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Test Agents (test + agent)

Distribution by Scientific Domains

Medical Sciences	77%

Selected Abstracts

Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosing

DRUG DEVELOPMENT RESEARCH, Issue 1 2007
Matthew A. McLean
Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub-pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non-linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10,mg/kg (therapeutic dose) and 0.0005,mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non-linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14,22, 2007. © 2007 Wiley-Liss, Inc. [source]

Semiparametric Bayes Multiple Testing: Applications to Tumor Data

BIOMETRICS, Issue 2 2010
Lianming Wang
Summary In National Toxicology Program (NTP) studies, investigators want to assess whether a test agent is carcinogenic overall and specific to certain tumor types, while estimating the dose-response profiles. Because there are potentially correlations among the tumors, a joint inference is preferred to separate univariate analyses for each tumor type. In this regard, we propose a random effect logistic model with a matrix of coefficients representing log-odds ratios for the adjacent dose groups for tumors at different sites. We propose appropriate nonparametric priors for these coefficients to characterize the correlations and to allow borrowing of information across different dose groups and tumor types. Global and local hypotheses can be easily evaluated by summarizing the output of a single Monte Carlo Markov chain (MCMC). Two multiple testing procedures are applied for testing local hypotheses based on the posterior probabilities of local alternatives. Simulation studies are conducted and an NTP tumor data set is analyzed illustrating the proposed approach. [source]

How to optimize patch testing with diphenylmethane diisocyanate

CONTACT DERMATITIS, Issue 3 2007
Malin Frick-Engfeldt
We have previously shown that patch test preparations of polymeric diphenylmethane diisocyanate (PMDI) are more stable than preparations of diphenylmethane-4,4'-diisocyanate (4,4'-MDI). This study was conducted to (i) investigate whether PMDIs yield as many positive reactions as 4,4'-MDI, (ii) study concurrent reactions to 4,4'-MDI and 4,4'-diaminodiphenylmethane (4,4'-MDA), and (iii) follow the course of positive reactions during 4 weeks. It was shown that PMDIs detect as many positive reactions as 4,4'-MDI. Thus, they are better patch test agents being more stable than preparations of 4,4'-MDI. We recommend that PMDIs with a monomer content of at least 35% is used in 2.0% petrolatum (pet.) (i.e. monomer patch test concentration approximately 0.7%). It was shown that reactions to 4,4'-MDI and PMDIs appear late and we recommend readings on both day (D) 3/4 and D7. 4,4'-MDA was shown to be a good marker for 4,4'-MDI and patch testing with 4,4'-MDA in 0.25% pet. can be used instead of PMDI. Concomitant reactions to 4,4'-MDI and 4,4'-MDA are probably not caused by conversion of 4,4'-MDI into 4,4'-MDA by reaction with water. Another explanation is a path of reactions leading to ureas and MDI conjugates with skin constituents, which are hydrolysed into 4,4'-MDA. This complex process depends upon several factors and might explain why positive MDI reactions appear after D7. [source]

P45 Neomycine sulfate patch tests

CONTACT DERMATITIS, Issue 3 2004
Bolli Bjarnason
Objective:, The purpose of this study is to investigate if patients with neomycin sulfate allergy may develop test responses that are unclassifiable by commonly used assessment scales but which should be considered positive. Materials:, 16 patients who tested positive to neomycin sulfate patch tests are retested with different dose levels and application times. Test areas are assessed visually up to 11 days. Results:, Three types of reactions were observed. The first type was characterized by erythema and diffuse infiltrate. Some of these had in addition either discrete papules or both papules and vesicles on their surface. The second type of reaction initially developed large perifollicular papules which later developed into coalescent erythema and diffuse infiltrate. The third type of reaction exhibited perifollicular papules only which declined over time. This type was unclassifiable by commonly used assessment scales. All types of reactions were of clinical significance. Conclusion:, The results support that universal assessment scales for patch-test responses due to different test agents may be inappropriate for assessment of neomycin sulfate patch tests. The clinician should only consider assessment scales as an aid in the assessment of test responses and be aware that morphology of test responses may differ between test agents and test techniques. [source]

Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosing

Evaluation of mutant frequencies of chemically induced tumors and normal tissues in ,/cII transgenic mice

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2005
Jon C. Mirsalis
Abstract Genomic instability has been implicated as an important component in tumor progression. Evaluation of mutant frequencies (MFs) in tumors of transgenic mice containing nontranscribed marker genes should be useful for quantitating mutation rates in tumors as the physiologically inactive transgene provides neither a positive nor a negative selective pressure on the tumor. We have conducted long-term carcinogenicity studies in ,/cII transgenic B6C3F1 mice using a variety of genotoxic and nongenotoxic test agents and have evaluated the mutant frequencies in both tumors and normal tissues from these animals. Mice were administered diethylnitrosamine (DEN) as three intraperitoneal injections of 15 mg/kg; phenobarbital (PB) or oxazepam (OXP) provided ad libitum at 0.1% or 0.25% in the diet, respectively; DEN initiation plus PB in the diet; or urethane (UTH) provided ad libitum at 0.2% in the drinking water. Normal tissues and tumors were isolated at various times over a 2-year period and half of each tissue/tumor was evaluated histopathologically and the other half was evaluated for MF in the cII transgene. Approximately 20 mutants from each of 166 individual tissues (tumor and nontumor) were sequenced to determine whether increases in MF represented unique mutations or were due to clonal expansion. UTH produced significant increases in MF in normal liver and lung. DEN either with or without PB promotion produced significant increases in MF in liver and correction of MF for clonality produced little change in the overall MF in these groups. PB produced a twofold increase in liver MF over controls after 27 weeks of treatment, but a similar increase was not observed with longer dosing times; at later time points, the MF in the PB groups was lower than that of the control group, suggesting that PB is not producing direct DNA damage in the liver. OXP failed to produce an increase in MF over controls, even after 78 weeks of treatment. Selected cases of genomic instability were observed in tumors from all treatments except OXP, with individual liver tumors showing very high MF values even after clonal correction. One rare and interesting finding was noted in a single mouse treated with UTH, where a mammary metastasis had an MF approximately 10-fold greater than the parent tumor, with 75% of the mutations independent, providing strong evidence of genomic instability. There was no clear correlation between tumor phenotype and MF except that pulmonary adenomas generally had higher MFs than normal lung in both genotoxic and nongenotoxic treatment groups. Likewise, there was no correlation between tumor size and MF after correction for clonality. The results presented here demonstrate that individual tumors can show significant genomic instability, with very significant increases in MF that are not attributed to clonal expansion of a single mutant cell. Environ. Mol. Mutagen., 2005. © 2004 Wiley-Liss, Inc. [source]

A synergistic chlorhexidine/chitosan combination for improved antiplaque strategies

JOURNAL OF PERIODONTAL RESEARCH, Issue 5 2005
E.-M. Decker
Background:, The minor efficacy of chlorhexidine (CHX) on other cariogenic bacteria than mutans streptococci such as Streptococcus sanguinis may contribute to uneffective antiplaque strategies. Methods and Results:, In addition to CHX (0.1%) as positive control and saline as negative control, two chitosan derivatives (0.2%) and their CHX combinations were applied to planktonic and attached sanguinis streptococci for 2 min. In a preclinical biofilm model, the bacteria suspended in human sterile saliva were allowed to attach to human enamel slides for 60 min under flow conditions mimicking human salivation. The efficacy of the test agents on streptococci was screened by the following parameters: vitality status, colony-forming units (CFU)/ml and cell density on enamel. The first combination reduced the bacterial vitality to ,0% and yielded a strong CFU reduction of 2,3 log10 units, much stronger than CHX alone. Furthermore, the first chitosan derivative showed a significant decrease of the surface coverage with these treated streptococci after attachment to enamel. Conclusions:, Based on these results, a new CHX formulation would be beneficial unifying the bioadhesive properties of chitosan with the antibacterial activity of CHX synergistically resulting in a superior antiplaque effect than CHX alone. [source]

2124: Src family tyrosine kinase activation is required for endothelin-1 to inhibit Na,K-ATPase in porcine lens epithelium

ACTA OPHTHALMOLOGICA, Issue 2010
NA DELAMERE
Purpose Earlier studies point to the involvement of Src family tyrosine kinases (SFKs) in the stimulation of of Na,K-ATPase activity by purinergic receptor agonists ATP and UTP. Src itself was activated (Tamiya, et al. 2007, Am. J. Physiol. 293: C790-6). Here, we examined the role of SFKs in the response to endothelin-1 (ET-1), an ET receptor agonist that causes Na,K-ATPase inhibition. Methods Porcine lenses were incubated 30 min in Krebs' solution with ET-1 or other test agents. The epithelium was removed, homogenized and analyzed by western blot or Na,K-ATPase activity assay. Results Exposure of the intact lens to ET-1 caused a reduction in Na,K-ATPase activity. The Na,K-ATPase response was not observed when lenses were pretreated with 10 uM PP2, a selective inhibitor of SFKs. ET-1 caused SFK activation evident from an increase in Y416 phosphorylation and decrease in Y527 phosphorylation of a ~61kDa SFK. The SFK inhibitor PP2 abolished the SFK phosphorylation response. Since SFKs Fyn, Src, Hck and Yes may contribute to the observed 61kDa band, these SFKs were isolated by immunoprecipitation and analyzed separately. Based on Y416 phosphorylation, ET-1 appeared to activate Fyn, while Src and Hck were inhibited. Yes activity was unaltered. Conclusion ET-1, which causes Na,K-ATPase inhibition, elicits a different pattern of SFK activation from that reported earlier for purinergic agonists which stimulate Na,K-ATPase activity. Previously, Na,K-ATPase stimulation was observed when Src was activated. The ET-1 response points to Na,K-ATPase inhibition when Fyn kinase is activated. [source]