Cases Of Thalidomide Embryopathy Research Articles

SAT678 Metabolic Disorders In Thalidomide Embryopathy

Abstract Disclosure: A. Tanabe: None. Thalidomide embryopathy (TE) is a disease that develops in neonates born from women who have taken thalidomide during early pregnancy. Most cases of TE are characterized by developmental abnormalities of the limbs and/or auditory organs. In Japan, thalidomide was marketed as an agent for sleep-induce and digestive ulcers from 1958 to 1962. Up to now, 309 patients have been certified and are supported by the government as drug-induced disease. Currently, many of the victims are in their late 50s, and in addition to congenital disabilities, various health issues such as lifestyle-related diseases can be developed. We investigated their metabolic condition using data of medical health checkup between 2017 and 2019. Sixty-five Japanese cases of TE (33 men and 32 women) were included in this study. The mean age was 56.3±1.5 years in men and 56.1±1.2 years in women. The prevalence of upper limb deformities was 70% in men and 72% in women. The mean body mass index (BMI) was 22.7±2.1 in men and 22.5±4.0 in women. Twelve percent of men and 9% of women had a BMI between 25-30, while 9% of women and no men had a BMI of 30 or greater. Liver dysfunction was seen in 67% of men and 19% of women. The mean low-density lipoprotein cholesterol level was 61±19 mg/dL in men and 69±22 mg/dL in women. The mean high-density lipoprotein (LDL) cholesterol level was 116±29 mg/dL in men and 142±35 mg/dL in women, with 21% of men and 56% of women had LDL level of 140 mg/dL or greater. The mean triglyceride (TG) level was 137±82 mg/dL in men and 121±70 mg/dL in women, with 39% of men and 22% of women had a level of 150 mg/dL or greater. The mean fasting blood glucose level was 114±31 mg/dL in men and 102±17 mg/dL in women. The mean HbA1c level was 5.9±0.9% in men and 5.9±0.4% in women. The prevalence of impaired glucose tolerance was 19% in men and 9% in women. Fatty liver evaluated by ultrasonography or CT scan was 56% in men and 41% in women. The patients with fatty liver showed significantly high BMI, body fat percentage and TGs in men, high alanine aminotransferase and TGs in women, respectively, compared to the patients without fatty liver. There was no significant difference in with or without the upper limb abnormalities in both groups. This is the second report of metabolic disorders in TE, following one from our research group in 2015. Although without obvious overweight, thirty percent of the patients had dyslipidemia and 50% of the patients had the fatty liver. Because there was no association between limb abnormalities and metabolic disorders, other factors could be involved in the development of metabolic disorders. The results of this study provide valuable information for future health management in thalidomide embryopathy. (This study was conducted by a research grant from the National Center for Global Health and Medicine, Japan: 21A1015 and a Grant-in-Aid from the Ministry of Health, Labour, and Welfare, Japan: 20KC2005, 23KC2017). Presentation: Saturday, June 17, 2023

Genetic susceptibility to thalidomide embryopathy in humans: Study of candidate development genes.

Thalidomide is a drug used worldwide for several indications, but the molecular mechanisms of its teratogenic property are not fully understood. Studies in animal models suggest the oxidative stress, the inhibition of angiogenesis, and the binding to E3-ubiquitin ligase complex as mechanisms by which thalidomide can change the expression of genes important to embryonic development. In this study, seven polymorphisms in genes related to development (FGF8, FGF10, BMP4, SHH, TP53, TP63, and TP73) were analyzed in people with thalidomide embryopathy (TE) and compared to people without malformations. The sample consisted of 36 people with TE and 135 unrelated and nonsyndromic people who had their DNA genotyped by PCR real-time. Although no allelic or genotypic differences were observed between the groups, we hypothesized that other regions in these genes and related genes may play an important role in thalidomide teratogenesis, which is known to have a genetic contribution. Identifying such molecular mechanisms is essential for the development of a molecule that will be analogue to thalidomide but safe enough to avoid the emergence of new cases of TE.

The impact of thalidomide use in birth defects in Brazil

Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.

Novel thalidomide analogues, “me too” drugs and the Brazilian law

In Brazil, thalidomide has been used virtually without interruption since it was launched as a new and revolutionary sedative drug in 1956. After 1965, when its efficacy to treat erythema nodosum leprosum (ENL) was discovered, it was regarded as an essential drug because the prevalence of Hansen’s disease is high in the country. In the 1990s and thereafter myriad novel therapeutic uses for thalidomide (autoimmmune diseases, multiple myeloma, aphthous ulcers in AIDS, and others) have emerged owing to its immunomodulatory and antiangiogenic activities. Owing to a marked teratogenicity, however, the prescription and dispensing of thalidomide to patients is strictly controlled in Brazil and elsewhere. Notwithstanding the stringent regulations, a number of post-1965 cases of thalidomide embryopathy have occurred in Brazil. In 2003, a federal law (Law 10.651/2003) prohibited the sale and dispensing of thalidomide in commercial pharmacies. The law, however, made no provision for teratogenic drug analogues such as lenalidomide and pomalidomide, which have been cleared for marketing in the USA, Europe and other countries. Although they are much more expensive than thalidomide, the clinical superiority of novel ana-logues over thalidomide in multiple myeloma and other conditions remains unproven. Therefore, so far novel analogues can be considered as thalidomide “me too” drugs. This author strongly recommends that an amendment to the current law prohibiting the sale and dispensing of thalid-omide in commercial pharmacies be extended to thalidomide analogues. Moreover, we consider that a demonstration of clinical superiority over thalidomide (through gold-standard comparative efficacy trials) should be an essential requirement for registration of any teratogenic analogue.

New cases of thalidomide embryopathy in Brazil

Thalidomide is the best known human teratogen. Although withdrawn from the market in 1961, thalidomide was remarketed after 1965 in several countries, for the treatment of erythema nodosum leprosum. Thalidomide has a potent immunomodulatory property and has now a number of approved and off-label uses in dermatologic, oncologic, infectious and gastrointestinal conditions. In the U.S., FDA approved the use of thalidomide in 1998, but no cases of thalidomide embriophaty were registered after that. Since 1996 no new cases were reported in Latin America. However, the Teratogen Information Service (TIS) Porto Alegre, recorded three new cases of thalidomide embriophaty born in Brazil since 2005. Considering that these three cases were not registered through a systematic surveillance system, but that came to our attention through a series of coincidental random events, it can be assumed that the actual occurrence of affected babies by thalidomide continues being as frequent as denounced ten years ago.

Cleft lip and palate in thalidomide-induced embryopathies

SUMMARYIn 3 out of 161 cases of thalidomide embryopathy seen in Hamburg, typical malformations of thalidomide causation were associated with cleft lip and/or palate. The same association was present in 6 out of 918 cases of thalidomide embryopathy reported by correspondence. Clefts of the face are more common in thalidomide children than in other children. Usually, they are associated with ear deformities. In cases of aplasia of the radius observed before the introduction of thalidomide but not in those connected with thalidomide intake, clefts are more common than in the general population. The association of clefts and ear deformities has been known before the introduction of thalidomide. Thalidomide is probably the cause of only some cases of association.