thalidomide Analogs in Brazil: Concern About teratogenesis

it has been more than 50 years since thalidomide was withdrawn from the world market due to its teratogenic potential. However, its widespread use around the world resumed due to its immunomodulatory and anti-angiogenic properties. the drug established itself in new therapies, and interest continued with the emergence of more potent analogs, the most notable being lenalidomide and pomalidomide, which are not approved in Brazil. the question that arises after analog synthesis is: Do these drugs also have the same teratogenic potential? the answer to this question is based only on experimental studies because exposure to humans is not authorized and has not yet been described. Although thalidomide has been recognized as a powerful human teratogen for many years, its molecular mechanisms of teratogenesis remain to be fully explained. Efforts with animal models and human genetic studies have clarified some important pathways that are most likely involved in the teratogenic action of thalidomide. However, it has not yet been possible to identify the teratogenic domain of the molecule from the therapeutic ones. Moreover, there are species-specific differences that must be taken into consideration when teratogenicity is evaluated.


Thalidomide: A controversial Drug
Thalidomide (α-[N-phthalimido]-glutarimide) was synthesized in 1954 in West germany by the german company Chemie Grünenthal. The first trials revealed that it had a depressant effect on the central nervous system (CNS) and induced sleep; therefore, it was indicated primarily as a sedative agent 1,2 .
in 1956, thalidomide was introduced into the market as a sedative, as well as for several other indications, such as the treatment of irritability, poor concentration, anxiety, insomnia, nausea, hyperthyroidism, and infectious diseases 2,3 .
After this, thalidomide quickly came to be manufactured and sold worldwide under more than 40 trade names and rea- the suspension of the sale of thalidomide in germany and England occurred in 1961, and subsequently in several other countries 3 . in August 1962, it was already possible to observe a significant decline in the number of limb malformations 1 , thus confirming the causal relationship between thalidomide use during pregnancy and the increase in the prevalence of these malformations. Even so, thousands of children had already been born with such anomalies -the estimated number was 10,000 children born around the world, and the number of miscarriages as a result of using the drug is unknown 10,11 . in the same decade, thalidomide was already being used for the treatment of an inflammatory reaction from leprosy.
in 1965, the israeli dermatologist Jacob Sheskin prescribed thalidomide as a sedative and analgesic for six patients with erythema nodosum leprosum (ENL), an immune condition resulting from infection caused by Mycobacterium leprae and characterized by hot, painful, mobile skin lesions, either associated or unassociated with a systemic condition of fever, malaise, arthralgia, myalgia, and other symptoms 12,13 .
Besides being a great sedative, the clinical signs and symptoms were dramatically reduced within 48 hours. thereafter, controlled placebo studies showed that thalidomide was responsible for the clinical improvement of the patients 14,15 .

undesirable Effects of Thalidomide
Due to the large amount of epidemiological data available in the 1960s, it was possible to determine the period of the gestation that is sensitive to the teratogenic action of thalidomide. the teratogenic window was established as being between the 34 th and 50 th day after the last menstrual period or 20 to 36 days after fertilization 16 . Within this period, it is also possible to make a correlation between the days of ingesting the drug and the observed malformations.
it is believed that between 10% and 50% of women who ingest thalidomide during this period of sensitivity have children affected by the embryopathy 16  Estimates of the mortality rate among victims of thalidomide indicate rates of between 40% and 45% 1 , with most of them due to heart, kidney, and gastrointestinal anomalies, which are less common among survivors due to their severities 2 .
resurgence and establishment of thalidomide in the 1990s, the mechanism of action involved in improving ENL symptoms was mainly attributed to the degradation of high levels of tumor necrosis factor alpha (TNF-α) 13,19 .

Thalidomide Analogs
At the same time that thalidomide was restoring its place and approval for use on the world stage, there was interest in the synthesis of analogs with higher therapeutic potency and reduced side effects. these side effects, especially the tera- greater ability to co-stimulate t cells, as well as less detrimental side effects 28,29 .
in Brazil, thalidomide is cheaply manufactured by the

Teratogenic Molecular Mechanisms of Thalidomide and its Analogs
the study of the teratogenic mechanisms of the iMiDs attempts to identify what the causes of the molecular teratogenesis are so that the moiety can be isolated and to obtain a safe medication. These targets remain to be identified, but many advances have been made in this area in recent decades, especially with thalidomide.
The hypotheses with greater scientific reliability are those Parman et al. 35 showed that thalidomide induces oxidation in the DNA of rabbit embryos exposed in utero to thalidomide, and that this is one of the indications that the formation of roS and oxidative stress are involved in the process. in this study, oxidation did not occur in mouse embryos, which are resistant to thalidomide teratogenesis, and this could be one reason for the resistance and species-specific teratogenicity. In agreement with this is the hypothesis that roS formation would reduce the capacity of the nuclear factor kappa beta (NF-KB) -a redox-sen- issues, such as species-specific mechanisms, tissue specificity, and phenotypic differences.

Thalidomide cases in brazil Explain the Fear Surrounding the Introduction of an Analog
The first cases of malformations associated with the use  probably be efforts to test these molecules under other conditions, particularly in ENL, which is still very common in Brazil.
thus, one would not be able to guarantee that this medication is totally out of the teratogenic range and that the first in ute- Meanwhile, because the drug has so many features that can benefit people with various debilitating conditions, it is necessary to implement new prevention approaches that seek to effectively control the drug and ensure its safe and rational use.