Background. The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. Methods. Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. Results. The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients(0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA(P=NS). Serum creatinine rose transiently in 35 patients(9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA(P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA(P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug(P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). Conclusions. MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.
The interest in alternative therapeutics use has increased over the past few decades. Valerian, also known as "plant Valium," is a popular choice as a natural remedy for insomnia or anxiety. In order to ensure patient safety, clinicians need to be knowledgeable about commonly used alternative therapeutic products, their mechanisms of action, and potential pharmacological interactions. We present an unusual case of encephalopathy due to the combination of Valerian root, a plant with putative sedating properties, along with a natural "γ-aminobutyric acid (GABA) supplement." This case highlights the importance of thoroughly exploring alternative therapies when evaluating encephalopathy as well as the importance of being educated on the commonly used agents.
Background. Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. Methods. Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. Results. At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149±58 μmol/L, compared with 158±102 μmol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. Conclusions. On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.
Technical Briefs A Photoelastic Re-Examination of Notched Tension Bars M. M. Frocht, M. M. Frocht Illinois Institute of Technology, Chicago, Ill. Search for other works by this author on: This Site PubMed Google Scholar R. Guernsey, Jr., R. Guernsey, Jr. Laboratory of Experimental Stress Analysis, Mechanics Department, Illinois Institute of Technology, Chicago, Ill. Search for other works by this author on: This Site PubMed Google Scholar D. Landsberg D. Landsberg Laboratory of Experimental Stress Analysis, Mechanics Department, Illinois Institute of Technology, Chicago, Ill. Search for other works by this author on: This Site PubMed Google Scholar Author and Article Information M. M. Frocht Illinois Institute of Technology, Chicago, Ill. R. Guernsey, Jr. Laboratory of Experimental Stress Analysis, Mechanics Department, Illinois Institute of Technology, Chicago, Ill. D. Landsberg Laboratory of Experimental Stress Analysis, Mechanics Department, Illinois Institute of Technology, Chicago, Ill. J. Appl. Mech. Mar 1952, 19(1): 124 (1 pages) https://doi.org/10.1115/1.4010418 Published Online: April 7, 2021 Article history Received: December 10, 1951 Published: March 1, 1952 Online: April 7, 2021
CARDIAC INVESTIGATIONS IN KIDNEY TRANSPLANT WAIT LIST CANDIDATES - RELIANCE ON CLINICAL INDICATIONS IS NOT EFFECTIVE. Irene Ma;John Gill;Nathan Johnson;David Landsberg;Adeera Levin; American Journal of Transplantation Supplement
