Activational Toxicity

Estrogenic Pharmaceuticals. Administration of estrogenic pharmaceuticals to children or adults can result in a variety of abnormalities associated largely with secondary sex characteristics that are reversible upon cessation of drug treatment. 

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Present research is devoted to investigation of application of luminol reactions in heterogeneous systems. Systems of rapid consecutive reactions usable for the determination of biologically active, toxic anions have been studied. Anions were quantitatively converted into chemiluminescing solid or gaseous products detectable on solid / liquid or gas / liquid interface. Methodology developed made it possible to combine concentration of microcomponents with chemiluminescence detection and to achieve high sensitivity of determination. 

Quantitative Structure-Activity Relationship studies search for a relationship between the activity/toxicity of chemicals and the numerical representation of their structure and/or features. The overall task is not easy. For instance, several environmental properties are relatively easy to model, but some toxicity endpoints are quite difficult, because the toxicity is the result of many processes, involving different mechanisms. Toxicity data are also affected by experimental errors and their availability is limited because experiments are expensive. A 3D-QSAR model reflects the characteristics of... 

Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of success, for a better anti-malarial activity/ toxicity balance <06BMCL1854>. A number of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55... 

Identification of metabolic reactions at an early phase can significantly affect the drug discovery process, because bioavailability, activity, toxicity, distribution and final elimination all depend on metabolic biotransformations [1], Once obtained, this information can help researchers judge whether or not a potential candidate should be eliminated from the pipeline or modified to reduce the affinity for CYP antitarget enzymes. 

Espuelas MS, et al. Polymeric carriers for amphotericin B in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice. J Antimicrob Chemother 2003 52 419. 

The active toxicant is not hexane, but the hexane metabolite called 2,5-hexanedione (II) ... 

The latter compound results from loss of two hydrogen atoms by metabolic oxidation at each of two of the carbon atoms of hexane, and their replacement by oxygen atoms. Schaumburg and Spencer not only demonstrated this, but also showed that the identical neurotoxic events result from direct exposure to compound II and also another common solvent called methyl-n-butyl ketone (III). Chemical III is, like hexane, readily metabolized to the active toxicant, molecule II. Because both I and III yield the same metabolite (II), and because this metabolite is the source of toxicity, then exposure to both of these chemicals produces the identical type of neuropathy. 

Particular attention has been focused on the toxic effects of aromatic hydrocarbons because these chemicals have proven highly carcinogenic to humans and marine life. Of greatest concern are the PAHs, which are toxic to the benthos at the ppb level. The most common compounds are shown in Figure 28.20 their structures are based on fused aromatic rings. These high-molecular-weight compoimds are very nonpolar and, hence, have low solubilities. Once in seawater, they tend to adsorb onto particles and become incorporated in the sediments. The toxicity of PAHs is enhanced by photochemical reaction with UV radiation. Photo-activated toxicity is especially problematic in shallow-water sediments, such as found in estuaries. 

Among fish we find some of the most potent toxins in animals. We dis-tinguish passivelj toxic fish from actively toxic fish. The former simply have toxins in their tissues, typically taken from some other source such as their diet. The latter produce the poison and have evolved apparatus to discharge, deliver, or inj ect the... 

There is, however, one means of achieving the conflicting properties required for apoplastic transport without resort to compromise. This is by using precursors which have characteristics favouring uptake and are then converted within the plant to active toxicants which are more readily translocated. The principle is best illustrated by the long-established organophosphorus insecticides of the systox type such as demeton, disulfoton and phorate which are relatively lipophilic... 

Preparation and pharmacological activity (anti-inflammatory, platelet aggregation inhibitory activity, toxicity)... 

AntiBase 2005 is a comprehensive database of 31 022 natural compounds from micro-organisms and higher fungi based on curated literature reports. In addition to descriptive chemical data, biological data (e.g. pharmacological activity, toxicity) and information on origin and isolation are included. 

Dextropropoxyphene 9-13 2.5 days Active toxic metabohte which in the elderly and in patients with decreased kidney function may build up (concentrate ) and cause confusion. Risk of pronounced respiratory depression together with alcohol intake. Low risk of abuse... 

Bioassay Detected effects Endpoint Levels Of indication Known active toxic compounds Performance characteristics (sensitivity detection limit variability reproducibility) Confounding factors Percentage false positive data... 

Once inside the body, extremely hydrophilic compounds tend to be excreted more readily by the kidney. That could be useful, because it lowers toxicity. Additionally, chemical classes and functional groups known to be toxic—as well as those that can be bioactivated into toxic substances—should be avoided when designing chemical products. Chemicals can also be designed to shield active toxic sites or to facilitate metabolic degradation to nontoxic metabolites. 

Fluoxetine Highly selective blockade of serotonin transporter (SERT) little effect on norepinephrine transporter (NET) Acute increase of serotonergic synaptic activity slower changes in several signaling pathways and neurotrophic activity Major depression, anxiety disorders panic disorder obsessive-compulsive disorder post-traumatic stress disorder perimenopausal vasomotor symptoms eating disorder (bulimia) Half-lives from 15-75 h oral activity Toxicity Well tolerated but cause sexual dysfunction Interactions Some CYP inhibition (fluoxetine 2D6, 3A4 fluvoxamine 1A2 paroxetine 2D6)... 

Pharmacokinetic principles, in addition to clinical factors such as the state of the patient, are utilized in determining dosage regimens. Factors that relate to the safety and efficacy of the drug, such as activity-toxicity relationships (therapeutic window and side effects), and pharmaceutical factors, such as dosage form and route of administration, must be considered.16... 

Toxicants may also be detoxified by xenobiotic-metabolizing enzymes such as cytochrome P450 or the flavin-containing monooxygenase. It should be borne in mind, however, that these enzymes may also activate toxicants to more reactive, and potentially more toxic, metabolites. 

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