Nous étudions les effets de la thalidomide chez le rat Sprague-Dawley.1- Nous administrons la thalidomide per os pendant dix semaines à des mâles adultes et les accouplons â des femelles non-traitées à intervalles définis. Les rejetons, issus de mâles traités pendant 2 semaines à 10 mg de thalidomide par jour et accouplés à des femelles vierges non-traitées, présentent un plus grand nombre de malformations. Toutes les malformations observées, se situent au niveau de la jonction, des os du crâne: frontal, pariétaux, occipital. 2- Chez des femelles adultes conçues par des mâles traités, à 10 mg et à 2.5 mg de thalidomide de 2 à 10 semaines, nous constatons une diminution de la réponse ovarienne â une stimulation de gonadotrophine exogène pour les femelles des deux groupes et une augmentation du poids des ovaires pour les femelles conçues par les mâles traités à 10 mg de thalidomide. 3- Chez les rejetons des femelles traitées per vaginam le 11e jour de gestation, à 10 mg de thalidomide, nous remarquons des malformations de types divers (hématome, malformations au niveau des membres, de la tête, etc.). 4- Chez les femelles adultes traitées le 11e jour de gestation, à 0.5 mg de thalidomide, et chez celles traitées le 1er jour de gestation, à 50 mg de thalidomide et à 0.5 mg de thalidomide, nous notons un accroissement du nombre de sites de résorption. 5- Lorsque nous traitons des femelles adultes, à 50 mg de thalidomide et à 2.5 mg de thalidomide pendant 20 jours, nous remarquons que le médicament ne produit aucun effet sur le cycle estrus. Par contre, nous observons une diminution dans le nombre de corps jaunes nouvellement formés.

Despite the many side effects of Thalidomide, (e.g. phocomelia and peripheral neuropathy), the drug is still used for the treatment of multiple myeloma (MM) and several other debilitating conditions. Regardless of the strict controls on Thalidomide use and distribution, several babies with Thalidomide embryopathy have been born in the last two decades. Most of these babies were from Brazil and Africa, where the drug is administered for leprosy treatment. I have been working with several structural analogs of Thalidomide to identify non or reduced teratogenic versions, negating the risk of embryonic exposure. I have developed several embryological models to screen compounds for inflammatory and teratogenic properties. I have shown Pomalidomide (an established Thalidomide analog), at potently anti-inflammatory doses, is non-anti-angiogenic, non-teratogenic and non-neurotoxic. This contrasts with Lenalidomide (a Thalidomide analog in clinical use for MM with reportedly reduced side-effects), which I have shown to be anti-angiogenic, teratogenic and neurotoxic. Furthermore, I have uncovered molecular differences between Lenalidomide and Pomalidomide that facilitates their different effects. I have also characterised the teratogenic properties of two potent anti-cancer drugs. This has allowed me to compare and contrast their functions with other Thalidomide analogs and shed further light on potential molecular targets of Thalidomide. Finally, one of the outstanding questions to be resolved in Thalidomide embryopathy is how the drug causes phocomelia (loss of proximal elements). I have examined this by using classical limb embryology transplantation techniques to experimentally induce phocomelia and analyse the cell biology underlying this defect. I have correlated changes in the signalling environment to the origins of phocomelia. I further show that phocomelia arises slightly later in development than previously thought.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Reproduction de : Thèse d'exercice : Médecine. Dermatologie-Vénéréologie : Nantes : 2008. / Bibliogr.

The adverse consequences of the use of thalidomide in the 1950s and 1960s by pregnant women, instigated law reform in the United Kingdom and Europe, in relation to product liability and the regulation of medicinal products. In this Thesis, it is suggested that a legislative framework should balance three elements: consumer safety, legal redress and pharmaceutical innovation. Chapter Three examines the development of the legislative framework in the United Kingdom following thalidomide and considers the impact of the Medicines Act 1968, the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994 and the Consumer Protection Act 1987, together with European legislation, on medicinal products. This Chapter also examines the role of regulatory bodies such as the Medicines Control Agency, the Committee on Safety of Medicines, the European Agency for the Evaluation of Medicinal Products and the Committee on Proprietary Medicinal Products. Chapter Four analyses the three above mentioned elements and, in particular, discusses: the centralised and decentralised licensing procedures; the definition of "relevant medicinal product"; the regulation of homeopathic products, herbal products and medical devices; conflicts of interest; transparency of licensing procedures; the legal status of medicinal products; promotion by the pharmaceutical industry; information supplied to patients; pharmacovigilance; and the development risks defence. The Author concluded that the legislative framework had struck an appropriate (albeit imperfect) balance between the elements of pharmaceutical innovation, consumer safety and legal redress. The Author further concluded that issues such as patents, prescribing errors and legal aid, which are outwith the control of the Medicines Act 1968 and the Consumer Protection Act 1987, impact on the balance of these three elements. In the future, the Author suggested that research should be conducted in areas such as transparency of regulatory action, the regulation of herbal products, and the improvement of prescribing and dispensing practices.

Made available in DSpace on 2014-06-11T19:35:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-08Bitstream added on 2014-06-13T19:05:32Z : No. of bitstreams: 1 putinatti_msma_dr_botfm.pdf: 533183 bytes, checksum: fbfe09d085cc95aa97f047c6dcf90273 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A hanseníase é uma doença crônica que pode ter seu curso alterado por episódios reacionais do tipo 1 e do tipo 2 ou de eritema nodoso hansênico (ENH) . A talidomida é a medicação de eleição para controle do episódio de ENH desde 1965. No entanto, esses episódios podem se apresentar de forma repetitiva, com consequentes danos ao paciente. Com o intuito de se evitar esses episódios, após o controle dos mesmos com a dose tradicional, utilizou-se a dose de 100mg/d, por um período de seis meses, com acompanhamento por outros seis meses após a suspensão da talidomida. Foram avaliados 42 pacientes multibacilares (MB), 39 (92,85%) da forma virchoviana (V) e três (7,15%) da dimorfa (D), que apresentaram ENH, quer fosse o primeiro episódio ou de repetição. Quanto ao sexo 33 (78,6%) do masculino e nove (21,4%) do feminino. As idades variaram de 18 a 84 anos, com predomínio acima de 49 anos. Observou-se que 100% dos pacientes não apresentaram episódio reacional durante o uso dessa dose de talidomida. Após a suspensão, durante o período de observação clinica, 33 (78,6%) dos pacientes não apresentaram episódio reacional e apenas nove (21,4%), todos da forma virchoviana, o apresentaram, de forma leve, sem outros sinais e sintomas, controlados apenas com anti-inflamatórios não hormonais, não sendo necessária a reintrodução da talidomida. Não foram observados efeitos adversos da droga. Os autores sugerem o uso da talidomida, na dose de 100mg/dia como manutenção, que se mostrou efetiva, impedindo a repetição dos episódios reacionais tipo 2 / Hansen’s disease is a chronic disease that can have its course interrupted by reactional episodes of type 1 and type 2 or ENL. Thalidomide is the election medication for the control of ENL episodes since 1965. However, these episodes can happen repeatedly with consequent damages to the patient. In order to avoid these episodes, after controlling them with the traditional dosage, an extra dose of 100mg/d was used in a period of six months, with attendance during other six months after suspending thalidomide. A total of 42 MB patients have been evaluated, 39 (92,85%) of type V and 3 (7,15%) of type D, that presented ENL, whether first episode or repeatedly. To mention their gender, 33 (78,6%) were male and 9 (21,4%) were female. The ages varied between 18 to 84 years old, but most were older then 49. It has been observed that 100% of patients did not present reactional episode during the usage of this dosage of thalidomide. After supension, during the period of clinic observation, 33 (78,6%) patients did not present reactional episode and only 9 (21,4%) patients, both with lepromatous type, presented it, in a light form, with no other signs and symptoms, controlled only with non hormonal anti-iflammatories, showing no need for thalidomide reintroduction. No adverse effect has been observed. The authors suggest the usage of thalidomide, in doses of 100mg/d for maintenance, which they showed to be effective, avoiding the repetition of the reactional episodes of type 2

The purpose of this investigation is to determine if differences exist between four inbred strains of mice in susceptibility to the drug thalidomide.

Orientador: Joel Carlos Lastoria / Banca: Hamilton Ometto Stolf / Banca: Vidal Haddas Junior / Banca: Marilda Aparecida Milanez Morgado de Abreu / Banca: Ivander Bastazini / Resumo: A hanseníase é uma doença crônica que pode ter seu curso alterado por episódios reacionais do tipo 1 e do tipo 2 ou de eritema nodoso hansênico (ENH) . A talidomida é a medicação de eleição para controle do episódio de ENH desde 1965. No entanto, esses episódios podem se apresentar de forma repetitiva, com consequentes danos ao paciente. Com o intuito de se evitar esses episódios, após o controle dos mesmos com a dose tradicional, utilizou-se a dose de 100mg/d, por um período de seis meses, com acompanhamento por outros seis meses após a suspensão da talidomida. Foram avaliados 42 pacientes multibacilares (MB), 39 (92,85%) da forma virchoviana (V) e três (7,15%) da dimorfa (D), que apresentaram ENH, quer fosse o primeiro episódio ou de repetição. Quanto ao sexo 33 (78,6%) do masculino e nove (21,4%) do feminino. As idades variaram de 18 a 84 anos, com predomínio acima de 49 anos. Observou-se que 100% dos pacientes não apresentaram episódio reacional durante o uso dessa dose de talidomida. Após a suspensão, durante o período de observação clinica, 33 (78,6%) dos pacientes não apresentaram episódio reacional e apenas nove (21,4%), todos da forma virchoviana, o apresentaram, de forma leve, sem outros sinais e sintomas, controlados apenas com anti-inflamatórios não hormonais, não sendo necessária a reintrodução da talidomida. Não foram observados efeitos adversos da droga. Os autores sugerem o uso da talidomida, na dose de 100mg/dia como manutenção, que se mostrou efetiva, impedindo a repetição dos episódios reacionais tipo 2 / Abstract: Hansen's disease is a chronic disease that can have its course interrupted by reactional episodes of type 1 and type 2 or ENL. Thalidomide is the election medication for the control of ENL episodes since 1965. However, these episodes can happen repeatedly with consequent damages to the patient. In order to avoid these episodes, after controlling them with the traditional dosage, an extra dose of 100mg/d was used in a period of six months, with attendance during other six months after suspending thalidomide. A total of 42 MB patients have been evaluated, 39 (92,85%) of type V and 3 (7,15%) of type D, that presented ENL, whether first episode or repeatedly. To mention their gender, 33 (78,6%) were male and 9 (21,4%) were female. The ages varied between 18 to 84 years old, but most were older then 49. It has been observed that 100% of patients did not present reactional episode during the usage of this dosage of thalidomide. After supension, during the period of clinic observation, 33 (78,6%) patients did not present reactional episode and only 9 (21,4%) patients, both with lepromatous type, presented it, in a light form, with no other signs and symptoms, controlled only with non hormonal anti-iflammatories, showing no need for thalidomide reintroduction. No adverse effect has been observed. The authors suggest the usage of thalidomide, in doses of 100mg/d for maintenance, which they showed to be effective, avoiding the repetition of the reactional episodes of type 2 / Doutor

nÃo hà / Uma formulaÃÃo de talidomida comprimido 100mg foi avaliada quanto a sua biodisponibilidade (Talidomida, FundaÃÃo Ezequiel Dias - FUNED) em 24 voluntÃrios saudÃveis do sexo masculino. O estudo realizado foi aberto, randomizado, cruzado, com dois tratamentos, dois perÃodos (duas sequÃncias), nos quais os voluntÃrios recebem, em cada perÃodo distinto, 200mg ou 400mg da talidomida com intervalo de sete dias entre os internamentos. O plasma foi obtido de um intervalo de 36 horas. As concentraÃÃes de talidomida foram analisadas por combinaÃÃo de cromatografia lÃquida de alta eficiÃncia (HPLC) acoplada à espectrometria de massas (MS-MS), com ionizaÃÃo em electrospray positivo (MRM). Os dados farmacocinÃticos (mÃdia  desvio padrÃo) obtidos para as formulaÃÃes contendo talidomida de 200mg e 400mg foram 12663,54  2123,99 e 23056,11  3437,08ng*h/mL para AUC0-24, 13282,84  2065,91 e 26292,67  4187,85ng*h/mL para AUC0-∞, 861,58  187,30 e 1131,63  266,93ng/mL para CmÃx, 4,52  1,53 e 6,88  4,71h para TmÃx, 6,89  1,44 e 11,01  4,36 h para t1/2, 0,10  0,02 e 0,07  0,03 1/h para Ke, respectivamente. A comparaÃÃo dos parÃmetros farmacocinÃticos, nas doses de 200 e 400mg, apresentou curvas proporcionais. Quando comparado os parÃmetros farmacocinÃticos deste estudo e os encontrados nos estudos de TEO et al., 1999, NOORMOHAMED et al., 1999 e PAGANOTTO, 2002 foi evidenciado que a formulaÃÃo FUNED apresenta absorÃÃo menor e mais lenta que as demais / formulation of thalidomide 100mg tablet was evaluated for its bioavailability (Thalidomide, FundaÃÃo Ezequiel Dias - FUNED) in 24 healthy male volunteers. The study conducted was open, randomized, with two treatments, and with a two-period crossover design, during which the volunteers were administered 200mg or 400mg of thalidomide with a seven day washout period. Plasma was obtained over a 36h interval. The thalidomide concentrations were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using selected daughter ion monitoring (MRM). The pharmacokinetic data (mean  standard deviation) obtained from the formulations containing thalidomide 200mg and 400mg were 12663.54  23056.11 2123.99 and 3437.08ng * h/mL for AUC0-24, 13282.84  2065.91 and 26292.67  4187.85ng * h/mL for AUC0-∞, 861.58  187.30 and 1131.63  266.93ng/mL for CmÃx, 4.52  1.53 and 6.88  4.71h to TmÃx, 6.89  1.44 and 11.01  4.36h to t1/2, 0.10  0.02 and 0.07  0.03 1/h for Ke, respectively. The comparison between pharmacokinetic parameters, at doses of 200 and 400mg, presented proportional curves. When comparing the pharmacokinetic parameters of this study and those found in studies of TEO et al., 1999, NOORMOHAMED et al., 1999 and PAGANOTTO, 2002 it was observed that the FUNED formulation presents smaller and slower absorption than the others

It is now well established that certain chemical compounds, administered to animals in early pregnancy, can adversely influence the development of the fetus, resulting in congenital malformations. Recently, it bas been shown that thalidomide, a sedative drug, may induce skeletal defects in the offspring of treated females when administered in the early stages of pregnancy. McColl, Globus and Robinson (1963) reported that certain skeletal defects could be produced in the offspring of Sprague-Dawley rats following chronic oral administration of thalidomide. Notable among the defects produced were malfomations of the sternum. [...]