Therapeutic drug monitoring of cyclosporine and tacrolimus. Update on Lake Louise Consensus Conference on cyclosporin and tacrolimus

The authorization of departments of community dentistry and public health in the nation's dental schools is a relatively recent innovation in dental education. Such a department was established at the University of Southern California School of Dentistry in 1966, as part of the School of Medicine's effort to share responsibility in providing both access and availability of health services in inner-city Los Angeles, California. Dentistry was included in the protocol submitted to the US Office of Economic Opportunity to build a neighborhood health center in Watts, operated under the joint jurisdiction of the medical and dental schools. The dental division of the health center was designated a satellite of the community dentistry department. The department envisioned future changes during the revolutionary 1960s when all aspects of the nation were experiencing upheaval as traditional concepts were challenged by new attitudes. The nation's leaders in government and education as well as in the health professions were stimulated by scientific and technologic discoveries. Dentistry had come of age, having gained the respect of other health-care disciplines. It was a time of expanded exploration of means toward a healthier populace and a more sensitive ethical provider of health care. In one decade, the USC community dentistry department accomplished a major shift in attitude about the specialty from one of pervasive opposition and antipathy to that of acceptance and even enthusiasm. The department became competitive with similar units nationwide in educating dental students and practitioners to fulfill their responsibilities at the highest level of proficiency and to be true to the trust bestowed on them by the public. In pursuit of these goals, the department reflected credit on dentistry and the University of Southern California.     

Pitfalls in monitoring tacrolimus (FK 506)

Tacrolimus (FK 506) is a new, potent immunosuppressive drug for primary and rescue therapy in liver and kidney transplantation. Therapeutic drug monitoring is essential for this drug because of its narrow therapeutic window. Blood levels are monitored routinely by enzyme linked immunoassay (ELISA) or by microparticle enzyme immunoassay (MEIA). In a 13-year-old recipient of a liver transplant who had poor hepatic function during the first postoperative week, the authors observed unusually high tacrolimus blood concentrations using either the ELISA (26.6 to 49.0 microg/l) or MEIA (58.5 to 64.5 microg/l). Parent drug levels measured in the same blood samples by high-performance liquid chromatography/mass spectrometry (HPLC/MS) were up to 10-fold lower (5.1 to 9.0 microg/l). The discrepancies between the immunoassay and HPLC/MS results could not be attributed to any of the known metabolites of tacrolimus.     

Therapeutic drug monitoring in special populations

Therapeutic drug monitoring (TDM) is commonly used to maintain "therapeutic" drug concentrations. Even in compliant patients, with "average" drug kinetics, TDM is useful to identify the causes of unwanted or unexpected responses, prevent unnecessary diagnostic testing, improve clinical outcomes, and even save lives. TDM has greatest promise in certain special populations who are: (a) prone to under- or overrespond to usual dosing regimens, (b) least able to tolerate, recognize, or communicate drug effects, or who are (c) intentionally or accidentally misdosed. TDM is especially useful in patients at the extremes of age, in adolescents, and in patients who are either taking multiple drugs or expressing unusual pharmacokinetics as a result of physiological, environmental, or genetic causes. Less-well-appreciated uses of TDM include prevention of dangerous underdosing of patients, investigation of adverse drug reactions, and identification of serious medication errors, even for a number of drugs that are not traditionally monitored. TDM can be useful for some drugs in any patient and for most drugs in some special populations.     

Therapeutic assessment of adult patients with isolated corrected transposition of the great arteries

Corrected transposition of the great arteries is a rare congenital heart disease, affecting 1% of children with cardiac malformation. Patients with transposition of the great arteries and without associated cardiovascular anomalies are very infrequent and may remain undiagnosed until adult life, because they usually are asymptomatic until the fourth or fifth decades. At this time, most symptoms occur in close connection with deterioration in systemic (right) ventricle performance and with an increase in left atrial pressure. In this report, we describe two new adult cases of isolated, corrected transposition of the great arteries, offering several considerations on their clinical profile and therapeutic assessment.     

Therapeutic effectiveness of setting and monitoring goals.

Investigated the therapeutic effects of goal-setting strategies on 32 adult patients whose behaviors were disintegrating but not fragmented nor disoriented. Two techniques of goal setting were introduced: (a) collaboration of patients, therapists, and "collaterals" (other persons significant to the patient) on 3-mo treatment goals and (b) weekly monitoring with structured feedback. 16 Ss were randomly assigned to a treatment group for which the Behavioral Monitoring Progress Record (BMPR) was used. The other 16 Ss were randomly assigned to the same individual therapy but without weekly goal setting or monitoring. Collateral persons and behavioral criteria were used at intake for collecting information in each problem area and were used at follow-up to validate the S's self-report. The Goal Attainment Scale and Follow-up Interview Schedule were used to evaluate change. All Ss improved from the time of intake to the time of the follow-up interview. BMPR Ss had greater success in the attainment of goals. (5 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fetal and pediatric origins of adult cardiovascular disease

Adult-onset cardiovascular disease has its origin in childhood. During the past year there have been a number of articles that have dealt with the effects of fetal nutrition on the development of cardiovascular disease in adult life, identification of the child at high risk for the development of essential hypertension, the effects of passive smoking as a risk factor for coronary artery disease, and strategies for diagnosis and treatment for familial hypercholesterolemia. Two of the most important observations over the past year are that there appears to be a significant relationship between fetal and early childhood nutrition and the risk of developing many of the cardiovascular diseases seen in adult individuals and that environmental tobacco smoking, including smoke at work, results in an increased risk of developing coronary heart disease.     

Analysis of tacrolimus (FK 506) in relation to therapeutic drug monitoring

Tacrolimus (FK506) is a macrolide lactone which is used as an immunosuppressant agent for organ transplantation. Patient monitoring during clinical trials initially involved use of extraction/enzyme immunoassays (ELISA) for plasma and whole blood concentrations of FK506. Therapeutic concentrations of FK506 are approximately 0.4-1.2 ng/ml in plasma and 5-20 ng/ml in whole blood. Blood:plasma ratios are variable among patients and range from 11 to 114. A validation and quality assurance program was established to standardize procedures and assure concordance of ELISA analytic results from clinical sites participating in liver/kidney trials. HPLC/ELISA methods have been used for assessing assay specificity. Comparison of the ELISA method with a HPLC-MS procedure (TexMS) shows good correlation, but indicates metabolite inclusion in the ELISA. This method may be of value in conditions of altered FK-506 metabolism. Commercialization of the immunoassay has been made by Incstar with the ELISA and Abbott Laboratories with an IMx procedure; the two methods are generally comparable. Additional methods offering clinical promise are radioreceptor and pentamer complex ELISA assays. There are diverse methods offering sensitive quantitation but with varying specificity for tacrolimus in patient plasma and whole blood.     

Abdominal aortic aneurysms in heart transplanted patients

BACKGROUND: Protein contact dermatitis is a form of contact dermatitis possibly triggered by proteinaceous allergens. MATERIALS AND METHODS: We report two patients with a history of erythematous and urticarial skin reactions followed by transformation into prolonged papular symptoms upon contact with proteinaceous material. RESULTS: The symptoms reported by the patients were reproducible by skin testing with meat (cow) and fish (salmon). Both patients experienced extracutaneous manifestations after ingestion of meat and fish, as proven by oral challenge. Specific immunoglobulin E (IgE) antibodies were detected in the patients' blood. CONCLUSIONS: Both cases meet all major criteria of protein contact dermatitis, suggesting IgE-mediated immediate-type hypersensitivity with late-phase cutaneous reactions.     

Therapeutic monitoring of teicoplanin in a severely burned patient

It is now well documented that E-cadherin expression correlates inversely with tumor grade in various carcinomas including prostate cancer. We also demonstrated a statistically significant correlation between decreased E-cadherin expression and progression-free period in early stage patients treated by radical prostatectomy and decreased survival in patients with advanced stage disease. We now study the relationship between E cadherin and alpha-catenin expression, because in prostate cancer cell lines, mutational inactivation of the alpha-catenin gene can be the cause of the impaired E-cadherin function. Twenty patients treated by radical prostatectomy and 32 advanced stage patients were evaluated immunohistochemically for E-cadherin and alpha-catenin expression. The results were related to tumor grade and disease progression. Four patients in the radical prostatectomy group had aberrant E-cadherin and alpha-catenin expression and showed disease progression. The other 16 patients were free of progression and had normal E-cadherin and alpha-catenin expression. In the advanced stage group, 4 of 13 patients with normal E-cadherin staining showed aberrant alpha-catenin expression and 2 patients (50%) progressed, compared with only 22% progression in patients with both normal E-cadherin and alpha-catenin expression. The other 19 patients with aberrant E-cadherin and alpha-catenin staining had the poorest prognosis. Our results suggest that loss of alpha-catenin expression could be one of the mechanisms responsible for the loss of E-cadherin-mediated cell-cell adhesion in human prostate cancer and might in some cases provide prognostic information.