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Theories of Tobacco Addiction
Published in Rajmohan Panda, Manu Raj Mathur, Tobacco Cessation, 2019
Sonu Goel, Susanta Kumar Padhy
No single factor can predict whether a person will become addicted to tobacco. Risk for TD is influenced by a combination of factors that include individual biology, age, or stage of development and social environment. The more risk factors and less protective factors (see Figure 3.2) an individual has, the greater the chance that taking tobacco can lead to dependence.5 For example, the genes people are born with, in combination with environmental influences—account for about half of their dependence vulnerability. Genetic and environmental factors interact with critical developmental stages to affect dependence vulnerability.6 Although taking drugs at any age can lead to dependence, the earlier nicotine use begins, the more likely that it will progress to more serious abuse. Adolescents may especially be prone to such addictive behaviors because the brain areas that govern decision making, judgment, and self-control are still in the developmental phase. Additionally, gender, ethnicity, and the presence of other mental disorders (such as schizophrenia, bipolar disorder, depression, and anxiety disorder) may influence the risk of tobacco dependence.
Evaluation of Associated Behavioral and Cognitive Deficits in Anticonvulsant Drug Testing
Published in Steven L. Peterson, Timothy E. Albertson, Neuropharmacology Methods in Epilepsy Research, 2019
TD50 is usually determined by using the tests already described for neurological impairment, such as the chimney, rotarod, or inverted screen test. Other undesirable effects (for example, memory impairments) can also serve to calculate protective indices. Anticonvulsive tests that are usually used to determine ED50 include MES-and PTZ-induced seizures.8 However, again by no means should the repertoire of convulsive tests be restricted to these two. Any other test can be used. When tests with fixed (maximal or supramaximal) seizure stimuli (MES and PTZ) are used, the ED50 of drugs is used to calculate PI.8 For threshold tests such as MES threshold or intravenous (IV) PTZ threshold tests a dose that increases the threshold (threshold increasing dose; TID) by 50% or 20% (TID50 and TID50, respectively) can be used as determined by log-linear regression analysis from dose-effect experiments.8 For the MES threshold model the TID50 is used for calculation of Pis, whereas the TID50 is used in the case of the IV PTZ seizure threshold model, because TTD20s determined in this model are more predictive of therapeutic plasma levels in humans than TID50s.8
Chemical Carcinogenesis and Mutagenesis
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Not all carcinogenic chemicals are equally successful in inducing neoplasia; that is, they exhibit different carcinogenic potencies. The carcinogenic potential of a chemical is defined as the slope of the dose–response curve for the induction of neoplasms. This definition, however, is not sufficient for estimating carcinogenic potential based on data from chronic carcinogenesis bioassays. Historically, several methods have been developed to measure the carcinogenic potential, particularly the tumorigenesis dose rate 50 (TD50). This value has been popular for the estimation of the carcinogenic potential for a number of chemicals. The TD50 is calculated as the dose rate (mg/kg body weight/day) of carcinogen, which when administered chronically for a standard period induces neoplasms in half of the test animals. The value is adjusted for spontaneous neoplasms and is an important component of carcinogenic risk assessment (Table 31.2).
Enhancing global and local decision making for chemical safety assessments through increasing the availability of data
Published in Toxicology Mechanisms and Methods, 2023
Adrian Fowkes, Robert Foster, Steven Kane, Andrew Thresher, Anne-Laure Werner, Antonio Anax F. de Oliveira
One key component of the CPDB is the presence of TD50 values, derived from the tumor incidence dose-response data, to represent the dose at which the probability of a test subject remaining tumor-free after a lifetime exposure to the test compound is halved. These values have been used extensively in safety assessments and can be considered as a measure of relative carcinogenic potency (Munro et al. 1996; Cheeseman et al. 1999; Boobis et al. 2017; Bercu et al. 2018). Upon reviewing the supporting data and original methodology to generate TD50 values (Peto et al. 1984) it was uncovered that not all the values were reproducible. To increase the confidence in the data and support transparency, a model was created and published to generate Lhasa TD50 values (Thresher et al. 2019), which could be stored in the LCDB alongside the original TD50 values for completeness. A high correlation was observed between the two sets of TD50 values (Figure 3). The fact that both models produce similar results provides confidence in the original calculations and that the database can progress using the new transparent and reproducible approach . The efforts in developing the LCDB have ensured sustainability of the CPDB data, but also provided additional information to increase the confidence in decisions based on its data. To further evolve the resource, research can examine how new data can be incorporated to expand coverage of new chemicals and uncover how to increase confidence each study result given the variations in protocols.
Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ahmed A. Gaber, Mohamed Sobhy, Abdallah Turky, Hanan Gaber Abdulwahab, Ahmed A. Al-Karmalawy, Mostafa. A. Elhendawy, Mohamed. M. Radwan, Eslam B. Elkaeed, Ibrahim M. Ibrahim, Heba S. A. Elzahabi, Ibrahim H. Eissa
In general, most of the synthesised compounds showed decreased toxicity potential. In detail, all compounds were predicted to be non-mutagenic and non-toxic against Ames mutagenicity and developmental toxicity potential models. In addition, all compounds were anticipated to be non-irritant and mild irritant against Skin Irritancy and Ocular Irritancy models, respectively. For, compounds 7a, 7b, 10, 13a, and 13b showed carcinogenic potency TD50 values ranging from 18.673 to 34.965 mg/kg body weight/day, which were higher than that of erlotinib (8.057 mg/kg body weight/day). the other compounds showed less carcinogenic potency TD50 values. In addition, the tested compounds showed rat maximum tolerated dose values ranging from 0.139 to 0.735 g/kg body weight. This range is higher than the rat's maximum tolerated dose value of erlotinib (0.083 g/kg body weight).
Cost-effectiveness of valbenazine compared with deutetrabenazine for the treatment of tardive dyskinesia
Published in Journal of Medical Economics, 2021
Michael L. Ganz, Ameya Chavan, Rahul Dhanda, Michael Serbin, Charles Yonan
Since the 1950s, when TD was first described, a number of drugs have been studied for potential effectiveness or used off-label for the treatment of TD, but none provided clear evidence of clinical benefit2. In 2017, however, the US Food and Drug Administration (FDA) approved valbenazine, a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor, for the treatment of TD in adults; FDA approval of a second VMAT2 inhibitor, deutetrabenazine, followed later that year. More recently, the American Psychiatric Association (APA) released its evidence-based practice guideline for treatment of patients with schizophrenia, that includes the recommendation (based on results from randomized clinical trials) that patients with moderate-to-severe TD be treated with a VMAT217.