL; and apparent clearance (Cl/F) was 0.094 L/hour/kg. During the 2 weeks of concomitant administration, prednisolone elimination decreased in relation to sirolimus dosages. These changes were modest, with mean increases of 18% in Cmax and 27% in t1/2 and mean decreases of 27% in Cl/F for the groups receiving 6 mg/m2/day to 13 mg/m2/day. Most patients initially had plasma cortisol concentrations indicative of adrenal suppression. With sirolimus treatment, the Cmax of cortisol did not decrease further, but the AUC (8:00 AM-8:00 PM) values were significantly lower, independent of sirolimus exposure. The AUC for cyclosporine did not correlate with sirolimus and prednisolone exposure. A 2-week course of sirolimus showed a slight pharmacokinetic interaction between sirolimus and prednisolone/prednisone/cortisol in stable patients with renal transplants.

Adult↗
PubMed1996

Disposition of intravenous amiodarone in subjects with normal and impaired renal function.

In a study designed to determine the influence of renal dysfunction on the disposition of amiodarone and its metabolite, desethylamiodarone (DEA), 30 subjects received a single 5 mg/kg intravenous dose of amiodarone over 15 minutes. Of the 30, 11 had normal renal function (group I; mean +/- SD glomerular filtration rate [GFR] = 118 +/- 20 mL/min/1.73 m2), 9 had renal impairment (group II; GFR = 23 +/- 10 mL/min/1.73 m2), and 10 were long-term hemodialysis patients (group III; 4 of these patients were studied during dialysis). Total and free concentrations of amiodarone and DEA were measured by high-performance liquid chromatography. There were no significant differences between the three groups in mean systemic clearance, steady state volume of distribution, or mean residence time of amiodarone. However, the area under the concentration-time curve (AUC) for amiodarone was significantly higher in group I than in group II, and this finding was related to total body weight. Free fraction was similar in groups I and III. The disposition of amiodarone and its metabolite DEA was similar in patients with normal renal function, moderate renal dysfunction, and end-stage renal disease. Thus, dosage adjustment in patients with renal impairment is not necessary based on this pharmacokinetic analysis.

Adult↗
PubMed1996

Pharmacokinetics of intravenous amiodarone in patients with impaired left ventricular function.

To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters. With the exception of the half-life (t1/2) of DEA, statistical comparisons revealed no significant between-group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysfunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short-term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.

Adult↗
PubMed1996

Antibody-dependent enhancement (ADE) of porcine reproductive and respiratory syndrome virus (PRRSV) infection in pigs.

Infection of porcine alveolar macrophages by the porcine reproductive and respiratory syndrome virus (PRRSV) was significantly enhanced in vitro by antibody raised against the PRRSV isolate ISU-P (p < 0.01). Increased yields and infection rates were highly correlated (r = 0.95) and the ratio of yield to infection rate was greater than 1.4, suggesting that more than one mechanism was responsible for enhanced infection. Antibody-dependent enhancement (ADE) of infection was also demonstrated in vivo using a completely randomized block design (n = 16). The mean level and duration of viremia were greater (p < 0.05) in pigs injected with subneutralizing amounts of PRRSV-specific IgG prior to virus challenge than in control pigs injected with normal IgG. In contrast, virus replication was significantly (p < 0.01) inhibited in pigs with neutralizing antibody titers of 4 log2. The period of time that subneutralizing levels of antibody can persist and contribute to ADE of PRRSV infection was estimated in 4 pigs injected with PRRSV-specific IgG to yield an initial neutralizing antibody titer of 3.8 log2. Neutralizing activity declined to undetectable levels by day 37 postinjection (PI). ADE activity was first detected in undiluted sera on day 20 PI and persisted through day 62 PI. Western immunoblot analysis of sera collected between days 37 and 62 PI detected antibodies specific for the 15-kDa nucleocapsid and 26-kDa glycosylated envelope proteins. These results strongly suggest that ADE has the potential to contribute to the pathogenesis of PRRSV infection and is mediated by antibody specific for the 26-kDa envelope protein.

Animals↗
PubMed1996

Bronchoalveolar oxyradical inflammatory elements herald bronchopulmonary dysplasia.

OBJECTIVES: To quantify oxyradical inflammatory markers in serial endotracheal tube aspirates obtained from premature neonates at risk for developing bronchopulmonary dysplasia, and to correlate these parameters with clinical manifestations of the disease. DESIGN: Prospective cohort study. SETTING: Tertiary neonatal intensive care unit. PATIENTS: Twenty-eight intubated, premature infants, with 15 infants displaying simple respiratory distress syndrome and 13 infants eventually developing bronchopulmonary dysplasia. INTERVENTIONS: Endotracheal tube aspirates were collected and clinical severity scores were calculated longitudinally from an inception cohort during the first week of life. Diagnosis of bronchopulmonary dysplasia by standard criteria was recorded at 30 days of life. Various biochemical analyses related to pulmonary oxyradical stress were determined on endotracheal tube aspirates and were normalized according to the magnitude of serum/aspirate urea ratios. The demographic, illness severity, and biochemical characteristics of infants with simple respiratory distress syndrome and those characteristics of infants developing bronchopulmonary dysplasia were evaluated by masked comparison. MEASUREMENTS AND MAIN RESULTS: Populations of respiratory distress syndrome and bronchopulmonary dysplasia infants could be differentiated during the first week of life by means of the following parameters: gestational age; birth weight; Score of Neonatal Acute Physiology; Neonatal Therapeutic Intervention Scoring System; epithelial lining fluid leukocytes; elastase; myeloperoxidase; xanthine oxidase and catalase enzyme activities; and total sulfhydryls. CONCLUSIONS: Infants with simple respiratory distress syndrome could be segregated from those infants who developed bronchopulmonary dysplasia by the magnitude of the epithelial lining fluid oxyradical inflammation markers. While infants developing bronchopulmonary dysplasia typically exhibited increased concentrations of these markers during the first week of life, those infants with simple respiratory distress syndrome displayed low, uniform, or decreasing values of these markers over this interval. Infants developing bronchopulmonary dysplasia demonstrate an early pulmonary inflammatory response, and one key aspect of this response involves various oxyradical-generating systems.

Bronchi↗
PubMed1996

Attenuation of endotoxin-induced pathophysiology by a new potent PAF receptor antagonist.

The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.

Animals↗
PubMed1995

Detection of porcine reproductive and respiratory syndrome virus in boar semen by PCR.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes a devastating disease in swine. The presence and transmission of PRRSV by boar semen has been demonstrated by using a swine bioassay. In this assay, 4- to 8-week-old pigs were inoculated intraperitoneally with semen from PRRSV-infected boars. Seroconversion of these piglets indicated the presence of PRRSV in semen. Seroconversion in gilts has also been demonstrated following artificial insemination with semen from PRRSV-infected boars. These methods of detecting PRRSV in boar semen are time-consuming, laborious, and expensive. The objective of this study was to develop a reliable and sensitive PCR assay to directly detect PRRSV in boar semen. Primers from open reading frames 1b and 7 of the PRRSV genome were used in nested PCRs. Virus was detected at concentrations as low as 10 infectious virions per ml in PRRSV-spiked semen. Specificity was confirmed by using a nested PCR and a 32P-labeled oligonucleotide probe. The primers did not react with related arteriviruses or other swine viruses. The PCR assay showed good correlation with the swine bioassay, and both methods were superior to virus isolation. To consistently identify PRRSV in boar semen, the cell fraction was separated by centrifugation at 600 x g for 20 min, a lysis buffer without a reducing agent (2-mercaptoethanol) was used, and nondiluted and 1:20-diluted cell fractions were evaluated by PCR. PRRSV was not reliably detected in the seminal plasma fraction of boar semen.

Animals↗
PubMed1995

Characterization of the humoral immune response to porcine reproductive and respiratory syndrome (PRRS) virus infection.

The development of the humoral immune response against porcine reproductive and respiratory syndrome (PRRS) virus was monitored by an indirect fluorescent antibody (IFA) test, immunoperoxidase monolayer assay (IPMA), enzyme-linked immunosorbent assay (ELISA), and serum virus neutralization (SVN) test over a 105-day period in 8 pigs experimentally infected with ATCC strain VR-2402. Specific antibodies against PRRS virus were first detected by the IFA test, IPMA, ELISA, and the SVN test 9-11, 5-9, 9-13, and 9-28 days postinoculation (PI), respectively, and reached their maximum values by 4-5, 5-6, 4-6, and 10-11 weeks PI, respectively, thereafter. After reaching maximum value, all assays showed a decline in antibody levels. Assuming a constant rate of antibody decay, it was estimated by regression analysis that the ELISA, IFA, IPMA, and SVN antibody titers would approach the lower limits of detection by approximately days 137, 158, 324, and 356 PI, respectively. In this study, the immunoperoxidase monolayer assay appeared to offer slightly better performance relative to the IFA test, ELISA, and SVN test in terms of earlier detection and slower rate of decline in antibody titers. Western immunoblot analysis revealed that antibody specific for the 15-kD viral protein was present in all pigs by 7 days PI and persisted throughout the 105-day observation period. Initial detection of antibodies to the 19-, 23-, and 26-kD proteins varied among pigs, ranging from 9 to 35 days PI. Thereafter, the antibody responses to these 3 viral proteins of PRRS virus continued to be detected throughout the 105-day study period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Persistence of porcine reproductive and respiratory syndrome virus in serum and semen of adult boars.

Four seronegative adult boars were intranasally inoculated with porcine reproductive and respiratory syndrome virus (PRRSV) isolate VR-2332. Serum and semen were collected 2-3 times weekly for over 100 days postinoculation (DPI). Serum samples were assayed for PRRSV by virus isolation (VI) and a polymerase chain reaction (PCR) and screened for antibodies to PRRSV using the indirect fluorescent antibody (IFA) and virus neutralization (VN) tests. Semen was assayed for PRRSV RNA by PCR. Virus and viral RNA was detected in the serum of all boars within 1 DPI by Vi and/or PCR. However, VI results indicated that viremia was transient and occurred from 1 to 9 DPI. Viral RNA was detected in serum from 1 to 31 DPI. In the acute stage of the infection, PRRSV RNA was detected in serum by PCR prior to the presence of viral RNA in semen. The PRRSV RNA was detected in semen as early as 3 DPI and persisted for 25 DPI in 2 of the boars and 56 and 92 DPI in the remaining 2 boars. Detection of PRRSV RNA in semen occurred 2-8 and 28-35 days prior to the detection of antibodies by IFA and VN, respectively. PRRSV was isolated from the bulbourethral gland of the boar that shed viral RNA in semen for 92 DPI. These results suggest that PRRSV RNA can be detected by PCR in boar serum and semen, and may persist for variable periods of time. Viremia and the serologic status of the boar are not adequate indicators of when PRRSV or PRRSV RNA is being shed in the semen. Preliminary findings also indicated that neither shipping stress nor reinoculation with homologous PRRSV resulted in viremia or viral RNA shedding in semen.

Animals↗
PubMed1995

Bronchoalveolar inflammatory pathophysiology of bronchopulmonary dysplasia.

It has been emphasized that to prevent BPD ultimately, society must prevent high-risk pregnancies that result in very low birthweight infants. This represents a problem of immense magnitude that demands utmost social science attention. While attempting to solve this complex dilemma, however, RDS and BPD continue to represent the major contributors toward infant mortality and morbidity in developed nations. Certainly elucidation of the pulmonary surfactant system coupled with pharmacologic intervention to replete deficiency of this system has represented a tremendous advance in understanding and therapy of neonatal lung injury. One might make the ethical argument, however, that decreasing mortality from RDS with exogenous pulmonary surfactant mandates an equally vigorous effort toward the prevention of BPD. Elucidation of the bronchoalveolar inflammatory response that characterizes the acute aspects of BPD offers a number of novel, therapeutic approaches that are only beginning to be explored. Although exogenous steroids may indeed have a beneficial effect in reducing the incidence and severity of BPD, there are undoubtedly a number of more specific approaches relating to various aspects of pulmonary inflammation that warrant investigation. Unlike ARDS, BPD represents an ideal disease in which to conduct clinical investigations, because individuals at risk for the disease may be identified early, even before the bronchoalveolar inflammatory response is established. Accordingly, prophylactic therapeutic intervention is plausible. Potentially modulation of the pulmonary inflammatory response associated with BPD will offer clinicians an alternative to current empiric, supportive therapy for BPD; namely therapy directed at one aspect of the very molecular basis of BPD pathophysiology.

Bronchitis↗
PubMed1994

Excretion of porcine reproductive and respiratory syndrome virus in semen after experimentally induced infection in boars.

Four boars intranasally inoculated with porcine reproductive and respiratory syndrome (PRRS) virus were monitored for 56 days after exposure for changes in semen characteristics and for the presence of virus in the semen. Clinically, 2 of 4 boars had mild respiratory signs of 1 day's duration after infection. Changes in appetite, behavior, or libido were not detected. All boars seroconverted on the indirect fluorescent antibody and serum virus neutralization tests by day 14 after inoculation. Virus was isolated from serum between days 7 and 14 after inoculation. During the monitoring period, semen volume decreased and pH correspondingly increased; however, this change began 7 to 10 days prior to infection. Differences in sperm morphologic features, concentration, or motility between the preinfection and postinfection samples were not observed. The PRRS virus was detected in semen at the first collection in each of the 4 boars (ie, 3 or 5 days after challenge exposure). Virus was detected in nearly all semen samples collected from the 4 infected boars through days 13, 25, 27, and 43, respectively. Neither gross nor microscopic lesions attributable to PRRS virus were observed in tissues collected at the termination of the experiment (day 56), and virus isolation results from reproductive tissues were negative.

Animals↗
PubMed1993

Longitudinal analysis of neutrophil superoxide anion generation in patients with septic shock.

OBJECTIVE: To examine polymorphonuclear leukocyte respiratory burst function serially in patients with septic shock. DESIGN: Prospective, longitudinal, descriptive study. SETTING: Adult and pediatric (university hospital) intensive care units. PATIENTS: Eight critically ill patients, with septic shock and eight critically ill patients without evidence of infection or sepsis. MEASUREMENTS AND MAIN RESULTS: Severity of patient illness was estimated serially using the Acute Physiology and Chronic Health Evaluation (APACHE II) scoring system. For each patient, neutrophil superoxide anion synthesis was assayed spectrophotometrically in multiple blood samples over a period of 7 to 12 days after clinical identification of septic shock. The initial sample was obtained < 12 hrs after admission. Reaction velocities initially, at 2 to 3 mins, and at 4 to 5 mins (nmol superoxide anion/min/10(6) neutrophils), and extent of reaction at 5 mins (nmol superoxide anion/5 mins/10(6) neutrophils) were determined for each assay. On the day of admission, the mean APACHE II score and initial velocity for the septic shock group were 21.5 +/- 10 and 4.6 +/- 2 nmol superoxide anion/min/10(6) neutrophils, respectively. Over the next 7 to 12 days, as the patients recovered, there was a significant (paired t-test) decrease in APACHE II scores (p < .005) and increase in initial velocity (p < .0005). The increase in initial velocity correlated with the accompanying decrease in APACHE II scores (r2 = .46). Neutrophil superoxide anion generation in the critically ill group was not suppressed compared with the septic shock group and remained normal throughout the evaluation period. CONCLUSIONS: In vitro neutrophil respiratory burst function is significantly depressed during early septic shock. As patients improve clinically, as quantitated by decreasing APACHE II scores, neutrophil respiratory burst function recovers, approaching normal values.

Adolescent↗