Minimal toxicity

Moreover, multivariate optimization, the simultaneous optimization of several properties, will increasingly come into focus. A drug should have high selectivity in binding to different receptors and minimal toxicity, good solubility and penetration, and so on. A hair color should have a brilliant shine, be absorbed well, not be washed out, not damage the hair, not be toxic, and be stable under sunlight, etc. 

Safety. The principal concerns regarding nuclear medical imaging are those associated with the radiopharmaceuticals. Much research has gone into the selection of radiopharmaceuticals exhibiting minimal toxicities, rapid elimination from the body, and short half-life. The radioisotope must be... 

Use less hazardous processes. Synthetic methods should use reactants and generate wastes with minimal toxicity to health and the environment. 

Design safer chemicals. Chemical products should be designed to have minimal toxicity. 

Tables 2.6 and 2.7 give examples of the modes of action of pollutants in animals and in plants/fungi, respectively. It is noteworthy that many of the chemicals represented are pesticides. Pesticides are designed to be toxic to target species. On the other hand, manufacturers seek to minimize toxicity to humans, beneficial organisms and, more generally, nontarget species. Selective toxicity is an important issue. Regardful of the potential risks associated with the release of bioactive compounds into the environment, regulatory authorities usually require evidence of the mode of toxic action before pesticides can be marketed. Other industrial chemicals are not subject to such strict regulatory requirements, and their mode of action is frequently unknown.

Inevitably, terrestrial invertebrates are susceptible to the toxicity of OPs used in the field. The honeybee is one species of particular importance, and the use of OPs and other insecticides on agricultural land has been restricted to minimize toxicity to this species. One practice has been to avoid application of hazardous chemicals to crops when there are foraging bees. The use of some compounds, for example, triazophos, has been restricted because of very high toxicity to honeybees. 

Molecular designers can exploit these rules and design chemicals that demonstrate characteristics that are likely to lead to decreased absorption and therefore minimize toxicity. Molecules that are permanently charged at physiological pH like the neurotoxin curare or... 

Several pharmacologic classes are available for the treatment and maintenance of IBD. Because there may be differences in the underlying disease process, distribution, and severity between CD and UC, response rates to drugs in the same pharmacologic class may differ between these two diseases. Therefore, initial selection of an appropriate agent for patients with active IBD should be designed to deliver maximum efficacy while minimizing toxicity. Response rates to individual classes of medications for both UC and CD will be discussed within the specific treatment section for each disease. 

The combination of cyclosporine with calcipotriol may be more efficacious than either agent used alone.21,37 Cyclosporine and SCAT may also be effective.21,38 However, cyclosporine should not be used concurrently with PIJVA there is a well-documented increased risk of squamous cell cancer and the combination may have a negative effect on lesion clearance.21 The combination of cyclosporine with methotrexate is extremely effective and minimizes toxicity from either agent as discussed. Cyclosporine has also been used successfully with mycophenolate mofetil38 and etanercept.29... 

Toxicity Monitor and assess for adverse effects and evaluate antimicrobial serum concentrations when appropriate to minimize toxicity and improve outcomes... 

Monitoring and treatment strategies to maximize efficacy and minimize toxicity for anti-infectives ... 

The goal of therapy with early and locally advanced breast cancer is to cure the disease. Breast cancer is currently incurable after it has advanced beyond local-regional disease. The goal of treatment of metastatic breast cancer is to improve symptoms, maintain quality of life, and extend survival. Thus it is important to choose therapy with good activity while minimizing toxicities. Treatment of metastatic breast cancer with either cytotoxic or endocrine therapy often results in regression of disease and improvements in quality of life. 

Treatment that induces the disease into remission with resolution of disease symptoms and minimal toxicity... 

Drinking large amounts of diisopropyl methylphosphonate kills animals. The amount needed to cause death in humans is not known for sure. Animal studies have shown no evidence that drinking or eating diisopropyl methylphosphonate causes fertility problems or birth defects. Animal studies have shown that eating diisopropyl methylphosphonate can affect some liver enzymes (indicating a response by the liver). However, test animals showed no liver disease. While most animal studies have shown only minimal toxic effects below a certain level of... 

The AEGL-3 values were derived based upon the 1-h LC50 value of 82 ppm reported for squirrel monkeys (Haun et al. 1970). As previously noted, there appears to be a critical and narrow threshold between an exposure that induces only minimal toxicity and one that causes death. For squirrel monkeys, 1-h exposure to a mean concentration of 82 ppm (range, 70-95 ppm) killed two of four animals. For derivation of the AEGL-3, the lethality threshold for squirrel monkeys was estimated by a 3-fold reduction of the LC50 (82 ppm) to obtain a value of 27.3 ppm. This estimate can be justified by the known steep exposure-response relationship for the toxic effects of monomethylhydrazine, and the fact that the resulting 27.3-ppm value represents an exposure concentration that does not produce overt toxicity in test animals. 

Human toxicity values have not been established or have not been published. However, based on available information, this agent appears to have minimal toxicity. 

Munition grade agents typically consist of at least one malodorant agent (10-90%) and an odor intensifier (0.5-5%) dissolved in a liquid carrier. Solvents include volatile hydrocarbons, plant/vegetable oils, and water. Solvents typically pose minimal toxic hazards themselves. Compositions are typically colorless to yellow liquids. As the agent ages and decomposes it may discolor and become brown. 

Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy because of their excellent efficacy and minimal toxicity with shortterm use. There is little evidence to support one NSAID as more efficacious than another, and three drugs (indomethacin, naproxen, and sulindac) have FDA approval for this indication (Table 1-1). 

This approach appears somewhat irrational and without much scientific merit, since many of these new molecules are minimally toxic or nontoxic by this sort of acute evaluation. As in the case of interferons or monoclonal antibodies, the toxic effects observed in humans might not be predicted from safety assessments in rodents. An appropriate test species should be selected. Is the rat or mouse the appropriate species to evaluate a species-specific rDNA protein such as human growth hormone or interferons, or would nonhuman primates be more suitable Does the nonhuman primate really offer any advantages There is some consensus that the nonhuman primate may be a more appropriate species for testing some rDNA human proteins. 

Amidases can be found in all kinds of organisms, including insects and plants [24], The distinct activities of these enzymes in different organisms can be exploited for the development of selective insecticides and herbicides that exhibit minimal toxicity for mammals. Thus, the low toxicity in mammals of the malathion derivative dimethoate (4.44) can be attributed to a specific metabolic route that transforms this compound into the nontoxic acid (4.45) [25-27]. However, there are cases in which toxicity is not species-selective. Indeed, in the preparation of these organophosphates, some contaminants that are inhibitors of mammalian carboxylesterase/am-idase may be present [28]. Sometimes the compound itself, and not simply one of its impurities, is toxic. For example, an insecticide such as phos-phamidon (4.46) cannot be detoxified by deamination since it is an amidase inhibitor [24],... 

Other Antidepressants. Antidepressant refinements for the next 30 years primarily consisted of the development of new TCAs. However, in 1988, a novel antidepressant class, the selective serotonin reuptake inhibitors (SSRIs), was introduced in the United States. The chief innovation of the SSRIs was that they afforded the comparable effectiveness of the TCAs with fewer side effects and minimal toxicity. The debut of the SSRIs coincided with the reworking of the nosology of the anxiety disorders in DSM-III and DSM-IV. As a result, the SSRIs have been studied extensively in each of the respective anxiety disorders and in many cases have obtained FDA approval for the treatment of one or more of these anxiety syndromes. The SSRIs currently available in the United States include citalopram (Celexa), escitalo-pram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). 

The phenotypic effects observed under the constitutive expression of GES may also be avoided by the use of inducible promoters. Transgenic Arabidopsis expressing GES controlled by the alcohol-inducible Ale A promoter did not show the lesion phenotype observed under constitutive expression of GES [58]. Recent experiments with wound- and insect-inducible promoters such as that of the potato proteinase inhibitor 11 have been reported [78]. The use of strong inducible promoters that respond to herbivore-feeding may not only minimize toxic effects or costs associated with the constitutive formation of a volatile compound but can also provide the advantage that parasitoids associate volatiles only with the presence of feeding damage by the respective host. 

In summary it can be said that besides being important in the development of therapeutic strategies to combat disease with minimal toxicity and maximal effects, drug targeting may be of interest for more basic studies on the mechanistic background of diseases and the identification of new molecules as targets for therapeutic intervention. 

After an antibiotic was selected, the primary concern should be to optimize the dosage for maximal efficacy and minimal toxicity. Other factors such as economics, frequency of animal handling and... 

---