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Biomedical subjects

A J Pesce

Publications and source records attributed to A J Pesce.

At least 55 records · Page 3Linked to original sources
PubMed1988

Clinical variability of cyclosporine pharmacokinetics in adult and pediatric patients after renal, cardiac, hepatic, and bone-marrow transplants.

The most important limitation associated with the clinical use of cyclosporine is the narrow therapeutic range between its efficacy and toxicity. Effective treatment is further complicated by significant variation in intrapatient and interpatient pharmacokinetics of the drug. We describe a practical approach to pharmacokinetic analysis that does not interfere with the cyclosporine dosage regimen or with clinical management of the patient. To optimize therapy, we individualized patient management by using noncompartmental pharmacokinetic analysis. Mean residence time (MRT) and volume of distribution at steady-state were calculated from data on concentration vs time after dose. We applied this approach to 24 kidney, 12 heart, 8 bone-marrow, 7 liver, and 5 pancreas transplants. Individualized requirements for cyclosporine dose and dosage interval can be predicted from these parameters. MRT is the most useful pharmacokinetic parameter, because it allows prediction of the optimal dosage interval.

Adult↗
PubMed1988

Comparison of Abbott TDx fluorescence polarization immunoassay, Sandoz radioimmunoassay, and high-performance liquid chromatography methods for the assay of serum cyclosporine.

We have had the opportunity to compare the new FPIA method for the measurement of serum Cs to established assays. The technique used a precipitation step prior to the fluorescence polarization measurement. We compared serum HPLC and RIA to the FPIA procedure. The within run coefficients of variation were 7.2%, 9.5%, and 4%, respectively. Between run CVs were 8.0%, 12.2%, and 3.8%. The correlation coefficient for HPLC and both of the immunoassays was less than 70%, showing the influence of the different specificities of the techniques. Medical centers that have based patient care on the HPLC assay that measures only parent drug will have difficulty using an immunoassay that measures a combination of parent and metabolites. There was a good correlation (R2 = 0.93) between the two immunoassays indicating that those currently using the serum RIA for monitoring could, through careful correlation studies in their patient population, use the FPIA technique. The regression equation was as follows: serum FPIA = 1.27 serum RIA + 1.9. This indicates the higher bias of the FPIA measurements. The advantages of the FPIA assay are that 20 assays could be done in less than one hour. This is in contrast to the longer turnaround time of the standard Sandoz RIA procedure. The technical competence required to perform the assay is less than that needed to perform the current RIA procedure. The assay can be recommended for replacement of the serum RIA; however, a correlation of levels with clinical experience is necessary in view of the difference in values between RIA and FPIA.

Chromatography, High Pressure Liquid↗
PubMed1988

Cyclosporine pharmacokinetics in pancreas transplant recipients.

Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA.

Adult↗
PubMed1987

Cationization of protein antigens. I. Alteration of immunogenic properties.

We have shown that a cationized form of bovine serum albumin (BSA) produced by substituting anionic side chain carboxylic groups with aminoethylamide groups possesses unique immunologic properties. The two forms of antigen, native (nBSA) and cationized (cBSA), cross-react at the level of the B cell, as evidenced by the ability of antibody raised against one form to react with the other and by inhibition assays using ELISA. T cell cross-reactivity was also observed in proliferation assays, but the amount of cBSA required for stimulation was 500 times less than the amount of native protein needed. In vivo, cBSA produced responses which, at their optimal levels, were at least double the response to nBSA and which showed a different kinetic pattern, peaking later and lasting longer than the response to the native molecule. Moreover, antibodies were produced in response to administration of cBSA but not nBSA when given i.v. in saline, without an adjuvant. Although a mechanism for these phenomena is not yet clear, we speculate that the cBSA may have a greater affinity for antigen-presenting cells or for the T cell receptor, or that the altered structure may enhance recognition of the molecule by APC and/or helper T cells.

Animals↗
PubMed1987

Analysis of polysorbate and its polyoxyethylated metabolite.

Polysorbates are used as emulsifiers in a number of pharmaceuticals and have been implicated as the possible toxic agent in the neonatal vitamin supplement, E-Ferol. In the investigation of the toxicity of this compound, it was necessary to find a method to separate and quantitate polysorbate and its polyoxyethylated metabolite from biological fluids. A high-performance liquid chromatography method was developed which combines the use of a 500 A mu Styragel size exclusion column with an ammonium cobaltothiocyanate complexation column and detection at 620 or 320 nm. The detection limit is approximately 5 micrograms. The method was used to demonstrate that polysorbate was metabolized in vitro by hepatocytes and that the urinary metabolite in humans is comparable to that produced by the rat.

Animals↗
PubMed1987

A high performance liquid chromatography method for trimethoprim utilizing solid-phase column extraction.

The antibiotic combination of sulfamethoxazole and trimethoprim was evaluated for treatment of peritonitis in patients in renal failure undergoing continuous ambulatory peritoneal dialysis. Although current methods of analysis were adequate for measurement of sulfamethoxazole, a review of the available methods of analysis for trimethoprim did not yield a satisfactory method. Therefore, a high performance liquid chromatography (HPLC) assay was developed to follow the pharmacokinetics of trimethoprim in serum and peritoneal dialysate fluid. In this assay, trimethoprim is extracted from plasma, serum, or dialysate fluid by solid-phase column chromatography that is efficient (82% recovery), quick, and simple to use. The HPLC method utilizes a common reverse-phase system with a 0.01 M sodium acetate and acetonitrile mobile phase and detection at 254 nm. The assay offers excellent between-run replication (p = 0.96), high sensitivity (0.05 microgram/mL), and linearity over a wide range (2-100 micrograms/ml; r = 0.99). The method offers freedom from interference by metabolites and a wide range of commonly administered drugs. It is suitable for other pharmacokinetic studies involving trimethoprim but not its metabolites, and also for clinical assay of trimethoprim in situations where high levels of the antibiotic are necessary to combat resistant organisms and in serious infections by opportunistic organisms such as Pneumocystis carinii.

Chromatography, High Pressure Liquid↗
PubMed1987

The effect of oral metoclopramide on the absorption of cyclosporine.

This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients. The study was conducted on two consecutive days. Ten patients were studied twice, and 4 patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole-blood cyclosporine levels were analyzed by high-performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/ml versus 388 ng/ml) and mean area under the blood-concentration-versus-time curve (4120 ng X hr/ml versus 3370 ng X hr/ml); and a significant decrease in mean time to reach maximum concentration. The mean increase in area under the blood-concentration-versus-time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine.

Adult↗
PubMed1987

An immune complex glomerulopathy associated with glomerular capillary thrombosis in the laboratory mouse. A highly reproducible accelerated model utilizing cationized antigen.

An accelerated, highly reproducible model of an immune complex glomerulopathy in the laboratory mouse was developed by using cationized bovine gamma-globulin (cat-BGG) as the nephritogenic agent. Preimmunized Balb/c mice given three 250-micrograms doses of cat-BGG consistently develop a nonproliferative glomerular lesion which becomes manifested clinically by the nephrotic syndrome and results in death within 14 days. Significant proteinuria is evident by day 4 (24 hours after the third dose of cat-BGG) at which time extensive deposits of cat-BGG, IgG, and C3 are localized along the glomerular capillary walls. At the ultrastructural level, subepithelial deposits and foot process effacement are evident. By day 6, subendothelial and mesangial deposits are also present, and by day 10, extensive glomerular capillary thrombosis and early crescent formation develop. The reproducibility and rapidity of the induction of disease, and the spectrum of pathological changes occurring in the glomeruli make this murine model of an immune complex glomerulopathy potentially useful for the study of the mechanisms underlying the induction and progression of glomerular injury and the evaluation of potential therapy.

Animals↗
PubMed1987

The effect of oral metoclopramide on the absorption of cyclosporine.

This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients with stable renal function. The study was conducted on two consecutive days. Ten patients were studied twice and four patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole blood cyclosporine levels were analyzed by high performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/mL nu 388 ng/mL) and mean area under the blood concentration nu time curve (4120 ng X h/mL nu 3370 ng X h/mL), and a significant decrease in mean time to reach maximum concentration: The mean increase in area under the blood concentration versus time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine.

Administration, Oral↗
PubMed1986

Cationic antigens. Problems associated with measurement by ELISA.

The measurement of the mouse antibody response to cationized bovine serum albumin (cat BSA) and bovine gammaglobulin (cat BGG) was complicated because of the unique properties of these antigens. Cat BGG non-specifically bound rabbit anti-mouse gammaglobulin conjugated to alkaline phosphatase. This was minimized by adding the polyanion, heparin. Cat BSA also reacted non-specifically with some conjugates, but the reaction with specific antibody was enhanced by the addition of the polyanions heparin or dextran sulfate. The non-specific reaction did not appear to be related to the concentration of antigen used to coat the plastic plates. In addition, in ELISA inhibition experiments high concentration of antigens (greater than 100 micrograms/ml) seemed to result in non-specific inhibition of the antibody antigen reaction. A proposed model to explain the problems is based on the polycationic surface formed by coating the plates with the cationized proteins. This cationic surface can be neutralized by polyanions, reducing the non-specific and enhancing the specific reactions. It appears that other polycationic molecules might share these unique properties and these factors must be considered when they are measured.

Alkaline Phosphatase↗
PubMed1986

Enzyme-linked immunoabsorbant assay of apolipoprotein AII in plasma, with use of a monoclonal antibody.

We produced a monoclonal antibody (C2-22) to human apolipoprotein (Apo) AII and describe its use in an enzyme-linked immunoabsorbant assay (ELISA) for Apo AII in human plasma and lipoprotein subfractions. No cross reactivity of the antibody with Apo CI, CII, CIII, E, or ablumin was detected. Apo AI and low- and very-low-density lipoprotein cross reacted by 0.25%, less than 0.2%, and less than 0.3%, respectively. Whole plasma high-density lipoprotein (HDL) and HDL subfractions (HDL2 and HDL3) produced parallel displacement curves. This quantitative ELISA is based on competition between solid-phase-bound Apo AII and free Apo AII. Bound C2-22 is detected by alkaline-phosphatase-labeled second antibody. The standard curve for the assay is linear for plasma diluted 500-fold originally containing 140 to 1140 mg of Apo AII per liter. Delipidation of plasma samples exposed no additional antigenic sites. Within- and between-run CVs were respectively 8.4% and 8.7% at 327 mg/L of Apo AII, and 6.8% and 7.4% at 587 mg/L. Results correlated well with those by a polyvalent-antisera-based RIA procedure: r = 0.916, p less than 0.01, RIA = 0.896 ELISA -19.1 mg/L.

Animals↗
PubMed1985

Evaluation of amitriptyline pharmacokinetics during peritoneal dialysis.

The pharmacokinetics of a single oral dose of amitriptyline were examined in five functionally anephric patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The concentration of the parent drug and its major metabolite nortriptyline in plasma were measured by high performance liquid chromatography. Patients on CAPD did not have a significantly extended elimination half-life (t 1/2) as compared to literature controls. However, the variation in t 1/2 was extremely large in both the CAPD and normal renal function groups (range 15-34 h and 24-70 h, respectively). No statistically significant change was observed (p less than 0.05). Although a major route of elimination was removed and there was no change in t 1/2, the drug levels in these patients should be closely monitored because of the large variability in patient metabolism.

Adult↗
PubMed1985

Animal model for theophylline--cimetidine drug interaction.

Cimetidine (300 mg I.V.) and theophylline (15 mg/kg I.V.) were studied in Beagle dogs for possible drug interaction. The drugs were administered alone and in combination using a crossover design. Although none of the determined pharmacokinetic parameters for theophylline changed significantly in the presence of cimetidine, a trend towards significance was found for the terminal half-life, area under the curve, and mean residence time. The magnitude in changes found in Beagles is representative of the changes reported in man.

Animals↗
PubMed1984

Analysis of humoral and cellular factors that contribute to impaired immune responsiveness in experimental uremia.

An experimental model in rats was developed to define the nature of humoral and cellular factors that contribute to impaired immune responsiveness in chronic renal failure. Addition of uremic rat serum to both normal and uremic lymphocytes significantly suppressed cellular responses, the suppression being more pronounced with uremic lymphocytes. Lymphocytes from uremic rats were only marginally less responsive than normal lymphocytes to concanavalin A stimulation when normal rat serum was added to the cultures, indicating that the cellular factors in impairment were less important than humoral ones. Antibody formation in rat splenocyte cultures to bovine serum albumin was suppressed by addition of uremic serum, but the response to sheep erythrocytes was unaffected. Thus the effect on antibody response in uremic animals is dependent upon the antigen tested.

Animals↗