Comparison of the safety and efficacy of oral vs constant-rate intravenous infusion cyclosporine immediately following orthotopic heart transplantation.
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Acute Kidney Injury↗
Biomedical subjects
A J Pesce
Publications and source records attributed to A J Pesce.
Lidocaine metabolism as an index of liver function in hepatic transplant donors and recipients.
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Biopsy↗
An evaluation of the cyclosporine and metabolites whole blood TDx assay.
The new Abbott TDx cyclosporine and metabolites fluorescent polarization immunoassay procedure provides a 20-min sample turn-around time, using 50 microliters of sample for the analysis of cyclosporine in whole blood. A precipitation agent and a lysing agent are utilized as a pretreatment step. The range of the whole blood assay is from 0 to 2,000 ng/ml, with a sensitivity of 50 ng/ml. Precision studies at 3 control levels provided coefficients of variation of 2.1-4.8% for both assays. In order to compare this assay with the currently used Sandoz polyclonal radioimmunoassay (RIA) method. 200 whole blood samples were obtained from 20 renal, cardiac, and hepatic transplant recipients. The mean whole blood cyclosporine concentrations for samples above the sensitivity level were as follows: TDx 754 ng/ml (+/- 31) and RIA 619 ng/ml (+/- 22). Blood TDx levels correlated strongly with RIA levels, with a regression coefficient of r = 0.915. This new assay provides reliable blood cyclosporine concentrations that correlate well with RIA measurements. This assay offers rapid sample turn-around times, making same-day results for outpatient drug monitoring possible.
Cyclosporins↗
Liquid-chromatographic monitoring of cytosine arabinoside and its metabolite, uracil arabinoside, in serum.
This is a "high-performance" liquid-chromatographic method for quantifying the antileukemic drug cytosine arabinoside (cytarabine; 1-beta-D-arabinofuranosylcytosine; Ara-C), with a structural analog, 5-methylcytidine, as the internal standard. We used a C18 reversed-phase column and ammonium acetate (0.5 mol/L, pH 6.5) as the mobile phase, monitoring the column effluent at 280 nm. Tetrahydrouridine was present in the sample-collection tubes to inhibit conversion of cytosine arabinoside to uracil arabinoside. The standard curve is linear to 100 mg/L. Analytical recovery is 98%. Coefficients of variation for within-run and between-run imprecision were 2.0% and 4.3% at 20 mg/L and 2.7% and 2.7% at 80 mg/L, respectively. Assay sensitivity was limited by the amount of endogenous material in each patient's serum, making assay of a pre-infusion sample necessary for accurate calculations. In a trial patient population, the assay was shown to have potential for the detection of toxic concentrations in patients receiving high doses of Ara-C.
Aged↗
Microplate measurement of urinary albumin and creatinine.
We describe microplate methods for measurement of human urinary albumin (HUA) by competitive enzyme-linked immunosorbant assay (ELISA) and creatinine with a modified commercial enzymatic kit. Incorporation of substrate mixing into the competitive ELISA changes the dynamic absorbance-concentration response, greatly simplifying calculations and improving sensitivity and accuracy. Measurement of creatinine in urine and plasma samples with a commercially available enzymatic kit modified for analysis by use of an inexpensive microplate reader produced values comparable in precision and accuracy to those obtained by an automated kinetic Jaffé method.
Adult↗
Hyperthermia, hypertension, hypertonia, and coma in a massive thioridazine overdose.
This report characterizes an atypical presentation of a thioridazine overdose. Clinical manifestations included wide Q.R.S. complex, hyperthermia, hypertension, hypertonia, and coma. Plasma catecholamine levels were markedly elevated. The patient was treated with dantrolene sodium and supportive care. The patient's condition improved over time, with questionable response to dantrolene sodium. Supportive care was the mainstay of treatment.
Acute Disease↗
Regulation of the immune response to allergens by immunosuppressive allergenic fragments. 1. Peptic fragments of honey bee venom phospholipase A2.
Nine patients with anaphylactic sensitivity to honey bee venom (HBV) were treated with P-1, a pepsin derived fragment of HBV phospholipase A2 (PLA2). P-1 caused only rare reactions with doses of 100 micrograms/injection. Treatment resulted in a substantial decrease in specific anti-PLA2 IgE and IgG antibodies as well as a decline in skin test sensitivity to PLA2. Another group of HBV-sensitive patients was treated with unaltered PLA2. Doses greater than 20 micrograms/injection were not tolerated. PLA2 injections caused an increase in anti-PLA2 IgG and IgE antibodies as well as increase in skin test sensitivity. This study demonstrates that a nonimmunogenic fragment derived from an allergen can downregulate immune responses and thus offer a new modality for therapy of allergic diseases.
Adult↗
C3 dependent, C5 independent immune complex glomerulopathy in the mouse.
This study examines the role of complement in a murine model of accelerated nonproliferative immune complex glomerulopathy. Two C5 deficient strains (DBA/2J and B10.D2oSnJ) as well as normocomplementemic mice consistently develop heavy proteinuria and glomeruli show loss of normal visceral epithelial cell architecture within 4 days of intravenous antigen administration. In contrast, animals depleted of C3 with cobra venom factor fail to develop proteinuria and retain discrete foot processes. Semiquantitative evaluation of antigen and antibody in glomeruli shows equivalent deposition in mice from all groups. The localization of these deposits, however, is different in C3-depleted mice. There is extensive accumulation of deposits along the subepithelial aspect of the glomerular basement membrane of normocomplementemic and C5 deficient mice while deposits in glomeruli of C3-depleted animals accumulate in the subendothelial region and do not cross the glomerular basement membrane. These data demonstrate that in this model, glomerular injury is dependent on complement components generated up thru C3 but not C5 or latter components. In addition, our data suggest that C3 is important in the movement of immune complexes across the glomerular basement membrane. Although the mechanism by which complement is mediating injury in this model is not known, it does not appear to involve an inflammatory cell infiltrate or the terminal complement components.
Animals↗
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↗
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↗
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↗
Use of cyclosporine by constant-rate intravenous infusion immediately after heart transplantation.
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Creatinine↗
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↗
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↗
Interaction between erythromycin and cyclosporine in a kidney and pancreas allograft recipient.
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Adult↗
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↗
Cyclosporine drug interactions: a review.
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Animals↗
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↗