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A meta-analysis of several rat toxicity studies for dimethoate was conducted to determine the most sensitive endpoint for use in risk assessment. The analysis was motivated by a recent developmental neurotoxicity (DNT) study, which identified the same no observed adverse effect level (NOAEL) for pup mortality and cholinesterase inhibition. The pup mortality NOAEL was lower than that determined in a range-finding study for the DNT and other reproduction studies, and was highly influenced by a single total litter loss in the middle dose group, which made interpretation difficult. First, a meta-analysis was conducted of four recent studies by gavage dosing with very similar designs, including the DNT. Benchmark dose (BMD) modeling was used to determine the appropriate point of departure for regulatory purposes, the lower limit of the BMD for a 5% incidence for pup mortality (BMDL(5)) and the lower limit of a 10% inhibition of brain cholinesterase (BMDL(10)*), the asterisk denotes that the BMD is based on continuous response variable as opposed to an incidence level. For pup mortality, the BMDL(5) for post-natal days (PND) 1-4 was 0.64 mg/kg/day. For cholinesterase inhibition, the lowest BMDL(10)* was 0.19 mg/kg/day for the dams at gestation day 20. These results show that the regulatory point-of-departure for cholinesterase inhibition is more than threefold lower than pup mortality. Thus, risk assessments protecting against cholinesterase inhibition are likely to also be protective of pup mortality. In addition, cholinesterase inhibition and pup mortality were evaluated in two 2-generation reproduction studies by dietary exposure. Also, cholinesterase inhibition was evaluated in a 28-day dietary study. Dietary exposure is more relevant than gavage exposures for many human risk assessment scenarios. There was no consistent pup mortality at the highest doses of the two 2-generation dietary studies (6.0 and 6.5mg/kg/day). The average BMD(10)s for brain cholinesterase inhibition for the 2-generation studies was 0.65 mg/kg/day, with a range of 0.49--0.96 mg/kg/day. This suggests that cholinesterase inhibition is at least a 10-fold more sensitive endpoint than pup mortality for dietary exposures. For the 28-day dietary study, the BMD(10) for brain cholinesterase inhibition was 1.1mg/kg/day for males and 0.70 mg/kg/day for females. The exposure duration in the 28-day dietary study is closest to the durations in the gavage studies. Compared to the dams in the gavage studies, which had a BMDL(10) of 0.19 mg/kg/day, the animals were more than threefold more sensitive to cholinesterase inhibition by gavage compared to dietary exposure.
An automated method for determining infectious bursal disease virus (IBDV) titration and neutralization endpoints is described. The method employs the fluorogenic ester carboxyfluorescein-diacetate (CFDA) to stain cell monolayers in 96-well plates and a fluorescence-concentration analyzer. Titration results are compared with immunofluorescence and plaque assay titers. Virus-neutralization endpoint determination is objective, and the endpoints of replicate tests were equivalent or within one dilution of variability. Tests can be automatically screened as any percentage of a positive control or any standard deviation from a negative control.
BACKGROUND: PCR techniques detecting interchromosomal translocation and clonal immunoglobulin gene rearrangement (IgH) as disease markers in non-Hodgkin's lymphomas (NHL) has been utilised past ten years. However, qualitative PCR detection of persisted minimal residual disease cannot provide clinically useful prognostic information and presently, quantitative approaches are required to predict patient outcome and assess response to the treatment. In some cases, "end-point" quantifying techniques, such as comparative PCR, are applicable and the relative estimation of differences in target quantity may serve in disease monitoring rather than absolute number of target copies. METHODS AND RESULTS: Our method of comparative PCR employs co-amplification of sequences of interest (clonal CDR3, bcl2/Jh) and the segment of Hras 1 gene(ras) as an internal standard. Serial dilutions of stored diagnostic DNAs from blood and bone marrow are examined in the same PCR and, after gel densitometry, the amount of initial target is assessed by comparing exponential products of co-amplification. The comparative PCR assay was utilized in monitoring of NHL patients cured either with conventional therapy, or with high-dose regimens and transplantation with stem cells, or with chimaeric anti-CD20 monoclonal antibody (Rituximab). Results from 50 monitored intervals obtained during several months up to several years were supplemented with clinical statements retrospectively. Some of patients became PCR-negative, reappearance of PCR-positivity was observed as well. The decrease or increase of disease marker corresponded to clinical observations. Results obtained from bone marrow were in agreement with those obtained from blood. CONCLUSIONS: End-point quantifying PCR comparative assay may provide an information on the increased risk of relapse and impact of the therapy. The predictive value of these methods depends on the frequency of sample taking and on the sensitivity of the method, which should be monitored in negative cases.
We have previously reported poor correlation between the in vitro fungicidal activity of LY303366 and MIC results in RPMI medium based upon the manufacturer's suggested susceptibility endpoint, lack of visual growth. Additionally, we have noted a significant trailing effect with LY303366 when MICs are determined in RPMI medium. These observations have led us to evaluate an alternative susceptibility endpoint for LY303366, an 80% reduction in growth compared with control (similar to that utilized for azoles). Two isolates each of Candida albicans, Candida glabrata, and Candida tropicalis were selected for testing. MICs were determined for LY303366 in RPMI 1640 medium buffered with morpholinepropanesulfonic acid. MICs were determined with suggested (MIC100) and experimental (MIC80) endpoints. The minimal fungicidal concentration (MFC) of LY303366 for each isolate was also determined. Time-kill curves were determined in RPMI medium with each isolate at concentrations of LY303366 ranging from 0.125 to 16x MIC80 to assess the correlation between MIC80 and fungicidal activity. Lastly, fungi exposed to LY303366 were examined via scanning electron microscope (SEM) for evidence of drug-induced ultrastructure change. MIC80s for test isolates ranged from 0.015 to 0.12 microgram/ml and were consistently three to five wells less than MIC100s. Good correlation was observed between fungicidal activity, as assessed by kill curves, and the MIC80. SEM data revealed significant ultrastructure changes induced by LY303366 even at sub-MIC80s. Based on our results demonstrating better correlation between MIC80 and fungicidal activity, i.e., time-kill curves and MFCs, we suggest that 80% reduction in visible growth be utilized as the endpoint for susceptibility determinations with LY303366 in RPMI medium.
Bronchial reactivity to inhaled agents in preschool children can be undertaken by auscultating the lungs to detect wheezing, but there is a lack of information on when wheeze first appears at the endpoint of the challenge and on the acoustic characteristics of the wheeze. We recorded breath sounds continuously during tidal breathing inhalation challenges with adenosine 5'-monophosphate, using sensors attached over each upper lobe in 80 preschool children. In 35 children, the challenge was considered positive by a pediatrician who determined the endpoint by detecting wheeze on auscultation after an inhalation. Using acoustic analysis, we determined that the first wheeze appeared during the 2-min period of nebulization in 31% of positive challenges; it was unilateral in 37%, and only inspiratory in 46%. A running window of 6 sec was used to detect at least two wheezes without reference to phase of breathing, and this index had a sensitivity of 97.6% and specificity of 99.7% for determining the endpoint of a challenge. Detecting wheeze acoustically adds safety to the technique by enabling the challenge to be stopped earlier, while the lack of a need to document the phase of breathing simplifies the technique.
A commercially available through-the-plate reading photometer (Titertek Multiskan, Flow Laboratories, McLean, Va.) was used to determine microdilution minimal inhibition concentrations (MICs) for 190 clinical isolates of bacteria (115 gram-negative rods and 75 gram-positive cocci). The performance of the instrument was evaluated by comparing its MIC readings to those that were visually determined. The MICs determined by the instrument were identical to those determined visually for 94% of the gram-negative rods and 89% of the gram-positive cocci tested. Of the MICs determined by the instrument, 99% was within one dilution of the MICs determined visually.
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Bioavailability and bioaccessibility are complex issues that determine whether or not adverse effects are to be expected when organisms or plants are exposed to contaminants. Clearly, the determinants of bioavailability and bioaccessibility must be understood if one is to monitor or, ultimately, predict the effects of metals. On the basis of a dynamic conceptual model, this article offers an analysis of the physicochemical and biological determinants underlying bioavailability and bioaccessibility. This analysis is used as the basis for a general monitoring strategy for assessing potentially and actually available and accessible metal fractions in the environmental matrices of water, soil, and sediment. We conclude that, lack of a universal expression of bioavailable and bioaccessible metal fractions precludes the presentation of a detailed monitoring strategy that is broadly applicable. Instead, we recommend that a critical assessment of the endpoints of determination become the basis for a need-specific monitoring strategy.
Acute renal failure research has been hampered by the lack of useful physiologic surrogate endpoints. Acute renal failure prevention and therapy studies using variables such as urine output and serum and urine chemistries have not yielded interventions proven to decrease the morbidity and mortality associated with acute renal dysfunction. Of those interventions that have been successful in smaller, phase II-level efficacy studies, none subsequently decreased the incidence of clinical (effectiveness) endpoints such as dialysis requirement or mortality in larger phase III trials. Suitable physiologic endpoints are needed to test the efficacy of new proposed therapies for the prevention and management of acute renal failure. Candidate endpoints for efficacy studies in acute renal failure prevention and management include glomerular filtration rate markers, renal blood flow, urine markers, and urine output. Possible endpoints for efficacy studies of renal replacement therapy in acute renal failure include serum markers of renal function and a variety of nonrenal markers. In this article, we present an approach to the choice of physiologic endpoints to determine the efficacy of interventions in acute renal failure.
Analysis of organ weight in toxicology studies is an important endpoint for identification of potentially harmful effects of chemicals. Differences in organ weight between treatment groups are often accompanied by differences in body weight between these groups, making interpretation of organ weight differences more difficult. Using data from control rats that were part of 26 toxicity studies conducted under similar conditions, we have evaluated the relationship between organ weight and body/brain weight to determine which endpoint (organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio) is likely to accurately detect target organ toxicity. This evaluation has shown that analysis of organ-to-body weight ratios is predictive for evaluating liver and thyroid gland weights, and organ-to-brain weight ratios is predictive for evaluating ovary and adrenal gland weights. Brain, heart, kidney, pituitary gland, and testes weights are not modeled well by any of the choices, and alternative analysis methods such as analysis of covariance should be utilized.
Obtaining a complete response (CR) is the most powerful predictor of survival in extensive-stage small cell lung cancer (SCLC). Improvements in long-term survival in extensive-stage SCLC can be made if the proportion of complete responders to induction therapy can be increased. We performed a phase II trial of the feasibility of adding paclitaxel to standard cisplatin/etoposide (EP regimen) in extensive-stage SCLC. The primary endpoint for this trial is the proportion of patients (pts) obtaining a CR rather than overall response. The null hypothesis for this trial consists of the absence of a CR rate >20%. Paclitaxel was given at doses of 135 (3 pts) or 170 mg/m(2) i.v. over 3 h on day 1. Cisplatin 60 mg/m(2) was given on day 1. On days 1-3 etoposide 80 mg/m(2) per day i.v. was given. G-CSF was used from days 5 to 14 of each cycle. Cycles were repeated q21 days. A two-stage design was used for patient accrual, based on the occurrence of complete responses. Initially, 16 patients were to be accrued. If more than three complete responses were to occur, a further 20 patients would be accrued to the study (Simon's optimal two stage design). Sixteen patients were enrolled. Two patients had a CR (13%) and nine patients had a partial response (56%) for an overall response rate of 69%. The trial was suspended due to the low CR rate. Review of the literature for paclitaxel based front-line treatment combined with EP therapy, in extensive stage SCLC, consistently shows a CR rate <20% but high overall response rate is maintained (thus most responses are partial). As virtually all long-term survivors in extensive-disease SCLC have had a CR to induction therapy and CR remains the strongest predictor of survival for this disease, this may suggest that paclitaxel added to standard EP may improve progression-free survival (and possibly median survival) but is unlikely to significantly improve long-term survival. Initial randomized phase III data confirm the absence of impact on survival for this triple-drug regimen compared to EP therapy alone. Furthermore, other regimens comparing favorably to the EP regimen have all shown consistent CR rates >20% in the phase II setting. In conclusion, consideration should be given to the use of CR rate as a phase II endpoint to determine if a particular regimen should be compared to the standard in a phase III setting for extensive-stage SCLC. A two-stage phase II design based on a minimum required completed responses for further patient accrual is recommended.
A sensitive, accurate, and reliable method is described for calibrating the rate immunonephelometric assay of rat and human plasma apolipoprotein A (Apo A). Pure Apo A and high-density lipoprotein (HDL) of known Apo A concentration were used in endpoint nephelometry to determine Apo A concentrations of rat and human plasma pools. The endpoint method had coefficients of variation of 7.96% and 4.35% for rat and human plasma pools, respectively. These plasma pools were then used as secondary standards for the rate nephelometric assay. Excellent agreement (+/- 6%) existed between the plasma Apo A values determined by endpoint nephelometry and rate nephelometry. The Apo A concentration of a frozen human plasma pool determined by endpoint nephelometry was 125.2 +/- 9.6 mg/dl. The value of the same pool determined by rate nephelometry over a 1-year period with the Centers for Disease Control WHO lyophilized plasma standard was 125.4 +/- 21.2 mg/dl. Furthermore, it was found that the rat HDL was also a suitable standard in the rate nephelometric assay of Apo A. In contrast, Apo A, purified to homogeneity, showed different reaction kinetics from that of Apo A in the whole plasma and therefore was not a suitable standard in the rate nephelometric assay. We therefore conclude that primary standard Apo A, purified to homogeneity, can be used by endpoint nephelometry to calibrate plasma pools that can then be used as secondary standards in the rate nephelometric determination of rat and human plasma Apo A. The ready applicability of this method in the accurate determination of plasma Apo A under well-defined experimental conditions such as in chronic ethanol-fed rats and in human subjects with normal lipid levels and those with hyperlipidemia is demonstrated.
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In clinical trials on the effectiveness of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA), it is common to apply a large number of endpoint measures. This practice has several disadvantages. To determine which endpoint measures are most valuable, reports of 32 clinical trials on six DMARDs were reviewed. The frequency with which each endpoint measure was used is described and discussed, as well as the frequency with which the values of each endpoint were significantly different in statistical comparisons within or between groups, thus showing ability to discriminate between drugs not equally effective. The results of this review are discussed and compared with other reports in the literature on the choice of endpoint measures in RA clinical trials. The authors conclude that it is still common practice to evaluate multiple outcome measures. The number of measures could be reduced by using only those that are generally considered important, are sensitive to change, and are able to differentiate between drugs in clinical trials. A joint count, assessment of pain, a questionnaire on functional status, and measurement of erythrocyte sedimentation rate are sufficient.
In many clinical trials, the primary focus is whether treatment groups differ with respect to the change from baseline to end of therapy in a continuous response variable. Randomized clinical trials often use a repeated measures design in which subjects are followed-up at fixed times throughout the study. With this design, testing for differences between treatment groups with respect to the average change from baseline to end of therapy in the response variable is equivalent to testing for differences between the rates of change in the response variable, assuming the rates of change in each treatment group are linear. This analysis can be performed quite easily using methods such as generalized estimating equations (GEE). However, if the rate of change in the response cannot be assumed linear, the average change from baseline is many times calculated using simply differences between baseline and final measurements and additional data points are not included in the analysis. Instead, we propose using all available data in a repeated measures model that is based on the nonlinear treatment response pattern to estimate the average change from baseline to end of therapy in each treatment group. GEE with robust variance estimation is used for obtaining these model-based estimates of the treatment effect and a simple test for appropriateness of the model is presented. The GEE model presented, in conjunction with the test for appropriateness of the model, form the basis for an adaptive analysis approach for determining the method of estimation of the primary endpoint. This approach results in more efficient estimates of the treatment effect when the response pattern is specified correctly and minimizes the bias in the estimate when the hypothesized response pattern is misspecified. We are motivated by examples in the cystic fibrosis (CF) clinical trial setting and demonstrate the potential for this approach in reducing the sample size required for future CF clinical trials.
The work group considered past and future Recommended Dietary Allowances (RDAs) for zinc. Past RDAs were based in large part on metabolic balance data. Balance measurements are technically difficult and it is uncertain that they reflect true requirements. Therefore other methods should be used to determine requirements and the RDA. The best approach at this time is the factorial method. In the future, data from measurements of zinc kinetics, in relation to diet and physiological functions will provide useful insights. Future RDAs should provide for at least three levels of bioavailability: low, moderate and high. Whether adjustments should be made in the RDA to account for life style factors is a matter of philosophy. The importance of the differences (gaps) between the RDA and usual intakes of zinc by persons who are apparently in good health, or between the RDA and other dietary guidelines, is an issue for consideration.