Diretrizes para o tratamento farmacológico da COVID-19 : consenso da Associação de Medicina Intensiva Brasileira, da Sociedade Brasileira de Infectologia e da Sociedade Brasileira de Pneumologia e Tisiologia

Introduction: Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidencebased information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. Methods: A group of 27 experts and methodologists integrated a taskforce formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. Results: Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. Conclusion: So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.Introdução: Há diversas terapias sendo utilizadas, consideradas ou propostas para o tratamento da COVID-19, muitas carecendo de apropriada avaliação de efetividade e segurança. O propósito deste documento é fornecer recomendações baseadas nas evidências científicas disponíveis e em sua interpretação transparente, para subsidiar decisões sobre o tratamento farmacológico da COVID-19 no Brasil. Métodos: Um grupo de 27 especialistas e metodologistas integraram a força-tarefa formada pela Associação de Medicina Intensiva Brasileira (AMIB), pela Sociedade Brasileira de Infectologia (SBI) e pela Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). Foram realizadas revisões sistemáticas rápidas, atualizadas até 28 de abril de 2020. A qualidade das evidências e a elaboração das recomendações seguiram o sistema GRADE. As recomendações foram elaboradas nos dias 5, 8 e 13 de maio de 2020. Resultados: Foram geradas 11 recomendações, embasadas em evidência de nível baixo ou muito baixo. Não há indicação para uso de rotina de hidroxicloroquina, cloroquina, azitromicina, lopinavir/ritonavir, corticosteroides ou tocilizumabe no tratamento da COVID-19. Heparina deve ser utilizada em doses profiláticas no paciente hospitalizado, mas não deve ser realizada anticoagulação na ausência de indicação clínica específica. Antibacterianos e oseltamivir devem ser considerados somente nos pacientes em suspeita de coinfecção bacteriana ou por influenza, respectivamente. Conclusão: Até o momento, não há intervenções farmacológicas com efetividade e segurança comprovada que justifiquem seu uso de rotina no tratamento da COVID-19, devendo os pacientes serem tratados preferencialmente no contexto de pesquisa clínica. As recomendações serão revisadas continuamente, de forma a capturar a geração de novas evidências

Bayliss-Hillman adducts as scaffolds for the construction of novel compounds with medicinal potential

This project has focused on exploring the application of Baylis-Hillman (BH) {a.k.a. Morita-Baylis-Hillman (MBH)} scaffolds in the construction of various compounds with medicinal potential. A series of 2-nitrobenzaldehydes has been treated under BH conditions, with two different activated alkenes, viz., (MVK) and methyl acrylate, using (DABCO) or (3-HQ) as catalyst. While most of the BH reactions were carried out at room temperature, some reactions were conducted using microwave irradiation. The resulting BH adducts have been subjected to dehydration, conjugate addition and allylic substitution to obtain appropriate intermediates, which have been used in turn, to synthesize possible lead compounds, viz., cinnamate esters as HIV-1 integrase inhibitors, 3-(aminomethyl)quinolines and quinolones as anti-malarials and cinnamate ester-AZT conjugates as dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Conjugate addition reactions of methyl acrylate-derived BH β-hydroxy esters with the amines, piperidine, propargylamine and 2-amino-5-(diethylamino)pentane, has afforded a range of products as diastereomeric mixtures in moderate to excellent yields. Catalytic hydrogenation of the aminomethy β-hydroxy esters derivatives, using a palladium-oncarbon (Pd-C) catalyst, has afforded the corresponding, novel 3-aminomethyl-2- quinolone derivatives in moderate yields. Effective allylic substitution reactions of the MVK-derived BH β-hydroxy ketones (via a conjugate addition-elimination pathway) using in situ-generated HCl has afforded the corresponding α-chloromethyl derivatives, which have been reacted with various amines, including piperidine, piperazine, propargylamine and 2-amino-5-(diethylamino)pentane, to yield α-aminomethyl derivatives. Catalytic hydrogenation of selected α-aminomethyl derivatives, using a Pd-C catalyst, has afforded the corresponding, novel 3- (aminomethyl)-2-methylquinoline derivatives in low to moderate yields. A bioassay, conducted on a 6-hydroxy-2-methyl-3-[(piperidin-1-yl)methyl]quinoline isolated early in the study indicated anti-malarial activity and prompted further efforts in the synthesis of analogous compounds. Reaction of the methyl acrylate-derived BH adducts with POCl3 has provided access to α-(chloromethyl)cinnamate ester derivatives, which have been aminated to afford α- (aminomethyl)cinnamate ester derivatives as potential HIV-1 integrase inhibitors. The α- (propargylaminomethyl)cinnamates were used, in turn, as substrates for the “click chemistry” reaction with 3'-azido-3'-deoxythymidine (AZT– an azide and an established reverse transcriptase HIV-1 inhibitor) to afford cinnamate ester-AZT conjugates as potential dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Computer modelling and docking studies of a cinnamate ester-AZT conjugate into the HIV-1 integrase and reverse transcriptase active-sites revealed potential hydrogen-bonding interactions with amino acid residues within the receptor cavities. The isolated products have been appropriately characterized using IR, 1- and 2-D NMR and HRMS techniques, while elucidation of the stereochemistry of the double bond in the BH-derived halomethyl derivatives has been assigned on the basis of NOE, computer modelling and X-ray crystallographic data

Chloroquine Related to Malaria and its Promising Applications for Covid-19 Treatment

Objective: this article described the use of chloroquine as an antimalarial agent with potential antiviral indications for COVID-19 infections. Methods: this article consisted of online searches and gray literature whose database included PUBMED Central, BVS/BIREME, Web of Science, Science Direct, Higher Level Personnel Improvement Coordinator (CAPES), Periodic Door (Portal de Periódicos da CAPES, The Cochrane Library, and PROSPERO). Results: chloroquine and hydroxychloroquine have shown appropriate clinical reports when associated with the antibiotic Azithromycin. It has been authorized for the clinical treatment of severe acute forms of COVID infections by countries such as Brazil and the USA. Conclusions: Chloroquine seems to have potential antiviral properties that may be useful in the treatment of these severe acute forms of COVID-19 associated with Azithromycin. Nevertheless, its indication must include ECG monitoring due to the risk of prolongation of QT interval, leading to sudden cardiac death.  

Chloroquine Related to Malaria and its Promising Applications for Covid-19 Treatment

Objective: this article described the use of chloroquine as an antimalarial agent with potential antiviral indications for COVID-19 infections. Methods: this article consisted of online searches and gray literature whose database included PUBMED Central, BVS/BIREME, Web of Science, Science Direct, Higher Level Personnel Improvement Coordinator (CAPES), Periodic Door (Portal de Periódicos da CAPES, The Cochrane Library, and PROSPERO). Results: chloroquine and hydroxychloroquine have shown appropriate clinical reports when associated with the antibiotic Azithromycin. It has been authorized for the clinical treatment of severe acute forms of COVID infections by countries such as Brazil and the USA. Conclusions: Chloroquine seems to have potential antiviral properties that may be useful in the treatment of these severe acute forms of COVID-19 associated with Azithromycin. Nevertheless, its indication must include ECG monitoring due to the risk of prolongation of QT interval, leading to sudden cardiac death.  

Formation primaquine-5, 6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics Short precorneal residence time and poor transocular membrane permeability are the major challenges associated with topical ocular drug delivery. In the present research, the efficiency of the electrolyte-triggered sol-to-gel-forming system of natamycin (NT) transfersomes was investigated for enhanced and prolonged ophthalmic delivery. Transfersomes were optimized by varying the molar ratios of phospholipid, sorbitan monostearate (Span) and tocopheryl polyethylene glycol succinate (TPGS). NT transfersome formulations (FNs) prepared with a 1:1 molar ratio of phospholipid-to-Span and low levels of TPGS showed optimal morphometric properties, and were thus selected to fabricate the in situ gelling system. Gellan gum-based (0.3% w/v) FN-loaded formulations (FNGs) immediately formed an in situ gel in the simulated tear fluid, with considerable viscoelastic characteristics. In vitro cytotoxicity in corneal epithelial cells and corneal histology studies demonstrated the ocular safety and cytocom-patibility of these optimized formulations. Transcorneal permeability of NT from these formulations was significantly higher than in the control suspension. Moreover, the ocular disposition studies of NT, from the FNs and FNGs, in New Zealand male albino rabbits demonstrated the superiority of the electrolyte-sensitive FNGs in terms of NT delivery to the ocular tissues

Public Health Rep

194918149805PMCnull605

Synthesis of chemotherapeutic agents derived from 2:3-benz-γ-carboline and 2:3:4':3'-quinoquinoline

1. From diethylethoxymethylene malonate and the appropriate aniline, 4-chloroquinoline, 6-methoxy-4-chloroquinoline and L.:6-dichloroquinoline have been prepared. 2. These chloro compounds have been used in the synthesis of 2:3-benz-γ-carboline, 15-methoxy-2:3-benz-γ-carboline and 15- chloro -2:3- benz -ycarboline. The unambiguous synthesis of the former base has cleared up certain discrepancies which existed in the literature. 3. The 2:3-benz-γ-carbolines have been treated with diethylaminoethyl chloride to obtain basic side chain derivatives. In this way, the following have been prepared: 1-diethylaminoethyl- 2:3-benz-γ- carboline . 4-diethylaminoethyl-2:3-benz-γ-isocarboline. 5-methoxy-4-diethylaminoethyl-2:3-benz-γ-isocarboline. 15-chloro-l-diethylaminoethyl-2:3-benz-γ-carboline. 15-chloro-4-diethylaminoethyl-2:3-benz-γ-isocarboline. In addition, 4-methyl-2:3-benz-γ-isocarboline and 15-chloro-4-methyl-2:3-benz-γ-isocarboline were also prepared. 4. The constitution of 1-diethylaminoethyl-2:3:4'-3'0benz-γ-carboline (and by analogy, of the corresponding 15-methoxy- and 15-chloro-compounds) has been established from a study of its methiodides. 5. The synthesis of 2:3:4':3'-quinoquinolo-4-one, 6'-methoxy-2:3:4':3'-quinoquinolo-4-one, 6'-chloro-2:3:4':3'-quinoquinolo-4-one, and of 4-chloro-2:3:4':3'-quinoquinoline, 6'-methoxy-4-chloro-2:3:4':3'-quinoquinoline and 4:6'-dichloro-2:3:4':3'-quinoquinoline from the corresponding 4-anilinoquinoline-3-carboxylic acids, has been described. These compounds are isomeric with the 5-chloropyridoacridines, which they resemble markedly in properties. 6. From the above chloroquinoquinolines, bases have been obtained by condensing them with amines such as ammonia, diethylaminoethylamine and 2-amino-5-diethylaminopentane. The constitution of the products obtained is still uncertain

GC-MS Fingerprinting and In-Vitro Biological Evaluation of Hydroalcohlic Extract of Rosemary Officinalis Linn leaves

The present study investigated phytochemical constituents of Rosemary officinalis. The preliminary phytochemical analysis revealed the presence of alkaloids, saponins, flavonoids, terpenoids, tannins and phenolic compounds, cardiac glycosides. The finger printing analysis by GCMS explored good to moderate amount of various major phytochemicals. The quantitative chemical evaluation on the hydroalcoholic extracts of Rosemary officinalis leaves leads to the isolation of phytoconstituents were subjected to chemical test, physical tests and spectral studies to elucidate their structures. From our study report, we found that the following compounds viz. Nanonedioic acid bis ( 2 methyl propyl ) ester, 10-octadecenoic acid methyl ester, 9- hexadecenoic acid, 1,3,4 thiadiazolidine-3,4-dicarboxylic acid, 2-spiro-2-adamantyl methyl ester, cyclopentanepropanoic acid, were reported. Hameed et al., 2015, reported that the methanol extract of Rosmarinus oficinalis leaves proved the presence of Alkenes, Aliphatic fluoro compounds, Alcohols, Ethers, Carboxylic acids, Esters, Nitro compounds, Alkanes, Aldehydes, Ketones compounds studied the constituents of rosemary essential oil from Algeria. They reported 1, 8-cineole, camphor, βpinene,and α-Pinene as the major constituents in the oil. Investigated chemical composition of the essential oil of anther sample of rosemary leaves from Spain. The major constituents identified were α-pinene, camphor, 1,8-cineole and camphene. Chemical composition of essential oils of rosemary from various geographic origins in Iran was determined by GC-MS. The main components detected in the oils were: α-pinene, 1, 8-cineole, camphene, camphor, myrcene and broneol. GC and GC-MS analysis of oils from rosemary leave samples from India revealed the presence of camphor, 1,8-cineole and α-pinene as major constituents in the oils. Further, the hydro alcohol extract and chloroform fraction were evaluated for in-vitro anti- inflammatory study (concentration 100μg/ml, 250μg/ml, and 500μg/ml) showed the inhibition of viz. HA: 19.79%, 54.16%, 69.79% and CH: 28.88%, 43.33%, 85.27%, respectively whereas, aspirin showed 89.60 % inhibition. Hydroalcohol extracts exhibited highest anti-inflammatory activity compared to that of standard owing to their high profile of secondary metabolites present with this leaves. CONCLUSION: As indicated by the after effect of fundamental secondary phytochemical screening it is inferred that the leaves of Rosemary officinalis contained considerable number of secondary bioactive compounds; for example, Alkaloid, Flavonoid, Phenolic compounds, Tannin, Saponin, Terpnoids, Cardiac glycosides. These secondary metabolites were identified using various techniques and can be utilized to cure different diseases. Quantitative estimation revealed higher quantities diverse phytoconstituents present in leaf extracts. The analysis was carried out by gas chromatography-mass spectrometry (GC–MS), one of the most widely used techniques for separation of phytoconstituents. The GC–MS investigation of Rosemary officinalis leaves and hydro alcoholic extracts and two fraction CH, NH are revealed the presence of 16 phytochemical compounds, which could contribute to the medicinal properties of this plant species. Nanonedioic acid bis ( 2 methyl propyl ) ester, 10-octadecenoic acid methyl ester, 9-hexadecenoic acid, 1,3,4 thiadiazolidine-3,4-dicarboxylic acid, 2-spiro-2- adamantyl methyl ester, cyclopentanepropanoic acid, 3,5-bis (acetyloxy)-2-(8-(acetyloxy)-3- (methoxyimino) octyl)-methyl ester. In-vitro anti-inflammatory results indicate that the hydro alcohol extracts of leaves of Rosemary officinalis possess minimum protein denaturation inhibition properties compared to chloroform fraction of Rosemary officinalis. These anti-inflammatory activities may be due to the occurrence of bioactive compounds, such as polyphenols, flavonoids, and carotenoids in these leafy types

Chloroquine and hydroxychloroquine for the prevention and treatment of COVID-19: A fiction, hope or hype? An updated review

In December 2019, the novel coronavirus disease pandemic (COVID-19) that began in China had infected so far more than 109,217,366 million individuals worldwide and accounted for more than 2,413,912 fatalities. With the dawn of this novel coronavirus (SARS-CoV-2), there was a requirement to select potential therapies that might effectively kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently available antiviral medications for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has been repurposed in China and was recommended by the National Health Commission, China in mid-February 2020. By this time, the selection of this regimen was based on its efficacy against the previous SARS-CoV-1 virus and its potential to inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive research effort has been made by several researchers worldwide to investigate whether this regimen is safe and effective for the management of COVID-19. In this review, we provided a comprehensive overview of the CQ/HCQ regimen, summarizing data from in vitro studies and clinical trials for the protection against or the treatment of SARS-CoV-2. Despite the initial promising results from the in vitro studies and the widespread use of CQ/HCQ in clinical settings during the 1st wave of COVID-19, current data from well-designed randomized controlled trials showed no evidence of benefit from CQ/HCQ supplementation for the treatment or prophylaxis against SARS-CoV-2 infection. Particularly, the two largest randomized controlled trials to date (RECOVERY and WHO SOLIDARITY trials), both confirmed that CQ/HCQ regimen does not provide any clinical benefit for COVID-19 patients. Therefore, we do not recommend the use of this regimen in COVID-19 patients outside the context of clinical trials