Which cyclosporin formulation?
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Biological Availability↗
Biomedical subjects
M M Meyer
Publications and source records attributed to M M Meyer.
Cyclosporine and vancomycin disposition during continuous venovenous hemodiafiltration.
OBJECTIVE: To report cyclosporine and vancomycin disposition during continuous venovenous hemodiafiltration (CVVHD) in a 41-year-old heart transplant patient while in the intensive care unit at a primary and tertiary care teaching hospital. CASE SUMMARY: The patient received a 60-mg infusion of cyclosporine over 24 hours and vancomycin 1 g over 1 hour. Blood samples subsequently were collected and analyzed using whole blood monoclonal radioimmunoassay and fluorescence polarization immunoassay, respectively. Blood samples were measured every hour from the arterial and venous lines of the apparatus, as were ultrafiltrate drug concentrations. Drug clearance rates into the ultrafiltrate subsequently were calculated. DISCUSSION: Measurements of ultrafiltrate detected no cyclosporine. A slight variation existed between arterial and venous drug concentrations, which was not statistically significant (p > 0.05, paired Student's t-test). Analysis of vancomycin samples revealed a steady decline of drug concentration, with 4.75% of the dose eliminated in the ultrafiltrate. Vancomycin arterial and venous concentrations decreased from 24.4 and 23.3 mg/L to 15.7 and 12.3 mg/L, respectively. CONCLUSIONS: Vancomycin is eliminated by CVVHD and it may be necessary for these patients to receive the drug more frequently. In contrast, cyclosporine is not removed effectively by CVVHD; therefore, replacement doses are not warranted.
Adult↗
T cell receptor V beta gene expression in monozygotic twins. Discordance in CD8 subset and in disease states.
The peripheral T cell repertoire is shaped by positive and negative selection. These intrathymic events are dependent on the direct interaction of MHC and TCR molecules. Inasmuch as one possible mechanism for HLA-linked disease involves the role that these molecules play in shaping the peripheral T cell repertoire, an understanding of how stable the repertoire remains is an important question that will influence future studies. The purpose of this study was to analyze the stability of the T cell repertoire in monozygotic twins. To investigate this question the percentage of CD4 and CD8 T cells expressing TCR V beta gene products was determined for seven sets of healthy monozygotic twins ages 2 through 44. V beta expression was determined by three-color flow cytometric analysis using antibodies to V beta-5.1, -5.2, -5.3, -6.7, -8, and -12. The percentage of CD4 cells expressing each V beta gene was highly concordant between twins. In contrast, differences were noted for V beta expression within the CD8 subset. This was especially marked when sets of twins were studied (n = 3) where one individual had an underlying disease. Although expression in the CD4 subset was again concordant, significant differences were noted within the CD8 subset compared to the healthy twin. These data indicate that in both health and disease, the CD4 T cell repertoire is tightly regulated although often sizable differences have developed in the CD8 compartment.
Adolescent↗
A prospective, double-blind, randomized study of high-versus low-dose OKT3 induction immunosuppression in cadaveric renal transplantation.
We undertook a prospective, double-blind study of high-(5-mg) versus low-(2-mg) dose OKT3 for induction immunosuppression (12 days) in cadaveric renal allograft transplantation. Maintenance immunosuppression was identical in both groups and consisted of azathioprine and prednisone initially, with cyclosporine beginning on the 5th postoperative day. Twenty-six patients were randomized. The groups were similar in terms of age, kidney ischemia time, peak PRA, and latest PRA. There were more diabetics and women in the high-dose group. Patient survival at 12 months was 100% in both groups. Graft survival at 12 months was 92% and 100% in the high- and low-dose groups, respectively. Infections were mostly minor and equal in frequency in the two groups. All patients receiving high- or low-dose OKT3 had manifestations of the cytokine release syndrome; these were delayed in onset in the low-dose group. Eleven patients (85%) in each group produced anti-OKT3 antibodies. Lymphocyte depletion after 1 day was major (> 98%) and identical in both groups. CD3 antigens were removed more slowly in the low-dose group but eventually at equal rates in both groups. Cost was significantly lower in the low-dose group. We conclude that while both doses of OKT3 were effective and safe for induction immunosuppression, it may be prudent to use a lower dose of OKT3 for induction immunosuppression because of its potential to reduce cytokine-mediated effects and to avoid the complications of overimmunosuppression and because of the lower costs associated with it.
Adolescent↗
Nitrofurantoin-induced pulmonary hemorrhage in a renal transplant recipient receiving immunosuppressive therapy: case report and review of the literature.
A 33-year-old woman received a cadaveric renal transplant for focal segmental glomerulosclerosis. Nitrofurantoin urinary prophylaxis was started on postoperative day 13 but coughing and mild hemoptysis began 2 days later. Diffuse infiltrates and worsening hemoptysis led to intubation and open lung biopsy. Clinical course, culture results and pathological evaluation excluded infectious etiologies and were consistent with a drug reaction. The case is described, and the literature on the nitrofurantoin pulmonary toxicity syndromes and pathophysiology is reviewed.
Adult↗
Outpatient vaginal hysterectomy in a community hospital.
From Sept 1, 1992 to Dec 31, 1993, 38 outpatient vaginal hysterectomy patients were evaluated for identification of complications after discharge, adequacy of pain relief at home, return to baseline lifestyle, and costs. No complications that would have necessitated an overnight or longer stay were identified. All patients reported adequate pain relief and a more rapid return to activity than they had expected. The hospital cost of outpatient vaginal hysterectomy was about half that of inpatient, and additional significant savings were realized in the cost of postoperative medication. Patients were positive about returning home the day of surgery and would recommend the protocol to others who qualified.
Adult↗
Efficacy of area under the curve cyclosporine monitoring in renal transplantation.
Previous studies suggest that area-under-the-curve (AUC) pharmacokinetic monitoring is superior to trough level monitoring for proper cyclosporin A (CSA) dosing, but AUC monitoring is expensive and unwieldy. The utility of a simplified AUC monitoring method was evaluated for predicting AUC on the basis of three timed levels. CSA pharmacokinetic profiles were studied in 27 renal transplant patients at steady state early (days), late (months), and in some patients, serially posttransplantation. Whole-blood RIA levels were obtained at 2, 4, 6, 10, 12, 14, and 24 h after a once-daily CSA dose. The 6- and 24-h levels were the best single-level predictors of AUC (r = 0.77 and 0.76, respectively). The best model predictive of AUC curves used three time points at 2, 6, and 24 h postdose: AUC predicted = 8.6 x (24 h) + 1.4 x (2 h) + 6.2 x (6 h) + 1.57 mg x h/L; r2 = 0.986, P = 0.00001. The greatest pharmacokinetic variability occurred between 0 and 10 h postdose (absorption and distribution) between patients and even within individual patients monitored serially over time. The 12- to 24-h postdose portion (elimination) of the curve was consistently flat and uniform among patients. AUC were not consistent in individual patients over time. An AUC of more than 13 mg x h/L correlated with nephrotoxicity, whereas a value of 8 mg x h/L correlated with protection from rejection in first-transplant recipients. This AUC, however, was not able to prevent rejection in reengrafted or highly sensitized patients.
Adult↗
Incidence and type of cancer following the use of OKT3: a single center experience with 557 organ transplants.
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Adenoma, Bile Duct↗
Cytokine-related encephalopathy induced by OKT3: incidence and predisposing factors.
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Azathioprine↗
Use of OKT4A (a murine monoclonal anti-CD4 antibody) in human organ transplantation: initial clinical experience.
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Animals↗
The amino acid substrate of bovine tyrosine hydroxylase.
Tyrosine hydroxylase catalyzes the tetrahydropterin-dependent hydroxylation of tyrosine to form 3,4-dihydroxyphenylalanine. Several nonphysiological aromatic amino acids have been examined as inhibitors and substrates for bovine adrenal tyrosine hydroxylase. The Ki values for para-substituted phenylalanines increase as the size of the substituent increases. For each A2 increase in surface area of the substituent, the free energy of binding becomes 50 cal more positive. Replacement of the phenyl ring with a pyridyl ring decreases the affinity about one order of magnitude. A number of these aromatic amino acids are also substrates for the enzyme. The KM values again increase in size with increasing size of the substituent, but the Vmax value is independent of the reactivity of the amino acid. The effect of size on binding is consistent with a tight interaction between the para position region of the substrate and the enzyme. The lack of a change in the Vmax value is consistent with the rate-limiting step in catalysis by bovine tyrosine hydroxylase being formation of the hydroxylating intermediate rather than hydroxylation of the amino acid. These results will be useful in designing mechanism-based inhibitors of catecholamine biosynthesis and establish that the mechanisms of rat and bovine tyrosine hydroxylase do not differ significantly.
Adrenal Glands↗
Can recognition of living things be selectively impaired?
Brain damage sometimes seems to impair recognition of living things, despite relatively preserved recognition of nonliving things. The most straightforward interpretation of this dissociation is that the recognition of living things depends on some specialized mechanisms that are not needed for the recognition of nonliving things. However, there are alternative interpretations of the dissociation in terms of the greater complexity or inter-item similarity of living things, or the more specific, within-category identifications that are usually required for living things. Surprisingly, the relevant tests to discriminate among these rival hypotheses have never been performed. We took the factors of visual complexity, inter-item similarity, specificity of identification, as well as others, into account in analyzing the visual recognition performance of two head-injured visual agnosic patients. In each case we found that recognition of living things was still disproportionately impaired when the effects of the other factors were accounted for.
Adult↗
T-cell receptor variable beta genes show differential expression in CD4 and CD8 T cells.
Studies in transgenic and inbred strains of mice have shown that the critical molecular interactions controlling positive selection involve major histocompatibility complex (MHC), T-cell receptor (TCR), and CD4 or CD8 coreceptor molecules. Correlations have been established between MHC gene products and the percentage of CD4 or CD8 T cells that express specific variable (V) beta-gene products as part of the alpha beta heterodimer. These studies have important implications regarding potential mechanisms of HLA-linked autoimmune diseases in humans. If similar interactions are required for positive selection in humans, one would predict that the TCR repertoire expressed by mature, peripheral blood CD4 and CD8 T cells would vary. To test this hypothesis the expression of specific TCR V beta-region genes by CD4 and CD8 T cells from healthy individuals was compared using both triple-color flow cytometry and polymerase chain reaction based experimental approaches. The results show that the TCR repertoire does vary as a function of CD4 and CD8 T-cell subsets. Among unrelated individuals certain V beta genes were consistently overrepresented in the CD4 population (V beta-5.1, -6.7a, and -18); some were skewed to the CD8 population (V beta-14) while others showed variable patterns (V beta-12 and -17). Deletion of entire V beta gene families was not observed suggesting that this is a rare event in humans. Attempts to correlate the expressed TCR repertoire in humans with HLA alleles will require consideration of these differences in expression as a function of subset.
Antibodies, Monoclonal↗
A note on randomization and selection bias in maintenance therapy clinical trials.
In this article we demonstrate that even in randomized controlled clinical trials, unobserved confounding variables can bias the outcome of a study. For the case of a two-phase maintenance therapy trial where patients who respond to treatment during the acute phase are then randomized to a maintenance therapy, we show explicitly the role that confounding may play in biasing the interpretation of the results of such a trial. We suggest an alternative design to deal with the problem of a selection effect for treatment responders in the acute phase of the trial by randomizing patients at the outset of the study to both an acute and maintenance therapy.
Bias↗
Outcome of renal transplantation at Oregon Health Sciences University: 1982 to 1990.
1. Graft survival increased over the 4 periods between 1982 and 1990 (82-84, 85-86, 87-88, 89-90). The largest increase was in the 89-90 period. 2. Immunosuppression was the key to improved outcome. Cadaveric graft recipients given OKT3 induction plus triple therapy with cyclosporine, azathioprine, and prednisone had significantly better graft survival compared with all other drug combinations. Other factors were improved patient selection, donor management, and outpatient care. 3. Mean serum creatinine levels did not change after cyclosporine was introduced for immunosuppression. The mean serum creatinine level was approximately 1.7 mg/dl at 3 months, 6 months, and 12 months post-transplantation in all 4 periods. 4. Living-related donor outcome was significantly better than cadaveric donor outcome. Half-life for 2-haplotype-matched kidneys was 37 years compared with 12 years for 1-haplotype matches and 6.5 years for cadaveric kidneys. 5. Immediate function and a rejection-free first month were both associated with significantly improved graft survival. 6. Neither peak PRA nor graft number (1st vs regraft) correlated with graft survival. Highly sensitized (PRA greater than 50%) patients and regrafted patients fared as well as less sensitized (PRA less than or equal to 50%) and first graft recipients. This outcome was attributed to a sensitive crossmatch. Because of the crossmatch, highly sensitized patients received much better HLA matches. 7. The incidence of early rejection and delayed function declined significantly between the earliest and latest periods. Improved immunosuppression, donor management, and renal preservation were cited as contributing factors.
Actuarial Analysis↗
Evidence for water channels in renal proximal tubule cell membranes.
Water transport mechanisms in rabbit proximal convoluted cell membranes were examined by measurement of: osmotic (Pf) and diffusional (Pd) water permeabilities, inhibition of Pf by mercurials, and activation energies (Ea) for Pf. Pf was measured in PCT brush border (BBMV) and basolateral membrane (BLMV) vesicles, and in viable PCT cells by stopped-flow light scattering; Pd was measured in PCT cells by proton NMR T1 relaxation times using Mn as a paramagnetic quencher. In BLMV, Pf (0.019 cm/sec, 23 degrees C) was inhibited 65% by 5 mM pCMBS and 75% by 300 microM HgCl2 (KI = 42 microM); Ea increased from 3.6 to 7.6 kcal/mole (15-40 degrees C) with 300 microM HgCl2. In BBMV, Pf (0.073 cm/sec, 23 degrees C, Ea = 2.8 kcal/mole, less than 33 degrees C and 13.7 kcal/mole, greater than 33 degrees C) was inhibited 65% with HgCl2 with Ea = 9.4 kcal/mole (15-45 degrees C). Mercurial inhibition in BLMV and BBMV was reversed with 10 microM mercaptoethanol. Viable PCT cells were isolated from renal cortex by Dounce homogenization and differential seiving. Impedence sizing studies show that PCT cells are perfect osmometers (100-1000 mOsm). Assuming a cell surface-to-volume ratio of 25,000 cm-1, Pf was 0.010 +/- 0.002 cm/sec (37 degrees C) and Pd was 0.0032 cm/sec. Pf was independent of osmotic gradient size (25-1000 mOsm) with Ea 2.5 kcal/mole (less than 27 degrees C) and 12.7 kcal/mole (greater than 27 degrees C). Cell Pf was inhibited 53% by 300 microM HgCl2 (23 degrees C) with Ea 6.2 kcal/mole. These findings indicate that cell Pf is not restricted by extracellular or cytoplasmic unstirred layers and that cell Pf is not flow-dependent. The high BLMV and BBMV Pf, inhibition by HgCl2, low Ea which increases with inhibition, and the measured Pf/Pd greater than 1 in cells in the absence of unstirred layers provide strong evidence for the existence of water channels in proximal tubule brush border and basolateral membranes. These channels are similar to those found in erythrocytes and are likely required for rapid PCT transcellular water flow.
Animals↗
Human platelet osmotic water and nonelectrolyte transport.
The osmotic water (Pf) and nonelectrolyte permeability (Ps) properties of human platelets were characterized using the stopped-flow light-scattering technique. At 37 degrees C, Pf = 0.007 +/- 0.001 cm/s, the urea reflection coefficient (sigma urea) = 0.95 +/- 0.04, and Ps for a series of permeant nonelectrolytes was (in cm X s-1 X 10(-6)) 2.1 (urea), 3.5 (glycerol), 3.8 (thiourea), 17 (ethylene glycol), 18 (acetamide), 23 (formamide), and 24 (butyramide). Pf did not depend on the size of the osmotic gradient or on the direction of volume flow. Mercurial sulfhydryl reagents did not inhibit osmotic water transport, and phloretin and phenylurea did not inhibit urea transport. There was a discontinuity in the temperature dependence for both Pf and urea permeability (P urea) at 36 degrees C; enthalpy (delta H) = 25 (greater than 36 degrees C) and 4.4 kcal/mol (less than 36 degrees C) for Pf, and delta H = 26 (greater than 36 degrees C) and 7 kcal/mol (less than 36 degrees C) for P urea. In contrast to the facilitated water and urea transport systems in the red blood cell, these results suggest that the mechanism for water and urea transport in the platelet is primarily by diffusion through membrane phospholipid. A computer-simulated model of platelet circulation through the renal medulla, based on the measured values for Pf, P urea, and sigma urea, indicated that platelets undergo an approximately 40% decrease in volume in the inner medulla and an approximately 20% overshoot in volume as they return to the external isosmotic environment.
Amides↗