Environmental exposure of a community to airborne trichloroethylene

School officials and community citizens in Georgia were concerned about the airborne trichloroethylene (TCE) that was emanating from a nearby industrial facility that used TCE as a degreaser. No measurements of airborne TCE in the community were taken by public health officials or the industrial facility. The regulation of release of TCE from this facility was governed, in part, by mathematical model predictions of dispersion into the community. In support of community health concerns, the authors collected a limited number of outdoor and indoor air samples in the affected community, including those from a school, a small business, and three homes, for the analysis of TCE. The mean outdoor air concentration of TCE for all affected sites was 0.96 microg/m3 with a peak TCE concentration of 4.59 microg/m3. The mean indoor air concentration of TCE for all affected sites was 1.40 microg/m3 with a peak TCE concentration of 4.66 microg/m3. All collected air samples were below the guideline level of 5 microg TCE/m3 of air as used by the state of Georgia in the United States, but sample levels were greater than those found in large population studies of TCE in indoor and outdoor air in Minnesota in the United States and in Ottawa in Canada. Additional air samples are needed to better characterize the exposure of the community to TCE.     

Drug pricing for a novel treatment for wet macular degeneration: using incremental cost-effectiveness ratios to ensure societal value

OBJECTIVE: Health economic models can assist policy-makers in determining the value of novel treatments from the viewpoint of society. In this context, value is defined as the benefit of treatment, given its cost. A new treatment for wet age-related macular degeneration (AMD), juxtascleral administration of anecortave acetate, 15 mg for depot suspension (Retaane), is now in a late-phase clinical trial. In a theoretical analysis, we sought to determine the cost at which this treatment might offer economic value to society, using incremental cost-effectiveness ratios (ICERs). METHODS: A series of 1-year cost-utility models was created for the investigational treatment and standard treatment (photodynamic therapy [PDT] with verteporfin [Visudyne]). Value to society was defined in terms of theoretical associated ICERs (in US dollars): $100,000 per quality-adjusted life-year (QALY), $50,000/QALY, $20,000/QALY and $0/QALY, the point of economic indifference. Models were created from the societal perspective and included a patient-derived utility assessment involving regression equations to estimate time trade-off preferences, event probabilities derived from a randomized clinical trial comparing the safety and efficacy of anecortave administration and PDT with verteporfin, decision analysis and relevant costing information. RESULTS: An ICER of $100,000/QALY would be associated with an anecortave cost of $3022/vial, an ICER of $50,000/QALY with an anecortave cost of $2986/vial and an ICER of $20,000/QALY with an anecortave cost of $2964/vial. The point of economic indifference between anecortave administration and standard therapy would occur with an anecortave cost of $2950/vial. INTERPRETATION: In theory, an anecortave cost of $2986/vial is associated with an ICER of $50,000/QALY, the threshold used by many health technology assessment and reimbursement agencies.     

Measurement of rate of expansion in the perception of radial motion

Optic flow generated by rigid surface patches can be decomposed into a small number of elementary motion types. In these experiments, we show that the human visual system can evaluate expansion, one of these motion types, metrically. Moreover, we show that the discrimination of rates of expansion are spatially local. Because the estimation of the focus of expansion is somewhat imprecise, this locality sometimes produces predictable errors in the estimation of rate of expansion. One can make predictions like this with a model adapted from one previously developed for angular-velocity discrimination.     

Cytokine gene polymorphism in sympathetic ophthalmia

PURPOSE: Sympathetic ophthalmia (SO) is a prototypical autoimmune disease in which injury to one eye causes sight-threatening inflammation in the otherwise normal contralateral eye. Previous work found that human leukocyte antigen alleles HLA-DRB1*04 and DQA1*03 are markers of increased susceptibility and severity in British and Irish patients. Evidence is accumulating that single nucleotide polymorphisms (SNPs) in cytokine genes can also influence the development of autoimmune disease through their effect on levels of cytokine production. The purpose of this study was to determine whether polymorphisms in the cytokine genes are important markers for disease severity and outcome in patients with SO. METHODS: Twenty-six British and Irish patients meeting well-defined criteria for the diagnosis of SO were compared with 48 matched controls. Genotyping of SNPs in the TNFalpha, TNFbeta, and IL-10 genes was performed using the polymerase chain reaction and sequence-specific primers (SSP-PCRs) and of the CTLA-4 and TNF receptor 2 genes using restriction length polymorphism-PCR (RFLP-PCR). RESULTS: Significant associations were found between the IL-10 -1082 SNP and disease recurrence from previously stable disease and the level of steroids required for maintenance therapy. In addition, the GCC IL-10 promoter haplotype (IL-10 -1082G, -819C, -592C) was found to be protective against disease recurrence. CONCLUSIONS: These results show that cytokine gene polymorphisms are markers for the severity of disease in SO. They were found to be associated with recurrence of previously stable disease and with the level of maintenance steroid treatment required to control inflammatory activity.     

Year of treatment as independent predictor of relapse-free survival in patients with localized prostate cancer treated with definitive radiotherapy in the PSA era

PURPOSE: To study the use of the year of therapy as an independent predictor of outcomes, serving as a proxy for time-related changes in therapy and tumor factors in the treatment of prostate cancer. Accounting for these changes would facilitate the retrospective comparison of outcomes for patients treated in different periods. METHODS AND MATERIALS: Nine institutions combined data on 4,537 patients with Stages T1 and T2 adenocarcinoma of the prostate who had a pretherapy prostate-specific antigen (PSA) level and biopsy Gleason score, and who had received > or = 60 Gy external beam radiotherapy without neoadjuvant androgen deprivation or planned adjuvant androgen deprivation. All patients were treated between 1986 and 1995. Two groups were defined: those treated before 1993 (Yr < or = 92) vs. 1993 and after (Yr > or = 93). Patients treated before 1993 had their follow-up truncated to make the follow-up time similar to that for patients treated in 1993 and after. Therefore, the median follow-up time was 6.0 years for both groups (Yr < or = 92 and Yr > or = 93). Two separate biochemical failure endpoints were used. Definition A consisted of the American Society for Therapeutic Radiology Oncology endpoint (three PSA rises backdated, local failure, distant failure, or hormonal therapy). Definition B consisted of PSA level greater than the current nadir plus two, local failure, distant failure, or hormonal therapy administered. Multivariate analyses for factors affecting PSA disease-free survival (PSA-DFS) rates using both endpoints were performed for all cases using the following variables: T stage (T1b, T1c, T2a vs. T2b, T2c), pretreatment PSA (continuous variable), biopsy Gleason score (continuous variable), radiation dose (continuous variable), and year of treatment (continuous variable). The year variable (defined as the current year minus 1960) ranged from 26 to 35. To evaluate the effect of radiation dose, the multivariate analyses were repeated with the 3,897 cases who had received < 72 Gy using the same variables except for radiation dose. RESULTS: For all 4,537 patients, the 5- and 8-year PSA-DFS estimate using definition A (ASTRO consensus definition) was 60% and 55%, respectively. The 8-year PSA-DFS estimate for Yr < 93 vs. Yr > or = 93 was 52% vs. 57%, respectively (p < 0.001). In the subgroup of patients receiving < 72 Gy, the 8-year PSA-DFS estimate for Yr < 93 vs. Yr > or = 93 was 52% and 55%, respectively (p = 0.004). The differences in PSA-DFS rates in the different subgroups were similar when definition B was used. The multivariate analyses for all 4,537 cases with either PSA-DFS definition revealed T stage (p < 0.001), pretherapy PSA level (p < 0.001), Gleason score (p < 0.001), radiation dose (p < 0.001), and year of treatment (p < 0.001) to be independent predictors of outcomes. The multivariate analyses restricted to the 3,897 cases receiving < 72 Gy still revealed year of treatment to be an independent predictor of outcomes (p < 0.001), in addition to T stage (p < 0.001), pretherapy PSA level (p < 0.001), and Gleason score (p < 0.001). CONCLUSIONS: Independent of tumor stage, radiation dose, failure definition, and follow-up parameters, the year in which RT was performed was an independent predictor of outcomes. These findings indicate a more favorable presentation of localized prostate cancer in current years that is not necessarily reflected in the patients' PSA levels or Gleason scores. This phenomenon is probably related to a combination of factors, such as screening, increased patient awareness leading to earlier biopsies and earlier diagnosis, more aggressive pretherapy staging, and unrecognized improvements in therapy, but perhaps also to changing tumor biology. Outcomes predictions should be based on contemporaneous series. Alternatively, the year of therapy could be incorporated as a variable in outcomes analyses of localized prostate cancer patients treated in different periods within the PSA era.     

An observational study of health-related quality of life and pain outcomes in chronic low back pain patients treated with fentanyl transdermal system

BACKGROUND: The analgesic effect of long-acting opioids, such as transdermal fentanyl, has been demonstrated in patients with cancer, neuropathic pain and chronic low back pain (CLBP). However, the broader effect of long-acting opioids on the patient's health-related quality of life (HRQoL) is less well known. OBJECTIVE: To evaluate HRQoL outcomes in CLBP patients treated with transdermal fentanyl. RESEARCH DESIGN AND METHODS: An observational study was conducted at 17 clinical centers in the US. Eligible patients had CLBP diagnosis for at least 3 months and were taking short-acting opioids chronically, and then initiated transdermal fentanyl treatment. Patients completed the Treatment Outcomes in Pain Survey (TOPS), which includes the SF-36 Health Survey, at baseline and > or = 9 weeks of treatment. The HRQoL burden of CLBP was determined by comparing CLBP patients' SF-36 scores to the general US population and low back pain patient norms. HRQoL outcomes were determined by comparing baseline and follow-up TOPS and SF-36 scores. Additionally, HRQoL outcomes were evaluated across patient groups stratified by changes in pain intensity ratings as measured by an 11-point numerical rating scale. RESULTS: At baseline CLBP patients (N = 131) scored one-to-two standard deviations (SD) below age and gender adjusted SF-36 general population norms (MANOVA F = 127.1, p < 0.0001) and significantly lower than low back pain norms (MANOVA F = 125.3, p < 0.0001). At follow-up, significant improvement (p < 0.05) was observed on six of the SF-36 scales and both SF-36 summary measures and five of the six TOPS pain-related scales. The magnitude of change in scores in effect size units among these scales ranged from 0.17 to 0.80, which are considered small to large effect size changes. HRQoL score improvement was greatest among patients experiencing the greatest pain relief. CONCLUSION: CLBP patients who chronically used short-acting opioids showed tremendous HRQoL burden. Favorable HRQoL outcomes were observed among patients who reported pain relief.     

Steady-state pharmacokinetics of a novel extended-release metformin formulation

BACKGROUND AND OBJECTIVE: Metformin is an effective treatment for type 2 diabetes mellitus. The pharmacokinetic characteristics of the conventional immediate-release (IR) formulation of metformin (Glucophage), however, necessitate two- or three-times-daily dosing. Development of a novel extended-release (XR) formulation of metformin (Glucophage XR) using GelShield Diffusion System technology provides a once-daily dosing option. The objective of this study was to assess the steady-state pharmacokinetics of metformin XR tablets. STUDY DESIGN: This was an open-label, multiple-dose, five-regimen, two-sequence clinical study lasting 5 weeks. METHODS: Subjects were 16 healthy volunteers aged 18-40 years. Three 1-week regimens of metformin XR (500, 1000 and 1500 mg once daily) were administered sequentially. Subjects were alternately given either metformin XR 2000 mg once daily or metformin IR 1000 mg twice daily during weeks 4 and 5. The pharmacokinetic properties of metformin XR were assessed on two separate days at steady state and compared with those of metformin IR. RESULTS: Absorption of metformin XR was slower than that of metformin IR (time to maximum plasma concentration = 7 versus 3 hours). Maximum plasma concentrations (Cmax) following the administration of metformin XR 2000 mg once daily was 36% higher than that following the evening dose of metformin IR 1000 mg twice daily. The extent of absorption, determined by area under the plasma concentration-time curve (AUC), was equivalent for both formulations. The mean accumulation ratio of metformin XR was 1.0, indicating no accumulation with multiple-dose administration. Intrasubject variabilities in Cmax and AUC of metformin were comparable between metformin XR and metformin IR. This novel formulation of metformin XR was well tolerated at single doses up to 2000 mg once daily for 7 days, and adverse events were similar to those reported with metformin IR. CONCLUSION: The pharmacokinetic parameters of metformin XR tablet using GelShield Diffusion System technology were similar to those of metformin IR. Metformin XR was well tolerated at single doses up to 2000 mg once daily.     

Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potent and selective nonsteroidal progesterone receptor agonist tanaproget

Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.