Drug repurposing clinical trials in the search for life-saving COVID-19 therapies; research targets and methodological and ethical issues

Introduction: So far, there is no vaccine, nor are there effective drugs to treat COVID-19, an emerging viral respiratory infection deadlier than influenza. Objective: To take a snapshot picture of planned and ongoing clinical research addressing drugs potentially useful for treating SAR-CoV-2 infections. Method: A search was conducted (20 April 2020) in an international registry of clinical studies (https://ClinicalTrials.gov, US NIH). After excluding observational studies and other interventions that fell outside the scope of this study, 294 research protocols (out of 516 retrieved protocols) were selected for analysis. Results: Of 294 included trials, 249 were Randomized Controlled Trials (RCT), 118 of which were double-, triple- or quadruple-blinded studies. The interventions (drug therapies) were compared with “standard-of-care” (SOC) or with the placebo plus SOC, or yet with presumed “active” comparators. RCT focused on the primary treatment of the disease (inhibitors of viral replication) or on the therapy for resolution of hyperinflammation in pneumonia/Acute Respiratory Distress Syndrome (ARDS) and thromboembolism associated with SARS-CoV-2. The trials found in the database involve existing antiviral compounds and drugs with multiple modes of antiviral action. Antiparasitic drugs, which inhibited viral replication in cell-culture assays, are being tested as well. Regarding the adjunctive immunomodulatory, anti-inflammatory and antithrombotic therapies, a number of drugs with distinct pharmacological targets are under investigation in trials enrolling patients with severe COVID-19. Conclusions: Although many clinical studies of drugs for COVID-19 are planned or in progress, only a minority of them are sufficiently large, randomized and placebo-controlled trials with masking and concealment of allocation. Owing to methodological limitations, only a few clinical trials found in the registry are likely to yield robust evidence of effectiveness and safety of drugs repurposable for COVID-19.TÍTULO PT: Ensaios clínicos para reposicionamento de medicamentos para COVID-19 na busca de terapias para salvar vidas; alvos de pesquisa, e questões metodológicas e éticas Introdução: Até agora, não há vacinas ou medicamentos eficazes para tratar COVID-19, uma infecção viral respiratória emergente mais letal do que a gripe. Objetivo: Desenhar um quadro das pesquisas planejadas e em curso sobre medicamentos potencialmente úteis para tratar infecções por SARS-CoV-2. Método: Um levantamento foi realizado (20 de abril de 2020) em um registro internacional de estudos clínicos (https://ClinicalTrials.gov, US NIH). Após excluir estudos observacionais e outras interveções fora do escopo deste estudo, 294 protocolos (de 516 identificados na busca) foram selecionados para análise. Resultados: De 294 ensaios incluídos, 249 eram Ensaios Controlados Randomizados (ECR), dos quais 118 eram estudos duplo-, triplo- ou quadruplo-cego. As intervenções (medicamentos testados) foram comparadas com o “tratamento padrão” (TP) ou com placebo mais TP, ou ainda com comparadores supostamente ativos. ECR abordaram o tratamento primário da doença (inibidores da replicação viral) ou a resolução da super-inflamação na pneumonia e Síndrome do Desconforto Respiratório Agudo (SDRA), e do tromboembolismo associados ao SARS-CoV-2. Os ensaios localizados no registro envolviam fármacos antivirais com múltiplos modos de ação e medicamentos anti-parasitários que inibem a replicação viral em cultura de células. Em relação às terapias imunomodulatória, antiinflamatória e antitrombótica adjuvantes, inúmeros medicamentos com alvos farmacológicos distintos também estão sendo investigados em ensaios envolvendo pacientes graves com COVID-19. Conclusões: Embora muitos ensaios clínicos de medicamentos para COVID-19 tenham sido planejados e estejam em andamento, apenas uma minoria deles são estudos suficientemente grandes, randomizados, controlados com placebo e com mascaramento, e ocultação da alocação. Em virtude das limitações metodológicas apontadas, provavelmente apenas uns poucos ensaios clínicos fornecerão evidências robustas da eficácia e segurança de medicamentos potencialmente redirecionáveis para COVID-19

Safety, efficacy and pharmacokinetic evaluations of a new coated chloroquine tablet in a single-arm open-label non-comparative trial in Brazil: a step towards a user-friendly malaria vivax treatment

Additional file 1. Co-blister preliminary design. The figure provided is an illustrative package design of the chloroquine and primaquine co-blister

Preliminarno ispitivanje antimikotskog i citotoksičnog djelovanja derivata cikloalkil[b]tiofena PLS-DA analizom

A series of 2-[(arylidene)amino]-cycloalkyl[b]thiophene-3-carbonitriles (2a-x) was synthesized by incorporation of substituted aromatic aldehydes in Gewald adducts (1a-c). The title compounds were screened for their antifungal activity against Candida krusei and Criptococcusneoformans and for their antiproliferative activity against a panel of 3 human cancer cell lines (HT29, NCI H-292 and HEP). Forantiproliferative activity, the partial least squares (PLS) methodology was applied. Some of the prepared compounds exhibited promising antifungal and proliferative properties. The most active compounds for antifungal activity were cyclohexyl[b]thiophene derivatives, and forantiproliferative activity cycloheptyl[b]thiophene derivatives, especially 2-[(1H-indol-2-yl-methylidene)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (2r), which inhibited more than 97 % growth of the three cell lines. The PLS discriminant analysis (PLS-DA)applied generated good exploratory and predictive results and showed that the descriptors having shape characteristics were strongly correlated with the biological data.Koristeći supstituirane aromatske aldehide u Gewaldovim aduktima 1a-c sintetizirani su derivati 2-[(ariliden)amino]-cikloalkil[b]tiofen-3-karbonitrila (2a-x). Ispitano je antimikotsko djelovanje tih spojeva na gljivice Candida krusei i Criptococcus neoformans te antiproliferativno djelovanje na tri humane tumorske stanične linije (HT29, NCI H-292 i HEP). Za antiproliferativno djelovanje primijenjena je metoda parcijalnih najmanjih kvadrata (PLS) koristeći softverski program Pentacle. Neki od ispitanih spojeva pokazuju obećavajuće antimikotsko i antiproliferativno djelovanje. Najjače antimikotsko djelovanje imaju cikloheksil[b]tiofen derivati, a najjače antiproliferativno djelovanje cikloheptil[b]tiofen derivati, posebice 2-[(1H-indol-2-il-metiliden)amino]-5,6,7,8-tetrahidro-4H-ciklohepta[b]tiofen-3-karbonitril (2r), koji inhibira više od 97 % rast svih triju ispitivanih staničnih linija. Primijenjena PLS diskriminirajuća analiza dala je dobre istraživačke i prognostičke rezultate i pokazala da deskriptori dobro koreliraju s biološkim rezultatima

Scanning acoustic microscope images for the localization of defects inside dummy pouch cells

The identification and location of critical defects inside battery cells before the performance decreases or safety issues arise remains a challenge. Here we show images acquired from Scanning Acoustic Microscopy (SAM) as a non-destructive testing methods for the 3D visualization of defects at different depths inside a pouch battery cell. A manufactured dummy pouch cell with 8 cathode sheets is used for this investigation. SAM using a 15 MHz transducer in reflection mode can detect defects with a lateral resolution of 150 µm in 2 min. The time intervals of each micrograph have a length of 30 ns. The images are acquired with a resolution of with a pixel dimension of 50 x 50 μm²/ pixel

The use of the electrochemical quartz crystal microbalance for the analysis of poly(aniline) composite films

The Electrochemical Quartz Crystal Microbalance has been largely used for the analysis of conducting polymers. Many groups quantify the mass increase or decrease on the surface of the quartz crystal directly from the changes in the resonant frequency of the crystal by applying the Sauerbrey equation. However this correlation can be used only if the material coated on the crystal is a thin, smooth and rigid layer. We treat the quartz crystal and the coating as a single resonator which can be represented as an equivalent electrical circuit (Butterworth-Van Dyke). The variation in the coating mass is compared to the changes in the inductance and the viscoelasticity is related to the resistance of the electrical circuit. Only in the case when the resistance is maintained close to zero throughout an experiment can the Sauerbrey equation be applied. The components of the equivalent electrical circuit are obtained by using the transfer function method, which is faster than an impedance measurement. The non-validity of the Sauerbrey equation is demonstrated for the hydration of a hydrophilic polymer film. The polymer swells considerably in water creating a very soft hydrated film. The use of mathematical simulations was then necessary in order to calculate of the rate of hydration, i.e. changes in the thickness of the film. We have applied the transfer function method on the Electrochemical Quartz Crystal Microbalance to study the electrodeposition and the redox switching of conducting polymers. The poly(aniline) films were electropolymerised in the presence of poly(vinylsulfonate) or poly(styrenesulfonate) counterions. The polymer films presented different morphology depending on the poly(anion) used during polymerisation. The polymer film which obeyed the Sauerbrey approximation was used in studies of ionic movement during voltammetric cycles in different inorganic acids.</p

Scanning acoustic microscope images for the localization of defects inside dummy pouch cells

The identification and location of critical defects inside battery cells before the performance decreases or safety issues arise remains a challenge. Here we show images acquired from Scanning Acoustic Microscopy (SAM) as a non-destructive testing methods for the 3D visualization of defects at different depths inside a pouch battery cell. A manufactured dummy pouch cell with 8 cathode sheets is used for this investigation. SAM using a 15 MHz transducer in reflection mode can detect defects with a lateral resolution of 150 µm in 2 min. The time intervals of each micrograph have a length of 30 ns. The images are acquired with a resolution of with a pixel dimension of 50 x 50 μm²/ pixel

Study of the statistical methods in the analysis of the biodisponibilidade relativa/bioequivalência for the registration of medications in Brazil

Made available in DSpace on 2014-09-24T12:58:26Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 172.pdf: 628089 bytes, checksum: 3763e5324edda128696e185d8098c259 (MD5) Previous issue date: 2004Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em SaúdeA ANVISA, órgão que regulamenta e controla a liberação dos medicamentos no Brasil, não indica um método estatístico específico para ser utilizado nos estudos de BD relativa/BE. Tendo em vista que existem vários métodos estatísticos possíveis, hipotetizamos aqui que, em determinados casos, poderíamos obter um resultado não bioequivalente com um determinado modelo estatístico e bioequivalente utilizando um outro modelo. Em nosso trabalho, comparamos os resultados dos seguintes métodos estatísticos: Filler, Anderson e Hauck, Shortest, Lehmann (NP), T-test, Westlake, Baseado ANOVA, Hauschke Trabalhamos com 49 estudos de bioequivalência e constatamos que 28 (57%)destes foram bioequivalentes, enquanto 9 (18,4%) se apresentaram bioinequivalentes em todos os métodos utilizados. Nos 12 (24,5%) restantes, obtivemos resultados contraditórios. Analisando o resultado de um determinado método em relação ao da maioria, demonstramos que o Teste t na diferença, Lehmann, Hauschke e o Anderson eHauck foram os que concluíram mais resultados diferentes da maioria dos método sem questão. Já o Teste t e o teste baseado na ANOVA, ambos utilizando a razão das médias, e o método de Westlake, foram os que obtiveram apenas um resultado diferente da maioria dos métodos estatísticos utilizados. Podemos ressaltar que a maior parte dos resultados em bioinequivalência foi em função do parâmetro Cmax com 67,36%. Já em relação ao parâmetro ASC, concluímos bioinequivalência em apenas 1,04% dos métodos. Além disso, obtivemos 31,61% dos resultados acusando não bioequivalência em ambos os parâmetros.ANVISA, organ that regulates and it controls the liberation of the medicines in Brazil, it doesn't indicate a statistical method specify to be used in the studies of BDrelative/BE. Tends in view that several possible statistical methods exist, we presume that, in certain cases, we could obtain a result no bioequivalente with a certain statistical model and bioequivalente if we use another model. In our work we compared the results of the following statistical methods: Filler, Anderson and Hauck, Shortest, Lehmann (NP), T-test, Westlake, Based ANOVA, Hauschke With the end of our study, where we worked with 49 bioequivalence studies and we verified that 28 (57%) studies were bioequivalentes and 9 (18,4%) they were bioinequivalentes in all of the used methods. In the 12 (24,5%) remaining studies had resulted contradictory. Analyzing the result of a certain method in relation to the result of most of the methods, we demonstrated that the Test t in the difference, Lehmann, Hauschke and Anderson and Hauck were the ones that ended more results different from most of the methods in subject. Already the Test t and the test based on ANOVA, both using the reason of the averages and the method of Westlake, they were the ones that just obtained one result different from most of the used statistical methods. We can stand out although most of the results in bioinequivalence was in function of the parameter Cmax with 67,36%. Already the parameter ASC concluded bioinequivalence in only 1,04% of the methods. Besides, we obtained 31,61% results of no bioequivalence with both parameters