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Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb
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Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.
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Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism.
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ObjectiveThe mechanism of paraquat poisoning (PQP) inducing acute lung injury is not clear. Nuclear factor erythroid 2-related factor 2 (Nrf2 )-antioxidant response element (ARE) is found to be a most important endogenous antioxidant defense pathway. This study aimed to explore the protective effect of 5- amino salicylic acid (5-ASA) against PQP-induced acute lung injury by activating the Nrf2-ARE pathway.MethodsEighty healthy adult male SD rats were randomly divided into four groups: blank control, 5-ASA control, PQP, and 5-ASA treatment. The animals in the PQP and 5-ASA treatment groups were injected with paraquat at 20 mg/kg into the left abdominal cavity for construction of the PQP model and those in the blank and 5-ASA control groups with isotonic saline at 1 mL. At 2 hours after modeling, the rats in the 5-ASA control and 5-ASA treatment groups received gavage of 5-ASA 75 at mg/kg for 3 successive days. At 1 and 3 days after observation, all the rats were sacrificed and the lower lobe of the right lung harvested for HE staining and observation of pathologic changes in the lung tissue. Meanwhile the left lung tissue was collected for determination of the expressions of Nrf2 and HO-1 proteins by Western blot.ResultsBehavioral changes were observed in the rats of the PQP and 5-ASA treatment groups, but less obvious in the latter. The alveolar wall capillaries of the rats in the PQP group were expanded and congested significantly, with widened alveolar septa and infiltration of a large number of inflammatory cells at 1 and 3 days, even severer at 3 days. The rats of the 5-ASA treatment group showed obviously reduced edema and the inflammatory cell infiltration at the corresponding time points as compared the PQP group. The lung tissue pathology scores were significantly higher in the 5-ASA treatment and PQP groups than in the blank control at 1 day (0.66±0.10 and 0.61±0.04 vs 0.18±0.05, P<0.05) and at 3 days (0.74±0.08 and 0.49±0.08 vs 0.16±0.02, P<0.05), but markedly lower in the 5-ASA treatment than in the PQP group (P<0.05). Both the expressions of Nrf2 and HO-1 proteins were remarkably higher in the 5-ASA control, PQP and 5-ASA treatment groups than in the blank control at 1 and 3 days (P<0.05), and so were they in the 5-ASA treatment than in the PQP group (P<0.05).Conclusion5-ASA can effectively reduce PQP-induced acute lung injury, which may be related to its up-regulation of the Nrf2 expression.
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Ulcerative colitis (UC) is one of the major clinical phenotypes of inflammatory bowel diseases. Although 5-aminosalicylic acid (5-ASA) is widely used for UC and its efficacy and safety have been demonstrated, a few patients paradoxically develop a severe exacerbation of colitis by 5-ASA administration. It is crucial to know clinical features including endoscopic findings in this condition for making a correct diagnosis and a prompt decision to withdraw the medication. Here, we report case series with UC exacerbated by 5-ASA. Medical records of 8 UC patients experiencing an exacerbation of colitis after induction of 5-ASA that was improved by the withdrawal of 5-ASA but also re-aggravated by dose increase or re-administration of 5-ASA were reviewed. The patients were newly diagnosed with UC, started 5-ASA and developed an exacerbation in approximately 2 to 3 weeks. They did not appear to have systemic allergic reactions. Seven of the 8 patients had a high fever. Three of 5 patients who undertook total colonoscopy showed right-side-dominant colitis. These findings suggest clinical characteristics in this condition. Further assessment of clinical and endoscopic features in more cases is necessary for establishing diagnostic criteria and understanding underlying mechanisms in those cases where 5-ASA aggravates the colitis.
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Humans , Colitis , Colitis, Ulcerative , Colonoscopy , Diagnosis , Fever , Hypersensitivity , Inflammatory Bowel Diseases , Medical Records , Mesalamine , Phenotype , UlcerABSTRACT
Objective To investigate the protective effect of 5-aminosalicylic acid (5-ASA) on renal injury poisoned by paraquat (PQ) in rats and its mechanism. Methods Twenty-four healthy clean male Sprague-Dawley (SD) rats were randomly divided into four groups: normal saline (NS) control group, 5-ASA control group, PQ model group and 5-ASA treatment group, with 6 rats in each group. The rat model of PQ poisoning was reproduced by intraperitoneal injection of 2% PQ solution 20 mg/kg, and the same volume of NS was given in NS control group and 5-ASA control group. Two hours later, the rats in 5-ASA control group and 5-ASA treatment group were intragastrically administered with 1 mL 5-ASA (75 mg/kg) for one time after NS or PQ administration, and those in NS control group and PQ model group were administered with 1 mL double distilled water. Behavioral changes were observed in rats. Then the rats were sacrificed at 24 hours after starting of the experiment for cardiac blood harvest which could be used to detect the biomarkers of renal injury and oxidative stress parameters. The kidney tissue was collected, and the hematein-eosin (HE) staining was conducted for observation of pathological changes in renal tissue, and protein expressions of Nrf 2 and heme oxygenase-1 (HO-1) were determined by Western Blot. Results At 30 minutes after PQ poisoning, rats appeared obvious poisoning symptoms and signs. Twenty-four hours after PQ poisoned, hemocoel of glomerular capillary, swelling of renal tubular epithelial cell and serious micronecrosis appeared under the light microscope. Compared with NS control group, blood urea nitrogen (BUN), serum creatinine (SCr), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione (GSH) levels were significantly abnormal in PQ model group, and Nrf 2 and HO-1 protein expressions in renal tissue were increased. After administration of 5-ASA, the morphological changes and pathological damage were mitigated as compared with those of PQ model group, the levels of BUN, SCr and MDA were decreased significantly [BUN (mmol/L): 11.98±1.81 vs. 18.56±2.32, SCr (μmol/L): 30.67±2.31 vs. 43.67±9.02, MDA (μmol/L):5.28±0.43 vs. 6.81±1.00], and the SOD activity, CAT and GSH contents were significantly increased [SOD (kU/L):125.49±7.63 vs. 106.76±7.94, CAT (ng/L): 30.68±3.51 vs. 23.05±1.55, GSH (μmol/L): 3.81±0.44 vs. 3.14±0.17], while the protein expressions of Nrf 2 and HO-1 were further increased [Nrf 2 protein (gray value): 0.76±0.04 vs. 0.52±0.03, HO-1 protein (gray value): 0.56±0.02 vs. 0.31±0.02, all P < 0.05]. Only 5-ASA intervention had no significant effect on behavior, pathology, renal injury markers and oxidative stress parameters, but it could induce the expressions of Nrf 2 and HO-1 protein in renal tissue, which were significantly higher than those of NS control group [Nrf 2 protein (gray value): 0.78±0.02 vs. 0.41±0.04, HO-1 protein (gray value): 0.51±0.03 vs. 0.23±0.01, both P < 0.01]. Conclusion 5-ASA attenuates the damage of acute renal injury (AKI) caused by PQ, which mechanism may be related with the activation of Nrf 2-antioxidant response element (ARE) signaling pathway.
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Objective:To optimize the formula of 5-aminosalicylic acid enema in situ gel. Methods:5-Aminosalicylic acid ene-mas in situ gel was prepared using a cold dissolution method with carbomer as the gel matrix and xanthan gum as the thickener. A 32 full factorial design was used to investigate the effects of the concentrations of carbomer and xanthan gum on the viscosity before and af-ter the gelling, duration of inversion tube and sedimentation rate. Response surface methodology was used to optimize the formula. Re-sults:The quantitative relationships between the two factors and the four evaluation indices were obtained. The optimum formula was as follows:the concentration of carbopol and xanthan gum in the enema was 0. 7% and 0. 15%, respectively. The viscosity before and af-ter the gelling was 500-1 000 mPa·s and 2 200-2 700 mPa·s, respectively. The duration of inversion tube test was 40-80 min and the sedimentation rate was more than 98. 5%. Conclusion:The multi-objective simultaneous optimization of the formula of 5-aminosal-icylic acid enema in situ gel is accomplished by factorial design and response surface methodology.
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Objective To investigate proliferation and apoptosis of colonic epithelial cells from ulcerative colitis (UC)patients with active new-onset,remission and active recurrent stages,and to study the effects of 5-aminosalicylic acid (5-ASA)on proliferation and apoptosis of colonic epithelial cells during the treatment of inducing remission and maintanence remission. Methods From January 2002 to December 2012,twelve patients with mild-to-moderate UC who received treatment and long-term follow-up and achieved remission with 5-ASA and received long-term maintanence treatment with it were assigned to UC group.At the same period,10 healthy individuals with negative endoscopy results or solitary colonic polyp were assigned to control group.The biopsy tissues from colonoscopy for pathological examination of patients in UC group at new-onset active stage,remission stage and recurrence stage were obtained.Levels of proliferation marker Ki-67 and apoptosis of colonic epithelial cells were determined by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)assay,respectively.Data were expressed by median(lower quartile,upper quartile).Kruskal-Wallis test and Mann-Whitney test were performed to compare the differences between groups and Bonferroni method was used for correction.Results The median proliferation indexes (PI)of colonic epithelial cells of UC patients at new-onset active period,remission period and recurrent active period were 31 .65 % (19.14%,39.66%), 12.30% (11 .11 %,14.10%) and 44.15 % (33.65 %,52.45 %), respectively,which were all higher than those of control group (7.89% (6.54%,8.86%))there were statistically significant differentes among four groups (H =30.033,P <0.01 );those of new onset active period and recurrent active period were both higher than remission period,and the differences were statistically significant (all P <0.05/6).The median apoptosis indexes (AI)of colonic epithelial cells in UC patients at new-onset active period,remission period and recurrent active period were 24.18%(17.81 %,27.16%),44.19% (43.41 %,50.55 %),41 .24% (33.78%,46.24%),respectively,which were all higher than those of control group (2.65 %(2.48%,2.98%)),there were statistically significant differences among four groups (H =31 .563,P <0.01);and those of remission and recurrent active period were both higher than new-onset active period (all P <0.05/6).The median apoptosis/proliferation ratios of control group,new onset active period,remission period and recurrent active period were 0.320 0 (0.275 5 ,0.425 0),0.749 9 (0.634 9,1 .115 8 ),3.282 8 (3.133 1 ,4.406 8 )and 1 .008 2 (0.801 9, 1 .099 2),respectively,there were statically significant differences among four groups (H =29.441 ,P <0.01);those of new onset active period and recurrent active period were both lower than that of remission period and the differnces were statistically significant (both P <0.05/6 ).Conclusions Proliferation and apoptosis imbalance in colonic epithelial cells of UC patients is one of the important mechanisms for the pathgensis of UC.5-ASA does not promote the proliferation of epithelial cells during UC remission period.
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Objective:To establish an HPLC method to determine 5-amino salicylic acid (5-ASA) and its related substances in the enemas. Methods:The liquid chromatograph was equipped with a Hypersil ODS C18 column (250 mm × 4. 6 mm,5. 0 μm) with gradient elution. The mobile phase A was composed of pH 7. 5 phosphate buffer ( PBS), tetrabutyl ammonium hydroxide solution (TBAH), methanol and water (600∶50∶50∶300), the mobile phase B was composed of pH 7. 5 PBS, TBAH, methanol and water (200∶50∶300∶450). The wavelength was 208nm, the column temperature was 40 ℃ and the injection volume was 20μl. Results:5-ASA and its two degradation products could be completely separated. The concentration of 5-ASA and the corresponding peak area had a good linear relationship within the range of 1-250μg·ml-1(r=0. 999 5). The average recovery was 99. 44%(RSD=0. 94%,n=9). Conclusion:The method is simple, sensitive and reproducible, and can be used in the determination of the content and related substances in the enemas.
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Objective To evaluate the efficacy and safety of two kinds of dosage of 5-aminosalicylic acid zinc enteric-coated capsule in treatment of active ulcerative colitis (UC). Methods The muhicentre, double blind, dosage reaction and contrast trial was conducted in six hospitals during March 2004 to Sep. 2004. One hundred and eight patients with UC were randomly allocated into the high dosage (n= 36, 1 g, bid) and the low dosage (n = 36, 0.5 g, bid) of 5-aminosalicylic acid zinc enteric-coated capsule groups, and the Olsalazine sodium group (n = 36, 1 g, tid) with a 8-week treatment. The efficacy and adverse events of 5-aminosalicylic acid zinc enteric-coated capsule were evaluated based on the clinical presentations and endoscopic findings. Results The clinical efficacy was 68.97% in high dosage group, 45. 45% in low dosage group and 62.86% in Olsalazine sodium group with no significant difference (P>0. 05). The endoscopic examination showed that the healing rate of UC in high dosage group and low dosage group was 51.72% and 21.21%, respectively, whereas the efficacy rate was 82.76% and 69.70% respectively. The results showed that high dosage was more effective than low dosage (P=0.023), but was similar to Olsalazine sodium (healing rate of 34.29% and effective rate of 88.57% ,P>0. 05). Diarrhea was main adverse event, which was accounted for 2.8% (1/36) in high dosage group and 2.8% (1/36) in the Olsalazine sodium group. There was no adverse event in low dosage group. Conclusions 5-aminosalicylic acid zinc enteric-coated capsule is an effective agent in treatment of UC, especially in high dosage. It is similar to Olsalazine sodium in treatment of UC, and has advantages in reducing medication times.
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Oral 5-aminosalicylic acid (5-ASA) has been known as a first-choice drug for ulcerative colitis. However, hypersensitivity reactions, including pancreatitis, hepatitis, and skin rash, have been reported with 5-ASA. Topical formulations of 5-ASA like suppositories have been rarely reported to induce adverse reactions because of their limited absorption rate. We recently experienced a case of acute pancreatitis caused by 5-ASA suppositories in a patient with ulcerative colitis. A 26-year-old male was admitted with abdominal pain and diagnosed as ulcerative colitis. Acute pancreatitis occurred soon after 24 hours of treatment with oral mesalazine. Drug-induced pancreatitis was suspected and administration of mesalazine was discontinued. Then 5-ASA suppositories were started instead of oral mesalazine. Twenty-four hours after taking 5-ASA suppositories, he experienced severe abdominal pain, fever, and elevation of amylase levels. The suppositories were immediately stopped and symptoms resolved over next 48 hours. Herein, we suggest that, in patients treated with 5-ASA suppositories who complain of severe abdominal pain, drug-induced pancreatitis should be suspected.
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Adult , Humans , Male , Acute Disease , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Colitis, Ulcerative/diagnosis , Mesalamine/administration & dosage , Pancreatitis/chemically induced , Suppositories , Tomography, X-Ray ComputedABSTRACT
The antioxidant effect of 5-Aminosalicylic acid (5-ASA) on copper-mediated LDL oxidation was followed either by the emitted chemiluminiscence (CL) or by UV-vis spectroscopy. 5-ASA addition extends the lag phase in a concentration-dependent manner without changes in the rate of the process in the autoaccelerated phase. The antioxidant behavior of 5-ASA was very similar to that of Trolox, a very efficient water soluble antioxidant. The copper-binding capacity of 5-ASA was evaluated by UV-visible spectroscopy. The addition of copper to a 5-ASA solution increases the absorbance at 332 nm and generates a new band at 298 nm. These changes in the UV-vis spectra indicate formation of a complex between 5-ASA and copper. However, LDL protection by 5-ASA is unrelated to its copper chelating capacity.
Subject(s)
Aminosalicylic Acids/pharmacology , Antioxidants/pharmacology , Copper/chemistry , Lipoproteins, LDL/metabolism , Aminosalicylic Acids/chemistry , Aminosalicylic Acids/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , Copper/toxicity , Luminescent Measurements , Oxidation-Reduction/drug effects , Spectrophotometry, Ultraviolet , Time FactorsABSTRACT
AIM: To investigate the effect and mechanism of 5-aminosalicylic acid (5-ASA) in topical treatment on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. METHODS: Colitis was induced by intracolonic administration of TNBS and was treated with 5-ASA at the dose of 100 mg?kg -1 for 2 weeks. Normal control group was administrated with normal saline and TNBS control group was treated with TNBS, not with 5-ASA. Macroscopic damage, histological changes and myeloperoxidase (MPO) activity were evaluated. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in colonic mucosa were detected by kits. The expression of interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?) mRNAs in colonic mucosa was determined by a reverse transcription and polymerase chain reaction method. RESULTS: Compared with TNBS control group, the macroscopic and histological changes and MPO activity in 5-ASA treated groups were improved. SOD activity was increased and the level of MDA in colonic mucosa was reduced significantly. The expression of IL-1? and TNF-? mRNAs in colonic mucosa was also decreased significantly. CONCLUSION: 5-ASA enema can significantly ameliorate TNBS-induced colitis in rats via antioxidant mechanism and attenuation of proinflammatory cytokine expression.
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OBJECTIVE:To establish an HPLC method for the determination of the drug loading rate of butyl-5-aminosalicylic acid-pectin conjugate.METHODS:The conjugate was hydrolyzed with base solution and neutralized with acid before being determined by HPLC.Kromasil C18 column was used as chromatographic column with mobile phase consisted of water(containing 0.15% triethylamine and 0.15% acetic acid)-methanol(95∶5,V/V).The detection wavelength was set at 240 nm.RESULTS:The calibration curve of 5-aminosalicylic acid was linear over the range of 1～100 ?g?mL-1(r=0.999 9) at an average recovery of 99.90%.Both intra-day and inter-day RSD were less than 2.25%.The drug loading rate of the conjugate was 12.76 %(n=3).CONCLUSION:The method is simple,rapid,accurate,and suitable for the determination of drug-loading rate of conjugate.