Priprava i karakterizacija čvrstih disperzija etorikoksiba s polietilenglikolom 4000 i polivinilpirolidonom K30

The objective of the present investigation was to study the influence of polyethylene glycol 4000 (PEG) and polyvinylpyrrolidone K30 (PVP) on in vitro dissolution of etoricoxib from solid dispersions. The preliminary studies were carried out using physical mixture of drug and carriers. The solid dispersions were prepared using the solvent evaporation method. A 32 factorial design was adopted in the solvent evaporation method using the concentration of PEG and PVP as independent variables. Full and reduced models were evolved for dependant variables, such as the percentage of drug release in 10 min (Q10), percentage of drug release in 30 min (Q30), percentage of drug release in 45 min (Q45) and percent dissolution efficiency (DE). The reduced models were validated using two check points. Q10 > 65%, Q30 > 75%, Q45 > 85% and DE > 80% were used as constraints for the selection of an optimized batch. Contour plots are presented for the selected dependant variables. PEG was found to be more effective in increasing the drug dissolution compared to PVP. Wettability study was carried out for pure drug and optimized batch. FT-IR spectroscopy, microscopic study, differential scanning calorimetry and X-ray diffraction study were carried out in order to characterize drug in the solid dispersions. Improved dissolution was attributed to decreased crystallinity of the drug, improved wetting and solubilizing effects of carriers such as PEG and PVP from the solid dispersion of etoricoxib. In conclusion, dissolution of etoricoxib can be modulated using appropriate levels of hydrophilic carriers.U radu je proučavan utjecaj polietilenglikola 4000 (PEG) i polivinilpirolidona K30 (PVP) na in vitro oslobađanje etorikoksiba iz čvrstih disperzija. Preliminarni pokusi provedeni su sa smjesom ljekovite tvari i polimernih nosača. Čvrste disperzije pripravljene su metodom uparavanja otapala. Za ovu metodu razvijen je 32 faktorijalni dizajn koristeći koncentraciju PEG i PVP kao nezavisne varijable. Za zavisne varijable razvijeni su potpuni i reducirani modeli, kao što su postotak oslobođene ljekovite tvari u 10 (Q10), 30 (Q30) ili 45 minuta (Q45) i postotak učinkovitosti oslobađanja (DE). Reducirani modeli su validirani pomoću dviju kontrolnih točaka. Q10 > 65%, Q30 > 80%, Q45 > 85% i DE > 80% su upotrebljeni kao ograničenja za izbor optimirane serije. Prikazane su konturne linije za pojedine zavisne varijable. Oslobađanje lijeka bilo je učinkovitije iz pripravaka s PEG-om. Vlaženje je proučavano za čistu ljekovitu supstanciju i omptimiranu seriju. Za karakterizaciju ljekovite tvari u čvrstim disperzijama korištene su FT-IR spektroskopija, mikroskopske studije, diferencijalna pretražna kalorimetrija i difrakcija rentgenskim zrakama. Povećano oslobađanje posljedica je smanjene kristaliničnosti ljekovite tvari, pojačanog vlaženja i solubilizacijskog učinka polimernih nosača u disperzijama. Može se zaključiti da se oslobađanje etorikoksiba može modulirati promjenom količine hidrofilnih nosača

Priprava kompleksa etorikoksiba s β-ciklodekstrinom metodom gnječenja i njihova karakterizacija

The binary system of etoricoxib with β-cyclodextrin (β-CD) was prepared by the kneading method. Drug-cyclodextrin interactions in solution were investigated by the phase solubility analysis. Differential scanning calorimetry, infrared spectroscopy, powder X-ray diffractometry and microscopic study were used to characterize the solid state of all binary systems, whereas their dissolution properties were evaluated according to the USP XXIII paddle method. The results indicate partial interaction of the drug with β-CD in the physical mixture and complete interaction in the kneaded complex. The dissolution of etoricoxib was notably increased as compared to pure drug as well as its physical mixture. The complex showed more than 75% drug released in 30 min.Metodom gnječenja pripravljen je binarni sustav etorikoksiba s β-ciklodekstrinom (β-CD). Tijekom 30 minuta iz kompleksa se oslobodilo više od 75% ljekovite tvari, što je značajno više u odnosu na fizičku smjesu etorikoksiba i β-CD ili na čistu ljekovitu tvar. Interakcije lijeka i ciklodekstrina u otopini ispitivane su analizom fazne topljivosti. Za karakterizaciju čvrstog stanja svih binarnih sustava korišteni su diferencijalna pretražna kalorimetrija, infracrvena spektroskopija, difrakcija rentgenskih zraka na praškastom uzorku i mikroskopija. Oslobađanje je praćeno metodom lopatice prema USP XXIII. Rezultati ukazuju na djelomičnu interakciju ljekovite tvari s β-CD u fizičkoj smjesi i potpunu interakciju u kompleksu

Design, synthesis, computational and biological evaluation of novel hydroxamic and carboxylic acid derivatives as histone decaetylase inhibitors

690-699One of the recent targets is histone deacetylase (HDAC) which provide a very promising new approach for anticancer drugs, which may combine clinical efficacy with relatively mild toxicological side effects. Modification of histone acetylation level, promoted by histone acetylase (HAT) and HDAC enzyme, has been recognize to play an important role in epigenetic modulation of gene expression, so HDAC inhibitors are considered a new class of anticancer agents. A new series of hydroxamic and carboxylic acid analogues based on the 1,3,4-thiadiazole scaffold has been designed and synthesized with the aim of exploring its potential as new antitumor agents. Biological results have revealed that the structural modifications proposed significantly affected inhibitory potency as well as selectivity for HDAC inhibitors. Most target compounds are significantly more active, specifically 5a, 5b, 5e with IC50 values in the low micromolar or, the most active compounds in the series. Selected compounds have been tested on the viability of MDA-MB-231 (breast cancer cell) and K562 (chronic myelogenous leukemia cell), A549 (human lung cancer), PC3 (Prostate cancer cell lines) using MTT assay. Docking simulations suggested that the most active compounds can recognize the binding site (PDB Code 1w22 reference compound) using a similar interactions network. These results have allowed us to rationalize the observed structure–activity relationships

Design, synthesis, computational and biological evaluation of novel hydroxamic and carboxylic acid derivatives as histone decaetylase inhibitors

One of the recent targets is histone deacetylase (HDAC) which provide a very promising new approach for anticancer drugs, which may combine clinical efficacy with relatively mild toxicological side effects. Modification of histone acetylation level, promoted by histone acetylase (HAT) and HDAC enzyme, has been recognize to play an important role in epigenetic modulation of gene expression, so HDAC inhibitors are considered a new class of anticancer agents. A new series of hydroxamic and carboxylic acid analogues based on the 1,3,4-thiadiazole scaffold has been designed and synthesized with the aim of exploring its potential as new antitumor agents. Biological results have revealed that the structural modifications proposed significantly affected inhibitory potency as well as selectivity for HDAC inhibitors. Most target compounds are significantly more active, specifically 5a, 5b, 5e with IC50 values in the low micromolar or, the most active compounds in the series. Selected compounds have been tested on the viability of MDA-MB-231 (breast cancer cell) and K562 (chronic myelogenous leukemia cell), A549 (human lung cancer), PC3 (Prostate cancer cell lines) using MTT assay. Docking simulations suggested that the most active compounds can recognize the binding site (PDB Code 1w22 reference compound) using a similar interactions network. These results have allowed us to rationalize the observed structure–activity relationships

Development and validation of dissolution method for carvedilol compression-coated tablets

The present study describes the development and validation of a dissolution method for carvedilol compression-coated tablets. Dissolution test was performed using a TDT-06T dissolution apparatus. Based on the physiological conditions of the body, 0.1N hydrochloric acid was used as dissolution medium and release was monitored for 2 hours to verify the immediate release pattern of the drug in acidic pH, followed by pH 6.8 in citric-phosphate buffer for 22 hours, to simulate a sustained release pattern in the intestine. Influences of rotation speed and surfactant concentration in medium were evaluated. Samples were analysed by validated UV visible spectrophotometric method at 286 nm. 1% sodium lauryl sulphate (SLS) was found to be optimum for improving carvedilol solubility in pH 6.8 citric-phosphate buffer. Analysis of variance showed no significant difference between the results obtained at 50 and 100 rpm. The discriminating dissolution method was successfully developed for carvedilol compression-coated tablets. The conditions that allowed dissolution determination were USP type I apparatus at 100 rpm, containing 1000 ml of 0.1N HCl for 2 hours, followed by pH 6.8 citric-phosphate buffer with 1% SLS for 22 hours at 37.0 ± 0.5 ºC. Samples were analysed by UV spectrophotometric method and validated as per ICH guidelines.O presente estudo descreve o desenvolvimento e a validação de método de dissolução para comprimidos revestidos de carvedilol. O teste de dissolução foi efetuado utilizando-se o aparelho para dissolução TDT-06T. Com base nas condições fisiológicas do organismo, utilizou-se ácido clorídrico 0,1 N como meio de dissolução e a liberação foi monitorada por 2 horas para se verificar o padrão de liberação imediata do fármaco em condições de pH baixo, seguidas por pH 6,8 em tampão cítrico-fosfato por 22 horas, para simular o padrão de liberação controlada no intestino. Avaliou-se a influência da velocidade de rotação e a concentração de tensoativo no meio. As amostras foram analisadas por método espectrofotométrico UV-visível validado, em 286 nm. O laurilsulfato sódico a 1% (SLS) mostrou-se ótimo para aumentar a solubilidade do carvedilol em pH 6,8 em tampão cítrico-fosfato. A análise da variância não mostrou diferença significativa entre os resultados obtidos a 50 e a 100 rpm. O método da dissolução discriminante foi desenvolvido com sucesso para os comprimidos revestidos de carvedilol. As condições que permitiram a determinação da dissolução foram: aparelho USP tipo I a 100 rpm, contendo 1000 mL de HCL 0,1 N por 2 horas, seguido de pH 6,8 com tampão cítrico-fosfato, com 1% de SLS por 22 horas a 37,0 ± 0,5 ºC. Amostras foram analisadas por método espectrofotométrico e validadas pelas normas ICH

Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study

Background: The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. Methods: We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. Results: Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age \u3e50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections. Conclusions: Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes

Spatial, temporal, and demographic patterns in prevalence of chewing tobacco use in 204 countries and territories, 1990-2019 : a systematic analysis from the Global Burden of Disease Study 2019

Interpretation Chewing tobacco remains a substantial public health problem in several regions of the world, and predominantly in south Asia. We found little change in the prevalence of chewing tobacco use between 1990 and 2019, and that control efforts have had much larger effects on the prevalence of smoking tobacco use than on chewing tobacco use in some countries. Mitigating the health effects of chewing tobacco requires stronger regulations and policies that specifically target use of chewing tobacco, especially in countries with high prevalence. Findings In 2019, 273 center dot 9 million (95% uncertainty interval 258 center dot 5 to 290 center dot 9) people aged 15 years and older used chewing tobacco, and the global age-standardised prevalence of chewing tobacco use was 4 center dot 72% (4 center dot 46 to 5 center dot 01). 228 center dot 2 million (213 center dot 6 to 244 center dot 7; 83 center dot 29% [82 center dot 15 to 84 center dot 42]) chewing tobacco users lived in the south Asia region. Prevalence among young people aged 15-19 years was over 10% in seven locations in 2019. Although global agestandardised prevalence of smoking tobacco use decreased significantly between 1990 and 2019 (annualised rate of change: -1 center dot 21% [-1 center dot 26 to -1 center dot 16]), similar progress was not observed for chewing tobacco (0 center dot 46% [0 center dot 13 to 0 center dot 79]). Among the 12 highest prevalence countries (Bangladesh, Bhutan, Cambodia, India, Madagascar, Marshall Islands, Myanmar, Nepal, Pakistan, Palau, Sri Lanka, and Yemen), only Yemen had a significant decrease in the prevalence of chewing tobacco use, which was among males between 1990 and 2019 (-0 center dot 94% [-1 center dot 72 to -0 center dot 14]), compared with nine of 12 countries that had significant decreases in the prevalence of smoking tobacco. Among females, none of these 12 countries had significant decreases in prevalence of chewing tobacco use, whereas seven of 12 countries had a significant decrease in the prevalence of tobacco smoking use for the period. Summary Background Chewing tobacco and other types of smokeless tobacco use have had less attention from the global health community than smoked tobacco use. However, the practice is popular in many parts of the world and has been linked to several adverse health outcomes. Understanding trends in prevalence with age, over time, and by location and sex is important for policy setting and in relation to monitoring and assessing commitment to the WHO Framework Convention on Tobacco Control. Methods We estimated prevalence of chewing tobacco use as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 using a modelling strategy that used information on multiple types of smokeless tobacco products. We generated a time series of prevalence of chewing tobacco use among individuals aged 15 years and older from 1990 to 2019 in 204 countries and territories, including age-sex specific estimates. We also compared these trends to those of smoked tobacco over the same time period. Findings In 2019, 273 & middot;9 million (95% uncertainty interval 258 & middot;5 to 290 & middot;9) people aged 15 years and older used chewing tobacco, and the global age-standardised prevalence of chewing tobacco use was 4 & middot;72% (4 & middot;46 to 5 & middot;01). 228 & middot;2 million (213 & middot;6 to 244 & middot;7; 83 & middot;29% [82 & middot;15 to 84 & middot;42]) chewing tobacco users lived in the south Asia region. Prevalence among young people aged 15-19 years was over 10% in seven locations in 2019. Although global age standardised prevalence of smoking tobacco use decreased significantly between 1990 and 2019 (annualised rate of change: -1 & middot;21% [-1 & middot;26 to -1 & middot;16]), similar progress was not observed for chewing tobacco (0 & middot;46% [0 & middot;13 to 0 & middot;79]). Among the 12 highest prevalence countries (Bangladesh, Bhutan, Cambodia, India, Madagascar, Marshall Islands, Myanmar, Nepal, Pakistan, Palau, Sri Lanka, and Yemen), only Yemen had a significant decrease in the prevalence of chewing tobacco use, which was among males between 1990 and 2019 (-0 & middot;94% [-1 & middot;72 to -0 & middot;14]), compared with nine of 12 countries that had significant decreases in the prevalence of smoking tobacco. Among females, none of these 12 countries had significant decreases in prevalence of chewing tobacco use, whereas seven of 12 countries had a significant decrease in the prevalence of tobacco smoking use for the period. Interpretation Chewing tobacco remains a substantial public health problem in several regions of the world, and predominantly in south Asia. We found little change in the prevalence of chewing tobacco use between 1990 and 2019, and that control efforts have had much larger effects on the prevalence of smoking tobacco use than on chewing tobacco use in some countries. Mitigating the health effects of chewing tobacco requires stronger regulations and policies that specifically target use of chewing tobacco, especially in countries with high prevalence. Copyright (c) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019 : a systematic analysis from the Global Burden of Disease Study 2019

Background Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally. Methods We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available. Findings Globally in 2019, 1.14 billion (95% uncertainty interval 1.13-1.16) individuals were current smokers, who consumed 7.41 trillion (7.11-7.74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27.5% [26. 5-28.5] reduction) and females (37.7% [35.4-39.9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0.99 billion (0.98-1.00) in 1990. Globally in 2019, smoking tobacco use accounted for 7.69 million (7.16-8.20) deaths and 200 million (185-214) disability-adjusted life-years, and was the leading risk factor for death among males (20.2% [19.3-21.1] of male deaths). 6.68 million [86.9%] of 7.69 million deaths attributable to smoking tobacco use were among current smokers. Interpretation In the absence of intervention, the annual toll of 7.69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a dear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe