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Pharmogenology: The Industrial New Drug Development Process
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
The industrial drug development process encompasses a toxicity evaluation program which is founded on and coordinated with biological and pharmaceutical investigations (15). The most commonly mentioned toxicity test is the LD50 (the estimation of a dose that is lethal to 50% of the animals in a test situation); it is also probably the least useful because it is a measure of acute single-dose toxicity and its real need is now being seriously questioned. In such an acute toxicity study a potent poison can be readily identified. Corrosive chemicals, organic solvents, and irreversible enzyme inhibitors having very low LD50 values are rarely considered for further drug development. The acute toxicity study is usually done in two or three species and by several routes of administration; in addition to identifying frank poisons, it provides limited information about the dose ranges that might be appropriate for the toxicity evaluation of longer duration or for initial human use. An interesting ancillary use for the LD50 is that one might obtain the first indication of the extent of gastrointestinal absorption by comparing LD50 values after oral and parenteral administration.
Acute toxicity test for the ethanolic extract of the white oyster mushroom
Published in Ade Gafar Abdullah, Isma Widiaty, Cep Ubad Abdullah, Medical Technology and Environmental Health, 2020
S.B. Rahimah, Y. Kharisma, M.K. Dewi, J. Hartati, W. Maharani
An acute toxicity test was carried out using the proposed method. This method was a new method recommended for testing the acute toxicity of drugs or natural substances. Acute toxicity is an undesirable effect due to the administration of certain substances, in single or repeated doses, in a short time in the first 24 hours. A dosage curve for undesirable effects can also be seen using this method, in addition to assessing mortality. The method used was the Proposed (New) Method (Chinedu et al. 2013). Experimental animals were divided into several stages; the next stage depended on the results of the previous stage. The first or initial stage used four groups containing one mouse for each group. All four were given different doses and were seen 1 hour after administration and in periodic examinations for 24 hours to assess their mortality. If no deaths occurred, the testing could be continued in the second stage. The second stage involved three animals given a higher dose than in the first stage. Observation was carried out the same as in the previous stage. If no mortality took place, then the testing continued to the third stage using three mice. The maximum dose given was 5,000 mg/kg body weight (Chinedu et al. 2013).
The Role of Toxicology
Published in Nicola Loprieno, Alternative Methodologies for the Safety Evaluation of Chemicals in the Cosmetic Industry, 2019
Most of the toxicity test methods currently available are descriptive and involve the use of animals. However, there is increasing progress in scientific research that allows the identification of the elementary biological mechanisms by which a toxic effect is produced. This continuous and further understanding of the basis of toxicological effects will promote the development of reliable and scientifically valid in vitro toxicity tests in the future. These tests also could be used in extrapolating results. It is obvious, however, that whole-animal toxicity testing will probably continue to be needed in the following cases: when searching for effects in previously unknown target organs; in evaluating effects that represent an interaction of multiple-organ systems; in monitoring metabolism and pharmacokinetics; in evaluating healing or diminished responsiveness to the toxic substance; and in risk-assessment decisions. Animal use in toxicity testing seems, at present, unlikely to be entirely discarded in the foreseeable future.
Is the 90-day dog study necessary for pesticide toxicity testing?
Published in Critical Reviews in Toxicology, 2023
Patricia L. Bishop, Vicki L. Dellarco, Douglas C. Wolf
This concept of testing on multiple species and the use of dogs as a standard laboratory animal was first introduced in the 1940s with a publication describing procedures for evaluating the toxicity of chemicals in food (Lehman et al. 1949). Based on further work by Lehman et al. (1955), a multi-species testing paradigm (rats, mice, dogs and rabbits) was adopted in 1965 by the United States Food and Drug Administration (FDA) to ensure the identification of any drug-induced effects not observed in rodents. By 1982, the USEPA had formalized health effects guidelines for testing chemical substances that called for subchronic and chronic testing in rodent and non-rodent species, usually rats and dogs (USEPA 1982). These principles are still applied today, for example, in the toxicity test guidance issued by the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the Organization for Economic Cooperation and Development (OECD), respectively, for pharmaceuticals and chemicals, including pesticides.
Macrophage membrane biomimetic drug delivery system: for inflammation targeted therapy
Published in Journal of Drug Targeting, 2023
Yulu Zhang, Yu Long, Jinyan Wan, Songyu Liu, Ai Shi, Dan Li, Shuang Yu, Xiaoqiu Li, Jing Wen, Jie Deng, Yin Ma, Nan Li
At present, the potential cytotoxicity of NPs still exists as a barrier to the development of nanomedicine, and many clinical trials of NPs are terminated due to toxic and side effects [68]. On the one hand, NPs are easy to be identified and removed after entering the human body. This phenomenon can compensate for a large number of drugs removed from the body through high-dose drugs, but there is a risk of increasing toxic and side effects [69]. On the other hand, there is a lack of effective toxicity test methods for nano materials and a limited understanding of their interaction with the human body, which makes its evaluation of human health risks complex. Common nanoparticle carriers include PLGA copolymer microspheres, magnetic nano carriers, etc. Among them, the PLGA nano microsphere has the characteristics of good biocompatibility, no accumulation in the body for long-term use, relatively long retention time in circulating blood, and the preparation method is relatively mature [70]. However, the PLGA nano microsphere can cause considerable cytotoxicity. After endocytosis, the nano microsphere enters the lysosome and destroys the lysosomal membrane, so as to activate the apoptosis signal pathway and finally induce apoptosis [71]. MM-NPs can solve some of the above problems. Using MM as the carrier can effectively reduce the number of nano materials, and then more effectively reduce the potential toxicity caused by excessive use of nano materials. In addition, MM-NPs can be targeted to deliver therapeutic drugs to reduce adverse non-target effects, avoid arbitrary drug distribution and reduce toxicity [37].
Chronic bisphenol A exposure induces temporal neurobehavioral transformation and augmented chromatin condensation in the periventricular gray zone of zebrafish brain
Published in Drug and Chemical Toxicology, 2022
Pradyumna Kumar Sahoo, Lilesh Kumar Pradhan, Saroj Kumar Das
The experimental protocols involving toxicity test, dose response, and duration-dependent studies were approved by the Institutional Animal Ethics Committee (IAEC), Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, India (IAEC No: IAEC/SPS/SOA/09/2020). A requisite number of wild-type adult zebrafish (4–6months of age) were supported at first in a 40-L capacity aquarium under ambient temperature, lighting, and aeration for 7days and were used for experiments afterward. The aquarium was filled with dechlorinated water with a pH of 7.5±0.3. Furthermore, the temperature was set to 27°C±1°C with a conductivity of 300–1500 µS. The other water quality parameters, such as the alkalinity, hardness, ammonia, nitrite, nitrate, dissolved oxygen, and CO2 levels, were maintained weekly (Avdesh et al. 2012). The animals were fed twice a day. The waterborne acute toxicity test for BPA was recorded in our recent report (Sahoo et al. 2020). The LC50 for BPA was found to be 26.28µM, and after neurobehavioral assessment, a rapid swing in behavioral response was observed at a BPA concentration of 17.52µM; this concentration was used to study the temporal neurobehavioral response of zebrafish. The BPA was solubilized in 100% ethanol (0.003% v/v) as the vehicle in the control and experimental groups, whereas the naïve group was not exposed to vehicle treatment to negate any possible effect of the vehicle.