Population pharmacokinetic-pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers.

PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent. To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure-response model was developed during the PB2452 first-in-human phase I study. From a randomized, double-blind, placebo-controlled, single-dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure-response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM. Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high-rate infusion, and then a slower-rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20-24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452.

Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins.

The impact of an anti-drug antibody (ADA) response on pharmacokinetic (PK) of a therapeutic protein (TP) requires an in-depth understanding of both PK parameters and ADA characteristics. The ADA and PK bioanalytical assays have technical limitations due to high circulating levels of TP and ADA, respectively, hence, significantly hindering the interpretation of this assessment. The goal of this study was to develop a population-based modeling and simulation approach that can identify a more relevant PK parameter associated with ADA-mediated clearance. The concentration-time data from a single dose PK study using five monoclonal antibodies were modeled using a non-compartmental analysis (NCA), one-compartmental, and two-compartmental Michaelis-Menten kinetic model (MMK). A novel PK parameter termed change in clearance time of the TP (α) derived from the MMK model could predict variations in α much earlier than the time points when ADA could be bioanalytically detectable. The model could also identify subjects that might have been potentially identified as false negative due to interference of TP with ADA detection. While NCA and one-compartment models can estimate loss of exposures, and changes in clearance, the two-compartment model provides this additional ability to predict that loss of exposure by means of α. Modeling data from this study showed that the two-compartment model along with the conventional modeling approaches can help predict the impact of ADA response in the absence of relevant ADA data.

Study of cardiovascular disease biomarkers among tobacco consumers. Part 3: evaluation and comparison with the US National Health and Nutrition Examination Survey.

Cardiovascular disease (CVD) biomarkers of biological effect (BoBE), including hematologic biomarkers, serum lipid-related biomarkers, other serum BoBE, and one physiological biomarker, were evaluated in adult cigarette smokers (SMK), smokeless tobacco consumers (STC), and non-consumers of tobacco (NTC). Data from adult males and females in the US National Health and Nutrition Examination Survey and a single site, cross-sectional study of healthy US males were analyzed and compared. Within normal clinical reference ranges, statistically significant differences were observed consistently for fibrinogen, C-reactive protein (CRP), hematocrit, mean cell volume, mean cell hemoglobin, hemoglobin, white blood cells, monocytes, lymphocytes, and neutrophils in comparisons between SMK and NTC; for CRP, white blood cells, monocytes, and lymphocytes in comparisons between SMK and STC; and for folate in comparisons with STC and NTC. Results provide evidence for differences in CVD BoBE associated with the use of different tobacco products, and provide evidence of a risk continuum among tobacco products and support for the concept of tobacco harm reduction.

Arsenic exposure and tobacco consumption: Biomarkers and risk assessment.

Arsenic is measurable in tobacco and cigarette mainstream smoke (MSS). Whether arsenic has an independent role in diseases associated with tobacco consumption is not known. Epidemiology and biomonitoring data and probabilistic risk assessment (PRA) methods were used to investigate this potential association. Analysis of data from the National Health and Nutrition Examination Survey (NHANES) showed that urine arsenic concentrations in tobacco consumers were not different or were lower than levels in non-consumers of tobacco. Additionally, urine arsenic levels from NHANES tobacco consumers were five-times or more lower than levels reported in epidemiology studies to be associated with adverse health effects. Results of PRA indicated that mean non-cancer hazard estimates and mean incremental lifetime cancer risk estimates were within accepted ranges. Taken together, these results suggest that arsenic may not be independently associated with tobacco consumption or diseases related to tobacco consumption.

Cadmium exposure and tobacco consumption: Biomarkers and risk assessment.

To investigate whether cadmium has an independent role in diseases associated with tobacco consumption, epidemiology data were reviewed, biomonitoring data were analyzed, and probabilistic risk assessment (PRA) was performed. Results from previous epidemiology studies have indicated that there are adverse health effects potentially in common between cadmium exposure and tobacco consumption. Analysis of publically available biomonitoring data showed that blood (B-Cd) and urine (U-Cd) cadmium were higher in cigarette smokers compared with smokeless tobacco (SLT) consumers, and B-Cd and U-Cd in SLT consumers were not significantly different than in non-consumers of tobacco. Comparison with previously established biomonitoring equivalent (BE) values indicated that B-Cd and U-Cd in the majority of these cigarette smokers and SLT consumers did not exceed the blood and urine BEs. Results of the PRA showed that the mean hazard estimate was below a generally accepted regulatory threshold for SLT consumers, but not for cigarette smokers. In total, this evaluation indicated that cadmium exposures in tobacco consumers differed by product category consumed; cadmium in tobacco may not be associated with tobacco consumption related diseases; if cadmium in tobacco contributes to tobacco consumption related diseases, differences in hazard and/or risk may exist by product category.

Differential exposure biomarker levels among cigarette smokers and smokeless tobacco consumers in the National Health and Nutrition Examination Survey 1999-2008.

Assessment of biomarkers is an appropriate way to estimate exposure to cigarette mainstream smoke and smokeless tobacco (SLT) constituents in tobacco consumers. Using the US National Health and Nutrition Examination Survey (NHANES, 1999-2008), biomarkers of volatile organic compounds, halogenated aromatic hydrocarbons (HAHs), polycyclic aromatic hydrocarbons (PAHs), acrylamide, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and metals were evaluated. In general, biomarker levels in SLT consumers were significantly lower than in smokers (excluding NNK and some HAHs) and were not significantly different compared with nonconsumers (excluding NNK and some PAHs). These results provide useful information for science-based risk assessment and regulation of tobacco products.

A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors.

PURPOSE: To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1-8 mg/m(2)/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. RESULTS: The MTD was defined as 7 mg/m(2) administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m(2) due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3-7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. CONCLUSION: The recommended dose of ispinesib is 7 mg/m(2) over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.

A Bayesian statistical analysis of mouse dermal tumor promotion assay data for evaluating cigarette smoke condensate.

The mouse dermal assay has long been used to assess the dermal tumorigenicity of cigarette smoke condensate (CSC). This mouse skin model has been developed for use in carcinogenicity testing utilizing the SENCAR mouse as the standard strain. Though the model has limitations, it remains as the most relevant method available to study the dermal tumor promoting potential of mainstream cigarette smoke. In the typical SENCAR mouse CSC bioassay, CSC is applied for 29 weeks following the application of a tumor initiator such as 7,12-dimethylbenz[a]anthracene (DMBA). Several endpoints are considered for analysis including: the percentage of animals with at least one mass, latency, and number of masses per animal. In this paper, a relatively straightforward analytic model and procedure is presented for analyzing the time course of the incidence of masses. The procedure considered here takes advantage of Bayesian statistical techniques, which provide powerful methods for model fitting and simulation. Two datasets are analyzed to illustrate how the model fits the data, how well the model may perform in predicting data from such trials, and how the model may be used as a decision tool when comparing the dermal tumorigenicity of cigarette smoke condensate from multiple cigarette types. The analysis presented here was developed as a statistical decision tool for differentiating between two or more prototype products based on the dermal tumorigenicity.

A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma.

BACKGROUND: Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range. METHODS: A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used. RESULTS: A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks. CONCLUSIONS: rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma.

A Bayesian population PK-PD model for ispinesib/docetaxel combination-induced myelosuppression.

PURPOSE: Ispinesib, a kinesin spindle protein inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. Docetaxel promotes tubulin assembly into microtubules while inhibiting microtubule de-polymerization leading to mitotic arrest. Prolonged (> or =5 days) Gr 4 neutropenia and/or febrile neutropenia were the observed dose-limiting toxicities with both agents. Both agents are substrates and inhibitors of CYP3A4; thus, the potential for a drug-drug interaction exists. The goal was to fit a Bayesian population PK/PD model to characterize the relationship between the ispinesib/docetaxel combination and absolute neutrophil counts (ANC). METHODS: Escalating doses of docetaxel (60-75 mg/m(2)) were administered over 1 h followed by a 1-h infusion of escalating doses of ispinesib (8-12 mg/m(2)) on a 21-day schedule. At least 3 pts were treated at each dose level. Limited PK samples were obtained. ANC were measured weekly on days 1, 8, 15, and 22. More ANC samples were taken from some subjects. The PK properties of ispinesib and docetaxel, and the relationship of PK with ANC were investigated using nonlinear mixed-effects models and Bayesian methods. With a limited dataset, informative prior distributions for the model parameters were needed. These prior distributions were formed using information from a previous study for ispinesib, and from the literature for docetaxel. RESULTS: Twenty-four pts were treated in this study. The PK of ispinesib and docetaxel were well characterized by a two-compartment model and a three-compartment model, respectively. There is no obvious PK interaction between ispinesib and docetaxel. The model for ANC consisted of a proliferating compartment, three transit compartments that represented maturation, and a compartment of circulating blood cells. This ANC model has been used previously for ispinesib given as monotherapy, and for other chemotherapeutic drugs in the literature. Using Bayesian methods, the model was successfully fit for the PK of both compounds and the PD simultaneously. CONCLUSIONS: The PK/PD model developed for ispinesib/docetaxel, may be used to examine different schedules, doses, and infusion times of both agents. Bayesian methods allow for the use of prior information available for the model parameters.

A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer.

PURPOSE: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. EXPERIMENTAL DESIGN: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. RESULTS: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 microg/kg (group A) or 100, 1,000, or 2,000 microg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, and IL-18-binding protein were observed following dosing. CONCLUSIONS: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.

Systemic exposure and urinary cortisol effects of fluticasone propionate formulated with hydrofluoroalkane in 4- to 11-year-olds with asthma.

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 mug twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUC(last) (area under the plasma fluticasone propionate concentration-time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24-hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24-hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic-pituitary-adrenal axis effects as measured by 24-hour urinary cortisol excretion.

Combining estimates from multiple early studies to obtain estimates of response: using shrinkage estimates to obtain estimates of response.

Development of anti-cancer therapies usually involve small to moderate size studies to provide initial estimates of response rates before initiating larger studies to better quantify response. These early trials often each contain a single tumor type, possibly using other stratification factors. Response rate for a given tumor type is routinely reported as the percentage of patients meeting a clinical criteria (e.g. tumor shrinkage), without any regard to response in the other studies. These estimates (called maximum likelihood estimates or MLEs) on average approximate the true value, but have variances that are usually large, especially for small to moderate size studies. The approach presented here is offered as a way to improve overall estimation of response rates when several small trials are considered by reducing the total uncertainty.The shrinkage estimators considered here (James-Stein/empirical Bayes and hierarchical Bayes) are alternatives that use information from all studies to provide potentially better estimates for each study. While these estimates introduce a small bias, they have a considerably smaller variance, and thus tend to be better in terms of total mean squared error. These procedures provide a better view of drug performance in that group of tumor types as a whole, as opposed to estimating each response rate individually without consideration of the others. In technical terms, the vector of estimated response rates is nearer the vector of true values, on average, than the vector of the usual unbiased MLEs applied to such trials.

Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer.

PURPOSE: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 in patients with advanced cancer. EXPERIMENTAL DESIGN: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements. RESULTS: Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkin's lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 microg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the 100 microg/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment. CONCLUSIONS: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted.

Ambient hydrogen sulfide, total reduced sulfur, and hospital visits for respiratory diseases in northeast Nebraska, 1998-2000.

This analysis examined associations between total reduced sulfur (TRS) and hydrogen sulfide (H(2)S) levels, and hospital visits for respiratory disease among residents of Dakota City and South Sioux City, Nebraska, from January 1998 to May 2000. For reference, the association between TRS, H(2)S, and digestive diseases was also examined. Time-series analyses of daily hospital visits in the selected outcome categories and measures of TRS and H(2)S were performed using generalized additive models with a Poisson link. TRS and H(2)S levels were categorized as high if at least one of the daily 30-min rolling averages was > or =30 ppb and as low if every rolling average was <30 ppb. Loess smoothers allowed for flexible modeling of the time effect and the effect of temperature and relative humidity. The measure of association used was the mean percent change in the average number of hospital visits recorded following a day with a high exposure versus a day with a low exposure. For children less than 18 years of age, a positive association was found between asthma hospital visits and 1-day lagged TRS levels. For adults, a positive association was found between asthma hospital visits and H(2)S levels on the previous day. A positive association also was found between hospital visits for all respiratory diseases, and H(2)S and TRS levels on the previous day for children but not for adults. No association was found between contaminant levels and hospital visits for all digestive diseases. These findings suggest that TRS or H(2)S levels may be associated with exacerbations of asthma or other respiratory diseases among the residents of Dakota City and South Sioux City.

Confirming the utility of four kidney biomarker tests in a longitudinal follow-up study.

In this follow-up study, 526 persons were followed for almost 5 years to assess the reversibility and predictive value of four kidney biomarkers in a field epidemiology setting. This study examined (a) whether elevations in urinary albumin, N-acetyl-beta-D-glucosaminidase, retinol-binding protein, and alanine aminopeptidase remained elevated at follow-up and (b) whether these initial elevations were predictive of kidney disease (as measured by markers of kidney dysfunction: serum creatinine, serum cystatin C, creatinine clearance, and urine osmolality) at follow-up. Study participants were 8-76 years of age at baseline and were followed for an average of 4.5 years. Approximately 50% of adults who had an elevated biomarker did not have an elevation at followup. Youths with elevated biomarkers at baseline, but who completed adolescence by the time of the follow-up, no longer had any elevations in biomarkers at follow-up. Adult participants who had elevated biomarkers and selected health conditions at baseline (diabetes and, to a lesser extent, heart disease, hypertension, gout, and urinary tract disease) were more likely to show early indicators of kidney impairment at follow-up. Participants with these health conditions and normal kidney biomarker values at baseline had kidney test results at follow-up that were similar to results of study participants who did not have these health conditions at baseline. The presence or absence of elevated biomarkers at baseline among generally healthy participants was not associated with the development of early indicators of kidney impairment at follow-up. This longitudinal study confirmed the utility of these four kidney biomarker tests as markers of preclinical organ dysfunction among adults with certain preexisting medical conditions.

Influence of environmental zinc on the association between environmental and biological measures of lead in children.

Exposure to lead, a common environmental contaminant found at hazardous waste sites, has been associated with adverse health effects to humans. Zinc, a nutritionally essential metal, may influence both the absorption and the toxicity of lead. The purpose of this study was to determine if zinc levels present in the environment affect the association between environmental lead measured in two small communities in the northeastern United States and biological measurements of lead in the residents of these communities. Soil and dust sampled in and around the homes of all participants were tested for lead and zinc. Residents aged 6 months to 14 years (n=214) provided blood samples for the determination of blood lead concentrations. Soil and dust measurements of environmental lead were positively associated with blood lead, regardless of the corresponding zinc levels in these samples. However, the magnitude of this association was 20% to 46% lower in areas with high environmental measures of zinc. The interactions between environmental lead and environmental zinc levels and blood lead concentrations suggest that zinc may influence the association between soil and dust lead and corresponding blood lead levels.

Effects of exposure to low levels of environmental cadmium on renal biomarkers.

We conducted a study among residents of a small community contaminated with heavy metals from a defunct zinc smelter and residents from a comparison community to determine whether biologic measures of cadmium exposure were associated with biomarkers of early kidney damage. Creatinine-adjusted urinary cadmium levels did not differ between the smelter and comparison communities; thus we combined individuals from both communities (n = 361) for further analyses. The overall mean urinary cadmium level was low, 0.26 microg/g creatinine, similar to reference values observed in the U.S. general population. For children ages 6-17 years, urinary concentration of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and albumin were positively associated with urinary cadmium, but these associations did not remain statistically significant after adjusting for urinary creatinine and other potential confounders. For adults ages 18 or older, urinary concentration of NAG, AAP, and albumin were positively associated with urinary cadmium. The associations with NAG and AAP but not with albumin remained statistically significant after adjusting for creatinine and other potential confounders. We found a positive dose-effect relationship between levels of creatinine-adjusted urinary cadmium and NAG and AAP activity, and statistically significant differences in mean activity for these two enzymes between the highest (> or =1.0 microg cadmium/g creatinine) and the lowest (< or =0.25 microg cadmium/g creatinine) exposure groups. The findings of this study indicate that biologic measures of cadmium exposure at levels below 2.0 microg/g creatinine may produce measurable changes in kidney biomarkers.

Prevalence estimates for MS in the United States and evidence of an increasing trend for women.

The purpose of this study was to provide current age-, sex-, and region-specific MS prevalence estimates and to identify trends using the National Health Interview Survey. The overall prevalence estimate was 85/100,000 population, or approximately 211,000 (+/-20,000) persons. A 50% increase was observed in the number of women reporting MS for 1991 through 1994 vs 1982 through 1986. The observed trend in higher numbers of self-reported MS among women is consistent with recent observations of higher prevalence and incidence.