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1
Amacher, David E., Jeanne Stadler, Shelli J. Schomaker e Christian Verseil. "The Comparative Testing of Eight Coded Chemicals in the Rat Limb Bud Micromass and Rat Embryo Culture Systems". Alternatives to Laboratory Animals 24, n. 6 (dicembre 1996): 945–52. http://dx.doi.org/10.1177/026119299602400609.
Abstract (sommario):
When cultured at high density, mesenchymal cells from rat limb buds proliferate and differentiate into chondrocytes. Inhibition of this in vitro chondrogenic process has been used for the preliminary evaluation of teratogenic potential. Alternatively, intact post-implantation rat embryos, maintained in short-term culture, provide a system for the in vitro study of abnormal development not limited to the skeletal system. Both systems isolate the test agent from maternal metabolism and pharmacokinetic restraints. In this study, drug-associated selective inhibition of alcian blue uptake by cartilage proteoglycans, in micromass cultures of limb bud cells prepared from 13-day-old rat embryos, was used to assess teratogenic potential in vitro following exposure for 48 hours to eight coded compounds (acetylsalicylic acid, isoniazid. penicillin G, saccharine, vincristine sulphate, 6-aminonicotinamide, retinoic acid, and amaranth). Following drug exposure, cultures were incubated for another 96 hours, and the cells were then fixed and stained with 0.5% alcian blue. Bound dye was then extracted and quantitated. In parallel cultures, cell viability was measured by neutral red uptake, and protein content was assayed by using the bicinchoninic acid method. Except for retinoic acid and vincristine sulphate, the maximum test concentration was 1000μg/ml. Inhibition of alcian blue uptake (> 50%) was noted at 0.001μg/ml vincristine sulphate, 0.5/μg/ml retinoic acid and 5μg/ml 6-aminonicotinamide, demonstrating that strong teratogens inhibit differentiation in micromass cultures at lower concentrations than those which affect limb cell viability. When the same eight compounds were tested in a 24-hour embryo culture model, dysmorphogenesis was evident at 0.005μg/ml vincristine sulphate, 0.1μg/ml retinoic acid and 0.3μg/ml 6-aminonicotinamide. For the other five chemicals, little or no toxicity was noted up to the maximum test concentration in either model. We conclude that the two test systems, both based on the developing rat embryo, are consistent with each other, and that either of them would be useful for the preliminary screening of potential teratogens.
2
Piersma, Aldert H., Rudolf Bechter, Nathalie Krafft, Beat P. Schmid, Jeanne Stadler, Aart Verhoef, Christian Verseil e Jacob Zijlstra. "An Interlaboratory Evaluation of Five Pairs of Teratogens and Non-teratogens in Post-implantation Rat Embryo Culture". Alternatives to Laboratory Animals 24, n. 2 (marzo 1996): 201–9. http://dx.doi.org/10.1177/026119299602400211.
Abstract (sommario):
The usefulness of the post-implantation rat embryo culture method in screening xenobiotic compounds for developmental toxicity was validated in four laboratories with five pairs of compounds. This approach was chosen to provide information on the interlaboratory reproducibility of the results and to compare the effects of chemical analogues in embryo culture. By testing analogous compounds which are known to have different embryotoxic potencies in vivo, the discriminating power of the embryo culture method for the compound classes under study could be optimally assessed. The classes selected for testing were triazole antifungals, phthalic ester metabolites, substituted pyridines, sulphonamides and methylated xanthines. In summary, it was possible to distinguish between the compounds in three of the pairs, it was not possible to discriminate between the compounds of one pair, and it was possible to discriminate between the compounds of the other pair at two out of the four laboratories. The embryo culture results generally show a good correspondence with the embryotoxic properties of the compounds tested in vivo, although the embryo culture method appeared to be able to discriminate between only some of the pairs of chemical analogues. Some discrepancies may have arisen among the laboratories, because of methodological differences. These results suggest that the post-implantation rat embryo culture method may be a useful tool for screening xenobiotics within classes of compounds known to interfere with embryogenesis during the period of development represented in culture.
3
Uretsky, Michael E., e Ralf G. Rahwan. "Problems of Conditioning Xenopus Laevis Tadpoles with Standard Avoidance-Response Learning Paradigms". Psychological Reports 79, n. 3 (dicembre 1996): 763–73. http://dx.doi.org/10.2466/pr0.1996.79.3.763.
Abstract (sommario):
The amphibian Xenopus laevis embryo (tadpole) provides a satisfactory alternative to mammalian screening for structural teratogens. Testing was undertaken to extend the usefulness of this species for behavioral teratogenicity testing. One simple and eight operant conditioning paradigms were examined: none elicited learning in Xenopus embryos. Adaptation to the conditioning stimulus (light) and freezing in response to the unconditioned stimulus (shock) were responses incompatible with conditioned learning.
4
Bell, Susan Givens. "Drug Screening in Neonates". Neonatal Network 35, n. 5 (2016): 321–26. http://dx.doi.org/10.1891/0730-0832.35.5.321.
Abstract (sommario):
AbstractGestational substance exposure continues to be a significant problem. Neonates may be exposed to various substances including illicit drugs, prescription drugs, and other legal substances that are best not used during pregnancy because of their potential deleterious effects as possible teratogens or their potential to create dependence and thus withdrawal in the neonate. Screening the newborn for gestational substance exposure is important for both acute care and early intervention to promote the best possible long-term outcomes. This column provides insight into what is known about the extent of substance use by pregnant women, an overview of neonatal biologic matrices for drug testing, and a discussion of the legal implications of neonatal substance screening.
5
Brent, Robert L. "Utilization of Animal Studies to Determine the Effects and Human Risks of Environmental Toxicants (Drugs, Chemicals, and Physical Agents)". Pediatrics 113, Supplement_3 (1 aprile 2004): 984–95. http://dx.doi.org/10.1542/peds.113.s3.984.
Abstract (sommario):
Toxicology studies using animals and in vitro cellular or tissue preparations have been used to study the toxic effects and mechanism of action of drugs and chemicals and to determine the effective and safe dose of drugs in humans and the risk of toxicity from chemical exposures. Studies in pregnant animals are used to determine the risk of birth defects and other reproductive effects. There is no question that whole animal teratology studies are helpful in raising concerns about the reproductive effects of drugs and chemicals, but negative animal studies do not guarantee that these agents are free from reproductive effects. There are examples in which drug testing was negative in animals (rat and mouse) but was teratogenic in the human (thalidomide), and there are examples in which a drug was teratogenic in an animal model but not in the human (diflunisal). Testing in animals could be improved if animal dosing using the mg/kg basis were abandoned and drugs and chemicals were administered to achieve pharmacokinetically equivalent serum levels in the animal and the human. Because most human teratogens have been discovered by alert physicians or epidemiology studies, not animal studies, animal studies play a minor role in discovering teratogens. In vitro studies play an even less important role, although they are helpful in describing the cellular or tissue effects of the drugs or chemicals. One cannot determine the magnitude of human risks from these in vitro studies. Performing toxicology studies on adult animals is performed by pharmaceutical companies, chemical companies, the Food and Drug Administration, many laboratories at the National Institutes of Health, and scientific investigators in laboratories throughout the world. Although a vast amount of animal toxicology studies are performed on pregnant animals and numerous toxicology studies are performed on adult animals, there is a paucity of animal studies using newborn, infant, and juvenile animals. This deficiency is compounded by the fact that there are very few toxicology studies performed in children. That is why pregnant women and children are referred to as “therapeutic orphans.” When animal studies are performed with newborn and developing animals, the results demonstrate that generalizations are less applicable and less predictable than the toxicology studies in pregnant animals. Although many studies reveal that the infant and the developing animal have difficulty in metabolizing drugs and are more vulnerable to the toxic effects of environmental chemicals, there are exceptions that indicate that infant and developing animals may be less vulnerable and more resilient to some drugs and chemicals. In other words, the generalization indicating that developing animals are always more sensitive to environmental toxicants is not valid. For animal toxicology studies to be useful, animal studies have to use modern concepts of pharmacokinetics and toxicokinetics, as well as method-of-action studies to determine whether animal data can be used for determining human risk. One example is the inability to determine carcinogenic risks in humans for some drugs and chemicals that produce tumors in rodents, because the oncogenesis is the result of peroxisome proliferation, a reaction that is of diminished importance in humans. Scientists can use animal studies to study the toxicokinetic and toxicodynamic aspects of environmental toxicants, but they have to be performed with the most modern techniques and interpreted with the highest level of scholarship and objectivity. Threshold exposures, maximum permissible exposures, and toxic effects can be estimated but have to be interpreted with caution when applying them to the human. Well-performed epidemiology studies are still the best method for determining the human risk and the effects of environmental toxicants.
6
Lauschke, Karin, Andreas Frederik Treschow, Mikkel Aabech Rasmussen, Nichlas Davidsen, Bjørn Holst, Jenny Emnéus, Camilla Taxvig e Anne Marie Vinggaard. "Creating a human-induced pluripotent stem cell-based NKX2.5 reporter gene assay for developmental toxicity testing". Archives of Toxicology 95, n. 5 (4 marzo 2021): 1659–70. http://dx.doi.org/10.1007/s00204-021-03018-y.
Abstract (sommario):
AbstractTo test large numbers of chemicals for developmental toxicity, rapid in vitro tests with standardized readouts for automated data acquisition are needed. However, the most widely used assay, the embryonic stem cell test, relies on the counting of beating embryoid bodies by visual inspection, which is laborious and time consuming. We previously developed the PluriBeat assay based on differentiation of human induced pluripotent stem cells (hiPSC) that we demonstrated to be predictive for known teratogens at relevant concentrations using the readout of beating cardiomyocytes. Here, we report the development of a novel assay, which we term the PluriLum assay, where we have introduced a luciferase reporter gene into the locus of NKX2.5 of our hiPSC line. This enabled us to measure luminescence intensities instead of counting beating cardiomyocytes, which is less labor intensive. We established two NKX2.5 reporter cell lines and validated their pluripotency and genetic stability. Moreover, we confirmed that the genetically engineered NKX2.5 reporter cell line differentiated into cardiomyocytes with the same efficiency as the original wild-type line. We then exposed the cells to valproic acid (25–300 μM) and thalidomide (0.1–36 µM) and compared the PluriBeat readout of the cardiomyocytes with the luminescence intensity of the PluriLum assay. The results showed that thalidomide decreased luminescence intensity significantly with a higher potency and efficacy compared to the beating readout. With this, we have developed a novel hiPSC-based assay with a standardized readout that may have the potential for higher throughput screening for developmental toxicity.
7
Sennsfelder, Laëtitia, Susie Guilly, Sébastien Leruste, Ludovic Hoareau, Willy Léocadie, Pauline Beuvain, Meïssa Nekaa et al. "Description of Copy Number Variations in a Series of Children and Adolescents with FASD in Reunion Island". Children 10, n. 4 (7 aprile 2023): 694. http://dx.doi.org/10.3390/children10040694.
Abstract (sommario):
Background: Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of neurocognitive impairment and social inadaptation, affecting 1 birth in 100. Despite the existence of precise diagnostic criteria, the diagnosis remains difficult, often confounded with other genetic syndromes or neurodevelopmental disorders. Since 2016, Reunion Island has been a pilot region for the identification, diagnosis, and care of FASD in France. Objective: To evaluate the prevalence and the types of Copy Number Variations (CNV) in FASD patients. Methods: A retrospective chart review of 101 patients diagnosed with FASD in the Reference Center for developmental anomalies and in the FASD Diagnostic Center of the University Hospital was performed. Records of all patients were reviewed to obtain their medical history, family history, clinical phenotype, and investigations, including genetic testing (CGH- or SNP-array). Results: A rate of 20.8% (n = 21) of CNVs was found including 57% (12/21) of pathogenic variants and 29% (6/21) of variants of uncertain signification (VUS). Conclusion: A particularly high number of CNVs was found in children and adolescents with FASD. It reinforces the plea for a multidisciplinary approach for developmental disorders to explore both environmental factors, such as avoidable teratogens and intrinsic vulnerabilities, especially genetic determinants.
8
Ting, Keh-Chuh, Modan Gill e Orlando Garbin. "GC/MS Screening Method for Phthalate Esters in Children's Toys". Journal of AOAC INTERNATIONAL 92, n. 3 (1 maggio 2009): 951–58. http://dx.doi.org/10.1093/jaoac/92.3.951.
Abstract (sommario):
Abstract Phthalate esters are commonly added into polyvinyl chloride (PVC) as softeners to make the plastic material flexible. Phthalates are suspected cancer-causing agents and possible teratogens; they have been linked to liver and kidney damage, as well as the underdevelopment of reproductive organs in humans and animals. Public safety concerns about human exposure to phthalates are on the rise because they do not chemically bond to PVC and leach from the material over time. Following the lead of the European Union and Japan in restricting the use of certain phthalates, a legal limit of 0.1 in children's toys was established by the California State Legislature (AB-1108). In addition to its mission to protect public health and the environment from toxic harm, the California Department of Toxic Substances Control (DTSC) has been delegated the role of lead agency for consumer product safety. To support DTSC's Green Chemistry activities, the Environmental Chemistry Laboratory Mobile Laboratory Team has developed an on-site screening method to monitor phthalates in children's toys. This method is simple, fast, and effective, with ample sensitivity to quantify the 6 restricted phthalates in children's toys at 100 ppm (limit of quantitation = 100 g/g) which is 10 times lower than the legal allowable level of 0.1. Additionally, the method has a high throughput capability and enables testing of approximately 610 samples per day, depending on the complexity of the sample matrix and concentration. This method is designed to survey the 6 phthalates in children's toys and other consumer products for compliance with the threshold of 0.1 (1000 ppm).
9
Sethi, Nikunj, Rohit Mahar, Sanjeev K. Shukla, Akhilesh Kumar e Neeraj Sinha. "A novel approach for testing the teratogenic potential of chemicals on the platform of metabolomics: studies employing HR-MAS nuclear magnetic resonance spectroscopy". RSC Advances 5, n. 33 (2015): 26027–39. http://dx.doi.org/10.1039/c5ra00671f.
Abstract (sommario):
The objective is to develop a quick, reliable method for testing the teratogenic potential of a new chemical entity (NCE) on the platform of metabonomics, as an alternative to conventional procedures.
10
Sethi, Nikunj, Rohit Mahar, Sanjeev K. Shukla, Akhilesh Kumar e Neeraj Sinha. "Correction: A novel approach for testing the teratogenic potential of chemicals on the platform of metabolomics: studies employing HR-MAS nuclear magnetic resonance spectroscopy". RSC Advances 5, n. 66 (2015): 53341. http://dx.doi.org/10.1039/c5ra90058a.
Abstract (sommario):
Correction for ‘A novel approach for testing the teratogenic potential of chemicals on the platform of metabolomics: studies employing HR-MAS nuclear magnetic resonance spectroscopy’ by Nikunj Sethi et al., RSC Adv., 2015, 5, 26027–26039.
11
Giavini, Erminio, Maria Luisa Broccia e Mariangela Prati. "Teratogenicity Testing In Vitro: Post-implantation Whole-embryo Culture". Alternatives to Laboratory Animals 19, n. 1 (febbraio 1991): 94–98. http://dx.doi.org/10.1177/026119299101900118.
Abstract (sommario):
Various in vitro models have recently been tested for the assessment of developmental toxicity. Since the mechanisms involved in chemically-induced embryotoxicity are complex and numerous, a good in vitro assay must be able to detect developmental toxicants which act via most or all of these mechanisms. The rodent whole-embryo culture seems to fit this requirement, because it undergoes all of the fundamental processes of development. Also physical relationships between cells and tissues are maintained and morphogenesis can proceed normally. In fact, in vitro development of early post-implantation embryos closely parallels that occurring in utero. This assay appears to be particulary relevant for the detection of teratogenic and embryotoxic chemicals.
12
Czeizel, Andrew E., Istvan Dudás e Ferenc Bánhidy. "Interpretation of Controversial Teratogenic Findings of Drugs Such As Phenobarbital". ISRN Obstetrics and Gynecology 2011 (4 settembre 2011): 1–8. http://dx.doi.org/10.5402/2011/719675.
Abstract (sommario):
Objective. To check the debated association between phenobarbital treatment during pregnancy and risk for congenital abnormalities (CAs) in their children. Study Design. It is a comparison of phenobarbital treatment in the mothers of cases with CA and matched controls without CAs in the Hungarian Case-Control Surveillance System of Congenital Abnormalities. Results. Of 22,843 cases with CA, 149 (0.65%) had mothers with phenobarbital treatment, while of 38,151 control newborn infants without CA, 209 (0.55%) were born to mothers with phenobarbital treatment (100–400 mg daily) (OR with 95% CI : 1.3, 1.1–1.7). Of 16 CA groups, only hypospadias had a higher risk after phenobarbital treatment in the critical period of this CA (OR with 95% CI : 2.4, 1.1–5.4). However, if only medically recorded phenobarbital treatments were evaluated and multiple testing bias was considered, this association would disappear. Conclusions. This study stresses the importance of the exclusion of recall bias and multiple testing bias.
13
Goyal, Monika K., Adam L. Hersh, Gia Badolato, Xianqun Luan, Maria Trent, Theoklis Zaoutis e James M. Chamberlain. "Underuse of Pregnancy Testing for Women Prescribed Teratogenic Medications in the Emergency Department". Academic Emergency Medicine 22, n. 2 (29 gennaio 2015): 192–96. http://dx.doi.org/10.1111/acem.12578.
14
Karlsson, Miriam, Bengt Danielsson, Mats Nilsson, Christian Danielsson e William Webster. "New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential". Current Pharmaceutical Design 13, n. 29 (1 ottobre 2007): 2979–88. http://dx.doi.org/10.2174/138161207782110471.
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Bălălău, Oana-Denisa, Octavian-Gabriel Olaru, Adrian V. Dumitru, Ioana Păunică e Anca Daniela Stănescu. "Maternal infections with an increased risk of transmission to the foetus; a literature review". Journal of Clinical and Investigative Surgery 5, n. 2 (1 novembre 2020): 66–72. http://dx.doi.org/10.25083/2559.5555/5.2/66.72.
Abstract (sommario):
Screening testing for infectious diseases with vertical transmission, from mother to foetus, decreases the prevalence of foetal malformations. The most common infections with teratogenic potential are found in the TORCH test (Toxoplasma, Other infections, Rubella, Cytomegalovirus, Herpes simplex virus). Early identification of these pathogens results in better neonatal outcomes. Most foetuses with congenital toxoplasmosis are asymptomatic or have no apparent birth defect, while the primary infection of pregnancy with varicella-zoster virus (VZV) can lead to congenital foetal abnormalities with devastating consequences. Treponema pallidum can easily infect the placenta, with transplacental transmission to the foetus that can occur from about 9-10 weeks of gestation. Also, hepatitis B and C are the most common causes of chronic viral hepatitis in children and adults. In the case of HIV-positive pregnant women, the early association of ART, together with the choice of birth by scheduled caesarean section and the complete lack of breastfeeding determine expected neonatal results, the risk of vertical transmission decreasing up to 1-2%. Primary rubella infection during pregnancy can significantly affect foetal development, as does Herpes simplex virus (HSV) infection, but if it occurs as close as possible to birth, the disease may be self-limiting with mild forms. No teratogenic agent should be described qualitatively, as a teratogenic exposure includes not only the agent but also the dose and time of pregnancy when the exposure will occur. Screening tests are recommended to be performed both preconceptionally and during pregnancy.
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Lampen, Alfonso, e Heinz Nau. "Teratogenic Effects of Valproate - New Systems of Testing and New Hypotheses of Possible Molecular Mechanisms". Aktuelle Neurologie 29 (aprile 2002): 35–36. http://dx.doi.org/10.1055/s-2002-27810.
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Asrar, Syed Shuja, Bandaru Revanth, Binaya Sapkota, Kanala Somasekhar Reddy e Praveen Kumar Pasala. "A Review on Unlocking Toxicity: How Zebrafish embryos Help Ensure Safe Chemicals". UTTAR PRADESH JOURNAL OF ZOOLOGY 45, n. 8 (9 aprile 2024): 158–71. http://dx.doi.org/10.56557/upjoz/2024/v45i84010.
Abstract (sommario):
Aquatic ecotoxicity testing has benefited greatly from zebrafish embryo toxicity testing (ZFET) because of its high throughput, low cost, sensitivity to a variety of toxicants, and ethical issues. This study highlights the benefits of ZFET over conventional fish toxicity testing, such as its capacity to detect teratogenic defects and possible long-term impacts. The limitations of ZFET are also addressed, notably its emphasis on acute dosages and difficulties with interspecies extrapolation. In addition to the generation of in vitro alternatives utilizing zebrafish cell lines, recent developments in ZFET technology are also highlighted, including the use of transgenic zebrafish lines and high-throughput screening techniques. The paper's conclusion includes a discussion of potential prospects for ZFET research. These include improving interspecies extrapolation methods, optimizing chronic toxicity assessment procedures, and integrating ZFET with other ecotoxicity testing strategies. ZFET is a great instrument for environmental protection and a crucial component in avoiding chemical contamination of aquatic ecosystems, so long as it is acknowledged for what it is and is open to future improvement
18
Schexnayder, Chandler D., Shani King e Oluchi Emelogu. "Documentation of contraceptive counseling in female veterans of reproductive age". American Journal of Health-System Pharmacy 77, Supplement_3 (24 luglio 2020): S71—S77. http://dx.doi.org/10.1093/ajhp/zxaa159.
Abstract (sommario):
Abstract Purpose To assess the rate at which contraceptive counseling is provided to women of childbearing age prescribed teratogenic medications at Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC). Women of childbearing age comprise a large demographic of women veterans and may require contraceptive counseling in the event a potentially teratogenic medication is prescribed. According to multiple studies, overall documentation of contraceptive counseling occurs in approximately half of this population or less. The rate of documented contraceptive counseling at MEDVAMC is unknown. Methods A retrospective chart review of electronic health records was conducted from January 2017 to August 2018. Patients included were female veterans between 18 and 45 years of age who made 2 or more visits to MEDVAMC prior to filling a prescription for a HMG-CoA reductase inhibitor (statin), angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker. Charts were screened for documentation of contraceptive counseling (including family planning counseling), prescribed contraception, and pregnancy testing prior to dispensing of a potentially teratogenic prescription. Results There were 172 female veterans included in this project. Documentation of contraceptive counseling occurred in 63% (n = 108) of patients; in total, 42% (n = 73) of patients were on some form of contraception, with the most common being oral contraceptive pill (used by 30% of women). Conclusion The rate of documentation of contraceptive counseling at MEDVAMC was found to be higher than rates reported in national studies. As we continue to strive to provide exceptional care for our women veterans, we would like to continue to increase the education and awareness on this matter.
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Diamante, Catherine, Monice Zondlo Fiume, Wilma F. Bergfeld, Donald V. Belsito, Ronald A. Hill, Curtis D. Klaassen, Daniel C. Liebler et al. "Final Safety Assessment of Thiodipropionic Acid and Its Dialkyl Esters as Used in Cosmetics". International Journal of Toxicology 29, n. 4_suppl (maggio 2010): 137S—150S. http://dx.doi.org/10.1177/1091581810373150.
Abstract (sommario):
Dilauryl thiodipropionate (DLTDP), dicetyl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, and ditridecyl thiodipropionate are dialkyl esters of their respective alcohols and thiodipropionic acid (TDPA) used in cosmetics. Ingested DLTDP was excreted in the urine as TDPA. Single-dose acute oral and parenteral studies and subchronic and chronic repeated dose oral studies did not suggest significant toxicity. Neither DLTDP nor TDPA was irritating to animal skin or eyes and they were not sensitizers. TDPA was neither a teratogen nor a reproductive toxicant. Genotoxicity studies were negative for TDPA and DLTDP. Clinical testing demonstrated some evidence of irritation but no sensitization or photosensitization. The Cosmetic Ingredient Review Expert Panel considered that the data from DLTDP reasonably may be extrapolated to the other dialkyl esters and concluded that these ingredients were safe for use in cosmetic products that are formulated to be nonirritating.
20
Moretto, Angelo, Francesca Di Renzo, Erminio Giavini, Francesca Metruccio e Elena Menegola. "The use of in vitro testing to refine cumulative assessment groups of pesticides: The example of teratogenic conazoles". Food and Chemical Toxicology 79 (maggio 2015): 65–69. http://dx.doi.org/10.1016/j.fct.2014.07.006.
21
Stigson, Michael, Kim Kultima, Måns Jergil, Birger Scholz, Henrik Alm, Anne-Lee Gustafson e Lennart Dencker. "Molecular Targets and Early Response Biomarkers for the Prediction of Developmental Toxicity In Vitro". Alternatives to Laboratory Animals 35, n. 3 (giugno 2007): 335–42. http://dx.doi.org/10.1177/026119290703500313.
Abstract (sommario):
There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers — even a single one — could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool in defining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a potentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.
22
TUDOSE, Adriana, Radu MATEESCU, Alexandru MATEI e Edu ANTOINE. "Allergic rhinitis and pregnancy – management". Romanian Journal of Medical Practice 12, n. 2 (31 marzo 2017): 38–40. http://dx.doi.org/10.37897/rjmp.2017.1.7.
Abstract (sommario):
Allergic rhinitis is a chronic inflammation produced by the action of IgE antibodies which fight against allergens inside the mucosal nazale. It is characterized by symptoms such as nasal obstruction and/or watery rhinorrhea, sneezing and itching. Pregnancy is a temporary testing contraindication. During the pregnancy to detect the allergens involved in the symptoms we advise you to only take in vitro tests. The best approach in the management of rhinitis is to avoid allergens. Patients with mild to moderate rhinitis can only control the symptoms using nasal saline solution administered topically. Antihistamines can be useful during the pregnancy. Immunotherapy has not been found to be teratogenic and is clinically useful in relieving symptoms. The usage of oral decongestans and/or topical is controversial.
23
Ding, Hao, Andras Nagy, David H. Gutmann e Abhijit Guha. "A review of astrocytoma models". Neurosurgical Focus 8, n. 4 (aprile 2000): 1–8. http://dx.doi.org/10.3171/foc.2000.8.4.2.
Abstract (sommario):
Despite tremendous technical improvements in neuroimaging and neurosurgery, the prognosis for patients with malignant astrocytoma remains devastating because of the underlying biology and growth characteristics of the tumor. However, our understanding of the molecular bases of these tumors has greatly increased due to study findings involving operative specimens, astrocytoma predisposing human syndromes, teratogen-induced animal and established human astrocytoma cell lines, and more recently transgenic mouse models. Appropriate small-animal models of spontaneously occurring astrocytomas, which replicate the growth and molecular characteristics found in human tumors, are essential to test the relevance and interactions of these molecular aberrations. In addition, it is hoped that relevant molecular targets will eventually be therapeutically exploited to improve patient outcomes. Appropriate animal models are also essential for testing these novel biological therapies, before they are brought to the clinic, requiring a large investment of time and money. In this paper, various astrocytoma models are discussed, with emphasis on transgenic mouse models that are of great interest to laboratory investigators.
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Jackson, S., J. Hunter e G. A. Van Norman. "Ethical Principles Do Not Support Mandatory Preanesthesia Pregnancy Screening Tests: A Narrative Review". Obstetric Anesthesia Digest 44, n. 1 (22 febbraio 2024): 11–12. http://dx.doi.org/10.1097/01.aoa.0001005300.71572.53.
Abstract (sommario):
(Anesth Analg. October 6, 2023. doi: 10.1213/ANE.0000000000006669. Online ahead of print) The process of informed consent upholds the principle of patient autonomy, rooted in US constitutional principles of privacy and noninterference. It has been legally required in the United States since 1914, ensuring that individuals have the right to determine what happens to their bodies, as Schloendorff v. New York Society Hospital ruled. The recent US Supreme Court decision on abortion has raised concerns about maternal-fetal conflicts and the rights of pregnant patients to undergo elective anesthesia and surgery. Ethical and legal requirements for informed consent in medical testing vary, with challenges in addressing routine laboratory testing. Not all medical tests carry the same ethical implications, but they should all consider beneficence, nonmaleficence, and patient autonomy. Focusing on the need for preanesthesia pregnancy testing remains a concern in anesthesia and surgery practices. The primary premise is preventing harm to the fetus, but this must be supported by medical evidence and adhere to ethical standards. No study conclusively demonstrates that anesthetic agents significantly increase rates of early human fetal loss or malformations. There is no evidence that anesthetic drugs are generally teratogenic or pose a significant risk of harm to the fetus. While such risks are small, they cannot be guaranteed to be absent.
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Marks, Thomas A. "A Retrospective Appraisal of the Ability of Animal Tests To Predict Reproductive and Developmental Toxicity in Humans". Journal of the American College of Toxicology 10, n. 5 (settembre 1991): 569–84. http://dx.doi.org/10.3109/10915819109078653.
Abstract (sommario):
The reproductive and developmental toxicology areas have undergone numerous changes in the 30 years since the thalidomide tragedy. It would be comforting if such changes have resulted in a greatly decreased likelihood that human conceptuses will develop malformations. However, there is little evidence that such testing has better enabled us to identify human reproductive or developmental toxicants. Although there may be justification for performing animal testing on drugs and pesticides, a simple acute toxicity test may be just as predictive as currently employed reproductive and developmental toxicity tests for other synthetic chemicals. Support for this premise is provided by comparing available acute toxicity information on many compounds, identified as (potential) human developmental or reproductive toxicants, with their respective likely human threshold doses. Acute LD50 values of other potential human reproductive or developmental toxicants, not documented as being a threat to humans, also were compared with their time-weighted averages or their lowest teratogenic dose in the same species. The data generated support the premise that most reproductive or developmental toxicants are a potential threat to humans only if exposure levels approach those that are lethal in the rat or mouse. In contrast, unequivocal evidence of developmental toxicity for drugs, such as thalidomide and isotretinoin, to which the human embryo is highly sensitive, were not apparent in the screens used now for routine developmental toxicology testing. Thus, requirements that all chemicals be tested for reproductive and developmental toxicity should await the development of testing methodology capable of better assessing human risk.
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Matsumori, Yoichi, Maki Aizawa, Yoshiko Sakai, Daisuke Inoue, Michiko Kodani, Osamu Tsuha, Akira Beppu et al. "Congenital abnormalities in calves associated with Peaton virus infection in Japan". Journal of Veterinary Diagnostic Investigation 30, n. 6 (11 settembre 2018): 855–61. http://dx.doi.org/10.1177/1040638718796269.
Abstract (sommario):
Peaton virus (PEAV; family Peribunyaviridae, genus Orthobunyavirus) appears to be capable of producing congenital malformations in ruminants; however, its pathogenicity remains unknown given its relatively low incidence. We evaluated the relationship between congenital abnormalities of calves and PEAV infection by serologic, epidemiologic, pathologic, and virologic investigations using specimens from 31 malformed calves in the years 1996–2016 in Japan. Antibody testing was carried out for known teratogenic viruses, including Akabane, Aino, Chuzan, and bovine viral diarrhea viruses, in the precolostral sera of these abnormal calves, but all results were negative. However, all 31 malformed calves were positive for antibodies against PEAV. A PEAV-specific gene was amplified from central nervous system tissues from a stillborn calf delivered in April 2007, and its nucleotide sequence was identical with that of PEAV isolated from healthy sentinel cattle in September 2006. These findings indicate that PEAV can cause bovine congenital anomalies.
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Rakitskii, Valery N., Sergei V. Kuzmin, Tatiana M. Epishina, Elena G. Chkhvirkiya e Ekaterina A. Mukhina. "Inactive doses of oxathiine derivative on long-term effects of the organism". Hygiene and sanitation 102, n. 3 (31 marzo 2023): 287–91. http://dx.doi.org/10.47470/0016-9900-2023-102-3-287-291.
Abstract (sommario):
Introduction. The study of the effects of the long-term effect of the active substances of pesticides on the body of warm-blooded animals is an obligatory stage
of their comprehensive toxicological and hygienic assessment.
The aim of the study was to establish the levels of inactive doses of the effects of the long-term (NOEL) action of a compound of the oxatiine class.
Materials and methods. In accordance with the planned purpose of the study in the biological testing laboratory of the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Supervision in Protection of the Rights of Consumer and Man Wellbeing еxperiments were conducted to establish the parameters of acute oral toxicity, the presence of possible teratogenic and embryotoxic effects, and the effect on the reproductive function
of a technical product of the oxatiin class (TPO) on the body of warm-blooded (rats). Previously, studies in this volume have not been conducted.
Results. LD50 of the studied compound with a single oral administration to male rats is more than 4500 mg/kg of body weight. When studying the embryotoxic effect, the inactive dose for the maternal organism and offspring is set at the level of – 1/52 LD50; the inactive dose for the teratogenic effect for the maternal organism is 1/52 LD50, offspring – 1/27 LD50. As a result of studying the effect of the oxatiine derivative on the indicators of reproductive function, the inactive dose for maternal, paternal organisms, and offspring, is 1/313 LD50.
Limitations. In our study to establish the levels of inactive doses of the long-term effects of toxicity of a technical product derived from oxatiines, there are no data on the results of the mutagenic effect of the studied compound on the body of warm-blooded (rats, mice).
Conclusion. It has been established that according to the “Hygienic classification of pesticides and agrochemicals according to the degree of danger” (Methodological Recommendations of MP No. 1.2.0235-21* dated 02/15/2022), the studied chemical product belongs to the 4th hazard class for acute oral toxicity (LD50) and teratogenic effect (low-hazard compound; for embryotoxic effect and reproductive toxicity to the 3rd hazard class (moderately dangerous compound).
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Carter, R. Colin, Antonio Di Narzo, Steven Zeisel, Neil Dodge, Ernesta Meintjes, Christopher Molteno, Joseph Jacobson e Sandra Jacobson. "Choline Metabolism Gene-Exposure Interactions in Fetal Alcohol-related Memory Deficits". Current Developments in Nutrition 6, Supplement_1 (giugno 2022): 627. http://dx.doi.org/10.1093/cdn/nzac061.011.
Abstract (sommario):
Abstract Objectives Animal and human studies have demonstrated the potential for the essential nutrient choline to ameliorate teratogenic effects of prenatal alcohol exposure (PAE), including growth and recognition memory deficits. We hypothesized that the presence of maternal SNPs in choline metabolism-related genes may modify fetal vulnerability to PAE. Methods Mothers from two prenatally recruited birth cohorts in Cape Town, South Africa (discovery cohort: n = 149; validation cohort: n = 153) were genotyped for 315 SNPs in choline metabolism-related genes. Primary outcomes were: height/length z-scores (disc. at age 9 yr; val. at 5 yr) and recognition memory (disc. = CVLT-C recognition discrimination score, age 9 yr; val. = Fagan Test of Infant Intelligence novelty preference score, 6.5 and 12 mo). Linear regression models were constructed using OLS: outcome ∼ PAE + gene dose (# effective alleles) + PAE x gene dose; significance of PAE-gene interaction was tested using a 2-sided Wald test on the PAE-gene dose interaction term with Benjamini-Hochberg (BH) multiple testing correction. Results PAE (drinking days/wk) was related to shorter height (disc. B(95% CI) = −.11(−.18, −.01); val. B = −.12(−.20, −.04) and poorer recognition memory (disc. B = −.11(−.26, −.02); val. B = −.11(−.19, −.03)). Gene-PAE interaction for recognition memory was seen in both cohorts for rs12262538 (discovery BH-adj. p = .0015; validation unadj. p = .004); for rs1043261, discovery BH-adj. p = .0235 and validation unadj. p = .0903. No gene-PAE interactions were seen for height. rs12262538 is in the 5’ flanking region near the Stearoyl-CoA Desaturase (SCD) gene. rs1043261 is in the 3’ flanking region near the choline dehydrogenase (CHDH) gene. Conclusions We identified two maternal SNPs that may confer higher fetal risk for teratogenic effects of PAE. These findings support the potential protective role of choline in fetal alcohol spectrum disorders prevention. Funding Sources National Institute on Alcohol Abuse and Alcoholism.
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Patra, Pratiksha. "Exploring the Relationship between Psoriasis and Pregnancy: A Systematic Literature Review". International Journal of Medical Students 11, n. 2 (30 giugno 2023): 128–33. http://dx.doi.org/10.5195/ijms.2023.1714.
Abstract (sommario):
This systematic literature review examines the relationship between psoriasis and pregnancy to elucidate possible new routes of treatment. Findings from this review help reduce the gap in the literature on the topic as well as educate physicians and pregnant women with psoriasis on how psoriasis may present along the course of pregnancy and thereafter. Searches were primarily conducted in three databases: PubMed, Scopus, and Embase. Articles considered for inclusion in this literature review focused on the presentation of psoriasis during pregnancy. The literature sample obtained consisted of 14 peer-reviewed articles published from 2012-2022. As codes were identified, a master code list was developed. Second cycle coding involved categorizing of the data allowing for codes to combine and emerge as themes. Five themes were identified through categorical analysis: immunology, general sex hormones, estrogen, progesterone, and the HLA-Cw6 allele. Collectively, these findings elucidate the individual nature of psoriasis and identify progesterone as a possible non-teratogenic therapy. Primarily, the presence of the HLA-Cw6 allele in a woman’s genome along with the individual variation of estrogen receptors reinforces the researcher’s recommendation of genetic testing following a psoriasis diagnosis. This genetic testing may allow patients and physicians to best understand what to expect of psoriasis during pregnancy as well as help determine the most efficacious treatment course to follow for therapy.
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Duy-Thanh, Dinh, Nguyen Bich-Ngoc, François Van den Bossche, Nguyen Lai-Thanh e Marc Muller. "Discovering Novel Bioactivities of Controversial Food Additives by Means of Simple Zebrafish Embryotoxicity (ZET) Assays". Toxics 11, n. 1 (22 dicembre 2022): 8. http://dx.doi.org/10.3390/toxics11010008.
Abstract (sommario):
The rising concerns about controversial food additives’ potential hazardous properties require extensive yet animal-minimized testing strategies. Zebrafish embryos are the ideal in vivo model representing both human and environmental health. In this study, we exposed zebrafish embryos to eight controversial food additives. Our results indicate that Sodium Benzoate is a Cat.3 aquatic toxicant, while Quinoline Yellow is a strong teratogen. At high concentrations, non-toxic chemicals induced similar phenotypes, suggesting the impact of ionic strength and the applicability of the darkened yolk phenotype as an indicator of nephrotoxicity. Three food additives showed unpredicted bioactivities on the zebrafish embryos: Brilliant Blue could weaken the embryonic yolk, Quinoline Yellow may interfere with nutrient metabolism, and Azorubine induced precocious zebrafish hatching. In conclusion, the zebrafish embryo is ideal for high throughput chemical safety and toxicity screening, allowing systematic detection of biological effects—especially those unexpected by targeted in vitro and in silico models. Additionally, our data suggest the need to reconsider the safety status of food additives Quinoline Yellow, Brilliant Blue, Sodium Benzoate, and other controversial food additives in further studies, as well as pave the way to further applications based on the newly found properties of Brilliant Blue and Azorubine.
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Goldspink, Rachel, Toni Pumipi, Sangeeta Dey e David B. Menkes. "Sodium valproate prescription to women of childbearing age in a New Zealand inpatient psychiatric unit". Australasian Psychiatry 28, n. 5 (25 giugno 2020): 555–58. http://dx.doi.org/10.1177/1039856220934317.
Abstract (sommario):
Objective: Sodium valproate’s teratogenicity has prompted increasing restriction in its use. It is still widely prescribed to women of childbearing age in New Zealand. To examine this problem, we audited the prescribing pattern of sodium valproate in a psychiatric inpatient unit in New Zealand. Method: We reviewed the clinical records of women admitted over a 2-year period (2016–2018). Results were analysed and compared with local and international guidelines. Results: Five hundred and thirty-four women of child-bearing age were admitted over the sampling period, 96 of whom (18%) were prescribed valproate on discharge. Half of these patients had diagnoses other than bipolar affective disorder, valproate’s only approved psychiatric indication in New Zealand. Pregnancy testing and contraception status were documented in a minority (29 and 10 cases, respectively). Teratogenic risk discussion was documented in only 11 cases. Conclusions: Prescription of valproate to women of childbearing age in our sample currently falls well short of best practice. Urgent action at both clinician and organisational levels is required to address this risk.
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Eastlake, Christian, e Kate Jeffers. "Implementation of a pregnancy screening protocol prior to chemotherapy for women of childbearing potential." Journal of Clinical Oncology 37, n. 27_suppl (20 settembre 2019): 246. http://dx.doi.org/10.1200/jco.2019.37.27_suppl.246.
Abstract (sommario):
246 Background: Many cancer therapies currently available are teratogenic in nature. Several patients cared for within our community ambulatory oncology infusion center are women of childbearing potential (WOCP). Pregnancy testing of these women within our oncology infusion center was sporadic at best. There currently are no standardized guidelines related to pregnancy testing of these women. Methods: A retrospective chart analysis of WOCP receiving chemotherapy was done to determine baseline pregnancy screening rates. Subsequently a protocol was developed in which WOCP was defined as women under 50 years of age, without a history of hysterectomy or tubal ligation. The nurse-driven protocol allowed the infusion nursing staff to order a pregnancy screen to be done within the infusion center if testing had not already taken place within 48 hours of initiation of treatment. Following protocol implementation a retrospective chart analysis was performed to re-examine screening rates. Results: Utilizing patients with an active treatment plan within a one month time period, retrospective analysis of pregnancy screening prior to initiation of chemotherapy was performed. Baseline pregnancy screening rate was 21%. Point of care pregnancy equipment was obtained and nursing staff was educated on the protocol to include a medical delegation. Post-implementation chart analysis of WOCP initiating chemotherapy within a six-week timeframe resulted in improved pregnancy screening to 57% compliance. Continued education and clarification of the protocol was provided to the nurses in an effort to further improve compliance. Conclusions: Lack of standard guidelines regarding pregnancy screening of WOCP led to the development and implementation of a protocol for pregnancy screening for this at-risk population. Medical delegation allowed nursing to initiate the screening for these patients allowing for improvements in the safety and quality of patient care provided.
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Goldenberg, Paula C., Betsy J. Adler, Ashley Parrott, Julia Anixt, Karen Mason, Jannel Phillips, David S. Cooper, Stephanie M. Ware e Bradley S. Marino. "High burden of genetic conditions diagnosed in a cardiac neurodevelopmental clinic". Cardiology in the Young 27, n. 3 (19 settembre 2016): 459–66. http://dx.doi.org/10.1017/s104795111600072x.
Abstract (sommario):
AbstractBackgroundThere is a known high prevalence of genetic and clinical syndrome diagnoses in the paediatric cardiac population. These disorders often have multisystem effects, which may have an important impact on neurodevelopmental outcomes. Taken together, these facts suggest that patients and families may benefit from consultation by genetic specialists in a cardiac neurodevelopmental clinic.ObjectiveThis study assessed the burden of genetic disorders and utility of genetics evaluation in a cardiac neurodevelopmental clinic.MethodsA retrospective chart review was conducted of patients evaluated in a cardiac neurodevelopmental clinic from 6 December, 2011 to 16 April, 2013. All patients were seen by a cardiovascular geneticist with genetic counselling support.ResultsA total of 214 patients were included in this study; 64 of these patients had a pre-existing genetic or syndromic diagnosis. Following genetics evaluation, an additional 19 were given a new clinical or laboratory-confirmed genetic diagnosis including environmental such as teratogenic exposures, malformation associations, chromosomal disorders, and single-gene disorders. Genetic testing was recommended for 112 patients; radiological imaging to screen for congenital anomalies for 17 patients; subspecialist medical referrals for 73 patients; and non-genetic clinical laboratory testing for 14 patients. Syndrome-specific guidelines were available and followed for 25 patients with known diagnosis. American Academy of Pediatrics Red Book asplenia guideline recommendations were given for five heterotaxy patients, and family-based cardiac screening was recommended for 23 families affected by left ventricular outflow tract obstruction.ConclusionGenetics involvement in a cardiac neurodevelopmental clinic is helpful in identifying new unifying diagnoses and providing syndrome-specific care, which may impact the patient’s overall health status and neurodevelopmental outcome.
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Belyaeva, N. F., V. N. Kashirtseva, N. V. Medvedeva, Yu Yu Khudoklinova, O. M. Ipatova e A. I. Archakov. "Zebrafish as a model system for biomedical studies". Biomeditsinskaya Khimiya 56, n. 1 (gennaio 2010): 120–31. http://dx.doi.org/10.18097/pbmc20105601120.
Abstract (sommario):
Zebrafish (Danio rerio) are now firmly established as a powerful research model for many areas of biology and medicine. Here, we review some achievements of zebrafish - based assays for modeling human diseases and for drug discovery and development. For drug discovery, zebrafish are especially valuable in the earlier stages of research as they provide a model organism to demonstrate a new treatment's efficacy and toxicity before more costly mammalian models are used. This review provides examples of compounds known to be toxic to humans that have been demonstrated to functional similarly in zebrafish. Major advantages of zebrafish embryons are that they are readily permeable to small molecules added to their incubation medium and the transparent chorion enables the easy observation of development. Assay of acute toxicity (LC50 estimation) in embryos can also include the screening for developmental disorders as an indicator of teratogenic effects. We used zebrafish for toxicity testing of new drugs on the base of phospholipid nanoparticles. The organization of the genome and the pathways controlling signal transduction appear to be highly conserved between zebrafish and humans that allow using zebrafish for modeling of human diseases some examples of which are illustrated in this paper.
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Borrego-Soto, Gissela, e Johann K. Eberhart. "Embryonic Nicotine Exposure Disrupts Adult Social Behavior and Craniofacial Development in Zebrafish". Toxics 10, n. 10 (15 ottobre 2022): 612. http://dx.doi.org/10.3390/toxics10100612.
Abstract (sommario):
Cigarette smoking remains the leading cause of preventable death and morbidity worldwide. Smoking during pregnancy is associated with numerous adverse birth outcomes, including craniofacial and behavioral abnormalities. Although tobacco smoke contains more than 4000 toxic substances, nicotine is addictive and is likely the most teratogenic substance in cigarette smoke. However, much remains to be determined about the effects of embryonic nicotine exposure on behavior and craniofacial development. Therefore, this study evaluated adult social behavior in zebrafish, craniofacial defects, and nicotine metabolism in embryos after embryonic nicotine exposure. Zebrafish embryos were exposed to different doses of nicotine beginning at 6 h post fertilization. To evaluate craniofacial defects, the embryos were collected at 4 days post fertilization and stained with Alizarin Red and Alcian Blue. For behavioral testing, embryos were reared to adulthood. To evaluate nicotine metabolism, cotinine levels were analyzed at various time points. Our findings demonstrate that embryonic exposure to nicotine modifies social behavior in adulthood, causes craniofacial defects with reduced size of craniofacial cartilages, and that zebrafish metabolize nicotine to cotinine, as in humans. Together, our data suggest that zebrafish are useful as a model for studying nicotine-related diseases.
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Lim, So-Yon, Christa E. Osuna, Katharine Best, Ray Taylor, Elsa Chen, Gyeol Yoon, Jessica L. Kublin et al. "A direct-acting antiviral drug abrogates viremia in Zika virus–infected rhesus macaques". Science Translational Medicine 12, n. 547 (10 giugno 2020): eaau9135. http://dx.doi.org/10.1126/scitranslmed.aau9135.
Abstract (sommario):
Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection against Zika virus infection. Galidesivir exhibited favorable pharmacokinetics with no observed teratogenic effects in rats or rabbits at any dose tested. The antiviral efficacy of galidesivir observed in the blood and central nervous system of infected animals warrants continued evaluation of this compound for the treatment of flaviviral infections.
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ADDIS, ANTONIO, e GIDEON KOREN. "Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies". Psychological Medicine 30, n. 1 (gennaio 2000): 89–94. http://dx.doi.org/10.1017/s0033291799001270.
Abstract (sommario):
Background. This study was designed to examine whether there is an increased risk for major malformations following the use of fluoxetine during the first trimester of pregnancy.Methods. Published and unpublished reports were identified through computerized and manual searches of bibliographical databases, reference lists from primary articles, and letters to editors, agencies, foundations and content experts. Meta-analysis was undertaken of prospective controlled and uncontrolled studies on the use of fluoxetine during first trimester of pregnancy.Results. The pooled relative risk and 95% confidence interval for major malformations does not suggest an association between the use of fluoxetine during the first trimester and an increased risk of major malformations. Combination of controlled and uncontrolled studies shows a weighted risk of 2·6% (95% CI 1–4·2%). The summary odds ratio from the two controlled studies (OR = 1·33, 95% CI 0·49–3·58) was not significant. Homogeneity testing shows that the effect sizes are similar throughout all studies. Power analysis indicates that 26 controlled studies of similar size, would be required, to reverse this finding.Conclusions. The use of fluoxetine during the first trimester of pregnancy is not associated with measurable teratogenic effects in human.
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Chiurciu, Irina-Adriana, Daniela Dana, Valentina Voicu, Elena Cofas, Aurelia-Ioana Chereji e Ruben Budău. "Management of Risks for Wheat Contamination with Fusarium graminearum". Romanian Agricultural Research 40 (2023): 549–55. http://dx.doi.org/10.59665/rar4051.
Abstract (sommario):
The topic is particularly important because toxins cause mycotoxins in plants and animals and remain in food products obtained from infected organisms and they are mutagenic, teratogenic and estrogenic effects in animal and human bodies. Also, may be a serious threat to human health. This study presents the mineral nutrition status of winter wheat in connection with the risks of wheat contamination by Fusarium toxins in the soil conditions at INCDA Fundulea. The plants selected for testing were ten wheat cultivars, identified as susceptible to infection with Fusarium graminearum. The soil from the experiment was Cambic Chernozem. Two types of parcels were included in the experiment: one with healthy plants and another with artificially infected plants. In order to quantify the mineral nutrition status of plant with macro and micronutrients, the plant analyses were being carried out in the ear emergence-flowering phase. The obtained results it was interpreted in connection with the optimum limits of mineral contents in dry matter, mentioned in the specialty literature. The N and K ratios between healthy plant and artificially infected plants it was processed based on analytical data.
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Suranjana Haldar e Atish Haldar. "Pyrrolizidine plant extracts as diagnostic biochemical markers on therapeutic consequences". International Journal of Scholarly Research in Biology and Pharmacy 3, n. 1 (30 luglio 2023): 001–9. http://dx.doi.org/10.56781/ijsrbp.2023.3.1.0028.
Abstract (sommario):
The consumption of cereals and bakery products contaminated with seeds of species containing Pyrrolizidine alkaloids (PAs) has been involved in mass poisonings in rural areas of Afghanistan, India, South Africa and the former USSR. Poisoning can manifest as acute or subacute veno-occlusive disease with specific symptoms such as persistent hepatomegaly, leading to cirrhosis or shown to have genotoxic, mutagenic, teratogenic and carcinogenic effects. Several such toxicity testing of PAs have been done in cultured animal cells with reference to mice model, to better understand the pathway of metabolic impairement. Also the pluripotent proprty of mice bone marrow cells show better analyzing capacity of differentiated cell lineages. Therefore this pre-analytic review aims to focus the risk evaluation methods of PA exposure on current knowledge and recent advances of metabolic pathways of different PAs. In addition, this review provides perspectives of precision toxicity assessment strategies and biomarker development for the risk control of human intoxication by PAs with eventual categorization of pyrrole-protein adducts like serum Alanine Transferase (ALT), Glutathione transferase (GSH-T), Alkaline Phosphatase (ALP) in different cell lineages grown by lab-based cell culture techniques.
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Garcia-Käufer, M., S. Gartiser, C. Hafner, S. Schiwy, S. Keiter, C. Gründemann e H. Hollert. "Genotoxic and teratogenic effect of freshwater sediment samples from the Rhine and Elbe River (Germany) in zebrafish embryo using a multi-endpoint testing strategy". Environmental Science and Pollution Research 22, n. 21 (5 dicembre 2014): 16341–57. http://dx.doi.org/10.1007/s11356-014-3894-4.
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Panggabean, Mayrissa Boru, Prisca Deviani Lidia e Kartini Lidia. "Seaweed Extract (Eucheuma cottonii) Antibacterial Potency Test in Gel Form On Staphylococcus aureus and Staphylococcus epidermidis Bacteria". Cendana Medical Journal (CMJ) 10, n. 2 (20 dicembre 2022): 350–62. http://dx.doi.org/10.35508/cmj.v10i2.9208.
Abstract (sommario):
Background: Incorrect medicine usage in treating acnes (acne vulgaris) may cause unwanted side effects. Teratogenic effects due to retinoid use in pregnancy and breastfeeding women as well as antibiotic resistance on account of irrational antibiotic use are a few of the effects that may emerge. Natural ingredients such as seaweeds (Eucheuma cottonii) formulated in topical form is an alternative to solve this problem. Objective: To ascertain seaweed extract (Eucheuma cottonii) antibacterial potency test in gel form on staphylococcus aureus and staphylococcus epidermidis bacteria. Method: This research is a true experimental research with posttest-only group design. Treatment groups are clindamycin gel positive control, sterile aquadest negative group, and seaweed infused extract group with 5%, 10%, 15%, and 20% concentrations with Staphylococcus aureus and Staphylococcus epidermidis bacteria as testing bacteria. Antibacterial testing method is done using disk diffusion method. Raw data is analyzed using Kruskal-Wallis statistical test. Result: The diameter of zone of inhibition of seaweed extract gel on Staphylococcus aureus bacteria on the 20% concentration (4,51 mm), 15% concentration (0,265 mm), 10% concentration (0,05 mm), and 5% concentration (0,22 mm) is categorized as weak antibacterial potential. The diameter of zone of inhibition of seaweed extract gel on Staphylococcus epidermidis bacteria on the 20% concentration (10,37 mm) is categorized as strong antibacterial potential, whereas 15% concentration (3,545 mm), 10% concentration (4,045 mm), and 5% concentration (0,725 mm) is categorized as weak antibacterial potential. Analysis shows that there are significant differences between treatment groups with p value < 0,05. Conclusion: Seaweed extract (Eucheuma cottonii) in gel form has an antibacterial potency towards Staphylococcus aureus and Staphylococcus epidermidis bacteria.
Keywords: Seaweed, Antibacterial, Acne, Gel
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Hendrickx, A. G., N. Makori e P. Peterson. "Nonhuman primates: their role in assessing developmental effects of immunomodulatory agents". Human & Experimental Toxicology 19, n. 4 (aprile 2000): 219–25. http://dx.doi.org/10.1191/096032700678815756.
Abstract (sommario):
There are close physiologic similarities between humans and macaques that make them well suited for preclinical testing of biopharmaceutics. These include menstrual cycles of similar length and hormonal control, comparable cellular and endocrine processes of implantation, and similar time-tables of prenatal development. Three teratogenic agents have induced abnormal development of the macaque thymus that is a key organ in the development of the fetal immune system. Embryonic exposure to triamcinolone acetonide, a potent corticosteroid, during critical periods of thymus development caused marked hypoplasia, depletion of thymic lymphocytes, and reduction of epithelial elements. Aplasia and hypoplasia of the thymus were a distinct feature of the “retinoid syndrome” in cynomolgus macaques following exposure to 13-cis-retinoic acid (Accutane) in early pregnancy, the time of neural crest migration. Experimentally induced zinc deficiency in rhesus macaques from conception to 1-year of age caused severe alterations in immunocompetence. More recent studies have shown that the levels of IgG and IgA in cervicovaginal lavages of the rhesus macaque exhibit specific temporal patterns during the normal menstrual cycle. Taken together, theses data suggest that several macaque species are appropriate animal models for preclinical safety assessment of immunomodulatory drugs. Current teratology protocols in these models may require slight modifications to adequately assess the safety of these biologics.
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Subebe, Merrah Joy Blaye, Josephine C. Ogaro, Melanie L. Dayon, Muhmin Michael E. Manting, Aki Murashima, Akiko Omori, Jaime Q. Guihawan, Mylene M. Uy, Ahmad Reza F. Mazahery e Mylah Villacorte-Tabelin. "Phytochemical evaluation, embryotoxic, and teratogenic effects of Buwakan (Decalobanthus peltatus (L.) A.R.Simões & Staples) leaf extracts on duck embryo". Environmental Analysis Health and Toxicology 39, n. 1 (27 febbraio 2024): e2024004. http://dx.doi.org/10.5620/eaht.2024004.
Abstract (sommario):
<i>Decalobanthus peltatus</i> is a woody vine that is commonly utilized in traditional Southeast Asian medicinal preparations. Despite the documented therapeutic uses of D. peltatus, there is hardly any information regarding its toxic effects on its consumers. In this study, crude leaf extracts (aqueous, methanol, ethyl acetate, and hexane) from <i>D. peltatus</i> were prepared and evaluated for their embryotoxicity and teratogenic effects. Phytochemical screening of bioactive compounds from the plants showed the presence of alkaloids, flavonoids, saponins, steroids, and tannins. In addition, investigations on the toxicity of the crude leaf extracts were determined using brine shrimp lethality assay, in which the LC50 was calculated. Results showed that the ethyl acetate leaf extract was the most toxic among the crude leaf extracts, with an LC50 of 14.54 ppm. Based on this result, ethyl acetate leaf extract was treated on duck embryos, and the alteration of vascular branching patterns in the chorioallantoic membrane was quantified. Gross morphological and histological analysis of the skin tissues from the treated duck embryos were also examined. We found significant reduction of primary and tertiary vessel diameters in the duck embryos treated with ethyl acetate leaf extracts in both concentrations compared to the control group. Treated duck embryos exhibited gross malformations, growth retardation, and hemorrhages on the external body surfaces at 1000 ppm. Histopathological analysis of the skin tissues from the 14-day-old treated duck embryos showed a reduced number of feather follicles compared to the control group. These results suggest that D. peltatus crude leaf extracts present risks when taken in significant dosages and comprehensive toxicity testing on therapeutic herbs should be performed to ensure their safety on the consumers.
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Grattarola, Carla, Lorenzo Minoia, Federica Giorda, Guia Consales, Francesca Capanni, Ilaria Ceciarini, Enrica Franchi et al. "Health Status of Stranded Common Bottlenose Dolphins (Tursiops truncatus) and Contamination by Immunotoxic Pollutants: A Threat to the Pelagos Sanctuary—Western Mediterranean Sea". Diversity 15, n. 4 (18 aprile 2023): 569. http://dx.doi.org/10.3390/d15040569.
Abstract (sommario):
Between 2019 and 2021, 21 bottlenose dolphins were found stranded dead along the Ligurian Pelagos Sanctuary coast (Italy). For 11 animals, out of a total of 14 recovered, the cause of death was classified as natural, anthropic, or not determined based on gross and histological pathology and ancillary testing. Hexachlorobenzene (HCB), dichlorodiphenyltrichloroethanes (DDTs), and polychlorinated biphenyls (PCBs) were examined in their blubber, and results were discussed according to their toxicological properties. All specimens showed the following trend: PCBs > DDTs >> HCB, and the levels of cancerogenic, mutagenic, and teratogenic organochlorine compounds (T-OCs) were >50% of total OCs. Immunosuppressant organochlorine compound (IS-OC) levels in 10 out of 11 animals were above 50% of the total OCs. PCB levels always exceeded the threshold of 17 mg/kg lipid weight for PCB-induced adverse health effects. The results suggest that bottlenose dolphins living in the Pelagos Sanctuary undergo a high level of exposure to pathogens and OCs, betraying the designation of the Cetacean Sanctuary and, consequently, of a region created for their conservation. Immune dysfunction and infectious disease susceptibility appear to be highly connected with high levels of OC xenobiotics. These data are useful to understand health and mortality trends in cetacean populations, as well as for developing policies for cetacean conservation and management in this important protected area of the Mediterranean.
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Rayburn, William F., e Luis A. Izquierdo. "Benefits and Limitations with Ultrasound Imaging in the First Trimester". Donald School Journal of Ultrasound in Obstetrics and Gynecology 10, n. 1 (2016): 9–13. http://dx.doi.org/10.5005/jp-journals-10009-1437.
Abstract (sommario):
ABSTRACT Widespread use of home pregnancy tests and the availability of first trimester genetic screening many ultrasound imaging studies being performed before 14 weeks gestation. While these scans are believed to be safe, the additional time and expense has led to questioning about its value unless indicated by vaginal bleeding, persistent nausea, potential teratogen exposure, medical complications associated with early reproductive loss or an congenital anomalies, repetitive early pregnancy loss, or desire for genetic testing. A scan at or beyond 7 weeks allows for confirmation of viability and accuracy of gestational dating by crown rump measurement. The observation of either a subchorionic hematoma or an abnormal configuration of the uterine cavity alerts the provider to the greater risk of a spontaneous abortion, placental abruption, preterm delivery, or fetal growth restriction. Gestational trophoblastic disease can be diagnosed earlier with subsequent performance of an ultrasound-directed suction curettage before morbid conditions worsen. Certain congenital anomalies can be diagnosed as early as the 11 to 14th week. Multifetal gestations can be diagnosed early with chorionicity determined between the 6th and 12th week. Nearly all maternal adnexal masses are small and require no follow-up imaging by the 15th week unless large (> 5 cm), complex, or discomfort ensues. Experience of the sonographer, resolution capabilities of the imaging machinery, maternal obesity, and fetal positioning limit interpretation capabilities. Technological refinements with three-dimensional (3D) imaging and higher definition resolution hold promise for improved accuracy in anatomic and blood flow studies. How to cite this article Rayburn WF, Izquierdo LA. Benefits and Limitations with Ultrasound Imaging in the First Trimester. Donald School J Ultrasound Obstet Gynecol 2016;10(1):9-13.
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Bailey, Stacy C., Allison P. Pack, Guisselle Wismer, Norma Calderon, Evelyn Velazquez, Stephanie Batio, Abbey Ekong et al. "Promoting REproductive Planning And REadiness in Diabetes (PREPARED) Study protocol: a clinic-randomised controlled trial testing a technology-based strategy to promote preconception care for women with type 2 diabetes". BMJ Open 13, n. 11 (novembre 2023): e078282. http://dx.doi.org/10.1136/bmjopen-2023-078282.
Abstract (sommario):
IntroductionWomen with type 2 diabetes (T2DM) are more likely to experience adverse reproductive outcomes, yet preconception care can significantly reduce these risks. For women with T2DM, preconception care includes reproductive planning and patient education on: (1) the importance of achieving glycaemic control before pregnancy, (2) using effective contraception until pregnancy is desired, (3) discontinuing teratogenic medications if pregnancy could occur, (4) taking folic acid, and (5) managing cardiovascular and other risks. Despite its importance, few women with T2DM receive recommended preconception care.Methods and analysisWe are conducting a two-arm, clinic-randomised trial at 51 primary care practices in Chicago, Illinois to evaluate a technology-based strategy to ‘hardwire’ preconception care for women of reproductive age with T2DM (the PREPARED (Promoting REproductive Planning And REadiness in Diabetes) strategy) versus usual care. PREPARED leverages electronic health record (EHR) technology before and during primary care visits to: (1) promote medication safety, (2) prompt preconception counselling and reproductive planning, and (3) deliver patient-friendly educational tools to reinforce counselling. Post-visit, text messaging is used to: (4) encourage healthy lifestyle behaviours. English and Spanish-speaking women, aged 18–44 years, with T2DM will be enrolled (N=840; n=420 per arm) and will receive either PREPARED or usual care based on their clinic’s assignment. Data will be collected from patient interviews and the EHR. Outcomes include haemoglobin A1c (primary), reproductive knowledge and self-management behaviours. We will use generalised linear mixed-effects models (GLMMs) to evaluate the impact of PREPARED on these outcomes. GLMMs will include a fixed effect for treatment assignment (PREPARED vs usual care) and random clinic effects.Ethics and disseminationThis study was approved by the Northwestern University Institutional Review Board (STU00214604). Study results will be published in journals with summaries shared online and with participants upon request.Trial registration numberClinicalTrials.gov Registry (NCT04976881).
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Nastyukha, Yuliya, Andriy Zimenkovsky e Diana Klapko. "PHARMACEUTICAL CARE OF ACNE PATIENTS USING SYSTEMIC RETINOIDS". Acta Medica Leopoliensia 29, n. 3-4 (27 dicembre 2023): 79–96. http://dx.doi.org/10.25040/aml2023.3-4.079.
Abstract (sommario):
Aim. The research aims to study of the issue of pharmaceutical care of acne patients when using systemic retinoids.
Materials and Methods. The following methods were used: systematic approach, bibliographic, questionnaire survey, statistical, pharmacoeconomic assessment. The objects of the study: relevant information sources; current standards of pharmacotherapy, instructions for medical use of isotretinoin of the State Register of Medicines of Ukraine (n=4), 14th edition of the State Drug Formulary; questionnaires of acne patients who use systemic retinoids (n=53); pharmacy quotes for isotretinoin drugs and laboratory quotes for liver biopsy and lipid testing. The subject of the study: appropriate pharmaceutical care of acne patients when using systemic retinoids.
Results and Discussion. The results of the questionnaire showed that, despite high awareness, the practice of patients' compliance with the recommendations regarding the use of isotretinoin needs to be optimized, in particular by means of pharmaceutical care, which was provided in only 30.2% (95CI: 18.3-44.3%) cases according to the patients. As a result of the analysis of current regulatory-legal documents, 6 main guidelines were identified, including 10 key messages of pharmaceutical care. Considering the extremely low level of proper implementation of the Pregnancy Prevention Program when using systemic retinoids (3.7%; 95CI: 0.1-19.0%) and the severity of the consequences of neglecting the recommendations (teratogenic effect), pharmaceutical care should include the issue of effective contraception and pregnancy testing by not only informing but also finding and using other strategies to increase patient compliance with the recommendations, in our opinion. We consider that the discussion with the patient regarding the costs of pharmacotherapy with systemic retinoids (according to the results of our study - from ₴ 17919.20 to ₴ 25307.50), in addition to the cost of isotretinoin (from ₴ 15417.20 to ₴ 21550.00), should include the costs of conducting laboratory control of liver tests (from ₴ 1530.00 to ₴ 2340.00), lipidogram (from ₴ 972.00 to ₴ 1417.50) and meeting some other individual patient needs.
Conclusions. Studying the issue of pharmaceutical care when using systemic retinoids allowed to determine the main guidelines (n=6) and key messages (n=10) that pharmacists can focus on during professional communication with acne patients, which makes it possible to increase the effectiveness and safety of pharmacotherapy.
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Stara, Jerry F. "First Generation of a New Science: Risk Assessment in Transition3". Toxicology and Industrial Health 5, n. 5 (dicembre 1989): 621–27. http://dx.doi.org/10.1177/074823378900500503.
Abstract (sommario):
The greatest challenge facing human populations today is that of extraordinary rapid change. Such a change in the society is illus trated by the increasing public awareness of environmental issues, accompanied by continuously expanding scientific investigations of chemical pollution. Our industrial civilization has developed and introduced into the various environmental media many compounds affecting human health individually and as a society. The science of toxicology is the evaluation of the effects of chemical and physical agents in various biological systems. Most chemical compounds cannot be tested in man due to their possible carcinogenic, muta genic, teratogenic, or other long-term toxic potential. Therefore, carefully designed toxicologic studies in other species, especially mammalian, are conducted to provide biological dose-response data, which can be used to predict human response. Toxicologists have the responsibility of providing accurate scientific dose- response data based on experiments employing, among others, "practical" concentrations of pollutants or toxicants. When the toxic effects are considered, the action of these agents in the atmosphere, water, and other environmental vehicles should be considered. There are always interacting events that co-exist in the environment. Multiple causality as a factor of a disease is well established but frequently overlooked. The various issues in envi ronmental health need to be tied together in order to be understood by scientists who are not intimately familiar with risk assessment procedures as they relate to the implementation of environmental laws. Much effort is needed both in the area of improved risk assessment methodology as well as in the area of toxicologic testing and validation of the theoretical approaches. The U.S. EPA is making every reasonable effort to improve its risk assessment approach.
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Mawson, Anthony R., e Ashley M. Croft. "Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism". International Journal of Environmental Research and Public Health 16, n. 19 (22 settembre 2019): 3543. http://dx.doi.org/10.3390/ijerph16193543.
Abstract (sommario):
Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%–13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development (‘regressive autism’). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.
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Belokon, S. V. "DROSOPHILA MELANOGASTER MG. ЯК ТЕСТ-ОБ’ЄКТ СКРИНІНГУ КСЕНОБІОТИКІВ НА АКАРИЦИДНУ АКТИВНІСТЬ". Biological Bulletin of Bogdan Chmelnitskiy Melitopol State Pedagogical University 5, n. 01 (30 aprile 2015): 145. http://dx.doi.org/10.15421/2015011.
Abstract (sommario):
<p> </p><p>The development of new effective test systems for screening xenobiotics on biological activity, including its possible harmful influence on the organism is the modern challenge. Test systems of eukaryotic origin are needed for testing of xenobiotics on their gonadotoxical, embryotoxic, teratogenic, and carcinogenic effects. Such testing should include the monitoring of genetic effects of bioactive compounds and the possible mutagenic effect. The <em>Drosophila melanogaster</em> Mg. is very convenient test object as a classical genetics object, for which the genome is fully sequenced. It is convenient and easy to find out the frequency of crossingover in different parts of the genome, and study the key indicators of vitality and ontogenetic adaptation (fertility, longevity, survival under stress conditions, etc.) on <em>Drosophila. </em>The crossover frequency, in our opinion, can be an integral factor for the general state of genotype.so we could use the mark of genetic recombination frequency as one of the indicators of the impact of xenobiotics.</p> <p>In this study we examined the possibility of using <em>Drosophila melanogaster</em> Mg. (Diptera, Drosophilidae) as a test object for screening xenobiotics on acaricidal activity. Sensitivity of flies to acaricides piridaben (<em>Sanmayt</em>) and proparhit (<em>Omayt</em>) was studied by their fitness, longevity, fertility, and frequency of meiotic recombination in the area b-vg second chromosome. It was found that the studied compounds - piridaben and proparhit have significant influence on vitality of <em>D. melanogaster.</em> The presence of these acaricides in the nutrition of flies testifies the harmful influence on their crossingover and reduced fecundity and longevity. We suggested to use the <em>D. melanogaster</em> as a test object for screening xenobiotics on acaricidal activity.</p> <p><em>Keywords: Drosophila, the test object, acaricides, crossingover, fertility, longevity.</em></p><p><strong><a href="http://dx.doi.org/10.7905/bbmspu.v5i1.970">http://dx.doi.org/10.7905/bbmspu.v5i1.970</a></strong><strong> </strong></p>