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Background: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. Methods: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. Results: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. Conclusions: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Objective: To achieve glycemic control, a combination of drugs is eventually necessary, especially the dual therapy of SGLT2 inhibitors with metformin. Despite the value of combination therapy, understanding the pharmacokinetic properties is critical. Therefore, this study aimed to conduct the combined and isolated administration of hypoglycemic drugs to understand their pharmacokinetic properties. Methodology: The study was performed by gavage in twenty-five rats that were divided into five groups: metformin alone (60 mg/kg), canagliflozin alone 20 mg/kg, canagliflozin and metformin (20 mg/kg and 60 mg/kg, respectively), dapagliflozin alone 2 mg/kg, and dapagliflozin and metformin (2 mg/kg and 60 mg/kg, respectively). Blood samples were collected between 0.25 and 36 hours postdose and quantified by an HPLC-MS/MS method. Results: The metformin pharmacokinetics showed values lower than those from literature, but the most relevant result was a significant change in Cmax (3400 ng/mL), AUC (872.4 ng.min/L) and CL/F (72 mL/min/kg) in the metformin with dapagliflozin group compared to metformin alone Cmax (523 ng/mL), AUC (106.8 ng.min/L) and CL/F (752 mL/min/kg). For canagliflozin, the Cmax of 6116.7 ng/mL observed in our study was similar to that observed in literature, while the clearance (5.1 mL/min/kg) was higher than that of literature, which was 3.5 mL/min/kg. Clearance of dapagliflozin CL/F was reported as 3.33 mL/min/kg, while our result was 4.6 mL/min/kg. The same study also published dapagliflozin half-life and MRT, which were slightly lower than our findings. In general, the parameters of canagliflozin and dapagliflozin were similar to the literature and did not change with simultaneous administration with metformin. Conclusion: Dapagliflozin significantly changed the pharmacokinetic disposition of metformin, while metformin coadministration had no influence on the pharmacokinetics of SGLT2 inhibitors

ImportanceThe number of innovations in health care based on the use of platforms, digital devices, apps, and artificial intelligence has grown exponentially in recent years. When used correctly, these technologies allow inequities in access to health care to be addressed by optimizing care and reducing social and geographic barriers. However, most of the technological health care solutions proposed have not undergone rigorous clinical studies.ObjectiveTo assess the concordance between measurements from a remote physical examination using a mobile medical device and measurements from a conventional in-person physical examination.Design, Setting, and ParticipantsThis nonrandomized controlled trial was conducted from January 1 to December 31, 2020. The clinical parameters compared were heart rate; body temperature; heart, lung, and abdominal auscultation; otoscopy; throat and oral examination; and skin examination. A total of 690 patients with clinical stability and various symptoms who were seen in the emergency department of 2 Brazilian pediatric hospitals were eligible to enter this study.Main Outcomes and MeasuresThe primary outcome was concordance between measurements from a telemedicine physical examination using a mobile medical device and measurements from a conventional in-person physical examination. The secondary outcome was the specificity and sensitivity of the digital device, considering the conventional in-person consultation as the gold standard.ResultsAmong 690 patients, the median (IQR) age at study entry was 5 (1-9) years; 348 (50.4%) were female, and 331 (48.0%) presented with a chronic disease. Regarding the primary outcome, the concordance values were 90% or greater for skin examination (94% for rash, 100% for hemorrhagic suffusion, and 95% for signs of secondary infection), characteristics of the mucosa (98% for hydration and 97% for coloring), and heart (95% for murmur, 97% for rhythms, and 98% for sounds), lung (91% for adventitious sounds, 97% for vesicular sounds, and 90% for fever), and abdominal (92% for abdominal sounds) auscultations. Concordance values were lower for otoscopy (72% for the ear canal and 86% for the tympanic membrane), throat and oral examination (72%), and rhinoscopy (79% for mucosa and 81% for secretion). The specificity was greater than 70% (ranging from 74.5% for the ear canal to 99.7% for hemorrhagic suffusion) for all variables. The sensitivity was greater than 52% for skin examination (58.0% for rash and 54.8% for signs of secondary infection), throat and oral examination (52.7%), and otoscopy (66.1% for the ear canal and 64.4% for the tympanic membrane).Conclusions and RelevanceIn this study, measurements from remote physical examination with a mobile medical device had satisfactory concordance with measurements from in-person physical examination for otoscopy, throat and oral examination, skin examination, and heart and lung auscultation, with limitations regarding heart and lung auscultation in infants and abdominal auscultation in children of all ages. Measurements from remote physical examination via a mobile medical device were comparable with those from in-person physical examination in children older than 2 years. These findings suggest that telemedicine may be an alternative to in-person examination in certain contexts and may help to optimize access to health care services and reduce social and geographic barriers.Trial RegistrationBrazilian Registry of Clinical Trials Identifier: RBR-346ymn

We investigated the predictors of delay in the diagnosis and mortality of patients with COVID-19 in Rio de Janeiro, Brazil. A cohort of 3,656 patients were evaluated (Feb-Apr 2020) and patients’ sociodemographic characteristics, and social development index (SDI) were used as determinant factors of diagnosis delays and mortality. Kaplan-Meier survival analyses, time-dependent Cox regression models, and multivariate logistic regression analyses were conducted. The median time from symptoms onset to diagnosis was eight days (interquartile range [IQR] 7.23-8.99 days). Half of the patients recovered during the evaluated period, and 8.3% died. Mortality rates were higher in men. Delays in diagnosis were associated with male gender (p = 0.015) and patients living in low SDI areas (p < 0.001). The age groups statistically associated with death were: 70-79 years, 80-89 years, and 90-99 years. Delays to diagnosis greater than eight days were also risk factors for death. Delays in diagnosis and risk factors for death from COVID-19 were associated with male gender, age under 60 years, and patients living in regions with lower SDI. Delays superior to eight days to diagnosis increased mortality rates.

Analytical validation has fundamental importance in the scope of Good Manufacturing Practice (GMP) for pharmaceutical products since it establishes scientific evidence that an analytical procedure provides reliable results. However, even with validation guidelines available it is very common to observe misunderstandings in the execution of validation and data interpretation. The misguided approaches of validation guidelines, allied with a disregard for the peculiarities of the analytical techniques, the nature of the sample, and the analytical purpose, have significantly contributed to oversights in analytical validation. This work aims to present a critical overview of the validation process in pharmaceutical analysis, addressing relevant aspects of various analytical performance parameters, their different means of accomplishment and limitations in face of the analytical techniques, the nature of the sample, and the analytical purpose. To help in the planning and execution of the validation process, some case studies are discussed, mainly in the area of high-performance liquid chromatography (HPLC).

not widely explored. The gastrointestinal environment can modify these compounds, resulting in new combinations with different bioactivity. This study aimed to evaluate the effects of simulated gastrointestinal digestion (SGD) on rose and nasturtium flower extracts. Using UPLC-HRMS, 38 phenolic compounds were identified, and the SGD caused significant changes, mainly in the glycosylated phenolic. Furthermore, antioxidant activity was correlated with the increase in the concentrations of some polyphenols. Tested Gram-negative bacteria showed sensitivity to the flower extracts; their growth was inhibited by up to 82.7%. SGD interrupted the bacterial growth inhibition power of the rose extracts. On the other hand, an increase in inhibition ranging from 52.25 to 54.72% was found for nasturtium extracts, correlated to the behavior of some bioactive. Hence, SGD resulted in significant changes in phenolic profiles of the edible flowers, increasing antioxidant activity and changing antimicrobial effects. The authors would like to thank the Federal University of Parana (UFPR), Federal University of Technology - Parana (UTFPR), Coordination of Superior Level Staff Improvement (CAPES, Contract 88881.624585/2021-01), and the National Council for Scientific and Technological Development (CNPq, Grant number 304722/2019-7) for financial support. In addition, the authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for the contracts of J. Pinela (CEECIND/01011/2018), through the individual scientific employment program-contract, and L. Barros, through the institutional scientific employment program-contract. info:eu-repo/semantics/publishedVersion

Blackberry fruit (Rubus spp. L., Rosaceae) is a source of natural antioxidants for cosmetic products due to its abundance of phenolic compounds. The aim of the present study was to characterize blackberry extracts of the cultivars ‘Tupy’, ‘Guarani’, and ‘Xavante’ and to develop niosomes loaded with blackberry extracts for future applications in cosmetic formulations. After fruit collection at the Experimental Central Stations of the Federal University of Parana, Quatro Barras, Brazil, the extracts were solubilized in different solvents. The choice of extraction solvent and blackberry cultivar was established by analysis to evaluate the total phenolic content, radical scavenging capacity, and chemical characterization by ultra-performance liquid chromatography couple to quadrupole time-of-flight-mass spectrometry. These tests revealed that fruits of Rubus ‘Xavante’ had the highest potential to be used as an active cosmetic ingredient. Niosomes formulated with the acetone/water extract obtained from the fruit of this cultivar showed both good performance and encapsulation efficiency. The results indicate that this type of niosome can be considered a promising delivery system with the potential to improve skin absorption, in addition to the antioxidant, anti-aging, and UV protective activities of the polyphenol-rich blackberry extracts.

An observational retrospective study was conducted over a 5-year period to assess survival and predictors of death in people with HIV-positive serology undergoing antiretroviral treatment with first-line regimens at the Military Hospital of Nampula, Mozambique. We collected data from 332 patient records. Kaplan-Meier boundary product estimator, log-rank, Gehan-Breslow, Tarone-Ware, time-dependent Cox models and estimates of hazard ratios (HR), with 95% confidence interval (CI) were calculated. Meantime survival for females and males was 54.8 months [95% CI 50.32-55.40] and 49.7 months [95% CI 45.89-53.53], respectively. Cox regressions indicated higher death rates significantly or potentially associated with: male sex (HR = 1.3; [95% CI 0.7-2.39]); suspected diagnosis reported only by the physician (HR = 3.6; [95% CI 1.8-7.4]); disease stages III (HR=1.2 [95% CI 0.3-3.6]) or IV (HR 1.4 [95% CI 0.4-5.8]); first TCD4+ lymphocyte count lower than 350 cells per ml (HR = 3.2; [95% CI 0.9-11.2]) or between 350-500 cells per ml (HR = 1.3; [95% CI 0.3-5.8]); or do not present cells count (HR = 3.6; [95% CI 1.2-10.2]). The above variables were significant for HIV prognosis and as predictors of death and should be considered in the clinical care of these patients.

Purpose To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. Methods A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. Results Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. Conclusion Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

High-resolution mass spectrometry is a powerful tool in clinical analysis but remains less explored due to its lower dynamic range and sensitivity compared to triple quadrupoles. Glycated hemoglobin (HbA1c) is the current gold standard biomarker to monitor the control of diabetes, representing long-term plasma glycemic levels. Due to its clinical importance, several methods have been developed for HbA1c quantification, using different principles; however, the results obtained with these techniques may differ according to the method adopted. Hence, there is a great need to standardize the current methods to quantify glycated hemoglobin. A new UPLC-QToF-MS method was fully validated and tested to quantify HbA1c in human samples. The peptides VHLTPE

ObjectiveWe assessed the extent of lag times in the publication and indexing of network meta-analyses (NMAs).Study designThis was a survey of published NMAs on drug interventions.SettingNMAs indexed in PubMed (searches updated in May 2020).Primary and secondary outcome measuresLag times were measured as the time between the last systematic search and the article submission, acceptance, online publication, indexing and Medical Subject Headings (MeSH) allocation dates. Time-to-event analyses were performed considering independent variables (geographical origin, Journal Impact Factor, Scopus CiteScore, open access status) (SPSS V.24, R/RStudio).ResultsWe included 1245 NMAs. The median time from last search to article submission was 6.8 months (204 days (IQR 95–381)), and to publication was 11.6 months. Only 5% of authors updated their search after first submission. There is a very slightly decreasing historical trend of acceptance (rho=−0.087; p=0.010), online publication (rho=−0.080; p=0.008) and indexing (rho=−0.080; p=0.007) lag times. Journal Impact Factor influenced the MeSH allocation process, but not the other lag times. The comparison between open access versus subscription journals confirmed meaningless differences in acceptance, online publication and indexing lag times.ConclusionEfforts by authors to update their search before submission are needed to reduce evidence production time. Peer reviewers and editors should ensure authors’ compliance with NMA standards. The accuracy of these findings depends on the accuracy of the metadata used; as we evaluated only NMA on drug interventions, results may not be generalisable to all types of studies.

Objective. To predict when different countries will reach 70% of fully vaccinated population against COVID-19 and to assess the effects of vaccine rejection on the number of patients admitted to ICU and on rates of omicron and other SARS-Cov-2 variants infections. Methods. Data on the ‘number of patients with COVID-19 admitted to ICU’, ‘share of people who received at least one dose of COVID-19 vaccine’ and ‘percentage of unvaccinated population (USA, Brazil, Europe, Africa, Asia) that refuses to receive the first dose of COVID-19 vaccine’ were collected from a public database from December 2020-January 2022. Time series-based models were used to predict when countries will reach 70% rate of fully vaccinated population. Results. ARIMA model was robust for predicting COVID-19 vaccination in different countries. In the USA, Brazil, the European Union and Asia 70% of the population was vaccinated against COVID-19 between September 2021-April 2022. In the Africa, the forecast is only in the beginning of 2024. The percentage of the unvaccinated population had a significant effect on the increase in ICU admissions and on the increase of omicron, alpha, delta, and gamma variant cases. Conclusion. Although the ARIMA model showed the best performance to predict vaccination patterns, its accuracy may decrease over time especially due the vaccination rejection rate. In this scenario, strategies to improve vaccination should be implemented.

Burkitt lymphoma/leukemia (BL/L) is an aggressive oncohematological disease. This study evaluated the population-based prognosis and survival on BL/L as well as if BL/L behaved as a risk factor for the development of second primary cancers (SPCs) and if other first tumors behaved as risk factors for the occurrence of BL/L as an SPC. A retrospective cohort using the Surveillance, Epidemiology and End Results (SEER) Program (2008–2016) was performed. Kaplan–Meier, time-dependent covariate Cox regression and Poisson regression models were conducted. Overall, 3094 patients were included (median, 45 years, IQR, 22–62). The estimated overall survival was 65.4 months (95% CI, 63.6–67.3). Significantly more deaths occurred for older patients, black race, disease at an advanced stage, patients without chemotherapy/surgery and patients who underwent radiotherapy. Hodgkin lymphomas (nodal) (RR, 7.6 (3.9–15.0, p &lt, 0.001)), Kaposi sarcomas (34.0 (16.8–68.9, 0.001)), liver tumors (3.4 (1.2–9.3, p = 0.020)) and trachea, mediastinum and other respiratory cancers (15.8 (2.2–113.9, p = 0.006)) behaved as risk factors for the occurrence of BL/L as an SPC. BL/L was a risk factor for the occurrence of SPCs as acute myeloid leukemias (4.6 (2.1–10.4, 0.001)), Hodgkin lymphomas (extranodal) (74.3 (10.0–549.8, 0.001)) and Kaposi sarcomas (35.1 (12.1–101.4, 0.001)). These results may assist the development of diagnostic and clinical recommendations for BL/L.

What is known and objective Hyperprolactinemia is a neuroendocrine disease that is responsible for a quarter of cases of secondary amenorrhea, which can lead to infertility in women. Dopaminergic agonists (bromocriptine, cabergoline, quinagolide) can be used in the treatment. However, there is a lack of secondary studies that compare their efficacy and safety, especially through a network meta-analysis. Thus, to contribute to the decision-making, a systematic review and network meta-analyses (NMA) were performed to evaluate the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. Methods Randomized clinical trials (RCT) were retrieved through PubMed, Web of Science and Scopus databases. The efficacy and safety of the drugs were compared, considering the following outcomes: prolactin (PRL) levels, number of patients with galactorrhoea, menstrual irregularities and adverse drug reactions. NMA was built for each outcome. Results were reported as odds ratios (OR) with 95% credibility intervals. Ranking probabilities were calculated by surface under the cumulative ranking analysis (SUCRA) and Stochastic multicriteria acceptability analysis (SMAA). Results and discussion Seventeen RCTs were included in the systematic review and fifteen in the meta-analyses. The drugs had similar efficacy, considering the PRL levels. The SUCRA analysis showed that quinagolide (0.075 and 0.05 mg/day) was superior for reducing irregular menstruation, whereas bromocriptine was the best (97%) for galactorrhoea. Cabergoline proved to be the safest drug, except for abdominal pain at a dose of 1 mg/week. The SMAA demonstrated similar results to SUCRA. What is new and conclusion This is the first network meta-analysis that evaluated the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. The results of this review revealed that these drugs have similar efficacy, but cabergoline has a better safety profile.

© 2019 The British Pharmacological Society Aims: Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events including haematological toxicities such as anaemia, leucopenia, neutropenia and thrombocytopenia. We designed a systematic review and network meta-analysis of randomised controlled trials to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib and radotinib) used by patients diagnosed with chronic myeloid leukaemia. Methods: We obtained data from the PubMed, Scopus, Web of Science, and SciELO databases. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve (SUCRA). Results: Seventeen studies were included in the network meta-analysis. Our data show that dasatinib was generally considered worse than the other TKIs, with SUCRA values ​​for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leucopenia, 90.6% for neutropenia and 97.2% for thrombocytopenia. In addition, nilotinib was shown to be safer, with SUCRA values ​​for 600 and 800 mg doses of 21.9 and 35.8% for anaemia, 23.8 and 14.6% for leucopenia, 33.0 and 17.7% for neutropenia, and 28.7 and 32.6% for thrombocytopenia, respectively. Conclusion: Dasatinib appeared as the least safe drug for chronic myeloid leukaemia, probably because it binds to multiple key kinase targets, being more prone to cause serious haematological adverse events. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity.

Summary Background & aims COVID-19 is an emergency public health problem of global importance. This study aimed to investigate the effect of foods and nutrients as complementary approaches on the recovery from COVID-19 in 170 countries, especially considering the complexity of the disease and the current scarcity of active treatments. Methods A retrospective study was performed using the Kaggle database, which links the consumption of various foods with recovery from COVID-19 in 170 countries, using multivariate analysis based on a generalized linear model. Results The results showed that certain foods had a positive effect on recovery from COVID-19: eggs, fish and seafood, fruits, meat, milk, starchy roots, stimulants, vegetable products, nuts, vegetable oil and vegetables. In general, consumption of higher levels of proteins and lipids had a positive effect on COVID-19 recovery, whereas high consumption of alcoholic beverages had a negative effect. In developed countries, where hunger had been eradicated, the effect of food on recovery from COVID-19 had a greater magnitude than in countries with a higher global hunger index (GHI), where there was almost no identifiable effect. Conclusion Several foods had a positive effect on COVID-19 recovery in developed countries, especially food groups with a higher content of lipids, proteins, antioxidants and micronutrients (e.g., selenium and zinc). In countries with extreme poverty (high GHI), foods presented little effect on recovery from COVID-19.

Phosphodiesterase inhibitors (PDE5i) are considered the first line therapy for erectile dysfunction. All PDE5i available on the market are structurally related; their main differences relate to their pharmacokinetic parameters. For these treatments to be effective and safe, it is necessary that these drugs are in the appropriate doses and that they reach adequate concentrations in the plasma. For this purpose, it is essential to perform therapeutic monitoring using bioanalytical methods. In this way, the present work aimed to develop and validate a new bioanalytical method, based on LC-MS/MS, for the simultaneous quantification of six commercially available PDE5i (avanafil, lodenafil, sildenafil, tadalafil, udenafil, and vardenafil). For this purpose, the human plasma was extracted with diethyl ether and sulfaquinoxaline was established as an internal standard. Separation was achieved using an Xbridge C18 column at 40 °C as the stationary phase, using water and acetonitrile as the mobile phase (both with formic acid and ammonium formate) in gradient mode. The method was validated according to the current guidelines and was found to be selective, linear (from 1 to 200 ng.mL−1 for all drugs except for tadalafil which is from 5 to 200 ng.mL−1), precise, accurate, and free of residual and matrix effects. The drugs were considered stable in plasma and in solution under different conditions. The method was applied to volunteerssamples, demonstrating that the method can be used routinely and may be useful in future studies on pharmacokinetics and therapeutic monitoring.

Highlights • RT-PCR followed by CT shows high sensitivity for detecting COVID-19 • Immunological tests should use a combination of IgG and IgM • The genes E and RdRp present high analytical sensitivity to detect the virus • Assays for molecular diagnosis should employ two-target systems • Studies of diagnostic tests for COVID-19 are of moderate methodological quality, Objective . To collate the evidence on the accuracy parameters of all available diagnostic methods for detecting SARS-CoV-2. Methods . A systematic review with meta-analysis was performed. Searches were conducted in Pubmed and Scopus (April 2020). Studies reporting data on sensitivity or specificity of diagnostic tests for COVID-19 using any human biological sample were included. Results . Sixteen studies were evaluated. Meta-analysis showed that computed tomography has high sensitivity (91.9% [89.8–93.7%]), but low specificity (25.1% [21.0–29.5%]). The combination of IgM and IgG antibodies demonstrated promising results for both parameters (84.5% [82.2%-86.6%]; 91.6% [86.0%-95.4%], respectively). For RT-PCR tests, rectal stools/swab, urine, and plasma were less sensitive while sputum (97.2% [90.3–99.7%]) presented higher sensitivity for detecting the virus. Conclusions . RT-PCR remains the gold standard for the diagnosis of COVID-19 in sputum samples. However, the combination of different diagnostic tests is highly recommended to achieve adequate sensitivity and specificity.

This paper presents the degradation of the most widely used antibiotics for the treatment of tuberculosis, isoniazid (INH), by Fenton, photo-Fenton on bench-scale, and solar photo–Fenton on a pilot scale. The INH dosage in tuberculosis treatment varies according to disease stage, between 300–400 mg d-1patient-1, and its excretion range via urine is 50–70% within 24 h. The photodegradation processes were performed with 25 mg L-1 of INH, 10 mg of Fe2+, and 125 mg L–1 of H2O2 for 120 min. The degradation of INH was monitored by HPLC–DAD and dissolved organic carbon (DOC). The degradation by-products were analyzed by UPLC QToF-MS and the toxicity was evaluated by Daphnia magna (acute toxicity) and Lactuca sativa (phytotoxicity). INH removal was higher than 99% at 60 min for Fenton, 10 min for photo-Fenton, and 15 min for solar photo–Fenton. The DOC results indicated that under light irradiation (photo–Fenton and solar photo–Fenton), the mineralization rate was > 70%. The nitrite ion analysis indicated the complete oxidation of nitrogen. Besides the main INH degradation by-products, isonicotinic acid, isonicotinamide, and N'-(pyridyl-4-carbonyl)-hydrazide, we detected four unknown by-products by mass spectrometry. The Fenton treatment decreased the toxicity of D. magna by 75% in 15 minutes, achieving 87% in 60 minutes of treatment, while the photo–Fenton process conducted with artificial radiation reduced 87% of the toxicity of D. magna and resulted in no significant effect in L. sativa seeds in 15 minutes (QUV-A 1.29 kJ L-1). However, solar photo-Fenton (QUV-A 3.38 kJ L–1) did not reduce toxicity.

Ethnopharmacological relevance Propolis extracts are widely used in traditional folk medicine and exhibit several properties such as antitumor, anti-inflammatory, and antimicrobial. However, these products have not been investigated in combination with medicines used in clinical practice. Aim of the study This study aimed to evaluate the chemical composition of propolis extracts from Apis mellifera scutellata and different Meliponini species and characterize their cytotoxicity against tumor cells, antibacterial effects, and interference with the actions of doxorubicin and gentamicin. Materials and methods Chromatographic and spectrometric analyses were performed using ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS). Propolis extracts were evaluated for cytotoxicity and synergism using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the antimicrobial activity was examined using the broth microdilution technique and synergism was investigated using checkerboard and time-kill assays. Results The chemical characterization revealed the presence of 63 compounds, and the extracts showed selective cytotoxicity against tumor cell lines. Propolis extracts of mandacaia and mirim exerted selective synergistic cytotoxicity in combination with doxorubicin. Except for the tubuna extract, all evaluated extracts exhibited antibacterial effects on gram-positive strains. Mandacaia and mirim extracts exerted a synergistic effect with gentamicin; however, only mandacaia extract exerted a selective effect. Conclusion Propolis could be a source of antineoplastics and antibiotics. These natural products may reduce the occurrence of doxorubicin and gentamicin related adverse effects, resistance, or both.

Currently, treatment of Chagas disease is restricted to the use of benznidazole and nifurtimox; however, nifurtimox was temporarily suspended in some countries. Based on the limitations in pharmacological treatments, it is essential to guarantee the quality of benznidazole. Therefore, this work aimed to identify the degradation products of benznidazole and to validate a stability indicating method. The stability test was performed through a forced degradation study, exposing benznidazole under a range of conditions. Benznidazole proved to be unstable under acidic and alkaline conditions, and three products were identified by liquid chromatography coupled to a hybrid quadrupole time-of-flight mass spectrometer (UPLC-QTOF-MS). Furthermore, a stability indicating method by high performance liquid chromatography with a diode array detector (HPLC-DAD) for benznidazole was developed and validated according to ICH (International Conference on Harmonisation) and ANVISA (Agência Nacional de Vigilância Sanitária) guidelines. The method was linear (180-420 µg mL-1 range), selective in the presence of degradation products, precise (relative standard deviation (RSD) < 0.6%), accurate (recovery > 99.2%), robust, and free of matrix effects. The method was successfully able to quantify the benznidazole in pharmaceutical formulations.

The occurrence of antibiotics in the natural environment has been a growing issue and correlations between this presence and developing resistance bacteria are explored. The purpose of this study was to investigate the presence of antibiotics of different classes and associated resistant bacteria, in water samples taken from urban river waters in Curitiba, Brazil. A method for the quantification of antibiotics (azithromycin, amoxicillin, norfloxacin ciprofloxacin, doxycycline and sulfamethoxazole) was developed and validated using liquid chromatography coupled with mass spectrometry. To investigate and identify coliforms resistant to these antibiotics, we performed selective microbiological culturing techniques. We detected antibiotics in our water samples; concentrations ranged from 0.13 to 4.63 μg L−1, with the highest being amoxicillin at 4.63 μg L-1. In all water samples this study, antibiotic resistant bacteria were detected. Escherichia coli was resistant to amoxicillin, norfloxacin, ciprofloxacin, doxycycline and sulfamethoxazole. Strains producing β-lactamase with extended spectrum (ESBL and AmpC) were also found in these isolates. Enterococcus spp. displayed resistance to norfloxacin and ciprofloxacin, and some isolates were resistant to vancomycin, gentamicin and streptomycin (complementary tests). No P. aeruginosa resistant strains were observed. It is possible these antibiotics came from domestic effluents and may be contributing to the spread of bacterial resistance

In this research, we developed and validated a liquid chromatography coupled to mass spectrometry (LC-QToF-MS) method for simultaneous quantification of the anti-tuberculosis drugs ethambutol, isoniazid, pyrazinamide and rifampicin in human plasma. Plasma samples spiked with cimetidine (internal standard) were extracted using protein precipitation with acetonitrile containing 1% formic acid. Separation was performed using a C18 column under flow gradient conditions with water and acetonitrile, both containing 5 mm ammonium formate and 0.1% formic acid. The method was validated according to the ANVISA and US Food and Drug Administration guidelines for bioanalytical method validation. The calibration curve was linear over a concentration range of 0.2-5 μg ml-1 for ethambutol, 0.2-7.5 μg ml-1 for isoniazid, 1-40 μg ml-1 for pyrazinamide and 0.25-2 μg ml-1 for rifampicin, all with adequate precision and accuracy. The method was reproducible, selective and free of carryover and matrix effects. The validated LC-QToF-MS method was successfully applied to real samples and shown to be applicable to future therapeutic and pharmacokinetic monitoring studies.

This systematic review (number register: CRD42018112736) was performed to compare the sensitivity and specificity of leprosy diagnostic methods. The search was conducted in 3 electronic databases in January 2021. Studies evaluating leprosy diagnostic tests were included according the eligibility criteria. Meta-analysis was performed to calculate the sensibility and specificity of the groups. We included 36 studies. The test sensitivity for paucibacillary patients was 0.31 (95%CI: 0.29-0.33) and the specificity was 0.92 (95%CI: 0.92-0.93). In multibacillary patients, the sensitivity was 0.78 (95%CI: 0.77-0.80) and specificity was 0.92 (95%CI: 0.92-0.93). Comparing the sensitivity and specificity of the different techniques included, it should be noted that polymerase chain reaction (PCR) test presented the highest sensitivity for paucibacillary patients, while the western blot technique showed the highest sensitivity for multibacillary patients. However, further studies are needed to optimise the diagnosis of leprosy, requiring research with a larger number of samples and more uniform protocols.

The bioaccessibility of bioactive compounds were increased in white and green teas that are normally degraded due to the adverse conditions of the human gastrointestinal system. The hypothesis was that the association of tea extracts with Saccharomyces cerevisiae during the biosorption process would protect bioactive compounds, making them more bioaccessible. Different treatments with yeast and extracts with pH changes were tested to assess whether there was an improvement in biosorptive capacity, which, occurred with alkaline treatments. Colorimetric analysis showed that >50% of the phenolic compounds from both extracts were biosorbed on yeast. This was consistent with the results using mass spectrometry and mid-infrared spectroscopy analyses. The in vitro gastrointestinal digestion test showed that bioaccessibility was higher in biosorbed yeasts than in pure extract (38% for white tea and 61% for green tea), which confirms the viability and potential of this application.

Objective This study aimed to implement and evaluate machine learning based-models to predict COVID-19’ diagnosis and disease severity. Methods COVID-19 test samples (positive or negative results) from patients who attended a single hospital were evaluated. Patients diagnosed with COVID-19 were categorised according to the severity of the disease. Data were submitted to exploratory analysis (principal component analysis, PCA) to detect outlier samples, recognise patterns, and identify important variables. Based on patients’ laboratory tests results, machine learning models were implemented to predict disease positivity and severity. Artificial neural networks (ANN), decision trees (DT), partial least squares discriminant analysis (PLS-DA), and K nearest neighbour algorithm (KNN) models were used. The four models were validated based on the accuracy (area under the ROC curve). Results The first subset of data had 5,643 patient samples (5,086 negatives and 557 positives for COVID-19). The second subset included 557 COVID-19 positive patients. The ANN, DT, PLS-DA, and KNN models allowed the classification of negative and positive samples with >84% accuracy. It was also possible to classify patients with severe and non-severe disease with an accuracy >86%. The following were associated with the prediction of COVID-19 diagnosis and severity: hyperferritinaemia, hypocalcaemia, pulmonary hypoxia, hypoxemia, metabolic and respiratory acidosis, low urinary pH, and high levels of lactate dehydrogenase. Conclusion Our analysis shows that all the models could assist in the diagnosis and prediction of COVID-19 severity.

Monitoring the plasma concentrations of metformin and sodium-glucose cotransporter-2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) is essential for pharmacokinetic and bioequivalence studies and therapeutic monitoring. The present work therefore aimed to develop and validate a high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous quantification of these drugs in human plasma. The analyses were performed using an Agilent 1200 HPLC system coupled to an Applied Biosystems API 3200 triple quadrupole MS/MS with electrospray ionization in positive ion mode. After one-step protein precipitation of plasma with acetonitrile containing 0.1% formic acid, chromatographic separation was achieved on an Xbridge C18 column, with a mobile phase consisting of a gradient of water and acetonitrile, both containing 1 mm ammonium formate and 0.1% formic acid. Quantification was performed in multiple reaction monitoring mode using m/z 130.1 → 71.1 for metformin, m/z 462.0 → 191.2 for canagliflozin, m/z 426.1 → 167.1 for dapagliflozin and m/z 468.0 → 354.9 for empagliflozin. The proposed method was validated and demonstrated to be adequate for the quantification of metformin, canagliflozin, dapagliflozin and empagliflozin for clinical monitoring, pharmacokinetics and bioequivalence studies.

Great efforts have been made to increase the bioaccessibility of bioactive compounds from plant sources. This can be achieved by the innovative and effective method of biosorption of these compounds in Saccharomyces cerevisiae obtained from the industrial fermentative process (waste yeast). In this context, this research evaluated if chemical modifications of depleted yeast can improve the capacity to biosorb the phenolic compounds and if through in vitro digestion tests, this approach can increase bioaccessibility of the secondary metabolites from yerba mate. The results showed that the chemical modification of the yeast promoted an increase in the biosorption efficiency of the bioactive compounds. Mass spectrometry peaks for the phenolic compounds reduced after biosorption as observed for the caffeic and dicaffeoylquinic acids and for kaempferol and rutin. In addition, a 10% reduction of caffeine was verified after biosorption, quantified by mass spectrometry chromatography. This showing that the compounds were retained in the cells, which was also observed by an increase of cell turgidity with scanning electron microscopy (SEM). Mid-infrared spectroscopy showed that the major bands related to the components of the compounds increased proportionally after biosorption. Furthermore, an increase of bioaccessibility of the yerba mate bioactive compounds adsorbed in S. cerevisiae was verified when compared with the crude extract.

© 2018 Elsevier Ltd Background: The pharmacotherapy of chronic myeloid leukaemia (CML) is mainly based on tyrosine kinase inhibitors (TKIs). The aim of this study was to compare the efficacy and safety of all TKIs in CML patients. Methods: We conducted a systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs), including imatinib, nilotinib, dasatinib, bosutinib, radotinib and ponatinib. Searches were performed in PubMed, Scopus, Web of Science and SciELo (March 2018). The NMAs were built for six outcomes at 12 months: complete cytogenetic response (CCyR), major cytogenetic response (MCyR), deep molecular response, major molecular response (MMR), complete haematologic response and incidence of serious adverse events. We conducted rank order and surface under the cumulative ranking curve (SUCRA) analyses. Results: Thirteen RCTs were included (n = 5079 patients). Statistical differences were observed for some comparisons in all outcomes. Imatinib 400 mg was considered the safest drug (SUCRA values of 10.3%) but presented low efficacy. Overall, nilotinib 600 mg was superior to the other TKI in efficacy (SUCRA values of 61.1% for CCyR, 81.0% for MMR, 90.0% for MCyR); however, no data on its safety profile at 12 months were reported. Interpretation: Our results suggest that nilotinib should be upgraded to first-line therapy for CML, although further cost-effectiveness analyses, including the new TKI (i.e., ponatinib, radotinib), are needed.

Objectives Extracts of parts Musa spp. have been used for the treatment of various diseases in traditional medicine. Studies have shown that these extracts have hypoglycaemic properties. The aim of this work was to gather evidence on the antidiabetic effects of Musa spp. inflorescence. Methods A systematic review was conducted with searches in three electronic databases, along with manual searches. Studies evaluating the antidiabetic properties of extracts of flower or bract of the genus Musa (in vitro or in vivo) were included. Key findings Overall, 16 studies were found. The reported assays were of hypoglycaemic effects, oral glucose tolerance, inhibitory activities in carbohydrate metabolism and digestive enzymes, enhanced glucose uptake activity and popular use of the extract in patients with diabetes type 2. In vitro studies showed that use of the extract was associated with antidiabetic effects (e.g. increased glucose uptake and inhibition of carbohydrate digestion enzymes). In induced diabetic models, Musa spp. extracts showed dose-dependent glycaemic level reductions compared with pharmacological drugs (P < 0.05). Summary In general, promising results regarding antidiabetic activity were found for inflorescence of Musa spp., suggesting that this plant could represent a natural alternative therapy for treating diabetes mellitus type 2.

Type 2 diabetes mellitus, a disease which prevalence has been progressively increasing worldwide, is characterized by chronic hyperglycemia resulting from the combination of inappropriate insulin secretion and/or resistance to insulin action. If left uncontrolled, diabetes is associated with complications such as dysfunction and failure of various organs, and even premature death. Along with lifestyle-modification strategies, several classes of oral antidiabetic agents can be employed for glycemic control. Thus, therapeutic drug monitoring of these drugs is essential to maintain appropriate treatment. This review discusses the most frequently employed analytical techniques and sample preparation systems to obtain a reliable and trustworthy method to quantify antidiabetic drugs in biological matrices. An adequate choice of internal standard, ideal chromatography conditions and most suitable analytical detector are reported.