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This paper presents a high-order low-pass filter for the equivalent-input-disturbance (EID) approach to improving the disturbance-rejection performance. The configuration characteristic of the presented filter clearly explains the reason why the disturbance-rejection performance is improved and provides a guideline to design it. Using the presented filter to replace the conventional filter derives a high-order EID (HEID) approach. It is easy to apply the small-gain theorem in deriving stability conditions of the HEID-based control system. Moreover, the presented filter is proved to be better than the conventional one. Finally, a comparison shows the validity and superiority of the presented method. And a simulation result shows that the HEID approach is easily extended in a multiple-input, multiple-output system even with effects of a white noise and parameter uncertainties.

Background The kidney function monitoring is recommended in routine practice to detect 5-aminosalicylic acid (5-ASA) related nephrotoxicity, although is not standardized. The optimal monitoring is unknown, especially the best timing and which tests to perform. We summarized why, how, and when to perform the monitoring for patients treated with 5-ASA and provided an overview of the current guidelines on this topic. Method Relevant studies on this topic were searched in PubMed, Embase, and Web of Science databases from July to August 2020. Results Serum creatinine, the estimated glomerular filtration rate, and 24-h proteinuria are the 3 main tests used for the monitoring in daily practice. Regarding the timing, several monitoring strategies have been proposed and guidelines are available too, but they provide conflicting information. To date, there is no medical evidence-based that one strategy is better than another. Comorbidities, chronic renal disease, use of nephrotoxic drugs or concomitant steroid therapy also impact the nephrotoxicity risk. Based on the literature review we proposed a kidney function monitoring strategy to guide physicians in clinical practice. Conclusion A baseline assessment should be performed in all patients treated with 5-ASA. The monitoring should be carried out according to the other nephrotoxic factors. A tight monitoring may reduce morbidity and mortality of drug nephrotoxicity.

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.

As one of the most important instruments for reducing emissions from fossil fuels, taxes have been widely used in government battles against air pollution and climate change across the world. However, the pass-through of taxes and their effect on emissions are not evident in all situations. This study investigates the pass-through of diesel consumption taxes to retail prices and estimates the consequent effect on diesel consumption and carbon emissions in China. The results show that the pass-through rate of diesel taxes in China is around 0.49. Also, there is a significant effect of an oil company's market share on the pass-through rate. Based on the pass-through rate and estimated price elasticity, we conduct further estimations of the impact on diesel consumption and carbon emissions and find that the increase in the diesel consumption tax in 2014/2015 reduces 1.64% of annual diesel consumption and 0.096% of annual carbon emissions in China.

Polyfluorinated analogues of salicylamide and p-aminosalicylic acid have been synthesized based on methyl polyfluorosalicylates. Polyfluorosalicylamides were obtained by the reaction with aqueous ammonia, while 4-aminopolyfluorosalicylic acids were prepared in two steps via regio-oriented nucleophilic replacement of para-positioned fluorine atom with azido group followed by its reduction. 3,4,5-Trifluorosalicylamide showed pronounced analgesic in vivo activity in hot plate test while 4-amino-3,5-difluorosalicylic acid revealed high tuberculostatic activity.

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 Sodium para-aminosalicylic acid (PAS-Na), an anti-tuberculosis drug, has been demonstrated its function in facilitating the Mn elimination in manganism patients and Mn-exposed models in vivo and improving the symptoms of Mn poisoning. But whether it can improve the growth retardation and inflammatory responses induced by Mn have not been reported. Objectives This study was designed to investigate the preventive effects of PAS-Na on the development of retardation and inflammatory responses in Mn-exposed rats. Methods Male Sprague Dawley (SD) rats (8 weeks old, weighing 180 ± 20 g) were randomly divided into normal control group and Mn-exposed group in the 4 weeks experiment observation and normal control group, Mn-exposed group, PAS-Na preventive group and PAS-Na control group in the 8 weeks experiment observation. The Mn-exposed group received an intraperitoneal injection (i.p.) of 15 mg/kg MnCl2 and the normal control group i.p. physiological Saline in the same volume once a day for 4 or 8 weeks, 5 days per week. The PAS-Na preventive group i.p. 15 mg/kg MnCl2 along with back subcutaneous (s.c.) injection of 240 mg/kg PAS-Na once a day for 8 weeks, 5 days per week. PAS-Na control group received s.c. injection of 240 mg/kg PAS-Na along with i.p. injection of saline once daily. The body weight was determined once a week until the end of the experiment. The manganese contents in the blood were detected by graphite furnace atomic absorption spectrometry. The inflammatory factor levels (TNF-α, IL-1β, IL-6, and PGE2) in the blood were detected by using enzyme-linked immunosorbent assay (Elisa) and each organ taking from rats were weighed and recorded. Results Mn exposure significantly suppressed the growth in rats and increased heart, liver, spleen and kidney coefficients as compared with the control group. The whole blood Mn level and serum levels of IL-1β, IL-6, PGE2, and TNF-α in sub-chronic Mn-exposure group were markedly higher than those in the control group. However, preventive treatment with PAS-Na obviously reduced the whole blood Mn level, the spleen and liver coefficients of the Mn-exposed rats. And serum levels of IL-1β and TNF-α were significantly reduced by 33.9% and 14.7% respectively in PAS-Na prevention group. Conclusions PAS-Na could improve the growth retardation and alleviate inflammatory responses in Mn-exposed rats.

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.

The effect of sodium para-aminosalicylate (PAS-Na) on litchi pericarp browning and the potential regulating mechanism was investigated in this study. Results showed that 0.3 g L−1 PAS-Na significantly inhibited the development of pericarp browning and reduced respiration rate of litchi fruit. PAS-Na inhibited the production of reactive oxygen species (ROS) and decreased the expression level of senescence-related genes. Additionally, PAS-Na treatment enhanced the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), which might contribute to the scavenging of ROS. Meanwhile, PAS-Na treatment maintained membrane integrity as indicated by reduced relative membrane leakage rate and malondialdehyde (MDA) content, as well as lower activities of membrane lipids-degrading enzymes: lipase and lipoxygenase (LOX). Amino acids, especially GABA, Glu, Met contents were also significantly affected by PAS-Na treatment. Taken together, we postulated that PAS-Na treatment might be a promising method for controlling postharvest browning and prolonging shelf-life of harvested litchi fruit.

En European Journal of Pharmaceutics and Biopharmaceutics. Amsterdam (Países Bajos) : Elsevier. Vol. 124 (march 2018), pp. 13-27. ISSN 0939-6411. e-ISSN 1873-3441. Este artículo se encuentra disponible en la página web de la revista en la siguiente URL: https://www.sciencedirect.com/science/article/abs/pii/S0939641117310639 En este artículo también participan los siguientes autores: Carolina Galiana, Maria Auxiliadora Dea- Ayuela y Anne Marie Healy. This is the pre-peer reviewed version of the following article: Serrano López, DR., Walsh, D., O'Connell, P., Mugheirbi, NA., Worku, ZA., Bolas Fernández, F. et al. (2018). Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating. European Journal of Pharmaceutics and Biopharmaceutics, vol. 124 (march), pp. 13-27, which has been published in final form at https://doi.org/10.1016/j.ejpb.2017.11.015. Este es el pre-print del siguiente artículo: Serrano López, DR., Walsh, D., O'Connell, P., Mugheirbi, NA., Worku, ZA., Bolas Fernández, F. et al. (2018). Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating. European Journal of Pharmaceutics and Biopharmaceutics, vol. 124 (march), pp. 13-27, que se ha publicado de forma definitiva en https://doi.org/10.1016/j.ejpb.2017.11.015 Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher Cmax), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.

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.

Spray drying is a well-established scale-up technique for the production of cocrystals. However, to the best of our knowledge, the effect of introducing a third component into the feed solution during the spray drying process has never been investigated. Cocrystal formation in the presence of a third component by a one-step spray drying process has the potential to reduce the number of unit operations which are required to produce a final pharmaceutical product (e.g. by eliminating blending with excipient). Sulfadimidine (SDM), a poorly water soluble active pharmaceutical ingredient (API), and 4-aminosalicylic acid (4ASA), a hydrophilic molecule, were used as model drug and coformer respectively to form cocrystals by spray drying in the presence of a third component (excipient). The solubility of the cocrystal in the excipient was measured using a thermal analysis approach. Trends in measured solubility were in agreement with those determined by calculated Hansen Solubility Parameter (HSP) values. The ratio of cocrystal components to excipient was altered and cocrystal formation at different weight ratios was assessed. Cocrystal integrity was preserved when the cocrystal components were immiscible with the excipient, based on the difference in Hansen Solubility Parameters (HSP). For immiscible systems (difference in HSP > 9.6 MPa0.5), cocrystal formation occurred even when the proportion of excipient was high (90% w/w). When the excipient was partly miscible with the cocrystal components, cocrystal formation was observed post spray drying, but crystalline API and coformer were also recovered in the processed powder. An amorphous dispersion was formed when the excipient was miscible with the cocrystal components even when the proportion of excipient used as low (10% w/w excipient). For selected spray dried cocrystal-excipient systems an improvement in tableting characteristics was observed, relative to equivalent physical mixtures.

Excessive manganese (Mn) accumulation in the brain may induce an extrapyramidal disorder known as manganism. Inflammatory processes play a critical role in neurodegenerative diseases. Therapeutically, non-steroidal anti-inflammatory drugs or analogous anti-inflammatory therapies have neuroprotective effects. As a non-steroidal anti-inflammatory drug, p-aminosalicylic acid (PAS) has anti-inflammatory effects, which are mediated by decreased prostaglandins E2 (PGE2) levels. The aim of the current study was to investigate whether PAS-Na treatment prevents Mn-induced behavioral changes and neuroinflammation in vivo. Male Sprague-Dawley rats were intraperitoneally (i.p.) injected with MnCl2·4H2O (15mg/kg) for 12 weeks, followed by 6 weeks PAS-Na treatment. Sub-chronic Mn exposure increased Mn levels in the whole blood, cortex, hippocampus and thalamus, and induced learning and memory deficits, concomitant with astrocytes activation in the cortex, hippocampus and thalamus. Moreover inflammatory cytokine levels in serum and brain of Mn-treated group were increased, including IL-1β, IL-6, TNF-αand PGE2, especially in the hippocampus and thalamus. Furthermore, sub-chronic Mn exposure also increased inflammatory cytokines and COX-2 in transcription levels concomitant with increased MAPK signaling and COX-2 in the same selected brain regions. PAS-Na treatment at the highest doses also decreased Mn levels in the whole blood and selected brain tissues, and reversed the Mn-induced learning and memory deficits. PAS-Na inhibited astrocyte activation as well as the Mn-induced increase in inflammatory cytokine levels, reducing p38, ERK MAPK pathway and COX-2 activity. In contrast PAS-Na had no effects on the JNK MAPK pathway. These data establish the efficacy of PAS-Na not only as a chelating agent to mobilize whole blood Mn, but also as an anti-inflammatory agent.

This study aimed to evaluate the comparative protective antioxidant effect of 5-aminosalicylic acid (5-ASA) and vitamin-E against acrylamide (ACR)-induced testicular toxicity in rats.This study was performed at King Fahad Medical Research Centre, Jeddah, KSA. A total of 49 adult Wistar rats (250 ± 20 gm) that were 60 days old were divided into seven groups (control, ACR alone, ACR + 5-ASA, ACR + Vitamin-E, ACR + 5-ASA + Vitamin-E, Vitamin-E alone, 5-ASA alone). Acrylamide [45 mg/kg (bw)/day] and vitamin-E [200 mg/kg (bw)/day] were gavaged orally, and 5-ASA [25 mg/kg (bw)/day] were injected intra-peritoneally for five consecutive days after one day of observation. Rats were sacrificed by cervical dislocation. Histopathology of the testis, enzyme linked immunosorbent assay (ELISA) of testosterone, the lactate dehydrogenase (LDH) assay and a caudal sperm count were performed.Rats treated with ACR showed signs of aggression and rough coats, with reduced food and water intake. ACR treated rats showed histopathological changes in the form of a sloughed seminiferous epithelium in the tubular lumen with no multinucleated giant cells. Shrinkage of seminiferous tubules with widening of the interstitial space was also observed with atrophy and the shedding of normal mucosa. Our results indicated that maximum protection was conveyed by the combined antioxidant effect of vitamin-E and 5-ASA on testicular histopathology.We conclude that acrylamide-induced degeneration of seminiferous tubules can be partially reversed by the administration of 5-ASA and vitamin-E and suggests restricting exposure to ACR.تهدف هذه الدراسة إلى التقييم المقارن للتأثير المضاد للأكسدة بين حمض ٥-أمينوساليسيليك وفيتامين “إي” في الحماية ضد تسمم خصى الفئران الناتج عن الأكريلاميد.أجريت هذه الدراسة في مركز الملك فهد للبحوث الطبية بجدة بالمملكة العربية السعودية. حيث تم تقسيم ما مجموعه ٤٩ من فئران ويستار البالغين (٢٥٠ ± ٢٠غم)، والبالغة من العمر ٦٠ يوما إلى سبع مجموعات؛ المجموعة الضابطة، ومجموعة الأكريلاميد وحدها، ومجموعة الأكريلاميد مع حمض ٥-أمينوساليسيليك، ومجموعة الأكريلاميد مع فيتامين إي، ومجموعة الأكريلاميد مع حمض ٥-أمينوساليسيليك وفيتامين إي، ومجموعة فيتامين إي وحدها، ومجموعة حمض ٥-أمينوساليسيليك وحده. أعطي الأكريلاميد (٤٥ ملغم/كغم من وزن الجسم يوميا) عن طريق الفم وفيتامين إي (٢٠٠ ملغم/كغم من وزن الجسم يوميا) عن طريق الفم، وتم حقن حمض ٥-أمينوساليسيليك (٢٥ ملغم/كغم من وزن الجسم يوميا) بالحقن داخل التجويف البريتوني لمدة خمسة أيام متتالية بعد يوم واحد من المراقبة. تم قتل الفئران عن طريق خلع فقرات العنق. ثم أجريت الفحوصات النسيجية المرضية على الخصى؛ وإنزيم “إليسا” المناعي المرتبط بالتستوستيرون، وفحص لاكتيت الاختزالي، وعد الحيوانات المنوية الذيلية.أظهرت الفئران التي عولجت بالأكريلاميد علامات العدوانية وخشونة الفروة مع انخفاض في استهلاك الماء والغذاء. كما أظهرت تغيرات نسيجية في صورة تساقط الغشاء السطحي للأنابيب المنوية داخل التجويف الأنبوبي مع عدم وجود الخلايا العملاقة متعددة النوى. كما لوحظ انكماش الأنابيب المنوية مع اتساع الفضاء الخلالي وضمور وسقوط الغشاء المخاطي الطبيعي. وأظهرت نتائجنا أن أقصى حماية نتجت عن محصلة الأثر المضاد للأكسدة الناتج عن فيتامين إي مع حمض ٥-أمينوساليسيليك على أنسجة الخصية.نستنتج أن الأكريلاميد يسبب تآكلا في القنوات المنوية وأن التآكل الذي يسببه الأكريلاميد يمكن عكسه جزئيا باستخدام حمض ٥-أمينوساليسيليك وفيتامين إي ونقترح التقليل من التعرض للأكريلاميد.

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.

The present study developed novel zinc ion cross-linked alginate/N-succinyl-chitosan (NSC) blend microspheres (MS) for co-delivery of zinc and 5-aminosalicylic acid (5-ASA) for synergistic therapy of colitis. Physicochemical characterization of blend MS was assessed using scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and energy dispersive X-ray spectrometer (EDS). In vitro release studies demonstrated that blend MS has a pH-dependent release property. Both 5-ASA and zinc have lower release in acid medium and higher release in colonic environment. The therapeutic efficacy of zinc cross-linked blend MS was evaluated using induced-colitis rat models, and showed a superior treatment effect in alleviating inflammation of colitis rats. No systemic toxicity was observed after oral administration of blend MS. Therefore, zinc ion cross-linked alginate/N-succinyl-chitosan blend MS appeared to be a good candidate for co-delivery of zinc and 5-ASA to colon, and had great potential application in inflammatory bowel diseases (IBD) treatment.

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.

Poly(aniline-co-5-aminosalicylic acid) (poly(Ani-co-5-ASA)) nanowires were successfully prepared by controlling potentials during the copolymerization of aniline and 5-aminosalicylic acid in acidic solutions. Poly(Ani-co-5-ASA) nanowires were 40–100 nm in diameter and 2–3.5 μm length when deposited at E = 0.95 V and 100–170 nm in diameter and 0.5–1.1 μm long when deposited at E = 1.10 V. The redox activity of poly(Ani-co-5-ASA) nanowires of smaller diameters was higher than that of nanowires of larger diameters, which could be taken as a strong evidence for the nanosize effect. The nanostructed poly(Ani-co-5-ASA) deposited on a graphite plate was used as a cathode in Zn-poly(Ani-co-5-ASA) rechargeable battery with ZnCl2/NH4Cl aqueous electrolyte of pH 4.8. This battery showed a high energy density of 140.2 W h kg−1 at a constant current discharge of 20 mA (5 mA cm−2). The capacity density of the battery loses were 2.8% and 14.2% after 100 and 200 cycles, respectively.

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.

Our previous study demonstrated that a combination of alternative medicine berberine and conventional 5-aminosalicylic acid (5-ASA) showed promise to be a novel therapeutic strategy for ulcerative colitis (UC). This present study aims to sketch the pre-clinical toxicity profile of this combination (1:10 dose ratio) on mice. In acute toxicity test, the determined median lethal dose (LD50) was 278.7 mg/kg berberine plus 2787 mg/kg 5-ASA. The results from subacute toxicity test demonstrated that no toxic signs of clinical symptoms, no significant changes in hematological or biochemical parameters were detected in mice treated with 14 + 140, 28 + 280 or 56 + 560 mg/kg of berberine plus 5-ASA treatment. Histological examinations revealed that accompanied with an increase in spleen weight, frequently recorded enlargement and white pulp hyperplasia of spleen were detected in mice when exposed to three doses of combination treatments. Further in vitro assessment suggested that the spleen toxicity was originated from berberine by its inhibition in cell viability and cell proliferation of lymphocytes. The results of this study indicate that the combination of berberine and 5-ASA shows a slight toxic effect on spleen, suggesting that this combination should be used with caution for patients.

Temperature-dependent solubility data of 3-aminosalicylic acid (3-ASA) are scarce in the literature and there is a particular need to explore cosolvency for this compound. Therefore, in the current study, the solubilization profile of 3-ASA along with density data in the mixtures of ethanol and water were measured at a temperature range of 293.2–313.2 K. The generated data were described by using some previously reported linear or non-linear mathematical models and their accuracies were investigated by calculating the mean relative deviations (MRD%). The apparent thermodynamic analysis for 3-ASA dissolution process was performed by the Gibbs and van't Hoff equations. Moreover, molecular insights in the local environment of the solute was obtained based on the inverse Kirkwood-Buff integrals, as it was observed that 3-ASA is preferentially solvated by water molecules from neat water to the mixture x1 = 0.24 and from x1 = 0.35 to neat ethanol. The experimental data and thermodynamic properties provide helpful information for the separation and purification of 3-ASA.

Summary Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI., Graphical Abstract, Highlights Inflammation impairs keratinocyte differentiation and worsens harlequin ichthyosis Harlequin ichthyosis mice can be used to assess therapies for this disease Aminosalicylic acids may be therapeutic treatments for harlequin ichthyosis 4ASA improves skin differentiation and barrier function in harlequin ichthyosis models, Harlequin ichthyosis arises because of the loss of lipid transport in the skin. Cottle et al. demonstrate that the treatment of mouse models of this disease with anti-inflammatory aminosalicylic acid drugs improves skin differentiation and protective barrier function.

Sulfisoxazole (SFX) is still used in combination with trimethoprim in cattle despite adverse drug reactions (e.g., urolithiasis). Recently, SFX is known to be a promising repositioned drug candidate for pulmonary hypertension and cancer. We developed a simultaneous determination method of SFX and its N-acetylated metabolites (N(1)-acetyl SFX, N1AS; N(4)-acetyl SFX, N4AS; diacetyl SFX, DAS) using HPLC-MS/MS for the first time, and examined the pharmacokinetics of SFX in mice. N1AS and DAS were converted rapidly to SFX and N4AS, respectively, in mouse plasma. The time courses of plasma SFX and N4AS concentrations were well-characterised following the oral administration of SFX to mice. The absorption, metabolism, and/or excretion of SFX given at >700mg/kg may be saturable, and in contrast to humans and rats, the extent of systemic exposure of mice to N4AS was much greater than that of SFX. Interestingly, the acetyl groups at both N1- and N4-positions were degraded during the ionisation required to generate precursor ions. In additional experiments the carboxyl group of N-acetyl-5-aminosalicylic acid (NA5AS) was lost instead of the acetyl group during the ionisation, and acetaminophen (AAP) appeared. As the acetyl and carboxyl groups of some substances can be degraded during ionisation in the mass spectrometer, caution is appropriate when it is sought to simultaneously quantify similar structures containing these moieties; chromatographic separation is essential.

In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5-aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease.

4-((3,5-Dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid (ZL006, 1) is a small-molecular inhibitor of the nNOS/PSD-95 interaction, that is under preclinical evaluation stage for cerebral ischemia. However, the fast metabolism and low permeability across the blood brain barrier (BBB) have restricted its further use. In this manuscript, the mass spectroscopy analysis showed that ZL006 mainly combined with glucuronic acid in mice plasma, which accelerated its metabolism and elimination. Hence, six ZL006 analogs were designed according to the probable metabolism sites of ZL006, and featured the alkylation at phenolic hydroxyl, secondary amine and carboxyl groups. These compounds were synthesized in moderate to good yields, and fully characterized with (1)H NMR and MS. Further metabolism investigation of ZL006 analogs showed that phenolic hydroxyl group of aromatic ring A was the major conjugation site with glucuronic acid, and ZL006 cyclohexyl ester (6) had a better permeability across BBB, which was a potent prodrug for cerebral ischemia.

The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets were successfully printed and formulations with different properties were fabricated by adding polyethylene glycol 300 (PEG 300) to the printing solution. The loading of paracetamol and 4-ASA in the printed tablets was 5.69% and 5.40% respectively. In a realistic dynamic dissolution simulation of the gastrointestinal tract, drug release from the tablets was dependent on the composition of the formulations, but independent of dissolution pH. In conclusion SLA 3DP technology allows the manufacture of drug loaded tablets with specific extended-release profiles. In the future this technology could become a manufacturing technology for the elaboration of oral dosage forms, for industrial production or even for personalised dose.

Unlike conventional polymeric drug delivery systems, where drugs are entrapped in polymers, this study focuses on the incorporation of the drug into the polymer backbone to achieve higher loading and sustained release. Crosslinked, biodegradable, xylitol based polyesters have been synthesized in this study. The bioactive drug moiety, p-aminosalicylic acid (PAS), was incorporated in xylitol based polyesters to impart its anti-mycobacterial activity. To understand the influence of the monomer chemistry on the incorporation of PAS and its subsequent release from the polymer, different diacids have been used. Controlled release profiles of the drug from these polyesters were studied under normal physiological conditions. The degradation of the polyesters varied from 48% to 76% and the release of PAS ranged from 54% to 65% of its initial loading in 7 days. A new model was developed to explain the release kinetics of PAS from the polymer that accounted for the polymer degradation and drug concentration. The thermal, mechanical, drug release and cytocompatibility properties of the polymers indicate their suitability in biomedical applications. The released products from these polymers were observed to be pharmacologically active against Mycobacteria. The high drug loading and sustained release also ensured enhanced efficacy. These polymers form biocompatible, biodegradable polyesters where the sustained release of PAS may be tailored for potential treatment of mycobacterial infections. Statement of significance In the present work, we report on novel polyesters with p-aminosalicylic acid (PAS) incorporated in the polymer backbone. The current work aims to achieve controlled release of PAS and ensures the delivered PAS is stable and pharmacologically active. The novelty of this work primarily involves the synthetic chemistry of polymerization and detailed analysis and efficacy of active PAS delivery. A new kinetic model has been developed to explain the PAS release profiles. These polymers are biodegradable, cytocompatible and anti-mycobacterial in nature. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Aims Ulcerative colitis (UC) has many complications, from colonic damage to colorectal cancer. The mystery of both etiology and effective treatment of UC still challenging process. The role of gut microbiota in UC is still unclear. In the current study we compare the difference in gut microbiota abundance in both UC and normal colon besides the therapeutic effect of Lactobacillus spp. in treating UC versus the standard drug. Materials and methods The experimental panel included five group of rats; normal control, UC diseased rats, sterilizing rats, ASA treated and Lactobacillus treated. The change in the microbiota abundance was investigated using conventional and real time PCR. In parallel, clinical evaluation of UC and macroscopic examination scoring was also done. Colonic oxidants/antioxidant stress biomarkers; MDA, GSH, catalase, myeloperoxidase activity, and SOD activity were assessed. Colon Nrf2, HO-1 contents and TNF-α was evaluated. Key findings The current study revealed a significant difference in the relative abundance of microbiota where, UC is associated with massive increase of E. coli and Fusobacterium spp., while enormous decrease in Bifidobacteria spp. in contrast with negative control. Both 5-ASA and Lactobacillus show a significant amelioration of all antioxidant enzymes and marked decline of inflammatory and oxidative stress markers. Both Lactobacillus and 5-ASA show significant increase of NrF2 and HO-1 and marked decrease of TNF-α. Significance Lactobacillus spp. exerted a beneficial effect on the inflammation, oxidative stress and the symbiosis of gut microbiota that improve structural intestinal defect and promote healing in UC.

Increasing the efficiency and specificity of drug delivery to the colon is recognized as advantageous for improving the treatment of inflammatory bowel diseases. Novel colon-specific delivery systems for 5-aminosalicylic acid (5-ASA) were developed by conjugating the active to chitosan as a drug carrier via a 4-aminobenzoyl spacer. Chitosan-5-ASA azoconjugates were synthesized from N-(4-aminobenzoyl)-chitosan by diazotization reaction with salicylic acid producing a 55–66% yield. FT-IR and UV–visible spectroscopy confirmed that the chitosan-5ASA azoconjugates were stable and did not release 5-ASA in simulated gastric fluid (SGF, hydrochloric acid pH 1.2), simulated intestinal fluid (SIF, phosphate buffer pH 6.8) and simulated colon fluid (SCF, phosphate buffer pH 7.4) for 24 h at 37 °C. The release of 5-ASA from the chitosan-5-ASA azoconjugates in SGF, SIF and SCF containing rat gastrointestinal contents was determined using HPLC and compared with 5-ASA release from sulfasalazine which employs sulfapyridine as the azoreductable carrier. Sulfasalazine released approximately 70% of the 5-ASA load in simulated colonic fluid containing rat colon content in 24 h, whereas the chitosan-5-ASA azoconjugates released around 25% of the drug load over the same time period. Although the colon targeting potential of chitosan-5-ASA azoconjugates has been demonstrated, improving the drug delivery efficiency suggests a requirement for formulation of the chitosan-5-ASA azoconjugate as nanoparticles to increase the specific surface area and azo bond exposure to bacterial enzymes.

This study investigated the anti-inflammatory action of cyanidin-3-glucoside (Cy3glc), an anthocyanin widely spread in diet, in comparison and in association with 5-aminosalicylic acid (5-ASA), an anti-inflammatory reference drug for ulcerative colitis. The efficacy, action mechanism and interaction between Cy3glc and 5-ASA were assessed in vitro, in an LPS-activated macrophage cell line. Our data showed a higher effectiveness of Cy3glc in counteracting inflammatory mediators as compared to 5-ASA at the same concentration. In addition, the mixture afforded a better protection than Cy3glc and a much better than 5-ASA, showing a synergistic effect in terms of reducing NO and ROS cellular production. Although neither Cy3glc nor the mixture counteracted LPS-induced NF-κB activation, the mixture strongly inhibited AP-1 translocation to the nucleus and prevented p38 MAPK and JNK phosphorylation suggesting that, the co-administration of a biologically active food ingredient and a medicine could be a potential strategy to increase the medicine therapeutic effect.

A combination of coformer screening and modeling, followed by characterization using calorimetry, structure elucidation, and solubility led to the identification of novel crystalline forms of the hepatitis C protease inhibitor, telaprevir. The lead crystalline form, a cocrystalline solid of telaprevir with 4-aminosalycilic acid, was identified among the list of possible cocrystals via modeling and confirmed by initial screening. It displayed the most significant aqueous solubility improvement over the neat crystalline form. Enhancement of in vivo performance was further demonstrated: a 10-fold increase in bioavailability was achieved for the cocrystal in comparison to the neat nanocrystalline telaprevir and it was found to be not statistically different from the lead amorphous spray-dried formulation.

Pro-inflammatory cytokines regulate the magnitude of allergic reactions during asthma. Tumor necrosis factor--alpha (TNF-α), interleukin-6 (IL-6) and interleukin-13 (IL-13) play a crucial role in aggravating the inflammatory conditions during allergic asthma. In addition, oxidative stress contributes to the pathogenesis of asthma by altering the physiological condition resulting in the development of status asthmaticus. Anti-inflammatory corticosteroids are being widely used for treating allergic asthma. In the present study 5-aminosalicylic acid (5-ASA), a salicylic acid derivative, was evaluated, in vivo for its potential to suppress TNF-α, IL-6 and IL-13 using ovalbumin (OVA) induced allergic asthma in Balb/C mice. Oral administration of 65, 130 and 195 mg/kg 5-ASA significantly reduced the OVA induced total and differential leucocyte count, TNF-α, IL-6, IL-13, nitrite, nitrate, MDA, MPO and TPL levels in the lung lavage samples. Collectively, these findings suggest that 5-ASA is a potent immunomodulator and suppresses key Th2 cytokines production and oxidative stress in OVA-induced asthma.

Azo-bonded prodrugs of 5-aminosalicylic acid (mesalazine)-sulfasalazine, balsalazide, and olsalazine, which are used in the treatment of ulcerative colitis, rely on colonic bacteria to cleave the azo bond and liberate the active drug in the large intestine. The aim of this study was to use an in vitro colonic simulator to determine the rates of metabolism of these three prodrugs in the presence of colonic bacteria, and to link the data to results obtained previously in humans. In individual fecal slurries prepared from five different donors, sulfasalazine degradation was rapid and virtually complete within 4 h, confirming the ubiquitous nature of azo-reduction between individuals. In pooled fecal slurry, the rate of degradation of sulfasalazine was faster (t1/2 , 32.8 min) than balsalazide (t1/2 , 80.9 min) and olsalazine (t1/2 , 145.1 min). These results are in agreement with data in humans, where it was found that sulfasalazine was more extensively metabolized on passage through the human colon than the other two drugs. These findings indicate that other than the azo bond itself, the broader chemical structure of the molecules play a role in the degradation of this class of compound, and highlight the utility of this in vitro model to evaluate the metabolism of drugs in the presence of colonic microbiota.

The release of reactive oxygen species (ROS) and pro-inflammatory mediators is a critical event in triggering and perpetuating inflammatory diseases, such as inflammatory bowel disease (IBD). 5-Aminosalicylic acid (5-ASA) is an antioxidant and anti-inflammatory drug currently used in IBD, but dietary compounds such as anthocyanins have been gaining popularity as a complementary strategy. Thus, this study aimed to evaluate the ability of cyanidin-3-glucoside (Cy3glc), a major dietary anthocyanin, to prevent inflammation in comparison and in association with 5-ASA, using a lipopolysaccharide (LPS)-activated macrophage cell line (RAW264.7) as a model. Our data show a higher effectiveness of Cy3glc in counteracting LPS-induced NO and PGE2 secretion, by inhibiting iNOS and COX-2 expression, respectively, as compared to 5-ASA. Moreover, the combination of Cy3glc and 5-ASA provides a better protection than the individual compounds. Similar results were achieved regarding ROS production. Data analysis by Chou-Talalay CI theorem demonstrates a synergistic effect between the two compounds, apparently resulting from inhibition of AP-1 signaling. Taken together, these results suggest that the co-administration of Cy3glc and 5-ASA could be a potential strategy to control inflammation in IBD.

Many carbohydrate polymers that have been used as carriers for colon-targeted drugs have shown benefits against colonic diseases. The objectives of this project were to (1) synthesize a derivative of 5-aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease, containing inulin, a carbohydrate polymer that has shown benefits against inflammatory bowel disease; (2) quantify the release of 5-ASA from the conjugate during in vitro digestion and fermentation; and (3) determine the in vitro fermentation properties of the conjugated inulin. Inulin was esterified with 5-formyl-aminosalicylic acid (5-fASA), a derivative of 5-ASA, with a degree of substitution of 0.185±0.014. During in vitro digestion and fermentation, 56.2±6.5% of 5-fASA was released in 24 h. Gut bacteria did not deformylate 5-fASA to 5-ASA as anticipated. Though conjugation of inulin with 5-fASA reduced bifidogenicity at 24 h compared with native inulin (8.26±0.03 log cfu/g versus 8.59±0.09 log cfu/g, respectively, p

This paper investigates desorption of 5-aminosalicilyc acid (5-ASA) adsorbed onto halloysite (HL). Desorption isotherms were fitted according to kinetic laws obtained considering release of 5-ASA from HL as the phase of desorption of the previously adsorbed drug molecules both inside the nanotubes of HL as onto the surface of clay particles and/or in the inter-particle spaces of their aggregates [28] . Desorption isotherms has been also fitted with other equations frequently used in drug release kinetics studies. The best fitting corresponded to the kinetic model proposed; in agreement with the results of adsorption [28] .

In situ electrochemical-ESR measurements of poly(aniline- co -5-aminosalicylic acid) (PAASA) were carried out in the aqueous solutions with different pH values and at various potentials. The ESR spectra of PAASA in a 0.20 M H 2 SO 4 solution show two types of the ESR signal. However, the ESR spectra of PAASA in a 0.30 M Na 2 SO 4 solution of pH 4.0 show only one ESR signal, but which occurs in a wide potential range of −0.20 to 1.20 V (vs. Ag/AgCl with a saturated KCl solution). To examine the origin of two types of the ESR signal in PAASA, the ESR spectra of poly(aniline- co - o -aminophenol) were also carried out in a 0.20 M H 2 SO 4 solution; its ESR spectra also show two types of the ESR signal at a potential range of 0.20–0.50 V. Therefore, two types of ESR signal can be attributed to unpaired spins situated on a nitrogen atom of aniline unit and the OH free radical from aminophenol unit in the both copolymer chains. A surprising result is that the ESR signal intensity of the deprotonated PAASA is much higher than that of the protonated PAASA in air, in which the experiments were performed under the same weight of PAASA and the same experimental conditions.

The copolymerization of aniline and 5-aminosalicylic acid (ASA) in H2SO4 solution was first carried out on a glassy carbon electrode using cyclic voltammetry. The spectra of IR and 1H NMR demonstrated the presence of –OH group, –COOH group, and free radical in the polymer, indicating that the copolymerization of aniline and ASA took place under the electrolysis to form poly(aniline-co-5-aminosalicylic acid) (PAASA). The electric properties of PAASA are strongly dependent on the monomer concentration ratio in a reaction mixture and the upper switching potential used for the synthesis of the copolymer and the electrode materials. PAASA synthesized under the optimal conditions has a good redox activity from pH

The purpose of this study was to examine chitosan (CS)-carboxymethyl starch (CMS) nanoparticles as drug delivery system to the colon. The 5-aminosalicylic acid (5-ASA) was chosen as model drug molecule. CS-CMS nanoparticles were formulated by a complex coacervation process under mild conditions. The influence of process variables, including the two ionic polymers, on particle size, and nanoparticles entrapment of 5-ASA was studied. In vitro release of 5-ASA was also evaluated, and the integrity of 5-ASA in the release fraction was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The release of 5-ASA from nanoparticle was based on the ion-exchange mechanism. The CS-CMS nanoparticles developed based on the modulation of ratio show promise as a system for controlled delivery of drug to the colon.

UV spectroscopy study of para -aminosalicylic acid behaviour in the presence of β -cyclodextrin and without it in buffer solutions was realized. Influence of duration of contact, acidity of solution, temperature, and content of reagents in the binary solutions on the complex formation between β -cyclodextrin and para -aminosalicylic acid was examined. The stability constants of the supramolecular complexes formed at pH = 1.00 and pH = 6.86 were calculated by the Ketelar equation at various temperatures. It was found that the inclusion interaction of β -cyclodextrin with protonated type of para -aminosalicylic acid is superior to that for its anionic one. From the temperature dependence of stability constants the thermodynamic parameters involved in the complex formation (ΔG, ΔH, ΔS) were calculated. It was proved that complex formation between β -cyclodextrin and para -aminosalicylic acid is spontaneous process accompanied by the release of heat and decrease of entropy. To characterize the solid product of para -aminosalicylic acid inclusion into the cavity of β -cyclodextrin supramolecular complex with a 1:1 mole ratio of components have been prepared by kneading method and studied by IR spectroscopy and X-ray diffraction.

The main aim of this research was to develop and evaluate a multiparticulate system of Ac-poly(amidoamine)(PAMAM)(G4)-chitosan (CS) hydrogels exploiting pH-sensitive and specific biodegradability properties for colon-targeted delivery of 5-aminosalicylic acid (5-ASA). All formulations were evaluated for particle size, encapsulation efficiency, swellability, and in vitro drug release. The size of the hydrogel was found to nanorange. The integrity of 5-ASA in the release fraction was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The CS-Ac-PAMAM hydrogel was developed based on the modulation of ratio show promise as a system for controlled delivery of drug.

Literature dealing with antituberculosis chemotherapy of tuberculous meningitis (TBM) in adults and children is reviewed and recommendations made for the chemotherapy of TBM. Publications relating to the chemotherapy of TBM were reviewed which contribute to understanding the efficacy of different drugs and regimens in TBM treatment. The established classification of disease severity into stages I (no neurological signs and fully conscious), II (patients conscious but with neurological signs) and III (comatose or stuporous or with severe pareses) was used to compare regimens of isoniazid (INH), para-amino salicylic acid and streptomycin (INH regimens) used up to approximately 1970 with those using INH and rifampicin (RMP), supported by pyrazinamide and ethambutol or streptomycin (RMP regimens). Mortality in studies at all disease stages in adults or adults and children, with the children not distinguished, following INH regimens (12.4%, 25.2% and 55% at stages I, II and III respectively) did not differ significantly from that following introduction of RMP regimens (9.7%, 22.2% and 56% at stages I, II and III respectively), In studies of children only, mortality fell significantly following the introduction of RMP to 0%, 5.9% and 28.2% in children at stage I, II and III having been 10.2%, 22.3% and 49.4% respectively with INH regimens (P = 0.006). Following RMP regimens of 6 months duration, only 2 (1%) relapses occurred amongst 197 patients, after RMP regimens of 9-24 months only 1 (0.16%) relapse was recorded amongst 632 patients. Where INH resistance rates are4% a directly observed INH, RMP, pyrazinamide and ethambutol for 2-months followed by INH and RMP for 4 months is recommended. If directly observed therapy cannot be practiced treatment duration should be extended to at least 9 months; if the risk of INH resistance or multidrug resistance is higher, the use of ethionamide and a fluoroquinolone and possibly cycloserine is recommended and pyrazinamide should be continued for full treatment duration. The penetration of RMP, ethambutol and streptomycin into cerebrospinal fluid is poor; higher dosages of RMP should be considered.

Biocomposites of chitosan (CS) and montmorillonite (VHS) were prepared by solid–liquid interaction of the components. The resultant composites were characterized by thermal analysis and the cation exchange capacity of the clay mineral was compared to polysaccharide retention. The composites were loaded with 5-amino salicylic acid (5-ASA), comparing the drug loading capacity and drug release behavior with those of the interaction products prepared with the drug and chitosan or montmorillonite alone. The results showed that chitosan was effectively retained by montmorillonite particles through cation exchange. In comparison with interaction products prepared using the drug and the individual components, there was a synergic effect between the clay mineral and the polysaccharide regarding both their ability to retain drug molecules, and also the control of drug release in acidic medium. In particular, the 5-ASA/CS/VHS composites showed higher drug loading and slower drug release compared to both 5-ASA/VHS and 5-ASA/CS interaction products, with almost linear release profile throughout test. According to the results, biocomposites of chitosan and montmorillonite were promising supports for modified formulations of 5-amino salicylic acid.