Testing, in vitro

In particular, in silico methods are expected to speed up the drug discovery process, to provide a quicker and cheaper alternative to in vitro tests, and to reduce the number of compounds with unfavorable pharmacological properties at an early stage of drug development. Bad ADMET profiles are a reason for attrition of new drug candidates during the development process [9, 10]. The major reasons for attrition of new drugs are ... 

Metabolic Functions. Chromium (ITT) potentiates the action of insulin and may be considered a cofactor for insulin (137,138). In in vitro tests of epididymal fat tissue of chromium-deficient rats, Cr(III) increases the uptake of glucose only in the presence of insulin (137). The interaction of Cr(III) and insulin also is demonstrated by experimental results indicating an effect of Cr(III) in translocation of sugars into ceUs at the first step of sugar metaboHsm. Chromium is thought to form a complex with insulin and insulin receptors (136). 

Corona.iy Hea.rt Disea.se, A theory for atherogenesis (120) has been developed whereby oxidation of low density Hpoprotein (LDL) within the arterial wall is the critical first step. It has been hypothesized that sufficient intake of antioxidants would prevent oxidation of LDL and reduce development of coronary heart disease (122). Interest in determining the role of antioxidants in blocking LDL oxidation has led to the development of in vitro test systems. 

Standardization and Testing". Potency is deterrained by titration of the amount of Hve vims Hi susceptible tissue culture and is mn Hi paraUel with a U.S. standard. Both in vivo and in vitro tests are used to assess safety (17). 

Sodium chlorite is not Hsted by the USEPA or any regulatory authority as a carcinogen. Studies conducted ia mice and rats did not show an increase in tumors in animals exposed to sodium chlorite in thek drinking water. Sodium chlorite has been found to have mutagenic activity in some in vitro test systems such as the Ames Salmonella reverse mutation assay without the presence of metaboHc activators. The significance of these test results in regard to human health is not clear because of the oxidizing effects of the chlorite ion (149). 

A good example of a surface-modified lens is the Sola/Bames-Hind Hydrocurve Flite lens, introduced in 1986. The material for the commercial Hydrocurve lens, bufilcon A [56030-52-5] contains methacrylic acid and has a high affinity for protein and subsequent deposition. The surface of the Flite lens was chemically modified with the addition of diazomethane (190) to reduce the surface charge. In vitro testing demonstrated a decrease in protein adsorption (191). 

It has been shown by various workers 3 that the action of alkaloids on protozoa is influenced in a marked degree by the pH of the medium in which the action is exerted, and at a pH of 6-2 to 6-3 aK-tetra-n-amyl-diamino-n-decane proved to be 3 to 5 times as active as emetine, and even in presence of blood at least as active. In view of these promising results of in vitro tests the synthetic product was tried clinically, but proved not to be sufficiently active to be of practical value. This work is being continued and extended by a team of workers led by Goodwin and Sharp, who have published two papers dealing (1) with amines which can be regarded, like Pyman s type A, as diamines derivable from the accepted emetine formula and (2) variants on the bis(diamylamino) decane referred to above. 

Gettleman, L., Cocks, F. H., Darmiento, L. A., Levine. P. A., Wright, S. and Nathanson, D. Measurement of In Vivo Corrosion Rates in Baboons and Correlation with In Vitro Tests , Journal of Dental Research, 59, 689-707 (1980)... 

An in-vitro test with mammalian cells (chromosomal damage or mouse lymphoma tk assay)... 

Tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. 

The vast majority of in vivo tests show no geno-toxicity of mono- and dialkyltins. Results from in vitro tests are variable, with little indication of DNA reactivity. There are, however, indications of clastogenicity and effects on spindle formation in mitosis in vitro. 

EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS... 

Tributyltin is well established as an aromatase inhibitor (IPCS, 1990). Quantitative comparisons of potency cannot be defined for other organotins, because a full range of in vitro tests has not been performed. 

Mayr U, Butsch A and Schneider S. 1992. Validation of two in vitro test systems for estrogenic activities with zearalenone, phytoestrogens and cereal extracts. Toxicology 74 135-149. 

The overall evidence indicates that endosulfan administered in vivo may be disruptive of reproductive hormone levels in male animals. On the other hand, endosulfan is neither estrogenic nor disruptive of thyroid or pituitary hormone levels in females in vivo, despite its weak estrogenicity in several in vitro test systems. 

Iversen (1991) stresses the need for some in vivo testing for neurotoxicity and emphasizes the value of sensitive behavioral tests. Behavioral tests are described for mice and rats, which provide measures of mood, posture, CNS excitation, motor coordination, sedation, exploration, responsiveness, learning, and memory function. Such assays can function as primary screens for neurotoxicity before adopting a stepwise scheme of in vitro tests to discover more about the initial site of action of neurotoxic compounds. It is argued that the requirement for animal testing can be drastically reduced by adopting structured in vitro protocols such as these. 

Atterwill, C.K. et al. (1991). Alternative Methods and Their Application in Neurotoxicity Testing—Describes a range of in vitro tests for neurotoxicity and proposes a stepwise scheme for neurotoxicity testing. 

Pelissero, C., Flouriot, G., and Foucher, J.L. (1993). Vitellogenin Synthesis in Cultured-Hepatocytes—an in vitro Test for the Estrogenic Potency of Chemicals. Journal of Steroid Biochemistry and Molecular Biology 44, 263-272. 

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