Pharmacokinetics of 2-oxothiazolidine-4-carboxylate, a cysteine prodrug, and cysteine

The pharmacokinetics of both 2-oxothiazolidine-4-carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2-hour intravenous infusion (56-66 mg/kg) or similarly infused (70-100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis-Menten kinetics with parallel first-order elimination. OTZ was efficiently removed from the plasma. The Michaelis-Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.     

Histopathology of coronary lesions with early loss of minimal luminal diameter after successful percutaneous transluminal coronary angioplasty: is thrombus a significant contributor?

BACKGROUND: Early loss of minimal luminal diameter of >0.3 mm after successful percutaneous transluminal coronary angioplasty (PTCA) is associated with a higher incidence of restenosis. The underlying mechanism of this early loss is unknown and thrombus may be a contributing factor. METHODS: We performed a prospective study using quantitative computerized planimetry on coronary tissue specimens obtained by directional coronary atherectomy of 24 lesions in which early loss occurred 22+/-9 minutes after successful PTCA. RESULTS: Thrombus was present in 9 (37%) of 24 coronary specimens. Segmental areas (mm2) and percentage of total area were distributed as follows: sclerotic tissue, 4.07+/-0.7 mm2 (63%+/-6%); fibrocellular tissue, 0.97+/-0.27 mm2 (16%+/-4%); hypercellular tissue, 0.99+/-0.29 mm2 (12%+/-3%); atheromatous gruel, 0.18+/-0.07 mm2 (3%+/-0.1%); and thrombus, 0.24+/-0.15 mm2 (6%+/-0.4%). There was no difference in the relative early loss index between lesions with or without thrombus (35%+/-7% vs 26%+/-2%, respectively; P= .87). Multiple stepwise regression analysis did not identify any histologic predictors of relative early loss index. CONCLUSION: Histopathologic analysis of coronary lesions with early loss after successful PTCA suggests that thrombus may not play a significant role in this angiographic phenomenon.     

Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer

Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents.     

Effect of recombinant erythropoietin on hospital admissions, readmissions, length of stay, and costs of dialysis patients

To examine the effects of recombinant human erythropoietin (rHuEPO) on hospital utilization, hospital costs, and Medicare reimbursements for hospital care, a longitudinal, matched cohort study was conducted using Medicare claims data of 23,806 Medicare-eligible, dialysis patients who received rHuEPO, did not have a transplant, and were alive for 18 mo or longer and 22,720 controls matched on age, sex, race, cause of ESRD, and dialysis modality. The relative odds (rHuEPO versus control) of admission for all causes and for specific causes over 9 mo, adjusted for admission in the prior 9 mo and the per patient change in total admissions, inpatient days, hospital costs, and Medicare hospital payments between the prior 9-mo period and the subsequent 9-mo period was examined. The adjusted relative odds (95% confidence interval) of admission (rHuEPO versus control) was: higher and statistically significant for all causes, 1.08 (1.03 to 1.14); seizure, 1.52 (1.28 to 1.75); vascular access revision, 1.11 (1.06 to 1.17), and heart failure, 1.17 (1.09 to 1.26); higher but not statistically significant for angina, 1.09 (0.99 to 1.20) and stroke, 1.08 (0.86 to 1.31); and lower but not statistically significant for myocardial infarction, 0.91 (0.72 to 1.10); peripheral vascular disease, 0.81 (0.60 to 1.02); anemia, 0.86 (0.56 to 1.17); and depression, 0.89 (0.37 to 1.40). The mean change per 1,000 patients in admissions was less by 38 (P = 0.03) because of fewer readmissions, and in days was 1,309 less (P < 0.001), for patients treated with rHuEPO versus controls. The mean change per patient in hospital costs was $371 less and was statistically significant (P = 0.03) and in Medicare hospital payments was $132 less but was not statistically significant (P = 0.43) for patients treated with rHuEPO versus controls. rHuEPO was associated with an increase in the probability of hospital admission (particularly admissions potentially related to adverse effects) but a decrease in readmissions, overall admissions, hospital days, and cost to hospitals in this cohort of patients surviving for 18 mo. Although not realized short term, Medicare savings from potential rHuEPO-related reductions in hospital care may be long term through future adjustments in diagnosis-related group-based hospital payment.     

Structural features of thyroid hormone response elements that increase susceptibility to inhibition by an RTH mutant thyroid hormone receptor

The chicken lysozyme silencer F2 (F2) thyroid hormone response element (TRE) contains an unusual everted palindromic arrangement, has a high affinity for thyroid hormone receptor (TR) homodimers, and is especially sensitive to dominant negative inhibition by, the T3 resistance (RTH) mutant TR beta P453H. We used various TREs and TR mutations to determine the mechanisms for this sensitivity. Changing the F2 orientation from an everted palindrome to a direct repeat with a 4-bp gap (DR+4) (F2-DR) decreased the sensitivity to inhibition at high T3 concentrations, while a loss of this sensitivity occurred with a palindromic arrangement of these same half-sites. F2 contains the dinucleotide TG 5' to each consensus half-site conforming to the optimal TR-binding octamer, YRRGGTCA. A T to A change in position 1 of both F2 half-sites markedly reduced T3-induction, yet only slightly reduced TR homodimer or TR-retinoid X receptor (RXR) heterodimer binding. The TR beta ninth heptad mutation, L428R, prevents TR heterodimerization with RXR and eliminates the inhibitory effect of the P453H mutant TR on the F2-DR, but not the F2 element. Structural features of a TRE that favor strong TR binding of both TR homodimers and TR-RXR heterodimers containing the mutant TR, such as the everted palindromic conformation or the optimal TR-binding consensus octamer, enhance the sensitivity of a TRE to inhibition by the mutant TR. Thus, both half-site orientation and sequence contribute to the sensitivity of a given TRE to dominant negative inhibition by a mutant TR.     

The Society of Gastrointestinal Radiologists: its future and relevance

The authors present a case of tremor isolated to the lower extremity that was treated with stereotactically guided thalamotomy in a patient with Parkinson's disease. The technology that makes this procedure effective for this particular manifestation of parkinsonism is discussed.