Talk:Abnormal Development - Thalidomide

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Cite this page: Hill, M.A. (2019, June 19) Embryology Abnormal Development - Thalidomide. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Abnormal_Development_-_Thalidomide

Historic Reference 1962

Arch Environ Health. 1962 Aug;5:100-5. Thalidomide embryopathy. LENZ W, KNAPP K.

LENZ W & KNAPP K. (1962). Thalidomide embryopathy. Arch. Environ. Health , 5, 100-5. PMID: 14464040

2019

Reference tables with centiles of limb to body height ratios of healthy human adults for assessing potential thalidomide embryopathy

Anthropol Anz. 2019 Mar 14. doi: 10.1127/anthranz/2019/0981.

Reimann A1, Beyer R2, Mumm R1, Scheffler C1.

Abstract

Background: Over 60 years ago the biggest drug catastrophe in Germany took place. The drug thalidomide, sold by the German pharmaceutical company Chemie Grünenthal GmbH starting in 1957 under the name "Contergan", caused severe birth defects in newborns. Chemie Grünenthal withdraw Contergan in 1961. Until nearly 30 years later in 1988 there were already over 10.000 children born with severe birth defects (e.g. dysmelia, amelia, congenital heart defect). Due to the high variability of the birth defects caused by thalidomide, later called thalidomide embryopathy, there is still no detailed information about the proportions of limbs. Aim: The aim is to develop reference centiles for limb measurements of men and women aged 19-70 years old. Method: For the calculation, data of healthy men and women (m = 2984, f = 2838) from former East Germany were used and centiles using the LMS-method were developed. Results: Centile tables for arm and leg length of men and women are presented in the results. The variability is small due to a homogeneous distribution of the measurements. A test with randomly chosen patient data shows that women under 171 cm stature and men under 180 cm stature can be assessed correctly. A severe shortening of limbs can be detected with this method.

PMID: 30869735 DOI: 10.1127/anthranz/2019/0981

A Cautious Note on Thalidomide Usage in Cancer Treatment: Genetic Profiling of the TBX2 Sub-Family Gene Expression is Required

Drug Res (Stuttg). 2019 Apr 1. doi: 10.1055/a-0873-3529. [Epub ahead of print]

Nemer G1, Khalil A1.

Abstract

Thalidomide is still by excellence the mysterious drug that fascinated, blurred, misled, and changed the scientific community perspectives and policies. It was introduced in the 1950's as a sedative drug, then shortly withdrawn because of the devastating birth defects that affected tens of thousands throughout more than 40 countries. Back into the market in the mid 1990's and 2000's the drug is now being used to treat skin immune-related conditions and some cancers like multiple myeloma. Despite numerous beneficial effects which led to the development of new analogs, its direct mechanisms of action are still elusive. The identification of CRBN and TBX5 as potential direct ligands for this drug have opened the way to better understand its efficiency and its failure.We hereby review these mechanisms and provide evidence that could explain why thalidomide failed to make it as a drug of choice in lung cancer treatment. Linking the genetic signature of TBX2 subfamily in these tumors to their inability to respond properly to thalidomide raises concerns of worsening lung cancer patients' health if this drug is utilized. © Georg Thieme Verlag KG Stuttgart · New York. PMID: 30934098 DOI: 10.1055/a-0873-3529


Zebrafish Yolk Sac Microinjection of Thalidomide for Assessment of Developmental Toxicology

Congenit Anom (Kyoto). 2019 Apr 1. doi: 10.1111/cga.12335. [Epub ahead of print]

Mikami I1,2, Takahashi Y1,2, Koiwa J1,2, Okamura M1,2, Tanaka T1,2.

Abstract

Zebrafish offer advantages over traditional rodent models in developmental toxicology studies, including low maintenance costs, high fecundity, genetic diversity, and reduced animal welfare concerns (1,2). This article is protected by copyright. All rights reserved. PMID: 30932217 DOI: 10.1111/cga.12335


Upcoming challenges in providing care for thalidomide impaired individuals

Pflege. 2019 Mar 19:1-9. doi: 10.1024/1012-5302/a000670. Article in German; Abstract available in German from the publisher

Samel C1, Albus C2, Tebest R3, Forster K2, Lüngen M4, Niecke A2, Pfaff H5, Peters KM6.

Abstractin English, German Upcoming challenges in providing care for thalidomide impaired individuals Abstract. BACKGROUND: Between 1957 and 1962 an approximate 5000 children were born in Germany with severe birth defects as their mothers took the substance Thalidomide during pregnancy as a sedative and effective relief from morning sickness. OBJECTIVE: The aim of this study was to describe the care and assistance needed by the individuals impaired by Thalidomide and indicate upcoming challenges. A further aim was to determine the association between the impairment type and the care needed. METHODS: Cross sectional study, 202 individuals impaired by Thalidomide were examined by two orthopedists as well as surveyed via questionnaire. They were also evaluated mentally by either a psychiatrist or psychotherapist. The need for care was determined by the acquired legal status for long-term care. RESULTS: The sample divides roughly into two groups: the ones with impairments in their extremities and those who are not affected in their extremities. Many of the ones affected in their extremities are already dependent on assistance and need to be nursed. Those who are depending on assistance and care are mostly informally cared for. CONCLUSIONS: The prevalence for long-term care is already higher than in the age-adjusted general population in Germany, while formal care is underutilized. Therefore a challenge will be to make a shift from informal care to professional care providers as the informally caring (sometimes actually the parents of the impaired) are aging along with the ones they care for. KEYWORDS: Contergan; Pflegebedarf; Thalidomide impaired; informal care; informelle Pflege; nursing; ungedeckte Bedarfe; unmet needs PMID: 30887894 DOI: 10.1024/1012-5302/a000670

Life situation of women impaired by Thalidomide embryopathy in North Rhine-Westphalia - a comparative analysis of a recent cross-sectional study with earlier data

BMC Womens Health. 2019 Apr 3;19(1):51. doi: 10.1186/s12905-019-0745-y.

Samel C1,2, Albus C3, Nippert I4, Niecke A3, Lüngen M5, Pfaff H6, Peters KM7.

Abstract

BACKGROUND: Between 1957 and 1961 the substance Thalidomide was sold in West Germany and taken by many women as a sedative during pregnancy. This lead to miscarriages and infants been born with several severe malformations. The aim of this study was to describe the current situation of women impaired by Thalidomide induced embryopahty in North Rhine-Westphalia (Nordrhein-Westfalen), Germany, in comparison with the results found in a study done in 2002 by Nippert et al. METHODS: Questionnaires as well as examinations were performed. Data were compared using descriptive and inductive statistical methods. RESULTS: Both studies show that women impaired by Thalidomide embryopathy face a poorer health status than women their age in the general population and live in fear of further deteriorating health. The majority can only work reduced hours or are already retired due to poor health. Most of those who need assistance are being assisted by their social environment, while professional care is still utilized in only few cases. CONCLUSIONS: An obvious need for a shift in the provision of assistance and/or care provided was found as the social environment supporting the impaired women is also aging and therefore in high danger of breaking apart. TRIAL REGISTRATION: The study has been registered at German Clinical Trials Register, DRKS00010593 , on 07.06.2016 retrospectively. KEYWORDS: Birth defects; Congenital disorder; Dysmelia; Embryopathy; Follow up study; Health outcomes; Healthcare; Thalidomide; Unmet medical needs PMID: 30943953 DOI: 10.1186/s12905-019-0745-y

2016

Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity

Nat Med. 2016 Jun 13. doi: 10.1038/nm.4128.

Eichner R1, Heider M1, Fernández-Sáiz V1,2,3, van Bebber F4, Garz AK1,2,3, Lemeer S5, Rudelius M6,7, Targosz BS1, Jacobs L1, Knorn AM1, Slawska J1, Platzbecker U8, Germing U9, Langer C10, Knop S11, Einsele H11, Peschel C1,2,3, Haass C4,12,13, Keller U1,2,3, Schmid B4,12, Götze KS1,2,3, Kuster B2,3,5,14, Bassermann F1,2,3.

Abstract

Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.


PMID 27294876

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4128.html

Congenital limb deficiency classification and nomenclature: The need for a consensus

Am J Med Genet A. 2016 Mar 30. doi: 10.1002/ajmg.a.37608. [Epub ahead of print]

Lowry RB1,2,3, Bedard T1.

Abstract

After the thalidomide epidemic in the early 1960s, many jurisdictions developed congenital anomaly surveillance systems. Congenital limb deficiencies can act as indicators of potential teratogens. The classification of congenital limb deficiencies is essential to determine the precise cause or causes of this anomaly. This article describes the different terminology and classification that have been used over time and the need for a consensus. While there are a variety of studies examining the epidemiology and etiology of congenital limb deficiencies, there is an inconsistent use of terminology and classification which makes comparisons between studies challenging. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc. KEYWORDS: classification; congenital limb deficiency; limb reduction defect; nomenclature PMID 27027980


New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors

Sci Rep. 2016 Mar 23;6:23404. doi: 10.1038/srep23404.

Kowalski TW1,2, Fraga LR1,2, Tovo-Rodrigues L2,3, Sanseverino MT1,2,4, Hutz MH2, Schuler-Faccini L1,2,4, Vianna FS1,2,4,5.

Abstract

Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (-786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles -786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2-5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue. PMID 27004986

2015

Thalidomide-induced teratogenesis: history and mechanisms

Birth Defects Res C Embryo Today. 2015 Jun;105(2):140-56. doi: 10.1002/bdrc.21096. Epub 2015 Jun 4.

Vargesson N.

Abstract

Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man-made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. © 2015 Wiley Periodicals, Inc. KEYWORDS: Fgf8; Shh; actin cytoskeleton; angiogenesis; cell death; cereblon; limb development; phocomelia; reactive oxygen species; vascular transition

PMID 26043938

http://onlinelibrary.wiley.com/doi/10.1002/bdrc.21096/abstract

Copyright © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


2014

Eight more people in UK sue Grünenthal and Diageo over thalidomide

BMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g3806 (Published 9 June 2014) Cite this as: BMJ 2014;348:g3806 http://www.bmj.com/content/348/bmj.g3806?etoc=

In 2012 Diageo settled a claim by an Australian thalidomide survivor, Lynette Rowe, for an undisclosed sum. The next year it agreed to pay A$89m ($50m; €61m; US$83m) to settle claims by more than 100 Australians and New Zealanders represented by Slater & Gordon. And in 2013 a Spanish court ordered Grünenthal to pay compensation to 22 Spaniards with disabilities caused by the drug.

2012

Stability of the reproductive variables and fetal malformations from control animals and animals treated with thalidomide in Kbl:JW rabbits over two decades

Congenit Anom (Kyoto). 2012 Dec;52(4):191-202. doi: 10.1111/j.1741-4520.2012.00380.x.

Kawamura Y, Matsumoto K, Sato K. Source Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.

Abstract

We retrospectively analyzed the reproductive variables and the spontaneous malformations in the historical control data from the embryo-fetal development studies conducted in our laboratories with Kbl:JW rabbits over two decades (1990-2010) and fetal malformations induced by thalidomide in 1988, 1995 and 2007. These analyses in the control animals revealed that the reproductive variables in dams, total frequencies and profile of external, visceral and skeletal abnormalities and/or variations in the fetuses were stable over two decades. In addition, the characteristics of the malformations induced by thalidomide were reproducible at the three time points. Therefore, it is concluded that Kbl:JW rabbit is one of the useful rabbit strains to evaluate the effects of test substances on embryo-fetal development, especially in view of the chronological stability of spontaneous or drug-induced malformations in the fetuses. © 2012 The Authors. Congenital Anomalies © 2012 Japanese Teratology Society.

PMID 23181494

Thalidomide: Chemistry, therapeutic potential and oxidative stress induced teratogenicity

Curr Top Med Chem. 2012 May 31. [Epub ahead of print] Kumar N, Sharma U, Singh C, Singh B. Source Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh-176061, INDIA. neerajnpp@rediffmail.com.

Abstract

Thalidomide and its one analogue, lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma. Multiple myeloma is characterized by an overproduction of malignant plasma cells in the bone marrow. The journey of thalidomide was started in 1956 when it was marketed as a non-barbiturate sedative agent. It was considered as a wonder drug that provided safe and sound sleep and hence, used to cure morning sickness in pregnant women. Later, in 1961, it was withdrawn from the world market due to its serious side effects, i.e., teratogenic activity. However, the recent decade has witnessed a true renaissance in interest in its broad biological activity. In particular, thalidomide was reevaluated and attracted significant attention due to its selective inhibitory activity of tumor necrosis factor-α (TNF-α), which is a clinically important activity against serious diseases such as rheumatoid arthritis, Crohns disease, leprosy, AIDS, and various cancers. The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL). Recently, the drug has got FDA approval for the treatment of multiple myeloma. In the last few years, number of thalidomide analogues have been synthesized and are in clinical development as a class of immunomodulatory drugs. Among these, lenalidomide is more potent than thalidomide, and is also non-neurotoxic. It was shown in vitro studies to induce apoptosis or arrest growth even in resistant multiple myeloma cell lines, decrease binding of the cells to bone marrow stromal cells, and stimulate host natural killer cell immunity. It also inhibits tumour growth and decreases angiogenesis. Earlier reviews have described the pharmacological aspects of thalidomide and a review has focused only on synthetic aspect of thalidomide. However, review focusing on chemistry and metabolism and mechanism of biological activity is still lacking. In this review, we will concisely describe the therapeutic aspects, metabolism and synthesis of thalidomide.

PMID 22650376

Deciphering the mystery of thalidomide teratogenicity

Congenit Anom (Kyoto). 2012 Mar;52(1):1-7. doi: 10.1111/j.1741-4520.2011.00351.x.

Ito T, Handa H. Source Solutions Research Laboratory Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.

Abstract

Thalidomide was originally developed in 1954 as a sedative that was commonly used to ameliorate morning sickness. However, thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g. phocomelia and amelia), affecting ∼10 000 children worldwide in the late 1950s and early 1960s. Thalidomide is now recognized as a clinically effective, albeit strictly restricted, drug for the treatment of leprosy and multiple myeloma. Investigators have studied thalidomide teratogenicity for half a century, proposing over 30 hypotheses to account for its actions. Among these, the anti-angiogenesis and oxidative stress models have gained widespread support. Nonetheless, the precise molecular mechanisms and direct targets of thalidomide have not heretofore been elucidated. We developed ferrite-glycidyl methacrylate beads that enable magnetic separation and efficient purification of ligand-binding molecules; the beads were recently employed to identify cereblon as a primary target of thalidomide. Cereblon forms an E3 ubiquitin ligase complex with DDB1, Cul4A, and Roc1, which is important for the expression of fibroblast growth factor 8, an essential regulator of limb development. Expression of a drug binding-deficient mutant of cereblon suppressed thalidomide-induced effects in zebrafish and chicks. This suggests that thalidomide downregulates fibroblast growth factor 8 expression and induces limb malformation by binding to wild-type cereblon, inhibiting the function of the associated E3 ubiquitin ligase. The present review summarizes the teratogenicity of thalidomide, including existing models for its mode of action, and discusses the identification of cereblon as a key molecule for deciphering the longstanding mystery of thalidomide teratogenicity.

© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.

PMID 22348778

http://onlinelibrary.wiley.com/doi/10.1111/j.1741-4520.2011.00351.x/pdf


Fifty years after thalidomide; what role for drug regulators?

Br J Clin Pharmacol. 2012 Feb 27. doi: 10.1111/j.1365-2125.2012.04255.x. [Epub ahead of print]

Eichler HG, Abadie E, Baker M, Rasi G. Source European Medicines Agency (EMA), United Kingdom Agence Française de Sécurité Sanitaire des Produits de Santé, France European Federation of Neurogical Associations (EFNA), United Kingdom.

Abstract

Fifty years ago, in December 1961, a letter from an Australian obstetrician alerted the world to thalidomide-induced teratogenicity. That tragedy became a key driver of the evolution of evidence standards for drug development and licensing. It also reinforced the notion that a knowledgeable and trusted third party - the drug regulator - is needed to protect patients’ interests and to decide for them which drugs would be available to them; this is allegedly because patients are not able to make informed decisions about such complex matters as drug treatment and manufacturers could not be trusted to present information on their products in an unbiased way.

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Accepted article

PMID 22369072

The thalidomide experience: review of its effects 50 years later

Med Clin (Barc). 2012 Jun 2;139(1):25-32. Epub 2011 Dec 15.

[Article in Spanish] Martínez-Frías ML. Source Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid. Madrid, España; Estudio Colaborativo Español de Malformaciones Congénitas, Centro de Investigación sobre Anomalías Congénitas, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, España; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, España.

Abstract

This year is the 50(th) anniversary of the discovery that the drug thalidomide causes birth defects and should therefore be considered as a teratogen. However, despite the existence of several other drugs that are also human teratogens, thalidomide continues to cause concern among health professionals as well as the general population. The objectives of this article are to make a short historical review of the discovery that this drug severely alters the embryo development, the critical period of gestation and the identification of the real effect of thalidomide. For the first time an analysis is provided to identify the type of malformations for which thalidomide really increases the risk. The proportions of the different types of malformations groups from the series of patients considered to be affected by thalidomide from the literature were compared with the proportions of the same malformations groups in non-exposed infants from the Spanish Collaborative Study of Congenital Malformation (ECEMC). The aim of the analysis was to calculate the relative frequencies of 13 groups of malformations observed in series of patients exposed to thalidomide, by comparison with the same groups of defects in 1,491 patients with limb malformations from the ECEMC consecutive newborn infants, non-exposed to thalidomide. The results showed that the groups with the most classical limb malformations attributed to thalidomide (phocomelia, thumb absence/hypoplasia) had a significantly very higher frequency in exposed cases than in the ECEMC's cases. However, cases presenting with only lower limb malformations were 3 times less frequent in thalidomide cases than in those of ECEMC. Finally, other groups presented the same frequency as those observed in the ECEMC's cases. The results of the 2 last groups, strongly suggests that they were not due to the effect of thalidomide. In addition to the short historical review of the teratogenicity risk of thalidomide, and their new therapeutic properties, it is documented that, as it happens with all other currently known human teratogens, not all malformations observed in infants prenatally exposed to thalidomide were caused by this drug. Finally, it is discussed the paradox that the «feared» thalidomide drug causing a great human drama affecting about 10,000 infants has led to a formidable contribution to the scientific knowledge, and large range of therapeutic applications. Copyright © 2011 Elsevier España, S.L. All rights reserved.

PMID 22177324

2011

Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide

Blood. 2011 Nov 3;118(18):4771-9. Epub 2011 Aug 22.


Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, Chang XB, Bjorklund CC, Fonseca R, Bergsagel PL, Orlowski RZ, Stewart AK. Source Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA.

Abstract

The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the antimyeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells, but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone, and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion, further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy.

PMID 21860026

Epidemiological surveillance of birth defects compatible with thalidomide embryopathy in Brazil

PLoS One. 2011;6(7):e21735. Epub 2011 Jul 6.

Vianna FS, Lopez-Camelo JS, Leite JC, Sanseverino MT, Dutra Mda G, Castilla EE, Schüler-Faccini L. Source Instituto Nacional de Genética Médica Populacional at Teratogen Information Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Abstract

The thalidomide tragedy of the 1960s resulted in thousands of children being born with severe limb reduction defects (LRD), among other malformations. In Brazil, there are still babies born with thalidomide embryopathy (TE) because of leprosy prevalence, availability of thalidomide, and deficiencies in the control of drug dispensation. Our objective was to implement a system of proactive surveillance to identify birth defects compatible with TE. Along one year, newborns with LRD were assessed in the Brazilian hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). A phenotype of LRD called thalidomide embryopathy phenotype (TEP) was established for surveillance. Children with TEP born between the years 2000-2008 were monitored, and during the 2007-2008 period we clinically investigated in greater detail all cases with TEP (proactive period). The period from 1982 to 1999 was defined as the baseline period for the cumulative sum statistics. The frequency of TEP during the surveillance period, at 3.10/10,000 births (CI 95%: 2.50-3.70), was significantly higher than that observed in the baseline period (1.92/10,000 births; CI 95%: 1.60-2.20), and not uniformly distributed across different Brazilian regions. During the proactive surveillance (2007-2008), two cases of suspected TE were identified, although the two mothers had denied the use of the drug during pregnancy. Our results suggest that TEP has probably increased in recent years, which coincides with the period of greater thalidomide availability. Our proactive surveillance identified two newborns with suspected TE, proving to be a sensitive tool to detect TE. The high frequency of leprosy and the large use of thalidomide reinforce the need for a continuous monitoring of TEP across Brazil.

  • Generic thalidomide is produced in Brazil by just one laboratory, under supervision of the Ministry of Health.
  • Around four million tablets of thalidomide are distributed yearly, by specific government programs, mostly for the treatment of erythema nodosum leprosum (ENL).
  • Until 2010, there was no information about the exact destination of these tablets. This lack of information can be accountable for the recent occurrence of cases of thalidomide syndrome.

1965 - Sheskin reported the effectiveness of thalidomide in the treatment of erythema nodosum leprosum (ENL), an inflammatory condition resulting from leprosy. In Brazil, thalidomide has always been available in the regions with endemic leprosy.

1998 - thalidomide was approved by the US FDA for the treatment of ENL and later, in 2006, for the treatment of multiple myeloma, under strict restrictions to prevent exposure in utero. Uhl K, Cox E, Rogan R, Zeldis JB, Hixon D, et al. (2006) Thalidomide use in the US : experience with pregnancy testing in the S.T.E.P.S. programme. Drug Saf 29: 321–329.


PMID 21754997

Thalidomide prevents the progression of peritoneal fibrosis in mice

Acta Histochem Cytochem. 2011 Apr 28;44(2):51-60. Epub 2011 Apr 21.

Arai H, Furusu A, Nishino T, Obata Y, Nakazawa Y, Nakazawa M, Hirose M, Abe K, Koji T, Kohno S.

Source Second Department of Internal Medicine, Nagasaki University School of Medicine.

Abstract

Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-β was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-β-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis.

PMID 21614166


Thalidomide: the tragedy of birth defects and the effective treatment of disease

Toxicol Sci. 2011 Jul;122(1):1-6. Epub 2011 Apr 19.

Kim JH, Scialli AR. Source ILSI Health and Environmental Sciences Institute, Washington, DC 20005, USA. jkim@hesiglobal.org

Erratum in Toxicol Sci. 2012 Feb;125(2):613.

Abstract

Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women. It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. Though the use of thalidomide was banned in most countries at that time, thalidomide proved to be a useful treatment for leprosy and later, multiple myeloma. In rural areas of the world that lack extensive medical surveillance initiatives, thalidomide treatment of pregnant women with leprosy has continued to cause malformations. Research on thalidomide mechanisms of action is leading to a better understanding of molecular targets. With an improved understanding of these molecular targets, safer drugs may be designed. The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols; the use of thalidomide as a tool in developmental biology led to important discoveries in the biochemical pathways of limb development. In celebration of the Society of Toxicology's 50th Anniversary, which coincides with the 50th anniversary of the withdrawal of thalidomide from the market, it is appropriate to revisit the lessons learned from the thalidomide tragedy of the 1960s.

  • The sensitive period during pregnancy for thalidomide effects in humans is approximately days 20–34 after fertilization (Miller and Strömland, 1999; Miller et al., 2009).

Toxicological Sciences 122, 1–6, 2011

In our article “Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease” (Toxicol Sci, 122(1): 1–6), there are inaccuracies we would like to address.

Wells et al. (2005) reported that phenytoin and not thalidomide embryopathy was increased in antioxidant enzyme-deficient mice, after glutathione depletion, or with inhibition of glutathione peroxidase or reductase. Thalidomide caused embryonic DNA oxidation in the thalidomide-susceptible rabbit species, but not in the resistant mouse species. In the p53 knockout studies that we described, benzo[a]pyrene rather than thalidomide was administered. Radiation, and not thalidomide-induced embryopathy, was observed in atm (ataxia telangiectasia mutated) mice, as reviewed by Wells et al. (2009).

The agent reported by Therapontos et al. (2009) to cause vascular disruption and limb defects in the chick embryo model was CPS49, a tetrafluorinated analogue of thalidomide and not thalidomide itself. As reported by Lee et al. (2011), fluorinated analogues of thalidomide may cause markedly different biological effects than the parent thalidomide.

PMID 21507989

mRNA distribution of the thalidomide binding protein cereblon in adult mouse brain

Neurosci Res. 2011 Jan 15. [Epub ahead of print]

Aizawa M, Abe Y, Ito T, Handa H, Nawa H.

Division of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata 951-8585, Japan.

Abstract

Cereblon is implicated in mild mental retardation and proved to bind to a teratogenic hypnotic, thalidomide. Here, we determined cereblon mRNA distributions in adult mouse brain. Almost all neurons expressed cereblon mRNA with various intensities whereas the signals in astrocytes and oligodendrocytes were modest or negligible. Intense mRNA signals were found in the hippocampus and cerebellum, especially in hippocampal pyramidal cells and Purkinje cells. Higher levels of cereblon mRNA were also detected in serotonergic and noradrenergic neurons in raphe nuclei and locus ceruleus, respectively. These observations indicate novel biological roles of cereblon in neuronal physiology and thalidomide pharmacology.


Sortable table
Region Intensity
Infralimbic cortex ++++
Cingulate cortex ++++
Other neocortex; layer V ++++
Other neocortex; other layers +++
Piriform cortex ++++
Accumbens nucleus ++
Caudate putamen ++
Lateral globus pallidus +
Pyramidal layer of the hippocampus +++++
Granular layer of dentate gyrus +++++
Habenular nucleus ++++
Paraventricular hypothalamic nucleus +++
Thalamus ++ ∼ +++
Substantia nigra compacta +++
Red nucleus, magnocellular part ++++
Raphe nuclei +++ ∼ ++++
Trigeminal nucleus +++++
Reticulotegmental nucleus of the pons ++++
Parvicellular reticular nucleus +++
Gigantocellular reticular nucleus ++++
Purkinje layer of the cerebellum +++++
Granular layer of the cerebellum ++++


Copyright © 2011. Published by Elsevier Ireland Ltd.

PMID 21241746

Teratogenic effects of thalidomide: molecular mechanisms

Cell Mol Life Sci. 2011 Jan 5. [Epub ahead of print]

Ito T, Ando H, Handa H.

Solutions Research Laboratory, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama, 226-8503, Japan, takumii@bio.titech.ac.jp.

Abstract

Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

PMID 21207098

Managing the teratogenic risk of thalidomide and lenalidomide: an industry perspective

Expert Opin Drug Saf. 2011 Jan;10(1):3-8. Epub 2010 Dec 2.

Bwire R, Freeman J, Houn F.

Abstract Celgene has developed and operated pregnancy prevention programs since 1998 with the first approval of thalidomide in the US. With the development and marketing of lenalidomide, an analog of thalidomide, the company further advanced its risk management activities, which now cover several territories across the globe. To date, the program is a success in as much as it has minimized the risk of fetal exposure and subsequent development of fetal malformations. Nonetheless, the company understands the need to provide a mechanism for intervention and remediation when at-risk behaviors are identified, and this forms an integral part of the risk management processes. The implementation of the thalidomide and lenalidomide pregnancy prevention program partners patients, healthcare professionals, regulators and the company in a spirit of shared responsibility. This paper also presents the authors' experience and perspective on the challenges of managing a pregnancy prevention program, which at its core aims at ensuring that the product's benefits outweigh the risk of fetal exposure.

PMID 21121869

Apoptosis induction by thalidomide: critical for limb teratogenicity but therapeutic potential in idiopathic pulmonary fibrosis?

Curr Mol Pharmacol. 2011 Jan 1;4(1):26-61.

Knobloch J, Jungck D, Koch A.

Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, D-50924 Cologne, Germany. juergen.knobloch@uk-koeln.de.

Abstract

Thalidomide is a powerful treatment for inflammatory and cancer-based diseases. However, its clinical use remains limited due to its teratogenic properties, which primarily affect limb development. A prerequisite for overcoming these limitations is to understand the cellular and molecular mechanisms underlying thalidomide teratogenicity, which involve induction of oxidative stress, suppression of ubiquitin-mediated protein degradation and disruption of angiogenesis. Here, we discuss the hypothesis that thalidomide-induced limb teratogenicity is primarily based on the generation of nuclear oxidative stress with subsequent induction of transient apoptosis in the outgrowing limb bud. To this end, we establish a model of the signaling network regulating cell proliferation, survival and endogenous apoptosis-induction required for correct limb outgrowth and patterning. We then summarize data showing how thalidomide interferes with this signaling network: thalidomide inhibits the activity of the redox-sensitive transcription factor NF-κB, shifts the balance of fibroblast growth factors and bone morphogenetic proteins (Bmps) towards pro-apoptotic Bmps, and suppresses Wnt/b-catenin- and Akt-dependent survival signaling in the limb bud. Consequently, prechondrogenic precursor cells that determine skeletal elements are eliminated leading to the development of truncated limbs. We further discuss the involvement of thalidomide effects on ubiquitin-mediated protein degradation and angiogenesis in the induction of apoptosis in the limb bud. Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance.

PMID: 20958261

Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B

Hum Mol Genet. 2011 Jan 15;20(2):271-85. Epub 2010 Oct 20.

Wang B, Sinha T, Jiao K, Serra R, Wang J.

Department of Cell Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Abstract

Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a. Wnt5a/Ror2 can activate multiple branches of non-canonical Wnt signaling, but it is unclear which branch(es) mediates Wnt5a/Ror2 function in limb skeletal development. Here, we provide evidence implicating the planar cell polarity (PCP) pathway as the downstream component of Wnt5a in the limb. We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges. Halving the dosage of Wnt5a in Vangl2 mutants enhances the severity and penetrance of the digit defects and causes long bone defects reminiscent of RRS, suggesting that Wnt5a and Vangl2 function in the same pathway and disruption of PCP signaling may underlie both BDB1 and RRS. Consistent with a role for PCP signaling in tissue morphogenesis, mutation of Vangl2 alters the shape and dimensions of early limb buds: the width and thickness are increased, whereas the length is decreased. The digit pre-chondrogenic condensates also become wider, thicker and shorter. Interestingly, altered limb bud dimensions in Vangl2 mutants also affect limb growth by perturbing the signaling network that regulates the balance between Fgf and Bmp signaling. Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect. These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS.

PMID 20962035

2010

Thalidomide

J Pain Symptom Manage. 2010 Oct 20.

Prommer EE, Twycross R, Mihalyo M, Wilcock A.

Mayo Clinic Arizona (E.E.P.) Scottsdale, Arizona, USA; Oxford University (R.T.) Oxford, United Kingdom; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom.

Abstract

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. The content is also available on www.palliativedrugs.com and will feature in future editions of the Hospice and Palliative Care Formulary USA and its British and Canadian counterparts. The series editors welcome feedback on the articles (hq@palliativedrugs.com).

Copyright © 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

PMID 20965689

Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia

Nat Med. 2010 Apr;16(4):420-8. Epub 2010 Apr 4.

Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Bréant C, Mathivet T, Larrivée B, Thomas JL, Arthur HM, Westermann CJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL.

Institut National de la Santé et de la Recherche Médicale U833, Collège de France, Paris, France. franck.lebrin@college-de-france.fr Comment in:

Nat Med. 2010 Apr;16(4):370-2. Nat Med. 2010 Apr;16(4):372. Gastroenterol Clin Biol. 2010 Sep;34(8-9):426-8. Abstract Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.

PMID 20364125

2009

Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC).

Rafiee P, Stein DJ, Nelson VM, Otterson MF, Shaker R, Binion DG. Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G167-76. Epub 2009 Nov 19. PMID 19926820

Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Proc Natl Acad Sci U S A. 2009 May 26;106(21):8573-8. Epub 2009 May 11.

Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N.

National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, United Kingdom.

Abstract

Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.

PMID: 19433787

http://www.pnas.org/content/106/21/8573.long

2008

Thalidomide as a multi-template for development of biologically active compounds.

Hashimoto Y. Arch Pharm (Weinheim). 2008 Sep;341(9):536-47. Review. PMID 18389516

Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects.

Cell Cycle. 2008 May 1;7(9):1121-7. Epub 2008 Feb 14.

Knobloch J, Rüther U.

Institute for Animal Developmental and Molecular Biology, Heinrich-Heine-University, Düsseldorf, Germany. juergen.knobloch@uk-koeln.de Abstract Many hypotheses have been proposed to explain the molecular mechanism of thalidomide teratogenicity, in particular regarding to limb defects. Most experimental evidence in vivo has been provided for a model that suggests the generation of oxidative stress by thalidomide with subsequent downregulation of Wnt and Akt survival pathways. As a consequence apoptosis is induced during early embryonic limb development resulting in limb truncations. Here we summarize and discuss the relevant data supporting this hypothesis. We extend this model by presenting new data demonstrating an involvement of the transcription factors Tbx5 and Sall4 in thalidomide-induced molecular pathology. Finally, we discuss a possible participation of other stress-responsive and/or pro-apoptotic transcription factors in the mechanism of thalidomide teratogenicity.

PMID 18418038

Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspase-dependent cell death

Mol Cell Biol. 2008 Jan;28(2):529-38.

Knobloch J, Schmitz I, Götz K, Schulze-Osthoff K, Rüther U.

University of Cologne, Medical Clinic III, Department of Pneumology, Kerpener Strasse 62, D-50924 Cologne, Germany. juergen.knobloch@uk-koeln.de

Abstract

Thalidomide, a drug used for the treatment of multiple myeloma and inflammatory diseases, is also a teratogen that causes birth defects, such as limb truncations and microphthalmia, in humans. Thalidomide-induced limb truncations result from increased cell death during embryonic limb development and consequential disturbance of limb outgrowth. Here we demonstrate in primary human embryonic cells and in the chicken embryo that thalidomide-induced signaling through bone morphogenetic proteins (Bmps) protects active PTEN from proteasomal degradation, resulting in suppression of Akt signaling. As a consequence, caspase-dependent cell death is stimulated by the intrinsic and Fas death receptor apoptotic pathway. Most importantly, thalidomide-induced limb deformities and microphthalmia in chicken embryos could be rescued by a pharmacological PTEN inhibitor as well as by insulin, a stimulant of Akt signaling. We therefore conclude that perturbation of PTEN/Akt signaling and stimulation of caspase activity is central to the teratogenic effects of thalidomide.

PMID: 18178729 http://www.ncbi.nlm.nih.gov/pubmed/18178729

PMCID: PMC2223408

2007

Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway

FASEB J. 2007 May;21(7):1410-21. Epub 2007 Feb 5.

Knobloch J, Shaughnessy JD Jr, Rüther U.

Institut für Entwicklungs-und Molekularbiologie der Tiere, Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.

Abstract

Thalidomide, a sedative originally used to treat morning sickness and now used to treat leprosy and multiple myeloma, is also a teratogen that induces birth defects in humans such as limb truncations and microphthalmia. However, the teratogenic mechanism of action of this drug remains obscure. Thalidomide induces limb and eye defects in the chicken embryo at an EC50 of 50 microg/kg egg wt and apoptosis in primary human embryonic fibroblasts (HEFs) at an EC50 of 8.9 microM. Using these model systems, we demonstrate by semiquantitative reverse transcriptase-polymerase chain reaction and whole-mount in situ hybridization that thalidomide-induced oxidative stress enhances signaling through bone morphogenetic proteins (Bmps). This leads to up-regulation of the Bmp target gene and Wnt antagonist Dickkopf1 (Dkk1) with subsequent inhibition of canonical Wnt/beta-catenin signaling and increased cell death as shown by trypan blue and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Thalidomide-induced cell death was dramatically reduced in HEFs and in embryonic limb buds by the use of inhibitors against Bmps, Dkk1, and Gsk3beta, a beta-catenin antagonist acting downstream of Dkk1 in the Wnt pathway. Most interestingly, blocking of Dkk1 or Gsk3beta dramatically counteracts thalidomide-induced limb truncations and microphthalmia. From this, we conclude that perturbing of Bmp/Dkk1/Wnt signaling is central to the teratogenic effects of thalidomide.

PMID 17283219

Hydrolyzed metabolites of thalidomide: synthesis and TNF-alpha production-inhibitory activity.

Chem Pharm Bull (Tokyo). 2007 Apr;55(4):651-4. Nakamura T, Noguchi T, Miyachi H, Hashimoto Y.

Institute of Molecular & Cellular Biosciences, The University of Tokyo, Japan. Abstract

Putative hydrolyzed metabolites of thalidomide were prepared and characterized, and their inhibitory activity on tumor necrosis factor (TNF)-alpha production in the human monocytic leukemia cell line THP-1 was evaluated. Alpha-(2-Carboxybenzamido)glutarimide was a more potent TNF-alpha production inhibitor than thalidomide.

PMID 17409565 Chem Pharm Bull (Tokyo).PDF

"Thalidomide (1) was developed in the 1950s as a nontoxic sedative/hypnotic drug, but was withdrawn from the market in the early 1960s because of its teratogenicity.1—5) However, it was subsequently identified as an effective agent for the treatment of multiple myeloma (MM), AIDS, Hansen’s dis- ease, and various cancers.1—5) The US Food and Drug Ad- ministration (FDA) approved it first for the treatment of ery- thema nodosum in Hansen’s disease in 1998, and then, in combination with dexamethasone, for the treatment of MM in 2006."

New cases of thalidomide embryopathy in Brazil

Birth Defects Res A Clin Mol Teratol. 2007 Sep;79(9):671-2.

Schuler-Faccini L, Soares RC, de Sousa AC, Maximino C, Luna E, Schwartz IV, Waldman C, Castilla EE. Source Federal University of Rio Grande do Sul Genetics Department; Fundacao Faculdade Federal de Ciencias Medicas, Clinical Genetics Department, Porto Alegre, Brazil. lavinia.faccini@ufrgs.br

Abstract

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.

PMID 17676592

Brazil - Teratogen Information Service (TIS)

2006

45 years later...where do we stand?

Benegbi M. 45 years later...where do we stand? Can J Clin Pharmacol. 2007 Winter;14(1):e37-9.

Li PK, Pandit B, Sackett DL, Hu Z, Zink J, Zhi J, Freeman D, Robey RW, Werbovetz K, Lewis A, Li C. A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities. Mol Cancer Ther. 2006 Feb;5(2):450-6.

2005

Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study

Gullestad L, Ueland T, Fjeld JG, Holt E, Gundersen T, Breivik K, Følling M, Hodt A, Skårdal R, Kjekshus J, Andreassen A, Kjekshus E, Wergeland R, Yndestad A, Frøland SS, Semb AG, Aukrust P.

Department of Cardiology, Rikshospitalet, 0027 Oslo, Norway. lars.gullestad@medisin.uio.no Abstract BACKGROUND: Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD).

METHODS AND RESULTS: Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-alpha, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage.

CONCLUSIONS: Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

PMID 16301340 Circulation. 2005 Nov 29;112(22):3408-14. Epub 2005 Nov 21.

1996

Thalidomide, a current teratogen in South America

Teratology. 1996 Dec;54(6):273-7.

Castilla EE, Ashton-Prolla P, Barreda-Mejia E, Brunoni D, Cavalcanti DP, Correa-Neto J, Delgadillo JL, Dutra MG, Felix T, Giraldo A, Juarez N, Lopez-Camelo JS, Nazer J, Orioli IM, Paz JE, Pessoto MA, Pina-Neto JM, Quadrelli R, Rittler M, Rueda S, Saltos M, Sánchez O, Schüler L. Source ECLAMC Departmento de Genetica, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.

Abstract

Thalidomide, mainly used for the treatment of leprosy, is a current teratogen in South America, and it is reasonable to assume that at present this situation is affecting many births in underdeveloped countries. Moreover, the potential re-marketing of thalidomide for the treatment of a large variety of diseases may extend the problem to the developed world. When the drug is available, the control of its intake during early pregnancy is very difficult since most pregnancies are unintended. The ongoing occurrence of thalidomide embryopathy cases went undetected by the ECLAMC, due to several factors: (1) low populational coverage through this monitoring system; (2) pre-existence of the teratogen with its effects present in both baseline (expected) and monitored (observed) materials; and (3) lack of a defined phenotype to be monitored. Thus, if thalidomide re-enters the market throughout the world, due to the wide range of new applications, occurrence of phocomelia alone might not be sufficient to detect its effects. By a case-reference approach, the ECLAMC registered 34 thalidomide embryopathy cases born in South America after 1965 whose birthplaces correspond to endemic areas for leprosy. Phocomelia was found in five of eleven fully described cases. Thus, phocomelia alone is neither specific nor sufficient to serve as a suitable phenotype to survey the teratogenic effects of thalidomide. Therefore, a thalidomide-like phenotype, defined as any bilateral upper and/or lower limb reduction defect of the preaxial and/or phocomelia types, should be included in the routine surveillance of birth defects in all programmes. PMID 9098920

1961

Neuropathy after intake of thalidomide (distaval)

Br Med J. 1961 Sep 30;2(5256):855-8.

FULLERTON PM, KREMER M. PMID13702560

1960

Pharmacological properties of thalidomide (alpha-phthalimido glutarimide), a new sedative hypnotic drug

Br J Pharmacol Chemother. 1960 Mar;15:111-6.

SOMERS GF.

Abstract

Thalidomide (alpha-phthalimidoglutarimide, "Distaval," "Contergan") is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses. This lack of toxicity may be due to limited absorption. The drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep. Unlike the barbiturate drugs it does not cause an initial excitation in mice, incoordination or narcosis. It potentiates the actions of other central nervous system depressants, in particular the barbiturates. Its sedative effects are counteracted by central nervous system stimulants. It has no deleterious side effects and does not affect the heart, respiration or autonomic nervous system.

PMID13832739

Research Groups

Japan

  • Hashimoto Y. - Institute of Molecular & Cellular Biosciences, The University of Tokyo, Japan.
  • Ito T, Ando H, Hiroshi Handa - Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.

Germany

  • Knobloch J, Jungck D, Koch A. - Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, D-50924 Cologne, Germany. juergen.knobloch@uk-koeln.de.
  • Knobloch J, Shaughnessy JD Jr, Rüther U. - Institut für Entwicklungs-und Molekularbiologie der Tiere, Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.

UK

  • Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N. - National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, United Kingdom.