ESTRATÉGIAS DE ENGENHARIA DE CRISTAIS NA SÍNTESE DE CO-CRISTAIS DO FÁRMACO ANTI-HIV EFAVIRENZ

Introdução e Objetivos: Efavirenz, um fármaco anti-retroviral de primeira linha, inibidor nãonucleosídeoda transcriptase reversa do vírus HIV, possui poucos dados sobre sua estruturacristalina, constando na literatura apenas dois co-cristais, sintetizados por Desiraju ecolaboradores (2010)1. Com base na escassez de dados sobre sua forma cristalina, utilizamos asestratégias de engenharia de cristais com o objetivo de obter novos co-cristais de efavirenz, atravésda substituição do co-cristalizante 4,4-bipiridina pelo trans-1,2-bis(4-piridil)etileno (BPE) e pelo1,2-bis(4-piridil)etano (BPA). Métodos: Os cristais foram obtidos a partir da evaporação lenta desolventes, presentes em soluções as quais continham dissolvidos o fármaco e o um agente cocristalizante,ambos em pó. Um único cristal, de cada sistema, foi escolhido e a sua estruturamolecular foi determinada por difração de raios X em monocristal, através do difratômetro APEXII. Resultados e Discussões: Os co-cristais de efavirenz cristalizaram no grupo espacial P1 esistema cristalino triclínico, com duas moléculas do fármaco e uma molécula do co-cristalizantena unidade assimétrica. Nos dois co-cristais, o fármaco atua como doador de ligação dehidrogênio e o co-cristalizante como receptor, originando uma organização em colunas.Conclusão: Presume-se que os cristais obtidos apresentem melhores propriedades físicoquímicas,sendo necessários testes de solubilidade e biodisponibilidade para comprová-los

Salts of the anti-HIV drug lamivudine with phthalic and salicylic acids

Salts of the anti-HIV drug lamivudine, with phthalic acid and salicylic acid as counterions, were investigated in this study. Neither the packing of the (lamivudine)(+)(phthalic acid)(-) ion pairs nor the conformation of the lamivudine moiety itself were similar to those found in other multicomponent molecular salts of the drug, such as hydrogen maleate and saccharinate ones, even though all three salts crystallize in the same P2(1)2(1)2(1) orthorhombic space group with similar unit cell metrics. Lamivudine salicylate assumes a different crystal structure to those of the hydrogen maleate and saccharinate salts, crystallizing in the P2(1) monoclinic space group as a monohydrate whose (lamivudine)(+)(salicylic acid)(-) ion pair is assembled through two hydrogen bonds with cytosine as a dual donor to both oxygens of the carboxylate, such as in the pairing of lamivudine with a phthalic acid counterion. In lamivudine salicylate monohydrate, the drug conformation is related to the hydrogen maleate and saccharinate salts. However, such a conformational similarity is not related to the intermolecular interaction patterns. Lamivudine and water molecules alternate into helical chains in the salicylate salt monohydrate.Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) [472623/2011-7 - Universal 14/2011

Síndrome de Seckel: relato de caso de uma rara condição genética / Seckel's Syndrome: case report of a rare genetic condition

O presente artigo objetivou relatar o caso clínico de uma paciente, sabidamente portadora de Síndrome de Seckel, em acompanhamento no ambulatório de endocrinologia e metabologia para avaliação de seu desenvolvimento. Trata-se de um estudo descritivo, do tipo relato de caso, que visou analisar as principais características clínicas apresentadas pela criança em questão e estabelecer comparativos com a literatura disponível até o momento. A paciente apresentou baixa estatura, baixo peso e dismorfismos clássicos desta alteração genética como nanismo, fronte curta, nariz proeminente com ponte e dorso elevados, face plana, orelhas pequenas e normoimplantadas e clinodactilia de 5 dedos. As manifestações evidenciadas neste relato de caso se assemelham àquelas retratadas na maioria dos estudos publicados. Ressalta-se o papel fundamental empenhado pelo conhecimento da doença, sobretudo no que tange à realização precoce do diagnóstico e ao estabelecimento do manejo multidisciplinar aos pacientes portadores da síndrome

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz

Submitted by Luciana Ferreira ([email protected]) on 2014-09-30T15:22:16Z No. of bitstreams: 2 Melo, Ariane Carla Campos de-2013-dissertação.pdf: 4034937 bytes, checksum: 463f8b0f4d2e9a65e273d336d96f0691 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)Approved for entry into archive by Luciana Ferreira ([email protected]) on 2014-09-30T15:24:53Z (GMT) No. of bitstreams: 2 Melo, Ariane Carla Campos de-2013-dissertação.pdf: 4034937 bytes, checksum: 463f8b0f4d2e9a65e273d336d96f0691 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)Made available in DSpace on 2014-09-30T15:24:53Z (GMT). No. of bitstreams: 2 Melo, Ariane Carla Campos de-2013-dissertação.pdf: 4034937 bytes, checksum: 463f8b0f4d2e9a65e273d336d96f0691 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-08-02Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqLamivudine and Efavirenz are anti-HIV drug largely used as, respectively a non-nucleoside and a nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. During the tests to obtain co-crystals of efavirenz with lamivudine it was obtained a novel crystalline phase, the polymorph of the hydrochloride salt of lamivudine. The structural and conformational analysis of this crystal modification showed that this keeps similarities, in intramolecular and intermolecular level, respectively with lamivudine hydrochloride and lamivudine hydrochloride monohydrate. Based on the intermolecular analysis and packing efficiency is expected that the polymorph of the hydrochloride salt of lamivudine is more soluble than the anhydrous phase. There are few reports on efavirenz solid state structures and behaviors. Crystal engineering strategies have not been well-exploited for this drug. In this sense, we delineate our synthesis strategy from the structural comparison and possibility of formation of intermolecular interactions patterns similar to those observed in the cocrystal of efavirenz and 4,4’-bipyridine. Two 4,4’-bipyridine-like compounds whose heterocycles are spaced by either an ethylene and an ethane moiety were cocrystallized together with efavirenz into solid state forms isostructural with respect to that of the drug cocrystal with 4,4’-bipyridine. The formation of a three-molecule entity based mainly on the hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. The introduction of spacer groups in the coformers has altered the pattern of weak non-classical hydrogen bonds of the type C— H· · ·O. This intriduction was also related to the formation of a π-π stacking interaction between pyridyl rings of the ethane-spaced conformer. Furthermore, a polymorphic form of efavirenz with only one molecule in the asymmetric unit is reported for the first time here. This polymorph crystallizes in the monoclinic system and space group C2, strictly similar to formLamivudina e Efavirenz são fármacos anti-VIH utilizados respectivamente como um inibidor não nucleosídeo da transcriptase reversa e inibidor nucleosídeo da transcriptase reversa como parte de terapias anti-retrovirais. Durante os ensaios destinados a obtenção dos co-cristais de efavirenz com lamivudina obteve-se uma fase cristalina inédita, o polimorfo do cloridrato de lamivudina. As análises conformacionais e estruturais desta modificação cristalina revelaram que a mesma guarda semelhanças em nível intramolecular e intermolecular, respectivamente com o cloridrato de lamivudina e com o cloridrato monohidratado de lamivudina. Baseada na análise intermolecular e na eficiência do empacotamento espera-se que o polimorfo do cloridrato de lamivudina seja mais solúvel que a fase anidra. Existem poucos registros de comportamento e estruturas da fase sólida do efavirenz. Estratégias de engenharia de cristais não têm sido bem exploradas com esse fármaco. Nesse sentindo, delineamos nossa estratégia de síntese a partir da comparação estrutural e possibilidade de formação de padrões de interações intermoleculares similares àquelas observadas no cocristal de efavirenz com 4,4’ - bipiridina. Dois compostos semelhantes a 4,4’- bipiridina, BPE e BPA, cujos heterociclos são respectivamente separados por um grupo etileno respectivamente e um grupo etano cristalizaram com o efavirenz em formas sólidas isoestruturais aquela obtida com a 4,4’- bipiridina. A formação de uma entidade tri-molecular baseada principalmente em doações de ligações de hidrogênio de duas moléculas de efavirenz para ambos os nitrogênios piridinícos de cada unidade do co-cristalizante foi mantida nos três cocristais de efavirenz. A introdução de grupos espaçadores nos co-cristais alterou o padrão das ligações de hidrogênio do tipo C—H· · ·O. A introdução destes grupos também está relacionada com a formação de interações do tipo π-π entre os anéis de piridil do cocristalizante espaçado com etano. Além disso, uma forma polimórfica do fármaco efavirenz com apenas uma molécula na unidade assimétrica é relatada pela primeira vez aqui. Este polimorfo, forma V, cristaliza no sistema monoclínico e grupo espacial C2, e estritamente similar à forma V

Preparo de novos complexos de Ru(II) com ligantes mistos como agentes fotocitotóxicos

Exportado OPUSMade available in DSpace on 2019-08-11T15:04:08Z (GMT). No. of bitstreams: 1 tese_11.09.2017_fimmmm___ariane_carla.pdf: 21023034 bytes, checksum: 370ec8e59fdd993d144b48304400b52b (MD5) Previous issue date: 4Uma das aplicações mais importantes de complexos metálicos é no tratamento do câncer. O aparecimento de resistência celular e os efeitos colaterais aos medicamentos atualmente disponíveis têm incentivado a pesquisa de novos compostos. Neste trabalho, sintetizamos onze complexos inéditos de Ru(II) do tipo [RuLL'2]PF6, onde L = sulfametizol (smz), sulfametoxazol (smx), sulfassalazina (ssz), sulfametoxipiridazina (smp), sulfapiridina (spd) ou hidrazida do ácido 2-tiofenocarboxílico (shyd), L' = 2,2'- bipiridina (bpy) ou 1,10-fenantrolina (phen). Os complexos foram caracterizados por análise elementar, condutimetria, temperatura de decomposição, espectroscopias no UV-vis e IV, RMN de 1H, espectrometria de massas (ESI-MS). Os complexos [Ru(bpy)2smp](PF6) (1) e [Ru(phen)2smp](PF6) (2) tiveram a estrutura determinada por difração de raios X de monocristal. Em todos os complexos a geometria em torno do íon metálico é octaédrica distorcida. Nos complexos de spd, smz, smx e smp, o Ru(II) está coordenado às sulfas através do nitrogênio sulfonamídico desprotonado e do nitrogênio do anel heterocíclico; nos complexos de ssz o rutênio está coordenado aos oxigênios docarboxilato bidentado; e no complexo da shyd, ao oxigênio da amida e ao nitrogênio da amina. A esfera de coordenação é completada por dois nitrogênios heterocíclicos das a,a-diiminas. Os complexos ligam-se à BSA por mecanismo estático com constantes de ligação variando de 104 a 106. O efeito dos complexos no crescimento de células de leucemia mielóide crônica foi avaliado. Todos os complexos possuem atividade citotóxica significativa e superior à dos ligantes livres. Os complexos 1 e 2 foram os mais ativos. As atividades fotocitotóxicas dos complexos 1, 2, [Ru(bpy)2smz](PF6) (3), [Ru(phen)2smz](PF6) (4), [Ru(bpy)2ssz](PF6) (9) e [Ru(phen)2ssz](PF6) (10) foram investigadas. A exposição à luz UV-A por 5 minutos induziu um aumento na atividade citotóxica dos complexos, com aumento de cerca de 100 vezes para o complexo 2. Os complexos 1 e 2 clivam o ADN de plasmídeo após irradiação com luz UV-A. A substituição de phen por bpy resultou na diminuição do efeito citotóxico e na clivagem de ADN. Os complexos 1 e 2 ligam-se ao CT-ADN com os valores de K = 2,8 × 104 mol L-1 e 2,5 × 105 mol L-1, respectivamente. Os complexos 1, 2, 3, 4, 9 e 10 interagem com o domínio regulatório SH3 da proteína c-Abl, que é responsável pelo desenvolvimento de leucemia mieolóide crônica. As constantes de ligação, determinadas por espectrofluorimetria, foram 1,50 × 105, 2,50 × 105, 9,78 × 103, 7,99 × 106, 4,16 × 104 e 4,02 × 105 L mol-1 para os complexos 1, 2, 3, 4, 9 e 10, respectivamente. Estudos da interação do complexo 2 com o domínio Abl-SH3 mostraram, através dos espectros de RMN, que os resíduos mais afetados foram T79, G97, W99 e Y115.One of the most important uses of metal compounds is in the treatment of cancer. The appearance of cellular resistance and the side effects associated to the known drugs have stimulated the search for new compounds. In this work, we have synthesized novel ternary complexes of Ru(II) with N-heterocyclic ligands. Eleven complexes of Ru(II) oftype [RuLL2]PF6, in which L = sulfamethizole (smz), sulfamethoxazole (smx), sulfasalazine (ssz), sulfamethoxypyridazine (smp), sulfapyridine (spd), or 2-thiophenecarboxylic acid hydrazide (shyd), L = 2,2-bipyridine (bpy) or 1,10-phenanthroline (phen) were prepared. The complexes were characterized by elemental and conductivity analyses, decomposition temperature, UV-vis, 1H NMR, and IR spectroscopies, electrospray ionization mass spectrometry (ESI-MS). The structures of[Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2) were determined by single crystal X-ray diffraction. In all complexes, the geometry around the metal ion is a distorted octahedron. In the complexes with smz, smx, spd and smp, Ru(II) is coordinated to the sulfa via the sulfonamidic nitrogen and the nitrogen of the heterocyclic ring; in the complexes with ssz Ru(II) is coordinated to the carboxylate as a chelating ligand; and inthe complex with shyd via the terminal nitrogen and the carbonyl oxygen. Two heterocyclic nitrogens of the aa-diimines complete the coordination sphere. The interactions between the Ru (II) complexes and bovine serum albumin (BSA) were investigated by fluorescence spectroscopy at pH 7.3. The experimental data indicate that both complexes bind to BSA by a static mechanism. The complexes bind to BSA with binding constants ranging from 104 to 106. The effect of complexes in the growth of chronic myelogenous leukemia cells was investigated. All complexes exhibit significant cytotoxic activity and higher than those of the corresponding free ligands. The photocytotoxic activity of the complexes 1, 2 [Ru(bpy)2smz](PF6) (3), [Ru(phen)2smz](PF6) (4), [Ru(bpy)2ssz](PF6) (9) and [Ru(phen)2ssz](PF6) (10) was also investigated. UV-light exposure for 5 min increases cytotoxicity of all complexes, withan increase of approximately 100 times in the case of 2. Complexes 1 and 2 cleave supercoiled DNA after UV light irradiation but not in dark conditions. Complexes 1 and 2 bind to CT-DNA with the values of K = 2.8 × 104 mol L-1 and 2.5 × 105 mol L-1, respectively. Complexes 1, 2, 3, 4, 9 and 10 interact with the regulatory domain SH3 of the c-Abl protein, which is responsible for the development of chronic myeloid leukemia. The binding constants, determined by spectrofluorimetry, were 1.50 × 105,2.50 × 105, 9.78 × 103, 7.99 × 106, 4.16 × 104 and 4.02 × 105 L mol-1 for complexes 1, 2, 3, 4, 9 and 10, respectively. NMR studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99 and Y115

Toward Novel Solid-State Forms of the Anti-HIV Drug Efavirenz: From Low Screening Success to Cocrystals Engineering Strategies and Discovery of a New Polymorph

Efavirenz is a first-line anti-HIV drug largely used as a non-nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. However, there are few reports on its solid-state structures and behaviors. Besides that, crystal engineering strategies have not been well-exploited for this drug and screening methods have been low promising as a source of new solid forms. To the best of our knowledge, only two efavirenz cocrystals have been reported thus far. On the basis of one of the two known cocrystals, namely, that with 4,4′-bipyridine, here we have used a rational approach for coformer selection and prediction of structurally defined multicomponent molecular crystals. Two 4,4′-bipyridine-like coformers, whose heterocycles are spaced by either an ethylene or an ethane moiety, were cocrystallized together with efavirenz into solid-state forms isostructural with respect to that of the drug cocrystal with the antecedent coformer. The formation of a three-molecule supramolecular entity based mainly on the NH hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. Nevertheless, the introduction of the spacer groups in the coformers has altered the pattern of weak nonclassical hydrogen bonds of the type C–H···O and was also related to the formation of a π–π stacking interaction between pyridyl rings of the ethane-spaced coformer. In addition, a polymorphic form of the drug with only one molecule in the asymmetry unit of a <i>C</i>-centered monoclinic lattice is reported for the first time here. It resembles a known orthorhombic form also with <i>Z</i>′ = 1 in terms of conformation and assembly of helical hydrogen-bonded catemers, but their organization is unlike

More about the role of 2,6-dichlorophenol in tick courtship: identification and olfactometer bioassay in Amblyomma cajennense and Rhipicephalus sanguineus

This study aimed to identify 2,6-dichlorophenol (2,6-DCP) in Amblyomma cajennense and to evaluate its role in A. cajennense and Rhipicephalus sanguineus courtship. Hexanic extract from attractive females was purified by solid phase extraction and the phenol was identified by the single ion monitoring method using GC/MS. In an olfactometer, the responses of A. cajennense and R. sanguineus males to females, control rubber septa or rubber septa impregnated with 2,6-DCP at 50, 500, and 5000 ng, respectively, were studied. 2,6-DCP was identified in A. cajennense extract and the males oriented themselves toward the concentration of 500 ng. These septa and the females were recognized as copula partners. The septa treated with 2,6-DCP did not attract and were not even recognized by the R. sanguineus males, whereas the females were recognized. Due to the presence of 2,6-DCP in A. cajennense and the results of biological bioassays, it was concluded that this compound acts as an attractant and mounting sex pheromone in this tick, but it does not play any role in R. sanguineus courtship