Toxicological activities

Chiral separations have become of significant importance because the optical isomer of an active component can be considered an impurity. Optical isomers can have potentially different therapeutic or toxicological activities. The pharmaceutical Hterature is trying to address the issues pertaining to these compounds (155). Frequendy separations can be accompHshed by glc, hplc, or ce. For example, separation of R(+) and 5 (—) pindolol was accompHshed on a reversed-phase ceUulose-based chiral column with duorescence emission (156). The limits of detection were 1.2 ng/mL of R(+) and 4.3 ng/mL of 3 (—) pindolol in semm, and 21 and 76 ng/mL in urine, respectively. 

Basak SC, Mills D, Cute BD, Natarajan R (2006) Predicting Pharmacological and Toxicological Activity of Heterocyclic Compounds Using QSAR and Molecular Modeling. 

The basis for the toxicological activity of this substance is the reaction of cobalt ion with cyanide ion to form a relatively nontoxic and stable ion complex. The hexacyanocobaltate ion contains a Co2+ central metal ion with six cyanide ions as ligands. This coordination complex involves six coordinate covalent bonds whereby each cyanide ion supplies a pair of electrons to form each covalent bond with the central cobalt ion. The formation constant for the hexacyanocobaltate ion is even larger than for dicobalt EDTA,3 and thus the cobalt ion preferentially exchanges an EDTA ligand for six cyano ligands ... 

Schwartz, T.R. and D.L. Stalling. 1991. Chemometric comparison of polychlorinated biphenyl residues and toxicologically active polychlorinated biphenyl congeners in the eggs of Forster s terns (Sterna forsteri). Arch. Environ. Contam. Toxicol. 20 183-199. 

These various examples underline various aspects of the metabolism and disposition of lactones in connection with their pharmacological or toxicological activities. Other cases also exist, namely the lactone prodrugs to be presented in Chapt. 8. 

A number of toxicologically active 2,3,7,8-substituted PCDDs and PCDFs, planar PCBs and PCDD, PCDF, and PCDT homologs were measured in fish, SPMDs, and sediments. Only two target compounds exceeded the detection limits of 0.2-1 pg g in SPMD field blanks (see definition in Chapter 5). These exceptions were octachlorodibenzo-p-dioxin (OCDD) and octachlorodibenzofuran (OCDF) which were present in SPMDs at about 5 pg g However, negative... 

DOE. 1986e. Effeets of eoal rank on the chemical composition and toxicological activity of coal liquefaction materials. Contraet no. DE-AC06-76RLO-1830. Washington, DC U.S. Department of Energy. Doeument no. DE86011015. 

These quantitative differences may often mean, however, that different metabolic routes are favored in different species, with a consequent difference in pharmacological or toxicological activity. 

Industrial chemicals are so numerous that testing them for toxicity or controlling exposure to those known to be toxic is a large area of toxicological activity. 

As implied by the representations of the water molecule in Figure 1.6, the atoms and bonds in F120 form an angle somewhat greater than 90°. The shapes of molecules are referred to as their molecular geometry, which is crucial in determining the chemical and toxicological activity of a compound and structure-activity relationships. 

Still another is the metabolites themselves, which may possess pharmacological and toxicological activity in their own right. Each metabolite has its... 

Prior to the initiation of chronic toxicity studies, there should be characterization of test chemical. Information on chemical identity and structure can sometimes be used in an analysis based on structure activity relationships to indicate biological or toxicologic activity. The physical and chemical characteristics of the test chemical provide important information for the selection of administration routes, study design, and handling and storage of the test chemical. 

It may seem too obvious to state, but it is fundamental that computer models allow for the effects of chemicals (i.e., physicochemical properties, toxicological activity, distribution, fate, etc.) to be predicted. These predictions may be obtained from a knowledge of chemical structure alone. For most methods, provided that the chemical structure can be described in two (or occasionally three) dimensions, the effects may be predicted. Information regarding the chemicals may be gained without chemical testing, or even the need to synthesize the chemical. 

Studies should be designed in a relevant model. Consideration should be given to the usefulness/ability of existing models to (1) mimic the disease/human population (activity/efhcacy) and (2) predict safety (toxicity) in the context of the similarity in anatomy and pathophysiology. A discussion of whether the disease status of the animal has an impact on pharmacologic/toxicologic activity and whether the investigative therapy has an impact on the disease status of the animal should be provided. 

Rats dosed and placed in open field and observed for signs of pharmacological or toxicological activity at 15,30, and 45 minutes, 1,2,3,4, and 24 hours following treatment... 

Because of the catabolism of proteins to (mostly) endogenous amino acids, classical biotransformation studies as performed for small molecules are not needed. Additionally, limitations of current analytical methods to detect and distinguish metabolites and the putative lack of pharmacological or toxicological activity of the metabolites, remain obstacles. Similarly mass balance studies... 

The two major independent in silico methods for the prediction of toxicity are quantitative-structure-activity-relationship (QSAR) and expert systems (e.g. DEREK, MultiCASE). QSAR means the quantitative relationship between a chemical structure and its biological/ toxicological activity with the help of chemical descriptors that are generated from the... 

Another approach to predict toxicity is basing on structure-activity-relationship (SAR), which means the qualitative relationship between a specific chemical structure and their biological/toxicological activity, e.g. the expert system DEREK is based on SAR prediction. In SAR the occurrence of specific substructures in a molecule are correlated to be responsible and necessary for a biological/toxicological activity. 

The statistical methods of QSAR modelling are based on the correlation of changes in biological/toxicological activity (AO) resulting from certain chemical modifications (AC), either directly by structural parameters, called Free Wilson-type relationships, or by the corresponding changes of molecular properties, called Hansch-type analyses (Kubinyi 2002) ... 

In the theory, it is possible to create new QSAR models with almost all datasets of compounds with known biological/toxicological activity. But practically it is a question of the quality and predictivity of a QSAR model to be applied in prediction of biological/toxicological activity. For this reason evaluation of each QSAR model is extremely important. The evaluation of a QSAR model can be preformed either by internal validation (cross validation) or external validation (use of a test-set). External validation is preferred, but is not always possible, e.g. because of the small size of a dataset (Dearden, 2003). 

In the second step of the prediction a new molecule is entered into MultiC ASE, then the program evaluates this molecule against this organized dictionary and the appropriate QS ARs it has created and makes a prediction of the toxicological activity of the molecule for the corresponding endpoint. To do this, MultiCASE identifies all relevant biophores and biophobes of the unknown molecule, combines these into an equation and calculates the toxicological activity expressed in... 

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