Enantioselective metabolism and cytotoxicity of R-ifosfamide and S-ifosfamide by tumor cell-expressed cytochromes P450.

The anticancer prodrug ifosfamide (IFA) contains a chiral phosphorous atom and is administered in the clinic as a racemic mixture of R-IFA and S-IFA. Hepatic cytochrome P450 (P450) enzymes exhibit enantioselective preferences in the metabolism of R-IFA and S-IFA; however, the impact of this selectivity on P450-dependent anticancer activity is not known. Presently, the metabolism and cytotoxicity of R-IFA and S-IFA were determined in 9L gliosarcoma and Chinese hamster ovary tumor cells expressing an IFA-activating P450 enzyme and by in vitro steady-state kinetic analysis using cDNA-expressed P450 enzymes. Tumor cells expressing P450 enzyme CYP3A4 were the most sensitive to R-IFA cytotoxicity, whereas tumor cells expressing CYP2B1 or CYP2B6 were most sensitive to cyclophosphamide (CPA), an isomer of IFA. Correspondingly, CYP3A4-expressing cells and cDNA-expressed CYP3A4 metabolized R-IFA to yield the active, 4-hydroxylated metabolite at a 2- to 3-fold higher rate than they metabolized S-IFA or CPA. CYP2B cells and cDNA-expressed CYP2B enzymes metabolized CPA almost exclusively by 4-hydroxylation, whereas R-IFA and S-IFA were substantially converted to inactive, N-dechloroethylated metabolites. Further investigation revealed that CYP3A1, a rat enzyme, exhibited superior kinetic properties compared with the human enzyme CYP3A4, with R-IFA and S-IFA both metabolized with high catalytic efficiency by 4-hydroxylation and with a K(m) value of 200 microM, approximately 5-fold lower than CYP3A4. Based on these kinetic parameters and metabolic profiles, R-IFA is expected to exert greater anticancer activity than S-IFA or CPA against tumors that express CYP3A enzymes, whereas tumors expressing CYP2B enzymes may be more sensitive to CPA treatment.     

Educational interventions to reduce use of unsafe abbreviations.

PURPOSE: Educational interventions to reduce the use of abbreviations and dosage designations that were deemed unsafe at a level 1 trauma center are described. SUMMARY: Strategies to reduce the use of unsafe abbreviations at Detroit Receiving Hospital were studied. Six abbreviations and dosage designations were deemed as unsafe by the site's medication-use and patient medical safety committees: (1) U for units, (2) microg for microgram, (3) TIW for three times a week, (4) the degree symbol for hour, (5) trailing zeros after a decimal point, and (6) the lack of leading zeros before a decimal point. Data on abbreviation use was collected starting in September 2003 by examining copies of patients' order sheets, which are sent from nursing units to the pharmacy for processing. Data were collected during three 24-hour periods each month, with 7-10 days between each period. A data collection sheet was developed to assist in documenting the number of opportunities for each unsafe abbreviation and the actual incidence of each. Educational strategies were developed and implemented starting in October 2003 to decrease the use of the unsafe abbreviations. These strategies included inservice education programs for the medical, pharmacy, and nursing staffs; laminated pocket cards; patient chart dividers; stickers; and interventions by pharmacists and nurses during medication prescribing. During the eight-month evaluation period, 20,160 orders were reviewed, representing 27,663 opportunities to use a designated unsafe abbreviation. Educational interventions successfully reduced the overall incidence of unsafe abbreviations from 19.69% to 3.31%. CONCLUSION: Educational interventions markedly reduced the use of unsafe abbreviations in medication orders over an eight-month evaluation period.     

Understanding the minimum clinically important difference: a review of concepts and methods.

BACKGROUND CONTEXT: The effectiveness of spinal surgery as a treatment option is currently evaluated through the assessment of patient-reported outcomes (PROs). The minimum clinically important difference (MCID) represents the smallest improvement considered worthwhile by a patient. The concept of an MCID is offered as the new standard for determining effectiveness of a given treatment and describing patient satisfaction in reference to that treatment. PURPOSE: Our goal is to review the various definitions of MCID and the methods available to determine MCID. STUDY DESIGN: The primary means of determining the MCID for a specific treatment are divided into anchor-based and distribution-based methods. Each method is further subdivided and examined in detail. METHODS: The overall limitations of the MCID concept are first identified. The basic assumptions, statistical biases, and shortcomings of each method are examined in detail. RESULTS: Each method of determining the MCID has specific shortcomings. Three general limitations in the accurate determination of an MCID have been identified: the multiplicity of MCID determinations, the loss of the patient's perspective, and the relationship between pretreatment baseline and posttreatment change scores. CONCLUSIONS: An ideal means of determining the MCID for a given intervention is yet to be determined. It is possible to develop a useful method provided that the assumptions and methodology are initially declared. Our efforts toward the establishment of a MCID will rely on the establishment of specific external criteria based on the symptoms of the patient and treatment intervention being evaluated.