Novel mitosenes substituted at the 6-position were synthesized for antineoplastic screening. More than 26 new compounds were made by two synthetic routes. A Nenitzescu-type synthesis provided ethyl 1-acetoxy-2,3-dihydro-5,8-dione-7-methoxy-1H-pyrrolo{1,2-a}indole-9-carboxylate. However, selective reduction of this ester could not be achieved satisfactorily. A more practical route via annelation of a commercially available indole was successful in completing the planned scheme of 6-substituted mitosene congeners. The third ring (pyrrolidine) was added by condensation of ethyl acrylate with ethyl 5-methoxyindole-2-carboxylate. After decarboxylation at position 2, the ketone at position 1 was reduced and acetylated. Then the carbon at the 9 position was introduced by Vilsmeier-Haack formylation and the quinone moiety was synthesized via a nitration, reduction, and oxidation sequence. Subsequently, the aldehyde was most satisfactorily reduced to an alcohol with sodium borohydride and the quinone was regenerated with Fremy's salt. 1-acetoxy-6-desmethyl-7-methoxymitosene was made by forming a carbamate at position 9 by treatment of the 9-alcohol with phenyl chloroformate and displacing the phenoxy group with ammonia. Other 1,6,7-substituted mitosene congeners were made using N-methylcarbamate formation via methyl isocyanate and the 9-alcohol. The 6-chloro and 6-bromo analogs were formed by treatment of the 6-H congener, 1-acetoxy-2,3-dihydro-5,8-dioxo-9-(hydroxymethyl)-7-methoxy-1H-pyrrolo{1,2-a}indole methylcarbamate, with the desired halogen in acetic acid and sodium acetate. The 7-methoxy group could be displaced by ammonia for the 6-bromo compound and by pyrrolidine for the 6-H compound to form respectively the 7-amino-6-bromo and 7-pyrrolidino-6-H 1-acetoxy-2,3-dihydro-5,8-dioxo-9-(hydroxymethyl)-1H-pyrrolo{1,2-a}indole methylcarbamates. The 6-methyl analog (1-acetoxy-7-methoxy-N-methyl-carbamoylmitosene) was made from a previously synthesized precursor. Attempted syntheses of the 6-azido and 6-amino analogs by displacing the 6-bromo substituent with sodium azide were met by gross rearrangement of the resulting adducts. Preliminary antitumor screening against P388 leukemia in mice showed these analogs to be too inactive for use as antineoplastic agents. The 6-methyl substituent was shown to be most potent in bacteriophage induction in E. coli for this series of 6-substituted mitosene analogs.

No description available.

No description available.

There is a rise of new phenomenon in drug use in the last few years. There has been increase in the incidence of new synthetic drugs, or the so-called "legal highs" and their use in the general population became more frequent. Legal highs are substances that mimic the effects of illegal drugs, but they are not controlled by the United Nations Single Convention on Narcotic Drugs of 1961 or the UN Convention on Psychotropic Substances of 1971. These substances can produce comparable risks and harms simmilar to the illegal drugs (EMCDDA, 2009c). The aim of research conducted for the purpose of this thesis is to reveal how the risks associated with the use of these products are percieved by their users, whether their legal status has any influence on the perception of their safety and how do the users minimize risks that may be associated with the use of these substances Qualitative research carried out for the needs of graduate work used data obtained by two methods. The first method was a content analysis of online discussion forums of new synthetic drugs users. 16 online discussion forums with a total number of 832 posts were analyzed. The second method were semi-structured interviews with users of new synthetic drugs. They were conducted with 9 respondents. Regarding the perception of risk, some...

After 2010, substances that have similar effects as opiate drugs and stimulant drugs started to appear in the Czech Republic as well as in other European countries and around the world, however they are not controlled by any legislation because of their "newness". The aim of this study is to evaluate whether under the current circumstances this is a problem that should be solved politically, including the assessment of its extent. The current solutions to this problem focused on its regulation shall be assessed on the basis of the results of this analysis. The thesis also aims to identify different perspectives of the drugs issue experts and to understand their involvement in the process of making the drug policy of the Czech Republic concerning these substances. The first part describes the current situation in the field of new psychoactive substances in the Czech Republic using a qualitative method of the documentary content analysis, and introduces the legislative approaches currently used at both national and international level. The research part employs the qualitative research methods (semi- structured interviews with experts in the field of drugs problems). The carried out research has found that the experts perceive new psychoactive substances as a problem whose extent however is not as intensive...

O acetato de ciproterona é um esteróide sexual sintético com atividade antiandrogênica, antigonadotrópica e progestagênica. O objetivo deste estudo foi avaliar a bioequivalência de duas marcas comerciais de comprimidos contendo 100 mg de acetato de ciproterona em voluntários sadios. O ensaio foi do tipo quantitativo direto, com delineamento aleatório, cruzado e aberto, formando-se dois grupos de voluntários, A e B. Entre as fases houve um período de \"wash out\" de 27 dias, correspondente a, no mínimo, 10 vezes o valor de meia-vida de eliminação de acetato de ciproterona. Amostras de sangue foram coletadas em tubo heparinizado até 216 horas após a administração dos produtos. A bioequivalência dos produtos foi avaliada quantificando-se o fármaco em plasma, através de metodologia bioanalítica desenvolvida e previamente validada. As curvas médias de decaimento plasmático obtidas para os produtos teste (Androsteron® 100 mg - Bergamo, lote PI0004) e referência (Androcur® 100 mg Schering, lote 14616A) foram semelhantes, da mesma forma que as médias dos parâmetros farmacocinéticos Cmax (referência: 159,05 ng/mL; teste: 170,40 ng/mL), tmax (referência: 3,59 h; teste: 3,50 h) e ASC0-t (referência: 5563,03 ngxh/mL; teste: 5453,80 ngxh/mL) e ASC0-∞ (referência: 6266,22 ngxh/mL; teste: 6218,31 ngxh/mL). No presente estudo, a análise de variância (ANOVA) realizada para avaliação do efeito de produto, grupo e período em relação aos parâmetros farmacocinéticos avaliados demonstrou ausência destes efeitos em ASC0-t e ASC0-∞ para os valores calculados com todos os picos da curva plasmática. A ANOVA indicou ainda ausência de efeito de produto e período para Cmax, mas presença de efeito grupo para este parâmetro. Entretanto a constatação do efeito grupo não significa que as formulações avaliadas não sejam bioequivalentes, apenas que há uma diferença entre os grupos de indivíduos. Os valores do intervalo de confiança 90% para a razão de Cmax, (91,0 a 117,9%), ASC0-t (88,4 a 107,8%) e ASC0-∞. (90,6 a 107,8%) encontram-se entre 80 a 125 %, intervalo proposto pelo FDA e ANVISA. Desta forma, a avaliação dos resultados obtidos permite concluir que não houve diferença significativa entre as formulações teste e referência, ou seja, as duas formulações possuem biodisponibilidades estatisticamente equivalentes, em termos de velocidade e extensão da absorção. / Cyproterone acetate (6-chloro-1β,2βα-dihydro-17-hydroxy-3\'H-cyclopropa[1,2] pregna - 1,4,6-triene-3,20-dione acetate) (CPA) is a synthetic steroid with antiandrogenic and progestogenic properties. The aim of the present study was to evaluate the bioequivalence of two cyproterone acetate formulations. The bioequivalence of cyproterone acetate 100 mg tablets was determined in healthy volunteers after a single dose in a randomized crossover study, with a 27 days washout period between the doses. Reference (Androcur®) and test (Androsteron®) products were administered to twenty-four volunteers with 200 mL water after overnight fasting. Blood samples were taken up to 216 h post dose, the plasma was separated and the concentrations of cyproterone acetate were measured using a simple and rapid chromatographic method (HPLC). The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, tmax and t(1/2)el were calculated for both formulations from plasma concentration time profiles. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands and no significant differences between the two studied formulations were found. The 90% geometric confidence intervals of the mean ratio of In-transformed Cmax, AUC0-t and AUC0-∞ values were between 91,0 and 117,9% (Cmax), 88,4 and 107,8% (AUC0-t) ando 90,6 and 107,8% (AUC0-∞), and thus within the acceptance ranges, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. In the Iight of the present study it can be concluded that the two evaluated cyproterone acetate formulations are bioequivalent in terms of the rate and extent of absorption.

Em 1968, um composto do tipo 5-nitroimidazol, o megazol, foi sintetizado por Berkelhammer e Asato e demonstrou largo espectro de ação biológica. Em 1980, pesquisadores brasileiros determinaram excelente atividade desta molécula contra o Tripanosoma cruzi, em ratos, por via oral. Constam da literatura quatro rotas para a obtenção deste fármaco, que podem ser otimizadas no tocante ao aumento da produtividade e minimização dos riscos. A nova rota, ora proposta, é uma alternativa para a síntese do megazol, realizada somente em três etapas de fácil execução, abrindo caminho para obtenção de seus análogos estruturais. / In 1968, Berkelhammer and Asato synthesized a compound of the 5-nitroimidazole group, called megazol. This compound demonstrated a high biological activity. In 1980, brazilian researchers tested the megazol in mices and they discovered an excellent activity of this against Chagas\' disease. There are four routes to synthesize these compound indicated in the literature. Actually, these routes can be optimized to achieve the yield and minimization of the risks involved in the unitary processo The new route proposed is an alternative to obtain the megazol in only three stages of easy perform. This method makes way to structural analogues of this drug.

O acetato de ciproterona é um esteróide sexual sintético com atividade antiandrogênica, antigonadotrópica e progestagênica. O objetivo deste estudo foi avaliar a bioequivalência de duas marcas comerciais de comprimidos contendo 100 mg de acetato de ciproterona em voluntários sadios. O ensaio foi do tipo quantitativo direto, com delineamento aleatório, cruzado e aberto, formando-se dois grupos de voluntários, A e B. Entre as fases houve um período de \"wash out\" de 27 dias, correspondente a, no mínimo, 10 vezes o valor de meia-vida de eliminação de acetato de ciproterona. Amostras de sangue foram coletadas em tubo heparinizado até 216 horas após a administração dos produtos. A bioequivalência dos produtos foi avaliada quantificando-se o fármaco em plasma, através de metodologia bioanalítica desenvolvida e previamente validada. As curvas médias de decaimento plasmático obtidas para os produtos teste (Androsteron® 100 mg - Bergamo, lote PI0004) e referência (Androcur® 100 mg Schering, lote 14616A) foram semelhantes, da mesma forma que as médias dos parâmetros farmacocinéticos Cmax (referência: 159,05 ng/mL; teste: 170,40 ng/mL), tmax (referência: 3,59 h; teste: 3,50 h) e ASC0-t (referência: 5563,03 ngxh/mL; teste: 5453,80 ngxh/mL) e ASC0-∞ (referência: 6266,22 ngxh/mL; teste: 6218,31 ngxh/mL). No presente estudo, a análise de variância (ANOVA) realizada para avaliação do efeito de produto, grupo e período em relação aos parâmetros farmacocinéticos avaliados demonstrou ausência destes efeitos em ASC0-t e ASC0-∞ para os valores calculados com todos os picos da curva plasmática. A ANOVA indicou ainda ausência de efeito de produto e período para Cmax, mas presença de efeito grupo para este parâmetro. Entretanto a constatação do efeito grupo não significa que as formulações avaliadas não sejam bioequivalentes, apenas que há uma diferença entre os grupos de indivíduos. Os valores do intervalo de confiança 90% para a razão de Cmax, (91,0 a 117,9%), ASC0-t (88,4 a 107,8%) e ASC0-∞. (90,6 a 107,8%) encontram-se entre 80 a 125 %, intervalo proposto pelo FDA e ANVISA. Desta forma, a avaliação dos resultados obtidos permite concluir que não houve diferença significativa entre as formulações teste e referência, ou seja, as duas formulações possuem biodisponibilidades estatisticamente equivalentes, em termos de velocidade e extensão da absorção. / Cyproterone acetate (6-chloro-1β,2βα-dihydro-17-hydroxy-3\'H-cyclopropa[1,2] pregna - 1,4,6-triene-3,20-dione acetate) (CPA) is a synthetic steroid with antiandrogenic and progestogenic properties. The aim of the present study was to evaluate the bioequivalence of two cyproterone acetate formulations. The bioequivalence of cyproterone acetate 100 mg tablets was determined in healthy volunteers after a single dose in a randomized crossover study, with a 27 days washout period between the doses. Reference (Androcur®) and test (Androsteron®) products were administered to twenty-four volunteers with 200 mL water after overnight fasting. Blood samples were taken up to 216 h post dose, the plasma was separated and the concentrations of cyproterone acetate were measured using a simple and rapid chromatographic method (HPLC). The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, tmax and t(1/2)el were calculated for both formulations from plasma concentration time profiles. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands and no significant differences between the two studied formulations were found. The 90% geometric confidence intervals of the mean ratio of In-transformed Cmax, AUC0-t and AUC0-∞ values were between 91,0 and 117,9% (Cmax), 88,4 and 107,8% (AUC0-t) ando 90,6 and 107,8% (AUC0-∞), and thus within the acceptance ranges, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. In the Iight of the present study it can be concluded that the two evaluated cyproterone acetate formulations are bioequivalent in terms of the rate and extent of absorption.

Em 1968, um composto do tipo 5-nitroimidazol, o megazol, foi sintetizado por Berkelhammer e Asato e demonstrou largo espectro de ação biológica. Em 1980, pesquisadores brasileiros determinaram excelente atividade desta molécula contra o Tripanosoma cruzi, em ratos, por via oral. Constam da literatura quatro rotas para a obtenção deste fármaco, que podem ser otimizadas no tocante ao aumento da produtividade e minimização dos riscos. A nova rota, ora proposta, é uma alternativa para a síntese do megazol, realizada somente em três etapas de fácil execução, abrindo caminho para obtenção de seus análogos estruturais. / In 1968, Berkelhammer and Asato synthesized a compound of the 5-nitroimidazole group, called megazol. This compound demonstrated a high biological activity. In 1980, brazilian researchers tested the megazol in mices and they discovered an excellent activity of this against Chagas\' disease. There are four routes to synthesize these compound indicated in the literature. Actually, these routes can be optimized to achieve the yield and minimization of the risks involved in the unitary processo The new route proposed is an alternative to obtain the megazol in only three stages of easy perform. This method makes way to structural analogues of this drug.

New synthetic drugs are a new phenomenon that is expanding in many countries. NSD mimic the effects of traditional drugs phenomenological, but retain the hallmark of legal substances. NSD legal status is due to the fact that theses new substances are controlled by the United Nations Single Convention on Narcotic Drugs of 1961 or the UN Convention on Psychotropic Substances, 1971. To the Czech Republic this trend came somewhat later than in neighboring countries, and especially in 2010, when sales NSD was mainly in shops. This sale was completed in April 2011 becouse of entering 33th NSD to the list of psychotropic and narcotic substances and moved mostly to the internet. NSD composition is often changing, due to disabling preparatory material, it follows that the risks associated with the use of NSD are unpredictable. The research objective of this study is to determine the acquisition and distribution of NSD between problem drug users and also to map the most widely used NSD among this population.The main purpose of the research is to bring knowledge (as it's called, how it look, what it contains, where and from whom it receives, how much it costs). The survey was made up of semi-structures interviews (qualitative part) and structured questionnaires (quantitative part). Respondents were selected...