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Daniel Bernstein - One of the best experts on this subject based on the ideXlab platform.
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Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats an experimental study
Transplant International, 2017Co-Authors: Katharine K Miller, D Wang, X Hu, T Deuse, Evgenios Neofytou, Thomas Renne, Joachim Velden, Hermann Reichenspurner, S Schrepfer, Daniel BernsteinAbstract:Background Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at five years post-transplantation. To date there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of Thalidomide on the development of CAV. Methods The effect of Thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n=6/group). Animals were left untreated or received Thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Results Animals that received Thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after Thalidomide treatment revealed down-regulation of matrix metalloproteinase 8 (MMP-8) and monocyte chemotactic protein 1 (MCP-1), cytokines involved in tissue remodeling and inflammation, respectively. Importantly, no negative side effects of Thalidomide were observed. Conclusions Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection.
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Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats an experimental study
Transplant International, 2017Co-Authors: Katharine K Miller, D Wang, T Deuse, Evgenios Neofytou, Thomas Renne, Joachim Velden, Hermann Reichenspurner, S Schrepfer, Xiaoqin Hua, Daniel BernsteinAbstract:Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post-transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of Thalidomide on the development of CAV. The effect of Thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received Thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received Thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after Thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of Thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection.
Norio Shibata - One of the best experts on this subject based on the ideXlab platform.
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Thalidomide and its metabolite 5 hydroxyThalidomide induce teratogenicity via the cereblon neosubstrate plzf
The EMBO Journal, 2021Co-Authors: Satoshi Yamanaka, Etsuko Tokunaga, Takayuki Suzuki, Hidetaka Murai, Daisuke Saito, Gembu Abe, Takahiro Iwasaki, Hirotaka Takahashi, Hiroyuki Takeda, Norio ShibataAbstract:Thalidomide causes teratogenic effects by inducing protein degradation via cereblon (CRBN)-containing ubiquitin ligase and modification of its substrate specificity. Human P450 cytochromes convert Thalidomide into two monohydroxylated metabolites that are considered to contribute to Thalidomide effects, through mechanisms that remain unclear. Here, we report that promyelocytic leukaemia zinc finger (PLZF)/ZBTB16 is a CRBN target protein whose degradation is involved in Thalidomide- and 5-hydroxyThalidomide-induced teratogenicity. Using a human transcription factor protein array produced in a wheat cell-free protein synthesis system, PLZF was identified as a Thalidomide-dependent CRBN substrate. PLZF is degraded by the ubiquitin ligase CRL4CRBN in complex with Thalidomide, its derivatives or 5-hydroxyThalidomide in a manner dependent on the conserved first and third zinc finger domains of PLZF. Surprisingly, Thalidomide and 5-hydroxyThalidomide confer distinctly different substrate specificities to mouse and chicken CRBN, and both compounds cause teratogenic phenotypes in chicken embryos. Consistently, knockdown of Plzf induces short bone formation in chicken limbs. Most importantly, degradation of PLZF protein, but not of the known Thalidomide-dependent CRBN substrate SALL4, was induced by Thalidomide or 5-hydroxyThalidomide treatment in chicken embryos. Furthermore, PLZF overexpression partially rescued the Thalidomide-induced phenotypes. Our findings implicate PLZF as an important Thalidomide-induced CRBN neosubstrate involved in Thalidomide teratogenicity.
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structural basis of Thalidomide enantiomer binding to cereblon
Scientific Reports, 2018Co-Authors: Tomoyuki Mori, Hideki Ando, Satoshi Sakamoto, Yuki Yamaguchi, Etsuko Tokunaga, Norio Shibata, Toshio HakoshimaAbstract:Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studies of (S)- and (R)-enantiomers bound to the primary target of Thalidomide, cereblon (CRBN). Our biochemical studies employed deuterium-substituted Thalidomides to suppress optical isomer conversion, and established that the (S)-enantiomer exhibited ~10-fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the (R)-enantiomer. The crystal structures of the Thalidomide-binding domain of CRBN bound to each enantiomer show that both enantiomers bind the tri-Trp pocket, although the bound form of the (S)-enantiomer exhibited a more relaxed glutarimide ring conformation. The (S)-enantiomer induced greater teratogenic effects on fins of zebrafish compared to the (R)-enantiomer. This study has established a mechanism by which Thalidomide exerts its effects in a stereospecific manner at the atomic level.
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Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
Nature Publishing Group, 2018Co-Authors: Etsuko Tokunaga, Takeshi Yamamoto, Emi Ito, Norio ShibataAbstract:Abstract Twenty years after the Thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of Thalidomide is teratogenic. However, other work has shown that the enantiomers of Thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-Thalidomide given the ready in vivo racemization (“Thalidomide paradox”)? Herein, we disclose a hypothesis to explain this “Thalidomide paradox” through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of Thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of Thalidomide enantiomers epimerizes in vivo, followed by precipitation of racemic Thalidomide in (R/S)-heterodimeric form. Thus, racemic Thalidomide is most likely removed from biological processes upon racemic precipitation in (R/S)-heterodimeric form. On the other hand, enantiomerically pure Thalidomide remains in solution, affording the observed biological experimental results: the (S)-enantiomer is teratogenic, while the (R)-enantiomer is not
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biological evaluation of both enantiomers of fluoro Thalidomide using human myeloma cell line h929 and others
PLOS ONE, 2017Co-Authors: Etsuko Tokunaga, Hidehiko Akiyama, Vadym Anatolievch Soloshonok, Yuki Inoue, Hideaki Hara, Norio ShibataAbstract:Over the last few years, Thalidomide has become one of the most important anti-tumour drugs for the treatment of relapsed-refractory multiple myeloma. However, besides its undesirable teratogenic side effect, its configurational instability critically limits any further therapeutic improvements of this drug. In 1999, we developed fluoro-Thalidomide which is a bioisostere of Thalidomide, but, in sharp contrast to the latter, it is configurationally stable and readily available in both enantiomeric forms. The biological activity of fluoro-Thalidomide however, still remains virtually unstudied, with the exception that fluoro-Thalidomide is not teratogenic. Herein, we report the first biological evaluation of fluoro-Thalidomide in racemic and in both (R)- and (S)-enantiomerically pure forms against (in vitro) H929 cells of multiple myeloma (MM) using an annexin V assay. We demonstrate that all fluoro-Thalidomides inhibited the growth of H929 MM cells without any in-vivo activation. Furthermore, we report that the enantiomeric forms of fluoro-Thalidomide display different anti-tumour activities, with the (S)-enantiomer being noticeably more potent. The angiogenesis of fluoro-Thalidomides is also investigated and compared to Thalidomide. The data obtained in this study paves the way towards novel pharmaceutical research on fluoro-Thalidomides.
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induction of human cytochrome p450 3a enzymes in cultured placental cells by Thalidomide and relevance to bioactivation and toxicity
Journal of Toxicological Sciences, 2017Co-Authors: Norie Murayama, Kazuyuki Arata, Yasuhiro Kazuki, F. Peter Guengerich, Daisuke Satoh, T. Harada, Norio Shibata, Hiroshi YamazakiAbstract:Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of Thalidomide due to oxidation to 5-hydroxyThalidomide and subsequent metabolic activation in livers. In this study, more relevant human placenta preparations and placental BeWo cells showed low but detectable P450 3A4/5 mRNA expression and drug oxidation activities. Human placental microsomal fractions from three subjects showed detectable midazolam 1´- and 4-hydroxylation and Thalidomide 5-hydroxylation activities. Human placental BeWo cells, cultured in the recommended media, also indicated detectable midazolam 1´- and 4-hydroxylation and Thalidomide 5-hydroxylation activities. To reduce any masking effects by endogenous hormones used in the recommended media, induction of P450 3A4/5 mRNA and oxidation activities were measured in placental BeWo cells cultured with a modified medium containing 5% charcoal-stripped fetal bovine serum. Thalidomide significantly induced P450 3A4/5, 2B6, and pregnane X receptor (PXR) mRNA levels 2 to 3-fold, but rifampicin only enhanced P450 3A5 and PXR mRNA under the modified media conditions. Under these modified conditions, Thalidomide also significantly induced midazolam 1´-hydroxylation and Thalidomide 5-hydroxylaion activities 3-fold but not bupropion hydroxylation activity. Taken together, activation of Thalidomide to 5-hydroxyThalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.
Katharine K Miller - One of the best experts on this subject based on the ideXlab platform.
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Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats an experimental study
Transplant International, 2017Co-Authors: Katharine K Miller, D Wang, X Hu, T Deuse, Evgenios Neofytou, Thomas Renne, Joachim Velden, Hermann Reichenspurner, S Schrepfer, Daniel BernsteinAbstract:Background Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at five years post-transplantation. To date there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of Thalidomide on the development of CAV. Methods The effect of Thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n=6/group). Animals were left untreated or received Thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Results Animals that received Thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after Thalidomide treatment revealed down-regulation of matrix metalloproteinase 8 (MMP-8) and monocyte chemotactic protein 1 (MCP-1), cytokines involved in tissue remodeling and inflammation, respectively. Importantly, no negative side effects of Thalidomide were observed. Conclusions Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection.
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Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats an experimental study
Transplant International, 2017Co-Authors: Katharine K Miller, D Wang, T Deuse, Evgenios Neofytou, Thomas Renne, Joachim Velden, Hermann Reichenspurner, S Schrepfer, Xiaoqin Hua, Daniel BernsteinAbstract:Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post-transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of Thalidomide on the development of CAV. The effect of Thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received Thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received Thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after Thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of Thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection.
Hiroshi Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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induction of human cytochrome p450 3a enzymes in cultured placental cells by Thalidomide and relevance to bioactivation and toxicity
Journal of Toxicological Sciences, 2017Co-Authors: Norie Murayama, Kazuyuki Arata, Yasuhiro Kazuki, F. Peter Guengerich, Daisuke Satoh, T. Harada, Norio Shibata, Hiroshi YamazakiAbstract:Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of Thalidomide due to oxidation to 5-hydroxyThalidomide and subsequent metabolic activation in livers. In this study, more relevant human placenta preparations and placental BeWo cells showed low but detectable P450 3A4/5 mRNA expression and drug oxidation activities. Human placental microsomal fractions from three subjects showed detectable midazolam 1´- and 4-hydroxylation and Thalidomide 5-hydroxylation activities. Human placental BeWo cells, cultured in the recommended media, also indicated detectable midazolam 1´- and 4-hydroxylation and Thalidomide 5-hydroxylation activities. To reduce any masking effects by endogenous hormones used in the recommended media, induction of P450 3A4/5 mRNA and oxidation activities were measured in placental BeWo cells cultured with a modified medium containing 5% charcoal-stripped fetal bovine serum. Thalidomide significantly induced P450 3A4/5, 2B6, and pregnane X receptor (PXR) mRNA levels 2 to 3-fold, but rifampicin only enhanced P450 3A5 and PXR mRNA under the modified media conditions. Under these modified conditions, Thalidomide also significantly induced midazolam 1´-hydroxylation and Thalidomide 5-hydroxylaion activities 3-fold but not bupropion hydroxylation activity. Taken together, activation of Thalidomide to 5-hydroxyThalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.
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Human Cytochrome P450 Oxidation of 5‑HydroxyThalidomide and Pomalidomide, an Amino Analogue of Thalidomide
2014Co-Authors: Goutam Chowdhury, Hiroshi Yamazaki, Norio Shibata, Peter F GuengerichAbstract:The sedative and antiemetic drug Thalidomide [α-(N-phthalimido)glutarimide] was withdrawn in the early 1960s because of its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of Thalidomide still remains unclear, but it is well-established that metabolism of Thalidomide is important for both teratogenicity and cancer treatment outcome. Thalidomide is oxidized by various cytochrome P450 (P450) enzymes, the major one being P450 2C19, to 5-hydroxy-, 5′-hydroxy-, and dihydroxyThalidomide. We previously reported that P450 3A4 oxidizes Thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possibly an arene oxide, that can be trapped by glutathione (GSH) to GSH adducts. We now show that the dihydroxyThalidomide metabolite can be further oxidized to a quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize 5-hydroxyThalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized Thalidomide itself. A recently approved amino analogue of Thalidomide, pomalidomide (CC-4047, Actimid), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding phthalimide ring-hydroxylated product
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in vivo drug interactions of the teratogen Thalidomide with midazolam heterotropic cooperativity of human cytochrome p450 in humanized tk nog mice
Chemical Research in Toxicology, 2013Co-Authors: Hiroshi Yamazaki, Norie Murayama, Norio Shibata, Hiroshi Suemizu, Masahiro Utoh, Masato Nakamura, Peter F GuengerichAbstract:In vivo drug interactions of the teratogen Thalidomide with the model cytochrome P450 (P450) 3A substrate midazolam were investigated in mice with humanized livers. The clearance of midazolam (administered intravenously, 10 mg kg–1) in chimeric mice was enhanced by orally co-administered Thalidomide (100 mg kg–1). A larger area under the curve of the major metabolite 1′-hydroxymidazolam (1.7-fold) was obtained with Thalidomide because of the heterotropic cooperativity of human P450 3A enzymes. A larger area under the curve of the minor metabolite 4-hydroxymidazolam (3.5-fold) was seen with daily pretreatment with Thalidomide for 3 days, presumably because of human P450 3A induction. These results demonstrate that livers of humanized mice mediate drug interactions of Thalidomide and suggest interactions of therapeutic agents during therapies with Thalidomide.
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drug interactions of Thalidomide with midazolam and cyclosporine a heterotropic cooperativity of human cytochrome p450 3a5
Drug Metabolism and Disposition, 2009Co-Authors: Yusuke Okada, Norie Murayama, Peter F Guengerich, Makiko Shimizu, Chihiro Yanagida, Hiroshi YamazakiAbstract:There is growing clinical interest of Thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about Thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of Thalidomide on cytochrome P450 (P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. Thalidomide inhibited S-mephenytoin 4′-hydroxylation activities of recombinant P450 2C19 and human liver microsomes: the apparent concentration of Thalidomide producing 50% inhibition was approximately 270 μM for P450 2C19. Midazolam 4-hydroxylation activities were suppressed by Thalidomide, but activities of 1′-hydroxylation and total midazolam oxidation and testosterone 6β-hydroxylation were enhanced in the presence of Thalidomide. Recombinant P450 3A5 was found to have altered kinetics at clinically relevant concentrations of Thalidomide (10–30 μM). P450 3A4 was also affected, but only at higher Thalidomide concentrations. Enhanced midazolam hydroxylation by Thalidomide was also seen in liver microsomal samples harboring the CYP3A5*1 allele. Similarly enhanced rates of cyclosporine A clearance were observed in P450 3A5 and liver microsomes expressing P450 3A5 in the presence of Thalidomide. A proposed effector constant for Thalidomide corresponded roughly to its clinical plasma levels. Docking studies with a P450 3A5 homology model, based on the published structure of P450 3A4, revealed close interaction between Thalidomide and the heme of P450 3A5. The present results suggest that total midazolam metabolism or cyclosporine A clearance may be increased by Thalidomide in a dose-dependent manner. Unexpected drug interactions involving Thalidomide might occur via heterotropic cooperativity of polymorphic P450 3A5.
Lavinia Schulerfaccini - One of the best experts on this subject based on the ideXlab platform.
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genomic and in silico analyses of crbn gene and Thalidomide embryopathy in humans
Reproductive Toxicology, 2016Co-Authors: Fernanda Sales Luiz Vianna, Maria Teresa Vieira Sanseverino, Thayne Woycinck Kowalski, Luciana Tovorodrigues, Alice Taglianiribeiro, Bibiane Armiliato De Godoy, Lucas Rosa Fraga, Mara H Hutz, Lavinia SchulerfacciniAbstract:Thalidomide causes Thalidomide Embryopathy (TE), but is largely used to treat several conditions. Investigations with Cereblon, a Thalidomide target protein encoded by CRBN gene, have helped to understand Thalidomide therapeutic and teratogenic properties. We sequenced CRBN-Thalidomide binding region in 38 TE individuals and 136 Brazilians without congenital anomalies, and performed in silico analyses. Eight variants were identified, seven intronic and one in 3'UTR. TE individuals had rare variants in higher frequency than the non-affected group (p=0.04). The genotype rs1620675 CC was related to neurological anomalies in TE individuals (p=0.004). Bioinformatics analysis suggested this genotype leads to potential alterations in splicing sites and binding to transcription factors. Comparison of the Cereblon-Thalidomide binding domains in mammals demonstrated that CRBN is highly conserved across species. All the variants require evaluation in functional assays in order to understand their role in Cereblon-Thalidomide binding and complex interactions that lead to TE.
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pharmacoepidemiology and Thalidomide embryopathy surveillance in brazil
Reproductive Toxicology, 2015Co-Authors: Fernanda Sales Luiz Vianna, Jorge S Lopezcamelo, Elaine F Morelo, Maria Teresa Vieira Sanseverino, Marcelo Zagonel De Oliveira, Dacio De Lyra Rabello Neto, Suzi Alves Camey, Lavinia SchulerfacciniAbstract:Abstract Introduction Thalidomide causes congenital defects in children, such as limb reduction defects. Currently, it is used for a few indications; in Brazil, where leprosy is endemic, Thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of Thalidomide embryopathy have been reported. Methods We analyzed the frequency of births with phenotypes consistent with Thalidomide embryopathy (TEP) and correlated this with the distribution of Thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil. Results A total of 5,889,210 Thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54–1.66) and TEP was 0.11 (CI95%: 0.10–0.13) per 10,000 births. Poisson regression showed an increase in cases of TEP and limb reduction defects per 100,000 tablets dispensed. Clusters and geographical isolates were identified in several regions. Conclusions There is a correlation between Thalidomide and TEP showing that Thalidomide embryopathy should be monitored in countries where this medication is available.
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recognition of the phenotype of Thalidomide embryopathy in countries endemic for leprosy new cases and review of the main dysmorphological findings
Clinical Dysmorphology, 2013Co-Authors: Fernanda Sales Luiz Vianna, Lavinia Schulerfaccini, Julio Cesar Loguercio Leite, Silvia Helena C De Sousa, Lea Marcia M Da Costa, Murilo F Dias, Elaine F Morelo, Maria Juliana Rodovalho Doriqui, Claudia M Maximino, Maria Teresa Vieira SanseverinoAbstract:Thalidomide is the best-known teratogen worldwide. It was first marketed as a sedative in the late 1950s, but the birth of ~10 000 children with birth defects resulted in the withdrawal of Thalidomide from the market in 1962. Thalidomide embryopathy affects almost all organs but the main defects are concentrated in the limbs, eyes, ears, and heart. Shortly after the withdrawal of Thalidomide from the market, its effectiveness in the treatment of erythema nodosum leprosum, an inflammatory condition resulting from leprosy, was reported and since the mid-1990s, the drug has been used widely in the treatment of cancers and autoimmune diseases, among other conditions. 40 000 new cases of leprosy are diagnosed every year in Brazil. Although there is a strict legislation for the prescription and use of Thalidomide in Brazil, cases of Thalidomide embryopathy have continued to be reported. Here, we present two new cases of Thalidomide embryopathy identified in 2011 and review the major clinical findings in the literature that can aid the identification of the embryopathy.
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new cases of Thalidomide embryopathy in brazil
Birth Defects Research Part A-clinical and Molecular Teratology, 2007Co-Authors: Lavinia Schulerfaccini, Claudia M Maximino, Rosa Castalia Soares, Artur Custodio Moreira De Sousa, Expedito Jose De Albuquerque Luna, Ida Vanessa Doderlein Schwartz, Carolina Waldman, Eduardo E CastillaAbstract: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.
