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Aim Tenofovir and para-aminosalicylic acid (PAS) may be co-prescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the two drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics. Methods Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (organic anion transporter 1 and 3 [OAT1 and OAT3]). Later, we estimated clinical drug interactions using static and physiologically based pharmacokinetic (PBPK) modeling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate pharmacokinetics in healthy male Korean subjects. Results PAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The PBPK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when co-administered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir pharmacokinetics showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (Cmax ) and area under the curve (AUC0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. Conclusions Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.

In this synopsis, we give an overview of recent research and propose a selection of best papers published in 2021 in the field of Clinical Information Systems (CIS).As CIS section editors, we annually apply a systematic process to retrieve articles for the IMIA Yearbook of Medical Informatics. For eight years now, we use the same query to find relevant publications in the CIS field. Each year we retrieve more than 2,400 papers which we categorize in a multi-pass review to distill a preselection of up to 15 candidate papers. External reviewers and yearbook editors then assess the selected candidate papers. Based on the review results, the IMIA Yearbook editorial board chooses up to four best publications for the section at a selection meeting. To get a comprehensive overview of the content of the retrieved articles, we use text mining and term co-occurrence mapping techniques.We carried out the query in mid-January 2022 and retrieved a deduplicated result set of 2,688 articles from 1,062 different journals. This year, we nominated ten papers as candidates and finally selected two of them as the best papers in the CIS section. As in the previous years, the content analysis of the articles revealed the broad spectrum of topics covered by CIS research, but - on the other side - no real innovations or new upcoming research trends. However, the significant impact of COVID-19 on CIS research was observable also this year.The trends in CIS research, as seen in recent years, continue to be observable. The content analysis revealed nothing really new in the CIS domain. What was very visible was the impact of the COVID-19 pandemic, which still effects our lives and also CIS.

Mesalazine, also known as 5-aminosalicylic acid (5-ASA), is a synthetic drug from the family of nonsteroidal anti-inflammatory drugs (NSAIDs) used for inflammatory diseases of the gastrointestinal tract. However, 5-ASA has also been used for various other diseases due to its pharmacological effects, but they are usually scattered across various publications, which may limit further research and clinical use of this drug. This review is a summary of published information on the biological and pharmacological effects of 5-ASA with the aim of identifying its anti-oxidant role and medicinal use. 5-ASA data have been collected from 1987 to February 2021 using major databases such as Web of Science, PubMed, Elsevier, Wiley Online Library, Springer, Google Scholar, etc. According to research, the pharmacological and biological effects of 5-ASA include treatment of inflammatory bowel disease, and anti-oxidant, anti-inflammatory, antibacterial, antifungal, anticancer, anti-amyloid, gastric protection (gastroprotective), and antidiverticulosis properties. Numerous pharmacological studies have shown that 5-ASA is an anti-oxidant and anti-ulcer compound with high therapeutic potential that, if the appropriate dose is discovered, its chemical structure changes and its effectiveness is optimized, 5-ASA has been used experimentally for other diseases.

Infraslow activity (ISA) is a biomarker that has recently become of interest in the characterization of seizure recordings. Recent data from a small number of studies have suggested that the epileptogenic zone may be identified by the presence of ISA. Investigation of low frequency activity in clinical seizure recordings, however, has been hampered by technical limitations. EEG systems necessarily include a high-pass filter early in the measurement chain to remove large artifactual drifts that can saturate recording elements such as the amplifier. This filter, unfortunately, attenuates legitimately seizure-related low frequencies, making ISA difficult to study in clinical EEG recordings. In this study, we present a deconvolution-based digital inverse filter that allows recovery of attenuated low frequency activity in intracranial recordings of temporal lobe epilepsy patients. First, we show that the unit impulse response (UIR) of an EEG system can be characterized by differentiation of the system’s step response. As proof of method, we present several examples that show that the low frequency component of a high-pass filtered signal can be restored by deconvolution with the UIR. We then demonstrate that this method can be applied to biologically relevant signals including clinical EEG recordings obtained from seizure patients. Finally, we discuss how this method can be applied to study ISA to identify and assess the seizure onset zone.

Background & Objectives Accurate determination of antimicrobial resistance profiles is of great importance to formulate optimal regimens against multidrug-resistant tuberculosis (MDR-TB). Although para-aminosalicylic acid (PAS) has been widely used clinically, the reliable testing methods for PAS susceptibility were not established. Herein, we aimed to establish critical test concentration for PAS on the Mycobacterial Growth Indicator Tube (MGIT) 960 in our laboratory settings. Methods A total of 102 clinical isolates were included in this study, including 82 wild-type and 20 resistotype isolates. Minimum inhibitory concentration (MIC) was determined by MGIT 960. Whole-genome sequencing was used to identify the mutation patterns potentially conferring PAS resistance. Sequence alignment and structure modelling were carried out to analyze potential drug-resistant mechanism of folC mutant. Results Overall, the Minimum inhibitory concentration (MIC) distribution demonstrated excellent separation between wild-type and resistotype isolates. The wild-type population were all at least 1 dilution below 4 μg/ml, and the resistotype population were no lower than 4 μg/ml, indicating that 4 μg/ml was appropriate critical concentration to separate these two populations. Of 20 mutant isolates, 12 (60.0%) harbored thyA mutations, 2 (10%) had a mutation on upstream of dfrA, and the remaining isolates had folC mutations. Overall, thyA and folC mutations were scattered throughout the whole gene without any one mutation predominating. All mutations within thyA resulted in high-level resistance to PAS (MIC > 32 μg/ml); whereas the MICs of isolates with folC mutations exhibited great diversity, ranged from 4 to > 32 μg/ml, and sequence and structure analysis partially provided the possible reasons for this diversity. Conclusions We propose 4 μg/ml as tentative critical concentration for MGIT 960. The major mechanism of PAS resistance is mutations within thyA and folC in MTB isolations. The whole-gene deletion of thyA locus confers high-level resistance to PAS. The diversity of many distinct mutations scattered throughout the full-length folC gene challenges the PCR-based mutation analysis for PAS susceptibility.

In this study, the effect of non-covalent interactions on the para-aminosalicylic acid complex is explored using density functional theory (DFT) in the gas phase and the solution. Our findings exhibit that the achieved binding energies considerably change on going from the gas phase to the solution. Based on the obtained results, the absolute value of the binding energy of the complex in the polar solvents is lower than the non-polar ones while in the gas phase it is higher than the solution. The atoms in molecules (AIM) and the natural bond orbital (NBO) analyses are applied to estimate the topological properties and the charge transfer during complexation, respectively. The results indicate that the presence of the cation-π interaction increases the strength of the intramolecular hydrogen bond in the studied complex. Finally, the various electronic descriptors such as energy gap, hardness, softness, and electronic chemical potential are investigated to gain further insight into these interactions. According to the achieved results, the high energy gap of the complex in the water solvent indicates high chemical stability and low reactivity compared to the others. On the other hand, the most reactive as well as the softest complex belongs to the gas phase.

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.

Para-aminosalicylic acid (PAS) is an antibiotic that was largely used for the multi-therapy of tuberculosis in the twentieth century. To try to overcome the inconvenience of its low efficacy and poor tolerance, we searched for novel chemical entities able to synergize with PAS using a combination screening against growing axenic Mycobacterium tuberculosis. The screening was performed at a sub-inhibitory concentration of PAS on a library of about 100,000 small molecules. Selected hit compounds were analyzed by dose–response and further probed with an intracellular macrophage assay. Scaffolds with potential additive effect with PAS are reported, opening interesting prospects for mechanism of action studies. We also report here evidence of a yet unknown bio-activation mechanism, involving activation of pyrido[1,2-a]pyrimidin-4-one (PP) derivatives through the Rv3087 protein.

Five-aminosalicylic acid (5-ASA) is an anti-inflammatory drug indicated in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Among the analytical methods of quantification of 5-ASA described in the literature, the High Efficiency Liquid Chromatography stands out, a sensitive technique but with a high cost. In recent years, alternative methods have been developed, presenting efficiency and reduced cost, such as UV/visible spectrophotometric, spectrofluorescent, and electrochemical methods, techniques recommended for the application in quality control and quantification of 5-ASA in pharmaceutical forms and biological fluids. This article aims to review the physicochemical characteristics, pharmacokinetics, mechanisms of action, controlled release systems, and the different analytical and bioanalytical methods for the quantification of 5-ASA.

Background Population-level data spanning different countries describing oral and parenteral treatment in pregnant women with inflammatory bowel disease (IBD) are scarce. We studied treatment with sulfasalazine/5-aminosalicylates, corticosteroids, thiopurines/immunomodulators, and tumor necrosis factor (TNF)-inhibitors in the United States (Optum Clinformatics Data Mart and the Medicaid Analytics Extract [MAX]) and in the Swedish national health registers. Methods We identified 2975 pregnant women in Optum (2004–2013), 3219 women in MAX (2001–2013), and 1713 women in Sweden (2006–2015) with a recorded diagnosis of IBD. We assessed patterns of use for each drug class according to filled prescriptions, assessing frequency of treatment continuation in those that were treated in the prepregnancy period. Results The proportion of women with Crohn’s disease and ulcerative colitis on any treatment during pregnancy was 56.1% and 56.3% in Optum, 47.5% and 49.3% in MAX, and 61.3% and 64.7% in Sweden, respectively, and remained stable over time. Sulfasalazine/5-aminosalicylates was the most commonly used treatment in Crohn’s disease, ranging from 25.1% in MAX to 31.8% in Optum, and in ulcerative colitis, ranging from 34.9% in MAX to 53.6% in Sweden. From 2006 to 2012, the TNF-inhibitor use increased from 5.0% to 15.5% in Optum, from 3.6% to 8.5% in MAX, and from 0.7% to 8.3% in Sweden. Continuing TNF-inhibitor treatment throughout pregnancy was more common in Optum (55.8%) and in MAX (43.0%) than in Sweden (11.8%). Conclusions In this population-based study from 2 countries, the proportion of women with IBD treatment in pregnancy remained relatively constant. TNF-inhibitor use increased substantially in both countries.

Our objective was to evaluate the performance of whole-genome sequencing (WGS) from early positive liquid cultures for predicting Mycobacterium tuberculosis complex (MTBC) drug resistance. Clinical isolates were obtained from tuberculosis patients at Shanghai Pulmonary Hospital (SPH). Antimicrobial susceptibility testing (AST) was performed, and WGS from early Bactec mycobacterial growth indicator tube (MGIT) 960-positive liquid cultures was performed to predict the drug resistance using the TB-Profiler informatics platform. A total of 182 clinical isolates were enrolled in this study. Using phenotypic AST as the gold standard, the overall sensitivity and specificity for WGS were, respectively, 97.1% (89.8 to 99.6%) and 90.4% (83.4 to 95.1%) for rifampin, 91.0% (82.4 to 96.3%) and 95.2% (89.1 to 98.4%) for isoniazid, 100.0% (89.4 to 100.0%) and 87.3% (80.8 to 92.1%) for ethambutol, 96.6% (88.3 to 99.6%) and 61.8% (52.6 to 70.4%) for streptomycin, 86.8% (71.9 to 95.6%) and 95.8% (91.2 to 98.5%) for moxifloxacin, 86.5% (71.2 to 91.5%) and 95.2% (90.3 to 98.0%) for ofloxacin, 100.0% (54.1 to 100.0%) and 67.6% (60.2 to 74.5%) for amikacin, 100.0% (63.1 to 100.0%) and 67.2% (59.7 to 74.2%) for kanamycin, 62.5% (24.5 to 91.5%) and 88.5% (82.8 to 92.8%) for ethionamide, 33.3% (4.3 to 77.7%) and 98.3% (95.1 to 99.7%) for para-aminosalicylic acid, and 0.0% (0.0 to 12.3%) and 100.0% (97.6 to 100.0%) for cycloserine. The concordances of WGS-based AST and phenotypic AST were as follows: rifampin (92.9%), isoniazid (93.4%), ethambutol (89.6%), streptomycin (73.1%), moxifloxacin (94.0%), ofloxacin (93.4%), amikacin (68.7%), kanamycin (68.7%), ethionamide (87.4%), para-aminosalicylic acid (96.2%) and cycloserine (84.6%). We conclude that WGS could be a promising approach to predict MTBC resistance from early positive liquid cultures.

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF

Objective: To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressive agents on the expression levels of multidrug-resistant genes in ucerative colitis (UC) patients, aiming to provide theoretical and therapeutic basis for the diagnosis, treatment and prevention of UC.Methods: Fresh specimen of colon mucosal tissues pathological mucosal tissues under endoscopy or postoperative pathological biopsy tissues were collected from 148 UC patients and then prepared for subsequent experiment.Immunohistochemical staining was conducted to detect the distribution site and pattern of P-glycoprotein （P-gp）. The effects of ASA glucocorticoids and immunosupresive agents on P-gp were statistically compared.The expression levels of Multidrug resistance gene （MDR1）mRNA before and after corresponding treatment were quantitatively measured by using RT-PCR. In addition, the effects of three agents upon MDR1 mRNA were also comparatively analyzed.Results: Administration of 5-aminosalicylic acid (5-ASA) drugs were not correlated with the expression of multidrug resistance genes in UC, whereas delivery of glucocorticoids and immunosuppressant drugs was positively correlated with the expression profile. The expression levels of MDR1 gene and its product P-gp were significantly up-regulated in patients who were nonresponsive to glucocorticoids and immunosuppressant agents.Conclusions: Overall, the findings in the present study demonstrate that 5-ASA exerts no effect upon the expression levels of MDR1 and its product P-gp in patients diagnosed with UC. Nevertheless, administration of glucocorticoids and immunosuppressant drugs can up-regulate the expression levels of MDR1.

Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis-associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.

Behçet's disease (BD) is a recurrent, multisystemic, inflammatory blood vessel disorder that can result in mouth, genital, and skin ulcers; arthritis; and eye and intestinal inflammation. We describe a 21-year-old Korean female patient with intestinal BD refractory to conventional medical treatment and biologic drugs. The patient was initially treated with high-dose steroids and sulfasalazine. Two months later, a skin rash occurred as a side effect of sulfasalazine. Therefore, infliximab (IFX) was administered, and disease activity decreased. However, IFX also induced a skin rash; hence, the patient was switched to adalimumab. After 12 months, the patient experienced a relapse of intestinal BD. Hence, treatment was initiated using a combination of methotrexate and adalimumab; however, this treatment was ineffective. Methotrexate was discontinued and replaced with 5‑aminosalicylic acid while maintaining adalimumab, and no recurrence has been observed to date. We report this novel strategy involving the use of anti-tumor necrosis factor‑α agents for patients with resistant BD; however, further large cohort studies are required to verify its usefulness.

We regret that this article is behind a paywall., BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens. METHODS: We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug. FINDINGS: 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed. INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.

Objectives Pasiniazid is a chemical complex of isoniazid (INH) and para-aminosalicylic acid (PAS). The aim of this study was to explore the cross-resistance of INH, PAS and pasiniazid against INH-resistant Mycobacterium tuberculosis isolates in China. Methods A Microplate alamarBlue® Assay was performed to determine the minimum inhibitory concentrations (MICs) of INH, PAS and pasiniazid against 109 INH-resistant M. tuberculosis isolates. A statistical analysis of the relationship between different genotypes, gene mutations, and INH, PAS or pasiniazid susceptibility was then performed. Results Among the 109 INH-resistant isolates, 13 (11.9%) and 21 (19.3%) showed resistance to PAS and pasiniazid, respectively. Among the 13 PAS-resistant M. tuberculosis isolates, 11 remained susceptible to pasiniazid. Of 63 INH-resistant isolates harbouring mutations in katG, the inhA promoter or the oxyR–ahpC intergenic region, 52 remained susceptible to pasiniazid. Moreover, 11 of 13 pasiniazid-resistant isolates carried mutations in katG, the inhA promoter or the oxyR–ahpC intergenic region. Conclusion Taken together, these results demonstrate that PAS resistance and mutations in thekatG gene, inhA promoter or oxyR–ahpC intergenic region in INH-resistant M. tuberculosis have little effect on pasiniazid susceptibility.

To develop a 5-aminosalicylic acid (5-ASA)-based anticolitic drug with enhanced therapeutic activity, a colon-targeted codrug constituting 5-ASA and a GPR109A agonist was designed. 5-ASA azo-coupled with nicotinic acid (ASA-azo-NA) was synthesized, and the colon specificity and anticolitic effects were evaluated. Approximately 89% of ASA-azo-NA was converted to 5-aminonicotinic acid (5-ANA) and 5-ASA after 24 h of incubation in the cecal contents. 5-ANA was identified as a GPR109A agonist (concentration that gives half-maximal response (EC50): 18 μM) in a cell-based assay. Upon oral gavage of ASA-azo-NA (oral ASA-azo-NA) and sulfasalazine (oral SSZ), a colon-targeted 5-ASA prodrug, cecal accumulation of 5-ASA was comparable, and 5-ANA was barely detectable in the blood, while it was detected up to 62.7 μM with oral 5-ANA. In parallel, oral ASA-azo-NA did not elicit an adverse skin response. In murine macrophage and human colon carcinoma cells, activation of GPR109A by 5-ANA elevated the level of the anti-inflammatory cytokine IL-10, suppressed NF-κB activation, and potentiated the inhibitory activity of 5-ASA on NF-κB. Oral ASA-azo-NA ameliorated rat colitis and was more effective than oral SSZ, which were substantially blunted following cotreatment with the GPR109A antagonist, mepenzolate. In conclusion, ASA-azo-NA is a colon-targeted anticolitic codrug with a reduced risk of skin toxicity induced by the GPR109A agonist, therapeutically surpassing a current 5-ASA-based anti-inflammatory bowel disease drug in a rat colitis model.

Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.

BACKGROUND: Knowing patients' ulcerative colitis history is essential to selecting the appropriate therapy according to risk stratification. OBJECTIVE: To evaluate and identify predictive factors of non-response to aminosalicylates judged as the need for a step-up approach over time. METHODS: A case-control study of ulcerative colitis patients treated with aminosalicylates after the diagnosis of disease flare included in the ENEIDA single-centre registry from 1997 to 2017. Long-term treatment maintenance with aminosalicylates and higher therapeutic requirements were recorded. The cumulative incidence of treatment escalation was estimated using Kaplan-Meier curves and compared by the log-rank test. Cox regression analysis was performed to identify predictive factors of treatment with immunomodulators, biological agents or surgery. RESULTS: A total of 457 patients were included, of whom 28% (n = 126) were non-responders to aminosalicylates. The cumulative probability for a step-up approach within 20 years of follow up was 35%, mainly due to steroid-dependent colitis. Risk factors for treatment escalation were age ≤27 years (hazard ratio 2.31, 95% confidence interval 1.36–3.92), extensive colitis (hazard ratio 1.65, 95% confidence interval 1.04–2.60), Mayo endoscopic subscore ≥2 (hazard ratio 1.45, 95% confidence interval 1.02–2.06) and extraintestinal manifestations (hazard ratio 2.04, 95% confidence interval 1.03–4.05). CONCLUSIONS: Aminosalicylates represent an effective maintenance therapy. Younger age, extensive colitis, endoscopic disease severity and extraintestinal manifestations are risk factors for higher therapeutic requirements.

Background and Aims. The efficacy of 5-aminosalicylic acid (5-ASA) in the long-term outcome of Crohn’s disease (CD) patients was uncertain. This study aimed to evaluate the efficacy of the 5-ASA in preventing disease behavior progression and intestinal resection in CD patients. Methods. CD patients were prospectively enrolled from January 2008 to September 2019 in Xijing Hospital. Disease behavior progression was defined as the development of stricturing (B2) or penetrating disease (B3) in patients with nonstricturing/nonpenetrating disease (B1) at diagnosis. Cox regression analyses were used to investigate the associations between disease location progression, disease behavior progression, and intestinal resection and multiple covariates. Results. In total, 122 CD patients were followed up for 4.3 years. At the time of diagnosis, disease location was ileal in 19.7% (24/122), colonic in 41.0% (50/122), and ileocolonic in 39.3% (48/122). A total of 87 (71.3%) patients had B1 at diagnosis. The disease behavior progression and intestinal resection rates were 42.5% (37/87) and 29.5% (36/122). The use of 5-ASA reduced the risk of disease behavior progression (HR 0.30, 95% CI 0.14–0.61, P = 0.001) and intestinal resection (HR 0.33, 95% CI 0.17–0.90, P = 0.027) in colonic and ileocolonic CD patients. Patients who presented with ileal disease at diagnosis did not have the same protective effects when taking 5-ASA ( P > 0.05). Conclusions. The use of 5-ASA could improve the long-term outcome of CD patients with colon involvement. The result emphasized the importance of early use of 5-ASA in the daily management of colonic involved CD.

Ethionamide is part of a group of drugs used in the treatment of drug resistant TB. With the advent of increasing drug resistance in pulmonary TB cases, use of Ethionamide, a second line anti tubercular drug is increasing. Vision changes are rare with ethionamide. Cyanopsia i.e., bluish tinted vision of surroundings with ethionamide is not known in literature. Here, we report a case of DRTB patient who developed cyanopsia soon after introducing ethionamide. Although reversible, ethionamide may sometimes need withdrawal because of significant distress caused to patient.

Background and aim Oral 5-aminosalicylic acid (5-ASA) is recommended for the therapy of mild to moderate intestinal Behcet's disease (BD). However, the induction remission efficacy and endoscopic outcomes of 5-ASA are unknown. We investigated remission induction at 8 weeks, endoscopic outcomes until 52 weeks, and event-free survival at 52 weeks in patients with intestinal BD treated with 5-ASA. Methods Forty-one patients with intestinal BD were treated with oral 5-ASA. Clinical remission was evaluated with the Crohn's disease activity index (CDAI). The endoscopic response was evaluated using the modified global gastrointestinal endoscopic assessment scores. Rescue therapy-free survival and surgery-free survival at 52 weeks were estimated, and predictive factors for a clinical response at weeks 8 and 52 were identified. Results Seven patients (17%) withdrew 5-ASA early (≤ 8 weeks) because of adverse events. At week 8, clinical efficacy could be accurately evaluated in 28 patients, and the response and remission rates were 61% and 57%, respectively, using the CDAI. Endoscopic evaluation was achieved in 17 patients up to 52 weeks, and the endoscopic response and remission rates were 71% and 35%, respectively. The probabilities of rescue therapy-free survival and surgery-free survival were 73% and 100%, respectively, at 52 weeks in all 41 patients. The predictive factors for therapeutic effectiveness at week 8 were a higher baseline C-reactive protein level and CDAI, but they were negative predictive factors for a 52-week response. Conclusions 5-ASA is effective for clinical and endoscopic induction and maintaining a response in patients with mild to moderate intestinal BD.

The repurposing of existing FDA-approved non-cancer drugs is a potential source of new treatment options for cancer patients. An anti-inflammatory drug, 5-aminosalicylic acid (5-ASA), has been clinically used to treat inflammatory bowel disease. Hyperthermia (HT) is widely applicable addendum therapy with the existing cancer treatment modalities. Here, we addressed how 5-ASA combined with HT induces lethal effects in human oral squamous cell carcinoma (OSCC) HSC-3 cells. We found that 5-ASA/HT combination significantly inhibited the viability of HSC-3 cells, while cytotoxic effects in primary human dermal fibroblast cells were minor. Apoptotic endpoints were significantly increased by the 5-ASA/HT combined treatment, as evidenced by presence of Annexin V-FITC/PI positive cells, loss of MMP, Bcl-2/Bax ratio alteration, and increased Fas, cleaved Bid, and caspase expression. Interestingly, the enhancement of apoptosis was reversed in the presence of ON/ONOO− scavengers. These findings indicate that the combination treatment enhances apoptosis via ON/ONOO− mediated ER stress-Ca2+-mitochondria signaling and caspase-dependent apoptotic pathways. Our findings provide novel evidence that the combination of 5-ASA and HT is a promising approach for the enhancement of apoptosis; it may serve as an effective strategy for treating human OSCC.

Background 5‐aminosalicylic acid (5‐ASA) is the first‐line therapy for ulcerative colitis (UC). 5‐ASA acts locally in the colonic mucosa by numerous proposed mechanisms, and is metabolised by N‐acetyltransferase (NAT). Large variations in mucosal 5‐ASA concentrations have been reported, but the underlying mechanisms are not understood. Aim To study the relationship between 5‐ASA concentration, 5‐ASA formulation, NAT genotype and bacterial microbiome in patients with UC. Methods Patients with quiescent UC, using monotherapy of Mezavant (n = 18), Asacol (n = 14) or Pentasa (n = 10), 4.0‐4.8 g/day were included. 5‐ASA was measured in colonic mucosal biopsies and serum by ultra‐high performance liquid chromatography. NAT genotypes were determined by Sanger sequencing. Bacterial microbiome was sequenced from faeces and mucosa by 16S rRNA sequencing using Illumina Miseq. Results Mezavant provided the highest mucosal 5‐ASA levels (geometric mean 2.39 ng/mg), followed by Asacol (1.60 ng/mg, 33% lower, P = 0.50) and Pentasa (0.57 ng/mg, 76% lower, P = 0.033). Mucosal 5‐ASA concentration was not associated with NAT genotype, but serum 5‐ASA concentration and NAT1 genotype was associated (P = 0.044). Mucosal 5‐ASA concentration was positively associated with mucosal bacterial diversity (P = 0.0005) and bacterial composition. High mucosal 5‐ASA concentration was related to reduced abundance of pathogenic bacteria such as Proteobacteria, and increased abundance of several favourable bacteria such as Faecalibacterium. Conclusions Mucosal 5‐ASA concentration is positively associated with bacterial diversity and a mucosal bacterial composition that are perceived favourable in UC. Mezavant yielded higher mucosal 5‐ASA concentrations than Pentasa. 5‐ASA may have beneficial effects on the mucosal microbiome, and high concentrations possibly amend dysbiosis in UC. © 2019 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors, the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure–activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

Bullo Saifullah,1,2 Palanisamy Arulselvan,3,4 Mohamed E El Zowalaty,3,5 Woan Sean Tan,3 Sharida Fakurazi,6 Thomas J Webster,7 Rabia Baby,1 Mohd Zobir Hussein1 1Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 2Department of Management Sciences and Technology, The Begum Nusrat Bhutto Women University Sukkur, Sukkur, Sindh, 65170, Pakistan; 3Laboratory for Vaccine and Immunotherapeutics, Institute of Biosciences, University Putra Malaysia, Serdang, Selangor, 43400, Malaysia; 4Muthayammal Centre for Advanced Research, Muthayammal College of Arts and Science, Namakkal, Tamil Nadu, 637408, India; 5Zoonosis Science Center, Department of Microbiology and Immunology, Uppsala University, Uppsala, Sweden; 6Department of Human Anatomy, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 7Department of Chemical Engineering, Northeastern University, Boston, MA, USACorrespondence: Mohd Zobir HusseinMaterials Synthesis and Characterization Laboratory, Institute of Advanced Technology, (ITMA), Universiti Putra Malaysia, Serdang, Selangor, MalaysiaTel +60 397698092Email mzobir@upm.edu.myIntroduction: Mycobacterium tuberculosis infections are associated with severe local inflammatory reactions, which may be life-threatening and lead to tuberculosis pathogenesis and associated complications. Inorganic nanolayers have been vastly exploited for biomedical applications (especially in drug delivery) because of their biocompatible and biodegradable nature with the ability to release a drug in a sustained manner. Herein, we report a new nanodelivery system of inorganic nanolayers based on magnesium layered hydroxides (MgLH) and a successfully intercalated anti-tuberculosis drug para-aminosalicylic acid (PAS).Methods: The designed anti-tuberculosis nanodelivery composite, MgLH-PAS, was prepared by a novel co-precipitation method using MgNO3 as well MgO as starting materials.Results: The designed nano-formulation, PAS-MgLH, showed good antimycobacterial and antimicrobial activities with significant synergistic anti-inflammatory effects on the suppression of lipopolysaccharide (LPS) stimulated inflammatory mediators in RAW 264.7 macrophages. The designed nano-formulation was also found to be biocompatible with human normal lung cells (MRC-5) and 3T3 fibroblast cells. Furthermore, the in vitro release of PAS from PAS-MgLH was found to be sustained in human body simulated phosphate buffer saline (PBS) solutions of pH 7.4 and pH 4.8.Discussion: The results of the present study are highly encouraging for further in vivo studies. This new nanodelivery system, MgLH, can be exploited in the delivery of other drugs and in numerous other biomedical applications as well.Keywords: Mycobacterium tuberculosis, magnesium layered hydroxides, biomaterial, sustained release, anti-tuberculosis, anti-inflammatory

BACKGROUND AND AIM 5-Aminosalicylic acid (5-ASA) nephrotoxicity is a rare and idiosyncratic condition in patients with inflammatory bowel disease (IBD), which may lead to end-stage kidney failure. Kidney function monitoring is recommended in clinical practice to prevent this complication. However, no data is available regarding the knowledge and adherence of patients with IBD to this monitoring. METHODS As a part of routine practice, patients with IBD under treatment or previously treated with 5-ASA were systematically interviewed about knowledge of 5-ASA nephrotoxicity and adherence to kidney function monitoring. We reported here the experience among the first 103 consecutive patients seen in a French referral center. RESULTS A total of 103 patients (93.2% ulcerative colitis, 5.8% Crohn's disease, and 1% unclassified colitis) were analyzed. Among them, 70% were informed about the need for kidney function monitoring, and in most cases, information was provided by their gastroenterologist (94.4%). The adherence rate to monitoring was very high (84.7%). Monitoring consisted of serum creatinine and estimated glomerular filtration rate in most cases (97.2%), while 24-h proteinuria was less frequently used (69.4%). These tests were performed twice or ≥3 times per year by 44.4 and 41.7% of patients, respectively. One case of isolated elevation of proteinuria related to 5-ASA treatment was observed. CONCLUSION We reported for the first time that patients with IBD are well informed and adherent to kidney function monitoring of treatment with 5-ASA. The monitoring performed by their treating physician was generally in accordance with current recommendations.

Human tuberculosis is caused by members of the Mycobacterium tuberculosis complex (MTBC) that vary in virulence and transmissibility. While genome-wide association studies have uncovered several mutations conferring drug resistance, much less is known about the factors underlying other bacterial phenotypes. Variation in the outcome of tuberculosis infection and diseases has been attributed primarily to patient and environmental factors, but recent evidence indicates an additional role for the genetic diversity among MTBC clinical strains. Here, we used metabolomics to unravel the effect of genetic variation on the strain-specific metabolic adaptive capacity and vulnerability. To define the functionality of single-nucleotide polymorphisms (SNPs) systematically, we developed a constraint-based approach that integrates metabolomic and genomic data. Our model-based predictions correctly classify SNP effects in pyruvate kinase and suggest a genetic basis for strain-specific inherent baseline susceptibility to the antibiotic para-aminosalicylic acid. Our method is broadly applicable across microbial life, opening possibilities for the development of more selective treatment strategies.

Contains fulltext : 229215.pdf (Publisher’s version ) (Closed access) Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.

In recent years, the therapeutic goals in ulcerative colitis (UC) have become increasingly stringent. Histological features seem to be a reliable predictor of disease outcomes after therapy, and histological remission (HR) is the new frontier in the treatment of UC. Here, we first provide a historical perspective before reviewing indexes in the era of biologics; histology as a treatment goal in UC trials; the poor correlation between symptoms, endoscopy, and histology; and the impact of histology on disease outcomes. HR seems to be a promising end point for the treatment of UC because it is typically associated with better outcomes. Two new validated indexes are available to assess histology more accurately in trials, and they may also be applicable to clinical practice. Additional interventional trials are now necessary to establish definitions of HR and its potential for disease modification.

Data are relatively scarce on gastro-intestinal tuberculosis (GITB). Most studies are old and from single centers, or did not include immunosuppressed patients. Thus, we aimed to determine the clinical, radiological, and laboratory profiles of GITB. We included adults with proven GITB treated between 2000 and 2018. Patients were enrolled from 21 referral centers in 8 countries (Belgium, Egypt, France, Italy, Kazakhstan, Saudi Arabia, UK, and Turkey). One hundred four patients were included. Terminal ileum (n = 46, 44.2%), small intestines except terminal ileum (n = 36, 34.6%), colon (n = 29, 27.8%), stomach (n = 6, 5.7%), and perianal (one patient) were the sites of GITB. One-third of all patients were immunosuppressed. Sixteen patients had diabetes, 8 had chronic renal failure, 5 were HIV positive, 4 had liver cirrhosis, and 3 had malignancies. Intestinal biopsy samples were cultured in 75 cases (78.1%) and TB was isolated in 65 patients (86.6%). PCR were performed to 37 (35.6%) biopsy samples and of these, 35 (94.6%) were positive. Ascites samples were cultured in 19 patients and M. tuberculosis was isolated in 11 (57.9%). Upper gastrointestinal endoscopy was performed to 40 patients (38.5%) and colonoscopy in 74 (71.1%). Surgical interventions were frequently the source of diagnostic samples (25 laparoscopy/20 laparotomy, n = 45, 43.3%). Patients were treated with standard and second-line anti-TB medications. Ultimately, 4 (3.8%) patients died and 2 (1.9%) cases relapsed. There was a high incidence of underlying immunosuppression in GITB patients. A high degree of clinical suspicion is necessary to initiate appropriate and timely diagnostic procedures; many patients are first diagnosed at surgery., SCOPUS: ar.j, info:eu-repo/semantics/published

5-aminosalicylate (5-ASA) is widely prescribed for the treatment of inflammatory bowel disease (IBD) and prevention of inflammation-associated colorectal cancer (CRC). Its clinical effect is widely attributed to modulation of host inflammatory responses. However, the recent association of intestinal dysbiosis and selective enrichment in Escherichia coli in patients with IBD and CRC raises the possibility that 5-ASA might also affect the enteric microflora. The aim of this study was to investigate the effect of 5-ASA on the growth and virulence of E. coli associated with IBD and CRC, and its impact on host cell inflammatory responses. Our results show that 5-ASA inhibited E. coli growth in a dose-dependent manner and downregulated the expression of bacterial virulence genes associated with IBD (fliC, fimH, ompC, yfgL, nlpL, lpfA, htrA, dsbA, fyuA, and chuA) and CRC (pks). 5-ASA inhibited E. coli motility (30–70%), epithelial adherence and invasion, and IL-8 secretion (p

5-Aminosalicylic acid (5-ASA) is an aminosalicylate anti-inflammatory drug, which is also known as mesalazine or mesalamine. Currently employed in treating inflammatory bowel disease, ulcerative colitis, inflamed anus or rectum, and maintain remission in Crohn's disease. Evidence from the researchers highlighted its significant re-epithelization in allergic asthma, aphthous, and gastric ulcerative conditions. The objective of the study was to formulate the pluronic lecithin organogel (PLO) containing 5-ASA and evaluate its wound-healing ability in a full thickness excision wound rat model. The data obtained from in silico docking studies revealed 5-ASA is having an affinity towards the transforming growth factor-beta (TGF-β) specifically towards beta1. Among various formulations prepared (F1 to F8), F1, and F6 have shown a maximum in vitro drug release with optimum pH and viscosity. From MTT assay it was found that selected PLO formulations showed no toxicity and enhanced cell proliferation in HaCaT cell lines. In vivo wound-healing studies in albino Wistar rats has revealed that PLO accelerates wound closure and reepithelization to the statistically significant level on day 3 (p .05) in comparison with untreated wounds. In conclusion, the overall results suggest that 5-ASA PLO gel is a potential therapeutic option for the treatments of wounds, however, further studies are highly warrened to determine the various mechanisms of 5-ASA in regulating the cell migration and reepithelization in wound healing to outspread its use in clinics.

Drug-resistant tuberculosis is an increasing healthcare challenge. Drug regimen building demands the use of different therapeutic groups, many of which harbor neurotoxicity as a side-effect, whether central or peripheral. Peripheral neuropathy is a major concern as it tends to be severe and usually irreversible. Anti-tubercular drugs that may contribute to peripheral neuropathy include INH, ethambutol, linezolid, cycloserine and para-amino salicylic acid. This potential adverse effect must be balanced against the intrinsically grave prognosis that drug resistant tuberculosis harbors. We present such a clinically challenging case of a 25 years-old female with extremely drug resistant tuberculosis whose treatment necessitated the use of several neurotoxic anti-tubercular drugs, leading to severe sensory peripheral neuropathy who did not improve despite the withdrawal of culprit drugs. She developed positive and negative sensory symptoms in both lower limbs. Nerve conduction studies were suggestive of sensory neuropathy affecting both lower limbs. Alternate causes of peripheral neuropathy including HIV, vasculitis, B12 deficiency and diabetes were ruled out. Despite drug withdrawal, the patient did not improve significantly. This case emphasizes the irreversibility of anti-tubercular therapy-induced peripheral neuropathy, demanding more rigorous clinical screening for the same while managing such patients.

OBJECTIVE To examine the clinical outcomes and associated prognostic factors among patients with multidrug-resistant tuberculosis (MDR-TB) in China. METHODS This retrospective study involved 243 patients with MDR-TB. All patients received standard regimens containing para-amino salicylic acid (PAS) and/or cycloserine (CS). The demographic, social and clinical characteristics of patients were recorded and the patients were followed up for 24 months. RESULTS Treatment success was closely associated with young age, non-farming occupations, shorter history or smoking, normal urine results, initial MDR-TB treatment regimen, increased haemoglobin, direct bilirubin, uric acid and thyroid stimulating hormone (TSH) levels, and lower white blood cell, neutrophil and blood platelet counts (all P < 0.05). On multivariable analysis, increased haemoglobin (hazard ratio [HR] 1.019, 95%CI 1.007-1.032, P = 0.002) and TSH levels (HR 1.002, 95%CI 1.006-1.039, P = 0.008), normal urine results (HR 1.541, 95%CI 1.008-2.358, P = 0.046) and initial MDR-TB treatment regimen (HR 2.238, 95%CI 1.090-4.597, P = 0.028) were prognostic factors for treatment success in MDR-TB. CONCLUSIONS Higher haemoglobin and TSH levels, normal urine results and initial MDR-TB treatment regimen might predict successful treatment of MDR-TB.

Background Multidrug-resistant and extensively drug-resistant tuberculosis infections cause public health concerns worldwide. Local epidemiologic data about the drug resistance of M ycobacterium tuberculosis isolate (Mtb) is critical to guide appropriate empirical therapy to cure patients and restrain the spread of tuberculosis. Methods Antituberculosis susceptibility testing was performed for 287 Mtbs, including 63 MDR-Mtbs collected in southern Taiwan from 2011 to 2015. Tuberculosis patients were classified into newly diagnosed cases and previously treated cases based on patients' medical history. Results Almost no resistance was found to the tested second-line antituberculosis drugs in non-MDR-Mtbs. Higher resistance rates to ethambutol, ofloxacin, and streptomycin were observed in MDR-Mtbs compared to non-MDR-Mtbs. Among 63 MDR-Mtbs, 61.9% of patients were newly diagnosed and 38.1% were previously treated cases. For MDR-Mtb, the drug-resistance rates in previously treated cases were significantly higher for ethambutol, pyrazinamide, ofloxacin, moxifloxacin, streptomycin, and p -aminosalicylic acid. When MDR-Mtbs are identified in previously treated cases, empirical administration of ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment. The resistance rates to these drugs were all more than 50%. Furthermore, 25% of MDR-Mtbs from previously treated patients were resistant to p -aminosalicylic acid. Conclusion We observed almost no resistance to the tested second-line antituberculosis drugs among non-MDR-Mtbs. Anti-tuberculosis regimen with pyrazinamide, ethambutol, fluoroquinolone, kanamycin, cycloserine and p-aminosalicylic acid can be empirically used for newly diagnosed MDR-TB cases. For previously treated MDR-TB patients, empirical ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment because the resistance rates to these drugs were all >50%.

Aloevera (AV) polysaccharide/acrylonitrile (AN) nanoparticles (AVA Np4 of ∼50 nm size) have been crafted via free radical polymerization method using persulfate/ascorbic acid (KPS/AA) and methylenebisacrylamide (MBA) as the redox initiator and crosslinker respectively. AVA Np4 was extensively characterized using FTIR, SEM, TEM, XRD, and Thermal analysis (TGA & DTG). Inclusion of AN in AV polysaccharide has been evidenced by nitrile stretching peak at 2244 cm −1 in FTIR spectrum of AVA Np4. Colon specific targeted in-vitro release of 5-Aminosalicylic acid from AVA Np4 has been studied in pH 1.2 and pH 7.4 buffer solutions at 37 °C. The controlled release was witnessed up to 48 h for AVA Np4 in contrast to AV for which the release exhausted within 7–8 h in both the buffers. The delayed release of the drug from AVA Np4 is attractive since it can allow the drug to reach colon rather than being released in the upper part of the gastrointestinal tract.

Mesalazine (5-aminosalicylic acid, 5-ASA), a currently used drug for anti-inflammatory bowel disease, is easily oxidized by HOCl, a strong oxidant generated in gut inflammation, to produce electrophilic quinones. We investigated whether this chemical feature has an implication in the anti-inflammatory pharmacology of 5-ASA. Human colon carcinoma HCT116 cells were treated with HOCl-reacted 5-ASA. Oxidized 5-ASA activated Nrf2 while 5-ASA itself was not effective. Activation of Nrf2 led to induction of hemeoxygenase (OH)-1, an anti-inflammatory enzyme. Western blot analysis of Keap1, a cytosolic repressor of Nrf2, following precipitation of biotin-labeled proteins in cell lysates treated with biotin-tagged 5-ASA, revealed a much greater amount of Keap1 when biotin-tagged 5-ASA was oxidized with HOCl. Precipitation of Keap1 was attenuated markedly by pretreatment with oxidized 5-ASA or a sulfhydryl donor. In addition, treatment with oxidized 5-ASA in cell lysates reduced the Keap1 amount that coimmunoprecipitated with Nrf2. In parallel, rectal administration of 5-ASA increased the level of HO-1 and nuclear Nrf2 in the inflamed colonic tissues, but not in normal colonic tissues. Moreover, oral gavage of sulfasalazine, a colon-specific prodrug of 5-ASA currently used clinically, activated the Nrf2-HO-1 pathway in the colonic tissues where inflammation was in progress, which was not observed when inflammation subsided. Collectively, our data suggest that Nrf2-HO-1 pathway is involved in the anti-inflammatory pharmacology of 5-ASA, which was likely being exerted exclusively in the inflammatory state.

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

This study investigated the involvement of nuclear factor erythroid 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathways in the protection afforded by two polyphenols abundant in diet, cyanidin-3-glucoside and resveratrol, against cytokine-induced inflammation and oxidative insult in HT-29 intestinal cells, in comparison with the drug 5-aminosalicylic acid (5-ASA). Our data show for the first time that in cytokine-challenged cells, cyanidin-3-glucoside and resveratrol induced Nrf2 activation, increased hemoxygenase-1 and glutamate cysteine ligase mRNA expression, enhanced reduced glutathione to oxidized glutathione ratio and inhibited reactive species production, at much lower concentrations than 5-ASA. Unlike cyanidin-3-glucoside, resveratrol and 5-ASA also increased nuclear levels of PPAR-γ in cytokine-stimulated cells. In conclusion, both polyphenols might be interesting as nutraceuticals, giving complementary benefits to conventional drugs against intestinal inflammation, typically present in patients with inflammatory bowel disease.

Summary Objectives The objectives of this study were to evaluate the interactions between linezolid (LZD) and second-line anti-tuberculosis (TB) agents in susceptible and multidrug-resistant (MDR) TB in vitro, and to validate the in vitro results in a murine TB model. Methods The minimum inhibitory concentrations of LZD and seven second-line anti-TB drugs against H37Rv and three multidrug-resistant clinical isolates were determined by Alamar Blue assay, and the interaction patterns of LZD and the seven second-line anti-TB agents against the four isolates were studied using a dynamic checkerboard method. The activities of these combinations against Mycobacterium tuberculosis were evaluated in a murine model of TB. Results The combination of LZD + capreomycin exhibited partial synergism for three of four isolates, LZD + para-aminosalicylic acid exhibited partial synergism for two of four isolates, and LZD + levofloxacin and LZD + amikacin exhibited partial synergism for one of four isolates; all other combinations showed indifference or an additive effect in vitro. The activities of six combinations and the standard regimen rifampicin + isoniazid + pyrazinamide were investigated in a murine model of TB (infection with H37Rv). Significant reductions in colony-forming units (CFU) were found in LZD + capreomycin and LZD + clofazimine groups when the CFU in the lungs on day 0 (the day of beginning treatment) was compared with the CFU in the lungs after 2 months of treatment. Conclusions These combinations of LZD and second-line anti-TB drugs were all active against MDR-TB with indifference or an additive effect, except LZD + capreomycin, which showed partial synergy.

Introduction: For 30 years, 5-aminosalicylic acid (5-ASA) has been the backbone of therapeutic management in patients with ulcerative colitis (UC). In the biologic era, it still remains the treatme...

Thymidylate synthase A (ThyA) is the key enzyme involved in the folate pathway in Mycobacterium tuberculosis. Mutation of key residues of ThyA enzyme which are involved in interaction with substrate 2′-deoxyuridine-5′-monophosphate (dUMP), cofactor 5,10-methylenetetrahydrofolate (MTHF), and catalytic site have caused para-aminosalicylic acid (PAS) resistance in TB patients. Focusing on R127L, L143P, C146R, L172P, A182P, and V261G mutations, including wild-type, we performed long molecular dynamics (MD) simulations in explicit solvent to investigate the molecular principles underlying PAS resistance due to missense mutations. We found that these mutations lead to (i) extensive changes in the dUMP and MTHF binding sites, (ii) weak interaction of ThyA enzyme with dUMP and MTHF by inducing conformational changes in the structure, (iii) loss of the hydrogen bond and other atomic interactions and (iv) enhanced movement of protein atoms indicated by principal component analysis (PCA). In this study, MD simulations framework has provided considerable insight into mutation induced conformational changes in the ThyA enzyme of Mycobacterium.

Mutations in myelin protein zero (MPZ) cause inherited peripheral neuropathies, including Charcot‑Marie‑Tooth disease (CMT) and Dejerine‑Sottas neuropathy. Mutant MPZ proteins have previously been reported to cause CMT via enhanced endoplasmic reticulum (ER) stress and Schwann cell (SC) death, although the pathological mechanisms have not yet been elucidated. In this study, we generated an in vitro model of rat SCs expressing mutant MPZ (MPZ V169fs or R98C) proteins and validated the increase in cell death and ER stress induced by the overexpression of the MPZ mutants. Using this model, we examined the efficacy of 3 different aminosalicylic acids (ASAs; 4‑ASA, sodium 4‑ASA and 5‑ASA) in alleviating pathological phenotypes. FACS analysis indicated that the number of apoptotic rat SCs, RT4 cells, induced by mutant MPZ overexpression was significantly reduced following treatment with each ASA. In particular, treatment with 4‑ASA reduced the levels of ER stress markers in RT4 cells induced by V169fs MPZ mutant overexpression and relieved the retention of V169fs mutant proteins in the ER. Additionally, the level of an apoptotic signal mediator (p‑JNK) was only decreased in the RT4 cells expressing R98C MPZ mutant protein following treatment with 4‑ASA. Although 4‑ASA is known as a free radical scavenger, treatment with 4‑ASA in the in vitro model did not moderate the level of reactive oxygen species, which was elevated by the expression of mutant MPZ proteins. On the whole, the findings of this study indicate that treatment with 4‑ASA reduced the ER stress and SC death caused by 2 different MPZ mutants and suggest that ASA may be a potential therapeutic agent for CMT.